ACTT-3: Multinational, Double-Blind RCT of Interferon Beta-1a and Remdesivir in Hospitalized Adults With COVID-191 |
Key Inclusion Criteria- Evidence of pneumonia (radiographic infiltrates, SpO2 ≤94% on room air, or supplemental oxygen)
- No MV required
Key Exclusion Criteria - AST or ALT >5 times ULN
- Impaired renal function
- Anticipated hospital discharge or transfer within 72 hours
Interventions - RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily for 9 days plus IFN beta-1a 44 µg SUBQ every other day for up to 4 doses (n = 487)
- RDV 200 mg IV on Day 1, then RDV 100 mg IV once daily for 9 days plus placebo (n = 482)
Primary Endpoint - Time to recovery by Day 28
Key Secondary Endpoints - Clinical status at Day 14, as measured by an OS
- Mortality by Day 28
| Participant Characteristics - Mean age 59 years; 38% were aged ≥65 years
- 58% men; 32% Latino, 60% White, 17% Black
- Mean of 8.6 days of symptoms before enrollment
- 90% had ≥1 comorbidity; 58% with HTN; 58% with obesity; 37% with DM
Primary Outcome - Median time to recovery for both arms was 5 days (rate ratio 0.99; 95% CI, 0.87–1.13; P = 0.88).
- In patients on high-flow oxygen or NIV (OS6) at baseline, median time to recovery was >28 days in IFN beta-1a arm and 9 days in placebo arm (rate ratio 0.40; 95% CI, 0.22–0.75; P = 0.0031).
Secondary Outcomes - No difference between arms in clinical status at Day 14 (OR 1.01; 95% CI, 0.79–1.28)
- No difference between IFN beta-1a arm and placebo arm in mortality by Day 28 in:
- All patients: 5% vs. 3% (HR 1.33; 95% CI, 0.69–2.55)
- Patients who were OS6 at baseline: 21% vs. 12% (HR 1.74; 95% CI, 0.51–5.93)
| Key Limitation- OS6 patients were excluded after 270 patients were enrolled because of an increased frequency of AEs in this group.
Interpretation - There was no clinical benefit of IFN beta-1a plus RDV in hospitalized patients compared to RDV alone.
- The use of IFN beta-1a was associated with worse outcomes among patients who were OS6 at baseline.
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WHO Solidarity Trial: Multinational, Open-Label, Adaptive RCT of IV or SUBQ Interferon Beta-1a or Other Repurposed Drugs in Hospitalized Adults With COVID-192 |
Key Inclusion Criteria- Diagnosis of COVID-19
- Not expected to be transferred elsewhere within 72 hours
Interventions - IFN beta-1a 44 µg SUBQ on day of randomization, Day 3, and Day 6 (n = 1,656)
- IFN beta-1a 10 µg IV daily for 6 days for patients on high-flow oxygen, ventilation, or ECMO (n = 394)
- IFN beta-1a (either SUBQ or IV) and LPV/RTV 400 mg/50 mg twice daily for 14 days (n = 651)
- Local SOC (n = 2,050)
Primary Endpoint Key Secondary Endpoint - Initiation of ventilation
| Participant Characteristics - 35% aged <50 years; 19% aged ≥70 years; 63% men
- 70% on supplemental oxygen; 7% on ventilation
- Approximately 50% received corticosteroids during the study
Primary Outcomes - In-hospital mortality: 11.9% for combined IFN beta-1a arms vs. 10.5% in SOC arm (rate ratio 1.16; 95% CI, 0.96–1.39).
- For IFN beta-1a only (without LPV/RTV) recipients vs. SOC recipients, rate ratio was 1.12 (95% CI, 0.83–1.51).
- Among those on ventilation at baseline, age-stratified rate ratio for in-hospital mortality was 1.40 (95% CI, 0.93–2.11).
Secondary Outcome - 10% initiated ventilation in the combined IFN beta-1a arms and SOC arm.
| Key Limitations- Open-label study
- IFN beta-1a given as IV or SUBQ formulations at different doses
Interpretation - IFN beta-1a did not reduce in-hospital mortality in hospitalized patients with COVID-19.
