key: cord-0802004-6lmhbla9
authors: ADER, F.; PEIFFER-SMADJA, N.; POISSY, J.; BOUSCAMBERT-DUCHAMP, M.; BELHADI, D.; DIALLO, A.; DELMAS, C.; SAILLARD, J.; DECHANET, A.; MERCIER, N.; DUPONT, A.; ALFAIATE, T.; LESCURE, F.-X.; RAFFI, F.; GOEHRINGER, F.; KIMMOUN, A.; JAUREGUIBERRY, S.; REIGNIER, J.; NSEIR, S.; DANION, F.; CLERE-JEHL, R.; BOUILLER, K.; NAVELLOU, J.-C.; TOLSMA, V.; CABIE, A.; DUBOST, C.; COURJON, J.; LEROY, S.; MOOTIEN, J.; GACI, R.; MOURVILLIER, B.; FAURE, E.; POURCHER, V.; GALLIEN, S.; LAUNAY, O.; LACOMBE, K.; LANOIX, J.-P.; MAKINSON, A.; MARTIN-BLONDEL, G.; BOUADMA, L.; BOTELHO-NEVERS, e.; GAGNEUX-BRUNON, A.; EPAULA,
title: Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial
date: 2021-01-09
journal: nan
DOI: 10.1101/2021.01.08.20248149
sha: af1dfdf13198f7bcced3e8583af2a126266a5620
doc_id: 802004
cord_uid: 6lmhbla9

Background: Lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-beta-1a and hydroxychloroquine efficacy for COVID-19 have been evaluated, but detailed evaluation is lacking. Objective: To determine the efficacy of lopinavir/ritonavir, lopinavir/ritonavir-IFN-beta-1a, hydroxychloroquine or remdesivir for improving the clinical, virological outcomes in COVID-19 inpatients. Design: Open-label, randomized, adaptive, controlled trial. Setting: Multi-center trial with patients from France. Participants: 583 COVID-19 inpatients requiring oxygen and/or ventilatory support Intervention: Standard of care (SoC, control), SoC plus lopinavir/ritonavir (400 mg lopinavir and 100 mg ritonavir every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-beta-1a (44 micrograms of subcutaneous IFN-beta-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (400 mg twice on day 1 then 400 mg once daily for 9 days) or SoC plus remdesivir (200 mg intravenously on day 1 then 100 mg once-daily for hospitalization duration or 10 days). Measurements: The primary outcome was the clinical status at day 15, measured by the WHO 7-point ordinal scale. Secondary outcomes included SARS-CoV-2 quantification in respiratory specimens and safety analyses. Results: Adjusted Odds Ratio (aOR) for the WHO 7-point ordinal scale were not in favor of investigational treatments: lopinavir/ritonavir versus control, aOR 0.83, 95%CI, 0.55 to 1.26, P=0.39; lopinavir/ritonavir-IFN-beta-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced. Lopinavir/ritonavir-containing treatments were significantly associated with more SAE. Limitations: Not a placebo-controlled, no anti-inflammatory agents tested. Conclusion: No improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings. Registration: NCT04315948. Funding: PHRC 2020, Dim OneHealth, REACTing

P=0.39; lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69, 95%CI, 0.45 to 1.04, P=0.08; hydroxychloroquine versus control, aOR 0.93, 95%CI, 0.62 to 1.41, P=0.75. No significant effect on SARS-CoV-2 RNA clearance in respiratory tract was evidenced.

Lopinavir/ritonavir-containing treatments were significantly associated with more SAE.

Limitations: Not a placebo-controlled, no anti-inflammatory agents tested.

No improvement of the clinical status at day 15 nor SARS-CoV-2 RNA clearance in respiratory tract specimens by studied drugs. This comforts the recent Solidarity findings.

Funding: PHRC 2020, Dim OneHealth, REACTing . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ;

The new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated coronavirus disease 2019 (COVID- 19) emerged in China in December 2019, subsequently causing a worldwide pandemic (1, 2) .

