# ent

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-032607-bn8g02gi
type: LAW
entity:
  the Findability Accessibility Interoperability and Reusability FAIR and Care and Five Safes Principles We


id: cord-032607-bn8g02gi
type: ORG
entity:
  CONSORT Extension for Trials Using Cohorts and Routinely Collected Health Data SPIRIT and Template for Intervention Description and Replication


id: cord-263088-zj14ro5j
type: WORK_OF_ART
entity:
  Proceedings of the Workshop on Trade and Conservation of Pangolins Native to South and Southeast Asia


id: cord-310272-utqyuy0n
type: WORK_OF_ART
entity:
  the Technology Acceptance Model Davis and Warshaw 1989 the Unified Theory of Acceptance and Use of Technology Venkatesh et al 2003


id: cord-310272-utqyuy0n
type: ORG
entity:
  The Improvisation Effect A Case Study of User Improvisation and Its Effects on Information System Evolution Qualitative


id: cord-310272-utqyuy0n
type: ORG
entity:
  Corporate Social Networking Sites Modes of Use and Appropriation through Co Evolution Australasian Conference on Information Systems


id: cord-135406-ztgrxucb
type: WORK_OF_ART
entity:
  Synthetic Difference in Differences Matching and Regression to the Mean in Difference in Differences Analysis Health Policy Data Science Lab Difference in Differences Evaluating Methods to Estimate the Effect of State Laws on Firearm Deaths


id: cord-283197-jjye8t6j
type: WORK_OF_ART
entity:
  Fact Versus Science Fiction Fighting Coronavirus Disease 2019 Requires the Wisdom to Know the Difference date 2020 04 29 journal


id: cord-283197-jjye8t6j
type: LAW
entity:
  Definition of Misinformation 2020 Available at Definition of Disinformation 2020 Available at Researchers Are Tracking Another Pandemic Tooof Coronavirus Misinformation How a Crisis Researcher Makes Sense of Covid 19 Misinformation Protecting


id: cord-267699-h7ftu3ax
type: ORG
entity:
  Interim Healthcare Infection Prevention and Control Recommendations for Patients Under Investigation


id: cord-018677-gmitz3gg
type: PROTEIN
entity:
  parenteral polysaccharide diphtheria protein conjugate Haemophilus influenzae type b Hib vaccine 16 17 18 19


id: cord-018677-gmitz3gg
type: ORG
entity:
  International Conference on Harmonisation Expert Working Group 1996 International Conference on Harmonisation Guideline for Good Clinical Practice E6


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-309582-ihrj84hr
type: PROTEIN
entity:
  rVSV G ZEBOV GP Vaccine Tolerability and Safety During the West Africa Ebola Outbreak Chloroquine diphosphate


id: cord-160526-27kmder5
type: ORG
entity:
  methods European Medicines Agency Committee For Medicinal Products For Human Use EMA CHMP Guidance to Sponsors


id: cord-160526-27kmder5
type: ORG
entity:
  Missing Data A General Statistical Principle for Changing a Design Any Time During the Course of a Trial Robust Inference


id: cord-281400-ho2m7nqn
type: WORK_OF_ART
entity:
  the Treatment of Covid 19 Preliminary Report A Trial of Lopinavir Ritonavir in Adults Hospitalized with Severe Covid 19 Efficacy


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


id: cord-286288-gduhterq
type: ORG
entity:
  the International Conference of Harmonization the International Organization for Standardization and the International Medical Device Regulators Forum


id: cord-331133-6zu44fn2
type: ORG
entity:
  the PROMIS Fatigue Short Form Delivering Value Through Personalized Medicine An Industry Perspective Rapid


id: cord-344705-co0nk7pt
type: LAW
entity:
  COVID 19 International Clinical Trials Registry Platform ICTRP Compassionate Use of Remdesivir for Patients with Severe Covid 19


# bib

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-004647-0fuy5tlp
author: Patson, Noel
date: 2020-03-20
txt: ./txt/cord-004647-0fuy5tlp.txt
cache: ./cache/cord-004647-0fuy5tlp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085184/
doi: 10.1186/s12936-020-03190-z
summary:
  METHODS: The search included five databases (PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials) to identify original English articles reporting Phase III randomized controlled trials (RCTs) on anti-malarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019. This review, therefore, aims at identifying applied statistical methods and their appropriateness in the analysis of safety data in anti-malarial drugs for malaria prevention during pregnancy clinical trials. This review sought to provide a detailed overview of the actual practice of the statistical analysis of safety data in the unique setting of drug trials for the preventions of malaria in pregnancy as reflected published literature. Advantageously, methods based on causal inference framework, such as mediation analysis [28] [29] [30] [31] could be adapted/extended to assess the influence of the AEs on non-adherence in RCTs. Despite about three-quarters of the trials reporting p-values after comparing safety outcomes by treatment arms, only about half of the reviewed trials adhered to International Harmonisation Conference Guideline E9 in reporting of confidence intervals in quantifying the safety effect size [3, 4] .

title:
  Systematic review of statistical methods for safety data in malaria chemoprevention in pregnancy trials

abstract:
  BACKGROUND: Drug safety assessments in clinical trials present unique analytical challenges. Some of these include adjusting for individual follow-up time, repeated measurements of multiple outcomes and missing data among others. Furthermore, pre-specifying appropriate analysis becomes difficult as some safety endpoints are unexpected. Although existing guidelines such as CONSORT encourage thorough reporting of adverse events (AEs) in clinical trials, they provide limited details for safety data analysis. The limited guidelines may influence suboptimal analysis by failing to account for some analysis challenges above. A typical example where such challenges exist are trials of anti-malarial drugs for malaria prevention during pregnancy. Lack of proper standardized evaluation of the safety of antimalarial drugs has limited the ability to draw conclusions about safety. Therefore, a systematic review was conducted to establish the current practice in statistical analysis for preventive antimalarial drug safety in pregnancy. METHODS: The search included five databases (PubMed, Embase, Scopus, Malaria in Pregnancy Library and Cochrane Central Register of Controlled Trials) to identify original English articles reporting Phase III randomized controlled trials (RCTs) on anti-malarial drugs for malaria prevention in pregnancy published from January 2010 to July 2019. RESULTS: Eighteen trials were included in this review that collected multiple longitudinal safety outcomes including AEs. Statistical analysis and reporting of the safety outcomes in all the trials used descriptive statistics; proportions/counts (n = 18, 100%) and mean/median (n = 2, 11.1%). Results presentation included tabular (n = 16, 88.9%) and text description (n = 2, 11.1%). Univariate inferential methods were reported in most trials (n = 16, 88.9%); including Chi square/Fisher’s exact test (n = 12, 66.7%), t test (n = 2, 11.1%) and Mann–Whitney/Wilcoxon test (n = 1, 5.6%). Multivariable methods, including Poisson and negative binomial were reported in few trials (n = 3, 16.7%). Assessment of a potential link between missing efficacy data and safety outcomes was not reported in any of the trials that reported efficacy missing data (n = 7, 38.9%). CONCLUSION: The review demonstrated that statistical analysis of safety data in anti-malarial drugs for malarial chemoprevention in pregnancy RCTs is inadequate. The analyses insufficiently account for multiple safety outcomes potential dependence, follow-up time and informative missing data which can compromise anti-malarial drug safety evidence development, based on the available data.


id: cord-005705-j765ruj1
title: Is it better to consent to an RCT or to care?: Μηδεν αγαν (“nothing in excess”)
author: Dreyfuss, Didier
date: 2004-12-17
txt: ./txt/cord-005705-j765ruj1.txt
cache: ./cache/cord-005705-j765ruj1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7095248/
doi: 10.1007/s00134-004-2493-0
abstract: nan
summary:
  Another contention of the present paper is this [14] : critical care physicians may still believe that RCTs remain the best tool for improving knowledge and care, and in this case they must accept to use the means needed to achieve the end and therefore to insist on mandatory informed consent from the patient or proxy; or they may realize that the game is not worth the candle and they must then turn to other forms of research that are ranked less highly in the pyramid of evidence-based medicine [15] . Before discussing the problem of informed consent to research a critical appraisal of the scientific and ethical validity of RCTs in critical care medicine is in order.


id: cord-018677-gmitz3gg
title: Sequential stages of clinical trials and overview of issues to be considered
author: Clemens, John D.
date: 2005
txt: ./txt/cord-018677-gmitz3gg.txt
cache: ./cache/cord-018677-gmitz3gg.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123620/
doi: 10.1007/3-7643-7381-4_11
abstract: nan
summary:
  In these studies volunteers are typically allocated at random to receive the vaccine or a comparison agent, usually a placebo, and are then challenged at a defined interval after vaccination with an inoculum of the pathogen predicted to cause the target disease in nearly 100% of the control group. Phase III studies are designed as randomized, controlled trials with clear hypotheses, and are conducted in the target group for whom vaccine licensure is desired and in a population that normally experiences the target infection. Definition of immunological correlates of vaccine protection is very important because such correlates permit assessments of the protection of the tested vaccine and ones suitably similar to it in small, short-term studies with immunological endpoints, without resort to full-scale, Phase III efficacy trials with clinical infection endpoints. The successive phases of clinical evaluation of vaccine candidates allow for acquisition of critical information about vaccine safety, immunogenicity, excretion, transmission, and protection in an incremental fashion, while minimizing the risks to subjects who volunteer to participate in these studies.


id: cord-026998-vlmoa5dr
title: COVID-19 has no effect on gravity
author: McCulloch, Peter
date: 2020-06-03
txt: ./txt/cord-026998-vlmoa5dr.txt
cache: ./cache/cord-026998-vlmoa5dr.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299649/
doi: 10.1136/bmjsit-2020-000046
abstract: nan
summary:
  The Adaptive COVID-19 Treatment Trial of remdesivir was highlighted before any details were available even on preprint servers, and inferences made publicly about mortality reduction, although the trial did not show this. The laws of scientific inference and statistics have not been affected by the virus, and studies whose design guarantees they cannot produce a valid result still will not do so during the crisis. The crisis has shown that the normal processes of peer review and prioritization, both in funding and in publication, can be radically accelerated, but should be robust to protect the conduct of meaningful clinical research. We hope the research world, like the rest of society, will keep some of the helpful adaptations it has made to cope with the crisis. FDA will reportedly authorize use of remdesivir for Covid-19 after trial shows ''positive effect'' on recovery time


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-031978-l6nlrv9h
title: Panel sampling in health research
author: Chauvenet, Alienor
date: 2020-09-16
txt: ./txt/cord-031978-l6nlrv9h.txt
cache: ./cache/cord-031978-l6nlrv9h.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494318/
doi: 10.1016/s2215-0366(20)30358-8
abstract: nan
summary:
  Carsten Hjorthøj and colleagues question the extent to which the effects of cannabidiol as a pharmacological treatment for cannabis use disorder might be clinically meaningful. The Lancet Psychiatry, Matthias Pierce and colleagues 1,2 identify the importance of sampling in studying mental health effects of COVID-19. It seems that self-selected commercial survey panels in general might be biased towards mentally unhealthy or unhappy individuals. Despite great interest in the discontinuation of antipsychotic medication, few individuals can equally accept either treatment group in a randomised discontinuation trial, because the decision to maintain or discontinue is too important to be left to randomisation. Second, clinical cohort studies including individuals who discontinue antipsychotic medication should be done to generate precise knowledge about the proportion and The Dutch MESIFOS study 1 found that more patients achieved long term functional remission in the group who were assigned to early discontinuation of antipsychotic medication after 6 months of remission, compared with those who were assigned to maintenance treatment.


id: cord-032607-bn8g02gi
author: Wake, Melissa
date: 2020-09-24
txt: ./txt/cord-032607-bn8g02gi.txt
cache: ./cache/cord-032607-bn8g02gi.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512047/
doi: 10.1186/s12874-020-01111-x
summary:
  Keywords: Research methodology, Randomization, Registry trials, Multiple baseline randomized trials, Trials within cohorts, Population studies, Generation Victoria (GenV), Clinical trial as topic, Children, Intervention Background Randomized controlled trials (RCT) provide high-quality evidence with regards to the effectiveness of therapies and prevention and are critical to guide translation and optimal resource allocation. If feasibility (potentially demonstrated through pilot studies) and mutual alignment appear likely [29] , the trial would proceed to a partnering agreement that defines at least the following 8 items: 1) Which GenV trial model is being followed; 2) Design and high-level (or draft) protocol; 3) Timelines; 4) Data sharing and governance plans; 5) Status of ethical approval; 6) Communication with participants, including information statement and consent; 7) Trial oversight and 8) Capacity assessment, including trial quality, human resource and funding.

