Cholera Anti-Secretory Treatment Trial

Phase 2

Completed

Conditions: Cholera

Interventions: Drug: Placebo
Drug: iOWH032
Other: V. cholerae Challenge
Drug: Antibiotics

Registration Number: NCT04150250

Lead Sponsor: PATH

Brief Summary: This trial was designed to assess safety and preliminary efficacy of oral doses of iOWH032 on diarrhea output and clinical symptoms after a cholera challenge in healthy adult participants.

Detailed Description: The study consists of a screening phase, an inpatient containment period with challenge with Vibrio cholerae on Day 1 followed by treatment with iOWH032 or placebo and a post-challenge observation period until discharge, an outpatient follow-up period of at least 28 days, and a final follow-up (by telephone) 6 months post-challenge (Day 180) for the collection of serious adverse events.

Participants will be randomized 1:1 to receive either iOWH032 500 mg every 8 hours for three days or matching placebo. Blinded therapeutic dosing will start at the onset of diarrhea or by 48 hours after ingesting the challenge inoculum of V. cholerae. The observation and management of cholera diarrhea and symptomatology will occur on an inpatient isolation research ward over a duration of approximately 11 days, including a three-day course of antibiotics to treat all participants prior to discharge from the inpatient unit.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 47

Inclusion Criteria

Willing and able to understand and provide written informed consent
Healthy male and female adults, age 18 to 44 years (inclusive), without clinically significant medical history, physical or clinical laboratory abnormalities (as per protocol-defined acceptable ranges), and protocol-defined abnormal electrocardiogram results at screening
All women must have a negative serum pregnancy test at screening and one day prior to challenge.
Agreement by participants to use an adequate method of contraception* during the study and for 4 weeks before and after the challenge.
Able to pass a written examination (comprehension assessment test) with a score of ≥ 70%, in order to demonstrate their comprehension of this study. If a participant scores at least 50%, then they will be given one more opportunity to re-test after further re-education.
Willing and able to comply with the study requirements and procedures.
- Adequate contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly and when applicable, in accordance with the product label; includes, but is not limited to, barrier with additional spermicidal foam or jelly, intrauterine device, hormonal contraception (started at least 4 weeks prior to study enrollment), or women who have intercourse limited to men who underwent vasectomy.

Exclusion Criteria

Clinically significant history of immunodeficiency, cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease, anal or rectal disorders, neurologic disease,
Current nicotine use or drug, alcohol abuse within the past 6 months
Recipient of bone marrow or solid organ transplant
Use of systemic chemotherapy in the past 5 years
Has a malignancy (excluding localized non-melanoma skin cancers) or lymphoproliferative disorders diagnosed or treated within the past 5 years
Received or plans to receive systemic immunosuppressive therapy, radiation therapy, parenteral or high-dosage inhaled steroids (> 800 µg/day of beclomethasone dipropionate or equivalent) within 6 months prior to the enrollment through 28 days after challenge
Have a history of hospitalization for psychiatric illness, suicide attempt, or confinement for danger to self or others, within the past 10 years. Participants with a psychiatric disorder (not meeting exclusion criteria, e.g., attention-deficit hyperactivity disorder) that is controlled for a minimum of 3 months and the investigator has determined that the participant's mental status will not compromise the participant's ability to comply with protocol requirements may be enrolled
Have an elevated blood pressure, systolic ≥ 150 mmHg or diastolic ≥ 90 mmHg, before challenge
Taking any of the the protocol-defined drugs that are metabolized by CYP2C9 or any of the following psychiatric medications: aripiprazole, carbamazepine, chlorpromazine, chlorprothixene, clozapine, divalproex sodium, fluphenazine, haloperidol, lithium carbonate, lithium citrate, loxapine, mesoridazine, molindone, olanzapine, perphenazine, pimozide, quetiapine, risperidone, thioridazine, thiothixene, trifluoperazine, triflupromazine, or ziprasidone
History of Guillain-Barré Syndrome
Too low or too high a body mass index (BMI < 18.5 or > 39)
Has an abnormal stool pattern defined as fewer than 3 stools per week or more than 2 stools per day within the past 6 months, and any loose stools (grade 3 or higher) during the 1-2 day acclimation period before challenge
Has regularly used laxatives in the past 6 months
Has a history of eating disorders (e.g. anorexia or bulimia) within the past 10 years
Known allergy or previous severe adverse effect to all of the following antibiotics: ciprofloxacin (or quinolones), azithromycin and doxycycline.
Previously received a licensed or investigational cholera vaccine, within 10 years
History of cholera or enterotoxigenic Escherichia coli (ETEC) infection (lab-confirmed natural infection or experimental challenge), within 10 years
Travel to a cholera-endemic area in the past 5 years
Pregnant or nursing
Positive serology for human immunodeficiency virus (HIV), hepatitis B antigen, or hepatitis C antibody
Protocol-defined clinically abnormal 12-lead electrocardiogram (ECG) at screening in the judgment of the Investigator, or based on the formal 12-lead ECG reading by a cardiologist; history of any cardiac abnormalities, including conduction abnormalities such as Wolff-Parkinson-White, dysrhythmias, or coronary artery disease
Presence of a clinically significant abnormality on physical examination, including (but not limited to): pathologic heart murmur, lymphadenopathy, hepatosplenomegaly, large abdominal scar of unclear origin
Has poor venous access, defined as the inability to obtain screening blood tests after three attempts
Currently on, or plans to be on, antibiotics (e.g., doxycycline) within 14 days prior to challenge and through 28 days after challenge
Presence of an acute illness or fever (> 100.4°F) within 72 hours of admission to the inpatient Clinical Research Unit
Taking any prescription or over-the-counter medications that contain aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), antacids, proton pump inhibitors (PPIs), anti-diarrheals, etc. within 72 hours prior to challenge
Received an investigational product within 30 days prior to randomization (90 days prior to randomization for monoclonal antibodies) or planned to participate in another research study involving an investigational product during the conduct of this study
Participants must not have donated blood in 8 weeks prior to study entry and agreed to not donate blood during and for 4 weeks following their active participation in this study
Lack of ability to fully understand the informed consent
Any other condition(s) that in the opinion of the investigator would jeopardize the safety or rights of a participant participating in the trial or would render the participant unable to comply with the protocol