While waiting for specific therapeutic treatments and/or vaccines against SARS-CoV-2, efforts initially focused on repurposing drugs that have previously shown broad-spectrum antiviral activity against other coronaviruses. Lopinavir/ritonavir, type I interferon (IFN), hydroxychloroquine, and remdesivir were among the first investigational treatments to be tested on the basis of their in vitro activity against SARS-CoV-2 (3) (4) (5) (6) (7) (8) (9) . Activity of combined anti-HIV agent lopinavir/ritonavir against novel coronaviruses occurs via inhibition of 3chymotrypsin-like protease-dependent proteolysis preventing cleavage into viral proteins (3, 4) . Activity of hydroxychloroquine occurs via affecting early stage of viral replication through increased endosomal pH resulting in inhibition of virus-endosome fusion(7-9). Activity of type I IFN is mediated by the heightening of antiviral cellular immune defenses(10). In addition, it was hypothesized that hydroxychloroquine and type I IFN may have intrinsic immunomodulatory effects(10-12). Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and results in pre-mature termination(13).

The DisCoVeRy trial is a phase 3 multicenter, open-label, randomized, adaptive, controlled trial to evaluate the clinical and the virological efficacy, as well as the safety, of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a, hydroxychloroquine, and remdesivir as compared with standard of care in adults hospitalized for COVID-19 (14) . The DisCoVeRy trial is part of the international Solidarity trial consortium sponsored by the World Health Organization (WHO). Interim results of the Solidarity trial were recently published. They were restricted to the analysis of in-hospital mortality, need for mechanical ventilation and time to hospital discharge. No treatment exhibited a significant effect on these critical . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.08.20248149 doi: medRxiv preprint outcomes when compared to standard of care (15) . The DisCoVeRy trial provides more detailed data on safety and clinical and laboratory surrogates, in particular virological data.

We report here the results from the lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine arms, which were prematurely stopped. The remdesivir arm is continuing and currently enrolling.

DisCoVeRy is an open-label, adaptive, multicenter, randomized controlled trial which evaluates the efficacy and safety of drugs in adults hospitalized for COVID-19.

Sponsored by the Institut national de la santé et de la recherche médicale (Inserm, France), the trial was approved by the Ethics Committee (CPP Ile-de-France-III, approval #20.03.06.51744). Written informed consent was obtained from all included participants or their legal representative if they were not able to consent. The trial was conducted in accordance with the Declaration of Helsinki and national laws and regulations and declared on the clinicatrials.gov registry (NCT 04315948) and on the European Clinical Trials Database (2020-000936-23). The present analysis is based on the protocol v7.0 of April, 5 th 2020, (14) with two secondary outcomes added in protocol v9.0 of June, 29 th 2020.

Eligible participants were adults (≥ 18-year old) hospitalized with a PCR-proven (< 72 hours) SARS-CoV-2 infection and pulmonary rales or crackles with a peripheral oxygen saturation ≤ 94%, or requirement of supplemental oxygen. Exclusion criteria included a contraindication to any of the investigational treatment or their use within 29 days before randomization; elevated liver enzyme > 5 times the upper limit, an estimated glomerular filtration rate below 30 mL/min, pregnancy or breast-feeding. Full inclusion and exclusion criteria are presented in the Supplementary Appendix. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 9, 2021. ;

Participants were randomly assigned in a 1:1:1:1:1 ratio through computer-generated blocks of various sizes and stratified by administrative region and severity of illness at enrolment (moderate disease: hospitalized participants receiving low-flow supplemental oxygen or not requiring oxygen ; severe disease: hospitalized participants requiring non-invasive ventilation or high-flow oxygen devices, invasive mechanical ventilation or ECMO). Randomization was implemented in the electronic Case Report Form to ensure appropriate allocation concealment. Investigational arms were standard of care (SoC, control), SoC plus lopinavir/ritonavir (tablets or oral suspension in nasogastric tube of 400 mg lopinavir and 100 mg ritonavir administered every 12h for 14 days), SoC plus lopinavir/ritonavir plus IFN-ß-1a (44 μ g of subcutaneous IFN-ß-1a on days 1, 3, and 6), SoC plus hydroxychloroquine (200 mg tablets adjusted to 400 mg twice on day 1 as a loading dose followed by 400 mg once daily for 9 days) (16) or SoC plus remdesivir (200 mg intravenously on day 1 as a loading dose followed by 100 mg once-daily for hospitalization duration or 10 days). Other supportive treatments, such as glucocorticoids or immunomodulatory agents, were allowed in all arms.

