# pos

id: cord-334956-pi8ifpcy
pos: NNP
token:
  http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standardprotocol-items-for-clinical-trials/

lemma:
  http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standardprotocol-items-for-clinical-trials/


# ent

id: cord-029112-u507i0t0
type: GGP
entity:
  troponin I IL interleukin MCP monocyte chemoattractant protein NT proBNP N terminal pro b type natriuretic peptide


id: cord-029112-u507i0t0
type: WORK_OF_ART
entity:
  Randomized Controlled Study to Evaluate the Efficacy and Safety of Intravenously Administered Ravulizumab


id: cord-255101-l5ssz750
type: CHEMICAL
entity:
  des changements dans leur sens du goût et de l odorat Sur une échelle allant de 0 pas de goût à 10 goût normal à combien évaluez vous votre goût aujourd Ce


id: cord-292544-m7jyydf1
type: FAC
entity:
  Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute


id: cord-004515-x22q1f21
type: ORG
entity:
  the French Ministry of Health Fédération Hospitalo Universitaire OMICARE Centre de Recherche d INSERM UMR_S


id: cord-004168-rqd9b13s
type: DNA
entity:
  Ottawa Hospital TOH Kingston General Hospital KGH Hamilton General Hospital HGH St Joseph s Health Centre SJHC Toronto and North York General Hospital


id: cord-004168-rqd9b13s
type: ORG
entity:
  Departments of Critical Care Medicine and Anesthesiology Pain Management and Perioperative Medicine Systematic


id: cord-350224-dt3li3bk
type: CL
entity:
  white blood cells neutrophils lymphocytes monocytes eosinophils basophils neutrophils lymphocytes monocytes eosinophils Acidic granulocyte


id: cord-334667-0cah15lg
type: ORG
entity:
  The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICH


id: cord-004646-zhessjqh
type: WORK_OF_ART
entity:
  Clinical Practice Guidelines for the Prevention and Management of Pain Agitation Sedation Delirium Immobility and Sleep Disruption in Adult Patients in the ICU Continuous


id: cord-032926-mrnsaexq
type: ORG
entity:
  Division of Neonatology Division of Pediatric Pulmonology Neonatology and Pediatric Intensive Care Medicine Hospital


id: cord-004450-daxz9yhp
type: PROTEIN
entity:
  ECMO X a X a X a X a X a X a X a Relaxation X a X a X a X a X a X a X a High frequency ventilation X a X a X a X a X a X a


id: cord-004450-daxz9yhp
type: CELL_TYPE
entity:
  thrombocytes X X X X X X X b X X X Anticoagulation Infection X X X X X X X b X X X Anti infective therapy X X X X X X X b X X X


id: cord-004450-daxz9yhp
type: GGP
entity:
  INR aspartate aminotransferase AST alanine aminotransferase ALT albumin cholinesterase CHE brain natriuretic peptide BNP


id: cord-004450-daxz9yhp
type: ORG
entity:
  the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH


id: cord-336058-xz26rbav
type: DISEASE
entity:
  impairment memory impairment fatigue pain dyspnea nausea vomiting insomnia anorexia diarrhea constipation


id: cord-331487-jh34klbg
type: PROTEIN
entity:
  thrombocytes C reactive protein CRP Na K albumin creatinine urea amylase alkalic phosphatase beta 2 Microglobulin fibrinogen


id: cord-331487-jh34klbg
type: GGP
entity:
  alkalic phosphatase beta 2 Microglubulin fibrinogen glucose TSH INR billirubin D dimer APTT calcium triglycerides ferritin


id: cord-331487-jh34klbg
type: GGP
entity:
  alkalic phosphatase beta 2 Microglobulin fibrinogen glucose TSH D dimer APTT calcium triglycerides ferritin bilirubin


id: cord-300465-19euup51
type: ORG
entity:
  Tulane University School of Public Health and Tropical Medicine institute for Clinical Effectiveness and Health Policy in


id: cord-031315-p7jb4gf2
type: ORG
entity:
  the Chinese Expert Consensus on the Diagnosis and Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease


id: cord-263628-ac9gld5l
type: CHEMICAL
entity:
  Ciprofloxacin piperacillin tazobactam ceftazidime meropenem colistin gentamycin amoxicillin amoxicillin clavulanic acid roxithromycin dicloxacillin penicillin azithromycin


id: cord-330573-rr2r8245
type: PROTEIN
entity:
  cord 330573 rr2r8245 authors Stockmann Helena Keller Theresa Büttner Stefan Jörres Achim Kindgen Milles Detlef Kunz Julius Valentin Leebmann Josef Spies Claudia Träger Karl Treskatsch Sascha Uhrig Alexander Willam Carsten Enghard Philipp Slowinski Torsten title CytoResc CytoSorb


id: cord-344491-93ggxzxu
type: PROTEIN
entity:
  cord 344491 93ggxzxu authors Husebo Bettina Sandgathe Allore Heather Achterberg Wilco Angeles Renira Corinne Ballard Clive Bruvik Frøydis Kristine Fæø


id: cord-336000-v88bq4bx
type: ORG
entity:
  the Uniform Requirements for Manuscripts Submitted to Biomedical Journals www icmje org October 2008


id: cord-336000-v88bq4bx
type: ORG
entity:
  Subcommittee on Control of Anticoagulation of the S Standardization Committee of the International Society on T Haemostasis Definition


id: cord-334956-pi8ifpcy
type: ORG
entity:
  Canberra AIHW Australian Institute of Health and Welfare Australian Institute of Health and Welfare BreastScreen Australia


id: cord-286237-x6dr6rsh
type: CL
entity:
  monocyte chemoattractant protein 1 macrophage inflammatory protein 1 α and tumour necrosis factor α 2


id: cord-286237-x6dr6rsh
type: DISEASE
entity:
  epithelial cell damage loss of type 1 pneumocytes that line the alveolar space initiation of the coagulation


id: cord-303322-d69o3z8d
type: ORG
entity:
  the Northern Territory 2006 Department of Health andCommunity Services Hospitalisation of Indigenous


id: cord-303322-d69o3z8d
type: DISEASE
entity:
  human rhinoviruses paramyxoviruses coronaviruses and bocavirus during acute respiratory tract infections


id: cord-349329-f0pbd968
type: WORK_OF_ART
entity:
  The Pleiotropic Effects of the GM CSF Rheostat on Myeloid Cell Differentiation and Function More Than a Numbers Game Frontline


# bib

id: cord-004168-rqd9b13s
author: Daneman, Nick
date: 2020-01-15
txt: ./txt/cord-004168-rqd9b13s.txt
cache: ./cache/cord-004168-rqd9b13s.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964073/
doi: 10.1186/s13063-019-4033-9
summary:
  The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot randomized clinical trial (RCT) determined that it was feasible to enroll and randomize intensive care unit (ICU) patients with bloodstream infection to 7 versus 14 days of treatment, and served as the vanguard for the ongoing BALANCE main RCT. METHODS: We conducted an open pilot RCT among a subset of six sites participating in the ongoing BALANCE RCT, randomizing patients with positive non-Staphylococcus aureus blood cultures on non-ICU wards to 7 versus 14 days of antibiotic treatment. Conclusion: It is feasible to enroll non-ICU patients in a trial of 7 versus 14 days of antibiotics for bloodstream infection, and expanding the BALANCE RCT hospital-wide has the potential to improve the timeliness and generalizability of trial results. Conclusion: It is feasible to enroll non-ICU patients in a trial of 7 versus 14 days of antibiotics for bloodstream infection, and expanding the BALANCE RCT hospital-wide has the potential to improve the timeliness and generalizability of trial results.

title:
  A pilot randomized controlled trial of 7 versus 14 days of antibiotic treatment for bloodstream infection on non-intensive care versus intensive care wards

abstract:
  BACKGROUND: The optimal treatment duration for patients with bloodstream infection is understudied. The Bacteremia Antibiotic Length Actually Needed for Clinical Effectiveness (BALANCE) pilot randomized clinical trial (RCT) determined that it was feasible to enroll and randomize intensive care unit (ICU) patients with bloodstream infection to 7 versus 14 days of treatment, and served as the vanguard for the ongoing BALANCE main RCT. We performed this BALANCE-Ward pilot RCT to examine the feasibility and impact of potentially extending the BALANCE main RCT to include patients hospitalized on non-ICU wards. METHODS: We conducted an open pilot RCT among a subset of six sites participating in the ongoing BALANCE RCT, randomizing patients with positive non-Staphylococcus aureus blood cultures on non-ICU wards to 7 versus 14 days of antibiotic treatment. The co-primary feasibility outcomes were recruitment rate and adherence to treatment duration protocol. We compared feasibility outcomes, patient/pathogen characteristics, and overall outcomes among those enrolled in this BALANCE-Ward and prior BALANCE-ICU pilot RCTs. We estimated the sample size and non-inferiority margin impacts of expanding the BALANCE main RCT to include non-ICU patients. RESULTS: A total of 134 patients were recruited over 47 site-months (mean 2.9 patients/site-month, median 1.0, range 0.1–4.4 patients/site-month). The overall recruitment rate exceeded the BALANCE-ICU pilot RCT (mean 1.10 patients/site-month, p < 0.0001). Overall protocol adherence also exceeded the adherence in the BALANCE-ICU pilot RCT (125/134, 93% vs 89/115, 77%, p = 0.0003). BALANCE-Ward patients were older, with lower Sequential Organ Failure Assessment scores, and higher proportions of infections caused by Escherichia coli and genito-urinary sources of bloodstream infection. The BALANCE-Ward pilot RCT patients had an overall 90-day mortality rate of 17/133 (12.8%), which was comparable to the 90-day mortality rate in the ICU pilot RCT (17/115, 14.8%) (p = 0.65). Simulation models indicated there would be minimal sample size and non-inferiority margin implications of expanding enrolment to increasing proportions of non-ICU versus ICU patients. CONCLUSION: It is feasible to enroll non-ICU patients in a trial of 7 versus 14 days of antibiotics for bloodstream infection, and expanding the BALANCE RCT hospital-wide has the potential to improve the timeliness and generalizability of trial results. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02917551. Registered on September 28, 2016.


id: cord-004339-7nwpic3d
author: Rennie, Katherine J.
date: 2020-02-13
txt: ./txt/cord-004339-7nwpic3d.txt
cache: ./cache/cord-004339-7nwpic3d.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020359/
doi: 10.1186/s13063-020-4081-1
summary:
  Secondly, consent to have the discussion about the NAIROS trial with the investigator audio-recorded and their details passed onto • Any prior septal surgery • Systemic inflammatory disease or the use of any current oral steroid treatment within the past 2 weeks • Granulomatosis with polyangiitis • Nasendoscopic evidence of unrelated associated pathology, e.g. adenoid pad, septal perforation, chronic rhinosinusitis indicated by the presence of polyposis or pus • Any history of intranasal recreational drug use within the past 6 months • Breast-feeding, pregnancy or intended pregnancy for the duration of involvement in the trial • Bleeding diathesis • Therapeutic anticoagulation (warfarin/novel oral anti-coagulant (NOAC) therapy) • Clinically significant contraindication to general anaesthesia • Patients known to be immuno-compromised • Those in whom an external bony deformity substantially contributes to the nasal obstruction a member of the qualitative team for a telephone interview.

title:
  Nasal Airway Obstruction Study (NAIROS): a phase III, open-label, mixed-methods, multicentre randomised controlled trial of septoplasty versus medical management of a septal deviation with nasal obstruction

abstract:
  BACKGROUND: Septoplasty (surgery to straighten a deviation in the nasal septum) is a frequently performed operation worldwide, with approximately 250,000 performed annually in the US and 22,000 in the UK. Most septoplasties aim to improve diurnal and nocturnal nasal obstruction. The evidence base for septoplasty clinical effectiveness is hitherto very limited. AIMS: To establish, and inform guidance for, the best management strategy for individuals with nasal obstruction associated with a deviated septum. METHODS/DESIGN: A multicentre, mixed-methods, open label, randomised controlled trial of septoplasty versus medical management for adults with a deviated septum and a reduced nasal airway. Eligible patients will have septal deflection visible at nasendoscopy and a nasal symptom score ≥ 30 on the NOSE questionnaire. Surgical treatment comprises septoplasty with or without reduction of the inferior nasal turbinate on the anatomically wider side of the nose. Medical management comprises a nasal saline spray followed by a fluorinated steroid spray daily for six months. The recruitment target is 378 patients, recruited from up to 17 sites across Scotland, England and Wales. Randomisation will be on a 1:1 basis, stratified by gender and severity (NOSE score). Participants will be followed up for 12 months post randomisation. The primary outcome measure is the total SNOT-22 score at 6 months. Clinical and economic outcomes will be modelled against baseline severity (NOSE scale) to inform clinical decision-making. The study includes a recruitment enhancement process, and an economic evaluation. DISCUSSION: The NAIROS trial will evaluate the clinical effectiveness and cost-effectiveness of septoplasty versus medical management for adults with a deviated septum and symptoms of nasal blockage. Identifying those individuals most likely to benefit from surgery should enable more efficient and effective clinical decision-making, and avoid unnecessary operations where there is low likelihood of patient benefit. TRIAL REGISTRATION: EudraCT: 2017–000893-12, ISRCTN: 16168569. Registered on 24 March 2017.


id: cord-004404-s6udpwxq
author: Seifi, Najmeh
date: 2020-02-24
txt: ./txt/cord-004404-s6udpwxq.txt
cache: ./cache/cord-004404-s6udpwxq.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041281/
doi: 10.1186/s13063-020-4136-3
summary:
  METHODS: This is a prospective, single-center, double-blind, parallel randomized controlled trial with the aim to evaluate the effects of synbiotic supplementation on energy and macronutrient homeostasis and muscle wasting in critically ill patients. DISCUSSION: Gut microbiota modulation through synbiotics is proposed to improve clinical prognosis and reduce infectious complications, ventilator dependency, and length of ICU stay by improving energy and macronutrient homeostasis and reducing muscle protein catabolism. Previous studies suggest that modulating gut microbiota by novel therapeutics, such as prebiotics, probiotics, or synbiotics, can have an effect on gastrointestinal tolerance and complications of enteral nutrition, which eventually lead to the regulation of energy intake. Considering the extreme dysbiosis in critically ill patients and related energy and macronutrients homeostasis disturbance and muscle wasting, prompted us to evaluate the effect of synbiotic supplementation on the elimination of this condition. The primary objective is to evaluate the effects of synbiotic supplementation on energy and macronutrient homeostasis and muscle wasting in patients under critical care.

title:
  Effects of synbiotic supplementation on energy and macronutrients homeostasis and muscle wasting of critical care patients: study protocol and a review of previous studies

abstract:
  BACKGROUND: An extreme and persistent dysbiosis occurs among critically ill patients, regardless of the heterogeneity of disease. Dysbiosis in critically ill patients may make them prone to hospital-acquired infections, sepsis, multi-organ failure (MOF), energy homeostasis disturbance, muscle wasting, and cachexia. Modulation of gut microbiota through synbiotics can be considered as a potential treatment for muscle wasting and macronutrient homeostasis disturbances. METHODS: This is a prospective, single-center, double-blind, parallel randomized controlled trial with the aim to evaluate the effects of synbiotic supplementation on energy and macronutrient homeostasis and muscle wasting in critically ill patients. A total of 40 hemodynamically stable, adult, critically ill patients who receive enteral nutrition via a nasogasteric tube (NGT) in the 24–48 h after admission to critical care will be included in this study. Eligible patients will be randomly assigned to receive Lactocare (ZistTakhmir) capsules 500 mg every 12 h or a placebo capsule, which contains only the sterile maize starch and is similar to synbiotic capsules for 14 days. The synbiotic and placebo capsules will be given through the nasogastric tube, separately from gavage, after feeding. DISCUSSION: Gut microbiota modulation through synbiotics is proposed to improve clinical prognosis and reduce infectious complications, ventilator dependency, and length of ICU stay by improving energy and macronutrient homeostasis and reducing muscle protein catabolism. TRIAL REGISTRATION: Iranian Registry of Clinical Trials, IRCT20190227042857N1. Registered on 17 March 2019.


id: cord-004450-daxz9yhp
author: Haeberle, Helene
date: 2020-03-04
txt: ./txt/cord-004450-daxz9yhp.txt
cache: ./cache/cord-004450-daxz9yhp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057516/
doi: 10.1186/s13063-020-4163-0
summary:
  Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. For safety reasons, after treatment of 100 patients (day 28 after last dose investigational medicinal product [IMP] Patient 100) within the study, an interim analysis for an increased risk for pulmonary hemorrhage ≥ grade III according to Common Terminology (Toxicity) Criteria for Adverse Events (CTCAE) Version 5.0 in the treatment (iloprost) arm will be performed and the results discussed with the Data and Safety Monitoring Board (DSMB). When possible, however, the patient or his legal representative is to be informed both in writing and verbally by the investigator before any study-specific procedure is Iloprost or NaCl 0.9% (control) X X X X X Clinical assessment including outcome X X X X X X X X X Laboratory testing X X X X X X X X Adverse/serious adverse event monitoring X X X X X X X Plasma biomarkers X X X X X X Barthel Index X X X X SOFA score X X X X X X X X Health-related questionnaire X VES X performed.

title:
  Therapeutic iloprost for the treatment of acute respiratory distress syndrome (ARDS) (the ThIlo trial): a prospective, randomized, multicenter phase II study

abstract:
  BACKGROUND: Acute respiratory distress syndrome (ARDS) is caused by rapid-onset (within hours) acute inflammatory processes in lung tissue, and it is a life-threatening condition with high mortality. The treatment of ARDS to date is focused on the prevention of further iatrogenic damage of the lung rather than the treatment of the initial inflammatory process. Several preclinical studies have revealed a beneficial effect of iloprost on the control of pulmonary inflammation, and in a small number of patients with ARDS, iloprost treatment resulted in improved oxygenation. Therefore, we plan to conduct a large multicenter trial to evaluate the effect of iloprost on ARDS. METHODS: The Therapeutic Iloprost during ARDS trial (ThIlo trial) is a multicenter, randomized, single blinded, clinical phase II trial assessing the efficacy of inhaled iloprost for the prevention of the development and progression of ARDS in critically ill patients. One hundred fifty critically ill patients suffering from acute ARDS will be treated either by nebulized iloprost or NaCl 0.9% for 5 days. Blood samples will be drawn at defined time points to elucidate the serum levels of iloprost and inflammatory markers during treatment. Mechanical ventilation will be standardized. In follow-up visits at days 28 and 90 as well as 6 months after enrollment, functional status according to the Barthel Index and a health care-related questionnaire, and frailty (Vulnerable Elders Survey) will be evaluated. The primary endpoint is the improvement of oxygenation, defined as the ratio of PaO(2)/FiO(2). Secondary endpoints include 90-day all-cause mortality, Sequential Organ Failure Assessment scores during the study period up to day 90, the duration of mechanical ventilation, the length of intensive care unit (ICU) stay, ventilator-associated pneumonia, delirium, ICU-acquired weakness, and discharge localization. The study will be conducted in three university ARDS centers in Germany. DISCUSSION: The results of the ThIlo trial will highlight the anti-inflammatory effect of iloprost on early inflammatory processes during ARDS, resulting in the improvement of outcome parameters in patients with ARDS. TRIAL REGISTRATION: EUDRA-CT: 2016-003168-37. Registered on 12 April 2017. ClinicalTrials.gov: NCT03111212. Registered on 4 June 2017.


id: cord-004515-x22q1f21
author: Pottecher, Julien
date: 2020-03-18
txt: ./txt/cord-004515-x22q1f21.txt
cache: ./cache/cord-004515-x22q1f21.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079402/
doi: 10.1186/s13063-020-4141-6
summary:
  title: Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The primary objective of the TRAUMADORNASE study is to demonstrate a reduction in the incidence of moderateto-severe hypoxaemia from 45% to 30% in severe trauma patients during the first 7 ICU days by providing aerosolized dornase alfa once during the first 2 ICU days as compared to equivalent provision of placebo (NaCl 0.9%).

