ACTT-1: Multinational, Double-Blind, Placebo-Controlled Trial of Remdesivir in Hospitalized Patients With COVID-19 in 10 Countries1 |
Key Inclusion Criteria- Laboratory-confirmed SARS-CoV-2 infection
- ≥1 of the following:
- Pulmonary infiltrates
- SpO2 ≤94% on room air
- Need for supplemental oxygen, HFNC oxygen, NIV, MV, or ECMO
Key Exclusion Criteria - ALT or AST >5 times ULN
- eGFR <30 mL/min
Interventions - RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily for up to 9 more days (n = 541)
- Placebo for up to 10 days (n = 521)
Primary Endpoint - Time to clinical recovery
Key Secondary Endpoints - Clinical status at Day 15, as measured by an OS
- Mortality by Day 29
- Occurrence of SAEs
| Participant Characteristics - Mean age 59 years; 64% men; 53% White, 21% Black, 13% Asian, 24% Hispanic/Latinx
- Coexisting conditions: 26% with 1; 55% with ≥2
- 13% not on oxygen; 41% on supplemental oxygen; 18% on HFNC oxygen or NIV; 27% on MV or ECMO
- Median time from symptom onset to randomization: 9 days (IQR 6–12 days)
- 23% received corticosteroids during study
Primary Outcomes - Time to clinical recovery: 10 days in RDV arm vs. 15 days in placebo arm (rate ratio for recovery 1.29; 95% CI, 1.12–1.49; P < 0.001)
- Benefit of RDV greatest in patients randomized during first 10 days after symptom onset and those who required supplemental oxygenation at enrollment
- No difference in time to recovery for patients on HFNC oxygen, NIV, MV, or ECMO at enrollment
Secondary Outcomes - Improvement in clinical status at Day 15 more likely in RDV arm (OR 1.5; 95% CI, 1.2–1.9; P < 0.001)
- No difference between arms in mortality by Day 29
- Occurrence of SAEs: 25% in RDV arm vs. 32% in placebo arm
| Key Limitations- Wide range of disease severity among patients; study not powered to detect differences within subgroups
- Study not powered to detect differences in mortality between arms
- No data on longer-term morbidity
Interpretation - In patients with severe COVID-19, RDV reduced the time to clinical recovery.
- The benefit was most apparent in hospitalized patients who were receiving supplemental oxygen.
- There was no observed benefit in those on HFNC oxygen, NIV, MV, or ECMO, but the study was not powered to detect differences within subgroups.
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CATCO: Multicenter, Open-Label, Pragmatic RCT of Remdesivir in Hospitalized Patients With COVID-19 in Canada2 |
Key Inclusion Criterion- Laboratory-confirmed SARS-CoV-2 infection
Key Exclusion Criterion Interventions - RDV 200 mg IV on Day 0, then RDV 100 mg IV once daily on Days 1–9 (n = 634)
- Local SOC (n = 647)
Primary Endpoint Key Secondary Endpoints - New need for MV
- Hospital LOS
- Incidence of hepatic dysfunction, incidence of need for dialysis, and change in SCr at Day 5
| Participant Characteristics - Median age 66 years; 60% men; 41% White
- Median time from symptom onset to randomization: 8 days
- At entry:
- 54% on low-flow oxygen
- 24% on HFNC oxygen
- 9% on MV
- Rates of comorbidities were similar between arms.
- 87% in both arms were receiving corticosteroids at baseline
Primary Outcome - In-hospital mortality: 19% in RDV arm vs. 23% in SOC arm (relative risk 0.83; 95% CI, 0.67–1.03)
Secondary Outcomes - New need for MV: 8% in RDV arm vs. 15% in SOC arm (relative risk 0.53; 95% CI, 0.38–0.75)
- No significant difference between arms in hospital LOS
- No difference between arms in incidence of new hepatic dysfunction, incidence of need for dialysis, or change in SCr at Day 5
| Key Limitations- Open-label study
- Information on comorbidities was not available for 26% of patients.
Interpretation - RDV did not decrease in-hospital mortality among patients with COVID-19 compared to SOC.
- Patients who received RDV were less likely to require MV than patients who received SOC.