Participants were assessed daily while hospitalized, and at days 3, 5, 8, 11, 15±2 and 29±3 if they were withdrawn at these dates. Clinical data, concomitant medications, adverse events (AEs) and measurements for blood cell counts, serum creatinine and liver aminotransferases were collected. Nasopharyngeal swab (NPS) and lower respiratory tract (LRT, i.e. bronchoalveolar lavage, protected specimen brushing or bronchial aspiration) specimens were collected for SARS-CoV-2 real-time (RT) PCR.

The primary outcome measure was the clinical status at day 15 as measured on the 7-point ordinal scale of the WHO Master Protocol (v3.0, March 3, 2020): 1. Not hospitalized, no . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 9, 2021. 

Hypotheses for sample size calculation are presented in Supplementary Appendix.

An independent data safety and monitoring board (DSMB) externally reviewed the trial data.

For efficacy and futility, the statistical analysis was performed on the primary outcome measure, and was based on the Haybittle-Peto rule (17, 18) . Consistently with its role of addon partner trial, DisCoVeRy periodically transferred data regarding three of its secondary outcomes to the WHO Solidarity trial: in-hospital mortality, time to hospital discharge, time to mechanical ventilation.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.08.20248149 doi: medRxiv preprint the hydroxychloroquine arm was suspended at the request of the French Agency of drug Security (Agence Nationale de Sécurité du Médicament). On June 13 th , based on the interim analysis of the Solidarity data, the Solidarity and DisCoVeRy trial DSMBs recommended to definitely stop the hydroxychloroquine arm due to futility. This decision was endorsed by the DisCoVeRy steering committee on June 17 th . The Solidarity DSMB advised to stop the lopinavir/ritonavir arm due to futility on June, 23 th . Thereafter, the DisCoVeRy DSMB further advised to stop both the lopinavir/ritonavir-containing arms due to additional safety concern on June, 25 th . This decision was endorsed by the DisCoVeRy steering committee on June 27 th with subsequent interruption on June, 29 th .

Statistical analyses compared each of the three stopped investigational treatment arms to the control arm. Due to the slowdown of inclusions in the trial between May and July, a single patient was included in the control arm between the hydroxychloroquine arm suspension and the permanent discontinuation of the lopinavir/ritonavir-containing arms. For simplification purpose, only one control group was constituted, which included participants from the control arm included before June 29 th . The intention-to-treat population included all randomized participants for whom a valid consent form was obtained. The modified intention-to-treat population included participants from the intention-to-treat population who received at least one dose of the treatment allocated by randomization.

Efficacy analyses were performed on the intention-to-treat population; handling of missing data is described in Supplementary Appendix. Safety analyses were performed on modified intention-to-treat population. Analyses were stratified by baseline severity but not by region of inclusion due to a low number of inclusions in some regions; all tests were two-sided with a type-I error of 0.05.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.08.20248149 doi: medRxiv preprint event data were analyzed using a Cox proportional hazard model. An analysis of covariance was performed for the comparison of oxygenation-and ventilator-free days between groups; 29-day mortality and the number of participants with detectable SARS-CoV-2 in the respiratory tract specimens at each time point were analyzed using a Cochran-Mantel-Haenszel test. Log 10 normalized SARS-CoV-2 load kinetics was analyzed using a mixedeffects linear model with test of treatment effect on slopes. For safety endpoints, nonprespecified statistical comparisons of the proportions of patients with any i) adverse event, ii) grade 3 or 4 adverse event, or iii) serious adverse event between each investigational treatment arm versus control were performed using the Fisher exact test.

The trial was funded by grants from Programme Hospitalier de Recherche Clinique (PHRC-20-0351) (Ministry of Health), from the DIM One Health Île-de-France (R20117HD) and from REACTing, a French multi-disciplinary collaborative network working on emerging infectious diseases. The funding sources had no role in the analysis of the data nor in the decision of publication.

Between March, 22 nd and June, 29 th , 603 participants were randomized to one of the 4 arms across 32 sites in France and Luxembourg and 583 were evaluable for analysis (Supplementary Figure S1 ): control arm, n=148; lopinavir/ritonavir arm, n=145; lopinavir/ritonavir plus IFN-ß-1a arm, n=145; hydroxychloroquine arm, n=145. Participants' baseline characteristics are presented in the Table 1. The median age was 63 years (IQR, 54; 71) and participants were mostly male (n=418, 71.7%). The median time from symptom onset to randomization was 9 days (IQR, 7; 12). The most frequent underlying conditions were . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. between groups was observed regarding concomitant anti-inflammatory drug used.