title:
  Protocol for TRAUMADORNASE: a prospective, randomized, multicentre, double-blinded, placebo-controlled clinical trial of aerosolized dornase alfa to reduce the incidence of moderate-to-severe hypoxaemia in ventilated trauma patients

abstract:
  BACKGROUND: Acute respiratory distress syndrome continues to drive significant morbidity and mortality after severe trauma. The incidence of trauma-induced, moderate-to-severe hypoxaemia, according to the Berlin definition, could be as high as 45%. Its pathophysiology includes the release of damage-associated molecular patterns (DAMPs), which propagate tissue injuries by triggering neutrophil extracellular traps (NETs). NETs include a DNA backbone coated with cytoplasmic proteins, which drive pulmonary cytotoxic effects. The structure of NETs and many DAMPs includes double-stranded DNA, which prevents their neutralization by plasma. Dornase alfa is a US Food and Drug Administration-approved recombinant DNase, which cleaves extracellular DNA and may therefore break up the backbone of NETs and DAMPs. Aerosolized dornase alfa was shown to reduce trauma-induced lung injury in experimental models and to improve arterial oxygenation in ventilated patients. METHODS: TRAUMADORNASE will be an institution-led, multicentre, double-blinded, placebo-controlled randomized trial in ventilated trauma patients. The primary trial objective is to demonstrate a reduction in the incidence of moderate-to-severe hypoxaemia in severe trauma patients during the first 7 days from 45% to 30% by providing aerosolized dornase alfa as compared to placebo. The secondary objectives are to demonstrate an improvement in lung function and a reduction in morbidity and mortality. Randomization of 250 patients per treatment arm will be carried out through a secure, web-based system. Statistical analyses will include a descriptive step and an inferential step using fully Bayesian techniques. The study was approved by both the Agence Nationale de la Sécurité du Médicament et des Produits de Santé (ANSM, on 5 October 2018) and a National Institutional Review Board (CPP, on 6 November 2018). Participant recruitment began in March 2019. Results will be published in international peer-reviewed medical journals. DISCUSSION: If early administration of inhaled dornase alfa actually reduces the incidence of moderate-to-severe hypoxaemia in patients with severe trauma, this new therapeutic strategy may be easily implemented in many clinical trauma care settings. This treatment may facilitate ventilator weaning, reduce the burden of trauma-induced lung inflammation and facilitate recovery and rehabilitation in severe trauma patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03368092. Registered on 11 December 2017.


id: cord-004646-zhessjqh
author: Bawazeer, Mohammed
date: 2020-03-20
txt: ./txt/cord-004646-zhessjqh.txt
cache: ./cache/cord-004646-zhessjqh.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085173/
doi: 10.1186/s13063-020-4216-4
summary:
  title: Adjunct low-dose ketamine infusion vs standard of care in mechanically ventilated critically ill patients at a Tertiary Saudi Hospital (ATTAINMENT Trial): study protocol for a randomized, prospective, pilot, feasibility trial The 2018 Pain, Agitation/sedation, Delirium, Immobility, and Sleep disruption guideline suggested low-dose ketamine infusion as an adjunct to opioid therapy to reduce opioid requirements in post-surgical patients in the intensive care unit (ICU). Therefore, we propose a prospective, randomized, active controlled, open-label, pilot, feasibility study to assess the effect and safety of Analgo-sedative ad-juncT keTAmine Infusion iN Mechanically vENTilated ICU patients (the ATTAINMENT trial) compared to standard of care alone. Physician decline after randomization Ketamine will be discontinued Subject will be included in the data analysis a In cases of death (either within the first 48 h, until ICU or hospital discharge, or 28 days after randomization, whichever comes first), detailed documentation will be carried out in the medical record for the cause of death, group allocation, and relation to study protocol allocation and initiation of the trial intervention.

title:
  Adjunct low-dose ketamine infusion vs standard of care in mechanically ventilated critically ill patients at a Tertiary Saudi Hospital (ATTAINMENT Trial): study protocol for a randomized, prospective, pilot, feasibility trial

abstract:
  BACKGROUND: A noticeable interest in ketamine infusion for sedation management has developed among critical care physicians for critically ill patients. The 2018 Pain, Agitation/sedation, Delirium, Immobility, and Sleep disruption guideline suggested low-dose ketamine infusion as an adjunct to opioid therapy to reduce opioid requirements in post-surgical patients in the intensive care unit (ICU). This was, however, rated as conditional due to the very low quality of evidence. Ketamine has favorable characteristics, making it an especially viable alternative for patients with respiratory and hemodynamic instability. The Analgo-sedative adjuncT keTAmine Infusion iN Mechanically vENTilated ICU patients (ATTAINMENT) trial aims to assess the effect and safety of adjunct low-dose continuous infusion of ketamine as an analgo-sedative compared to standard of care in critically ill patients on mechanical ventilation (MV) for ≥ 24 h. METHODS/DESIGN: This trial is a prospective, randomized, active controlled, open-label, pilot, feasibility study of adult ICU patients (> 14 years old) on MV. The study will take place in the adult ICUs in the King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh, Saudi Arabia, and will enroll 80 patients. Patients will be randomized post-intubation into two groups: the intervention group will receive an adjunct low-dose continuous infusion of ketamine plus standard of care. Ketamine will be administered over a period of 48 h at a fixed infusion rate of 2 μg/kg/min (0.12 mg/kg/h) in the first 24 h followed by 1 μg/kg/min (0.06 mg/kg/h) in the second 24 h. The control group will receive standard of care in the ICU (propofol and/or fentanyl and/or midazolam) according to the KFSH&RC sedation and analgesia protocol as clinically appropriate. The primary outcome is MV duration until ICU discharge, death, extubation, or 28 days post-randomization, whichever comes first. DISCUSSION: The first patient was enrolled on 1 September 2019. As of 10 October 2019, a total of 16 patients had been enrolled. We expect to complete the recruitment by 31 December 2020. The findings of this pilot trial will likely justify further investigation for the role of adjunct low-dose ketamine infusion as an analgo-sedative agent in a larger, multicenter, randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04075006. Registered on 30 August 2019. Current controlled trials: ISRCTN14730035. Registered on 3 February 2020.


id: cord-012934-c6pbr64i
author: Hao, Weiming
date: 2020-07-22
txt: ./txt/cord-012934-c6pbr64i.txt
cache: ./cache/cord-012934-c6pbr64i.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477872/
doi: 10.1186/s13063-020-04579-6
summary:
  title: Vestibular prognosis in idiopathic sudden sensorineural hearing loss with vestibular dysfunction treated with oral or intratympanic glucocorticoids: a protocol for randomized controlled trial The primary outcomes will be vestibular function outcomes assessed by sensory organization test, caloric test, video head impulse test, cervical vestibular evoked myogenic potential, and ocular vestibular evoked myogenic potential; the secondary outcomes include self-reported vestibular dysfunction symptoms; dizziness-related handicap, visual analogue scale for vertigo and tinnitus; and pure tone audiometry. To evaluate the recovery of vestibular function, we set the recovery rates of the whole battery of vestibular function tests (SOT/caloric test/vHIT/VEMPs) as the primary outcome, which is the proportion of patients whose abnormal results of vestibular function tests at baseline recover to normal at 4-/8-week follow-up: in this study, we define a 10-dB PTA criterion as clinically significant difference based on a previous RCT [9] .

title:
  Vestibular prognosis in idiopathic sudden sensorineural hearing loss with vestibular dysfunction treated with oral or intratympanic glucocorticoids: a protocol for randomized controlled trial

abstract:
  BACKGROUND: Idiopathic sudden sensorineural hearing loss (ISSNHL) is a rapid-onset sensorineural hearing impairment with unclear etiology and unsatisfying treatment effects. Vestibular dysfunction has been considered as a poor indicator in the clinical manifestations and prognosis of ISSNHL, which occurred in approximately 28–57% cases. Glucocorticoids, administered through oral or intratympanic way, are currently regularly and standardly applied for ISSNHL to improve the hearing outcome. However, the vestibular prognosis of ISSNHL after routine treatments remains seldom explored. This study aims to compare the effectiveness of oral and intratympanic glucocorticoids in ISSNHL with vestibular dysfunction in terms of the pattern and trajectory of possible process of vestibular function recovery. METHODS/DESIGN: A randomized, outcome-assessor- and analyst-blinded, controlled, clinical trial (RCT) will be carried out. Seventy-two patients with ISSNHL complaining of vestibular dysfunction appearing as vertigo or imbalance will be recruited and randomized into either oral or intratympanic glucocorticoid therapy group with a 1:1 allocation ratio. The primary outcomes will be vestibular function outcomes assessed by sensory organization test, caloric test, video head impulse test, cervical vestibular evoked myogenic potential, and ocular vestibular evoked myogenic potential; the secondary outcomes include self-reported vestibular dysfunction symptoms; dizziness-related handicap, visual analogue scale for vertigo and tinnitus; and pure tone audiometry. Assessments of primary outcomes will be performed at baseline and at 4 and 8 weeks post-randomization, while assessments of secondary outcomes will be performed at baseline and 1, 2, 4, and 8 weeks post-randomization. DISCUSSION: Previous intervention studies of ISSNHL included only hearing outcomes, with little attention paid on the prognosis of vestibular dysfunction. This trial will be the first RCT study focusing on the progress and prognosis of vestibular dysfunction in ISSNHL. The efficacy of two commonly used therapies of glucocorticoids will be compared in both auditory and vestibular function fields, rather than in the hearing outcome alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT03974867. Registered on 23 July 2019


id: cord-029112-u507i0t0
author: Smith, Keisha
date: 2020-07-13
txt: ./txt/cord-029112-u507i0t0.txt
cache: ./cache/cord-029112-u507i0t0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355517/
doi: 10.1186/s13063-020-04548-z
summary:
  Study ALXN1210-COV-305 is a multicenter Phase 3, open-label, randomized, controlled study designed to evaluate the safety and efficacy of intravenous (IV) ravulizumab + best supportive care (BSC), compared with BSC alone in patients with a confirmed diagnosis of SARS-CoV-2 infection, and a clinical presentation consistent with COVID-19 severe pneumonia, acute lung injury, or ARDS.

title:
  A Phase 3 Open-label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Intravenously Administered Ravulizumab Compared with Best Supportive Care in Patients with COVID-19 Severe Pneumonia, Acute Lung Injury, or Acute Respiratory Distress Syndrome: A structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: Primary Objective • To evaluate the effect of ravulizumab, a long-acting complement (C5) inhibitor plus best supportive care (BSC) compared with BSC alone on the survival of patients with COVID-19. Secondary Objectives • Number of days free of mechanical ventilation at Day 29 • Duration of intensive care unit stay at Day 29 • Change from baseline in Sequential Organ Failure Assessment (SOFA) score at Day 29 • Change from baseline in peripheral capillary oxygen saturation/ fraction of inspired oxygen (SpO2 /FiO2) at Day 29 • Duration of hospitalization at Day 29 • Survival (based on all-cause mortality) at Day 60 and Day 90 Safety • Incidence of treatment-emergent adverse events and treatment-emergent serious adverse events. PK/PD/Immunogenicity • Change in serum ravulizumab concentrations over time • Change in serum free and total C5 concentrations over time • Incidence and titer of anti-ALXN1210 antibodies Biomarkers • Change in absolute level of soluble biomarkers in blood associated with complement activation, inflammatory processes, and hypercoagulable states over time Exploratory • Incidence of progression to renal failure requiring dialysis at Day 29 • Time to clinical improvement (based on a modified 6-point ordinal scale) over 29 days • SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores at Day 29 (or discharge), Day 60, and Day 90 • EuroQol 5-dimension 5-level (EQ-5D-5L) scores at Day 29 (or discharge), Day 60, and Day 90 TRIAL DESIGN: This is a multicenter Phase 3, open-label, randomized, controlled, study. The study is being conducted in acute care hospital settings in the United States, United Kingdom, Spain, France, Germany, and Japan. PARTICIPANTS: Male or female patients at least 18 years of age, weighing ≥ 40 kg, admitted to a designated hospital facility for treatment will be screened for eligibility in this study. Key Inclusion criteria • Confirmed diagnosis of SARS-CoV-2 infection (eg, via polymerase chain reaction [PCR] and/or antibody test) presenting as severe COVID-19 requiring hospitalization • Severe pneumonia, acute lung injury, or ARDS confirmed by computed tomography (CT) or X-ray at Screening or within the 3 days prior to Screening, as part of the patient’s routine clinical care • Respiratory distress requiring mechanical ventilation, which can be either invasive (requiring endotracheal intubation) or non-invasive (with continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]) Key Exclusion criteria • Patient is not expected to survive for more than 24 hours • Patient is on invasive mechanical ventilation with intubation for more than 48 hours prior to Screening • Severe pre-existing cardiac disease (ie, NYHA Class 3 or Class 4, acute coronary syndrome, or persistent ventricular tachyarrhythmias) • Patient has an unresolved Neisseria meningitidis infection Excluded medications and therapies • Current treatment with a complement inhibitor • Intravenous immunoglobulin (IVIg) within 4 weeks prior to randomization on Day 1 Excluded prior/concurrent clinical study experience • Treatment with investigational therapy in a clinical study within 30 days before randomization, or within 5 half-lives of that investigational therapy, whichever is greater • Exceptions a. Investigational therapies will be allowed if received as part of best supportive care through an expanded access protocol or emergency approval for the treatment of COVID-19. b. Investigational antiviral therapies (such as remdesivir) will be allowed even if received as part of a clinical study. INTERVENTION AND COMPARATOR: The study consists of a Screening Period of up to 3 days, a Primary Evaluation Period of 4 weeks, a final assessment at Day 29, and a Follow-up Period of 8 weeks. For patients randomized to ravulizumab plus BSC, a weight-based dose of ravulizumab (≥40 to < 60 kg/2400 mg, 60 to < 100 kg/2700 mg, ≥ 100 kg/3000 mg) will be administered on Day 1. On Day 5 and Day 10, additional doses of 600 mg (≥40 to <60 kg) or 900 mg (>60 kg) ravulizumab will be administered and on Day 15 patients will receive 900 mg ravulizumab. There is no active or placebo comparator in this open-label clinical trial. The total duration of each patient’s participation is anticipated to be approximately 3 months. MAIN OUTCOMES: The primary efficacy outcome of this study is survival (based on all-cause mortality) at Day 29. RANDOMISATION: Patients will be randomized in a 2:1 ratio (ravulizumab plus BSC:BSC alone). Randomization will be stratified by intubated or not intubated on Day 1. Computer-generated randomization lists will be prepared by a third party under the direction of the sponsor. Investigators, or designees, will enrol patients and then obtain randomization codes using an interactive voice/web response system. The block size will be kept concealed so that investigators cannot select patients for a particular treatment assignment. Blinding (masking): This is an open-label study. Numbers to be randomised (sample size): Approximately 270 patients will be randomly assigned in a 2:1 ratio to ravulizumab plus BSC (n=180) or BSC alone (n=90). TRIAL STATUS: Protocol Number: ALXN1210-COV-305 Original Protocol: 09 Apr 2020 Protocol Amendment 1 (Global): 13 Apr 2020 Protocol Amendment 2 (Global): 17 Apr 2020 Protocol Amendment 3 (Global): 09 Jun 2020 Recruitment is currently ongoing. Recruitment was initiated on 11 May 2020. We expect recruitment to be completed by 30 Nov 2020. TRIAL REGISTRATION: Clinicaltrials.gov: Protocol Registry Number: NCT04369469; First posted; 30 Apr 2020 EU Clinical Trials Register: EudraCT Number: https://www.clinicaltrialsregister.eu/ctr-search/search?query=ALXN1210-COV-305, Start date: 07 May 2020 FULL PROTOCOL: The full redacted protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-030531-4uucx9ss
author: Randremanana, Rindra Vatosoa
date: 2020-08-17
txt: ./txt/cord-030531-4uucx9ss.txt
cache: ./cache/cord-030531-4uucx9ss.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429934/
doi: 10.1186/s13063-020-04642-2
summary:
  All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. The secondary objective is to collect data on the effectiveness of ciprofloxacin in the treatment of pneumonic plague, although the trial is not able to formally assess the non-inferiority of ciprofloxacin monotherapy compared to streptomycin and ciprofloxacin combination therapy in pneumonic plague, Considering the operational and practical complexities of a plague RCT, the study also has additional exploratory objectives to optimize investments: to evaluate the level and kinetics of anti-Y.

title:
  An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial

abstract:
  BACKGROUND: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. METHODS: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague ‘seasons’. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. DISCUSSION: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. TRIAL REGISTRATION: ClinicalTrials.gov NCT04110340. Registered on 1 October 2019


id: cord-031315-p7jb4gf2
author: Kong, Qing
date: 2020-09-03
txt: ./txt/cord-031315-p7jb4gf2.txt
cache: ./cache/cord-031315-p7jb4gf2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468179/
doi: 10.1186/s13063-020-04669-5
summary:
  title: Efficacy and safety of Jia Wei Bushen Yiqi formulas as an adjunct therapy to systemic glucocorticoids on acute exacerbation of COPD: study protocol for a randomized, double-blinded, multi-center, placebo-controlled clinical trial The present study aims to evaluate the efficacy and safety of Jia Wei Bushen Yiqi (JWBY) formulas in patients who suffer from COPD exacerbations and to investigate whether the short-term (5-days) systemic glucocorticoid therapy is non-inferior to the long-term (9-day) regime. On one hand, a dose of 40 mg prednisone (a common oral systemic glucocorticoid) daily for 5 days has been recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Science Committee Report based on the REDUCE randomized clinical trial since 2015 [24] . We conducted a randomized and placebo-controlled trial enrolling stable COPD patients in 2014, which illustrated that TCM formulas called Bushen Yiqi (BY) formulas can improve the lung function, reduce the frequency of acute exacerbation of COPD, and modulate the HPA axis [35] .

title:
  Efficacy and safety of Jia Wei Bushen Yiqi formulas as an adjunct therapy to systemic glucocorticoids on acute exacerbation of COPD: study protocol for a randomized, double-blinded, multi-center, placebo-controlled clinical trial

abstract:
  BACKGROUND: Systemic glucocorticoids are effective for the management of chronic obstructive pulmonary disease (COPD) exacerbation but have serious adverse effects. Traditional Chinese medicine (TCM) can bring additional benefits to these patients but has few adverse effects. The present study aims to evaluate the efficacy and safety of Jia Wei Bushen Yiqi (JWBY) formulas in patients who suffer from COPD exacerbations and to investigate whether the short-term (5-days) systemic glucocorticoid therapy is non-inferior to the long-term (9-day) regime. METHODS: In this multi-center, randomized, double-blinded trial, eligible inpatients with COPD exacerbation are randomly assigned to four groups (A, B, C, and D). Group A will receive placebo plus 5-day prednisone, group B will receive placebo plus 9-day prednisone, group C will receive JWBY formulas plus 5-day prednisone, and group D will receive JWBY formulas plus 9-day prednisone. The primary outcomes are the time interval to the patient’s next exacerbation during a 180-day following up and the COPD assessment test (CAT) during treatment. Secondary outcomes include lung function, TCM syndrome assessment, laboratory tests, and safety. The changes of the hypothalamic pituitary adrenaline axis (HPA axis) and inflammatory cytokine will be measured as well. DISCUSSION: By demonstrating the advantages of utilizing TCM and an appropriate duration of systemic glucocorticoids, this effectiveness comparison trial will provide new references to physicians on how to improve the management of COPD exacerbation. The results of HPA axis and inflammation cytokine measurements will shed light on the molecular mechanisms and entail further mechanism studies. TRIAL REGISTRATION: www.chictr.org.cn ChiCTR1900023364. Registered on 24 May 2019.


id: cord-032926-mrnsaexq
author: Waitz, Markus
date: 2020-10-01
txt: ./txt/cord-032926-mrnsaexq.txt
cache: ./cache/cord-032926-mrnsaexq.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527266/
doi: 10.1186/s13063-020-04660-0
summary:
  BACKGROUND: Nasal continuous positive airway pressure (CPAP) applies positive end-expiratory pressure (PEEP) and has been shown to reduce the need for intubation and invasive mechanical ventilation in very low birth weight infants with respiratory distress syndrome. Results of a secondary analysis from a cohort study in 34 international centers that participated in a nasal intermittent positive pressure ventilation trial indicate a large variation of PEEP levels used in clinical practice during neonatal resuscitation and the first 28 days of life (i.e., 3-9 cmH 2 O) [10] . The primary hypothesis of this study is that the use of a higher PEEP range in preterm infants born at 26 + 0-29 + 6 weeks gestational age (GA) receiving prophylactic nasal CPAP support after birth reduces the incidence of intubation and/or meeting predefined CPAP failure criteria within the first 120 h of life when compared to the application of a lower PEEP range.