title:
  Integrating trials into a whole-population cohort of children and parents: statement of intent (trials) for the Generation Victoria (GenV) cohort

abstract:
  BACKGROUND: Very large cohorts that span an entire population raise new prospects for the conduct of multiple trials that speed up advances in prevention or treatment while reducing participant, financial and regulatory burden. However, a review of literature reveals no blueprint to guide this systematically in practice. This Statement of Intent proposes how diverse trials may be integrated within or alongside Generation Victoria (GenV), a whole-of-state Australian birth cohort in planning, and delineates potential processes and opportunities. METHODS: Parents of all newborns (estimated 160,000) in the state of Victoria, Australia, will be approached for two full years from 2021. The cohort design comprises four elements: (1) consent soon after birth to follow the child and parent/s until study end or withdrawal; retrospective and prospective (2) linkage to clinical and administrative datasets and (3) banking of universal and clinical biosamples; and (4) GenV-collected biosamples and data. GenV-collected data will focus on overarching outcome and phenotypic measures using low-burden, universal-capable electronic interfaces, with funding-dependent face-to-face assessments tailored to universal settings during the early childhood, school and/or adult years. RESULTS: For population or registry-type trials within GenV, GenV will provide all outcomes data and consent via traditional, waiver, or Trials Within Cohorts models. Trials alongside GenV consent their own participants born within the GenV window; GenV may help identify potential participants via opt-in or opt-out expression of interest. Data sharing enriches trials with outcomes, prior data, and/or access to linked data contingent on custodian’s agreements, and supports modeling of causal effects to the population and between-trials comparisons of costs, benefits and utility. Data access will operate under the Findability, Accessibility, Interoperability, and Reusability (FAIR) and Care and Five Safes Principles. We consider governance, ethical and shared trial oversight, and expectations that trials will adhere to the best practice of the day. CONCLUSIONS: Children and younger adults can access fewer trials than older adults. Integrating trials into mega-cohorts should improve health and well-being by generating faster, larger-scale evidence on a longer and/or broader horizon than previously possible. GenV will explore the limits and details of this approach over the coming years.


id: cord-048447-chz8luni
title: Surfactant therapy for acute respiratory failure in children: a systematic review and meta-analysis
author: Duffett, Mark
date: 2007-06-15
txt: ./txt/cord-048447-chz8luni.txt
cache: ./cache/cord-048447-chz8luni.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2206432/
doi: 10.1186/cc5944
summary:
  The primary objective of the systematic review is to assess the effect of the administration of pulmonary surfactant compared with no therapy or with placebo on all-cause mortality (at or before hospital discharge) in mechanically ventilated children with acute respiratory failure. We used the following characteristics to assess the methodologic quality: allocation concealment (sealed envelopes or central randomization were considered adequate), blinding (which of the trial personnel and caregivers were blinded, and the methods used to ensure blinding), completeness of followup (assessed by the number of patients randomized for whom there were no outcomes), similarity of the groups at baseline (with respect to known prognostic factors: age, aetiology, severity of illness as measured by the Pediatric Risk of Mortality score, and immunosuppression), whether a standard or recommended strategy for mechanical ventilation was used, and whether a priori criteria for the use of co-interventions were used.

abstract:
  INTRODUCTION: Exogenous surfactant is used to treat acute respiratory failure in children, although the benefits and harms in this setting are not clear. The objective of the present systematic review is to assess the effect of exogenous pulmonary surfactant on all-cause mortality in children mechanically ventilated for acute respiratory failure. METHODS: We searched the MEDLINE, EMBASE, CINAHL and Ovid Healthstar databases, the bibliographies of included trials and review articles, conference proceedings and trial registries. We included prospective, randomized, controlled trials of pulmonary surfactant that enrolled intubated and mechanically ventilated children with acute respiratory failure. We excluded trials that exclusively enrolled neonates or patients with asthma. Two reviewers independently rated trials for inclusion, extracted data and assessed the methodologic quality. We quantitatively pooled the results of trials, where suitable, using a random effects model. RESULTS: Six trials randomizing 314 patients were included. Surfactant use reduced mortality (relative risk = 0.7, 95% confidence interval = 0.4 to 0.97, P = 0.04), was associated with increased ventilator-free days (weighted mean difference = 2.5 days, 95% confidence interval = 0.3 to 4.6 days, P = 0.02) and reduced the duration of ventilation (weighted mean difference = 2.3 days, 95% confidence interval = 0.1 to 4.4 days, P = 0.04). CONCLUSION: Surfactant use decreased mortality, was associated with more ventilator-free days and reduced the duration of ventilation. No serious adverse events were reported.


id: cord-135406-ztgrxucb
title: A trial emulation approach for policy evaluations with group-level longitudinal data
author: Ben-Michael, Eli
date: 2020-11-11
txt: ./txt/cord-135406-ztgrxucb.txt
cache: ./cache/cord-135406-ztgrxucb.txt
extension: .txt
mime: text/plain
url: https://arxiv.org/pdf/2011.05826v1.pdf
doi: nan
summary:
  While these methods are less common in epidemiology, epidemiologic researchers are well accustomed to handling similar complexities in studies of individual-level interventions."Target trial emulation"emphasizes the need to carefully design a non-experimental study in terms of inclusion and exclusion criteria, covariates, exposure definition, and outcome measurement -and the timing of those variables. We argue that policy evaluations using group-level longitudinal ("panel") data need to take a similar careful approach to study design, which we refer to as"policy trial emulation."This is especially important when intervention timing varies across jurisdictions; the main idea is to construct target trials separately for each"treatment cohort"(states that implement the policy at the same time) and then aggregate. 4 5 In this paper, we argue that policy evaluations using panel data need to take a similarly careful approach to study design, which we refer to as "policy trial emulation." The main idea is to construct target trials separately for each "treatment cohort" (states that implement the policy at the same time) and then aggregate.

abstract:
  To limit the spread of the novel coronavirus, governments across the world implemented extraordinary physical distancing policies, such as stay-at-home orders, and numerous studies aim to estimate their effects. Many statistical and econometric methods, such as difference-in-differences, leverage repeated measurements and variation in timing to estimate policy effects, including in the COVID-19 context. While these methods are less common in epidemiology, epidemiologic researchers are well accustomed to handling similar complexities in studies of individual-level interventions."Target trial emulation"emphasizes the need to carefully design a non-experimental study in terms of inclusion and exclusion criteria, covariates, exposure definition, and outcome measurement -- and the timing of those variables. We argue that policy evaluations using group-level longitudinal ("panel") data need to take a similar careful approach to study design, which we refer to as"policy trial emulation."This is especially important when intervention timing varies across jurisdictions; the main idea is to construct target trials separately for each"treatment cohort"(states that implement the policy at the same time) and then aggregate. We present a stylized analysis of the impact of state-level stay-at-home orders on total coronavirus cases. We argue that estimates from panel methods -- with the right data and careful modeling and diagnostics -- can help add to our understanding of many policies, though doing so is often challenging.


id: cord-160526-27kmder5
title: Statistical Issues and Recommendations for Clinical Trials Conducted During the COVID-19 Pandemic
author: Meyer, R. Daniel
date: 2020-05-21
txt: ./txt/cord-160526-27kmder5.txt
cache: ./cache/cord-160526-27kmder5.txt
extension: .txt
mime: text/plain
url: https://arxiv.org/pdf/2005.10248v1.pdf
doi: nan
summary:
  A number of strategies and recommendations are put forward to assess and address issues related to estimands, missing data, validity and modifications of statistical analysis methods, need for additional analyses, ability to meet objectives and overall trial interpretability. It should continue throughout the conduct of the study in light of the evolving situation and accumulating data, considering regional differences in the infection status and pandemic Determine what additional information needs to be collected in the study database or in the form of input from study investigators in order to adequately monitor, document, and address pandemic-related issues (feasibility to obtain such information and its quality may vary and this needs to be considered as part of the risk factors);  Understand reasons for treatment or study discontinuation and the impact on planned estimands and intercurrent events;

abstract:
  The COVID-19 pandemic has had and continues to have major impacts on planned and ongoing clinical trials. Its effects on trial data create multiple potential statistical issues. The scale of impact is unprecedented, but when viewed individually, many of the issues are well defined and feasible to address. A number of strategies and recommendations are put forward to assess and address issues related to estimands, missing data, validity and modifications of statistical analysis methods, need for additional analyses, ability to meet objectives and overall trial interpretability.


id: cord-263088-zj14ro5j
author: DiPaola, Joshua D.
date: 2020-06-17
txt: ./txt/cord-263088-zj14ro5j.txt
cache: ./cache/cord-263088-zj14ro5j.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-65898-x
doi: 10.1038/s41598-020-65898-x
summary:
  All trials across the ''olfactory'' , ''visual'' , and ''acoustic'' conditions of phase I were pseudo-randomised within a session so that each session consisted of an equal number of trials of left and right correct choices (based on the side of the chamber in which a container was placed), no one side was baited with food more than three consecutive times in a row, and the first three trials for each session across all conditions were always tests rather than controls to avoid a frustration effect. Phase I control containers (i.e., opaque with solid lids) were used as the stimulus containers in the test trials for this condition as we wanted the subject to make olfactory decisions based on the trail scent without being influenced by the odor of the food inside the container.

title:
  Investigating the use of sensory information to detect and track prey by the Sunda pangolin (Manis javanica) with conservation in mind

abstract:
  Pangolins are of conservation concern as one of the most heavily poached, yet least understood mammals. The Sunda pangolin (Manis javanica) in particular is a critically endangered species. Here, we investigate the behaviour of these pangolins, for the first time, using a battery of cognitive tasks based on a manipulation of available sensory information. In an object-choice task in which only one of two containers was baited with food, the pangolins were able to find the food with olfactory information alone (N = 2), but not with visual or acoustic information alone (N = 1). The single subject tested on all three domains was further tested on how he used smell to find food by providing him with an opportunity to find it from a controlled distance or by using scent trails as a guide. The results suggest that our subject may have the capacity to exploit scent trails left by prey which can be tracked to a final source, though we found no evidence to suggest that he had the ability to initiate hunts based on distant prey odors. Despite the small sample size, this is the first controlled experiment to investigate pangolin foraging behaviour and cognition, which may have implications for the future protection of pangolin habitat based on the location of prey species.


id: cord-266573-vfl08i2p
title: Paying Participants in COVID-19 Trials
author: Largent, Emily A
date: 2020-05-29
txt: ./txt/cord-266573-vfl08i2p.txt
cache: ./cache/cord-266573-vfl08i2p.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1093/infdis/jiaa284
doi: 10.1093/infdis/jiaa284
summary:
  Given increased risk of undue influence against pandemic background conditions, incentive payment should be avoided unless essential to recruitment and retention in important trials whose social value outweighs this risk. Given the pandemic''s devastating economic effects, as well as the fact that risks may be higher or more uncertain in COVID-19 trials than in nonpandemic research, there is an increased likelihood of undue influence stemming from incentive payments. Rather, in light of pandemic circumstances-similar features of which may be replicated in other contexts, including research conducted in low-and middle-income countries or with participants whose nonresearch options are limited even in the absence of a pandemic-offers of compensation may raise ethical concerns akin to incentives [14] . Acknowledging this challenge, the best IRBs can do is to minimize the possibility of undue influence for trial participants on the whole by making it unlikely for research participation to constitute an objectively unreasonable choice for members of the target study population.

abstract:
  Trials are in development and underway to examine potential interventions for treatment and prophylaxis of coronavirus disease 2019 (COVID-19). How should we think about offering payment to participants in these trials? Payment for research participation is ethically contentious even under ideal circumstances. Here, we review 3 functions of research payment—reimbursement, compensation, and incentive—and identify heightened and novel ethical concerns in the context of a global pandemic. We argue that COVID-19 trial participants should usually be offered reimbursement for research-related expenses, and compensation for their time and effort, as for other types of research under usual circumstances. Given increased risk of undue influence against pandemic background conditions, incentive payment should be avoided unless essential to recruitment and retention in important trials whose social value outweighs this risk. Where essential, however, incentives can be ethically permissible, so long as reasonable efforts are made to minimize the possibility of undue influence.