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DisCoVeRy Solidarity Trial Add-On: Open-Label, Adaptive RCT of Interferon Beta-1a Plus Lopinavir/Ritonavir, Lopinavir/Ritonavir, or Hydroxychloroquine in Hospitalized Adults With COVID-19 in France3 |
Key Inclusion Criteria- Positive SARS-CoV-2 PCR result
- Patients had pulmonary rales or crackles with SpO2 ≤94% on room air or they required supplemental oxygen
Interventions - IFN beta-1a 44 ug SUBQ on Days 1, 3, and 6 plus LPV/RTV 400 mg/100 mg PO twice daily for 14 days plus SOC (n = 145)
- LPV/RTV 400 mg/100 mg PO twice daily for 14 days plus SOC (n = 145)
- HCQ 400 mg twice on Day 1, then HCQ 400 mg daily for 9 days plus SOC (n = 145)
- SOC alone, which included corticosteroids, anticoagulants, or immunomodulatory agents but not antivirals (n = 148)
Primary Endpoint - Clinical status at Day 15, as measured by an OS
Key Secondary Endpoints - Clinical status at Day 29
- Rate of SARS-CoV-2 viral clearance
- Time to SARS-CoV-2 viral clearance by Day 29
- Time to improvement of 2 OS categories by Day 29
- Time to hospital discharge by Day 29
| Participant Characteristics - Median age 63 years; 72% men
- 29% were obese; 26% with chronic cardiac disease; 22% with DM
- 36% had severe disease
- Median of 9 days of symptoms before randomization
- 30% received steroids during the study
Primary Outcome - No difference in clinical status at Day 15 for any intervention compared to SOC:
- IFN beta-1a plus LPV/RTV: aOR 0.69 (95% CI, 0.45–1.04; P = 0.08)
- LPV/RTV: aOR 0.83 (95% CI, 0.55–1.26; P = 0.39)
- HCQ: aOR 0.93 (95% CI, 0.62–1.41; P = 0.75)
Secondary Outcomes - No difference in clinical status at Day 29 between arms
- No difference in rate and time to SARS-CoV-2 viral clearance between arms
- Time to improvement of 2 OS categories and hospital discharge by Day 29 longer in LPV/RTV plus IFN beta-1a and LPV/RTV arms than in SOC arm
| Key Limitations- Open-label study
- Most patients had moderate disease
- No IFN beta-1a arm without LPV/RTV
- Study stopped early for futility
Interpretation - Compared to SOC alone, the use of IFN-beta-1a plus LPV/RTV did not improve clinical status, rate of viral clearance, or time to viral clearance in hospitalized patients with COVID-19.
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TOGETHER: Double-Blind, Adaptive RCT of Pegylated Interferon Lambda in Nonhospitalized Patients With COVID-19 in Brazil and Canada4 |
Key Inclusion Criteria - Positive SARS-CoV-2 antigen test result
- Within 7 days of symptom onset
- ≥1 high-risk factor for disease progression (e.g., age ≥50 years, comorbidities, immunosuppression)
- Up to 25% of patients could have no high-risk factors
Key Exclusion Criteria - Need for hospitalization
- SpO2 ≤93% on room air
Interventions - Single dose of PEG-IFN lambda 180 μg SUBQ (n = 931)
- Placebo (n = 1,018; 825 received a single SUBQ injection and 193 received PO placebo)
Primary Endpoint - Composite of ED observation >6 hours or hospitalization for COVID-19 by Day 28
Key Secondary Endpoints - Composite of COVID-19–related hospitalization or death by Day 28
- SARS-CoV-2 viral clearance at Day 7
- Occurrence of AEs
| Participant Characteristics - Median age 43 years; 57.1% women; 95.1% self-identified as mixed race
- 1,919 (98.5%) from Brazil, 30 (1.5%) from Canada
- 50% with obesity
- 59.4% were randomized within 3 days of symptom onset
- 83% had received COVID-19 vaccine
Primary Outcome - Composite of ED observation >6 hours or hospitalization by Day 28 (ITT): 25 (2.7%) in PEG-IFN lambda arm vs. 57 (5.6%) in placebo arm (relative risk 0.49; 95% Bayesian CrI, 0.30–0.76)
- 61 events (74%) were hospitalizations (ITT)
Secondary Outcomes - Composite of COVID-19–related hospitalization or death by Day 28: 22 (2.4%) in PEG-IFN lambda arm vs. 40 (3.9%) in placebo arm (relative risk 0.61; 95% CrI, 0.36–0.99)
- SARS-CoV-2 viral clearance at Day 7 among the 15% of patients with VL >192 million copies/mL at baseline: 50.5% in PEG-IFN lambda arm vs. 32.9% in placebo arm (OR 2.13; 95% CrI, 1.14–4.00)
- Occurrence of AEs: 141 (15.1%) in PEG-IFN lambda arm vs. 172 (16.9%) in placebo arm (relative risk 0.90; 95% CrI, 0.73–1.10)
| Key Limitations - Health care facility capacity may have influenced the number and duration of ED observations.