title:
  Application of two different nasal CPAP levels for the treatment of respiratory distress syndrome in preterm infants—“The OPTTIMMAL-Trial”—Optimizing PEEP To The IMMAture Lungs: study protocol of a randomized controlled trial

abstract:
  BACKGROUND: Nasal continuous positive airway pressure (CPAP) applies positive end-expiratory pressure (PEEP) and has been shown to reduce the need for intubation and invasive mechanical ventilation in very low birth weight infants with respiratory distress syndrome. However, CPAP failure rates of 50% are reported in large randomized controlled trials. A possible explanation for these failure rates is the application of insufficient low levels of PEEP during nasal CPAP treatment to maintain adequate functional residual capacity shortly after birth. The optimum PEEP level to treat symptoms of respiratory distress in very low birth weight infants has not been assessed in clinical studies. The aim of the study is to compare two different PEEP levels during nasal CPAP treatment in preterm infants. METHODS: In this randomized multicenter trial, 216 preterm infants born at 26 + 0–29 + 6 gestational weeks will be allocated to receive a higher (6–8 cmH(2)O) or a lower (3–5 cmH(2)O) PEEP during neonatal resuscitation and the first 120 h of life. The PEEP level within each group will be titrated throughout the intervention based on the FiO(2) (fraction of inspired oxygen concentration) requirements to keep oxygenation within the target range. The primary outcome is defined as the need for intubation and mechanical ventilation for > 1 h or being not ventilated but reaching one of the two pre-defined CPAP failure criteria (FiO(2) > 0.5 for > 1 h or pCO(2) ≥ 70 mmHg in two consecutive blood gas analyses at least 2 h apart). DISCUSSION: Based on available data from the literature, the optimum level of PEEP that most effectively treats respiratory distress syndrome in preterm infants is unknown, since the majority of large clinical trials applied a wide range of PEEP levels (4–8 cmH(2)O). The rationale for our study hypothesis is that the early application of a higher PEEP level will more effectively counteract the collapsing properties of the immature and surfactant-deficient lungs and that the level of inspired oxygen may serve as a surrogate marker to guide PEEP titration. Finding the optimum noninvasive continuous distending pressure during early nasal CPAP is required to improve CPAP efficacy and as a consequence to reduce the exposure to ventilator-induced lung injury and the incidence of chronic lung disease in this vulnerable population of very preterm infants. TRIAL REGISTRATION: drks.de DRKS00019940. Registered on March 13, 2020


id: cord-033331-giku34r9
author: Manrique-Saide, Pablo
date: 2020-10-08
txt: ./txt/cord-033331-giku34r9.txt
cache: ./cache/cord-033331-giku34r9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542575/
doi: 10.1186/s13063-020-04780-7
summary:
  METHODS/DESIGN: We are pursuing a two-arm, parallel, unblinded, cluster randomized controlled trial to quantify the overall efficacy of TIRS in reducing the burden of laboratory-confirmed ABV clinical disease (primary endpoint). Fitting such entomological information to an agent-based model of Yucatan State, Mexico, showed that high levels of TIRS coverage (75% of houses treated once per year) applied preemptively before the typical dengue season (before July) could reduce DENV infections by 89.7% in year 1 and 78.2% cumulatively over the first 5 years of an annual program [32] . Additionally, our project will access the online ABV database managed by Mexico''s National Center of Preventive Programs and Diseases Control (CENAPRECE) [51] to identify all reported symptomatic cases (including all ages, not only children) residing within study clusters in real time, and to map routine vector control actions performed by SSY.

title:
  The TIRS trial: protocol for a cluster randomized controlled trial assessing the efficacy of preventive targeted indoor residual spraying to reduce Aedes-borne viral illnesses in Merida, Mexico

abstract:
  BACKGROUND: Current urban vector control strategies have failed to contain dengue epidemics and to prevent the global expansion of Aedes-borne viruses (ABVs: dengue, chikungunya, Zika). Part of the challenge in sustaining effective ABV control emerges from the paucity of evidence regarding the epidemiological impact of any Aedes control method. A strategy for which there is limited epidemiological evidence is targeted indoor residual spraying (TIRS). TIRS is a modification of classic malaria indoor residual spraying that accounts for Aedes aegypti resting behavior by applying residual insecticides on exposed lower sections of walls (< 1.5 m), under furniture, and on dark surfaces. METHODS/DESIGN: We are pursuing a two-arm, parallel, unblinded, cluster randomized controlled trial to quantify the overall efficacy of TIRS in reducing the burden of laboratory-confirmed ABV clinical disease (primary endpoint). The trial will be conducted in the city of Merida, Yucatan State, Mexico (population ~ 1million), where we will prospectively follow 4600 children aged 2–15 years at enrollment, distributed in 50 clusters of 5 × 5 city blocks each. Clusters will be randomly allocated (n = 25 per arm) using covariate-constrained randomization. A “fried egg” design will be followed, in which all blocks of the 5 × 5 cluster receive the intervention, but all sampling to evaluate the epidemiological and entomological endpoints will occur in the “yolk,” the center 3 × 3 city blocks of each cluster. TIRS will be implemented as a preventive application (~ 1–2 months prior to the beginning of the ABV season). Active monitoring for symptomatic ABV illness will occur through weekly household visits and enhanced surveillance. Annual sero-surveys will be performed after each transmission season and entomological evaluations of Ae. aegypti indoor abundance and ABV infection rates monthly during the period of active surveillance. Epidemiological and entomological evaluation will continue for up to three transmission seasons. DISCUSSION: The findings from this study will provide robust epidemiological evidence of the efficacy of TIRS in reducing ABV illness and infection. If efficacious, TIRS could drive a paradigm shift in Aedes control by considering Ae. aegypti behavior to guide residual insecticide applications and changing deployment to preemptive control (rather than in response to symptomatic cases), two major enhancements to existing practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT04343521. Registered on 13 April 2020. The protocol also complies with the WHO International Clinical Trials Registry Platform (ICTRP) (Additional file 1). PRIMARY SPONSOR: National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID).


id: cord-033772-uzgya4k9
author: Strömmer, Sofia
date: 2020-10-15
txt: ./txt/cord-033772-uzgya4k9.txt
cache: ./cache/cord-033772-uzgya4k9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557314/
doi: 10.1186/s13063-020-04761-w
summary:
  The EACH-B intervention consists of three linked elements: professional development for teachers including training in communication skills to support health behaviour change; the LifeLab educational module comprising in-school teaching of nine science lessons linked to the English National Curriculum and a practical day visit to the LifeLab facility; and a personalised digital intervention that involves social support and game features that promote eating better and being more active. i) Professional development for teachers including training in communication skills to support health behaviour change, known as ''Healthy Conversation Skills'' (HCS), explained in detail below ii) LifeLab educational module comprising in-school teaching of nine science lessons linked to the English National Curriculum and a hands-on practical day visit to LifeLab, held part way through the module iii) A personalised digital intervention (the ''app'') with social support and game features

title:
  Engaging adolescents in changing behaviour (EACH-B): a study protocol for a cluster randomised controlled trial to improve dietary quality and physical activity

abstract:
  BACKGROUND: Poor diet and lack of physical activity are strongly linked to non-communicable disease risk, but modifying them is challenging. There is increasing recognition that adolescence is an important time to intervene; habits formed during this period tend to last, and physical and psychological changes during adolescence make it an important time to help individuals form healthier habits. Improving adolescents’ health behaviours is important not only for their own health now and in adulthood, but also for the health of any future children. Building on LifeLab—an existing, purpose-built educational facility at the University of Southampton—we have developed a multi-component intervention for secondary school students called Engaging Adolescents in Changing Behaviour (EACH-B) that aims to motivate and support adolescents to eat better and be more physically active. METHODS: A cluster randomised controlled trial is being conducted to evaluate the effectiveness of the EACH-B intervention. The primary outcomes of the intervention are self-reported dietary quality and objectively measured physical activity (PA) levels, both assessed at baseline and at 12-month follow-up. The EACH-B intervention consists of three linked elements: professional development for teachers including training in communication skills to support health behaviour change; the LifeLab educational module comprising in-school teaching of nine science lessons linked to the English National Curriculum and a practical day visit to the LifeLab facility; and a personalised digital intervention that involves social support and game features that promote eating better and being more active. Both the taught module and the LifeLab day are designed with a focus on the science behind the messages about positive health behaviours, such as diet and PA, for the adolescents now, in adulthood and their future offspring, with the aim of promoting personal plans for change. The EACH-B research trial aims to recruit approximately 2300 secondary school students aged 12–13 years from 50 schools (the clusters) from Hampshire and neighbouring counties. Participating schools will be randomised to either the control or intervention arm. The intervention will be run during two academic years, with continual recruitment of schools throughout the school year until the sample size is reached. The schools allocated to the control arm will receive normal schooling but will be offered the intervention after data collection for the trial is complete. An economic model will be developed to assess the cost-effectiveness of the EACH-B intervention compared with usual schooling. DISCUSSION: Adolescents’ health needs are often ignored and they can be difficult to engage in behaviour change. Building a cheap, sustainable way of engaging them in making healthier choices will benefit their long-term health and that of their future children. TRIAL REGISTRATION: ISRCTN 74109264. Registered on 30 August 2019. EACH-B is a cluster randomised controlled trial, funded by the National Institute for Health Research (RP-PG-0216-20004).


id: cord-034257-kl2ccmz5
author: de Jonge, Jeroen C.
date: 2020-10-26
txt: ./txt/cord-034257-kl2ccmz5.txt
cache: ./cache/cord-034257-kl2ccmz5.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586648/
doi: 10.1186/s13063-020-04717-0
summary:
  title: PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke—statistical analysis plan of a randomised, open, phase III, clinical trial with blinded outcome assessment AIMS AND DESIGN: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) is an international, multi-centre, 3 × 2 factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment, which will assess whether prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, respectively, or any combination of these in the first 4 days after stroke onset improves functional outcome at 90 days in elderly patients with acute stroke. The primary objective is to assess whether prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first 4 days after stroke onset improves functional outcome at 90 days in older patients with acute stroke.

title:
  PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke—statistical analysis plan of a randomised, open, phase III, clinical trial with blinded outcome assessment

abstract:
  RATIONALE: Aspiration, infections, and fever are common in the first days after stroke, especially in older patients. The occurrence of these complications has been associated with an increased risk of death or dependency. AIMS AND DESIGN: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke (PRECIOUS) is an international, multi-centre, 3 × 2 factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment, which will assess whether prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, respectively, or any combination of these in the first 4 days after stroke onset improves functional outcome at 90 days in elderly patients with acute stroke. DISCUSSION: This statistical analysis plan provides a technical description of the statistical methodology and unpopulated tables and figures. The paper is written prior to data lock and unblinding of treatment allocation. TRIAL REGISTRATION: ISRCTN registry ISRCTN82217627. Registered on 22 September 2015. The trial was prospectively registered.


id: cord-253129-v5lck9l7
author: Kim, Kyeong Tae
date: 2020-02-01
txt: ./txt/cord-253129-v5lck9l7.txt
cache: ./cache/cord-253129-v5lck9l7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32007099/
doi: 10.1186/s13063-019-4035-7
summary:
  BACKGROUND: Positive end-expiratory pressure (PEEP) at minimum respiratory elastance during mechanical ventilation (MV) in patients with acute respiratory distress syndrome (ARDS) may improve patient care and outcome. The Clinical utilisation of respiratory elastance (CURE) trial is a two-arm, randomised controlled trial (RCT) investigating the performance of PEEP selected at an objective, model-based minimal respiratory system elastance in patients with ARDS. Secondary outcomes include length of time of MV, ventilator-free days (VFD) up to 28 days, ICU and hospital length of stay, AUC of oxygen saturation (SpO(2))/FiO(2) during MV, number of desaturation events (SpO(2) < 88%), changes in respiratory mechanics and chest x-ray index scores, rescue therapies (prone positioning, nitric oxide use, extracorporeal membrane oxygenation) and hospital and 90-day mortality. Following the study, a phase-2 randomised controlled trial (RCT) was designed to assess mechanical ventilation at minimal elastance PEEP in patients with ARDS versus standard practice of care in a single-centre hospital.

title:
  Model-based PEEP titration versus standard practice in mechanical ventilation: a randomised controlled trial

abstract:
  BACKGROUND: Positive end-expiratory pressure (PEEP) at minimum respiratory elastance during mechanical ventilation (MV) in patients with acute respiratory distress syndrome (ARDS) may improve patient care and outcome. The Clinical utilisation of respiratory elastance (CURE) trial is a two-arm, randomised controlled trial (RCT) investigating the performance of PEEP selected at an objective, model-based minimal respiratory system elastance in patients with ARDS. METHODS AND DESIGN: The CURE RCT compares two groups of patients requiring invasive MV with a partial pressure of arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio ≤ 200; one criterion of the Berlin consensus definition of moderate (≤ 200) or severe (≤ 100) ARDS. All patients are ventilated using pressure controlled (bi-level) ventilation with tidal volume = 6–8 ml/kg. Patients randomised to the control group will have PEEP selected per standard practice (SPV). Patients randomised to the intervention will have PEEP selected based on a minimal elastance using a model-based computerised method. The CURE RCT is a single-centre trial in the intensive care unit (ICU) of Christchurch hospital, New Zealand, with a target sample size of 320 patients over a maximum of 3 years. The primary outcome is the area under the curve (AUC) ratio of arterial blood oxygenation to the fraction of inspired oxygen over time. Secondary outcomes include length of time of MV, ventilator-free days (VFD) up to 28 days, ICU and hospital length of stay, AUC of oxygen saturation (SpO(2))/FiO(2) during MV, number of desaturation events (SpO(2) < 88%), changes in respiratory mechanics and chest x-ray index scores, rescue therapies (prone positioning, nitric oxide use, extracorporeal membrane oxygenation) and hospital and 90-day mortality. DISCUSSION: The CURE RCT is the first trial comparing significant clinical outcomes in patients with ARDS in whom PEEP is selected at minimum elastance using an objective model-based method able to quantify and consider both inter-patient and intra-patient variability. CURE aims to demonstrate the hypothesized benefit of patient-specific PEEP and attest to the significance of real-time monitoring and decision-support for MV in the critical care environment. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, ACTRN12614001069640. Registered on 22 September 2014. (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366838&isReview=true) The CURE RCT clinical protocol and data usage has been granted by the New Zealand South Regional Ethics Committee (Reference number: 14/STH/132).


id: cord-255101-l5ssz750
author: Daval, Mary
date: 2020-07-20
txt: ./txt/cord-255101-l5ssz750.txt
cache: ./cache/cord-255101-l5ssz750.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32690074/
doi: 10.1186/s13063-020-04585-8
summary:
  Objectif principal: Evaluer l''efficacité du budésonide en traitement local intranasal (lavage de nez), en complément de la rééducation olfactive, dans la prise en charge de la perte d''odorat de patients COVID-19 sans signes de gravité et présentant une persistance de l''hyposmie 30 jours après le début des symptômes. L''objectif de cet essai randomisé contrôlé, bicentrique, est d''évaluer l''efficacité du budésonide en traitement local intranasal (lavage de nez), en complément de la rééducation olfactive, dans la prise en charge de la perte d''odorat de patients COVID-19 sans signes de gravité et présentant une persistance de l''hyposmie 30 jours après le début des symptômes. Evaluer l''efficacité du budésonide en traitement local intranasal (lavage de nez), en complément de la rééducation olfactive, dans la prise en charge de la perte d''odorat de patients COVID-19 sans signes de gravité et présentant une persistance de l''hyposmie 30 jours après le début des symptômes.

title:
  Efficacy of local budesonide therapy in the management of persistent hyposmia in COVID-19 patients without signs of severity: A structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: To assess the efficacy of local intranasal treatment with budesonide (nasal irrigation), in addition to olfactory rehabilitation, in the management of loss of smell in COVID-19 patients without signs of severity and with persistent hyposmia 30 days after the onset of symptoms. To search for an association between the presence of an obstruction on MRI and the severity of olfactory loss, at inclusion and after 30 days of treatment. TRIAL DESIGN: Two center, open-label, 2-arm (1:1 ratio) parallel group randomized controlled superiority trial. PARTICIPANTS: Inclusion criteria - Patient over 18 years of age; - Patient with a suspected SARS-CoV-2 infection, whether or not confirmed by PCR, or close contact with a PCR-confirmed case, typical chest CT scan (unsystematic frosted glass patches with predominantly sub-pleural appearance, and at a later stage, alveolar condensation without excavation or nodules or masses) or positive serology ; - Patient with isolated sudden onset hyposmia persisting 30 days after the onset of symptoms of CoV-2 SARS infection; - Affiliate or beneficiary of a social security scheme; - Written consent to participate in the study. Non-inclusion criteria - Known hypersensitivity to budesonide or any of the excipients; - Hemostasis disorder or epistaxis; - Oral-nasal and ophthalmic herpes virus infection; - Long-term corticosteroid treatment; - Treatment with potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and HIV protease inhibitors); - Severe forms of SARS-CoV-2 with respiratory or other signs; - Hyposmia persisting for more than 90 days after the onset of symptoms - Other causes of hyposmia found on interrogation or MRI; - Patient benefiting from a legal protection measure; - Pregnant or breastfeeding women. The participants will be recruited from: Hôpital Fondation Adolphe de Rothschild and Hôpital Lariboisière in Paris, France INTERVENTION AND COMPARATOR: Intervention: Experimental group: Nasal irrigation with budesonide and physiological saline (Budesonide 1mg/2mL diluted in 250mL of physiological saline 9°/00): 3 syringes of 20mL in each nasal cavity, morning and evening, for 30 days, in addition to olfactory rehabilitation twice a day. Control group: Nasal irrigation with physiological saline 9°/00 only: 3 syringes of 20cc in each nasal cavity, morning and evening, for 30 days, in addition to olfactory rehabilitation twice a day. MAIN OUTCOMES: Percentage of patients with an improvement of more than 2 points on the ODORATEST score after 30 days of treatment. RANDOMISATION: Patients will be randomized (1:1) between the experimental and control groups, using the e-CRF. The randomization list will be stratified by centre. BLINDING (MASKING): Participants and caregivers are aware of the group assignment. People assessing the outcomes are blinded to the group assignment Numbers to be randomised (sample size) 120 patients are planned to be randomized into two groups of 60 patients. TRIAL STATUS: MDL_2020_10. Version number 2, May 22, 2020. Recruitment started on May 22, 2020. The trial will finish recruiting by August 2020. TRIAL REGISTRATION: EUDRACT number: 2020-001667-85; date of trial registration: 15 May 2020 Protocol registered on ClinicalTrial.gov, registration number: NCT04361474; date of trial registration: 24 April 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-263628-ac9gld5l
author: Sivapalan, Pradeesh
date: 2020-10-20
txt: ./txt/cord-263628-ac9gld5l.txt
cache: ./cache/cord-263628-ac9gld5l.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04795-0
doi: 10.1186/s13063-020-04795-0
summary:
  The ProPac-COVID trial evaluates whether combination therapy with macrolide azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy, and pre-emptive treatment of supra-infections can shorten hospitalization duration and reduce the risk of non-invasive ventilation, treatment in the intensive care unit, and death in patients with acute hospital admission and a positive test for 2019-nCoV and symptoms of COVID-19 disease. The objective of this randomized, placebo-controlled, double-blinded multi-center trial is to investigate whether 15-day treatment with azithromycin and hydroxychloroquine added to standard of care can shorten hospitalization and reduce the risk of non-invasive ventilation, admittance to ICU, and death. The interim analysis will focus on reporting the following: selected baseline data (those readily available from the baseline data list below), primary outcome (in an O'' Brien-Fleming Plot), and all-cause mortality at 30 days (chi-square or Fisher''s exact test, whichever appropriate).

title:
  Proactive prophylaxis with azithromycin and hydroxychloroquine in hospitalized patients with COVID-19 (ProPAC-COVID): a statistical analysis plan

abstract:
  BACKGROUND: There is an urgent need for treatments that can shorten hospitalization and lower the risk of secondary infection and death in patients with corona disease. The ProPac-COVID trial evaluates whether combination therapy with macrolide azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy, and pre-emptive treatment of supra-infections can shorten hospitalization duration and reduce the risk of non-invasive ventilation, treatment in the intensive care unit, and death in patients with acute hospital admission and a positive test for 2019-nCoV and symptoms of COVID-19 disease. METHODS: The ProPAC-COVID is a multi-center, randomized, placebo-controlled, double-blinded clinical trial. The primary outcome is number of days spent alive and out of hospital within 14 days from randomization. Randomization will be in blocks of unknown size, and the final allocation will be stratified for age, site of recruitment, and whether the patient has any chronic lung diseases. Data is analyzed using intention-to-treat (ITT) principles, and main analyses will also be subject to modified ITT analysis and per protocol analysis. DISCUSSION: This paper describes the detailed statistical analysis plan for the evaluation of primary and secondary endpoints of the ProPAC-COVID study. Enrolment of patients to the ProPAC-COVID study is still ongoing. The purpose of this paper is to provide primary publication of study results to prevent selective reporting of outcomes, data-driven analysis, and to increase transparency. TRIAL REGISTRATION: ClinicalTrials.gov NCT04322396. Registered on 26 March 2020.


