Table 4d. Interferons: Selected Clinical Data

• 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 improvement at 14 days (OR 1.01; 95% CI, 0.79–1.28).
• No difference between arms in mortality by Day 28 in:
  • All patients: 5% vs. 3% (HR 1.33; 95% CI, 0.69–2.55)
  • Patients with OS6 at baseline: 21% vs. 12% (HR 1.74; 95% CI, 0.51–5.93)

• 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.

• 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

• In-hospital mortality

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 was 11.9% for combined IFN beta-1a arms and 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 entry, 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.

• Open-label study
• IFN beta-1a given as IV or SUBQ formulations at different doses

Interpretation

• IFN beta-1a does not improve mortality for hospitalized patients.

• Positive PCR result for SARS-CoV-2
• Patients had pulmonary rales or crackles with SpO₂ ≤94% 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
• Time to improvement of 2 OS categories
• Time to hospital discharge

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 from symptom onset to 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 the arms.
• No difference in rate and time to SARS-CoV-2 viral clearance between the arms.
• Time to 2 OS-category improvement and hospital discharge by Day 29 was longer in LPV/RTV plus IFN beta-1a and LPV/RTV arms than in SOC arm.

• 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.

• Aged 18–65 years
• Asymptomatic or symptomatic
• Positive RT-PCR result for SARS-CoV-2 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

• Hospitalizations 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).

• Small sample size

Interpretation

• PEG-IFN lambda-1a provided no virologic or clinical benefit compared to placebo among outpatients with uncomplicated COVID-19.

• 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 at Day 7

Key Secondary Endpoints

• Quantitative change in SARS-CoV-2 RNA over time
• Hospitalizations 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 arms 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.

• Small sample size

Interpretation

• PEG-IFN lambda may accelerate VL decline and clearance in outpatients with COVID-19; however, the clinical significance of this finding is unclear.