Efficacy of Niclosamide vs Placebo in SARS-CoV-2 Respiratory Viral Clearance, Viral Shedding, and Duration of Symptoms Among Patients With Mild to Moderate COVID-19: A Phase 2 Randomized Clinical Trial

Abstract

Importance: Oral anthelmintic niclosamide has potent in vitro antiviral activity against SARS-CoV-2. Repurposed niclosamide could be a safe and efficacious COVID-19 therapy.

Objective: To investigate whether niclosamide decreased SARS-CoV-2 shedding and duration of symptoms among patients with mild to moderate COVID-19.

Design, setting, and participants: This randomized, placebo-controlled clinical trial enrolled individuals testing positive for SARS-CoV-2 by polymerase chain reaction with mild to moderate symptoms of COVID. All trial participants, investigators, staff, and laboratory personnel were kept blind to participant assignments. Enrollment was among individuals reporting at Tufts Medical Center and Wellforce Network in Massachusetts for outpatient COVID-19 testing. The trial opened to accrual on October 1, 2020; the last participant enrolled on April 20, 2021. Trial exclusion criteria included hospitalization at time of enrollment or use of any experimental treatment for COVID-19, including vaccination. Enrollment was stopped before attaining the planned sample size when COVID-19 diagnoses decreased precipitously in Massachusetts. Data were analyzed from July through September 2021.

Interventions: In addition to receiving current standard of care, participants were randomly assigned on a 1:1 basis to receive niclosamide 2 g by mouth daily for 7 days or identically labeled placebo at the same dosing schedule.

Main outcomes and measures: Oropharyngeal and fecal samples were self-collected for viral shedding measured by reverse-transcriptase-polymerase-chain-reaction on days 3, 7, 10, and 14, and an additional fecal sample was collected on day 21. A telehealth platform was developed to conduct remote study visits, monitor symptoms, and coordinate sample collection via couriers. The primary end point was the proportion of participants with viral clearance in respiratory samples at day 3 based on the intention-to-treat sample. Mean times to viral clearance and symptom resolution were calculated as restricted mean survival times and accounted for censored observations.

Results: Among 73 participants, 36 individuals were enrolled and randomized to niclosamide and 37 individuals to placebo. Participant characteristics were similar across treatment groups; among 34 patients receiving placebo and 33 patients receiving niclosamide in the intention-to-treat sample, mean (SD) age was 36.0 (13.3) years vs 36.8 (12.9) years and there were 21 (61.8%) men vs 20 (60.6%) men. The overall mean (SD) age was 36.4 (13.0) years. For the primary end point, 66.67% (95% CI, 50.74% to 81.81%) of participants receiving niclosamide and 55.88% (95% CI, 40.27% to 72.73%) of participants receiving placebo had oropharyngeal SARS-CoV-2 clearance at day 3 (P = .37). Among 63 participants with symptoms, niclosamide did not significantly shorten symptom duration, which was 12.01 (95% CI, 8.82 to 15.2) days in the niclosamide group vs 14.61 (95% CI, 11.25 to 17.96) days in the placebo group (mean difference, -2.6 [95% CI, -7.23 to 2.03] days). Niclosamide was well-tolerated; the most commonly reported adverse events in the placebo and niclosamide groups were headaches (11 patients [32.4%] vs 7 patients [21.2%]; P = .31) and cough (8 patients [23.5%] vs 7 patients [21.2%]; P = .82).

Conclusions and relevance: In this randomized clinical trial, there was no significant difference in oropharyngeal clearance of SARS-CoV-2 at day 3 between placebo and niclosamide groups. Confirmation in larger studies is warranted.

Trial registration: ClinicalTrials.gov Identifier: NCT04399356.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Golan reported receiving personal fees from Pfizer, Merck, and Appili Therapeutics outside the submitted work. Dr Beaulac reported receiving personal fees from Astellas Pharma and Allergan-AbbVie and grants from Diatherix outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flow Diagram

The flow diagram summarizes the number of participants who were assessed for eligibility at screening, eligible at screening, eligible and randomized, withdrawn prior to receiving first dose, and randomized and included in the primary analysis. The flow diagram also depicts those who were eligible but not randomized, did not receive the randomized allocation, were lost to follow-up, and discontinued the intervention. aParticipant cohabited with a previously enrolled participant.

Figure 2.. SARS-CoV-2 Shedding Among Participants With and Without Fecal Shedding

A-B, Oropharyngeal and fecal shedding of SARS-CoV-2 is presented among all 65 participants and 29 participants with fecal shedding. C, Normalized baseline capsid expression (points) and mean viral load (shaded areas) among all 65 participants, including those without fecal shedding and those with fecal shedding, based on expression of SARS-CoV-2–specific nucleocapsid N1 (normalized using RNase P values) on day 1. Whiskers indicate 95% CIs. D, Oropharyngeal clearance of SARS-CoV-2 is presented among all 65 patients, including those without and those with fecal shedding. E-F, Oropharyngeal clearance of SARS-CoV-2 is presented by treatment group among 36 patients without and 29 patients with fecal shedding.

Figure 3.. Mean Time to Symptom Resolution Among Patients With COVID-19

A-D, Mean time to all symptom resolution is presented among patients with COVID-19 for all 63 participants, 27 patients with fecal shedding, 25 patients with body mass index (BMI) scores less than 25, and 28 patients with BMI scores of 25 or greater. E-F, Mean time to resolution of oropharyngeal and respiratory symptoms related to COVID-19 is presented among all participants.