id: cord-282474-74273qgk
author: Roehrig, Stefan
date: 2020-09-11
txt: ./txt/cord-282474-74273qgk.txt
cache: ./cache/cord-282474-74273qgk.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04708-1
doi: 10.1186/s13063-020-04708-1
summary:
  title: Flow controlled ventilation in Acute Respiratory Distress Syndrome associated with COVID-19: A structured summary of a study protocol for a randomised controlled trial OBJECTIVES: This study aims to demonstrate the positive effects on oxygenation of flow-controlled ventilation compared to conventionally ventilated patients in patients suffering from Acute respiratory distress syndrome (ARDS) associated with COVID-19.We define ARDS according to the "Berlin" definition integrating the oxygenation index (P/F ratio), the level of Positive End Expiratory Pressure (PEEP), radiological and clinical findings. TRIAL REGISTRATION: The protocol was registered before starting subject recruitment under the title: "Flow controlled ventilation in ARDS associated with COVID-19" in ClinicalTrials.org with the registration number: NCT04399317. Although the severely ill patients will need intubation and invasive ventilation according to ARDS treatment strategies including low tidal volumes and low end-expiratory pressures, not all patients recover their pulmonary function [3, 4] .

title:
  Flow controlled ventilation in Acute Respiratory Distress Syndrome associated with COVID-19: A structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: This study aims to demonstrate the positive effects on oxygenation of flow-controlled ventilation compared to conventionally ventilated patients in patients suffering from Acute respiratory distress syndrome (ARDS) associated with COVID-19.We define ARDS according to the “Berlin” definition integrating the oxygenation index (P/F ratio), the level of Positive End Expiratory Pressure (PEEP), radiological and clinical findings. TRIAL DESIGN: This is a prospective, randomized (1:1 ratio), parallel group feasibility study in adult patients with proven COVID-19 associated ARDS. PARTICIPANTS: All adult patients admitted to the ICU of Hamad Medical Corporation facilities in Qatar because of COVID-19 infection who develop moderate to severe ARDS are eligible. The inclusion criteria are above 18 years of age, proven COVID-19 infection, respiratory failure necessitating intubation and mechanical ventilation, ARDS with a P/F ratio of at least 200mmHg or less and a minimum PEEP 5cmH2O, BMI less 30 kg/ m2. The following exclusion criteria: no written consent, chronic respiratory disease, acute or chronic cardiovascular disease, pregnancy or need for special therapy (prone position and/or Extracorporeal membrane oxygenation). INTERVENTION AND COMPARATOR: After randomisation, the group A patients will be ventilated with the test-device for 48 hours. The settings will be started with the pre-existing-PEEP. The upper pressure will be determined to achieve a tidal volume of 6 ml/kg lean body mass, while the respiratory rate will be set to maintain an arterial pH above 7.2. In group B, the ventilator settings will be adjusted by the attending ICU team in accordance with lung-protective ventilation strategy. All other treatment will be unchanged and according to our local policies/guidelines. MAIN OUTCOMES: The primary end point is PaO2. As this is a dynamic parameter, we will record it every 6-8 hours and analyse it sequentially. RANDOMISATION: The study team screens the ventilated patients who fulfil the inclusion criteria and randomise using a 1:1 allocation ratio after consenting using a closed envelope method. The latter were prepared and sealed in advance by an independent person. BLINDING (MASKING): Due to the technical nature of the study (use of a specific ventilator) blinding is only possible for the data-analysts and the patients. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size calculation based on the assumption of an effect size (change in PaO2) of 1.5 SDS in the primary endpoint (PaO2), an intended power of 80%, an alpha error of 5% and an equal sample ratio results in n=7 patients needed to treat. However, to compensate for dropouts we will include 10 patients in each group, which means in total 20 patients. TRIAL STATUS: The local registration number is MRC-05-018 with the protocol version number 3. The date of approval is 14(th) April 2020. Recruitment began 28th May 2020 and is expected to end in September 2020. TRIAL REGISTRATION: The protocol was registered before starting subject recruitment under the title: “Flow controlled ventilation in ARDS associated with COVID-19” in ClinicalTrials.org with the registration number: NCT04399317. Registered on 22 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-286237-x6dr6rsh
author: Maes, Bastiaan
date: 2020-06-03
txt: ./txt/cord-286237-x6dr6rsh.txt
cache: ./cache/cord-286237-x6dr6rsh.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04453-5
doi: 10.1186/s13063-020-04453-5
summary:
  -mechanical ventilation > 24 h at randomization -clinical frailty scale above 3 -active bacterial or fungal infection -unlikely to survive beyond 48h -neutrophil count below 1500 cells/microliter -platelets below 50.000/microliter -Patients enrolled in another investigational drug study -patients on high dose systemic steroids (> 8 mg methylprednisolone or equivalent for more than 1 month) for COVID-19 unrelated disorder -patients on immunosuppressant or immunomodulatory drugs -patients on current anti-IL1 or anti-IL6 treatment -signs of active tuberculosis -serum transaminase levels >5 times upper limit of normal, unless there are clear signs of cytokine release syndrome defined by LDH >300 IU/L and ferritin >700 ng/ml -history of (non-iatrogenic) bowel perforation or diverticulitis -Pregnant or breastfeeding females (all female subjects deemed of childbearing potential by the investigator must have negative pregnancy test at screening) 5.2.1.

title:
  Treatment of severely ill COVID-19 patients with anti-interleukin drugs (COV-AID): A structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6, IL-6 receptor and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome. TRIAL DESIGN: A phase 3 prospective, multi-center, interventional, open label, 6-arm 2x2 factorial design study. PARTICIPANTS: Subjects will be recruited at the specialized COVID-19 wards and/or ICUs at 16 Belgian participating hospitals. Only adult (≥18y old) patients will be recruited with recent (≤16 days) COVID-19 infection and acute hypoxia (defined as PaO2/FiO2 below 350mmHg or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation) and signs of systemic cytokine release syndrome characterized by high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those, who have not been on mechanical ventilation for more than 24 hours before randomisation. Patients should have had a chest X-ray and/or CT scan showing bilateral infiltrates within the last 2 days before randomisation. Patients with active bacterial or fungal infection will be excluded. INTERVENTION AND COMPARATOR: Patients will be randomized to 1 of 5 experimental arms versus usual care. The experimental arms consist of Anakinra alone (anti-IL-1 binding the IL-1 receptor), Siltuximab alone (anti-IL-6 chimeric antibody), a combination of Siltuximab and Anakinra, Tocilizumab alone (humanised anti-IL-6 receptor antibody) or a combination of Anakinra with Tocilizumab in addition to standard care. Patients treated with Anakinra will receive a daily subcutaneous injection of 100mg for a maximum of 28 days or until hospital discharge, whichever comes first. Siltuximab (11mg/kg) or Tocilizumab (8mg/kg, with a maximum dose of 800mg) are administered as a single intravenous injection immediately after randomization. MAIN OUTCOMES: The primary end point is the time to clinical improvement defined as the time from randomization to either an improvement of two points on a six-category ordinal scale measured daily till day 28 or discharge from the hospital or death. This ordinal scale is composed of (1) Death; (2) Hospitalized, on invasive mechanical ventilation or ECMO; (3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; (4) Hospitalized, requiring supplemental oxygen; (5) Hospitalized, not requiring supplemental oxygen; (6) Not hospitalized. RANDOMISATION: Patients will be randomized using an Interactive Web Response System (REDCap). A 2x2 factorial design was selected with a 2:1 randomization regarding the IL-1 blockade (Anakinra) and a 1:2 randomization regarding the IL-6 blockade (Siltuximab and Tocilizumab). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 342 participants will be enrolled: 76 patients will receive usual care, 76 patients will receive Siltuximab alone, 76 patients will receive Tocilizumab alone, 38 will receive Anakinra alone, 38 patients will receive Anakinra and Siltuximab and 38 patients will receive Anakinra and Tocilizumab. TRIAL STATUS: COV-AID protocol version 3.0 (15 Apr 2020). Participant recruitment is ongoing and started on April 4(th) 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 1st, 2020 (ClinicalTrials.gov Identifier: NCT04330638) and on EudraCT on April 3rd 2020 (Identifier: 2020-001500-41). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-288344-8dar2p3j
author: Yang, Xiaoyu
date: 2020-11-04
txt: ./txt/cord-288344-8dar2p3j.txt
cache: ./cache/cord-288344-8dar2p3j.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33148308/
doi: 10.1186/s13063-020-04830-0
summary:
  title: The rescue intervention strategy for asthma patients under severe air pollution: a protocol for a single-centre prospective randomized controlled trial Therefore, we hypothesize that the rescue intervention strategy of budesonide/formoterol plus original treatments under severe pollution may reduce the risk of asthma exacerbations caused by air pollution before patients have symptoms. When the air quality index (AQI) reported by the air pollution monitoring station for the study is no less than 200, participants in the RIS group will receive budesonide/formoterol (160 μg/4.5 μg/dose, 1 dose/time, b.i.d.) plus original treatments until the end of severe pollution (AQI < 200). This singlecentre, prospective, randomized and standard treatment parallel control clinical trial aimed to determine whether the rescue intervention strategy will reduce the risk of air pollution-related asthma exacerbations. This is a single-centre, prospective, randomized and standard treatment parallel control study aimed at decreasing the risk of asthma exacerbations under severe air pollution with a novel rescue intervention strategy.

title:
  The rescue intervention strategy for asthma patients under severe air pollution: a protocol for a single-centre prospective randomized controlled trial

abstract:
  BACKGROUND: Asthma is a common chronic airway inflammatory disease. Exacerbations of asthma not only accelerate the progression of the disease but also increase the incidence of hospitalization and death. Studies have shown that air pollution is a high-risk factor for asthma exacerbations. However, few treatment strategies have been recommended to reduce the risk of severe air pollution-related asthma exacerbations. METHODS/DESIGN: This is a single-centre, prospective, randomized and standard treatment parallel control clinical trial. Seventy-two asthma patients in the nonexacerbation stage according to GINA guidelines 2017 will be recruited and randomized into the rescue intervention strategy (RIS) group and control group. Original treatments for the participants will include no use of inhaled medicine, the use of short-acting β-agonists (SABA) on demand or the use of budesonide/formoterol (160 μg/4.5 μg/dose, 1–2 dose/time, b.i.d.). The rescue intervention strategy for the RIS group will be budesonide/formoterol plus the original treatment until the severe pollution ends (air quality index, AQI < 200). The control group will maintain the original treatment. The follow-up observation period will last 1 year. The primary outcome is the frequency of asthma exacerbations per year. Secondary outcomes include the mean number of unplanned outpatient visits, emergency visits, hospitalizations, medical costs and mortality caused by asthma exacerbations per patient per year. DISCUSSION: The results of this trial will provide a novel strategy to guide clinical practice in decreasing the risk of asthma exacerbations under severe air pollution. TRIAL REGISTRATION: ChiCTR ChiCTR1900026757. Registered on 20 October 2019—retrospectively registered


id: cord-292544-m7jyydf1
author: Grau-Pujol, Berta
date: 2020-07-29
txt: ./txt/cord-292544-m7jyydf1.txt
cache: ./cache/cord-292544-m7jyydf1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04621-7
doi: 10.1186/s13063-020-04621-7
summary:
  OBJECTIVES: The aim of this study is to assess the efficacy of the use of pre-exposure prophylaxis (PrEP) with hydroxychloroquine against placebo in healthcare workers with high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in reducing their risk of coronavirus disease 2019 (COVID-19) disease during an epidemic period. As secondary endpoints, we will obtain: i) the SARS-CoV-2 seroconversion in the PrEP group compared to placebo during the 6 months of follow-up in healthcare workers with negative serology at day 0; ii) the occurrence of any adverse event related with hydroxychloroquine treatment; iii) the incidence of SARS-CoV-2 infection and COVID-19 among healthcare workers in the non-PrEP group, among the total of healthcare workers included in the non-PrEP group during the study period; iv) the risk ratio for the different clinical, analytical and microbiological conditions to develop COVID-19; v) a repository of serum samples obtained from healthcare workers confirmed COVID-19 cases for future research on blood markers to predict SARS-CoV-2 infection.

title:
  Pre-exposure prophylaxis with hydroxychloroquine for high-risk healthcare workers during the COVID-19 pandemic: A structured summary of a study protocol for a multicentre, double-blind randomized controlled trial

abstract:
  OBJECTIVES: The aim of this study is to assess the efficacy of the use of pre-exposure prophylaxis (PrEP) with hydroxychloroquine against placebo in healthcare workers with high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in reducing their risk of coronavirus disease 2019 (COVID-19) disease during an epidemic period. As secondary objectives, we would like to: i) assess the efficacy of the use of PrEP with hydroxychloroquine against placebo in healthcare workers with high risk of SARS-CoV-2 infection in reducing their risk of exposure to SARS-CoV-2 (defined by seroconversion) during an epidemic period, ii) evaluate the safety of PrEP with hydroxychloroquine in adults, iii) describe the incidence of SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 infection, iv) identify clinical, analytical and microbiological predictors of COVID-19 among healthcare workers at high risk of SARS-CoV-2 infection, v) set up a repository of serum samples obtained from healthcare workers at high risk of SARS-CoV-2 infection for future research on blood markers to predict SARS-CoV-2 infection. TRIAL DESIGN: Multicentre double-blind parallel design (ratio 1:1) randomized controlled clinical trial. PARTICIPANTS: Approximately 440 healthcare workers of four Spanish hospitals (Hospital Clínic of Barcelona, Hospital de la Santa Creu i Sant Pau of Barcelona, Hospital Plató of Barcelona, Hospital General de Granollers, Barcelona) will be recruited. Participants are considered to be at high-risk of SARS-CoV-2 infection due to their frequent contact with suspected and confirmed cases of COVID-19. For eligibility, healthcare workers with 18 years old or older working at least 3 days a week in a hospital with both negative SARS-CoV-2 polymerase chain reaction (PCR) assays and serological COVID-19 rapid diagnostic tests (RDT) are invited to participate. Participants with any of the following conditions are excluded: pregnancy, breastfeeding, ongoing antiviral, antiretroviral or corticosteroids treatment, chloroquine or hydroxychloroquine uptake the last month or any contraindication to hydroxychloroquine treatment. INTERVENTION AND COMPARATOR: Intervention group (PrEP): participants will receive the standard of care and will take 400mg of hydroxychloroquine (2 tablets of 200 mg per Dolquine® tablet) daily the first four consecutive days, followed by 400 mg weekly for a period of 6 months. Control group: participants will receive placebo tablets with identical physical appearance to hydroxychloroquine 200 mg (Dolquine®) tablets following the same treatment schedule of the intervention group. Both groups will be encouraged to use the personal protection equipment (PPE) for COVID-19 prevention according to current hospital guidelines. MAIN OUTCOMES: The primary endpoint will be the number of confirmed cases of a COVID-19 (defined by a positive PCR for SARS-CoV-2 or symptoms compatible with COVID-19 with seroconversion) in the PrEP group compared to the placebo group at any time during the 6 months of the follow-up in healthcare workers with negative SARS-CoV-2 PCR and serology at day 0. As secondary endpoints, we will obtain: i) the SARS-CoV-2 seroconversion in the PrEP group compared to placebo during the 6 months of follow-up in healthcare workers with negative serology at day 0; ii) the occurrence of any adverse event related with hydroxychloroquine treatment; iii) the incidence of SARS-CoV-2 infection and COVID-19 among healthcare workers in the non-PrEP group, among the total of healthcare workers included in the non-PrEP group during the study period; iv) the risk ratio for the different clinical, analytical and microbiological conditions to develop COVID-19; v) a repository of serum samples obtained from healthcare workers confirmed COVID-19 cases for future research on blood markers to predict SARS-CoV-2 infection. RANDOMISATION: Participants meeting all eligibility requirements will be allocated to one of the two study arms (PrEP with hydroxychloroquine or non-PrEP control group) in a 1:1 ratio using simple randomisation with computer generated random numbers. BLINDING (MASKING): Participants, doctors and nurses caring for participants, and investigators assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Each intervention group will have 220 participants, giving a total of 440 participants. TRIAL STATUS: The current protocol version is 1.5, 2(nd) of June 2020. Two hundred and seventy-fiveparticipants were recruited and completed first month follow-up until date. The estimated sample size could not be reached yet due to the declining national epidemic curve. Thus, 275 is the total number of participants included until date. The study has been suspended (26(th) of June) until new epidemic curve occurs. TRIAL REGISTRATION: This trial was registered on April 2(nd) 2020 at clinicaltrials.gov with the number NCT04331834. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-293440-qoo2t1wt
author: Wilkinson, Tom
date: 2020-07-31
txt: ./txt/cord-293440-qoo2t1wt.txt
cache: ./cache/cord-293440-qoo2t1wt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32736596/
doi: 10.1186/s13063-020-04584-9
summary:
  title: ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial TRIAL DESIGN: ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. PARTICIPANTS: The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised – mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale.

title:
  ACCORD: A Multicentre, Seamless, Phase 2 Adaptive Randomisation Platform Study to Assess the Efficacy and Safety of Multiple Candidate Agents for the Treatment of COVID-19 in Hospitalised Patients: A structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: Stage 1: To evaluate the safety and efficacy of candidate agents as add-on therapies to standard of care (SoC) in patients hospitalised with COVID-19 in a screening stage. Stage 2: To confirm the efficacy of candidate agents selected on the basis of evidence from Stage 1 in patients hospitalised with COVID-19 in an expansion stage. TRIAL DESIGN: ACCORD is a seamless, Phase 2, adaptive, randomised controlled platform study, designed to rapidly test candidate agents in the treatment of COVID-19. Designed as a master protocol with each candidate agent being included via its own sub-protocol, initially randomising equally between each candidate and a single contemporaneous SoC arm (which can adapt into 2:1). Candidate agents currently include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin. For each candidate a total of 60 patients will be recruited in Stage 1. If Stage 1 provides evidence of efficacy and acceptable safety the candidate will enter Stage 2 where a total of approximately 126 patients will be recruited into each study arm sub-protocol. Enrollees and outcomes will not be shared across the Stages; the endpoint, analysis and sample size for Stage 2 may be adjusted based on evidence from Stage 1. Additional arms may be added as new potential candidate agents are identified via candidate agent specific sub-protocols. PARTICIPANTS: The study will include hospitalised adult patients (≥18 years) with confirmed SARS-CoV-2 infection, the virus that causes COVID-19, that clinically meet Grades 3 (hospitalised – mild disease, no oxygen therapy), Grades 4 (hospitalised, oxygen by mask or nasal prongs) and 5 (hospitalised, non-invasive ventilation or high flow oxygen) of the WHO Working Group on the Clinical Characteristics of COVID-19 9-point category ordinal scale. Participants will be recruited from England, Northern Ireland, Wales and Scotland. INTERVENTION AND COMPARATOR: Comparator is current standard of care (SoC) for the treatment of COVID-19. Current candidate experimental arms include bemcentinib, MEDI3506, acalabrutinib, zilucoplan and nebulised heparin with others to be added over time. Bemcentinib could potentially reduce viral infection and blocks SARS-CoV-2 spike protein; MEDI3506 is a clinic-ready anti-IL-33 monoclonal antibody with the potential to treat respiratory failure caused by COVID; acalabrutinib is a BTK inhibitor which is anti-viral and anti-inflammatory; zilucoplan is a complement C5 inhibitor which may block the severe inflammatory response in COVID-19 and; nebulised heparin has been shown to bind with the spike protein. ACCORD is linked with the UK national COVID therapeutics task force to help prioritise candidate agents. MAIN OUTCOMES: Time to sustained clinical improvement of at least 2 points (from randomisation) on the WHO 9-point category ordinal scale, live discharge from the hospital, or considered fit for discharge (a score of 0, 1, or 2 on the ordinal scale), whichever comes first, by Day 29 (this will also define the “responder” for the response rate analyses). RANDOMISATION: An electronic randomization will be performed by Cenduit using Interactive Response Technology (IRT). Randomisation will be stratified by baseline severity grade. Randomisation will proceed with an equal allocation to each arm and a contemporaneous SoC arm (e.g. 1:1 if control and 1 experimental arm; 1:1:1 if two experimental candidate arms etc) but will be reviewed as the trial progresses and may be changed to 2:1 in favour of the candidate agents. BLINDING (MASKING): The trial is open label and no blinding is currently planned in the study. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This will be in the order of 60 patients per candidate agent for Stage 1, and 126 patients for Stage 2. However, sample size re-estimation may be considered after Stage 1. It is estimated that up to 1800 patients will participate in the overall study. TRIAL STATUS: Master protocol version ACCORD-2-001 - Master Protocol (Amendment 1) 22(nd) April 2020, the trial has full regulatory approval and recruitment is ongoing in the bemcentinib (first patient recruited 6/5/2020), MEDI3506 (first patient recruited 19/5/2020), acalabrutinib (first patient recruited 20/5/2020) and zilucoplan (first patient recruited 19/5/2020) candidates (and SoC). The recruitment dates of each arm will vary between candidate agents as they are added or dropped from the trial, but will have recruited and reported within a year. TRIAL REGISTRATION: EudraCT 2020-001736-95, registered 28(th) April 2020. FULL PROTOCOL: The full protocol (Master Protocol with each of the candidate sub-protocols) is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-300465-19euup51
author: Paniagua-Avila, Alejandra
date: 2020-06-09
txt: ./txt/cord-300465-19euup51.txt
cache: ./cache/cord-300465-19euup51.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32517806/
doi: 10.1186/s13063-020-04345-8
summary:
  This study will generate urgently needed data on effective, adoptable, and sustainable interventions and implementation strategies to improve hypertension control in Guatemala and other LMICs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03504124. Specifically, these strategies include team-based care, health coaching sessions, home-based blood pressure (BP) monitoring, clinical decision support, BP audit and feedback, and training of healthcare providers. This study is an implementation-effectiveness, hybrid, type 2, cluster randomized control trial that will evaluate a multilevel and multicomponent hypertension control program within the Guatemalan primary care system [17] . The multicomponent program includes a protocol-based hypertension treatment and five implementation strategies: team-based collaborative care, health provider education, health coaching sessions, home blood pressure monitoring, and blood pressure audit and feedback. The overarching aim of this study is to evaluate the clinical effectiveness and implementation outcomes of a hypertension control multicomponent program within the first and second levels of care in Guatemala, compared to usual care.