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	V. cholerae Challenge	On Day 1, participants were challenged with 10\^6 CFU of freshly-harvested wild-type V. cholerae. At the onset of diarrhea, or at 48 hours after challenge, whichever occurred first, participants received oral matching iOWH032 placebo tablets every 8 hours for 3 days. Participants received a 3-day course of antibiotics starting 4 days post-challenge, or sooner if the participant met the criterion for severe cholera diarrhea.
iOWH032	Antibiotics	On Day 1, participants were challenged with 10\^6 colony-forming units (CFU) of freshly-harvested wild-type V. cholerae. At the onset of diarrhea, or at 48 hours after challenge, whichever occurred first, participants received oral iOWH032 500 mg tablets every 8 hours for 3 days. Participants received a 3-day course of antibiotics starting 4 days post-challenge, or sooner if the participant met the criterion for severe cholera diarrhea.
Placebo	Antibiotics	On Day 1, participants were challenged with 10\^6 CFU of freshly-harvested wild-type V. cholerae. At the onset of diarrhea, or at 48 hours after challenge, whichever occurred first, participants received oral matching iOWH032 placebo tablets every 8 hours for 3 days. Participants received a 3-day course of antibiotics starting 4 days post-challenge, or sooner if the participant met the criterion for severe cholera diarrhea.
iOWH032	V. cholerae Challenge	On Day 1, participants were challenged with 10\^6 colony-forming units (CFU) of freshly-harvested wild-type V. cholerae. At the onset of diarrhea, or at 48 hours after challenge, whichever occurred first, participants received oral iOWH032 500 mg tablets every 8 hours for 3 days. Participants received a 3-day course of antibiotics starting 4 days post-challenge, or sooner if the participant met the criterion for severe cholera diarrhea.
Placebo	Placebo	On Day 1, participants were challenged with 10\^6 CFU of freshly-harvested wild-type V. cholerae. At the onset of diarrhea, or at 48 hours after challenge, whichever occurred first, participants received oral matching iOWH032 placebo tablets every 8 hours for 3 days. Participants received a 3-day course of antibiotics starting 4 days post-challenge, or sooner if the participant met the criterion for severe cholera diarrhea.
iOWH032	iOWH032	On Day 1, participants were challenged with 10\^6 colony-forming units (CFU) of freshly-harvested wild-type V. cholerae. At the onset of diarrhea, or at 48 hours after challenge, whichever occurred first, participants received oral iOWH032 500 mg tablets every 8 hours for 3 days. Participants received a 3-day course of antibiotics starting 4 days post-challenge, or sooner if the participant met the criterion for severe cholera diarrhea.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-emergent Serious Adverse Events	Day 1 - Day 180	A serious adverse event (SAE) is any adverse event that resulted in any of the following outcomes: 1. Death 2. A life-threatening event. 3. Required inpatient hospitalization or prolongation of existing hospitalization 4. Resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5. Congenital abnormality or birth defect 6. Important medical event that may not result in one of the above outcomes but may jeopardize the health of the study participant and/or requires medical or surgical intervention to prevent one of the outcomes listed in the above definition of serious adverse event.
Diarrheal Stool Output Rate	Day 1 - Day 5 (up to first dose of antibiotic therapy)	Diarrheal stool output rate is defined as the total volume of diarrheal stools (in mL, Grade 3 and above) divided by the number of hours between initiation of study drug (iOWH032 or placebo) and initiation of antibiotic therapy. Stools were graded based on consistency as follows: * Grade 1 - well formed (normal stool, does not take the shape of the container) * Grade 2 - soft (normal stool, does not take the shape of the container) * Grade 3 - thick liquid (diarrhea, takes the shape of the container readily) * Grade 4 - opaque watery diarrhea * Grade 5 - rice water diarrhea (clear watery) The definition of diarrhea is a grade 3 or higher stool.
Diarrheal Stool Output Rate Including Participants With Symptom Onset After 48 Hours	Day 1 - Day 5 (up to first dose of antibiotic therapy)	Stools were graded based on consistency as follows: * Grade 1 - well formed (normal stool, does not take the shape of the container) * Grade 2 - soft (normal stool, does not take the shape of the container) * Grade 3 - thick liquid (diarrhea, takes the shape of the container readily) * Grade 4 - opaque watery diarrhea * Grade 5 - rice water diarrhea (clear watery) The definition of diarrhea is a grade 3 or higher stool. For participants with symptom onset within 48 hours of challenge diarrheal stool output rate is defined as the total volume of diarrheal stools (mL, Grade 3 and above) divided by the number of hours between initiation of study product dosing and initiation of antibiotic therapy. For participants with symptom onset after 48 hours diarrheal stool output rate is defined as the total volume of diarrheal stools (mL, Grade 3 and above) divided by the number of hours between onset of symptoms and initiation of antibiotic therapy.

