Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial
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Abstract
Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized, single-blind, placebo-controlled trial (NCT04331899) in 120 outpatients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) within 72 hours of diagnosis could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39). Both Lambda and placebo were well-tolerated, though liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.
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SciScore for 10.1101/2020.11.18.20234161: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The study was performed as an investigator initiated clinical trial with the FDA (IND 419217), and approved by the Institutional Review Board of Stanford University.
Consent: After confirming eligibility and providing informed consent in the patient’s primary language, participants underwent a standardized history and physical exam, and completed bloodwork.Randomization Trial Design and Oversight: We conducted a Phase 2, single-blind, randomized placebo-controlled trial to evaluate the efficacy of Lambda in reducing the duration of viral shedding in outpatients. Blinding Since the nurse administering the medication might see syringe differences, the study was … SciScore for 10.1101/2020.11.18.20234161: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement IRB: The study was performed as an investigator initiated clinical trial with the FDA (IND 419217), and approved by the Institutional Review Board of Stanford University.
Consent: After confirming eligibility and providing informed consent in the patient’s primary language, participants underwent a standardized history and physical exam, and completed bloodwork.Randomization Trial Design and Oversight: We conducted a Phase 2, single-blind, randomized placebo-controlled trial to evaluate the efficacy of Lambda in reducing the duration of viral shedding in outpatients. Blinding Since the nurse administering the medication might see syringe differences, the study was not strictly “double-blind” even though all participants and investigators were blinded to treatment arm. Power Analysis Sample Size Determination: Assuming 1:1 randomization and the use of a two-sided log rank test at the alpha=0.04999 level of significance for the final analysis, we anticipated the occurrence of 79 shedding cessation events, which provided 80% power to detect a hazard ratio of 2.03. Sex as a biological variable Additional effect modifiers specified a priori were 1) having a CT value < 30 (vs ≥ 30) on baseline oropharyngeal swab, 2) IgG seropositivity at baseline, and 3) number of risk factors or predictors for severe disease present at baseline (temperature ≥ 99.5, cough, or shortness of breath present at randomization [symptoms count as a single risk factor], age ≥ 60, male sex, Black race, Hispanic ethnicity, body mass index ≥ 30, and lab values of baseline lymphocyte counts < 1000 and baseline ALT ≥ 94) Table 2: Resources
Antibodies Sentences Resources 25 Briefly, heat inactivated serum samples at enrolment were diluted 5-fold starting at 1:50 and IgG antibody titers against RBD determined by ELISA. IgGsuggested: NoneSoftware and Algorithms Sentences Resources This dose is also currently being used in hepatitis D trials, and was provided by Eiger BioPharmaceuticals for use in this study. Eiger BioPharmaceuticalssuggested: NoneParticipant Follow Up: Participants completed a daily symptom questionnaire using REDCap Cloud version 1.5. REDCapsuggested: (REDCap, RRID:SCR_003445)Oropharyngeal swabs were tested for SARS-CoV-2 in the Stanford Clinical Virology Laboratory using an emergency use authorized, laboratory-developed, RT-PCR.38,39 40 Centers for Disease Control and Prevention guidelines identify oropharyngeal swabs as acceptable upper respiratory specimens to test for the presence of SARS-CoV-2 RNA,24 and detection of SARS-CoV-2 RNA swabs using oropharyngeal swabs was analytically validated in the Stanford virology laboratory. Stanford Clinical Virology Laboratorysuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:The study did have a few limitations. We recruited both symptomatic and asymptomatic patients. Asymptomatic patients contributed less to secondary outcomes since they presented with lower viral RNA levels and could not contribute to analyses of symptom alleviation. However, these patients represented <10% of the enrolled cohort. Additionally, despite a reported median duration of symptoms prior to randomization of only 5 days, 40% of participants were already seropositive at enrollment. Unpublished data from a Regeneron outpatient monoclonal antibody study with similar study design (REGN-COV2) found similar rates of baseline SARS-CoV-2 IgG seropositivity (45%).37 These data suggest that enrolling COVID-19 outpatients early in the course of disease, before they develop an antibody response, may be challenging. Nonetheless, we found no suggestion of benefit of Lambda in seronegative individuals. Finally, the median time to cessation in the placebo arm was shorter than assumed in our sample size calculations, potentially due to less severe disease in this population. However, our original sample size estimates based on the number of events and median time to event were conservative; a shorter time to cessation, keeping all other assumptions the same, increases the power to detect differences between groups. In conclusion, a single dose of subcutaneous Peginterferon Lambda-1a, while safe, neither reduced time to cessation of viral shedding nor symptom duration in outpatients with...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04331899 Active, not recruiting Single-Blind Study of a Single Dose of Peginterferon Lambda-… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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