The distribution of the 7-point ordinal scale at day 15 is presented in the Figure 1 and Table 2 .

There was no significant difference between any of the treatment arm and the control arm, and adjusted OR (aOR) were not in favor of investigational treatments (i.e., below 1): 

The distribution of the 7-point ordinal scale at day 29 is presented in the Figure 1 and Table 2 .

There was no significant difference between any of the treatment arm and the control arm.

The time to improvement of 2 categories of the 7-point ordinal scale or hospital discharge within day 29 was significantly higher in both lopinavir/ritonavir-containing arms than in the control arm. The time to NEWS ≤ 2 or hospital discharge within 29 days and time to hospital discharge within day 29 were significantly higher in the lopinavir/ritonavir plus IFN-ß-1a arm than in the control arm (Table 2) . No other significant difference was observed for any other secondary outcomes between treatment arms and the control arm (Table 2 and Supplementary   Figures S2-S4 ).

No significant difference in the proportion of participants with detectable log 10 normalized viral loads in NPS at each sampling time was demonstrated (Supplementary Table S2 ). The . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.08.20248149 doi: medRxiv preprint proportion of participants having severe disease with detectable log 10 normalized viral loads in the LRT at each sampling time is presented in Supplementary Table S3 .

The slope of decrease of the log 10 normalized viral loads quantified in NPS over time was not significantly affected by any of the investigational treatment (Figure 2, panel A) .

A total of 579 participants were included in the safety analysis (control, n=148; lopinavir/ritonavir, n=144; lopinavir/ritonavir plus IFN-β-1a, n=144; hydroxychloroquine, n=143). Safety outcomes are presented in the Table 3 . Among the 2399 reported AEs, 477

were graded 3 or 4 in 205 patients and mostly reported in the lopinavir/ritonavir arms (Table   3) . is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.08.20248149 doi: medRxiv preprint

Only 4 non-pulmonary-related deaths were linked to investigational treatments by the investigators (lopinavir/ritonavir arm, n=1; lopinavir/ritonavir plus IFN-ß-1a arm, n=3).

We report here the results of the DisCoVeRy clinical trial evaluating lopinavir/ritonavir with or without IFN-ß-1a, or hydroxychloroquine in comparison with control for the treatment of inpatients with COVID-19. As reported by the Solidarity interim analysis of critical endpoints, we report that these investigational treatments failed to improve the clinical course of COVID-19, nor to enhance SARS-CoV-2 clearance and were associated with more SAEs. Two randomized trials conducted in hospitalized COVID-19 patients found no difference between the lopinavir/ritonavir and the SoC arms in terms of 28-day mortality or of probability of progression to mechanical ventilation or death(23, 24). The hypothesis that severe COVID-19 is associated with an impaired type I IFN response characterized by no or low IFN production and activity supported testing IFN with lopinavir/ritonavir. In an openlabel randomized trial, the combination of lopinavir/ritonavir, IFN-β-1b and ribavirin was superior to lopinavir/ritonavir in alleviating symptoms and shortening the duration of SARS-CoV-2 shedding in mild-to-moderate COVID-19(25). Conversely, our data suggest longer time to NEW2 improvement or hospital discharge in the lopinavir/ritonavir plus IFN-β-1a vs.

lopinavir/ritonavir arm as well as no virological effect (Supplementary Figure S3) . In . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.08.20248149 doi: medRxiv preprint addition, we observed a higher rate of SAEs in the lopinavir/ritonavir-containing arms.

Participants from the investigational arms experienced more acute kidney injury, although the difference was not significant. In the first series of COVID-19, acute renal failure incidence ranged from 3 to 25% among heterogeneous patients in terms of disease severity and treatment management, although predominantly in critically ill patients(26, 27). COVID-19 has been associated with renal endotheliitis(28). Elevation of serum creatinine has been associated with high levels of D-dimers (> 500 ng/mL)(29), which resonates with elevated DisCoVeRy is an adaptive, randomized trial initiated in France and that has been now extended to other European countries with the support of the European commission and the task of becoming a pan-European platform trial for Emerging infectious Diseases treatment.