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DisCoVeRy: Open-Label, Adaptive RCT of Remdesivir in Hospitalized Patients With Moderate or Severe COVID-19 in Europe3 |
Key Inclusion Criteria- Laboratory-confirmed SARS-CoV-2 infection
- Illness of any duration
- SpO2 ≤94% on room air or use of supplemental oxygen, HFNC oxygen, NIV, or MV
Key Exclusion Criteria - ALT or AST >5 times ULN
- Severe chronic kidney disease
Interventions - RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily for up to 9 days (n = 429)
- SOC (n = 428)
Primary Endpoint - Clinical status at Day 15, as measured by an OS
Key Secondary Endpoints - Mortality by Day 29
- Occurrence of SAEs
| Participant Characteristics - Median age 64 years; 70% men; 69% White
- 74% with ≥1 coexisting condition
- 40% received corticosteroids
- Median time from symptom onset to randomization: 9 days in both arms
- 61% with moderate disease; 39% with severe disease
Primary Outcome - No difference between arms in clinical status at Day 15 (OR 0.98; 95% CI, 0.77–1.25; P = 0.85)
- A prespecified subgroup analysis based on duration of symptoms found no significant difference in clinical status between arms.
Secondary Outcomes - Mortality by Day 29: 8% in RDV arm vs. 9% in SOC arm
- Occurrence of SAEs: 33% in RDV arm vs. 31% in SOC arm (P = 0.48)
| Key Limitations- Open-label study
- 440 participants in this study also enrolled in the WHO Solidarity trial.
Interpretation - There was no clinical benefit of RDV in hospitalized patients who were symptomatic for >7 days and who required supplemental oxygen.
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WHO Solidarity Trial, Final Report: Multinational, Open-Label, Adaptive RCT in Hospitalized Patients With COVID-19 in 35 Countries4 |
Key Inclusion Criterion- Not known to have received any study drug
Interventions - RDV 200 mg IV on Day 0, then RDV 100 mg IV once daily on Days 1–9 (n = 4,146)
- Local SOC (n = 4,129)
Primary Endpoint Key Secondary Endpoint | Participant Characteristics - 46% aged 50–69 years; 22% aged ≥70 years; 63% men
- Rates of comorbidities were similar between arms
- At entry:
- 71% on supplemental oxygen
- 9% on MV
- 68% received corticosteroids during study; 4.6% received IL-6 inhibitors
Primary Outcome - In-hospital mortality: 14.5% in RDV arm vs. 15.6% in SOC arm (rate ratio 0.91; 95% CI, 0.82–1.02; P = 0.12)
- On MV: 42.1% vs. 38.6% (rate ratio 1.13; 95% CI, 0.89–1.42; P = 0.32)
- Not on MV but receiving oxygen: 14.6% vs. 16.3% (rate ratio 0.87; 95% CI, 0.76–0.99; P = 0.03)
- Not on oxygen initially: 2.9% vs. 3.8% (rate ratio 0.76; 95% CI, 0.46–1.28; P = 0.30)
Secondary Outcome - Initiation of MV: 14.1% in RDV arm vs. 15.7% in SOC arm (rate ratio 0.88; 95% CI, 0.77–1.00; P = 0.04)
| Key Limitations- Open-label study
- No data on time from symptom onset to enrollment
- Data analysis did not separate receipt of low-flow and high-flow oxygen
Interpretation - There was no benefit of RDV in patients who were on MV at baseline.
- Compared to SOC, RDV had a modest but statistically significant effect on reducing the risk of death or progression to MV in hospitalized patients who required oxygen.
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GS-US-540-5774 Study: Multinational, Open-Label RCT of 10 Days or 5 Days of Remdesivir Compared With Standard of Care in Hospitalized Patients With Moderate COVID-19 in Asia, Europe, and the United States5 |
Key Inclusion Criteria- Laboratory-confirmed SARS-CoV-2 infection
- Pulmonary infiltrates
- SpO2 >94% on room air
Key Exclusion Criteria- ALT or AST >5 times ULN
- CrCl <50 mL/min
Interventions - RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily for 9 days (n = 193)
- RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily for 4 days (n = 191)
- Local SOC (n = 200)
Primary Endpoint - Clinical status at Day 11, as measured by an OS
| Participant Characteristics - Demographic and baseline disease characteristics were similar across arms.
- Median age 57 years; 61% men; 58% White
- 84% required no supplemental oxygen; 15% required low-flow oxygen; 1% required HFNC oxygen or NIV
- Concomitant medication use in the 10-day RDV, 5-day RDV, and SOC arms:
- Steroids: 15%, 17%, 19%
- Tocilizumab: 1%, 1%, 5%
- HCQ or CQ: 11%, 8%, 45%
- LPV/RTV: 6%, 5%, 22%
- AZM: 21%, 18%, 31%
- Median duration of therapy: 6 days in 10-day RDV arm vs. 5 days in 5-day RDV arm
Primary Outcome - Clinical status at Day 11:
- Significantly better in 5-day RDV arm than in SOC arm (OR 1.65; 95% CI, 1.09–2.48; P = 0.02)
- No difference between 10-day RDV arm and SOC arm (P = 0.18)
| Key Limitations- Open-label design may have affected decisions on concomitant medications (e.g., more patients in SOC arm received AZM, HCQ or CQ, and LPV/RTV) and time of hospital discharge.
