Efficacy of iOWH032 in Dehydrating Cholera

The primary hypothesis is that administration of iOWH032 to adult and pediatric males and females with acute cholera due to V. cholerae O1 reduces stool output in the first 24 hours significantly more than does the current standard of care.

This is a Phase 2, randomized, double-blind, placebo-controlled study of iOWH032 in adult patients (Part A) and then pediatric patients (Part B) with acute watery diarrhea of less than 24 hours' duration due to cholera. All subjects will be treated with standard of care (IV rehydration fluids, ORS, and azithromycin less than/equal to1 g po) in addition to study drug (iOWH032 active drug or placebo). Patients will be admitted, undergo a 4- to 6-hour screening/observation period, be randomized in the study and treated with study drug (active or placebo) for up to 3 days (ie, up to 9 doses), with a follow-up visit on Day 7.

In Part A, approximately 170 adult patients with severe dehydrating diarrhea due to cholera will be enrolled and randomized 1:1 to receive iOWH032 500 mg or placebo TID for up to 3 days. Following completion of Part A, the data and safety monitoring board (DSMB) will review the unblinded data to assess safety and efficacy and conduct a futility analysis prior to proceeding to Part B.

Following the DSMB recommendation of dose and dosing schedule for pediatric patients, Part B will be initiated. Approximately 156 pediatric patients with severe dehydrating diarrhea due to cholera will be enrolled and randomized 1:1 to receive iOWH032 or placebo at the recommended dose and dosing regimen.

The primary efficacy population for Parts A and B will consist of patients who tolerate the first 3 doses of study drug (0, 8, and 16 hours post-randomization) without vomiting and whose diagnosis is subsequently confirmed by a positive culture for V. cholerae O1.

The International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) Ethics Committee and Western Institutional Review Board (WIRB) will be informed of any serious adverse event (SAE). Occurrence of 2 or more drug-related SAEs within a group of 10 patients (20% of cumulative completed patients in the treatment group) in Part A or Part B will result in unblinding of those patients and review by the DSMB. The study can be halted, discontinued, or amended according to the recommendations of the icddr,b DSMB.

Eligibility Criteria:
Approximately 170 adult (male and female) patients must be enrolled to ensure that 96 patients (48 active and 48 placebo) are evaluable in Part A. In Part B, approximately 156 pediatric patients will be enrolled to ensure that 120 pediatric patients (60 active and 60 placebo) are evaluable for the analysis of 24 hour stool output, the primary outcome measure.

PART A - ADULTS

\*\*\*Inclusion Criteria\*\*\*

A patient will be considered eligible for participation in the study if the following inclusion criteria are satisfied on admission (Day 1) to the Dhaka Hospital of icddr,b:

* Adults aged 18 years to 55 years
* Duration of illness: History of acute watery diarrhea of less than 24 hours' duration without fever or visible blood in feces
* Clinical signs and symptoms of severe dehydration (\>10% loss of body weight based on rehydration weight)
* Stool RDT and/or stool DF microscopy demonstrating presence of V. cholerae
* Must have a purging rate greater than/equal to 20 mL/kg (5 mL/kg/h) during the initial 4- to 6-hour screening/observation period, and signs of clinical dehydration must be corrected
* Written informed consent for participation in the study (see Section 6.1.2 for details of the consent process)
* Negative urine pregnancy test for all female patients
* Nonpregnant and nonlactating females of childbearing potential agree to either abstain from sex or use double barrier contraception (2 contraceptive methods at a time) during the study and until 1 month after the last dose of study drug

\*\*\*Exclusion Criteria\*\*\*

A patient with any of the following criteria at screening for study enrollment will not qualify for the study:

* Received antidiarrheal medication (eg, loperamide, diphenoxylate) within 7 days before screening
* Abnormal ECG findings, with the exception of sinus tachycardia, premature atrial contractions, or ECG intervals within normal limits for sinus rate
* Use of drugs metabolized predominantly via CYP2C9 within 7 days before screening (see Section 5.7)
* Concomitant infection requiring antimicrobial therapy other than the study drug that may interfere with the evaluation of either the efficacy or safety of the study drug
* Patients unwilling or unable to take part in this study or refusing to sign informed consent (patients who participate on the basis of proxy consent will be re-consented at the end of the screening/observation period; those refusing consent at that time will be excluded from further study participation)
* Patients previously enrolled in this or any other investigational study within the past 30 days

PART B - PEDIATRIC

\*\*\*Inclusion Criteria\*\*\*

A patient will be considered eligible for participation in the study if the following inclusion criteria are satisfied on admission (Day 1) to the Clinical Research Ward (CRW) of Dhaka Hospital:

* Pediatric population aged ≥ 5 years to \< 18 years of age
* Duration of illness: History of acute watery diarrhea of less than 24 hours' duration without fever or visible blood in feces
* Clinical signs and symptoms of severe dehydration (\>10% loss of body weight based on rehydration weight)
* Stool RDT and/or stool DF microscopy demonstrating presence of V. cholerae
* Must have a purging rate ≥5 mL/kg/h average during the initial 4- to 6-hour screening/observation period and signs of clinical dehydration must be corrected
* Parental consent for all pediatric patients participating in the study and written informed assent for children aged 11-17 years (see Section 6.1.2 for details of the consent process)
* Negative urine pregnancy test for female postmenarchal patients
* Nonpregnant and nonlactating females of childbearing potential agree to either abstain from sex or use double-barrier contraception (2 contraceptive methods at a time) during the study and until 1 month after the last dose of study drug

\*\*\*Exclusion Criteria\*\*\*

A patient with any of the following criteria at screening for study enrollment will not qualify for the study:

* Received antidiarrheal medication (eg, loperamide, diphenoxylate) within 7 days before screening
* Abnormal ECG findings, with the exception of sinus tachycardia, premature atrial contractions, or ECG intervals within normal limits for sinus rate
* Use of drugs metabolized predominantly via CYP2C9 (see Section 5.7) within 7 days before screening
* Concomitant infection requiring antimicrobial therapy other than the study drug that may interfere with evaluation of either the efficacy or safety of the study drug
* Children or parents/guardians unwilling or unable to take part in this study or refusing to sign informed assent/consent; applicable patients who participate on the basis of proxy assent/consent will be re-assented at the end of the screening/observation period; those refusing assent/consent at that time will be excluded from further study participation
* Patients previously enrolled in this or any other investigational study with the past 30 days