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Review 3: "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 11, 2020
Review 3: "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:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review:

General comments

This manuscript provides a clearly written summary of important results from a well-conducted research study. I have some specific comments focusing on the Methods section, which are relatively minor and could easily be addressed in revision.

Specific comments

1.   Methods, 1st paragraph: The randomization procedure and definition of controls should be explained in more detail. First, if control designation is synonymous with "local standard-of- care," this should be stated and not left as a parenthetical remark. Also, some sense of what constitutes standard of care should also be provided. In particular, is it established that this excluded the study drugs or similar alternatives? What randomization procedures were used? Was any attempt made to balance assignment to the five options across sites? (The Results imply this was not the case, but the procedure should be specified in Methods/Supplementary materials.

2.   Statistical analyses, 2nd paragraph, 1st sentence: I suggest replacing "methods plot" with "were used to plot mortality risk through 28 days post-randomization."

3.   Statistical analyses, 2nd paragraph, 3rd sentence: This sentence is awkward, partially because of the conditional interpretation implied by starting with "if". Ending with "and assumed to be asymptotically normally distributed" would be clearer. Also, the definition of "expected" isn't clear without further detail (e.g. specifying the null hypothesis). An additional sentence clarifying calculation of expected counts would help. This could also be footnoted in Table 3. Overall, I don't feel the (O-E)/V notation and the inclusion of log-rank statistics in Table 3 add much over the confidence intervals and RR estimates.

Although not likely to substantively affect reported results, I note that hazard ratios estimated via the log-rank procedure are known to be inconsistent estimators (ref: Lin DY, Dai L, Cheng G, Sailer MO. On confidence intervals for the hazard ratio in randomized clinical trials. Biometrics, 2016, 72(4):1098-1102.) An alternative analysis accounting for this would be preferable. For example, a standard Cox regression analysis adjusting for age (as a continuous or more finely stratified variable) and ventilation status, based on midpoint imputation of interval-censored death times, and accounting for tied event times could have been used (NB: A Cox approach was included in supplementary material).

4.   Statistical analyses, 2nd paragraph, 4th sentence: The choice to impute all "uncertain" event times at 7 days is unjustified and the frequency of these is unreported.

5.   Statistical analyses, 2nd paragraph, 5th sentence: The frequency of patients censored at day 0 is not reported and needs to be. This sentence could be written more clearly as follows: "Event times for patients with unknown outcomes at the time of analyses were censored at day 0." This implies that these patients were removed from the analysis entirely, and therefore the analysis was technically a "modified intention to treat" approach.

6.   Statistical analyses, 2nd paragraph, 6th sentence: How were randomized patients that were discharged treated in the mortality analysis if they were not censored or counted as outcomes? In the prior Endpoints section it is stated: "follow-up ceased at discharge."

7.   Statistical analyses, 3rd paragraph, 1st sentence: Denoting the logRR as "b" here serves no purpose in understanding the methods/results.

8.   Results, 2nd paragraph, 3rd sentence: The meaning of "Deaths were at median day 8" is not immediately clear. Something like "Median time to death was 8 (IQR 4-14)" seems clearer to me.

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