- No data on time to return to activity for discharged patients
Interpretation - Hospitalized patients with moderate COVID-19 who received 5 days of RDV had better clinical status at Day 11 than those who received SOC.
- There was no difference in clinical status at Day 11 between patients who received 10 days of RDV and those who received SOC.
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GS-US-540-5773 Study: Multinational, Open-Label RCT of 10 Days or 5 Days of Remdesivir Compared With Standard of Care in Hospitalized Patients With Severe COVID-19 in Asia, Europe, and the United States6 |
Key Inclusion Criteria- Laboratory-confirmed SARS-CoV-2 infection
- Aged ≥12 years
- Pulmonary infiltrates and SpO2 ≤94% on room air or receipt of supplemental oxygen
Key Exclusion Criteria- Need for MV or ECMO
- Multiorgan failure
- ALT or AST >5 times ULN
- Estimated CrCl <50 mL/min
Interventions - RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily for 4 days (n = 200)
- RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily for 9 days (n = 197)
Primary Endpoint - Clinical status at Day 14, as measured by an OS
| Participant Characteristics - Median age: 61 years in 5-day RDV arm vs. 62 years in 10-day RDV arm
- 60% men in 5-day RDV arm; 68% men in 10-day RDV arm
- Oxygen requirements at baseline for 5-day RDV arm and 10-day RDV arm:
- None: 17%, 11%
- Low-flow oxygen: 56%, 54%
- HFNC oxygen or NIV: 24%, 30%
- MV or ECMO: 2%, 5%
- Baseline clinical status worse in 10-day arm than in 5-day arm (P = 0.02)
Primary Outcome - After adjusting for baseline clinical status:
- Proportion with clinical improvement at Day 14: 65% in 5-day RDV arm vs. 54% in 10-day RDV arm (P = 0.14)
| Key Limitations- Open-label study
- Lack of placebo arm
- Baseline imbalances in clinical status of patients in 5-day RDV and 10-day RDV arms
Interpretation - In hospitalized patients with severe COVID-19 who were not receiving MV or ECMO, using RDV for 5 or 10 days had similar clinical benefits.
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PINETREE: Double-Blind, Placebo-Controlled Trial of Remdesivir for 3 Days in Nonhospitalized Patients With COVID-19 Who Were at High Risk of Disease Progression in Denmark, Spain, the United Kingdom, and the United States7 |
Key Inclusion Criteria- Laboratory-confirmed SARS-CoV-2 infection ≤4 days from screening
- Aged ≥12 years
- ≥1 risk factor for disease progression or aged ≥60 years
- Symptom onset ≤7 days from randomization
- ≥1 ongoing COVID-19 symptom
Key Exclusion Criteria- COVID-19 vaccination
- Receipt of supplemental oxygen
- Previous hospitalization or treatment for COVID-19
Interventions - RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily on Days 2 and 3 (n = 279)
- Placebo (n = 283)
Primary Endpoints - COVID-19-related hospitalization or death from any cause by Day 28
- Occurrence of AEs
Key Secondary Endpoint - COVID-19-related, medically attended visit or death from any cause by Day 28
| Participant Characteristics - Mean age 50 years; 30% aged ≥60 years; 52% men; 80% White, 8% Black
- 62% with DM; 55% with obesity; 48% with HTN
- Median duration of symptoms before first infusion: 5 days (IQR 3–6 days)
- Median time from RT-PCR confirmation: 2 days (IQR 1–4 days)
Primary Outcomes - COVID-19-related hospitalization or death from any cause by Day 28: 2 (0.7%) in RDV arm vs. 15 (5.3%) in placebo arm (HR 0.13; 95% CI, 0.03–0.59; P = 0.008)
- Occurrence of AEs: 42% in RDV arm vs. 46% in placebo arm
Secondary Outcome - COVID-19-related, medically attended visit or death from any cause by Day 28: 4 (1.6%) in RDV arm vs. 21 (8.3%) in placebo arm (HR 0.19; 95% CI, 0.07–0.56)
| Key Limitations- Study halted early due to administrative issues.
- Vaccinated individuals were excluded.
Interpretation - 3 consecutive days of IV RDV resulted in an 87% relative reduction in the risk of hospitalization or death when compared to placebo.
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