title:
  Evaluating a multicomponent program to improve hypertension control in Guatemala: study protocol for an effectiveness-implementation cluster randomized trial

abstract:
  BACKGROUND: Hypertension is a major risk factor for cardiovascular disease (CVD). Despite advances in hypertension prevention and treatment, the proportion of patients who are aware, treated and controlled is low, particularly in low-income and middle-income countries (LMICs). We will evaluate an adapted version of a multilevel and multicomponent hypertension control program in Guatemala, previously proven effective and feasible in Argentina. The program components are: protocol-based hypertension treatment using a standardized algorithm; team-based collaborative care; health provider education; health coaching sessions; home blood pressure monitoring; blood pressure audit; and feedback. METHODS: Using a hybrid type 2 effectiveness-implementation design, we will evaluate clinical and implementation outcomes of the multicomponent program in Guatemala over an 18-month period. Through a cluster randomized trial, we will randomly assign 18 health districts to the intervention arm and 18 to enhanced usual care across five departments, enrolling 44 participants per health district and 1584 participants in total. The clinical outcomes are (1) the difference in the proportion of patients with controlled hypertension (< 130/80 mmHg) between the intervention and control groups at 18 months and (2) the net change in systolic and diastolic blood pressure from baseline to 18 months. The context-enhanced Reach, Efficacy, Adoption, Implementation, Maintenance (RE-AIM)/Practical Robust Implementation and Sustainability Model (PRISM) framework will guide the evaluation of the implementation at the level of the patient, provider, and health system. Using a mixed-methods approach, we will evaluate the following implementation outcomes: acceptability, adoption, feasibility, fidelity, adaptation, reach, sustainability, and cost-effectiveness. DISCUSSION: We will disseminate the study findings, and promote scale up and scale out of the program, if proven effective. This study will generate urgently needed data on effective, adoptable, and sustainable interventions and implementation strategies to improve hypertension control in Guatemala and other LMICs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03504124. Registered on 20 April 2018.


id: cord-302448-2r4rtixg
author: Kharma, Nadir
date: 2020-09-07
txt: ./txt/cord-302448-2r4rtixg.txt
cache: ./cache/cord-302448-2r4rtixg.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04689-1
doi: 10.1186/s13063-020-04689-1
summary:
  title: Anticoagulation in critically ill patients on mechanical ventilation suffering from COVID-19 disease, The ANTI-CO trial: A structured summary of a study protocol for a randomised controlled trial OBJECTIVES: To assess the effect of anticoagulation with bivalirudin administered intravenously on gas-exchange in patients with COVID-19 and respiratory failure using invasive mechanical ventilation. RANDOMISATION: After inclusion, the patients will be randomized using a closed envelope method into the conventional treatment group, which uses the standard strategy and the experimental group which receives anticoagulation treatment with bivalirudin using an allocation ratio of 1:1. TRIAL REGISTRATION: The protocol is registered before starting subject recruitment under the title: "Anticoagulation in patients suffering from COVID-19 disease. To prove the positive effect of anticoagulation with bivalirudin intravenously on gas-exchange in patients with COVID-19 and respiratory failure on invasive mechanical ventilation. Inclusion criteria: all adult patients admitted to the ICU who are COVID positive tested and in need for mechanical ventilation are eligible for inclusion.

title:
  Anticoagulation in critically ill patients on mechanical ventilation suffering from COVID-19 disease, The ANTI-CO trial: A structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: To assess the effect of anticoagulation with bivalirudin administered intravenously on gas-exchange in patients with COVID-19 and respiratory failure using invasive mechanical ventilation. TRIAL DESIGN: This is a single centre parallel group, superiority, randomized (1:1 allocation ratio) controlled trial. PARTICIPANTS: All patients admitted to the Hamad Medical Corporation -ICU in Qatar for COVID-19 associated respiratory distress and in need of mechanical ventilation are screened for eligibility. Inclusion criteria: all adult patients admitted to the ICU who test positive for COVID-19 by PCR-test and in need for mechanical ventilation are eligible for inclusion. Upon crossing the limit of D-dimers (1.2 mg/L) these patients are routinely treated with an increased dose of anticoagulant according to our local protocol. This will be the start of randomization. Exclusion criteria: pregnancy, allergic to the drug, inherited coagulation abnormalities, no informed consent. INTERVENTION AND COMPARATOR: The intervention group will receive the anticoagulant bivalirudin intravenously with a target aPTT of 45-70 sec for three days while the control group will stay on the standard treatment with low-molecular-weight heparins /unfractionated heparin subcutaneously (see scheme in Additional file 1). All other treatment will be unchanged and left to the attending physicians. MAIN OUTCOMES: As a surrogate parameter for clinical improvement and primary outcome we will use the PaO2/FiO2 (P/F) ratio. RANDOMISATION: After inclusion, the patients will be randomized using a closed envelope method into the conventional treatment group, which uses the standard strategy and the experimental group which receives anticoagulation treatment with bivalirudin using an allocation ratio of 1:1. BLINDING (MASKING): Due to logistical and safety reasons (assessment of aPTT to titrate the study drug) only the data-analyst will be blinded to the groups. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): We performed a sample size calculation and assumed the data for P/F ratio (according to literature) is normally distributed and used the mean which would be: 160 and SD is 80. We expect the treatment will improve this by 30%. In order to reach a power of 80% we would need 44 patients per group (in total 88 patients). Taking approximately 10% of dropout into account we will include 100 patients (50 in each group). TRIAL STATUS: The local registration number is MRC-05-082 with the protocol version number 2. The date of approval is 18th June 2020. Recruitment started on 28(th) June and is expected to end in November 2020. TRIAL REGISTRATION: The protocol is registered before starting subject recruitment under the title: “Anticoagulation in patients suffering from COVID-19 disease. The ANTI-CO Trial” in ClinicalTrials.org with the registration number: NCT04445935. Registered on 24 June 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 2). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-303322-d69o3z8d
author: Chang, Anne B
date: 2011-04-14
txt: ./txt/cord-303322-d69o3z8d.txt
cache: ./cache/cord-303322-d69o3z8d.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/1745-6215-12-94
doi: 10.1186/1745-6215-12-94
summary:
  Our randomised, placebo-controlled trial of azithromycin in Indigenous infants hospitalised with bronchiolitis is designed to determine whether it can reduce short-term (and potentially long-term) morbidity from respiratory illness in Australian Indigenous infants who are at high risk of developing chronic respiratory illness. Indigenous infants (aged ≤ 24-months, expected number = 200) admitted to one of two regional hospitals (Darwin, Northern Territory and Townsville, Queensland) with a clinical diagnosis of bronchiolitis and fulfilling inclusion criteria are randomised (allocation concealed) to either azithromycin (30 mg/kg/dose) or placebo administered once weekly for three doses. Indigenous infants (aged ≤ 24-months, expected number = 200) admitted to one of two regional hospitals (Darwin, Northern Territory and Townsville, Queensland) with a clinical diagnosis of bronchiolitis and fulfilling inclusion criteria are randomised (allocation concealed) to either azithromycin (30 mg/kg/dose) or placebo administered once weekly for three doses.

title:
  Randomized placebo-controlled trial on azithromycin to reduce the morbidity of bronchiolitis in Indigenous Australian infants: rationale and protocol

abstract:
  BACKGROUND: Acute lower respiratory infections are the commonest cause of morbidity and potentially preventable mortality in Indigenous infants. Infancy is also a critical time for post-natal lung growth and development. Severe or repeated lower airway injury in very young children likely increases the likelihood of chronic pulmonary disorders later in life. Globally, bronchiolitis is the most common form of acute lower respiratory infections during infancy. Compared with non-Indigenous Australian infants, Indigenous infants have greater bacterial density in their upper airways and more severe bronchiolitis episodes. Our study tests the hypothesis that the anti-microbial and anti-inflammatory properties of azithromycin, improve the clinical outcomes of Indigenous Australian infants hospitalised with bronchiolitis. METHODS: We are conducting a dual centre, randomised, double-blind, placebo-controlled, parallel group trial in northern Australia. Indigenous infants (aged ≤ 24-months, expected number = 200) admitted to one of two regional hospitals (Darwin, Northern Territory and Townsville, Queensland) with a clinical diagnosis of bronchiolitis and fulfilling inclusion criteria are randomised (allocation concealed) to either azithromycin (30 mg/kg/dose) or placebo administered once weekly for three doses. Clinical data are recorded twice daily and nasopharyngeal swab are collected at enrolment and at the time of discharge from hospital. Primary outcomes are 'length of oxygen requirement' and 'duration of stay,' the latter based upon being judged as 'ready for respiratory discharge'. The main secondary outcome is readmission for a respiratory illness within 6-months of leaving hospital. Descriptive virological and bacteriological (including development of antibiotic resistance) data from nasopharyngeal samples will also be reported. DISCUSSION: Two published studies, both involving different patient populations and settings, as well as different macrolide antibiotics and treatment duration, have produced conflicting results. Our randomised, placebo-controlled trial of azithromycin in Indigenous infants hospitalised with bronchiolitis is designed to determine whether it can reduce short-term (and potentially long-term) morbidity from respiratory illness in Australian Indigenous infants who are at high risk of developing chronic respiratory illness. If azithromycin is efficacious in reducing the morbidly of Indigenous infants hospitalised with bronchiolitis, the intervention would lead to improved short term (and possibly long term) health benefits. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000326099


id: cord-310169-yn7pu9i8
author: Marietta, Marco
date: 2020-06-26
txt: ./txt/cord-310169-yn7pu9i8.txt
cache: ./cache/cord-310169-yn7pu9i8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32586394/
doi: 10.1186/s13063-020-04475-z
summary:
  title: Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): a structured summary of a study protocol This dose is commonly used in Italy when a bridging strategy is required for the management of surgery or invasive procedures in patients taking anti-vitamin K oral anticoagulants The treatment with Enoxaparin will be initiated soon after randomization (maximum allowed starting time 12h after randomization). Assuming an alpha of 5% (two tailed) and a percentage of patients who experience clinical worsening in the control group being between 25% and 30%, the study will have 80% power to detect at least 50% relative reduction in the risk of death between low and high doses of heparin. Lack or withdrawal of informed consent Intervention and comparator: Control Group (Low-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at standard prophylactic dose (i.e., 4000 UI subcutaneously once day).

title:
  Randomised controlled trial comparing efficacy and safety of high versus low Low-Molecular Weight Heparin dosages in hospitalized patients with severe COVID-19 pneumonia and coagulopathy not requiring invasive mechanical ventilation (COVID-19 HD): a structured summary of a study protocol

abstract:
  OBJECTIVES: a. 1. Death. 2. Acute Myocardial Infarction [AMI]. 3. Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]. 4. a. Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) or b. IMV in patients who at randomisation were receiving standard oxygen therapy. 5. IMV in patients who at randomisation were receiving non-invasive mechanical ventilation. b. Similar in terms of major bleeding risk. TRIAL DESIGN: Multicentre, randomised controlled, superiority, open label, parallel group, two arms (1:1 ratio), in-hospital study. PARTICIPANTS: Inpatients will be recruited from 7 Italian Academic and non-Academic Internal Medicine Units, 2 Infectious Disease Units and 1 Respiratory Disease Unit. INCLUSION CRITERIA (ALL REQUIRED): 1. Age > 18 and < 80 years. 2. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material). 3. a. Respiratory Rate ≥25 breaths /min. b. Arterial oxygen saturation≤93% at rest on ambient air. c. PaO2/FiO2 ≤300 mmHg. 4. a. D-dimer >4 times the upper level of normal reference range. b. Sepsis-Induced Coagulopathy (SIC) score >4. 5. No need of IMV. EXCLUSION CRITERIA: 1. Age <18 and >80 years. 2. IMV. 3. Thrombocytopenia (platelet count < 80.000 mm3). 4. Coagulopathy: INR >1.5, aPTT ratio > 1.4. 5. Impaired renal function (eGFR calculated by CKD-EPI Creatinine equation < 30 ml/min). 6. Known hypersensitivity to enoxaparin. 7. History of heparin induced thrombocytopenia. 8. Presence of an active bleeding or a pathology susceptible of bleeding in presence of anticoagulation (e.g. recent haemorrhagic stroke, peptic ulcer, malignant cancer at high risk of haemorrhage, recent neurosurgery or ophthalmic surgery, vascular aneurysms, arteriovenous malformations). 9. Concomitant anticoagulant treatment for other indications (e.g. atrial fibrillation, venous thromboembolism, prosthetic heart valves). 10. Concomitant double antiplatelet therapy. 11. Administration of therapeutic doses of LMWH, fondaparinux, or unfractionated heparin (UFH) for more than 72 hours before randomization; prophylactic doses are allowed. 12. Pregnancy or breastfeeding or positive pregnancy test. 13. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition). 14. Lack or withdrawal of informed consent. INTERVENTION AND COMPARATOR: Control Group (Low-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at standard prophylactic dose (i.e., 4000 UI subcutaneously once day). Intervention Group (High-Dose LMWH): patients in this group will be administered Enoxaparin (Inhixa®) at dose of 70 IU/kg every 12 hours, as reported in the following table. This dose is commonly used in Italy when a bridging strategy is required for the management of surgery or invasive procedures in patients taking anti-vitamin K oral anticoagulants The treatment with Enoxaparin will be initiated soon after randomization (maximum allowed starting time 12h after randomization). The treatment will be administered every 12 hours in the intervention group and every 24 hours in the control group. Treatments will be administered in the two arms until hospital discharge or the primary outcomes detailed below occur. MAIN OUTCOMES: Primary Efficacy Endpoint: 1. Death. 2. Acute Myocardial Infarction [AMI]. 3. Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]. 4. a. Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) or b. IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces. 5. Need for IMV, in patients who at randomisation were in Cpap or NIV. Time to the occurrence of each of these events will be recorded. Clinical worsening will be analysed as a binary outcome as well as a time-to-event one. Secondary Efficacy Endpoints: : 1. Death. 2. Acute Myocardial Infarction [AMI]. 3. Objectively confirmed, symptomatic arterial or venous thromboembolism [TE]. 4. a. Continuous Positive Airway Pressure (Cpap) or Non-Invasive Ventilation (NIV) or b. IMV in patients who at randomisation were in standard oxygen therapy by delivery interfaces. 5. Need for IMV in patients who at randomisation were in Cpap or NIV. 6. o D-dimer level; o Plasma fibrinogen levels; o Mean Platelet Volume; o Lymphocyte/Neutrophil ratio; o IL-6 plasma levels. MORTALITY AT 30 DAYS: Information about patients’ status will be sought in those who are discharged before 30 days on Day 30 from randomisation. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Primary safety endpoint: Decrease in haemoglobin of 2 g/dl or more; Transfusion of 2 or more units of packed red blood cells; Bleeding that occurs in at least one of the following critical sites [intracranial, intraspinal, intraocular (within the corpus of the eye; thus, a conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular with compartment syndrome, or retroperitoneal]; Bleeding that is fatal (defined as a bleeding event that was the primary cause of death or contributed directly to death); Bleeding that necessitates surgical intervention. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. Secondary safety endpoint: 1. Any bleeding compromising hemodynamic. 2. Spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic cause. 3. Intramuscular hematoma documented by ultrasonography. 4. Epistaxis or gingival bleeding requiring tamponade or other medical intervention. 5. Bleeding from venipuncture for >5 minutes. 6. Haematuria that was macroscopic and was spontaneous or lasted for more than 24 hours after invasive procedures. 7. Haemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other medical intervention. 8. Any other bleeding requiring temporary cessation of a study drug. Time to the occurrence of each of these events will be recorded. Each of these events will be analysed as a binary outcome and as a time-to-event one. RANDOMISATION: Randomisation (with a 1:1 randomisation ratio) will be centrally performed by using a secure, web-based system, which will be developed by the Methodological and Statistical Unit at the Azienda Ospedaliero-Universitaria of Modena. Randomisation stratified by 4 factors: 1) Gender (M/F); 2) Age (<75/≥75 years); 3) BMI (<30/≥30); 4) Comorbidities (0-1/>2) with random variable block sizes will be generated by STATA software. The web-based system will guarantee the allocation concealment. Blinding (masking) The study is conceived as open-label: patients and all health-care personnel involved in the study will be aware of the assigned group. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The target sample size is based on the hypothesis that LMWH administered at high doses versus low doses will significantly reduce the risk of clinical worsening. The overall sample size in this study is expected to be 300 with 150 in the Low-Dose LMWH control group and 150 in the High-Dose LMWH intervention group, recruited over 10-11 months. Assuming an alpha of 5% (two tailed) and a percentage of patients who experience clinical worsening in the control group being between 25% and 30%, the study will have 80% power to detect at least 50% relative reduction in the risk of death between low and high doses of heparin. TRIAL STATUS: Protocol version 1.2 of 11/05/2020. Recruitment start (expected): 08/06/2020 Recruitment finish (expected): 30/04/2021 Trial registration EudraCT 2020-001972-13, registered on April 17th, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-311697-2w9qody4
author: Liu, Xi
date: 2020-07-08
txt: ./txt/cord-311697-2w9qody4.txt
cache: ./cache/cord-311697-2w9qody4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32641091/
doi: 10.1186/s13063-020-04478-w
summary:
  title: Efficacy of chloroquine versus lopinavir/ritonavir in mild/general COVID-19 infection: a prospective, open-label, multicenter, randomized controlled clinical study Remdesivir (GS-5734) and chloroquine (Sigma-C6628) can effectively inhibit SARS-CoV-2 infection [17] This study will compare the efficacy, safety, and impact on patient compliance between the chloroquine phosphate regimen with the lopinavir/ritonavir regimen in mild/general COVID-19 infection. The PP group will include participants who satisfy the following conditions among the ITT group: (1) those who completed all planned visits and (2) those who did not receive and use drugs or treatments that may affect the evaluation of efficacy during the study. For the primary outcome of this trial, the clinical recovery time of no more than 28 days after the completion of therapy and follow-up will be estimated as the proportion with a 95% confidence interval (CI) for each treatment group. The purpose of this prospective, open-label, multicenter randomized controlled, comprehensive clinical study is to evaluate the efficacy and safety of chloroquine phosphate and lopinavir/ritonavir in patients with mild/general COVID-19 infection.