- As this was an adaptive platform trial where multiple investigational treatments or placebos were being evaluated simultaneously, not all patients in the placebo arm received a placebo that was matched to PEG-IFN lambda.
Interpretation - In outpatients with COVID-19 who were within 7 days of symptom onset, PEG-IFN lambda reduced the need for ED observations >6 hours or hospitalization when compared with placebo.
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Single-Blind RCT of Peginterferon Lambda-1a for Treatment of Outpatients With Uncomplicated COVID-19 in the United States5 |
Key Inclusion Criteria- Aged 18–65 years
- Asymptomatic or symptomatic
- Positive SARS-CoV-2 RT-PCR result within 72 hours of enrollment
Key Exclusion Criteria - Current or imminent hospitalization
- Respiratory rate >20 breaths/min
- SpO2 <94% on room air
- Decompensated liver disease
Interventions - Single dose of PEG-IFN lambda-1a 180 µg SUBQ (n = 60)
- Placebo (n = 60)
Primary Endpoint - Time to first negative SARS-CoV-2 RT-PCR result
Key Secondary Endpoints - Hospitalization by Day 28
- Time to complete symptom resolution
| Participant Characteristics - Median age 36 years; 42% women; 63% Latinx, 28% White
- 7% were asymptomatic
- Median of 5 days of symptoms before randomization
Primary Outcome - Median time to cessation of viral shedding was 7 days in both arms (aHR 0.81; 95% CI, 0.56–1.19; P = 0.29).
Secondary Outcomes - No difference between PEG-IFN lambda-1a and placebo arms in:
- Proportion of patients hospitalized by Day 28: 3.3% for each arm
- Time to resolution of symptoms: 8 days vs. 9 days (HR 0.94; 95% CI, 0.64–1.39)
Other Outcomes - Patients who received PEG-IFN lambda-1a were more likely to have transaminase elevations than patients who received placebo (25% vs. 8%; P = 0.027).
| Key Limitation Interpretation - PEG-IFN lambda-1a provided no virologic or clinical benefit compared to placebo among outpatients with uncomplicated COVID-19.
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Double-Blind RCT of Peginterferon Lambda in Outpatients With Laboratory-Confirmed COVID-19 in Canada6 |
Key Inclusion Criteria- Positive SARS-CoV-2 PCR result
- Patients were within 7 days of symptom onset, or, if asymptomatic, were within 7 days of first positive SARS-CoV-2 test result
Key Exclusion Criterion - Immunosuppression or condition that could be worsened by PEG-IFN lambda
Interventions - Single dose of PEG-IFN lambda 180 µg SUBQ (n = 30)
- Placebo (n = 30)
Primary Endpoint - Proportion of participants with negative nasal mid-turbinate swab for SARS-CoV-2 RNA at Day 7
Key Secondary Endpoints - Quantitative change in SARS-CoV-2 RNA over time
- Hospitalization by Day 14
| Participant Characteristics - Median age 46 years; 58% women; 52% White
- 19% were asymptomatic
- Mean of 4.5 days of symptoms before randomization
Primary Outcome - 80% in PEG-IFN lambda arm and 63% in placebo arm were negative for SARS-CoV-2 RNA at Day 7 (P = 0.15).
Secondary Outcomes - VL decline by Day 7 was greater in PEG-IFN lambda arm than in placebo arm (P = 0.0041).
- 1 participant in each arm was admitted to the hospital by Day 14.
Other Outcomes - 3 participants in each arm had mild elevation of aminotransferase concentrations. Increase was greater in PEG-IFN lambda arm.
| Key Limitation Interpretation - PEG-IFN lambda may accelerate VL decline and clearance in outpatients with COVID-19; however, the clinical significance of this finding is unclear.
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