id: cord-267608-0odu8lus
title: Innovative highlights of clinical drug trial design
author: Chen, Daohong
date: 2020-06-03
txt: ./txt/cord-267608-0odu8lus.txt
cache: ./cache/cord-267608-0odu8lus.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.trsl.2020.05.007
doi: 10.1016/j.trsl.2020.05.007
summary:
  Accordingly taking the advantage of interim analysis based on novel biomarker approach for detecting the pathogenesis-specific molecular alteration(s), an adaptive clinical study can select the drug-sensitive sub-population from patients with initially targeted disease or an alternative indication, to continue the investigation for an optimized therapeutic efficacy [7] . While human bioequivalence study is increasingly contributing to evaluation of emerging formulation and bio-similar agents besides chemical generics [4] , several adaptive trial designs have been capable of translating the scientific breakthroughs into novel therapeutic benefits with shorter processing time and lower financial costs, to address the unmet clinical needs [3, 19] . Of note, to preserve the strength of clear defining efficacy and safety of tested drugs, the innovative designs of clinical study are substantially overlapped with classic trial protocols of three phases which still serve as the mainstream approach of clinical investigation [3, 7] .

abstract:
  Clinical trials serve as the gold standard to evaluate the efficacy and safety of tested drugs prior to marketing authorization. Nevertheless, there have been a few challenging issues well noted in traditional clinical trials such as tedious processing duration and escalating high costs among others. To improve the efficiency of clinical studies, a spectrum of expedited clinical trial modes has been designed, and selectively implemented in contemporary drug developing landscape. Herein this article presents an update on the innovated human trial designs that are corroborated through coming up with approval of notable therapeutic compounds for clinical utilization including delivery of several blockbuster products. It is intended to inspire clinical investigators and pharmaceutical development not only timely communicating with the regulatory agencies, but also insightful translating from cutting-edge scientific discoveries.


id: cord-267699-h7ftu3ax
author: MacIntyre, C. Raina
date: 2020-04-30
txt: ./txt/cord-267699-h7ftu3ax.txt
cache: ./cache/cord-267699-h7ftu3ax.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0020748920301139
doi: 10.1016/j.ijnurstu.2020.103629
summary:
  title: A RAPID SYSTEMATIC REVIEW OF THE EFFICACY OF FACE MASKS AND RESPIRATORS AGAINST CORONAVIRUSES AND OTHER RESPIRATORY TRANSMISSIBLE VIRUSES FOR THE COMMUNITY, HEALTHCARE WORKERS AND SICK PATIENTS METHODS: A systematic review of randomized controlled clinical trials on use of respiratory protection by healthcare workers, sick patients and community members was conducted. A systematic review of randomized controlled clinical trials on use of respiratory protection by healthcare workers, sick patients and community members was conducted. The aim of this study was to review the randomised controlled trials evidence for use of masks and respirators by the community, health care workers and sick patients for prevention of infection. (17) We conducted a randomised controlled trial comparing the targeted strategy tested in the two North American studies, with the wearing of respiratory protection during an entire shift, and showed efficacy for continual (but not targeted) use of a respirator (19) .

title:
  A RAPID SYSTEMATIC REVIEW OF THE EFFICACY OF FACE MASKS AND RESPIRATORS AGAINST CORONAVIRUSES AND OTHER RESPIRATORY TRANSMISSIBLE VIRUSES FOR THE COMMUNITY, HEALTHCARE WORKERS AND SICK PATIENTS

abstract:
  BACKGROUND: The pandemic of COVID-19 is growing, and a shortage of masks and respirators has been reported globally. Policies of health organizations for healthcare workers are inconsistent, with a change in policy in the US for universal face mask use. The aim of this study was to review the evidence around the efficacy of masks and respirators for healthcare workers, sick patients and the general public. METHODS: A systematic review of randomized controlled clinical trials on use of respiratory protection by healthcare workers, sick patients and community members was conducted. Articles were searched on Medline and Embase using key search terms. RESULTS: A total of 19 randomised controlled trials were included in this study – 8 in community settings, 6 in healthcare settings and 5 as source control. Most of these randomised controlled trials used different interventions and outcome measures. In the community, masks appeared to be more effective than hand hygiene alone, and both together are more protective. Randomised controlled trials in health care workers showed that respirators, if worn continually during a shift, were effective but not if worn intermittently. Medical masks were not effective, and cloth masks even less effective. When used by sick patients randomised controlled trials suggested protection of well contacts. CONCLUSION: The study suggests that community mask use by well people could be beneficial, particularly for COVID-19, where transmission may be pre-symptomatic. The studies of masks as source control also suggest a benefit, and may be important during the COVID-19 pandemic in universal community face mask use as well as in health care settings. Trials in healthcare workers support the use of respirators continuously during a shift. This may prevent health worker infections and deaths from COVID-19, as aerosolisation in the hospital setting has been documented.


id: cord-269716-x3b0qphd
title: Problem solving flexibility across early development
author: Hopper, Lydia M.
date: 2020-08-26
txt: ./txt/cord-269716-x3b0qphd.txt
cache: ./cache/cord-269716-x3b0qphd.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0022096520304203
doi: 10.1016/j.jecp.2020.104966
summary:
  For all children and action sequences used, in the first trial of Phase 2, 7 of the 20 2year-olds (35.00%), 14 of the 22 3-year-olds (63.64%), and 13 of the 19 4-year-olds (68.42%) used the (newly available) most efficient method (i.e., they removed only the lower two of five straws from the tube), highlighting their recognition of the changed task demands. In spite of this, after correcting for multiple comparisons, post hoc pairwise comparisons revealed no significant difference across age groups when comparing the numbers of children whose responses in the first trial of Phase 2 responses were efficient: 4-year-olds versus 2year-olds, t(35.92) = À2.41, p = .021, 95% CI [À0.68, À0.06]; 4-year-olds versus 3-year-olds, Considering all 4 trials that children completed in Phase 2, on average children removed significantly fewer straws per trial in Phase 2 than they did in Phase 1, highlighting their understanding of the changed task demands.

abstract:
  Cognitive flexibility allows individuals to adapt to novel situations. However, this ability appears to develop slowly over the first few years of life, mediated by task complexity and opacity. We used a physically simple novel task, previously tested with nonhuman primates, to explore the development of flexible problem solving in 2-, 3-, and 4-year-old children from a developmental and comparative perspective. The task goal was to remove barriers (straws) from a clear tube to release a ball. The location of the ball, and therefore the number of straws necessary to retrieve it, varied across two test phases (four of five straws and two of five straws, respectively). In Test Phase 1, all children retrieved the ball in Trial 1 and 83.61% used the most efficient method (removing only straws below the ball). Across Phase 1 trials, 4-year-olds were significantly more efficient than 2-year-olds, and solve latency decreased for all age groups. Test Phase 2 altered the location of the ball, allowing us to explore whether children could flexibly adopt a more efficient solution when their original (now inefficient) solution remained available. In Phase 2, significantly more 4-year-olds than 2-year-olds were efficient; the older children showed greater competency with the task and were more flexible to changing task demands than the younger children. Interestingly, no age group was as flexible in Phase 2 as previously tested nonhuman primates, potentially related to their relatively reduced task exploration in Phase 1. Therefore, this causally clear task revealed changes in cognitive flexibility across both early childhood and species.


id: cord-271514-sls3bsm0
title: Ensemble Forecast Modeling for the Design of COVID-19 Vaccine Efficacy Trials
author: Dean, Natalie E.
date: 2020-09-15
txt: ./txt/cord-271514-sls3bsm0.txt
cache: ./cache/cord-271514-sls3bsm0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33012602/
doi: 10.1016/j.vaccine.2020.09.031
summary:
  We recommend the use of ensemble forecast modeling – combining projections from independent modeling groups – to guide investigators identifying suitable sites for COVID-19 vaccine efficacy trials. In this paper, we describe a simplified framework for the use of ensemble modeling to guide the selection and continued evaluation of sites for a vaccine efficacy trial, with a focus on the COVID-19 pandemic. Suggested guidelines are the ability to: (i) capture all geographic areas in the candidate list of sites, (ii) disaggregate to at least the first administrative level (e.g. state, province), though finer levels may be preferred for certain planning activities, (iii) project the COVID-19 symptomatic cumulative incidence, i.e. the number of new symptomatic infections of any severity divided by the total population size during a pre-specified period (three months suggested), and (iv) produce a minimum of 1000 simulated epidemics. We describe an ensemble modeling procedure to inform site selection for a vaccine efficacy trial planned during an ongoing epidemic.

abstract:
  To rapidly evaluate the safety and efficacy of COVID-19 vaccine candidates, prioritizing vaccine trial sites in areas with high expected disease incidence can speed endpoint accrual and shorten trial duration. Mathematical and statistical forecast models can inform the process of site selection, integrating available data sources and facilitating comparisons across locations. We recommend the use of ensemble forecast modeling – combining projections from independent modeling groups – to guide investigators identifying suitable sites for COVID-19 vaccine efficacy trials. We describe an appropriate structure for this process, including minimum requirements, suggested output, and a user-friendly tool for displaying results. Importantly, we advise that this process be repeated regularly throughout the trial, to inform decisions about enrolling new participants at existing sites with waning incidence versus adding entirely new sites. These types of data-driven models can support the implementation of flexible efficacy trials tailored to the outbreak setting.


id: cord-276092-4e4muqnu
title: Waste in COVID-19 clinical trials conducted in western Europe
author: Dal-Re, Rafael
date: 2020-07-07
txt: ./txt/cord-276092-4e4muqnu.txt
cache: ./cache/cord-276092-4e4muqnu.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32653152/
doi: 10.1016/j.ejim.2020.07.002
abstract: nan
summary:
  A cross-sectional analysis was carried out based on a series of searches conducted on May 20-21, 2020 looking for non-industry-sponsored, ongoing trials, aiming to assess medicines or convalescent plasma for the treatment of COVID-19 patients, in the 5 largest European countries and 2 regions (Benelux, Scandinavia). The following information was extracted from each trial: single-arm or randomized controlled trial (RCT), blinding, and planned sample size; whether the trial was multicenter, had a control (standard of care) arm and a Data Monitoring Committee. Limited useful information should be expected from single-arm trials, RCTs recruiting ≤50 participants/arm and those with no standard of care arm. However, it should be highlighted that it is rather surprising why some trials carried out in all the countries/regions included in this study seemed not to be registered on the EudraCT database (from which the EU-CTR obtains all the information), something that should be expected from all trials conducted with medicines in Europe.


id: cord-279197-cesemos0
title: Integrative Cancer Therapies: Learning From COVID-19
author: Block, Keith I.
date: 2020-06-21
txt: ./txt/cord-279197-cesemos0.txt
cache: ./cache/cord-279197-cesemos0.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1177/1534735420932652
doi: 10.1177/1534735420932652
abstract: nan
summary:
  Not only has COVID-19 suddenly converted us to a reliance on telehealth that is likely to persist in the future, it has also highlighted the use of some integrative therapies commonly used by cancer patients that have previously been thought to be too controversial for conventional clinics, but that might bear further research attention. For instance, 3 meta-analyses of randomized trials of chemotherapy in colorectal cancer patients found that performance status predicted mortality, [12] [13] [14] in addition to treatment side effects. Along with the previously published beneficial effects of parenteral fish oil emulsions in cancer patients, 30 these vitamin C trials raise the question of the potentials of other unconventional intravenous treatments in cancer patients. Pooled safety and efficacy analysis examining the effect of performance status on outcomes in nine first-line treatment trials using individual data from patients with metastatic colorectal cancer


id: cord-279637-n8acd6hj
title: How to expedite early phase SARS‐CoV‐2 vaccine trials in pandemic setting – a practical perspective
author: van der Plas, J.L.
date: 2020-06-19
txt: ./txt/cord-279637-n8acd6hj.txt
cache: ./cache/cord-279637-n8acd6hj.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1111/bcp.14435
doi: 10.1111/bcp.14435
abstract: nan
summary:
  authors: van der Plas, J.L.; Roestenberg, M.; Cohen, A.F.; Kamerling, I.M.C. title: How to expedite early phase SARS‐CoV‐2 vaccine trials in pandemic setting – a practical perspective After preclinical studies and manufacturing processes, a rate-limiting step in vaccine development is the conduct of clinical trials. In the current COVID-19 pandemic it is more important than ever to identify and select the most promising vaccine candidates as early as possible and stop clinical development for failing candidates to avoid wasting valuable time and resources. Here, we discuss several practical suggestions that could accelerate early phase vaccine trials in the COVID-19 pandemic. Recruitment and screening of participants are time consuming activities in early phase clinical trials. Significant time can be saved if potential participants can be identified, counseled and general health status assessed before the formal clinical trial approval.