title:
  Efficacy of chloroquine versus lopinavir/ritonavir in mild/general COVID-19 infection: a prospective, open-label, multicenter, randomized controlled clinical study

abstract:
  BACKGROUND: The outbreak of COVID-19 (caused by SARS-Cov-2) is very serious, and no effective antiviral treatment has yet been confirmed. The adage “old drug, new trick” in this context may suggest the important therapeutic potential of existing drugs. We found that the lopinavir/ritonavir treatment recommended in the fifth edition of the Treatment Plan of China can only help to improve a minority of throat-swab nucleic-acid results (3/15) in hospitals. Our previous use of chloroquine to treat patients with COVID-19 infection showed an improvement in more throat-swab nucleic-acid results (5/10) than the use of lopinavir/ritonavir. METHODS/DESIGN: This is a prospective, open-label, randomized controlled, multicenter clinical study. The study consists of three phases: a screening period, a treatment period of no more than 10 days, and a follow-up period for each participant. Participants with COVID-19 infection who are eligible for selection for the study will be randomly allocated to the trial group or the control group. The control group will be given lopinavir/ritonavir treatment for no more than 10 days. The trial group will be given chloroquine phosphate treatment for no more than 10 days. The primary outcome is the clinical recovery time at no more than 28 days after the completion of therapy and follow-up. The secondary outcomes include the rate of treatment success after the completion of therapy and follow-up, the time of treatment success after no more than 28 days, the rate of serious adverse events during the completion of therapy and follow-up, and the time to return to normal temperature (calculated from the onset of illness) during the completion of therapy and follow-up. Comparisons will be performed using two-sided tests with a statistical significance level of 5%. DISCUSSION: This experiment should reveal the efficacy and safety of using chloroquine versus lopinavir/ritonavir for patients with mild/general COVID-19 infection. If the new treatment including chloroquine shows a higher rate of throat-swab SARS-CoV-2 real-time fluorescent reverse transcription polymerase chain reaction (RT-PCR) negativity and is safe, it could be tested as a future COVID-19 treatment. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ID: ChiCTR2000029741. Registered on 11 February 2020.


id: cord-315149-71bmj5il
author: Caballero Bermejo, Antonio F.
date: 2020-09-16
txt: ./txt/cord-315149-71bmj5il.txt
cache: ./cache/cord-315149-71bmj5il.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04633-3
doi: 10.1186/s13063-020-04633-3
summary:
  The aim of the present study is to evaluate if an earlier therapeutic intervention with sarilumab plus SOC (including corticosteroids) may be more effective than current standard of care alone, in preventing progression to respiratory failure in COVID-19 infected patients with interstitial pneumonia. The aim of the present study is to evaluate if an earlier therapeutic intervention with sarilumab plus SOC may be more effective than current standard of care alone, which according to our local protocol includes weight adjusted corticosteroids doses, in preventing progression to respiratory failure in COVID-19 infected patients with interstitial pneumonia. Patients randomized to the control arm (CS + SOC group without sarilumab) progressing to severe respiratory failure fulfilling criteria for treatment with anti-IL6 inhibitors according to clinical practice guidelines, as defined by the presence of Brescia-COVID SARTRE STUDY EudraCT Number: 2020-002037-15 Version 2.0 (May 05th 2020) Scale 2-3 plus inflammatory markers, will be offered the option to be rescued with sarilumab at the same doses and be included in an open-label follow-up phase.

title:
  Sarilumab versus standard of care for the early treatment of COVID-19 pneumonia in hospitalized patients: SARTRE: a structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: In some patients, acute, life-threatening respiratory injury produced by viruses such as SARS-CoV and other viral pneumonia are associated with an over-exuberant cytokine release. Elevated levels of blood IL-6 had been identified as a one of the risk factors associated with severe COVID-19 disease. Anti-IL6 inhibitors are among the therapeutic armamentarium for preventing the fatal consequences of acute respiratory and multi organ failure in around 20% of the COVID-19 infected patients. At present, their use is prioritized to patients with severe interstitial pneumonia (Brescia-COVID Scale-COVID 2-3) with hyperinflammation as determined by the presence of elevated IL6 and/or d-dimer, or progressive d-dimer increase, in patients who otherwise are subsidiary to ICU admission. However, many uncertainties remain on the actual role of anti-IL6 inhibitors in this setting, and whether current use and timing is the right one. There is the hypothesis that the use of anti-IL6 inhibitors at an earlier state during the hyperinflammatory syndrome would be beneficial and may avoid progressing to ARDS. On the other hand, the standard of care has changed and nowadays the use of corticosteroids has become part of the SOC in the treatment of COVID-19 pneumonia. Our limited experience suggests that better treatment outcomes can be achieved when combining IL6-inhibitors (e.g. sarilumab) with corticosteroids. The aim of the present study is to evaluate if an earlier therapeutic intervention with sarilumab plus SOC (including corticosteroids) may be more effective than current standard of care alone, in preventing progression to respiratory failure in COVID-19 infected patients with interstitial pneumonia. This study will also provide supportive evidence to that provided by currently ongoing studies on the efficacy and safety of sarilumab in this clinical context. TRIAL DESIGN: A phase two multi-center randomised controlled trial (RCT) with two parallel arms (1:1 ratio). PARTICIPANTS: They will be hospitalized patients, of at least 18 years of age, with severe COVID-19 who have positive RT-PCR test and have radiographic evidence of pulmonary infiltrates by imaging or rales/crackles on exam and SpO2 ≤ 94% on room air that requires supplemental oxygen. Patients must present elevation of inflammatory parameters (IL-6 > 40 pg/mL or d-dimer >1.0 mcg/ml) or, alternatively, progressive worsening in at least two of these inflammatory parameters in the prior 24-48h: CRP, LDH, serum ferritin, lymphopenia, or d-dimer. Exclusion criteria: high oxygen requirements (including face mask with reservoir, non-invasive mechanical ventilation or high flow nasal cannula, or mechanical ventilation), admission to ICU, pregnancy or lactation, allergy or hypersensitivity to sarilumab or corticoesteroids, immunosuppressive antibody therapy within the past 5 months, AST/ALT values > 10 x ULN, neutropenia (< 0.5 x 109/L), severe thrombocytopenia (< 50 x 109/L), sepsis caused by an alternative pathogen, diverticulitis with risk of perforation or ongoing infectious dermatitis. The study will be conducted in several hospitals in Spain. INTERVENTION AND COMPARATOR: Patients randomised to the experimental arm will receive sarilumab + methylprednisolone plus SOC for COVID-19. Patients included in the control arm will receive methylprednisolone plus SOC for COVID-19. Corticosteroids will be given to all patients at a 1mg/kg/d of methylprednisolone for at least 3 days. Clinical follow-up visits will be performed at 3, 5, and 15 days after treatment randomization. Patients in the control group (SOC group without sarilumab) progressing to Brescia- COVID 2-3 plus inflammatory markers, will be given the option to be rescued with sarilumab at the same doses and, in that case, be included in an open-label phase and be followed up for additional weeks (with visits at 3, 7 and 15 days after sarilumab rescue administration). Patients randomly assigned to sarilumab therapy at baseline progressing to Brescia-COVID 2-3 will be rescued according to local clinical practice protocols. A final follow-up visit will be conducted for all patients at day 29 from randomization, regardless of initial treatment assignment. MAIN OUTCOMES: Primary end point is the proportion of patients progressing to either severe respiratory failure (Brescia-COVID ≥2), ICU admission, or death. RANDOMIZATION: Randomization codes were produced by means of the PROC PLAN of the SAS system, with a 1:1 assignment ratio, stratifying by centre and using blocks multiple of 2 elements. The randomization schedule will be managed through the eCRF in a concealed manner. BLINDING (MASKING): All study drugs will be administered as open label. No blinding methods will be used in this trial. NUMBERS TO BE RANDOMISED (SIMPLE SIZE): The target sample size will be 200 COVID-19 patients, who will be allocated randomly to control arm (100) and treatment arm (100). TRIAL STATUS: Protocol Code: SARTRE Protocol Date: May 05th 2020. Version: 2.0 The study has been approved by the Spanish Competent Authority (AEMPS) as a low intervention clinical trial. Start of recruitment: August, 2020 End of recruitment: May, 2021 TRIAL REGISTRATION: Identifier: EudraCT Number: 2020-002037-15; Registration date: 26 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


id: cord-315175-51wuz9i1
author: Kaddam, Lamis
date: 2020-09-05
txt: ./txt/cord-315175-51wuz9i1.txt
cache: ./cache/cord-315175-51wuz9i1.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04707-2
doi: 10.1186/s13063-020-04707-2
summary:
  title: Potential Role of Acacia Senegal (Gum Arabic) as Immunomodulatory Agent among newly diagnosed COVID 19 Patients: A structured summary of a protocol for a randomised, controlled, clinical trial OBJECTIVES: To investigate the potential efficacy of Acacia Senegal extract Gum Arabic (GA) supplementation as immunomodulatory and anti-inflammatory dietary intervention among newly diagnosed COVID 19 Sudanese patients. Age 8-90 years Both genders Exclusion criteria: Intubated patients on parenteral treatment Allergy to Gum Arabic The study will be conducted in COVID Isolation Centres and Soba University Hospital Khartoum State Sudan. Mortality rate: The percentage of deaths among COVID 19 patients received Gum Arabic compared to placebo (Four weeks from the start of randomization]). Gum Arabic has anti-inflammatory effect which has been investigated in various diseases and conditions. Gum Arabic anti-inflammatory effect has been investigated in clinical trials (10, 12) . Gum Arabic Fibers Decreased Inflammatory Markers and Disease Severity Score among Rheumatoid Arthritis Patients, Phase II Trial

title:
  Potential Role of Acacia Senegal (Gum Arabic) as Immunomodulatory Agent among newly diagnosed COVID 19 Patients: A structured summary of a protocol for a randomised, controlled, clinical trial

abstract:
  OBJECTIVES: To investigate the potential efficacy of Acacia Senegal extract Gum Arabic (GA) supplementation as immunomodulatory and anti-inflammatory dietary intervention among newly diagnosed COVID 19 Sudanese patients. To study the effect of GA on the level of cytokines, TNFα, IL8, IL6 IL10, CRP and the viral load. Secondary outcomes will be the effect of GA oral intake on mortality rate and days of hospital admission. TRIAL DESIGN: Quadruple blind, randomized placebo-controlled clinical trial Phase II & III. Prospective, two-arm, parallel-group, randomised (1:1 allocation ratio) superiority trial of oral GA among seropositive COVID-19 patients. PARTICIPANTS: Inclusion criteria: COVID-19 infected (newly diagnosed) as proved by real-time PCR within 72 hours of PCR. Age 8-90 years Both genders Exclusion criteria: Intubated patients on parenteral treatment Allergy to Gum Arabic The study will be conducted in COVID Isolation Centres and Soba University Hospital Khartoum State Sudan. INTERVENTION AND COMPARATOR: Experimental: Intervention Group This arm will receive 100% natural Gum Arabic provided in a powder form in 30-grams-dose once daily for four weeks Placebo Comparator: Control group: This group will be provided with pectin powder provided as one-gram-dose once daily for four weeks Both GA and placebo will be in addition to standard care treatment based on local clinical guidelines. MAIN OUTCOMES: Mean change from baseline score of Immune Response to end of the trial. Changes of the level of Tumor Necrosis Factor (TNFα), interleukin IL8, IL6, and IL10 from the baseline values (Four weeks from the start of randomization). Mortality rate: The percentage of deaths among COVID 19 patients received Gum Arabic compared to placebo (Four weeks from the start of randomization]). RANDOMISATION: Randomization (1:1 allocation ratio) and will be conducted using a sequence of computer-generated random numbers by an independent individual. Each participating centre will be assigned a special code generated by the computer. The randomization will be kept by the PI and a research assistant. BLINDING (MASKING): Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 110 eligible patients will be randomly assigned to either GA (n=55) or placebo (n=55) groups. TRIAL STATUS: Protocol Version no 2, 30(th) June 2020. Recruitment will start on 15(th) September 2020. The intended completion date is 15(th) January 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04381871. Date of trial registration: 11 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-316666-qif1k62t
author: Ghati, Nirmal
date: 2020-10-30
txt: ./txt/cord-316666-qif1k62t.txt
cache: ./cache/cord-316666-qif1k62t.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33126910/
doi: 10.1186/s13063-020-04840-y
summary:
  title: Atorvastatin and Aspirin as Adjuvant Therapy in Patients with SARS-CoV-2 Infection: A structured summary of a study protocol for a randomised controlled trial Patients with a critical illness (WHO clinical improvement ordinal score > 5), documented significant liver disease/dysfunction (aspartate transaminase [AST] / alanine aminotransferase [ALT] > 240), myopathy and rhabdomyolysis (creatine phosphokinase [CPK] > 5x normal), allergy or intolerance to statins or aspirin, prior statin or aspirin use within 30 days, history of active gastrointestinal bleeding in past three months, coagulopathy, thrombocytopenia (platelet count < 100000/ dl), pregnancy, active breastfeeding, or inability to take oral or nasogastric medications will be excluded. INTERVENTION AND COMPARATOR: In this study, the benefit and safety of atorvastatin (statin) and/or aspirin as adjuvant therapy will be compared with the control group receiving usual care for management of COVID-19.

title:
  Atorvastatin and Aspirin as Adjuvant Therapy in Patients with SARS-CoV-2 Infection: A structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: To assess the impact of adding statin (atorvastatin) and/or aspirin on clinical deterioration in patients infected with SARS-CoV-2 who require hospitalisation. The safety of these drugs in COVID-19 patients will also be evaluated. TRIAL DESIGN: This is a single-centre, prospective, four-arm parallel design, open-label, randomized control trial. PARTICIPANTS: The study will be conducted at National Cancer Institute (NCI), Jhajjar, Haryana, which is a part of All India Institute of Medical Sciences (AIIMS), New Delhi, and has been converted into a dedicated COVID-19 management centre since the outbreak of the pandemic. All RT-PCR confirmed cases of SARS-CoV-2 infection with age ≥ 40 years and < 75 years requiring hospital admission (patients with WHO clinical improvement ordinal score 3 to 5) will be included in the trial. Written informed consent will be taken for all recruited patients. Patients with a critical illness (WHO clinical improvement ordinal score > 5), documented significant liver disease/dysfunction (aspartate transaminase [AST] / alanine aminotransferase [ALT] > 240), myopathy and rhabdomyolysis (creatine phosphokinase [CPK] > 5x normal), allergy or intolerance to statins or aspirin, prior statin or aspirin use within 30 days, history of active gastrointestinal bleeding in past three months, coagulopathy, thrombocytopenia (platelet count < 100000/ dl), pregnancy, active breastfeeding, or inability to take oral or nasogastric medications will be excluded. Patients refusing to give written consent and taking drugs that are known to have a significant drug interaction with statin or aspirin [including cyclosporine, HIV protease inhibitors, hepatitis C protease inhibitor, telaprevir, fibric acid derivatives (gemfibrozil), niacin, azole antifungals (itraconazole, ketoconazole), clarithromycin and colchicine] will also be excluded from the trial. INTERVENTION AND COMPARATOR: In this study, the benefit and safety of atorvastatin (statin) and/or aspirin as adjuvant therapy will be compared with the control group receiving usual care for management of COVID-19. Atorvastatin will be prescribed as 40 mg oral tablets once daily for ten days or until discharge, whichever is earlier. The dose of aspirin will be 75 mg once daily for ten days or until discharge, whichever is earlier. All other therapies will be administered according to the institute’s COVID-19 treatment protocol and the treating physician’s clinical judgment. MAIN OUTCOMES: All study participants will be prospectively followed up for ten days or until hospital discharge, whichever is longer for outcomes. The primary outcome will be clinical deterioration characterized by progression to WHO clinical improvement ordinal score ≥ 6 (i.e., endotracheal intubation, non-invasive mechanical ventilation, pressor agents, renal replacement therapy, ECMO requirement, and mortality). The secondary outcomes will be change in serum inflammatory markers (C-reactive protein and Interleukin-6), Troponin I, and creatine phosphokinase (CPK) from time zero to 5th day of study enrolment or 7th day after symptom onset, whichever is later. Other clinical outcomes that will be assessed include progression to Acute Respiratory Distress Syndrome (ARDS), shock, ICU admission, length of ICU admission, length of hospital admission, and in-hospital mortality. Adverse drug effects like myalgia, myopathy, rhabdomyolysis, hepatotoxicity, and bleeding will also be examined in the trial to assess the safety of the interventions. RANDOMISATION: The study will use a four-arm parallel-group design. A computer-generated permuted block randomization with mixed block size will be used to randomize the participants in a 1:1:1:1 ratio to group A (atorvastatin with conventional therapy), group B (aspirin with conventional therapy), group C (aspirin + atorvastatin with conventional therapy), and group D (control; only conventional therapy). BLINDING (MASKING): The study will be an open-label trial. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): As there is no existing study that has evaluated the role of aspirin and atorvastatin in COVID-19 patients, formal sample size calculation has not been done. Patients satisfying the inclusion and exclusion criteria will be recruited during six months of study period. Once the first 200 patients are included in each arm (i.e., total 800 patients), the final sample size calculation will be done on the basis of the interim analysis of the collected data. TRIAL STATUS: The institutional ethical committee has approved the study protocol (Protocol version 3.0 [June 2020]). Participant recruitment starting date: 28(th) July 2020 Participant recruitment ending date: 27(th) January 2021 Trial duration: 6 months TRIAL REGISTRATION: The trial has been prospectively registered in Clinical Trial Registry – India (ICMR- NIMS): Reference no. CTRI/2020/07/026791 (registered on 25 July 2020)]. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-020-04840-y.


id: cord-322534-eikz07zz
author: Allahyari, Abolghasem
date: 2020-06-26
txt: ./txt/cord-322534-eikz07zz.txt
cache: ./cache/cord-322534-eikz07zz.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04485-x
doi: 10.1186/s13063-020-04485-x
summary:
  title: Effect of hydroxychloroquine on COVID-19 prevention in cancer patients undergoing treatment: a structured summary of a study protocol for a randomised controlled trial OBJECTIVES: In this study, we investigate the effect of hydroxychloroquine on the prevention of Novel Coronavirus Disease (COVID-19) in cancer patients being treated. Trial registration: This trial has been registered by the title of "Effect of Hydroxychloroquine on Novel Coronavirus Disease (COVID-19) prevention in cancer patients under treatment" in Iranian Registry of Clinical Trials (IRCT) with code "IRCT20200405046958N1", https://www.irct.ir/trial/46946. Trial registration: This trial has been registered by the title of "Effect of Hydroxychloroquine on Novel Coronavirus Disease (COVID-19) prevention in cancer patients under treatment" in Iranian Registry of Clinical Trials (IRCT) with code "IRCT20200405046958N1", https://www.irct.ir/trial/46946. Also, the help of Clinical Research Development Unit of Akbar Hospital (affiliated to Mashhad University of Medical Sciences, Mashhad, Iran) in designing the study and methodological issues is highly appreciated. The trial has been approved by the Ethical Committee of Mashhad University of Medical Sciences, Iran.

