Remdesivir – In patients 1 – Evid summ

Summary of findings Table

Summary of Findings Table 1

Explanations

a. Downgraded by one level for serious risk of bias; Spinner 2020, Mahajan, and Karim Ali 2022 has a high risk of bias and two studies reported Some concerns.

b. Downgraded by one level of serious risk of bias; Spinner 2020 was at high risk of bias and contributed to 36.1% of the weight in the meta-analysis

c. Downgraded by one level for serious indirectness; Spinner 2020 has moderate severity of patients only and ACTT Beigel 2020 had a mixture of patients of different severity.

d. Downgraded by one level of serious risk of bias; Spinner 2020 was at high risk of bias and contributed 17.3% and Ader F 2021 contributed to 33.5% of the weight in the meta-analysis and reported some concerns in risk of bias

e. Downgraded by one level for serious risk of bias; Karim Ali 2021 has a high risk of bias and AderF 2021 Elsalam 2021 has some concerns;

f. Downgraded by one level for serious imprecision: the 95% CI includes both benefit and harm

g. Downgraded to one level for serious imprecision; RR 0.72 95% CI is 0.52 - 0.98 and it does not meet the Optimal information size (OIS) criteria

h. Downgraded by one level for serious inconsistency: The I 2 is 82%

i. Downgraded by one level for serious risk of bias; Mahajan 2021 has a high risk of bias and AderF 2021 Elsalam 2021 has some concerns

j. Downgraded by one level for serious inconsistency: The I 2 is 63 %

Summary of Findings Table 2

Explanations

a. Downgraded by two levels for serious imprecision; the number of events were few and the 95% CI of the effect estimate included clinically important reductions and increases in thrombotic events with Remdesivir. OIS criteria not met

b. Downgraded to one level for serious imprecision; RR 0. 59 (95% CI is 0.36 - 0.96) and it does not meet the Optimal information size (OIS) criteria

c. Downgraded by one level of serious risk of bias; Spinner 2020 was at high risk of bias and contributed to 19.4% and Ader 2021 has some concerns which contributed to 30.3% of the weight in the meta-analysis and Elsalam 2021 also reported some concerns

d. Downgraded by one level of serious risk of bias; Spinner 2020 was at high risk of bias

e. Downgraded by one level for serious inconsistency: The I 2 is 76%

f. Downgraded by two levels for serious imprecision: the 95% CI is wide (0.46 to 6.09)

g. Downgraded by one level of serious risk of bias; Spinner 2020 was at high risk of bias and contributed to 12.4% and Ader 2021 has some concerns which contributed to 35.5% of the weight in the meta-analysis

h. Downgraded by one level for serious inconsistency: The I 2 is 63%

i. Downgraded by one level for serious imprecision: the 95% CI is wide (0.63-1.06)

Background

Remdesivir is a prodrug that is converted to an active triphosphate form that inhibits viral RNA production through RNA dependent RNA polymerase.(1). It was developed as a therapeutic agent for treating RNA-based viruses such as Ebola virus, MERS, SARS-CoV-1 and other zoonotic coronaviruses (2). It has demonstrated in vitro and in vivo antiviral activity against SARS-CoV-2 (3).

Remdesivir is widely used across the world and a number of guidelines have recommended its use in hospitalized hypoxic COVID-19 patients (4). The WHO recently recommended the use of Remdesivir with caution in individuals with non-severe COVID-19 who are at high risk of hospitalisation(5). It is also approved by the FDA for the treatment of COVID-19 in nonhospitalized and hospitalised paediatric patients weighing 3.5 kg to 40 kg or <12 years and weighing ≥3.5 kg(6).

Currently Remdesivir is a widely available antiviral drug in the country. The Ministry of Health & Family Welfare recommends Remdesivir for moderate to severe COVID-19 hospitalized patients on supplemental oxygen (7) as it appears to have a relatively good safety profile.

This review aims to provide a summary of the available evidence from randomized clinical trials of Remdesivir for treatment of acute COVID-19, for any duration, which could guide clinicians and researchers regarding the appropriate use of this drug in the future.

Methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Epistemonikos, and the COVID‐19‐specific resource www.covid‐nma.com, for studies of any publication status and in any language. We also reviewed reference lists of systematic reviews and included studies. We performed all searches up to 4^th May 2022. We included randomized controlled trials (RCTs) testing Remdesivir in people with COVID‐19, and extracted data for the following pre-defined outcomes:

Critical (primary for this review):

- Mortality (all-cause): at 28-30 days, or in-hospital
- Progression to:
  - Oxygen therapy
  - Ventilation: non-invasive or invasive
  - Critical/Intensive care (any reason)
- Time to clinical improvement
- Time to clinical recovery
- Adverse events: all and serious

Important (secondary):

- Time to negative PCR for SARS-CoV-2
- Duration of hospitalization
- Complications of COVID-19:
- Thrombotic events
- Pulmonary function/fibrosis
- Long COVID/post-acute sequelae COVID
- Secondary infections

Two reviewers independently assessed eligibility of search results. One reviewer extracted data from each included study, and assessed risk of bias using the Cochrane Risk of bias (RoB) v2.0 tool. Data and RoB assessments were checked by the second reviewer. The entire RoB assessment was scrutinized by the whole team for this review, to reach consensus.

We used RevMan 5.4 to perform meta‐analysis using a random‐effects model for outcomes where pooling of effect estimates was appropriate. We used risk ratios (RR) for dichotomous outcomes and hazard ratios for continuous outcomes, with 95% confidence intervals (CIs). We performed a subgroup analysis to explore the effect on mortality stratified by different oxygen and ventilation requirements at baseline.

We used the I² statistic to measure residual heterogeneity. We used GRADE methodology to assess the certainty in the evidence, and documented this in a ‘Summary of findings’ table using GradeProGDT.

Results

We included eight trials involving 12,537 participants, all of whom were adults, and 6408 of whom received Remdesivir(8–15). Four trials were reported, one each from China(9),Canada (12),Egypt (13)and India (11); three from multiple countries in North America, Europe and Asia (8,10,14); one recruited worldwide (15). All trials were done in hospitalized patients. Disease severity, prevalence of comorbidities, and use of co‐interventions (e.g., steroids) varied substantially between trials. Out of the eight trials, three (8,9,15) were found to have low risk of bias across all domains for all outcomes and three(10–12) had high risk of bias across multiple domains. Risk of bias for each domain per trial is displayed alongside the forest plots below. WHO solidarity trial’s interim report has been added for additional data(16).

The following comparisons were investigated in the trials (we compared outcomes for arms randomized to Remdesivir vs. outcomes for arms randomized to standard of care or placebo):

Two trials(8,9) compared Remdesivir with placebo (1299 participants) whereas, six trials (10–15) compared Remdesivir with standard of care (8414 participants). Of these, one trial (10) had two arms with different duration of Remdesivir (5 days arm and 10 days arm) compared with a standard of care arm (596 participants).

Our expert working group classified progression to oxygen, non-invasive ventilation (NIV) and invasive mechanical ventilation (IMV) as critical outcomes and mortality, time to clinical improvement and thrombotic or secondary infections as important outcomes. However, as the situation in the country evolved, the guidelines group upgraded mortality, time to clinical recovery and time to clinical improvement as critical outcomes, as a benefit observed in these outcomes, could reduce pressure on the overwhelmed health system.

Critical (primary) Outcomes

As presented in the ‘Summary of findings’ table, the evidence is moderate for all-cause mortality, time to clinical improvement, progression to NIV/HFNO, secondary infections and any adverse event. The evidence is low for time to clinical recovery, progression to oxygen therapy, progression to ventilation (NIV/HFNO/ECMO/IMV) and thrombotic complications. Also we found very low certainty for progression to IMV, adverse events leading to drug discontinuation and serious adverse events.

(a) All-cause mortality: Moderate certainty of evidence in 12537 patients in eight RCTs (8–15) found that Remdesivir probably reduces mortality when compared to placebo or standard of care (RR 0.90; 95% CI 0.83 to 0.98)).

(b) Time to clinical recovery (time to achieve WHO score 1,2,3 or not requiring hospitalization for oxygen or medical care): Low certainty evidence In 1459 patients from two RCTs (8,10), revealed that Remdesivir may reduce time to clinical recovery in participants receiving Remdesivir compared with those receiving placebo or standard of care; Hazard ratio (HR) was 1.22 (95% CI 1.06 to 1.41). The median time reported in two studies ranged from 6-10 days in the Remdesivir group vs 7-15 days in the control groups (See Results Table 1 for results from each trial). A mean difference to quantify the magnitude of potential benefit was not available.

