Efficacy of iOWH032 in Dehydrating Cholera
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.
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