id: cord-280020-nrnc8u28
title: Appealing for Efficient, Well Organized Clinical Trials on COVID-19
author: Zhao, Yang
date: 2020-03-07
txt: ./txt/cord-280020-nrnc8u28.txt
cache: ./cache/cord-280020-nrnc8u28.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.03.05.20031476
doi: 10.1101/2020.03.05.20031476
summary:
  We reviewed the characteristics of interventional trials from Chinese Clinical Trial Registration (ChiCTR) and ClinicalTrials.gov. We found some studies with potential defects including unreasonable design, inappropriate primary endpoint definition, insufficient sample size and ethical issue. Herein, we reviewed the characteristics of interventional trials from Chinese Clinical Trial Registration (ChiCTR) and Two authors (Zhao and Shen) were independently responsible for collecting the relevant information, including clinical phase, study design, presence or absence of randomization, blinding, sample size, severity of disease and source of samples. Through analyzing currently-registered interventional trials, we found some studies with potential defects including unreasonable design, inappropriate PE definition, small sample size and ethical issue. https://doi.org/10.1101/2020.03.05.20031476 doi: medRxiv preprint As appealed by some Chinese scientists recently, clinical trials on COVID-19 should be designed based on scientific rules (appropriate controls, randomization, blinding, and sufficient sample size)，ethics and patients'' benefits 5 CC-BY-NC 4.0 International license It is made available under a author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

abstract:
  The rapid emergence of clinical trials on COVID-19 stimulated a wave of discussion in scientific community. We reviewed the characteristics of interventional trials from Chinese Clinical Trial Registration (ChiCTR) and ClinicalTrials.gov. A total of 171 COVID-19-related interventional trials were identified on Feb 22nd, 2020. These trials are classified into 4 categories based on treatment modalities, including chemical drugs, biological therapies, traditional Chinese medicine treatments and other therapies. Our analysis focused on the issues of stage, design, randomization, blinding, primary endpoints definition and sample size of these trials. We found some studies with potential defects including unreasonable design, inappropriate primary endpoint definition, insufficient sample size and ethical issue. Clinical trials on COVID-19 should be designed based on scientific rules, ethics and benefits for patients.


id: cord-281400-ho2m7nqn
author: Nguyen, Van Thu
date: 2020-10-21
txt: ./txt/cord-281400-ho2m7nqn.txt
cache: ./cache/cord-281400-ho2m7nqn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33096223/
doi: 10.1016/j.jclinepi.2020.10.010
summary:
  We systematically search the platform every week for all RCTs evaluating preventive interventions and treatments for COVID-19 and created a publicly available interactive mapping tool at https://covid-nma.com to visualize all trials registered. We systematically search the platform every week for all RCTs evaluating preventive interventions and treatments for COVID-19 and created a publicly available interactive mapping tool at https://covid-nma.com to visualize all trials registered. Up to August J o u r n a l P r e -p r o o f In certain countries, the sample size is relatively small for trials evaluating COVID-19 treatments ( Timing of research response to the evolution of the pandemic In Europe, Spain registered only 2/93 trials (2%) before the peak (i.e., March 27, 2020. Our interactive living mapping of COVID-19 research was designed to help decision makers use data from clinical registries for an up-to-date picture of all research questions being investigated so as to prioritize research and avoid waste in research (26) .

title:
  Research response to COVID-19 needed better coordination and collaboration: a living mapping of registered trials

abstract:
  Background Researchers worldwide are actively engaging in research activities to search for preventive and therapeutic interventions against COVID-19. Our aim was to describe the planning of randomized controlled trials (RCTs) in terms of timing related to the course of the COVID-19 epidemic and research question evaluated. Method We performed a living mapping of RCTs registered in the WHO International Clinical Trials Registry Platform. We systematically search the platform every week for all RCTs evaluating preventive interventions and treatments for COVID-19 and created a publicly available interactive mapping tool at https://covid-nma.com to visualize all trials registered. Results By August 12, 2020, 1,568 trials for COVID-19 were registered worldwide. Overall, the median ([Q1-Q3]; range) delay between the first case recorded in each country and the first RCT registered was 47 days ([33-67]; 15-163). For the 9 countries with the highest number of trials registered, most trials were registered after the peak of the epidemic (from 100% trials in Italy to 38% in the United States). Most trials evaluated treatments (1,333 trials; 85%); only 223 (14%) evaluated preventive strategies and 12 post-acute period intervention. A total of 254 trials were planned to assess different regimens of hydroxychloroquine with an expected sample size of 110,883 patients. Conclusion This living mapping analysis showed that COVID-19 trials have relatively small sample size with certain redundancy in research questions. Most trials were registered when the first peak of the pandemic have passed.


id: cord-282261-wcmc5mh6
title: COVID-19 and geriatric clinical trials research
author: Rhodus, Elizabeth K.
date: 2020-09-16
txt: ./txt/cord-282261-wcmc5mh6.txt
cache: ./cache/cord-282261-wcmc5mh6.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32939681/
doi: 10.1007/s40520-020-01705-x
abstract: nan
summary:
  The COVID-19 crisis affects every aspect of clinical trial research engagement including: recruitment and retention; ability to ensure participant safety while engaged in experimental interventions; study procedures, including consideration of remote assessments, impact on populations with health disparities, and generalizability of future results; outcome measures, including biomarker assessment; impact on the clinical trial workforce, including attrition; impact on dissemination of results and scientific collaborations, which move the clinical trial infrastructure forward; current and future funding allocations; and regulatory considerations in regards to management of altered study conduct and change of outcome measures (Fig. 1) . The purpose of this article is to highlight the impact of disasters such as the COVID-19 pandemic on geriatric clinical trials research and propose approaches for the scientific community to continue pushing forward. The vulnerability of older adults to COVID-19 is a critical reminder for the need to prepare for disasters during clinical trial design.


id: cord-283197-jjye8t6j
author: Ingraham, Nicholas E.
date: 2020-04-29
txt: ./txt/cord-283197-jjye8t6j.txt
cache: ./cache/cord-283197-jjye8t6j.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1097/cce.0000000000000108
doi: 10.1097/cce.0000000000000108
abstract: nan
summary:
  This commentary uses a recent study of hydroxychloroquine to demonstrate the dire need for randomized clinical trials, but more importantly, to explore the potential consequences of misinformation, how fear fuels its impact, and offer guidance to maintain scientific integrity without relinquishing hope. As of March 25, there remains no randomized control trial in humans with evidence that chloroquine or hydroxychloroquine is beneficial in SARS-CoV or SARS-CoV-2. Premature acceptance of efficacy is not new (swine flu vaccination [10] or recombinant human activated protein C [11] ), but it is these prior experiences that influence current standards to require high quality and often multiple randomized control trials to change practice. However, despite warnings from healthcare leaders and public health agencies, there continues to be a premature adoption of hydroxychloroquine as treatment based on limited preclinical data and misinformed interpretation of a nonrandomized study.

title:
  Fact Versus Science Fiction: Fighting Coronavirus Disease 2019 Requires the Wisdom to Know the Difference


id: cord-284502-nesvd10a
title: Clinical trials during COVID‐19
author: Singh, Arjun Gurmeet
date: 2020-05-02
txt: ./txt/cord-284502-nesvd10a.txt
cache: ./cache/cord-284502-nesvd10a.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32348582/
doi: 10.1002/hed.26223
summary:
  Sponsors need to take into account the national guidelines and restrictive measures imposed including limitations of trial participants and staff confinements and their ability to perform visits, interviews and forms, and notification of adverse effects. The risk-benefit section of protocols should include the additional risks that the participant and trial workers could encounter due to COVID-19 with adequate risk mitigation measures. Clinical investigators and sponsors should consult their Institutional Review Boards (IRBs) or Institutional Ethics Committees (IECs) in deciding if the participants'' safety and rights are best served and protected by participating in the ongoing study or by discontinuing the IMP, intervention or even participation in the trial. Since trial participants may not be able to visit the site for the protocol specific visits and investigations, sponsors should evaluate if alternate measures such as virtual visits, alternate locations for assessment, including imaging centers and labs, could suffice when necessary, only after ensuring the safety of the participant.

abstract:
  As this ever‐evolving pandemic lays itself, more of its impact is being understood. Until recently, most guidelines were reported to aid in managing and treating suspected or confirmed cases. Research institutions around the world are responding with a sense of confusion. Some are continuing routinely, especially those who are overseeing clinical trials that could offer life‐saving therapies, particularly against the novel coronavirus. Since research must continue even in the face of a shutdown, we aim to collate the currently available recommendations from various organizations and provide guidance to head and neck researchers across the world during these trying times.


id: cord-286144-6wtk5y7c
author: Tini, Giulia
date: 2020-06-29
txt: ./txt/cord-286144-6wtk5y7c.txt
cache: ./cache/cord-286144-6wtk5y7c.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3389/fmed.2020.00367
doi: 10.3389/fmed.2020.00367
summary:
  Results: We observe a clear prevalence of monocentric trials with highly heterogeneous endpoints and a significant disconnect between geographic distribution and disease prevalence, implying that most countries would need to recruit unrealistic percentages of their total prevalent cases to fulfill enrolment. In the present work, we defined structured semantic ontologies with controlled vocabularies to categorize trial interventions, study endpoints, and study designs, and we conducted an analysis of the growth rate, geographical distribution, and trial characteristics of COVID-19-related trials, highlighting a number of relevant features that may impair the possibility of obtaining reliable and transferable results within the current framework. We highlight a number of peculiar characteristics of this clinical research landscape: extremely rapid growth, substantial geographical and methodological incoherence, an unusual funding pattern, prevalence of monocentric trials, and extreme heterogeneity in the interventions tested.

title:
  Semantic and Geographical Analysis of COVID-19 Trials Reveals a Fragmented Clinical Research Landscape Likely to Impair Informativeness

abstract:
  Background: The unprecedented impact of the COVID-19 pandemic on modern society has ignited a “gold rush” for effective treatment and diagnostic strategies, with a significant diversion of economic, scientific, and human resources toward dedicated clinical research. We aimed to describe trends in this rapidly changing landscape to inform adequate resource allocation. Methods: We developed an online repository (COVID Trial Monitor) to analyze in real time the growth rate, geographical distribution, and characteristics of COVID-19 related trials. We defined structured semantic ontologies with controlled vocabularies to categorize trial interventions, study endpoints, and study designs. Analyses are publicly available at https://bioinfo.ieo.it/shiny/app/CovidCT. Results: We observe a clear prevalence of monocentric trials with highly heterogeneous endpoints and a significant disconnect between geographic distribution and disease prevalence, implying that most countries would need to recruit unrealistic percentages of their total prevalent cases to fulfill enrolment. Conclusions: This geographically and methodologically incoherent growth casts doubts on the actual feasibility of locally reaching target sample sizes and the probability of most of these trials providing reliable and transferable results. We call for the harmonization of clinical trial design criteria for COVID-19 and the increased use of larger master protocols incorporating elements of adaptive designs. COVID Trial Monitor identifies critical issues in current COVID-19-related clinical research and represents a useful resource with which researchers and policymakers can improve the quality and efficiency of related trials.


id: cord-286288-gduhterq
title: Cardiovascular Clinical Trials in a Pandemic: Immediate Implications of Coronavirus Disease 2019
author: Spitzer, Ernest
date: 2020-05-01
txt: ./txt/cord-286288-gduhterq.txt
cache: ./cache/cord-286288-gduhterq.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.15420/cfr.2020.07
doi: 10.15420/cfr.2020.07
summary:
  Nevertheless, new or ongoing clinical trials, not related to the disease itself, remain important for the development of new therapies, and require interactions among patients, clinicians and research personnel, which is challenging, given isolation measures. Trials in patient populations with acute presentations (e.g. ST-elevation MI [STEMI]) may identify potentially suitable trial candidates; however, the capacity to comply with study procedures needs to be assessed, as well as considerations related to patient safety during follow-up. Participants in the follow-up phase (when they are generally at home) constitute a higher-risk population in the Reduced capacity at investigational sites will impact on availability to perform study visits (or phone calls) to assess and confirm eligibility, enter data in electronic case report forms (eCRFs), to report (serious) adverse events and to follow the protocol in general. The participation of several committees in clinical trials ensures proper scientific and operational oversight, data integrity and quality, as well as patient safety.

