A Phase 2a randomized, single-center, double-blind, placebo-controlled study to evaluate the safety and preliminary efficacy of oral iOWH032 against cholera diarrhea in a controlled human infection model

Abstract

Cholera remains a major cause of infectious diarrhea globally. Despite the increased availability of cholera vaccines, there is still an urgent need for other effective interventions to reduce morbidity and mortality. Furthermore, increased prevalence of antibiotic-resistant Vibrio cholerae threatens the use of many drugs commonly used to treat cholera. We developed iOWH032, a synthetic small molecule inhibitor of the cystic fibrosis transmembrane conductance regulator chloride channel, as an antisecretory, host-directed therapeutic for cholera. In the study reported here, we tested iOWH032 in a Phase 2a cholera controlled human infection model. Forty-seven subjects were experimentally infected with V. cholerae El Tor Inaba strain N16961 in an inpatient setting and randomized to receive 500 mg iOWH032 or placebo by mouth every 8 hours for 3 days to determine the safety and efficacy of the compound as a potential treatment for cholera. We found that iOWH032 was generally safe and achieved a mean (± standard deviation) plasma level of 4,270 ng/mL (±2,170) after 3 days of oral dosing. However, the median (95% confidence interval) diarrheal stool output rate for the iOWH032 group was 25.4 mL/hour (8.9, 58.3), compared to 32.6 mL/hour (15.8, 48.2) for the placebo group, a reduction of 23%, which was not statistically significant. There was also no significant decrease in diarrhea severity and number or frequency of stools associated with iOWH032 treatment. We conclude that iOWH032 does not merit future development for treatment of cholera and offer lessons learned for others developing antisecretory therapeutic candidates that seek to demonstrate proof of principle in a cholera controlled human infection model study. Trial registration: This study is registered with ClinicalTrials.gov as NCT04150250.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Consolidated Standards for Reporting of Trials flow diagram.

Fig 2. Reverse cumulative distribution plot for diarrheal stool output rate overall in the modified intent-to-treat population.

The curve for the iOWH032 is shifted to the left of the placebo group, indicating a lower diarrheal stool output rate; however, this difference was not statistically significant (Van Elteren test: p = 0.2254).

Fig 3. Scatterplot of iOWH032 plasma concentrations versus diarrheal stool output rate.

Blue dots: plasma levels at 7 hours after dose 1; orange dots: plasma levels at 7 hours after dose 9. Dotted lines: linear regression plots. The Pearson correlation coefficients for these lines are –0.2997 for post dose 1 data and –0.3937 for post dose 9 data.