title:
  Effect of hydroxychloroquine on COVID-19 prevention in cancer patients undergoing treatment: a structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: In this study, we investigate the effect of hydroxychloroquine on the prevention of Novel Coronavirus Disease (COVID-19) in cancer patients being treated. TRIAL DESIGN: This is a multi-centre, two-arm, parallel-group, triple-blind, phase 2-3 randomised controlled trial. PARTICIPANTS: All patients over the age of 15 from 5 types of cancer are included in the study. Patients with acute lymphoid and myeloid leukemias in the first line treated with curative intent, patients with high-grade non-Hodgkin's lymphoma treated with leukemia protocols and patients with non-metastatic breast and colon cancer in the first line of treatment will enter the study. The exclusion criteria will include known sensitivity to Hydroxychloroquine, weight below 35 kilograms, history of retinopathy, history of any cardiac disease, acute respiratory tract infection in the last 2 months, having COVID-19 in the first two weeks of entering the trial, having Diabetes Mellitus, having an immuno-suppressive disease other than cancer, having chronic pulmonary disease and taking immuno-suppressant drug other than chemotherapeutic agents for current cancer. This study is performed in five academic centres affiliated to Mashhad University of Medical Sciences, Mashhad, Iran. INTERVENTION AND COMPARATOR: Patients are randomly assigned to two groups; one being given hydroxychloroquine and the other is given placebo. During two months of treatment, the two groups are treated with either hydroxychloroquine (Amin® Pharmaceutical Company, Isfahan, Iran) or placebo (identical in terms of shape, colour, smell) as a single 200 mg tablet every other day. Patients will be monitored for COVID-19 symptoms during the follow-up period. If signs or symptoms occur (fever, cough, shortness of breath), they will be examined and investigated with a high-resolution computed tomography (CT) scan of the lungs, COVID-19 specific IgM, IgG antibody assay and a nucleic acid amplification test (NAT) for the SARS-CoV-2 virus. MAIN OUTCOMES: The primary end point of this study is to investigate the incidence of COVID-19 in patients being treated for their cancer over a 2-month period. RANDOMISATION: Randomisation will be performed using randomly permuted blocks. By using an online website (www.randomization.com) the randomization sequence will be produced by quadruple blocks. The allocation ratio in intervention and control groups is 1:1. BLINDING (MASKING): Participants and caregivers do not know whether the patient is in the intervention or the control group. The outcome assessor and the data analyst are also blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The calculated total sample size is 60 patients, with 30 patients in each group. TRIAL STATUS: The trial began on April 14, 2020 and recruitment is ongoing. Recruitment is anticipated to be completed by June 14, 2020 There has been no change in study protocol since approval, protocol version 1 was approved April 12, 2020. TRIAL REGISTRATION: This trial has been registered by the title of “Effect of Hydroxychloroquine on Novel Coronavirus Disease (COVID-19) prevention in cancer patients under treatment” in Iranian Registry of Clinical Trials (IRCT) with code “IRCT20200405046958N1”, https://www.irct.ir/trial/46946. Registration date is April 14, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-324786-8k81jetq
author: Chang, Anne B
date: 2012-08-31
txt: ./txt/cord-324786-8k81jetq.txt
cache: ./cache/cord-324786-8k81jetq.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/1745-6215-13-156
doi: 10.1186/1745-6215-13-156
summary:
  Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Early and effective management of bronchiectasis exacerbations in children may lead to reduced hospitalisations, better quality of life (QOL) and improved future adult lung function. Our study tests the primary hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo in improving the resolution rate of respiratory exacerbations by day 14 in children with non-CF bronchiectasis. We are conducting a multicentre, parallel group, double-blind placebo RCT (with concealed allocation) to assess the impact of treatment with antibiotics (azithromycin or amoxicillinclavulanic acid) in children with an exacerbation of bronchiectasis.

title:
  Antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial

abstract:
  BACKGROUND: Despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. It is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. Inadequately treated exacerbations may risk lung function deterioration. Our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. METHODS: We are conducting a bronchiectasis exacerbation study (BEST), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (Brisbane, Perth, Darwin, Melbourne, Auckland). In the component of BEST presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. Clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. In most children, blood and deep nasal swabs are also collected at the same time points. The primary outcome is the proportion of children whose exacerbations have resolved at day 14. The main secondary outcome is the paediatric cough-specific quality of life score. Other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. Descriptive viral and bacteriological data from nasal samples and blood markers will also be reported. DISCUSSION: Effective, evidence-based management of exacerbations in people with bronchiectasis is clinically important. Yet, there are few randomised controlled trials (RCTs) in the neglected area of non-cystic fibrosis bronchiectasis. Indeed, no published RCTs addressing the treatment of bronchiectasis exacerbations in children exist. Our multicentre, double-blind RCT is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. Our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR) number ACTRN12612000011886.


id: cord-330573-rr2r8245
author: Stockmann, Helena
date: 2020-06-26
txt: ./txt/cord-330573-rr2r8245.txt
cache: ./cache/cord-330573-rr2r8245.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04501-0
doi: 10.1186/s13063-020-04501-0
summary:
  title: CytoResc – "CytoSorb" Rescue for critically ill patients undergoing the COVID-19 Cytokine Storm: A structured summary of a study protocol for a randomized controlled trial TRIAL DESIGN: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of "CytoSorb" to standard of care without "CytoSorb". Intervention and comparator: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional "CytoSorb" therapy via a shaldon catheter for 3-7 days. Keywords: COVID-19, Randomized controlled trial, protocol, cytokine storm, vasoplegic shock, extracorporeal cytokine elimination Authors'' contributions TS, PE and HS designed the trial, wrote the study protocol, obtained ethical approval and applied for BMBF funding. TK did the biostatistic design of the trial and wrote the statistical section of the study protocol, ethical approval and BMBF application. Furthermore, the study protocol, the statistical analysis plan, the patient information and the patient consent form will be made available to all interested persons.

title:
  CytoResc – “CytoSorb” Rescue for critically ill patients undergoing the COVID-19 Cytokine Storm: A structured summary of a study protocol for a randomized controlled trial

abstract:
  OBJECTIVES: Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies. TRIAL DESIGN: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of “CytoSorb” to standard of care without “CytoSorb”. PARTICIPANTS: Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 μg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication. INTERVENTION AND COMPARATOR: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional “CytoSorb” therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of “CytoSorb” filter in order to prevent underdosing due to “CytoSorb” treatment. MAIN OUTCOMES: Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of “CytoSorb” and acute kidney injury. RANDOMIZATION: An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité – Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center. BLINDING (MASKING): The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group. TRIAL STATUS: Please see the study protocol version from April 24 2020. Recruitment of patients is still pending. TRIAL REGISTRATION: The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-331487-jh34klbg
author: Sivapalan, Pradeesh
date: 2020-06-10
txt: ./txt/cord-331487-jh34klbg.txt
cache: ./cache/cord-331487-jh34klbg.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32522282/
doi: 10.1186/s13063-020-04409-9
summary:
  OBJECTIVES: The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of noninvasive ventilation, treatment in the intensive care unit and death. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms).

title:
  Proactive Prophylaxis With Azithromycin and HydroxyChloroquine in Hospitalised Patients With COVID-19 (ProPAC-COVID): A structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: The aim of this randomised GCP-controlled trial is to clarify whether combination therapy with the antibiotic azithromycin and hydroxychloroquine via anti-inflammation/immune modulation, antiviral efficacy and pre-emptive treatment of supra-infections can shorten hospitalisation duration for patients with COVID-19 (measured as "days alive and out of hospital" as the primary outcome), reduce the risk of non- invasive ventilation, treatment in the intensive care unit and death. TRIAL DESIGN: This is a multi-centre, randomised, Placebo-controlled, 2-arm ratio 1:1, parallel group double-blind study. PARTICIPANTS: 226 participants are recruited at the trial sites/hospitals, where the study will take place in Denmark: Aalborg, Bispebjerg, Gentofte, Herlev, Hillerød, Hvidovre, Odense and Slagelse hospitals. Inclusion criteria: • Patient admitted to Danish emergency departments, respiratory medicine departments or internal medicine departments • Age≥ 18 years • Hospitalized ≤48 hours • Positive COVID-19 test / diagnosis during the hospitalization (confirmed). • Men or non-fertile women. Fertile women* must not be pregnant, i.e. negative pregnancy test must be available at inclusion • Informed consent signed by the patient *Defined as after menarche and until postmenopausal (no menstruation for 12 months) Exclusion criteria: • At the time of recruitment, the patient uses >5 LO2/min (equivalent to 40% FiO2 if measured) • Known intolerance/allergy to azithromycin or hydroxychloroquine or hypersensitivity to quinine or 4-aminoquinoline derivatives • Neurogenic hearing loss • Psoriasis • Retinopathy • Maculopathy • Visual field changes • Breastfeeding • Severe liver diseases other than amoebiasis (INR> 1.5 spontaneously) • Severe gastrointestinal, neurological and hematological disorders (investigator-assessed) • eGFR <45 ml/min/1.73 m2 • Clinically significant cardiac conduction disorders/arrhythmias or prolonged QTc interval (QTc (f) of> 480/470 ms). • Myasthenia gravis • Treatment with digoxin* • Glucose-6-phosphate dehydrogenase deficiency • Porphyria • Hypoglycaemia (Blood glucose at any time since hospitalization of <3.0 mmol/L) • Severe mental illness which significantly impedes cooperation • Severe linguistic problems that significantly hinder cooperation • Treatment with ergot alkaloids *The patient must not be treated with digoxin for the duration of the intervention. For atrial fibrillation/flutter, select according to the Cardiovascular National Treatment Guide (NBV): Calcium antagonist, Beta blocker, direct current (DC) conversion or amiodarone. In case of urgent need for digoxin treatment (contraindication for the aforementioned equal alternatives), the test drug should be paused, and ECG should be taken daily. INTERVENTION AND COMPARATOR: Control group: The control group will receive the standard treatment + placebo for both types of intervention medication at all times. If part or all the intervention therapy being investigated becomes standard treatment during the study, this may also be offered to the control group. Intervention group: The patients in the intervention group will also receive standard care. Immediately after randomisation to the intervention group, the patient will begin treatment with: Azithromycin: Day 1-3: 500 mg x 1 Day 4-15: 250 mg x 1 If the patient is unable to take the medication orally by themselves, the medication will, if possible, be administered by either stomach-feeding tube, or alternatively, temporary be changed to clarithromycin 500 mg x 2 (this only in agreement with either study coordinator Pradeesh Sivapalan or principal investigator Jens-Ulrik Stæhr Jensen). This will also be done in the control group if necessary. The patient will switch back to azithromycin when possible. Hydroxychloroquine: Furthermore, the patient will be treated with hydroxychloroquine as follows: Day 1-15: 200 mg x 2 MAIN OUTCOMES: • Number of days alive and discharged from hospital within 14 days (summarises both whether the patient is alive and discharged from hospital) ("Days alive and out of hospital") RANDOMISATION: The sponsor (Chronic Obstructive Pulmonary Disease Trial Network, COP:TRIN) generates a randomisation sequence. Randomisation will be in blocks of unknown size and the final allocation will be via an encrypted website (REDCap). There will be stratification for age (>70 years vs. <=70 years), site of recruitment and whether the patient has any of the following chronic lung diseases: COPD, asthma, bronchiectasis, interstitial lung disease (Yes vs. No). BLINDING (MASKING): Participants and study personnel will both be blinded, i.e. neither will know which group the participant is allocated to. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): This study requires 226 patients randomised 1:1 with 113 in each group. TRIAL STATUS: Protocol version 1.8, from April 16, 2020. Recruitment is ongoing (first patient recruited April 6, 2020; final patient expected to be recruited October 31, 2020). TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04322396 (registered March 26, 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


id: cord-334667-0cah15lg
author: Arabi, Yaseen M.
date: 2020-01-03
txt: ./txt/cord-334667-0cah15lg.txt
cache: ./cache/cord-334667-0cah15lg.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31900204/
doi: 10.1186/s13063-019-3846-x
summary:
  title: Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial ABSTRACT: The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-β1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. Baseline characteristics will be presented for the two study groups (Additional file 1: Table S1 ) including age, sex, and body mass index, the presence of co-infections, nosocomial versus community-acquired MERS infection, Acute Physiology and Chronic Health Evaluation (APA-CHE) II scores, Sequential Organ Failure Assessment scores, and the Karnofsky Performance Status Scale score [3] . The MIRACLE trial investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant Interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS.

title:
  Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-β1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial

abstract:
  ABSTRACT: The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-β1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-β1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02845843. Registered on 27 July 2016.


id: cord-334956-pi8ifpcy
author: Chan, Raymond Javan
date: 2020-10-15
txt: ./txt/cord-334956-pi8ifpcy.txt
cache: ./cache/cord-334956-pi8ifpcy.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33059741/
doi: 10.1186/s13063-020-04740-1
summary:
  title: Implementing a nurse-enabled, integrated, shared-care model involving specialists and general practitioners in breast cancer post-treatment follow-up: a study protocol for a phase II randomised controlled trial (the EMINENT trial) This study aims to test the feasibility of the EMINENT intervention for implementing an integrated, shared-care model involving both cancer centre specialists and community-based general practitioners for early breast cancer post-treatment follow-up. The objective of the study is to test the feasibility of a prospective, pragmatic randomised controlled trial (RCT) of the EMINENT intervention-a nurse-enabled, integrated, shared-care model involving cancer specialists and GPs for early breast cancer post-treatment follow-up. Training includes provision of study manual containing • Generic study information: standard operating procedures, study overview, reporting and documentation guidelines, communication flowchart, rationale for the study treatment, completion of survivorship care plan, self-management goal setting, and health coaching • Specialist Cancer Nurse-specific information: job description, intervention protocol, quality assurance, and monitoring An 8-h training program will be delivered by Experts in Cancer Survivorship and motivational interviewing.

title:
  Implementing a nurse-enabled, integrated, shared-care model involving specialists and general practitioners in breast cancer post-treatment follow-up: a study protocol for a phase II randomised controlled trial (the EMINENT trial)

abstract:
  BACKGROUND: Due to advances in early detection and cancer treatment, 5-year relative survival rates for early breast cancer surpass 90% in developed nations. There is increasing focus on promotion of wellness in survivorship and active approaches to reducing morbidity related to treatment; however, current models of follow-up care are heavily reliant on hospital-based specialist-led care. This study aims to test the feasibility of the EMINENT intervention for implementing an integrated, shared-care model involving both cancer centre specialists and community-based general practitioners for early breast cancer post-treatment follow-up. METHODS: We describe a protocol for a phase II, randomised controlled trial with two parallel arms and 1:1 allocation. A total of 60 patients with early-stage breast cancer will be randomised to usual, specialist-led, follow-up care (as determined by the treating surgeons, medical oncologists, and radiation oncologists) or shared follow-up care intervention (i.e. EMINENT). EMINENT is a nurse-enabled, pre-specified shared-care pathway with follow-up responsibilities divided between cancer centre specialists (i.e. surgeons and oncologists) and general practitioners. The primary outcome is health-related quality of life as measured by the Functional Assessment of Cancer Therapy—Breast Cancer. Secondary outcomes include patient experience, acceptance, and satisfaction of care; dietary, physical activity, and sedentary behaviours; financial toxicity; adherence; health resource utilisation; and adverse events. DISCUSSION: The trial is designed to identify the barriers to implementing a shared-care model for breast cancer survivors following treatment. Results of this study will inform a definitive trial testing the effects of shared-care model on health-related quality of life of breast cancer survivors, as well as its ability to alleviate the growing demands on the healthcare system. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12619001594112. Registered on 19 November 2019


id: cord-336000-v88bq4bx
author: Barco, Stefano
date: 2020-09-09
txt: ./txt/cord-336000-v88bq4bx.txt
cache: ./cache/cord-336000-v88bq4bx.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04678-4
doi: 10.1186/s13063-020-04678-4
summary:
  OBJECTIVES: The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. The OVID study will show whether prophylactic-dose enoxaparin improves survival and reduces any hospitalizations in ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. <30% of the expected number of patients six months after the enrolment of the first patient, also based on the course of SARS-CoV2 infections in Switzerland;  when the safety of the participants is doubtful or at risk, respectively, based on recommendations received from DSMB committee;  changes in accepted clinical practice that make the continuation of a clinical trial unwise, including the results of similar studies or the publication of international guidances.

title:
  Enoxaparin for primary thromboprophylaxis in ambulatory patients with coronavirus disease-2019 (the OVID study): a structured summary of a study protocol for a randomized controlled trial

abstract:
  OBJECTIVES: The OVID study will demonstrate whether prophylactic-dose enoxaparin improves survival and reduces hospitalizations in symptomatic ambulatory patients aged 50 or older diagnosed with COVID-19, a novel viral disease characterized by severe systemic, pulmonary, and vessel inflammation and coagulation activation. TRIAL DESIGN: The OVID study is conducted as a multicentre open-label superiority randomised controlled trial. PARTICIPANTS: Inclusion Criteria 1. Signed patient informed consent after being fully informed about the study’s background. 2. Patients aged 50 years or older with a positive test for SARS-CoV2 in the past 5 days and eligible for ambulatory treatment. 3. Presence of respiratory symptoms (i.e. cough, sore throat, or shortness of breath) or body temperature >37.5° C. 4. Ability of the patient to travel to the study centre by private transportation, performed either by an accompanying person from the same household or by the patient themselves 5. Ability to comply with standard hygiene requirements at the time of in-hospital visit, including a face mask and hand disinfectant. 6. Ability to walk from car to study centre or reach it by wheelchair transport with the help of an accompanying person from the same household also complying with standard hygiene requirements. 7. Ability to self-administer prefilled enoxaparin injections after instructions received at the study centre or availability of a person living with the patient to administer enoxaparin. Exclusion Criteria 1. Any acute or chronic condition posing an indication for anticoagulant treatment, e.g. atrial fibrillation, prior venous thromboembolism (VTE), acute confirmed symptomatic VTE, acute coronary syndrome. 2. Anticoagulant thromboprophylaxis deemed necessary in view of the patient's history, comorbidity or predisposing strong risk factors for thrombosis: a. Any of the following events occurring in the prior 30 days: fracture of lower limb, hospitalization for heart failure, hip/knee replacement, major trauma, spinal cord injury, stroke, b. previous VTE, c. histologically confirmed malignancy, which was diagnosed or treated (surgery, chemotherapy, radiotherapy) in the past 6 months, or recurrent, or metastatic, or inoperable. 3. Any clinically relevant bleeding (defined as bleeding requiring hospitalization, transfusion, surgical intervention, invasive procedures, occurring in a critical anatomical site, or causing disability) within 30 days prior to randomization or sign of acute bleeding. 4. Intracerebral bleeding at any time in the past or signs/symptoms consistent with acute intracranial haemorrhage. 5. Haemoglobin <8 g/dL and platelet count <50 x 10(9) cells/L confirmed by recent laboratory test (<90 days). 6. Subjects with any known coagulopathy or bleeding diathesis, including known significant liver disease associated with coagulopathy. 7. Severe renal insufficiency (baseline creatinine clearance <30 mL/min calculated using the Cockcroft-Gault formula) confirmed by recent laboratory test (<90 days). 8. Contraindications to enoxaparin therapy, including prior heparin-induced thrombocytopenia and known hypersensitivity. 9. Current use of dual antiplatelet therapy. 10. Participation in other interventional studies over the past 30 days. 11. Non-compliance or inability to adhere to treatment or lack of a family environment or support system for home treatment. 12. Cognitive impairment and/or inability to understand information provided in the study information. Patient enrolment will take place at seven Swiss centres, including five university hospitals and two large cantonal hospitals. INTERVENTION AND COMPARATOR: Patients randomized to the intervention group will receive subcutaneous enoxaparin at the recommended dose of 4,000 IU anti-Xa activity (40 mg/0.4 ml) once daily for 14 days. Patients randomized to the comparator group will receive no anticoagulation. MAIN OUTCOMES: Primary outcome: a composite of any hospitalization or all-cause death occurring within 30 days of randomization. Secondary outcomes: (i) a composite of cardiovascular events, including deep vein thrombosis (including catheter-associated), pulmonary embolism, myocardial infarction/myocarditis, arterial ischemia including mesenteric and extremities, acute splanchnic vein thrombosis, or ischemic stroke within 14 days, 30 days, and 90 days of randomization; (ii) each component of the primary efficacy outcome, within 14 days, 30 days, and 90 days of randomization; (iii) net clinical benefit (accounting for the primary efficacy outcome, composite cardiovascular events, and major bleeding), within 14 days, 30 days, and 90 days of enrolment; (iv) primary efficacy outcome, within 14 days, and 90 days of enrolment; (v) disseminated intravascular coagulation (ISTH criteria, in-hospital diagnosis) within 14 days, 30 days, and 90 days of enrolment. RANDOMISATION: Patients will undergo block stratified randomization (by age: 50-70 vs. >70 years; and by study centre) with a randomization ratio of 1:1 with block sizes varying between 4 and 8. Randomization will be performed after the signature of the informed consent for participation and the verification of the eligibility criteria using the electronic data capture software (REDCAP, Vanderbilt University, v9.1.24). BLINDING (MASKING): In this open-label study, no blinding procedures will be used. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The sample size calculation is based on the parameters α = 0.05 (2-sided), power: 1−β = 0.8, event rate in experimental group, pexp = 0.09 and event rate in control group, pcon = 0.15. The resulting total sample size is 920. To account for potential dropouts, the total sample size was fixed to 1000 with 500 patients in the intervention group and 500 in the control group. TRIAL STATUS: Protocol version 1.0, 14 April 2020. Protocol version 3.0, 18 May 2020 Recruiting start date: June 2020. Last Patient Last Visit: March 2021. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04400799 First Posted: May 26, 2020 Last Update Posted: July 16, 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-336058-xz26rbav
author: Wintner, Lisa M.
date: 2020-10-13
txt: ./txt/cord-336058-xz26rbav.txt
cache: ./cache/cord-336058-xz26rbav.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04745-w
doi: 10.1186/s13063-020-04745-w
summary:
  title: Evaluating the use of the EORTC patient-reported outcome measures for improving inter-rater reliability of CTCAE ratings in a mixed population of cancer patients: study protocol for a randomized controlled trial Patients aged 18 or above Any cancer diagnosis (no more than 20% per diagnostic group) Current treatment with chemotherapy or immunotherapy Inpatient or day clinic setting Scoring 3 or above on an initial screening question ("On a scale from 0 to 10, to what degree did you experience physical or emotional symptoms/ problems during the last week?") No psychiatric or mental problems (i.e., no such diagnosis in the medical records) Written informed consent Participating providers are requested to be either a medical, surgical, or radiation oncologist by training or a specially trained nurse authorized to perform CTCAE assessments in clinical trials, both with at least 1-year experience in oncology.