abstract:
  The coronavirus disease 2019 (COVID-19) pandemic started in Wuhan, Hubei Province, China, in December 2019, and by 24 April 2020, it had affected >2.73 million people in 185 countries and caused >192,000 deaths. Despite diverse societal measures to reduce transmission of the severe acute respiratory syndrome coronavirus 2, such as implementing social distancing, quarantine, curfews and total lockdowns, its control remains challenging. Healthcare practitioners are at the frontline of defence against the virus, with increasing institutional and governmental supports. Nevertheless, new or ongoing clinical trials, not related to the disease itself, remain important for the development of new therapies, and require interactions among patients, clinicians and research personnel, which is challenging, given isolation measures. In this article, the authors summarise the acute effects and consequences of the COVID-19 pandemic on current cardiovascular trials.


id: cord-287507-1xb2hipt
author: Rubio-San-Simón, A.
date: 2020-05-29
txt: ./txt/cord-287507-1xb2hipt.txt
cache: ./cache/cord-287507-1xb2hipt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32472454/
doi: 10.1007/s12094-020-02399-3
summary:
  title: Challenges in early phase clinical trials for childhood cancer during the COVID-19 pandemic: a report from the new agents group of the Spanish Society of Paediatric Haematology and Oncology (SEHOP) METHODS: A questionnaire was sent to all five ITCC-accredited Spanish Paediatric Oncology Early Phase Clinical Trial Units, including questions about impact on staff activities, recruitment, patient care, supply of investigational products, and legal aspects. Cancer research is particularly challenging, because patients are remarkably vulnerable: their baseline condition needs close surveillance and delays in diagnosis or treatment are potentially fatal [9] ; in parallel, cancer patients are at increased risk for severe COVID-19 disease [10] [11] [12] We evaluated the impact of the COVID-19 pandemic on the early phase clinical trial activity in paediatric oncology during the first month of state of alarm in Spain (14th March-12th April 2020).

title:
  Challenges in early phase clinical trials for childhood cancer during the COVID-19 pandemic: a report from the new agents group of the Spanish Society of Paediatric Haematology and Oncology (SEHOP)

abstract:
  PURPOSE: The COVID-19 pandemic has forced healthcare stakeholders towards challenging decisions. We analyse the impact of the pandemic on the conduct of phase I–II trials for paediatric cancer during the first month of state of alarm in Spain. METHODS: A questionnaire was sent to all five ITCC-accredited Spanish Paediatric Oncology Early Phase Clinical Trial Units, including questions about impact on staff activities, recruitment, patient care, supply of investigational products, and legal aspects. RESULTS: All units suffered personnel shortages and difficulties in enrolling patients, treatment continuity, or performing trial assessments. Monitoring activity was frequently postponed (73%), and 49% of on-going trials interrupted recruitment. Only two patients could be recruited during this period (75% reduction in the expected rate). CONCLUSIONS: The COVID-19 crisis has significantly impacted clinical research practice and access to innovation for children with cancer. Structural and functional changes are under way to better cope with the expected future restrictions.


id: cord-294651-iy0h2pyf
author: Nasrallah, Ali A.
date: 2020-06-08
txt: ./txt/cord-294651-iy0h2pyf.txt
cache: ./cache/cord-294651-iy0h2pyf.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.jclinepi.2020.06.005
doi: 10.1016/j.jclinepi.2020.06.005
summary:
  Abstract Background There is a pressing need for evidence-based interventions to address the devastating clinical and public health effects of the Coronavirus disease 2019 (COVID-19) pandemic. Randomized control trials (RCTs) are needed to provide unbiased evidence to guide the clinical care and public health practices aimed to control COVID-19 outbreak [16] . We included the following variables for our analysis: study ID, source register unique identifier, original registry, public title, primary sponsor, location (country and region), recruitment status, age range, gender, target size, study design, phase, publication (yes/no, count, and URL), intervention (category, subcategory, and name), primary outcomes, registration date, enrollment date, retrospective label, and trial URL. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. No evidence of clinical efficacy of hydroxychloroquine in patients hospitalized for COVID-19 infection with oxygen requirement: results of a study using routinely collected data to emulate a target trial

title:
  A large number of COVID-19 interventional clinical trials were registered soon after the pandemic onset: a descriptive analysis

abstract:
  Abstract Background There is a pressing need for evidence-based interventions to address the devastating clinical and public health effects of the Coronavirus disease 2019 (COVID-19) pandemic. The number of registered trials related to COVID-19 is increasing by the day. Objectives To describe the characteristics of the currently registered clinical trials related to COVID-19. Methods We searched the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) on May 15, 2020. We included any entry that is related to COVID-19. We abstracted then descriptively analyzed the following characteristics of the registered trials: study design, status, phase, primary endpoints, experimental interventions, and geographic location among other qualifiers. Results We identified 1,308 eligible registered trials. The majority of trials were initially registered with ClinicalTrials.gov (n= 703; 53.7%) and the Chinese Clinical Trial Registry (ChiCTR) (n= 291; 22.2%). The number of participants to be enrolled across these trials was 734,657, with a median of 110 participants per trial. The most-commonly studied intervention category was pharmacologic (n=763; 58.3%), with antiparasitic medications being the most common subcategory. While over half of trials were already recruiting, we identified published peer-reviewed results for only 8 of those trials. Conclusion There is a relatively large number of registered trials but very few results published so far. While our findings suggest an appropriate initial response by the research community, the real challenge will be to get these trials completed, published, and translated into practice and policy.


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-309582-ihrj84hr
title: Medical research during the COVID-19 pandemic
author: AlNaamani, Khalid
date: 2020-08-06
txt: ./txt/cord-309582-ihrj84hr.txt
cache: ./cache/cord-309582-ihrj84hr.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32874970/
doi: 10.12998/wjcc.v8.i15.3156
summary:
  Despite the dedication of enormous resources, the advancement in health care systems and collaboration between different investigators across the world, only a small number of patients over the last decade have in fact benefited from clinical research performed during different outbreaks of respiratory viruses such as was the case for the severe acute respiratory syndrome (SARS), the HIN1 flu virus (swine flu) or the Middle East Respiratory Syndrome. An example of unpublished results that need to be widely acknowledged because of a negative outcome leading to early termination is that of a Brazilian study (CloroCovid19 ) which was a parallel, double-blind, randomized, phase IIb clinical trial, which started on March 23, 2020, aiming to assess safety and efficacy of Chloroquine diphosphate (CQ) in the treatment of hospitalized patients with severe respiratory syndrome secondary to SARS-CoV-2 infection.

abstract:
  The current pandemic of coronavirus disease 2019 (COVID-19) which was first detected in Wuhan, China in December 2019 is caused by the novel coronavirus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The virus has quickly spread to a large number of countries leading to a great number of deaths. Unfortunately, till today there is no specific treatment or vaccination for SARS-CoV-2. Most of the suggested treatment medications are based on in vitro laboratory investigations, experimental animal models, or previous clinical experience in treating similar viruses such as SARS-CoV-1 or other retroviral infections. The running of any clinical trial during a pandemic is affected at multiple levels. Reasons for this include patient hesitancy or inability to continue investigative treatments due to self-isolation/quarantine, or limited access to public places (including hospitals). Additional barriers relate to health care professionals being committed to other critical tasks or quarantining themselves due to contact with COVID-19 positive patients. The best research approaches are those that adapt to such external unplanned obstacles. Ongoing clinical trials before COVID-19 pandemic have the potential for identifying important therapies in the long-term if they can be completed as planned. However, these clinical trials may require modifications due a pandemic such as this one to ensure the rights, safety, and wellbeing of participants as well as medical staff involved in the conduction of clinical trials. Clinical trials initiated during the pandemic must be time-efficient and flexible due to high contagiousness of severe acute respiratory syndrome coronavirus 2, the significant number of reported deaths, and time constraints needed to perform high quality clinical trials, enrolling adequate sample sizes. Collaboration between different countries as well as implementation of innovative clinical trial designs are essential to successfully complete such initiatives during the current pandemic. Studies looking at the long term sequalae of COVID-19 are also of importance as recent publications describe multi-organ involvement. Long term follow-up of COVID-19 survivors is thus also important to identify possible physical and mental health sequellae.


id: cord-310272-utqyuy0n
title: Appropriating Information Technology Artefacts through Trial and Error: The Case of the Tablet
author: Zamani, Efpraxia D.
date: 2020-09-18
url: https://www.ncbi.nlm.nih.gov/pubmed/32982571/
doi: 10.1007/s10796-020-10067-8
abstract:
  The concept of appropriation is of paramount importance for the lasting use of an Information Technology (IT) artefact following its initial adoption, and therefore its success. However, quite often, users’ original expectations are negatively disconfirmed, and instead of appropriating the IT artefact, they discontinue its use. In this study we examine the use of IT artefacts following negative disconfirmation and use Grounded Theory Method techniques to analyse 136 blogposts, collected between March 2011 – July 2017, to investigate how users appropriate or reject the tablet when technology falls short of users’ expectations. Our findings show that users overcome negative disconfirmation through a trial and error process. In doing so, we identify that users appropriate the tablet when the attained benefits significantly outweigh the risks or sacrifices stemming out of its use. We discuss our contribution within the context of the appropriation literature, and highlight that the success of IT lies with the user’s success in identifying personal use scenarios within and across diverse contexts of use.


id: cord-316626-258rbcwb
title: Will Evidence-based Medicine Survive the COVID-19 Pandemic?
author: Serpa Neto, Ary
date: 2020-09-17
txt: ./txt/cord-316626-258rbcwb.txt
cache: ./cache/cord-316626-258rbcwb.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1513/annalsats.202006-587ed
doi: 10.1513/annalsats.202006-587ed
abstract: nan
summary:
  One major challenge during the pandemic is to design clinical trials that can mitigate these concerns and quickly identify effective or harmful interventions to improve patient outcomes. In a pandemic with more than 75,000 new cases per day, the use of a Bayesian adaptive trial design can quickly incorporate existing evidence, drop interventions that have a higher probability of futility, redirect patients to be randomized to the most promising ones, and constantly include new and potential candidate interventions. 1144-1153) (13) describe the study protocol of a randomized, doubleblind, placebo-controlled clinical trial (ORCHID trial) assessing the impact of hydroxychloroquine in hospitalized adults with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) and symptoms of acute respiratory infection. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial Rationale and design of ORCHID: a randomized placebo-controlled clinical trial of hydroxychloroquine for adults hospitalized with COVID-19


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-324607-rpwccvqi
title: Core Minimal Datasets to Advance Clinical Research for Priority Epidemic Diseases
author: Rojek, Amanda M
date: 2020-02-15
txt: ./txt/cord-324607-rpwccvqi.txt
cache: ./cache/cord-324607-rpwccvqi.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1093/cid/ciz760
doi: 10.1093/cid/ciz760
summary:
  Among the noteworthy successes of vaccine trials, and the commendable efforts to implement clinical treatment trials during Ebola outbreaks, we should also focus on strengthening the collection and curation of epidemiological and observational data that can improve the conception and design of clinical research. Table 1 identifies some key domains that could contribute to a core minimal dataset that informs clinical trial design for each priority pathogen. While these data have their most important benefits in improving patient management (through better recognition of disease complications and informing supportive care) and public health control, patient-based data are also used to determine key parameters for clinical trials, such as the inclusion criteria, the nature and rate of clinically relevant outcomes, and potential confounders. A systematic review and meta-analysis of patient data from the west Africa (2013-16) Ebola virus disease epidemic

abstract:
  The Ebola virus disease outbreak in west Africa has prompted significant progress in responding to the clinical needs of patients affected by emerging infectious disease outbreaks. Among the noteworthy successes of vaccine trials, and the commendable efforts to implement clinical treatment trials during Ebola outbreaks, we should also focus on strengthening the collection and curation of epidemiological and observational data that can improve the conception and design of clinical research.


