health care

1. WHO Solidarity Trial Interim Result on Remdesivir
Critical Appraisal
26th
October 2020
Citation: WHO Solidarity Trial consortium. Repurposed antiviral drugs for COVID-19 –
interim WHO SOLIDARITY trial results. (Pre print results – Not peer reviewed). medRxiv
preprint doi: https://doi.org/10.1101/2020.10.15.20209817; this version posted October 15,
2020 .
Background: WHO solidarity trial is a multicounty research Randomized control Trial to
identify 4 repurposed drugs for the treatment of COVID-19 pneumonia. This includes
Remdesvir, HCQ, Lopinavir and Interferon B1a compared with local standard of care. This is
a 30 country initiative involving 405 hospitals including in India. At the time of publication
of this study based on NIH trial in USA Remdesvir is being widly used to treat COVID
pneumonia.
Patients: Patients over the age 18 years admitted to hospital with diagnosis of COVID 19
pneumonia og all severity. With nearly 9% who were already ventilated at admission from
many countries including India
Intervention: Remdesvir IV 200 mgs Day 1 followed by 100 mgs OD for 10 days.
Control: Local Standard of care – No placebo
Outcome : In hospital mortality at discharge.
Critical Appraisal
Was the design appropriate : YES – and No
Simple Mega Clinical Trials is a forte of Richard Peto who is an outstanding statistician of
our time. He can be called the father of meta-analysis. Some of these trials have changed
the way modern medicine is practiced today particularly in cardiology. Most the earlier trials
were done not on COVID setting. Standardization and Training of investigators is a very
important component in Mega trials involving many centers. In the emergency setting of
COVID – None of these things could be done. Travel to hospitals for quality control and
protocol adherence was probably not feasible. The validity of trial depends on the degree of
protocol deviations and simplicity of the trial. A more optimum design in this setting is a
high quality randomized Control trial involving one or few centres rather than multicountry,
multichospital trial.
Did the Randomization work: Don’t Know
Base line data shows that demographic data is similar in the two groups. The randomization
has worked. But unfortunately some important base line prognostic factors like
Hypertensive across two groups have not been provided. Another important prognostic
variable is delay to treatment and SPO2 at admission. These data are needed to assess

2. similarity of groups . Though time from hospital admission is shown to be similar time from
1st
symptom is not provided. But it can be presumed that being a large trial with more than
10,000 patients, these factors could have been equally distributed in the two groups.
Was Intervention Blinded No
There has been no attempt to blind the intervention. However mortality is a hard end point
and this could be considered as valid if unblinding did not have influence on the health care
professional behavior in patient receiving differential treatment. Being an open labeled
study the proportion of patients receiving Steroids in the two groups is important to
determine if systematic bias existed in the study. This information is not provided in the
table of results ?? . Co-intervention has certainly occurred as the standard of care was left
unspecified in the trial protocol.
Was the follow up Complete? Yes
Total of 11330 patients recruited overall and data included intention to treat analysis of
11266 patients with a loss of only 0.6% of patients. Of these 2750 was allocated to
Remdesvir treatment and compared with 4088 with local standard of care. Of these 2708
were selected as controls for Remdesvir. Probably by random method but not specified. The
outcome on all these patients were measured. But if patients were discharged at rquest or
against medical advice they were not considered as case fatality.
Validity:
In my view the preliminary results have purposefully not revealed some of the
imperfections of the study. Being a management rial report it falls short of the rigours of a
true experimental design. I will only give it 60-70% validity score.
Results
Results: Shows no statistically significant benefit to Remdesvir. There is also no benefit
shown in the subgroup analysis in different age groups and severity at presentation. 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).
What does this result indicate: The best estimate shows no statistically significant benefit for
Remdesvir but if you repeat this study. The relative risk could be as low as 0.81 (meaning
nearly 20% benefit in reducing case fatality. In spite of studying large number of patinets the
reason why this occurred can only be due to wide variability in results across study centers.

3. Would you stop Treating Patients with Remdesvir in view of these preliminary results: NO
While the best estimate was not significant, the result of study clearly is not conclusive. The
benefit could be as high as 14% if it is repeated. The design of the study is not truly high
quality experimental design being open labeled and allowing for wide variation in the
protocol . The comparative group was also not specified rigidly with significant variation in
the standard of care. The control group received more antiviral agents and other co-
interventions.
The publication is still preliminary. The validity is less than adequate to change behavior.
This being an on-going trial final report is awaited and we will have to await the final results
to change behavior.

4. Result of Meta-Analysis of Available Studies
I would continue to give Remdesvir in selected patients who are of moderate severity till
more definitive data emerges. The meta -analysis of all trials show nearly 20% benefit when
given in mild disease (meaning early in the course of illness) Odds 0.80 (CI: 0.63-1.01). At
this point I will go with the meta-analysis result.
Dr.Kurien Thomas MBBS, MD, MSc
Professor and Head
Department of General Medicine
Pondicherry Institute of Medical Sciences
****