Peginterferon lambda for the treatment of outpatients with COVID-19: a phase 2, placebo-controlled randomised trial

Abstract

Background To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. MethodsIn this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 µg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computergenerated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ² test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259.Findings Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2•42 log copies per mL at day 7 (p=0•0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0•15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4•12 [95% CI 1•15-16•73; p=0•029). Of those with baseline viral load above 10⁶ copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6•25 [95% CI 1•49-31•06]; p=0•012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported.Interpretation Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding.

Evaluation of Dried Blood Spot Testing for SARS-CoV-2 Serology Using a Quantitative Commercial Assay

“…Matched plasma and dried blood spots were also collected from 52 PCR-positive confirmed patients, 90 days or greater from diagnosis, and 11 healthy controls ( Table S2 ). These 52 patients were recruited from a phase II randomized clinical trial of COVID-19 treatment [ 33 ]. Blood was collected by finger prick to fill the spots on a Whatman 903 Protein Saver card.…”

Characterising SARS-CoV-2 viral clearance kinetics to improve the design of antiviral pharmacometric studies

“…This has led the WHO to recommend against its use in COVID-19 [13]. Indeed, no antiviral small molecule drug has yet shown life saving benefit in COVID-19 infections, nor is there any definitive evidence yet that any antiviral drugs accelerate viral clearance [14], although a randomised placebo controlled trial of peginterferon lambda (a large molecule biological antiviral) in 60 COVID-19 outpatients showed greater viral decline in the peginterferon group [15]. We note that the primary endpoint in this trial was the proportion qPCR negative 7 days after enrolment, an endpoint which has the same disadvantages as time to clearance.…”

“…We note that the primary endpoint in this trial was the proportion qPCR negative 7 days after enrolment, an endpoint which has the same disadvantages as time to clearance. In addition, 15 out of the 60 patients had undetectable virus at baseline [15] emphasising the need to select patients shortly after symptom onset. The final analysis did adjust for baseline viral load but most studies describing viral clearance ‘rates’ are reporting the time to a negative nasopharyngeal swab without adjustment for the baseline viral load.…”

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

“…An alternative suggested by the IRAP model might be to stimulate a natural interferon release using RIG1, NOD1 and, perhaps, TLR3 agonists (Figure 12). Indeed, a just-released clinical study demonstrated that COVID-19 patients treated with the hepatitis drug peg-interferon are four times more likely to recover quickly and clear their SARS-CoV-2 infection than equivalently treated patients not given that drug [273].…”