id: cord-326331-g4o3forj
author: Rai, Ansaar T
date: 2020-06-30
txt: ./txt/cord-326331-g4o3forj.txt
cache: ./cache/cord-326331-g4o3forj.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1136/neurintsurg-2020-016502
doi: 10.1136/neurintsurg-2020-016502
summary:
  METHODS: A survey-based study focused on randomized controlled trials (RCTs) and single-arm studies for acute ischemic stroke and cerebral aneurysms was developed by a group of senior neurointerventionalists and sent to sites identified through the clinical trials website (https://clinicaltrials.gov/), study sponsors, and physician investigators. The Food and Drug Administration (FDA) published its guidance on the ''Conduct Of Clinical Trials Of Medical Products During COVID19 Pandemic'' for the industry, investigators, and institutional review boards in March 2020 and updated these on April 2, 2020 (https://www. These were identified by the writing group and fell into four categories: general disruption caused by trial suspensions and missed opportunities of enrollment, compromised trial quality due to inability of timely clinical and imaging follow-up, inability to enroll neurologically debilitated patients because legally authorized representatives were not at hand for face to face consent and dated remote consent procedures did not apply and, finally, personal effect of compensation or working conditions on study staff.

title:
  Neuroendovascular clinical trials disruptions due to COVID-19 potential future challenges and opportunities

abstract:
  To assess the impact of COVID-19 on neurovascular research and deal with the challenges imposed by the pandemic. METHODS: A survey-based study focused on randomized controlled trials (RCTs) and single-arm studies for acute ischemic stroke and cerebral aneurysms was developed by a group of senior neurointerventionalists and sent to sites identified through the clinical trials website (https://clinicaltrials.gov/), study sponsors, and physician investigators. RESULTS: The survey was sent to 101 institutions, with 65 responding (64%). Stroke RCTs were being conducted at 40 (62%) sites, aneurysm RCTs at 22 (34%) sites, stroke single-arm studies at 37 (57%) sites, and aneurysm single-arm studies at 43 (66%) sites. Following COVID-19, enrollment was suspended at 51 (78%) sites—completely at 21 (32%) and partially at 30 (46%) sites. Missed trial-related clinics and imaging follow-ups and protocol deviations were reported by 27 (42%), 24 (37%), and 27 (42%) sites, respectively. Negative reimbursements were reported at 17 (26%) sites. The majority of sites, 49 (75%), had put new trials on hold. Of the coordinators, 41 (63%) worked from home and 20 (31%) reported a personal financial impact. Remote consent was possible for some studies at 34 (52%) sites and for all studies at 5 (8%) sites. At sites with suspended trials (n=51), endovascular treatment without enrollment occurred at 31 (61%) sites for stroke and 23 (45%) sites for aneurysms. A total of 277 patients with acute ischemic stroke and 184 with cerebral aneurysms were treated without consideration for trial enrollment. CONCLUSION: Widespread disruption of neuroendovascular trials occurred because of COVID-19. As sites resume clinical research, steps to mitigate similar challenges in the future should be considered.


id: cord-327738-i400ynjp
author: Milner, Ross
date: 2020-04-27
txt: ./txt/cord-327738-i400ynjp.txt
cache: ./cache/cord-327738-i400ynjp.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1016/j.surg.2020.04.024
doi: 10.1016/j.surg.2020.04.024
summary:
  We discuss here the ethics of clinical trial care within the surgical specialties and the the pros and cons of participation in clinical trial during the COVID-19 pandemic, with a specific focus on surgical oncology and vascular surgery. The current need for social distancing and limitations of health care resources has shifted priorities appropriately, but completely halting clinical trials would hinder dramatically the delopment of novel treatment sand leave patients currently enrolled in these trials without access to potentially life-saving medications. Before continuing to enroll patients in surgical trials, we believe that surgeons must carefully consider the type of trial, the institutional status with respect to scarce resources, and the potential risk/benefit ratio to patients and health care workers involved. Medically-necessary, time-sensitive procedures: A scoring system to ethically and efficiently manage resource scarcity and provider risk during the COVID-19 pandemic

title:
  Is it Ethically Appropriate to Continue Surgical Clinical Trials During the COVID-19 Pandemic? EDITED BY DR SARR

abstract:
  COVID-19 has greatly impacted surgical care and decision-making. The status of surgical clinical trials during this pandemic has not been addressed. We provide a framework and recommendations for the management of patients involved in surgical clinical trials.


id: cord-331133-6zu44fn2
title: Rapid, responsive, relevant (R3) research: a call for a rapid learning health research enterprise
author: Riley, William T
date: 2013-05-10
txt: ./txt/cord-331133-6zu44fn2.txt
cache: ./cache/cord-331133-6zu44fn2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/23663660/
doi: 10.1186/2001-1326-2-10
summary:
  To produce more rapid, responsive, and relevant research, we propose approaches that increase relevance via greater stakeholder involvement, speed research via innovative designs, streamline review processes, and create and/or better leverage research infrastructure. Research infrastructures such as rapid learning systems and other health information technologies can be leveraged to rapidly evaluate new and existing treatments, and alleviate the extensive recruitment delays common in traditional research. What are needed are "rapid-learning research systems" that integrate researchers, funders, health systems, practitioners, and community partners asking clinically relevant questions, using efficient and innovative research designs, and leveraging rich, longitudinal data sets from millions of patients. Broad stakeholder engagement involving patients, providers, health plans, policy makers and other relevant stakeholders may seem counterintuitive as a strategy to speed research, but this time investment has the potential to improve the recruitment and retention of study participants, thus increasing the pace of conducting the study.

abstract:
  Our current health research enterprise is painstakingly slow and cumbersome, and its results seldom translate into practice. The slow pace of health research contributes to findings that are less relevant and potentially even obsolete. To produce more rapid, responsive, and relevant research, we propose approaches that increase relevance via greater stakeholder involvement, speed research via innovative designs, streamline review processes, and create and/or better leverage research infrastructure. Broad stakeholder input integrated throughout the research process can both increase relevance and facilitate study procedures. More flexible and rapid research designs should be considered before defaulting to the traditional two-arm randomized controlled trial (RCT), but even traditional RCTs can be designed for more rapid findings. Review processes for grant applications, IRB protocols, and manuscript submissions can be better streamlined to minimize delays. Research infrastructures such as rapid learning systems and other health information technologies can be leveraged to rapidly evaluate new and existing treatments, and alleviate the extensive recruitment delays common in traditional research. These and other approaches are feasible but require a culture shift among the research community to value not only methodological rigor, but also the pace and relevance of research.


id: cord-331206-m938suxh
title: Missing clinical trial data: the knowledge gap in the safety of potential COVID-19 drugs
author: Rodgers, F.
date: 2020-06-03
txt: ./txt/cord-331206-m938suxh.txt
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mime: text/plain
url: https://doi.org/10.1101/2020.05.30.20117523
doi: 10.1101/2020.05.30.20117523
summary:
  However, availability of safety information is limited by a lack of timely reporting of clinical trial results on public registries or through academic publication. We aimed to analyse the knowledge gap in safety data by quantifying the number of missing clinical trial results for drugs potentially being repurposed for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for timely result reporting (within 395 days of the primary completion date). We reviewed the number of completed or terminated trials that have not reported results for an extensive, list of medications being repurposed for COVID-19, looking at all previous indications for these drugs. . https://doi.org/10.1101/2020.05.30.20117523 doi: medRxiv preprint Discussion 40.4% of the completed clinical trials for drugs that may be repurposed for COVID-19 were not found to report results on either ClinicalTrials.gov or through academic publication (Table 2 ).

abstract:
  Abstract (290/300 words) Objectives: Several drugs are being repurposed for the treatment of the coronavirus disease 2019 (COVID-19) pandemic based on in vitro or early clinical findings. As these drugs are being used in varied regimens and dosages, it is important to enable synthesis of existing safety data from clinical trials. However, availability of safety information is limited by a lack of timely reporting of clinical trial results on public registries or through academic publication. We aimed to analyse the knowledge gap in safety data by quantifying the number of missing clinical trial results for drugs potentially being repurposed for COVID-19. Design: ClinicalTrials.gov was searched for 19 drugs that have been identified as potential treatments for COVID-19. Relevant clinical trials for any prior indication were listed by identifier (NCT number) and checked for timely result reporting (within 395 days of the primary completion date). Additionally, PubMed and Google Scholar were searched using the NCT number to identify publications of results not listed on the registry. A second, blinded search of 10% of trials was conducted to assess reviewer concordance. Results: Of 3754 completed trials, 1516 (40.4%) did not post results on ClinicalTrials.gov or in the academic literature. 1172 (31.2%) completed trials had tabular results on ClinicalTrials.gov. A further 1066 (28.4%) completed trials had results from the literature search, but did not report results on ClinicalTrials.gov. Key drugs missing clinical trial results include hydroxychloroquine (37.0% completed trials unreported), favipiravir (77.8%) and lopinavir (40.5%). Conclusion: There is an important evidence gap for the safety of drugs being repurposed for COVID-19. This uncertainty could cause a large burden of additional morbidity and mortality during the pandemic. We recommend caution in experimental drug use for non-severe disease and urge clinical trial sponsors to report missing results retrospectively.


id: cord-331487-jh34klbg
author: Sivapalan, Pradeesh
date: 2020-06-10
txt: ./txt/cord-331487-jh34klbg.txt
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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-334433-oudvxb4d
title: Conducting Clinical Trials in the Time of a Pandemic
author: Beane, Joal D.
date: 2020-06-08
txt: ./txt/cord-334433-oudvxb4d.txt
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mime: text/plain
url: https://doi.org/10.1097/sla.0000000000004114
doi: 10.1097/sla.0000000000004114
abstract: nan
summary:
  Responses to mitigate the effects of the pandemichave included: 1) thedevelopment of strategies to support research programs during unforeseen economic loss, 2)establishment of institutionalguidelines for clinical trials, 3)measures to ensure a healthy clinical research team, 4) useof innovative technologies to maintain access to clinical trials, 5) amendment of protocols to avoid costly trial closures, and 6) the strategic reopening of suspended clinical trials. Efforts to modify protocols in order to comply with the emergency public health response and the guidelines established by the FDA and IRBareencouraged.Investigators need to prioritize collection of data, focusing on the primary endpoint and important secondary endpoints to remain in compliance.Clinical protocols should be reexamined thoroughly and amendments should be made to reduce superfluous clinical visits.While many protocol changes typically required an amendment and lengthy review process, to avoid costly delays, reviews of amendments at our institution are being waived or expedited if the adjustment pertains to patient safety in the setting of COVID-19.


id: cord-334667-0cah15lg
author: Arabi, Yaseen M.
date: 2020-01-03
txt: ./txt/cord-334667-0cah15lg.txt
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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-335198-qp964238
title: Pandemic Treatments on Trial: The bigger picture
author: Kotsimbos, T.
date: 2020-08-03
txt: ./txt/cord-335198-qp964238.txt
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extension: .txt
mime: text/plain
url: https://doi.org/10.1183/13993003.02281-2020
doi: 10.1183/13993003.02281-2020
summary:
  Given the stated extremes above, there is a clear trade-off between "doing all that one can for individual patients with currently available information in a timely manner and despite significant uncertainty" and "group treatment of individuals to be enrolled in properly conducted but costly (effort, time and money) clinical trials for specific therapeutic approaches that will help inform the evidence-base for future patients". And how do we quickly establish and conduct difficult and costly randomized, controlled clinical trials for the most promising old and new therapies where there is a clear equipoise between possible benefits and potential risks? Paradoxically, the almost immediate establishment of a well-designed RCT to test the combination antiviral treatment lopinavir-ritonavir in Wuhan, China during the beginning of the pandemic exemplified this tension in a most unusual way when trial recruitment ceased early due to falling COVID19 case numbers (7).

abstract:
  The tension between immediately using any potentially useful novel therapy in COVID19 and trialling all novel therapies as rigorously as possible is addressed from a bigger picture perspective.