Furthermore, DisCoVeRy is an add-on trial to Solidarity and importantly contributes to Solidarity data acquisition and early interruption of treatment arms for futility. In agreement with Solidarity, our objective was to complement knowledge acquisition with granular safety and virological data. The design and the philosophy of DisCoVeRy trial will be of even greater importance when new investigational drugs will be evaluated, for which scarce safety . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.08.20248149 doi: medRxiv preprint data might be available, unlike repurposed drugs. The trial has some limitations: it is not a placebo-controlled, double-blinded trial due to the complexity of blinding treatments with different mode of administration (intravenous, subcutaneous or oral) and the need to initiate the trial very rapidly. DisCoVeRy did not target patients at the early phase of the disease nor include arms testing anti-inflammatory agents that can be used as part of the standard of care in any arm.

In patients admitted to hospital with COVID-19, lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine were not associated with clinical improvement at day 15 and day 29, nor reduction in viral shedding, and generated substantial SAEs. These findings do not support the use of these investigational treatments for patients hospitalized with COVID-19. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.08.20248149 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ; https://doi.org/10.1101/2021.01.08.20248149 doi: medRxiv preprint

L/r, Lopinavir/ritonavir (blue line); L/r + IFN, Lopinavir/ritonavir + interferon ß-1a (yellow line); HCQ, Hydroxychloroquine (red line); control (black line).

LSMD, least-square mean difference; 95%CI, 95% confidence interval.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. ;

NPS, Nasopharyngeal swabs; LRT, Lower respiratory tract.

* denotes variables with missing data. Data on chronic cardiac disease, chronic pulmonary disease, mild liver disease, chronic neurological disorder, active cancer and diabetes mellitus were missing for 2 patients; data on chronic kidney disease were missing for 3 patients; data on auto-inflammatory disease were missing for 1 patient; data on obesity were missing for 5 patients; data on smoking status were missing for 30 patients; data on the time from symptoms onset to randomization were missing for 8 patients; data on BMI were missing for 83 patients; data on randomization site were missing for 1 patient; data on viral load from NPS were missing for 234 patients; data on viral load from LRT specimens were missing for 527 patients; data for lymphocyte count were missing for 90 patients; data for neutrophil count were missing for 136 patients; data on creatinine were missing for 15 patients; data on AST/SGOT were missing for 56 patients; data on ALT/SGPT were missing for 51 patients; data on CRP were missing for 137 patients; data on D-Dimers were missing for 299 patients; data on PCT were missing for 356 patients; data on ferritin were missing for 421 patients. .

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. Table 3 . Summary of adverse events according treatment group in the modified intention to treat population.

In the "Overall" column, numbers refer to number of events and number of patients. In other columns, number refer to number of patients (%). Some patients had more than a single SAE. Analyses were performed on the modified Intention-to-treat population. SAE, Serious Adverse Event. -Arrhythmia 41 / 35 3 (2%) 8 (6%) 12 (8%) 12 (8%) -Pulmonary embolism 27 / 27 6 (4%) 10 (7%) 5 (3%) 6 (4%) -Transaminases increased 25 / 25 2 (1%) 5 (3%) 12 (8%) 6 (4%) -Sepsis 21 / 21 2 (1%) 6 (4%) 7 (5%) 6 (4%) -Cholestasis 6 / 6 0 (0%) 2 (1%) 3 (2%) 1 (1%)

.

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted January 9, 2021. 

A Novel Coronavirus from Patients with Pneumonia in China

Clinical course and risk factors for 13

Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys

Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults

Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results

Rationale of a loading dose initiation for hydroxychloroquine treatment in COVID-19 infection in the DisCoVeRy trial

Repeated assessment of results in clinical trials of cancer treatment

Design and analysis of randomized clinical trials requiring prolonged observation of each patient

Introduction and design

Hydroxychloroquine 29

Kidney disease is associated with in-hospital death of patients with COVID-19

Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics

Immune activation mediated change in alpha-1-acid glycoprotein: impact on total and free lopinavir plasma exposure

Lopinavir pharmacokinetics in COVID-19 patients

Effect of Systemic Inflammatory Response to SARS-CoV-2 on Lopinavir and Hydroxychloroquine Plasma Concentrations

n (%) 1. Not hospitalized, no limitations on activities 146