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Review 4: "Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results"

This reliable study suggests four antivirals have no effect on important clinical outcomes in hospitalized COVID-19 patients. While the randomized control trial is thorough, reviewers note missing descriptions of study protocol, patient eligibility, & adverse reactions.

Published onNov 16, 2020
Review 4: "Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY trial results"
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key-enterThis Pub is a Review of
Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results
Description

BACKGROUND WHO expert groups recommended mortality trials in hospitalized COVID-19 of four re-purposed antiviral drugs. METHODS Study drugs were Remdesivir, Hydroxychloroquine, Lopinavir (fixed-dose combination with Ritonavir) and Interferon-β1a (mainly subcutaneous; initially with Lopinavir, later not). COVID-19 inpatients were randomized equally between whichever study drugs were locally available and open control (up to 5 options: 4 active and local standard-of-care). The intent-to-treat primary analyses are of in-hospital mortality in the 4 pairwise comparisons of each study drug vs its controls (concurrently allocated the same management without that drug, despite availability). Kaplan-Meier 28-day risks are unstratified; log-rank death rate ratios (RRs) are stratified for age and ventilation at entry. RESULTS In 405 hospitals in 30 countries 11,266 adults were randomized, with 2750 allocated Remdesivir, 954 Hydroxychloroquine, 1411 Lopinavir, 651 Interferon plus Lopinavir, 1412 only Interferon, and 4088 no study drug. Compliance was 94-96% midway through treatment, with 2-6% crossover. 1253 deaths were reported (at median day 8, IQR 4-14). Kaplan-Meier 28-day mortality was 12% (39% if already ventilated at randomization, 10% otherwise). Death rate ratios (with 95% CIs and numbers dead/randomized, each drug vs its control) were: Remdesivir RR=0.95 (0.81-1.11, p=0.50; 301/2743 active vs 303/2708 control), Hydroxychloroquine RR=1.19 (0.89-1.59, p=0.23; 104/947 vs 84/906), Lopinavir RR=1.00 (0.79-1.25, p=0.97; 148/1399 vs 146/1372) and Interferon RR=1.16 (0.96-1.39, p=0.11; 243/2050 vs 216/2050). No study drug definitely reduced mortality (in unventilated patients or any other subgroup of entry characteristics), initiation of ventilation or hospitalisation duration. CONCLUSIONS These Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appeared to have little or no effect on hospitalized COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay. The mortality findings contain most of the randomized evidence on Remdesivir and Interferon, and are consistent with meta-analyses of mortality in all major trials. (Funding: WHO. Registration: ISRCTN83971151, NCT04315948)

RR:C19 Evidence Scale rating by reviewer:

  • Potentially informative. The main claims made are not strongly justified by the methods and data, but may yield some insight. The results and conclusions of the study may resemble those from the hypothetical ideal study, but there is substantial room for doubt. Decision-makers should consider this evidence only with a thorough understanding of its weaknesses, alongside other evidence and theory. Decision-makers should not consider this actionable, unless the weaknesses are clearly understood and there is other theory and evidence to further support it.

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Review:

The SOLIDARITY Therapeutics Trial1, coordinated by the WHO, is the largest randomized trial of pharmaceuticals for management of COVID-19 in hospitalized patients. Presently, 405 hospital sites across 30 countries are participating in the trial, with 11,266 adult patients randomized so far. The design of the trial is “adaptive”—meaning that study drugs may be dropped if they are determined to be ineffective or harmful, and new study drugs may be added. To improve feasibility for participating sites, very limited data reporting was required and the study does not stipulate requirements for management of patients randomized to “standard of care” or for supportive care to be provided in addition to pharmaceutical agents for patients randomized to any group. Thus, while not reported in interim results, there was likely considerable variation across participating sites in management of patients that could influence key study outcomes (mortality, disease progression, length of hospital stay). 

Key limitations of this study include:

·       Variation in control condition. Likelihood of substantial variation in locally defined “standard of care” as the control condition across study sites.

·       Variation and uncertainty in other assigned treatments. Lack of information about other supportive care provided to hospitalized patients. Given that this study was performed across hundreds of hospitals in 30 countries, there was likely significant variation in the other supportive interventions that participants received while in hospital that were not tracked or reported in the study.

·       Symptoms of participants not reported or tracked. The majority of participants (~60%) were randomized on day 0-1 of hospitalization, but duration of infection and associated symptoms were not reported or tracked.

·       Disease severity is not clearly categorized or described. The report indicates the proportion of patients on ventilation when treatment is initiated (a sub-group analysis is performed for 28-mortality by ventilated vs. not ventilated participants who received remdesivir). However, baseline disease severity is not reported. It is possible that the distribution of participants with differing disease severity at baseline was uneven.

·       Variation in available study drugs by study site. Participants in any given study hospital were randomized in equal proportion to control and whichever study drugs were locally available. Reporting of which drugs were available at specific study sites/participating countries is not included in the publication. The availability of all four study drugs may not be equally distributed across sites.

·       Diagnostic confirmation of SARS-CoV-2 infection was not required. It is not clear that the distribution of those with diagnostic confirmation of infection is equal across groups as this is not required or reported in the publication.

How does evidence from this trial fit with existing evidence?

The available results for mortality risk from the SOLIDARITY trial are in accordance with the existing understanding of remdesivir for COVID-19. However, the SOLIDARITY trial reports no benefit of remdesivir for disease progression and length of hospital stay. In contrast, other evidence suggests that remdesivir may significantly reduce disease progression.

For example, a rapid response brief published in June 2020 for Alberta Health Services includes evidence from the phase III NIAID Adaptive COVID-19 Treatment Trial (ACTT).2 Interim results from ACTT demonstrated a benefit of remdesivir therapy over placebo for time to recovery:

·       Median time to recovery: remdesivir was 11 days (95% CI: 9-12) vs. placebo was 15 days (95% CI: 13-19); p<0.0001

 

References: 

1.         Pan H, Peto R, Karim QA, et al. Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results. medRxiv. 2020:2020.2010.2015.20209817.

2.         Kania-Richmond A, al. e. COVID-19 Scientific Advisory Group Rapid Response Brief - Key Research Question: What is the evidence for effectiveness of remdesivir as a treatment for COVID-19 disease? 2020; https://www.albertahealthservices.ca/assets/info/ppih/if-ppih-covid-19-sag-effectiveness-of-remdesivir-rapid-review.pdf.

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