id: cord-338588-rc1h4drd
title: Seven decades of chemotherapy clinical trials: a pan-cancer social network analysis
author: Li, Xuanyi
date: 2020-10-16
txt: ./txt/cord-338588-rc1h4drd.txt
cache: ./cache/cord-338588-rc1h4drd.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33067482/
doi: 10.1038/s41598-020-73466-6
summary:
  Seminal events (Fig. 1C) are likely a driver of preferential attachment 35 , and may The network is overwhelmingly dominated by men until 1980, when a trend towards increasing authorship by women begins to be seen; however, representation by women in first/last authorship remains low; gray shaded lines are 95% confidence intervals of the LOESS curves; (B) Men tend on average to have a longer productive period and to achieve a higher author impact score than women (P < 0.001 for both comparisons); (C) Men tend on average to be more central and have more collaborations outside of their subspecialty. While there is much to be applauded in the continued success of translating research findings into the clinic, we observed clear gender disparities within the cancer clinical trialist network: women have a statistically significantly lower final impact score, shorter productive period, less centrality, and less collaboration with those outside of their primary subspecialty.

abstract:
  Clinical trials establish the standard of cancer care, yet the evolution and characteristics of the social dynamics between the people conducting this work remain understudied. We performed a social network analysis of authors publishing chemotherapy-based prospective trials from 1946 to 2018 to understand how social influences, including the role of gender, have influenced the growth and development of this network, which has expanded exponentially from fewer than 50 authors in 1946 to 29,197 in 2018. While 99.4% of authors were directly or indirectly connected by 2018, our results indicate a tendency to predominantly connect with others in the same or similar fields, as well as an increasing disparity in author impact and number of connections. Scale-free effects were evident, with small numbers of individuals having disproportionate impact. Women were under-represented and likelier to have lower impact, shorter productive periods (P < 0.001 for both comparisons), less centrality, and a greater proportion of co-authors in their same subspecialty. The past 30 years were characterized by a trend towards increased authorship by women, with new author parity anticipated in 2032. The network of cancer clinical trialists is best characterized as strategic or mixed-motive, with cooperative and competitive elements influencing its appearance. Network effects such as low centrality, which may limit access to high-profile individuals, likely contribute to the observed disparities.


id: cord-344491-93ggxzxu
author: Husebo, Bettina Sandgathe
date: 2020-06-09
txt: ./txt/cord-344491-93ggxzxu.txt
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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-344705-co0nk7pt
title: Clinical trials for Covid‐19: can we better use the short window of opportunity?
author: Eichler, Hans‐Georg
date: 2020-05-14
txt: ./txt/cord-344705-co0nk7pt.txt
cache: ./cache/cord-344705-co0nk7pt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32407539/
doi: 10.1002/cpt.1891
summary:
  We here discuss actions that all stakeholders in the clinical trial ecosystem need to take to ensure that the window of opportunity during this pandemic will not shut, both for patients in need of treatment and for researchers to conduct decision‐relevant clinical trials. Many small stand-alone trials and observational studies of single-agent interventions are currently running or in planning; many of these will likely not deliver robust results that could support regulatory and patient-level treatment decisions. We here discuss actions that all stakeholders in the clinical trial ecosystem need to take to ensure that the window of opportunity during this pandemic will not shut, both for patients in need of treatment and for researchers to conduct decision-relevant clinical trials. Now is the time to ensure that the window of opportunity will not shut, both for patients in need of treatment and for researchers to conduct clinical trials that deliver.

abstract:
  The scientific community has risen to the Covid‐19 challenge, coming up with an impressive list of candidate drugs and vaccines targeting an array of pharmacological and immunological mechanisms. Yet, generating clinical evidence of efficacy and safety of these candidate treatments may be frustrated by the absence of comprehensive trial coordination mechanisms. Many small stand‐alone trials and observational studies of single‐agent interventions are currently running or in planning; many of these will likely not deliver robust results that could support regulatory and patient‐level treatment decisions. We here discuss actions that all stakeholders in the clinical trial ecosystem need to take to ensure that the window of opportunity during this pandemic will not shut, both for patients in need of treatment and for researchers to conduct decision‐relevant clinical trials.


id: cord-345095-1li57v0j
title: Clinical Research in the Time of COVID-19
author: Felix, Carol
date: 2020-10-01
txt: ./txt/cord-345095-1li57v0j.txt
cache: ./cache/cord-345095-1li57v0j.txt
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mime: text/plain
url: https://www.sciencedirect.com/science/article/pii/S0360301620313468
doi: 10.1016/j.ijrobp.2020.06.059
abstract: nan
summary:
  The need for clinical trials, the improved treatments they elucidate, and the US Food and Drug Administration (FDA) approval providing public access to these new and better treatments will remain. The pandemic does not end medical research, and it may, in fact, point us in a new and better direction for implementing clinical trials. 1 Academic institutions will do robust research again, and those institutions most prepared to pick up research at prepandemic levels will be those that follow FDA guidelines to facilitate and continue running clinical trials even during the spread of COVID-19. So, how do we run clinical trials in the time of COVID-19? Until a vaccine is developed, and likely even after that if COVID-19 becomes a seasonal norm, we will have to weigh the risks and benefits of everything we do, including medical visits and research appointments. FDA Guidance on conduct of clinical trials of medical products during COVID-19 public health emergency: guidance for industry, investigators, and institutional review boards


id: cord-345762-khvcoqti
title: COVID‐19 pandemic and the tension between the need to act and the need to know
author: Scott, Ian A.
date: 2020-08-06
txt: ./txt/cord-345762-khvcoqti.txt
cache: ./cache/cord-345762-khvcoqti.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1111/imj.14929
doi: 10.1111/imj.14929
abstract: nan
summary:
  The false promise of rushed science A pandemic as serious as COVID-19 will compel some clinicians and patients to try unproven therapies based on theory, in vitro data, animal models, clinical anecdotes, observational studies and uncontrolled trials that may later be shown to be misleading. Hopefully, the same problems will not occur with remdesivir, whichdespite limited and conflicting evidence of clinical improvement from only two placebo-controlled RCT 19, 20 and one non-controlled cohort study 5has now become a ''standard of care'' in the United States for COVID-19 patients with severe pneumonia. Separating out these effects, and determining which drugs to use and when (early in the disease course or only at deterioration), will likely require large-scale trials with multiple treatment arms that are sufficiently powered to enable analyses of primary and, where indicated, secondary outcomes across different patient subgroups.


id: cord-346842-ip4i3bdk
title: The Impact of COVID-19 on the Conduct of Clinical Trials for Medical Products in Korea
author: Jeon, JuYeun
date: 2020-09-07
txt: ./txt/cord-346842-ip4i3bdk.txt
cache: ./cache/cord-346842-ip4i3bdk.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.3346/jkms.2020.35.e329
doi: 10.3346/jkms.2020.35.e329
summary:
  METHODS: The impact on subject''s scheduled visits and major milestones of clinical trials in Korea were measured by conducting a survey among clinical project manager (CPMs) working at global clinical research organization. New approaches were necessary in clinical trials to eliminate the risk of infection by complying with the guideline and enable subjects to continue to participate in trials if no better alternative treatment options were available, for protecting the subjects'' safety and well-being. The study evaluated the impact of the COVID-19 epidemic and the KCDC disease control guideline on the conduct of clinical research in Korea, on subjects, investigators, monitor, pharmaceutical companies, Institutional Review Boards (IRBs) and regulatory authorities (RAs), in order to suggest recommendations for conducting clinical trials during the pandemic. The survey was distributed to total 140 clinical project manager (CPMs) who were working at global clinical research organization and responsible for trials performed in Korea, according to method of simple random sampling from February 24, 2020 to March 7, 2020.

abstract:
  BACKGROUND: The number of clinical trials conducted in Korea continues to increase and an increasing proportion focus on severe and rare incurable diseases. After the start of the severe acute respiratory syndrome, coronavirus disease 2019 (COVID-19), Korea Centers for Disease Control and Prevention (KCDC) developed guidelines to prevent the spread of infection. This study evaluated the impact of COVID-19 and the KCDC guideline on the conduct of clinical research in Korea. The purpose was to develop recommendations on how to minimize the risk of infection while enabling subjects to take part in the trials if no better alternative treatment options were available. METHODS: The impact on subject's scheduled visits and major milestones of clinical trials in Korea were measured by conducting a survey among clinical project manager (CPMs) working at global clinical research organization. The policy on monitor's access to hospital and site initiation meetings was investigated through correspondence with clinical trial center of 39 hospitals. The Top 25 pharmaceutical companies' official press and public clinical trial registry database were used to analyze companies' trial strategy during the pandemic and COVID-19 clinical research status, respectively. RESULTS: Of 85 CPMs, 12% reported that trial subjects' scheduled visits had been affected in their project. Monitors' access to hospital for source data verification was restricted at all sites in February 2020. Accordingly, 43% of 105 CPMs reported that the COVID-19 epidemic had an effect on study major milestones and data cleaning and database lock accounted for > 60% of milestones affected. In addition, 87% sites advised not to have site initiation meetings and 52% pharmaceutical companies suspended recruitment or new study start-up due to the pandemic. On the other hands, the number of COVID-19 related clinical trials increased rapidly in Korea and worldwide, with investigator-initiated trials accounting for 47% and 63% of all trials locally and globally, respectively. Most trials were phase 2 and were in the recruitment stage. CONCLUSION: The COVID-19 and the KCDC guideline influenced all parties involved in clinical trials in Korea. In order to ensure the safety and well-being of trial subjects during the pandemic, new approaches are required for clinical trials to respond to the impact actively. Method of non-contact is developed to replace and supplement the face-to-face contact and alternatives to reduce the travel is introduced to decrease the risk of infection for all trial participants in whole trial process. The relevant regulations should be developed and the guidelines for foreign countries need to be adopted in accordance with the situation in Korea. COVID-19 trial is rapidly increasing worldwide and continuous support of health authorities, regulation, and facilities is required for developing the treatments with protecting all trial participants.


id: cord-347189-i9rzo3j0
title: Clinical research disruption in the post-COVID-19 era: will the pandemic lead to change?
author: Lorusso, Domenica
date: 2020-10-13
txt: ./txt/cord-347189-i9rzo3j0.txt
cache: ./cache/cord-347189-i9rzo3j0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33051193/
doi: 10.1136/esmoopen-2020-000924
abstract: nan
summary:
  The COVID-19 pandemic suggests that it is possible to alleviate redundancy in clinical trials, and while preserving the rigour of a study, can offer a new, less burdened and more inclusive vision of clinical research for the scientific community of tomorrow. Data from China reported that patients with cancer who are infected with COVID-19 are at 3.5 times the risk of requiring mechanical ventilation or intensive care unit (ICU) admission, compared with the general population. 4 Although conversion to telemedicine has maintained the continuity of care for many patients, the COVID-19 pandemic has massively disrupted clinical research and many cancer centres halted clinical trial activities including patient recruitment. COVID-19 has pointed out that sometimes, high level of bureaucracy in research rules place unnecessary burdens on patients and clinicians and it suggests that it is time to alleviate bureaucracy and introduce some practical changes into research organisation that will possibly promote patient access to trials and reduce the costs of the clinical research.


id: cord-348244-1py0k53e
title: Central statistical monitoring of investigator-led clinical trials in oncology
author: Buyse, Marc
date: 2020-06-23
txt: ./txt/cord-348244-1py0k53e.txt
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url: https://doi.org/10.1007/s10147-020-01726-6
doi: 10.1007/s10147-020-01726-6
summary:
  We describe the principles of central statistical monitoring, provide examples of its use, and argue that it could help drive down the cost of randomized clinical trials, especially investigator-led trials, whilst improving their quality. Yet, there is no evidence showing that extensive data monitoring has any major impact on the quality of clinical-trial data, and none of the randomized studies assessing more intensive versus less intensive monitoring has shown any difference in terms of clinically relevant treatment outcomes [18] [19] [20] [21] [22] . Both types of trials may benefit from central statistical monitoring of the data; industry-sponsored trials to target centers that are detected as having potential data quality issues, which may require an on-site audit, and investigatorled trials as the primary method for checking data quality. An evidence-based study of the cost for data monitoring in clinical trials A statistical approach to central monitoring of data quality in clinical trials

abstract:
  Investigator-led clinical trials are pragmatic trials that aim to investigate the benefits and harms of treatments in routine clinical practice. These much-needed trials represent the majority of all trials currently conducted. They are however threatened by the rising costs of clinical research, which are in part due to extensive trial monitoring processes that focus on unimportant details. Risk-based quality management focuses, instead, on “things that really matter”. We discuss the role of central statistical monitoring as part of risk-based quality management. We describe the principles of central statistical monitoring, provide examples of its use, and argue that it could help drive down the cost of randomized clinical trials, especially investigator-led trials, whilst improving their quality.


