A multicenter, double-blind, randomized, parallel-group, placebo-controlled study to evaluate the efficacy and safety of camostat mesilate in patients with COVID-19 (CANDLE study)
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Abstract
Background
In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19).
Methods
This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2.
Results
One-hundred fifty-five patients were randomized to receive camostat mesilate ( n = 78) or placebo ( n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0–12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0–13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified.
Conclusions
Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms.
Trial registration
ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.
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SciScore for 10.1101/2022.03.27.22271988: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: The protocol and patient consent forms were approved by the ethics committees or institutional review boards at all participating institutions (appendix p 1).
IRB: The protocol and patient consent forms were approved by the ethics committees or institutional review boards at all participating institutions (appendix p 1).Sex as a biological variable not detected. Randomization Study design: The study comprised a double-blind phase (up to 14 days) in which they were randomised to receive camostat mesilate or placebo, and a 2-week follow-up period after the last dose of the study drug. Blinding not detected. Power Analysis (appendix p 2 [sample size calculation]). Table 2: Resources
Antibodies S… SciScore for 10.1101/2022.03.27.22271988: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: The protocol and patient consent forms were approved by the ethics committees or institutional review boards at all participating institutions (appendix p 1).
IRB: The protocol and patient consent forms were approved by the ethics committees or institutional review boards at all participating institutions (appendix p 1).Sex as a biological variable not detected. Randomization Study design: The study comprised a double-blind phase (up to 14 days) in which they were randomised to receive camostat mesilate or placebo, and a 2-week follow-up period after the last dose of the study drug. Blinding not detected. Power Analysis (appendix p 2 [sample size calculation]). Table 2: Resources
Antibodies Sentences Resources Changes in viral load, antibody responses (IgG and IgM), and safety outcomes were analysed descriptively in terms of the number and percentage of patients or summary statistics, as appropriate. IgMsuggested: NoneSoftware and Algorithms Sentences Resources SARS-CoV-2 infection must have been tested using a standard method at the time the study was conducted (e.g., reverse transcriptase-polymerase chain reaction [RT-PCR] test, loop-mediated isothermal amplification [LAMP] test, or antigen test). LAMPsuggested: (LAMP, RRID:SCR_001740)SAS version 9.4 (SAS Institute, Cary, NC, USA) was used for all statistical analyses. SAS Institutesuggested: (Statistical Analysis System, RRID:SCR_008567)Results 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:A limitation of this study is that the improvement of the ordinal scale of severity could not be evaluated correctly because most patients were hospitalised for daily viral testing regardless of the presence or absence of symptoms and were hence classified as grade 3. Another possible limitation is that the effects of camostat mesilate against SARS-CoV-2 were evaluated using nasopharyngeal and nasal swab samples in the majority of patients. However, the appropriateness of an index of upper airway viral load in asymptomatic to moderate cases remains questionable. It is considered that the epidemic strain at the time was a D614G strain, but no data on the type of strain were collected for this study. Efficacy against currently circulating variants is unknown. There are some strengths of this study that should be mentioned. In particular, this was a double-blind, randomised, placebo-controlled study with robust randomisation as demonstrated by the high similarity of both groups. In addition, this study used a dose that was four to eight times higher than the clinical doses in Japan used for the acute symptoms of chronic pancreatitis and postoperative reflux oesophagitis based on the preclinical and early clinical evidence. Furthermore, the efficacy of camostat mesilate was assessed using multiple clinically relevant endpoints, including local and central laboratory tests for SARS-CoV-2 infection and viral load. Although the study results were negative, there were several lessons...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04657497 Completed A Study of FOY-305 in Patients With SARS-Cov-2 Infection (CO… 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.
Results from scite Reference Check: We found no unreliable references.
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