title:
  Evaluating the use of the EORTC patient-reported outcome measures for improving inter-rater reliability of CTCAE ratings in a mixed population of cancer patients: study protocol for a randomized controlled trial

abstract:
  BACKGROUND: In oncology, detection and tracking of adverse events are of top priority and rely mostly on the Common Terminology Criteria for Adverse Events (CTCAE). Besides, clinical trials use as well patient-reported outcomes (PROs) to assess those adverse events, which are only accessible through patient self-reporting, such as fatigue, pain, and sleep disorders. Especially those issues that are not visible from the outside are often misinterpreted and underestimated by mere provider ratings. This trial aims at evaluating the impact of providing PRO data to providers on the accuracy of adverse event assessment in terms of inter-rater reliability of CTCAE ratings. METHODS: The trial uses a cross-sectional, unblinded, randomized controlled trial design with two trial arms and a single assessment time point. Eligible patients (aged 18 and above, any cancer diagnosis, currently under treatment, inpatient or day clinic setting, present symptom burden, no psychiatric or mental problems, written informed consent) complete an electronic version of the EORTC QLQ-C30 and 16 additional questions taken from the EORTC Item Library. PRO data is immediately processed and made available to CTCAE rating providers for conducting their ratings during the medical encounter. Patients are randomly assigned 1:1 to the intervention group (providers see PRO results on the same screen as the CTCAE rating) and the control group (no access to PRO data during the CTCAE rating). A superiority analysis will compare the inter-rater reliability (using intra-class correlation (ICC) coefficients) between the control and the intervention groups for each adverse event evaluated. DISCUSSION: The presented trial will demonstrate potential benefits of using PRO measures to improve the reliability of CTCAE ratings in cancer trials and the identification of adverse events. The new insights gained may lead to a new strategy for evaluating adverse events in clinical trials by combining patient and provider ratings. This might also have implications for daily clinical practice and cancer registries. TRIAL REGISTRATION: ClinicalTrials.gov NCT04066868. Registered on August 26, 2019. Competence Center for Clinical Trials of the Medical University of Innsbruck 20190513-2007. Registered on May 14, 2019. (version 6.0, March 18, 2019)


id: cord-336368-sudi4mdx
author: Thiruvenkatarajan, Venkatesan
date: 2020-05-29
txt: ./txt/cord-336368-sudi4mdx.txt
cache: ./cache/cord-336368-sudi4mdx.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32471494/
doi: 10.1186/s13063-020-04378-z
summary:
  title: High-flow nasal cannula versus standard oxygen therapy assisting sedation during endoscopic retrograde cholangiopancreatography in high risk cases (OTHER): study protocol of a randomised multicentric trial METHODS/DESIGN: This is a prospective, randomised, multicentre trial comparing the efficacy of oxygen supplementation through HFNC versus low-flow nasal cannula during ERCP, in a cohort of patients at risk of adverse respiratory events. The secondary outcomes include parameters centred on oxygenation, requirement of airway manoeuvres, successful completion of procedure, perioperative complications, patient satisfaction and cost analysis of the consumables. The aim of the OTHER (Oxygen Therapy in High risk ERCP) trial is to assess the efficacy and safety of oxygen supplementation achieved through HFNC compared with low-flow nasal cannula during ERCP in a cohort of patients at risk of adverse respiratory events. Our study is the first multicentre randomised controlled trial comparing low-flow versus high-flow nasal oxygen therapy for improving oxygenation in high-risk patients for ERCP.

title:
  High-flow nasal cannula versus standard oxygen therapy assisting sedation during endoscopic retrograde cholangiopancreatography in high risk cases (OTHER): study protocol of a randomised multicentric trial

abstract:
  BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is an increasingly common intervention in the treatment of pancreaticobiliary disorders. Patients are often elderly with complex co-morbidities. While monitored anaesthesia care with sedation is commonly used for most cases, few would require general anaesthesia with an endotracheal tube. Both low-flow and high-flow nasal cannulas (HFNC) are established ways of delivering supplemental oxygen, but it is unclear whether one technique is better than the other. HFNC seems a promising tool for advanced procedures but evidence to support its application in high-risk ERCP cases is limited. The rate of oxygen desaturation during endoscopy has been reported to be as high as 11%–50% and the method of oxygen delivery for ERCP merits further study. METHODS/DESIGN: This is a prospective, randomised, multicentre trial comparing the efficacy of oxygen supplementation through HFNC versus low-flow nasal cannula during ERCP, in a cohort of patients at risk of adverse respiratory events. A total of 132 patients will be recruited across three sites and randomly assigned to either the low-flow or the HFNC group. The primary outcome is the proportion of patients experiencing hypoxia, defined by any event of SpO2 < 90%. The secondary outcomes include parameters centred on oxygenation, requirement of airway manoeuvres, successful completion of procedure, perioperative complications, patient satisfaction and cost analysis of the consumables. An intention-to-treat principle will be applied while analysing. DISCUSSION: The demand for ERCPs is likely to increase in the future with the aging population. Our study results may lead to improved outcomes and reduce airway-related complications in patients undergoing ERCPs. The results will be presented at national and international meetings and published in peer-reviewed journals. TRIAL REGISTRATION: www.ANZCTR.org.au, CTRN12619000397112. Registered on 12 March 2019.


id: cord-344491-93ggxzxu
author: Husebo, Bettina Sandgathe
date: 2020-06-09
txt: ./txt/cord-344491-93ggxzxu.txt
cache: ./cache/cord-344491-93ggxzxu.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04414-y
doi: 10.1186/s13063-020-04414-y
summary:
  In the COSMOS trial, a randomized implementation hybrid trial carried out in Norwegian nursing homes during 2014-2015, our group successfully developed, implemented and effect evaluated a multicomponent intervention addressing COmmunication, Systematic assessment and treatment of pain, Medication review, Organization of activities and Safety [22] . In practice in the LIVE@Home.Path: the coordinator will encourage and facilitate that both the PWD and the caregiver participate in local educational programs arranged by the municipality or the specialist health services several times yearly. PWDs are eligible for inclusion if they: are aged ≥ 65 years; are home-dwelling; have a minimum 1 h/week regular face-to-face contact with the caregiver; are diagnosed with dementia according to standardized protocol [60] ; have Mini-Mental State Examination (MMSE) score of 15-25; have a Functional Assessment Staging Test (FAST) score of 4-7; and provide written informed consent. A randomized controlled trial of a community-based dementia care coordination intervention: effects of MIND at Home on caregiver outcomes

title:
  LIVE@Home.Path—innovating the clinical pathway for home-dwelling people with dementia and their caregivers: study protocol for a mixed-method, stepped-wedge, randomized controlled trial

abstract:
  BACKGROUND: The global health challenge of dementia is exceptional in size, cost and impact. It is the only top ten cause of death that cannot be prevented, cured or substantially slowed, leaving disease management, caregiver support and service innovation as the main targets for reduction of disease burden. Institutionalization of persons with dementia is common in western countries, despite patients preferring to live longer at home, supported by caregivers. Such complex health challenges warrant multicomponent interventions thoroughly implemented in daily clinical practice. This article describes the rationale, development, feasibility testing and implementation process of the LIVE@Home.Path trial. METHODS: The LIVE@Home.Path trial is a 2-year, multicenter, mixed-method, stepped-wedge randomized controlled trial, aiming to include 315 dyads of home-dwelling people with dementia and their caregivers, recruited from 3 municipalities in Norway. The stepped-wedge randomization implies that all dyads receive the intervention, but the timing is determined by randomization. The control group constitutes the dyads waiting for the intervention. The multicomponent intervention was developed in collaboration with user-representatives, researchers and stakeholders to meet the requirements from the national Dementia Plan 2020. During the 6-month intervention period, the participants will be allocated to a municipal coordinator, the core feature of the intervention, responsible for regular contact with the dyads to facilitate L: Learning, I: Innovation, V: Volunteering and E: Empowerment (LIVE). The primary outcome is resource utilization. This is measured by the Resource Utilization in Dementia (RUD) instrument and the Relative Stress Scale (RSS), reflecting that resource utilization is more than the actual time required for caring but also how burdensome the task is experienced by the caregiver. DISCUSSION: We expect the implementation of LIVE to lead to a pathway for dementia treatment and care which is cost-effective, compared to treatment as usual, and will support high-quality independent living, at home. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04043364. Registered on 15 March 2019.


id: cord-349329-f0pbd968
author: Bosteels, Cedric
date: 2020-06-05
txt: ./txt/cord-349329-f0pbd968.txt
cache: ./cache/cord-349329-f0pbd968.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32503663/
doi: 10.1186/s13063-020-04451-7
summary:
  -Presence of acute hypoxic respiratory failure defined as (either or both)  saturation below 93% on minimal 2 l/min O2  PaO2/FiO2 below 350 -Admitted to specialized COVID-19 ward -Age 18-80 -Male or Female -Willing to provide informed consent Exclusion criteria -Patients with known history of serious allergic reactions, including anaphylaxis, to human granulocyte-macrophage colony stimulating factor such as sargramostim, yeast-derived products, or any component of the product. Study Interventions Confirmed or highly suspect COVID-19 patients with acute hypoxic respiratory failure (saturation below 93% on minimal 2 l/min O2 or PaO2/FiO2 <350) will be randomized to receive sargramostim 125mcg twice daily for 5 days as a nebulized inhalation on top of standard of care (active group), or to receive standard of care treatment (control group).

title:
  Sargramostim to treat patients with acute hypoxic respiratory failure due to COVID-19 (SARPAC): A structured summary of a study protocol for a randomised controlled trial

abstract:
  OBJECTIVES: The hypothesis of the proposed intervention is that Granulocyte-macrophage colony-stimulating factor (GM-CSF) has profound effects on antiviral immunity, and can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. Sargramostim is a man-made form of the naturally-occurring protein GM-CSF. TRIAL DESIGN: A phase 4 academic, prospective, 2 arm (1:1 ratio), randomized, open-label, controlled trial. PARTICIPANTS: Patients aged 18-80 years admitted to specialized COVID-19 wards in 5 Belgian hospitals with recent (< 2 weeks prior to randomization) confirmed COVID-19 infection and acute respiratory failure defined as a PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen. Patients were excluded from the trial in case of (1) known serious allergic reactions to yeast-derived products, (2) lithium carbonate therapy, (3) mechanical ventilation prior to randomization, (4) peripheral white blood cell count above 25.000/μL and/or active myeloid malignancy, (5) high dose systemic steroid therapy (> 20 mg methylprednisolone or equivalent), (6) enrolment in another investigational study, (7) pregnant or breastfeeding or (8) ferritin levels > 2000 μg/mL. INTERVENTION AND COMPARATOR: Inhaled sargramostim 125 μg twice daily for 5 days in addition to standard care. Upon progression of disease requiring mechanical ventilation or to acute respiratory distress syndrome (ARDS) and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125 μg/m(2) body surface area once daily until the 5 day period is reached. From day 6 onwards, progressive patients in the active group will have the option to receive an additional 5 days of IV sargramostim, based on the treating physician's assessment. Intervention will be compared to standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards in the standard of care group will have the option (clinician's decision) to initiate IV sargramostim 125m μg/m(2) body surface area once daily for 5 days. MAIN OUTCOMES: The primary endpoint of this intervention is measuring oxygenation after 5 days of inhaled (and intravenous) treatment through assessment of a change in pretreatment and post-treatment ratio of PaO2/FiO2 and through measurement of the P(A-a)O2 gradient (PAO2= Partial alveolar pressure of oxygen, PaO2=Partial arterial pressure of oxygen; FiO2= Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 1:1 ratio. Randomization will be done using REDCap (electronic IWRS system). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 80 patients with confirmed COVID-19 and acute hypoxic respiratory failure will be enrolled, 40 in the active and 40 in the control group. TRIAL STATUS: SARPAC protocol Version 2.0 (April 15 2020). Participant recruitment is ongoing in 5 Belgian Hospitals (i.e. University Hospital Ghent, AZ Sint-Jan Bruges, AZ Delta Roeselare, University Hospital Brussels and ZNA Middelheim Antwerp). Participant recruitment started on March 26(th) 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on March 30(th), 2020 (ClinicalTrials.gov Identifier: NCT04326920) - retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT04326920?term=sarpac&recrs=ab&draw=2&rank=1 and on EudraCT on March 24th, 2020 (Identifier: 2020-001254-22). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


id: cord-350224-dt3li3bk
author: Ye, Qingsong
date: 2020-06-12
txt: ./txt/cord-350224-dt3li3bk.txt
cache: ./cache/cord-350224-dt3li3bk.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1186/s13063-020-04380-5
doi: 10.1186/s13063-020-04380-5
summary:
  title: Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I / II) The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10(7) human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10 7 human DPSCs in 30ml saline solution) on day 1, 4 and 7; Full study protocol.Authors'' contributions QY, ZW and SLW conceived the research idea; QY, HW, XX, YH and GZ designed the study protocol and developed the research plan; CZ and QY obtained the ethics approval; QY and ZL coordinated the tasks among different investigators; CZ, ZZ, ZL and QY YZ and KH recruited the participants and collected data.

title:
  Safety and efficacy assessment of allogeneic human dental pulp stem cells to treat patients with severe COVID-19: structured summary of a study protocol for a randomized controlled trial (Phase I / II)

abstract:
  OBJECTIVES: To assess the safety and therapeutic effects of allogeneic human dental pulp stem cells (DPSCs) in treating severe pneumonia caused by COVID-19. TRIAL DESIGN: This is a single centre, two arm ratio 1:1, triple blinded, randomized, placebo-controlled, parallel group, clinical trial. PARTICIPANTS: 1. Adults aged 18-65 years; 2. Voluntarily participate in this clinical trial and sign the “informed consent form” or have consent from a legal representative. 3. Diagnosed with severe pneumonia of COVID-19: nucleic acid test SARS-CoV-2 positive; respiratory distress (respiratory rate > 30 times / min); hypoxia (resting oxygen saturation < 93% or arterial partial pressure of oxygen / oxygen concentration < 300 mmHg). 4. COVID-19 featured lung lesions in chest X-ray image. 1. Patients have received other experimental treatment for COVID-19 within the last 30 days; 2. Patients have severe liver condition (e.g., Child Pugh score >=C or AST> 5 times of the upper limit); 3. Patients with severe renal insufficiency (estimated glomerular filtration rate <=30mL / min/1.73 m(2)) or patients receiving continuous renal replacement therapy, hemodialysis, peritoneal dialysis; 4. Patients who are co-infected with HIV, hepatitis B, tuberculosis, influenza virus, adenovirus or other respiratory infection viruses; 5. Female patients who have no sexual protection in the last 30 days prior to the screening assessment; 6. Pregnant or lactating women or women using estrogen contraception; 7. Patients who are planning to become pregnant during the study period or within 6 months after the end of the study period; 8. Other conditions that the researchers consider not suitable for participating in this clinical trial. INTERVENTION AND COMPARATOR: There will be two study groups: experimental and control. Both will receive all necessary routine treatment for COVID-19. The experimental group will receive an intravenous injection of dental pulp stem cells suspension (3.0x10(7) human DPSCs in 30ml saline solution) on day 1, 4 and 7; The control group will receive an equal amount of saline (placebo) on the same days. Clinical and laboratory observations will be performed for analysis during a period of 28 days for each case since the commencement of the study. MAIN OUTCOMES: 1. Primary outcome The primary outcome is Time To Clinical Improvement (TTCI). By definition, TTCI is the time (days) it takes to downgrade two levels from the following six ordered grades [(grade 1) discharge to (grade 6) death] in the clinical state of admission to the start of study treatments (hDPSCs or placebo). Six grades of ordered variables: 2. Secondary outcomes 2.1 vital signs: heart rate, blood pressure (systolic blood pressure, diastolic blood pressure). During the screening period, hospitalization every day (additional time points of D1, D4, D7 30min before injection, 2h ± 30min, 24h ± 30min after the injection) and follow-up period D90 ± 3 days. 2.2 Laboratory examinations: during the screening period, 30 minutes before D1, D4, D7 infusion, 2h ± 30min, 24h ± 30min after the end of infusion, D10, D14, D28 during hospitalization or discharge day and follow-up period D90 ± 3 days. 2.3 Blood routine: white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, neutrophils, lymphocytes, monocytes, eosinophils Acidic granulocyte count, basophil count, red blood cell, hemoglobin, hematocrit, average volume of red blood cells, average red blood cell Hb content, average red blood cell Hb concentration, RDW standard deviation, RDW coefficient of variation, platelet count, platelet specific platelet average Volume, platelet distribution width,% of large platelets; 2.4 Liver and kidney function tests: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, prealbumin, total protein, albumin, globulin, white / globule ratio , Total bilirubin, direct bilirubin, cholinesterase, urea, creatinine, total carbon dioxide, uric acid glucose, potassium, sodium, chlorine, calcium, corrected calcium, magnesium, phosphorus, calcium and phosphorus product, anion gap, penetration Pressure, total cholesterol, triacylglycerol, high density lipoprotein cholesterol, Low density lipoprotein cholesterol, lipoprotein a, creatine kinase, lactate dehydrogenase, estimated glomerular filtration rate. 2.5 Inflammation indicators: hypersensitive C-reactive protein, serum amyloid (SAA); 2.6 Infectious disease testing: Hepatitis B (HBsAg, HBsAb, HBeAg, HBeAb, HBcAb), Hepatitis C (Anti-HCV), AIDS (HIVcombin), syphilis (Anti-TP), cytomegalovirus CMV-IgM, cytomegalovirus CMV-IgG; only during the screening period and follow-up period D90 ± 3. 2.7 Immunological testing: Collect peripheral blood to detect the phenotype of T lymphocyte, B lymphocyte, natural killer cell, Macrophage and neutrophil by using flow cytometry. Collect peripheral blood to detect the gene profile of mononuclear cells by using single-cell analyses. Collect peripheral blood serum to detect various immunoglobulin changes: IgA, IgG, IgM, total IgE; Collect peripheral blood serum to explore the changes of cytokines, Th1 cytokines (IL-1 β, IL-2, TNF-a, ITN-γ), Th2 cytokines (IL-4, IL-6, IL -10). 2.8 Pregnancy test: blood β-HCG, female subjects before menopause are examined during the screening period and follow-up period D90 ± 3. 2.9 Urine routine: color, clarity, urine sugar, bilirubin, ketone bodies, specific gravity, pH, urobilinogen, nitrite, protein, occult blood, leukocyte enzymes, red blood cells, white blood cells, epithelial cells, non-squamous epithelial cells , Transparent cast, pathological cast, crystal, fungus; 2.10 Stool Routine: color, traits, white blood cells, red blood cells, fat globules, eggs of parasites, fungi, occult blood (chemical method), occult blood (immune method), transferrin (2h ± 30min after the injection and not detected after discharge). RANDOMIZATION: Block randomization method will be applied by computer to allocate the participants into experimental and control groups. The random ratio is 1:1. BLINDING (MASKING): Participants, outcomes assessors and investigators (including personnel in laboratory and imaging department who issue the sample report or image observations) will be blinded. Injections of cell suspension and saline will be coded in accordance with the patient’s randomisation group. The blind strategy is kept by an investigator who does not deliver the medical care or assess primary outcome results. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Twenty participants will be randomized to the experimental and control groups (10 per group). TRIAL STATUS: Protocol version number, hDPSC-CoVID-2019-02-2020 Version 2.0, March 13, 2020. Patients screening commenced on 16(th) April and an estimated date of the recruitment of the final participants will be around end of July. . TRIAL REGISTRATION: Registration: World Health Organization Trial Registry: ChiCTR2000031319; March 27,2020. ClinicalTrials.gov Identifier: NCT04336254; April 7, 2020 Other Study ID Numbers: hDPSC-CoVID-2019-02-2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