id: cord-348306-e8hdx4u2
author: Li, Jie
date: 2020-07-24
txt: ./txt/cord-348306-e8hdx4u2.txt
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url: https://doi.org/10.1016/j.jcrc.2020.07.020
doi: 10.1016/j.jcrc.2020.07.020
summary:
  title: Meta-trial of awake prone positioning with nasal high flow therapy: Invitation to join a pandemic collaborative research effort We take the example of such a meta-trial, set up to investigate prone positioning among awake patients undergoing nasal high flow therapy and invite journal readers to join this collaborative research effort.  A meta-trial, with harmonized inclusion and outcome criteria and a global interim analysis plan, may enable to get a high level of evidence within the short period of time required by the pandemic, through performing a prospective meta-analysis of the generated data across countries.  A meta-trial, with harmonized inclusion and outcome criteria and a global interim analysis plan, may enable to get a high level of evidence within the short period of time required by the pandemic, through performing a prospective meta-analysis of the generated data across countries.

title:
  Meta-trial of awake prone positioning with nasal high flow therapy: Invitation to join a pandemic collaborative research effort

abstract:
  • Awake prone positioning is a promising intervention to improve patient's oxygenation and likely to reduce the need for intubation. Despite reports of its use during the COVID-19 pandemic, controlled evidence is lacking. • A meta-trial, with harmonized inclusion and outcome criteria and a global interim analysis plan, may enable to get a high level of evidence within the short period of time required by the pandemic, through performing a prospective meta-analysis of the generated data across countries. • Clinicians and researchers around the world are invited to join the “Meta-trial of awake prone positioning with nasal high flow therapy” project by contacting the core investigator group: Awake.Prone.Meta.Trial@gmail.com.


id: cord-350062-6xsh2pis
author: Juul, Sophie
date: 2020-09-17
txt: ./txt/cord-350062-6xsh2pis.txt
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mime: text/plain
url: https://doi.org/10.1371/journal.pmed.1003293
doi: 10.1371/journal.pmed.1003293
summary:
  Meta-analyses and trial sequential analyses showed that we could exclude the possibility that hydroxychloroquine versus standard care reduced the risk of all-cause mortality (RR 1.07; 95% CI 0.97–1.19; p = 0.17; I(2) = 0%; 7 trials; low certainty) and serious adverse events (RR 1.07; 95% CI 0.96–1.18; p = 0.21; I(2) = 0%; 7 trials; low certainty) by 20% or more, and meta-analysis showed evidence of a harmful effect on nonserious adverse events (RR 2.40; 95% CI 2.01–2.87; p < 0.00001; I(2) = 90%; 6 trials; very low certainty). Random-effects meta-analysis showed no evidence of a difference between lopinavir-ritonavir versus standard care on serious adverse events (RR 0.64; 95% CI 0.39-1.04; p = 0.07, I 2 = 0%; 2 trials; very low certainty) (S10 Fig, S7 Table) . Random-effects meta-analysis showed no evidence of a difference between lopinavir-ritonavir versus standard care on adverse events not considered as serious (RR 1.14; 95% CI 0.85-1.53; p = 0.38, I 2 = 75%; 2 trials; very low certainty) (S12 Fig; S7 Table) .

title:
  Interventions for treatment of COVID-19: A living systematic review with meta-analyses and trial sequential analyses (The LIVING Project)

abstract:
  BACKGROUND: Coronavirus disease 2019 (COVID-19) is a rapidly spreading disease that has caused extensive burden to individuals, families, countries, and the world. Effective treatments of COVID-19 are urgently needed. METHODS AND FINDINGS: This is the first edition of a living systematic review of randomized clinical trials comparing the effects of all treatment interventions for participants in all age groups with COVID-19. We planned to conduct aggregate data meta-analyses, trial sequential analyses, network meta-analysis, and individual patient data meta-analyses. Our systematic review is based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Cochrane guidelines, and our 8-step procedure for better validation of clinical significance of meta-analysis results. We performed both fixed-effect and random-effects meta-analyses. Primary outcomes were all-cause mortality and serious adverse events. Secondary outcomes were admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and nonserious adverse events. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. We searched relevant databases and websites for published and unpublished trials until August 7, 2020. Two reviewers independently extracted data and assessed trial methodology. We included 33 randomized clinical trials enrolling a total of 13,312 participants. All trials were at overall high risk of bias. We identified one trial randomizing 6,425 participants to dexamethasone versus standard care. This trial showed evidence of a beneficial effect of dexamethasone on all-cause mortality (rate ratio 0.83; 95% confidence interval [CI] 0.75–0.93; p < 0.001; low certainty) and on mechanical ventilation (risk ratio [RR] 0.77; 95% CI 0.62–0.95; p = 0.021; low certainty). It was possible to perform meta-analysis of 10 comparisons. Meta-analysis showed no evidence of a difference between remdesivir versus placebo on all-cause mortality (RR 0.74; 95% CI 0.40–1.37; p = 0.34, I(2) = 58%; 2 trials; very low certainty) or nonserious adverse events (RR 0.94; 95% CI 0.80–1.11; p = 0.48, I(2) = 29%; 2 trials; low certainty). Meta-analysis showed evidence of a beneficial effect of remdesivir versus placebo on serious adverse events (RR 0.77; 95% CI 0.63–0.94; p = 0.009, I(2) = 0%; 2 trials; very low certainty) mainly driven by respiratory failure in one trial. Meta-analyses and trial sequential analyses showed that we could exclude the possibility that hydroxychloroquine versus standard care reduced the risk of all-cause mortality (RR 1.07; 95% CI 0.97–1.19; p = 0.17; I(2) = 0%; 7 trials; low certainty) and serious adverse events (RR 1.07; 95% CI 0.96–1.18; p = 0.21; I(2) = 0%; 7 trials; low certainty) by 20% or more, and meta-analysis showed evidence of a harmful effect on nonserious adverse events (RR 2.40; 95% CI 2.01–2.87; p < 0.00001; I(2) = 90%; 6 trials; very low certainty). Meta-analysis showed no evidence of a difference between lopinavir–ritonavir versus standard care on serious adverse events (RR 0.64; 95% CI 0.39–1.04; p = 0.07, I(2) = 0%; 2 trials; very low certainty) or nonserious adverse events (RR 1.14; 95% CI 0.85–1.53; p = 0.38, I(2) = 75%; 2 trials; very low certainty). Meta-analysis showed no evidence of a difference between convalescent plasma versus standard care on all-cause mortality (RR 0.60; 95% CI 0.33–1.10; p = 0.10, I(2) = 0%; 2 trials; very low certainty). Five single trials showed statistically significant results but were underpowered to confirm or reject realistic intervention effects. None of the remaining trials showed evidence of a difference on our predefined outcomes. Because of the lack of relevant data, it was not possible to perform other meta-analyses, network meta-analysis, or individual patient data meta-analyses. The main limitation of this living review is the paucity of data currently available. Furthermore, the included trials were all at risks of systematic errors and random errors. CONCLUSIONS: Our results show that dexamethasone and remdesivir might be beneficial for COVID-19 patients, but the certainty of the evidence was low to very low, so more trials are needed. We can exclude the possibility of hydroxychloroquine versus standard care reducing the risk of death and serious adverse events by 20% or more. Otherwise, no evidence-based treatment for COVID-19 currently exists. This review will continuously inform best practice in treatment and clinical research of COVID-19.


id: cord-352177-05sku8a8
author: Pahus, Laurie
date: 2020-08-13
txt: ./txt/cord-352177-05sku8a8.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32791969/
doi: 10.1186/s12910-020-00509-y
summary:
  To additionally explain patient willingness to participate in new-drug studies or research associated with pharmaceutical companies or with public institutions, further models used the same predictive variables as for the first model, plus distrustgroup-membership as an additional explanatory variable. Our study aimed at evaluating variables associated with patient willingness to participate in different categories of clinical trials and at identifying a potential recruitment bias in clinical trials related to patient distrust in the pharmaceutical industry and healthcare systems. Several studies have previously evaluated such rates and highlighted that altruism, hope for personal benefit, contribution to advances in science as well as financial benefit are the main reasons for agreeing to participate, whereas fear of adverse events, impossibility to cope with the logistic constraints accompanying participation, poor knowledge about or negative perception of clinical trials and distrust in pharmaceutical industry are potential barriers [20] [21] [22] [23] . Distrust in pharmaceutical companies is associated with a specific patient profile and with refusal to participate in pre-marketing industry-sponsored drug trials.

title:
  Patient distrust in pharmaceutical companies: an explanation for women under-representation in respiratory clinical trials?

abstract:
  BACKGROUND: Patient skepticism concerning medical innovations can have major consequences for current public health and may threaten future progress, which greatly relies on clinical research. The primary objective of this study is to determine the variables associated with patient acceptation or refusal to participate in clinical research. Specifically, we sought to evaluate if distrust in pharmaceutical companies and associated psychosocial factors could represent a recruitment bias in clinical trials and thus threaten the applicability of their results. METHODS: This prospective, multicenter survey consisted in the administration of a self-questionnaire to patients during a pulmonology consultation. The 1025 questionnaires distributed collected demographics, socio-professional and basic health literacy characteristics. Patients were asked to rank their level of trust for pharmaceutical companies and indicate their willingness to participate in different categories of research (pre or post marketing, sponsored by an academic institution or pharmaceutical company). Logistic regression was used to determine factors contributing to “trust” versus “distrust” group membership and willingness to participate in each category of research. RESULTS: One thousand patients completed the survey, corresponding to a response rate of 97.5%. Data from 838 patients were analyzed in this study. 48.3% of respondents declared that they trusted pharmaceutical companies, while 35.5% declared distrust. Being female (p = 0.042), inactive in the employment market(p = 0.007), and not-knowing the name of one’s disease(p = 0.010) are factors related to declared distrust. Distrust-group membership is associated with unwillingness to participate in certain categories of trials such as pre-marketing and industry-sponsored trials. CONCLUSION: Distrust in pharmaceutical companies is associated with a specific patient profile and with refusal to participate in certain subcategories of trials. This potential recruitment bias may explain the under-representation of certain categories of patients such as women in pre-marketing drug trials.


id: cord-356040-qdpkidn8
author: Ghazawi, Feras M.
date: 2020-07-03
txt: ./txt/cord-356040-qdpkidn8.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32621284/
doi: 10.1111/ijd.15028
summary:
  Recommendations were made recently to limit or stop the use of oral and systemic immunotherapies for skin diseases due to potential risks to the patients during the current severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) COVID‐19 pandemic. We performed a literature review to approximate the risk of SARS‐CoV‐2 infection, including available data on the roles of relevant cytokines, cell subsets, and their mediators in eliciting an optimal immune response against respiratory viruses in murine gene deletion models and humans with congenital deficiencies were reviewed for viral infections risk and if possible coronaviruses specifically. A randomized, open-label, controlled trial for the efficacy and safety of Adalimumab Injection in the treatment of patients with severe novel coronavirus pneumonia (COVID-19) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2)

title:
  Infection risk of dermatologic therapeutics during the COVID‐19 pandemic: an evidence‐based recalibration

abstract:
  Recommendations were made recently to limit or stop the use of oral and systemic immunotherapies for skin diseases due to potential risks to the patients during the current severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) COVID‐19 pandemic. Herein, we attempt to identify potentially safe immunotherapies that may be used in the treatment of cutaneous diseases during the current COVID‐19 pandemic. We performed a literature review to approximate the risk of SARS‐CoV‐2 infection, including available data on the roles of relevant cytokines, cell subsets, and their mediators in eliciting an optimal immune response against respiratory viruses in murine gene deletion models and humans with congenital deficiencies were reviewed for viral infections risk and if possible coronaviruses specifically. Furthermore, reported risk of infections of biologic and non‐biologic therapeutics for skin diseases from clinical trials and drug data registries were evaluated. Many of the immunotherapies used in dermatology have data to support their safe use during the COVID‐19 pandemic including the biologics that target IgE, IL‐4/13, TNF‐α, IL‐17, IL‐12, and IL‐23. Furthermore, we provide evidence to show that oral immunosuppressive medications such as methotrexate and cyclosporine do not significantly increase the risk to patients. Most biologic and conventional immunotherapies, based on doses and indications in dermatology, do not appear to increase risk of viral susceptibility and are most likely safe for use during the COVID‐19 pandemic. The limitation of this study is availability of data on COVID‐19.