(c) Time to clinical improvement (>2 point reduction in the WHO ordinal score):

Moderate certainty evidence from in four RCTs (8–10,14) suggested that Remdesivir probably decreases time to clinical improvement (HR 1.19; 95% CI 1.09 to 1.31). The median and IQR ranged from 6-21 days in the Remdesivir group vs. 6-23 days in the control group. (See Results Table 1 for results from each trial). A mean difference to quantify the magnitude of potential benefit was not available.

(d) Progression to oxygen therapy: Low certainty evidence in 1095 patients from three RCTs(8,12,14) found that Remdesivir may reduce progression to oxygen therapy vs. standard of care (SOC)/placebo (RR 0.83 ; 95% CI 0.64 to 1.08 ).

(e) Progression to non-invasive ventilation (NIV) or high flow oxygen (HFO): Moderate certainty evidence from 1405 patients in two RCTs(8,14) found that Remdesivir probably reduces progression to NIV or HFO (RR 0.72; 95% CI; 0.52 to 0.98 ) and varied as widely as 2% to 48% with small sample size and few events.

(f) Progression to invasive mechanical ventilation:Very low certainty evidence from 7931 patients in five RCTs (8,12–15) found an uncertain effect of Remdesivir on progression to invasive mechanical ventilation (RR 0.74 ; 95% CI 0.51 to 1.06 ).

(g) Progression to ventilation (NIV/HFNO/IMV/ECMO): Low certainty evidence from 10247 patients in five RCTs(8,9,11,14,16) found that Remdesivir may reduce progression to ventilation (NIV/HFNO/IMV/ECMO) (RR 0.78; 95% CI 0.61 to 0.99).

(h) Adverse events: Moderate certainty evidence from 2889 patients in five RCTs (3,8,10,13,14) revealed Remdesivir probably contribute to few or no additional adverse events as compared to placebo (RR 1.00; 95% CI 0.90 to 1.10 ). In addition, very low certainty evidence from 1877 patients in three RCTs (3,8,10) found an uncertain effect of Remdesivir on drug discontinuation due to adverse effects (RR1.68; 95% CI 0.46 to 6.09) and serious adverse events from 2689 patients in four RCTs (8–10,14) [RR 0.82;95% CI 0.63-1.06].

(i) Duration of hospitalization: This was reported in four studies as a median and hence a meta-analysis could not be performed. Wang 2020 (9)] reported a median (IQR) of 21 (12 to 31) days in the Remdesivir group vs. 21 (13.5 to 28.5) days in the SOC or placebo groups. ACTT Beigel 2020 (8)reported median (IQR) as 12 (6-28) days vs. 17 (8-28) days in the SOC/placebo groups.Abd-Elsalam 2022 (13)reported median (IQR) as 10(8-13.5) days vs. 16(12-21) days in the SOC/placebo groups. Ali K 2022 (12) reported median (IQR) as 10(6-18) days vs. 9(6-17) days in the SOC/placebo groups.

Important (secondary) outcomes:

(1) Thrombotic events: Low certainty evidence from three RCTs (8,9,14) in 2105 participants suggests that Remdesivir may make little to no difference to occurrence of thrombotic events when compared to placebo or SOC (RR 0.80; 95% CI 0.45 to 1.43)

(2) Secondary infections: Moderate certainty evidence from three RCTs (8,9,14) in 2105 participants suggests that Remdesivir may reduce secondary infections when compared to placebo or SOC (RR ; 95% CI 0.36 to 0.96 ).

No comparative data could be extracted for time to negative PCR; or post-acute COVID-19 pulmonary function/fibrosis or other sequelae.

Subgroup analysis

A subgroup analysis was attempted as pre-specified by the Expert Working Group.

In three RCTs (3,8,12) with 1332 participants, in the subgroup with low flow oxygen it did show a mortality benefit (RR 0.57; 95% CI 0.34 to 0.95).

In one RCT (9) Remdesivir showed no mortality benefit when participants were stratified by shorter duration of symptoms (<10 days; RR 0.76; 95% CI 0.29 to 1.95) or ≥10 days of symptoms (RR 1.48; 95% CI 0.45 to 4.88).

Disaggregated data could not be obtained for co-morbidities, inflammatory markers or different age groups. Subgroups of pregnancy, lactation, renal failure, liver failure were excluded from most trials. No data were available separately for immunocompromised individuals in any of the trials.

Table 1: Time to clinical improvement and recovery