Critical appraisal of the remdesivir randomized clinical trial in patients with severe Covid-19 published in The Lancet

1. Remdesivir in adults with severe
COVID-19: a randomised,
double-blind, placebo-controlled,
multicentre trial
Published on-line 29-April-2020
Critical appraisal to:
By José Ramón Paño

2. Outline
D-PICO-O
Design
Patients
Intervention
Control
Outcome
Opinion

3. Design
• Investigator-initiated
• Placebo-controlled, double-blind randomized trial
• Multicentre: 10 hospitals in Wuhan from Feb 6 to
March 12, 2020

4. Patients
Inclusion criteria
• Microbiologically confirmed SARS-CoV-2 infection (RT-PCR)
• Non-pregnant adults
• Radiologically confirmed pneumonia
• Hypoxemia: SatO2 <94% or PAFI ≤300
• Number of days since symptom onset ≤12

5. Patients
Intervention (n=158) Control (n=79)
Age 66 (57-73) 64 (53-70)
Sex (men) 89 (56%) 51 (65%)
Comorbidity (any) 112 (71%) 55 (71%)
Lymphopenia (<1.0) 106 (68%) 55 (71%)
AST > 40 46 (30%) 29 (37%)
LDH > 245 112 (76%) 58 (77%)
6-point ordinal scale =3 129 (82%) 65 (83%)
6-point ordinal scale ≥4 29 (19%) 10 (13%)
IFN-a-2b at baseline 29 (19%) 15 (19%)
LPV/r at baseline 27 (17%) 15 (19%)
Steroids at baseline 61 (38%) 31 (40%)

6. Intervention
- Day 1: 200 mg
• Remdesivir (iv) x 10 days
Other drugs allowed: LPV/r, INF-a-b, corticosteroids
- Days 2-10: 100 mg QD
Study drug Ratio intervention : control 2:1
Randomization was stratified according to the level of
respiratory support

7. Control
• Placebo (iv) x 10 days
Other drugs allowed: LPV/r, INF-a-b, corticosteroids
Control arm
Remdesivir Placebo
Time from symptom onset to randomization (<10d) 46% 60%
IFN a-2b 29% 38%
LPV/r 28% 29%
Corticosteroids 65% 68%

8. Outcome
• Time to clinical improvement within 28 days after
randomization:
Primary outcome variable
1 Discharged or having reached discharge criteria
2 Hospital admission but not requiring O2 therapy
3
Hospital admission requiring O2 therapy (non
high-flux or non-invasive ventilation)
4
Hospital admission for noninvasive
ventilation or high-flow oxygen therapy
5
Hospital admission for ECMO or mechanical
ventilation
6 Death
1. Two-point reduction in
patient admission status on a
6-point ordinal scale OR
2. Discharge alive
• Intention to treat analysis

9. Outcome (ii)
Considerations about ITT analysis
Primary outcome variable
• One patient in the remdesivir group was dead baseline
• Three patients did not start remdesivir
Figure 1: Trial profile

10. Outcome (iii)
Secondary outcome variables
• Proportions of patients in each category of the six-point scale at
day 7, 14, and 28 after randomisation
• All-cause mortality at day 28;
• Frequency of invasive mechanical ventilation;
• Duration of oxygen therapy
• Duration of hospital admission
• Proportion of patients with nosocomial infection
• Proportion of patients with RNA detected (& viral load)

11. Outcome (iv)
Sample size calculation
Assumptions
• Statistical power: 80%
• One sided type I error: 2-5%
• Clinically significant difference: HR 1.4 (Patients with
remdesivir would reach primary outcome 6 days
faster than placebo (15 vs 21)
Calculation: 453 patients (remdesivir: placebo 302:151)
Number of patients actually recruited
• 237 patients (remdesivir: placebo 158:79)
• Representing 52% of planned sample size

12. Outcome (v)
Intervention
(n=158)
Control
(n=79)
Difference
Time to clinical improvement
Early (≤10 day from symptom onset)
21
18
23
23
1.23 (0.87 to 1.75)
1.52 (0.95-2.42)
Day 28 mortality
Early (≤10 day from symptom onset)
Late (>10 days from symptom onset)
14%
11%
14%
13%
15%
10%
1.1% (–8.1 to 10.3)
–3.6% (–16.2 to 8.9)
4.6% (–8.2 to 17.4)
Duration of invasive
mechanical ventilation, days
Duration of invasive mechanical
ventilation in survivors, days‡
7
19
15.5
42
–4.0?(–14.0 to 2.0)
–12.0 (–41.0 to 25.0)
Adverse events
Serious adverse events
Discontinuation of the study drug
66%
18%
12%
64%
26%
5%

13. Outcome (vi)

14. Outcome (vii)

15. Opinion
• Remdesivir did not show statistically significant improvement for the
primary clinical outcome or the secondary variables
• When remdesivir was started earlier (≤10 days from symptom onset),
point estimates of most outcome variables were more favourable to
remdesivir, which is biologically consistent
• …but the study was clearly underpowered to detect the impact of
remdesivir on primary outcome variable…so this study does not prove
the inefficacy of the drug (the jury is still out)
• Even if a larger sample size proves the efficacy of remdesivir its clinical
impact will likely be less relevant than expected / needed