ACTT-1: Multinational, Placebo-Controlled, Double-Blind RCT of Remdesivir in Hospitalized Patients With COVID-191 |
Key Inclusion Criteria: - Laboratory-confirmed SARS-CoV-2 infection
- ≥1 of the following criteria:
- Pulmonary infiltrates
- SpO2 ≤94% on room air
- Need for supplemental oxygen, high-flow oxygen, NIV, MV, or ECMO
Key Exclusion Criteria: - ALT or AST >5 times ULN
- eGFR <30 mL/min
- Pregnancy or breastfeeding
Interventions: - RDV 200 mg IV on Day 1, then RDV 100 mg 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 58.9 years
- 53.3% White, 21.3% Black, 12.7% Asian, 23.5% Hispanic/Latinx
- Coexisting conditions: 26.2% with 1; 55.2% with ≥2
- 13.0% not on oxygen; 41.0% on supplemental oxygen; 18.2% on high-flow oxygen or NIV; 26.8% on MV or ECMO
- Median time from symptom onset to randomization: 9 days (IQR 6–12 days)
- Received corticosteroids during study: 21.6% in RDV arm; 24.4% in placebo arm
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 high-flow oxygen, NIV, MV, or ECMO at enrollment
Secondary Outcomes: - Clinical status at Day 15: improvement more likely in RDV arm (OR 1.5; 95% CI, 1.2–1.9; P < 0.001)
- Mortality by Day 29: no difference between arms
- Proportion of patients with SAEs: similar between arms (25% vs. 32%)
| Key Limitations: - Wide range of disease severity among patients; study not powered to detect differences within subgroups
- Powered to detect differences in clinical improvement, not mortality
- No data on longer-term morbidity
Interpretation: - In patients with severe COVID-19, RDV reduced 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 high-flow oxygen, NIV, MV, or ECMO, but study was not powered to detect differences within subgroups.
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DisCoVeRy: Open-Label, Adaptive RCT of Remdesivir in Hospitalized Patients With Moderate or Severe COVID-19 in Europe2 |
Key Inclusion Criteria: - Laboratory-confirmed SARS-CoV-2 infection
- Illness of any duration
- SpO2 ≤94% on room air or use of supplemental oxygen, high-flow oxygen devices, 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 Endpoint: - Mortality at Day 29
- Occurrence of SAEs
| Participant Characteristics: - Median age 64 years; 70% men; 69% White
- 74% with ≥1 coexisting condition
- 40% received corticosteroids during study
- Median days from symptom onset to randomization: 9 days in both arms
- 61% with moderate disease; 39% with severe disease
Primary Outcomes: - Clinical status at Day 15: no difference between arms (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: no difference between arms (8% in RDV arm vs. 9% in SOC arm)
- Proportion of patients with SAEs: no difference between arms (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: Multinational, Open-Label, Adaptive RCT of Repurposed Drugs in Hospitalized Patients With COVID-193 |
Key Inclusion Criteria: - Aged ≥18 years
- Not known to have received any study drug
- Not expected to be transferred elsewhere within 72 hours
Interventions: - RDV 200 mg IV on Day 0, then RDV 100 mg daily on Days 1–9 (n = 2,743)
- Local SOC (n = 2,708)
Primary Endpoint: Key Secondary Endpoint: | Participant Characteristics: - 47% aged 50–69 years; 18% aged ≥70 years
- At entry: 67% on supplemental oxygen; 9% on MV
- Rates of comorbidities similar between arms
- 48% in both arms received corticosteroids during study
Primary Outcome: - In-hospital mortality: 11.0% in RDV arm vs. 11.2% in SOC arm (rate ratio 0.95; 95% CI, 0.81–1.11)
Secondary Outcome: - Initiation of MV: 10.8% in RDV arm vs. 10.5% in SOC arm
| Key Limitations: - Open-label design limits ability to assess time to recovery, as RDV may have been continued even if patient improved.
- No data on time from symptom onset to enrollment
- No assessment of outcomes post hospital discharge
Interpretation: - RDV did not decrease in-hospital mortality or the need for MV compared to SOC.
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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-194 |
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 daily for 9 days (n = 193)
- RDV 200 mg IV on Day 1, then RDV 100 mg 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 similar across arms
- Ranges for participant characteristics across the 3 arms:
- Median age 56–58 years
- Men: 60% to 63%
- 81% to 87% required no supplemental oxygen; 12% to 18% required low-flow oxygen; 1% required high-flow 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/CQ: 11%, 8%, 45%
- LPV/RTV: 6%, 5%, 22%
- AZM: 21%, 18%, 31%
- Median length of therapy: 6 days in 10-day RDV arm; 5 days in 5-day RDV arm
Primary Outcomes: - 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 in clinical status at Day 11 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 the 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 the 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 Moderate COVID-195 |
Key Inclusion Criteria: - Laboratory-confirmed SARS-CoV-2 infection
- 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 daily for 4 days (n = 200)
- RDV 200 mg IV on Day 1, then RDV 100 mg daily for 9 days (n = 197)
Primary Endpoint: - Clinical status at Day 14, as measured by an OS
Key Secondary Endpoint: - Time to clinical improvement
- Time to recovery
| Participant Characteristics: - Median age 61 years in 5-day arm; 62 years in 10-day arm
- 60% men in 5-day arm; 68% men in 10-day arm
- Oxygen requirements at baseline for the 5-day and 10-day arms:
- None: 17%, 11%
- Low-flow supplemental oxygen: 56%, 54%
- High-flow 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: - Day 14 distribution in clinical status after adjusting for baseline clinical status: similar between arms (P = 0.14)
Secondary Outcomes: - Time to clinical improvement: similar between arms (10 days in 5-day arm vs. 11 days in 10-day arm)
- Time to recovery: Median hospitalization duration for patients discharged on or before Day 14: similar between arms (7 days in 5-day arm vs. 8 days in 10-day arm)
| Key Limitations: - Open-label trial
- Baseline imbalances in clinical status of patients in 5-day and 10-day 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 RCT of Remdesivir for 3 Days in Nonhospitalized Patients With COVID-19 at High Risk for Disease Progression6 |
Key Inclusion Criteria: - Laboratory-confirmed SARS-CoV-2 infection ≤4 days from screening
- Aged ≥12 years
- ≥1 risk factor for disease progression
- Symptom onset ≤7 days from randomization
- ≥1 ongoing COVID-19 symptom
Key Exclusion Criteria: - COVID-19 vaccination
- Supplemental oxygen
- Previous hospitalization or treatment for COVID-19
Interventions: - RDV 200 mg IV on Day 1, then RDV 100 mg daily on Days 2 and 3 (n = 279)
- Placebo (n = 283)
Primary Endpoints: - COVID-19-related hospitalizations or death from any cause by Day 28
- Any AE
Key Secondary Endpoint: - COVID-19-related, medically attended visit or death from any cause by Day 28
| Participant Characteristics: - Mean age 50 years; 30.2% aged ≥60 years; 52.1% men
- 80.4% White, 7.5% Black, 41.8% Hispanic/Latinx
- 61.6% with DM; 55.2% with obesity; 47.4% 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)
- AEs: 42.3% in RDV arm vs. 46.3% 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. 2 (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: - Three 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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