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Table 4d. Interferons: Selected Clinical Trial Data

Last Updated: December 20, 2023

The clinical trials described in this table do not represent all the trials that the Panel reviewed while developing the recommendations for interferons. The studies summarized below are the randomized controlled trials that have had the greatest impact on the Panel’s recommendations.

Table 4d. Interferons: Selected Clinical Trial Data
Methods Results Limitations and Interpretation
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
  • Hospital discharge or transfer anticipated 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% Latinx, 60% White, 17% Black
  • Mean of 8.6 days of symptoms before enrollment
  • 90% had ≥1 comorbidities; 58% with HTN; 58% with obesity; 37% with DM

Primary Outcome

  • Median time to recovery: 5 days in both arms (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: >28 days in IFN beta-1a arm vs. 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

  • After 270 patients were enrolled, OS6 patients were excluded because of an increased frequency of AEs in this group.

Interpretation

  • There was no clinical benefit of adding IFN beta-1a to RDV in hospitalized patients with COVID-19.
  • The use of IFN beta-1a was associated with worse outcomes among patients who were OS6 at baseline.
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

  • 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 Outcome

  • In-hospital mortality: 11.9% in 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.
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 required supplemental oxygen

Interventions

  • IFN beta-1a 44 µg 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% with obesity; 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 between arms in clinical status at Day 29
  • No difference between arms in rate or time to SARS-CoV-2 viral clearance
  • Time to improvement of 2 OS categories and hospital discharge by Day 29 was 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.
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 single SUBQ injection, 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% received ≥1 COVID-19 vaccine dose. 

Primary Outcome

  • Composite of ED observation >6 hours or hospitalization for COVID-19 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.
Single-Blind RCT of Pegylated Interferon 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: 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 Outcome

  • Patients who received PEG-IFN lambda-1a were more likely to have elevations of transaminase concentrations than patients who received placebo (25% vs. 8%; P = 0.027).

Key Limitation

  • Small sample size

Interpretation

  • PEG-IFN lambda-1a provided no virologic or clinical benefit compared to placebo among outpatients with uncomplicated COVID-19.
Double-Blind RCT of Pegylated Interferon 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 patients with negative SARS-CoV-2 test result on nasal mid-turbinate swab 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 vs. 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 hospitalized by Day 14

Other Outcome

  • 3 participants in each arm had mild elevations of aminotransferase concentrations. Increase was greater in PEG-IFN lambda arm.

Key Limitation

  • 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.

References

  1. Kalil AC, Mehta AK, Patterson TF, et al. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, Phase 3 trial. Lancet Respir Med. 2021;9(12):1365-1376. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34672949.
  2. WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID-19—interim WHO Solidarity trial results. N Engl J Med. 2021;384(6):497-511. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33264556.
  3. Ader F, Peiffer-Smadja N, Poissy J, et al. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-beta-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clin Microbiol Infect. 2021;27(12):1826-1837. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34048876.
  4. Reis G, Moreira Silva EAS, Medeiros Silva DC, et al. Early treatment with pegylated interferon lambda for COVID-19. N Engl J Med. 2023;388(6):518-528. Available at: https://pubmed.ncbi.nlm.nih.gov/36780676.
  5. Jagannathan P, Andrews JR, Bonilla H, et al. Peginterferon lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial. Nat Commun. 2021;12(1):1967. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33785743.
  6. Feld JJ, Kandel C, Biondi MJ, et al. Peginterferon lambda for the treatment of outpatients with COVID-19: a Phase 2, placebo-controlled randomised trial. Lancet Respir Med. 2021;9(5):498-510. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33556319.