Efficacy of the TMPRSS2 inhibitor camostat mesilate in patients hospitalized with Covid-19-a double-blind randomized controlled trial

Abstract

Background: The trans-membrane protease serine 2 (TMPRSS2) is essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry and infection. Efficacy and safety of TMPRSS2 inhibitors in patients with coronavirus disease 2019 (Covid-19) have not been evaluated in randomized trials.

Methods: We conducted an investigator-initiated, double-blind, randomized, placebo-controlled multicenter trial in patients hospitalized with confirmed SARS-CoV-2 infection from April 4, to December 31, 2020. Within 48 h of admission, participants were randomly assigned in a 2:1 ratio to receive the TMPRSS2 inhibitor camostat mesilate 200 mg three times daily for 5 days or placebo. The primary outcome was time to discharge or clinical improvement measured as ≥2 points improvement on a 7-point ordinal scale. Other outcomes included 30-day mortality, safety and change in oropharyngeal viral load.

Findings: 137 patients were assigned to receive camostat mesilate and 68 to placebo. Median time to clinical improvement was 5 days (interquartile range [IQR], 3 to 7) in the camostat group and 5 days (IQR, 2 to 10) in the placebo group (P = 0·31). The hazard ratio for 30-day mortality in the camostat compared with the placebo group was 0·82 (95% confidence interval [CI], 0·24 to 2·79; P = 0·75). The frequency of adverse events was similar in the two groups. Median change in viral load from baseline to day 5 in the camostat group was -0·22 log₁₀ copies/mL (p <0·05) and -0·82 log₁₀ in the placebo group (P <0·05).

Interpretation: Under this protocol, camostat mesilate treatment was not associated with increased adverse events during hospitalization for Covid-19 and did not affect time to clinical improvement, progression to ICU admission or mortality. ClinicalTrials.gov Identifier: NCT04321096. EudraCT Number: 2020-001200-42.

Fig. 1

CONSORT 2010 flow diagram.

Fig. 2

Score on 7-point ordinal scale over time. Cumulative percentage of 7-point ordinal scale at baseline, day 5, 14 and 30 in the camostat mesilate and placebo group (Table S1 for absolute numbers). IMV denotes invasive mechanical ventilation, and NIV noninvasive ventilation.

Fig. 3

Kaplan-meier estimates of cumulative recoveries. Cumulative recovery estimates are shown in the modified intention-to-treat population (Panel A), in the per-protocol population (Panel B), in patients with a baseline 7-point ordinal scale of 3 (hospitalized, not requiring supplemental oxygen; Panel C), in those with a baseline 7-point ordinal scale of 4 (requiring supplemental oxygen; Panel D), in those receiving remdesivir during admission (Panel E), and in those not receiving remdesivir during admission (Panel F).

Fig. 4

SARS-CoV-2 viral load and cytokine profiling at baseline and day 5. The baseline viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal swab decreases (in log10 copies per milliliter) in overall population according to longer time since onset of symptoms (Panel A). SARS-CoV-2 viral load for each patient per group and group median (interquartile ranges and 1.5 times IQR whiskers) are shown in Panel B for camostat mesilate and placebo groups, and in camostat mesilate (Panel C) or placebo (Panel D) group receiving either remdesivir or not. The lower limit of quantification was set to 200 copies/ml. Plots show median values (line) and 25th to 75th percentiles (box). Wilcoxon signed-rank test was used to compare median between groups. Cytokine profiling of 65 patients, 24 receiving placebo and 41 receiving camostat mesilate. Values are log2 transformed ratio between day 5 and 1 for individual patients. Heatmap of log2 transformed day 5-to-1 ratio of individual patients in the two treatment groups (Panel E). ‘X’ indicates missing value. Comparison between cytokine mean change between treatment groups (camostat mesilate-placebo) were analyzed using 2-way ANOVA, and Šidák's multiple comparison test (Panel F). IL3, IL17, IL21, and IL31 did not meet quality criteria and were omitted.