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.
Dong, Steven D
Mercer, Laina D
Tennant, Sharon M
Chen, Wilbur H
de Hostos, Eugenio L
Choy, Robert K M
JournalPLoS Neglected Tropical Diseases
PublisherPublic Library of Science
MetadataShow full item record
AbstractCholera 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.
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/17266
- Randomized, double-blind, placebo-controlled, multicentered trial of the efficacy of a single dose of live oral cholera vaccine CVD 103-HgR in preventing cholera following challenge with Vibrio cholerae O1 El tor inaba three months after vaccination.
- Authors: Tacket CO, Cohen MB, Wasserman SS, Losonsky G, Livio S, Kotloff K, Edelman R, Kaper JB, Cryz SJ, Giannella RA, Schiff G, Levine MM
- Issue date: 1999 Dec
- Developing novel antisecretory drugs to treat infectious diarrhea.
- Authors: de Hostos EL, Choy RK, Nguyen T
- Issue date: 2011 Aug
- Randomized, controlled human challenge study of the safety, immunogenicity, and protective efficacy of a single dose of Peru-15, a live attenuated oral cholera vaccine.
- Authors: Cohen MB, Giannella RA, Bean J, Taylor DN, Parker S, Hoeper A, Wowk S, Hawkins J, Kochi SK, Schiff G, Killeen KP
- Issue date: 2002 Apr
- New drug targets for cholera therapy.
- Authors: Thiagarajah JR, Verkman AS
- Issue date: 2005 Apr
- The vaccine candidate Vibrio cholerae 638 is protective against cholera in healthy volunteers.
- Authors: García L, Jidy MD, García H, Rodríguez BL, Fernández R, Año G, Cedré B, Valmaseda T, Suzarte E, Ramírez M, Pino Y, Campos J, Menéndez J, Valera R, González D, González I, Pérez O, Serrano T, Lastre M, Miralles F, Del Campo J, Maestre JL, Pérez JL, Talavera A, Pérez A, Marrero K, Ledón T, Fando R
- Issue date: 2005 May