Secondary Outcome Measures

Name	Time	Method
Area Under the Curve (AUC) of Diarrheal Stool Volume Between Challenge Dose and Initiation of Antibiotics	Day 1 to Day 5 (prior to first dose of antibiotic)	The AUC of diarrheal stool volume and cholera organisms was computed via the trapezoidal rule.
Number of Participants With Solicited Adverse Effects	Day 1 - Day 8	Solicited adverse events (AEs) include nausea, abdominal discomfort and pain, abdominal cramps, headache, malaise, anorexia, pollakiuria, micturition urgency, sinus tachycardia, increased alertness, and were collected by interview through 7 days post-challenge (Days 1-8)
Attack Rate of Any Diarrhea Following Cholera Challenge	Day 1 - Day 5 (up to first dose of antibiotic therapy)	Attack rate of any diarrhea following cholera challenge is defined as the number of participants with 2 or more loose stools (Grade 3-5) totaling \> 200 mL or 1 loose (Grade 3-5) stool \> 300 mL, respectively, with onset within 48 hours of cholera challenge.
Peak Shedding of Cholera Organisms	Day 1 to Day 5 (prior to first dose of antibiotic)	Quantitative cultures were performed on the first two stool samples of each 24-hour period prior to the initiation of antibiotics to determine the number of cholera organisms per gram of stool. Peak shedding represents the highest colony-forming unit (CFU) counts observed for each participant.
Duration of Diarrheal Episodes	Day 1 to Day 5 (prior to first dose of antibiotics)	Duration of diarrheal episodes was calculated using Kaplan-Meier methods as the time from cholera challenge to the time of the first formed stool (Grade 1), after which all following stools were also formed.
Percentage of Participants With Fever Following Cholera Challenge	Day 1 to Day 5, prior to first dose of antibiotics	The presence of fever was defined as a body temperature of ≥ 39°C (102.1°F).
Percentage of Participants With Vomiting Following Cholera Challenge	Day 1 to Day 5, prior to first dose of antibiotics
Percentage of Participants With Moderate to Severe Diarrhea With Onset Within 48 Hours Following Cholera Challenge	Day 1 - Day 5 (up to first dose of antibiotic therapy)	The percentage of participants with moderate to severe diarrhea with onset within 48 hours following cholera challenge. Diarrhea was defined as a grade 3 or higher stool based on the following scale: * Grade 1 - well formed (normal stool, does not take the shape of the container) * Grade 2 - soft (normal stool, does not take the shape of the container) * Grade 3 - thick liquid (diarrhea, takes the shape of the container readily) * Grade 4 - opaque watery diarrhea * Grade 5 - rice water diarrhea (clear watery) Diarrheal stools (Grade 3-5) were graded for severity according to the following: Mild: ≤ 3 liters loose stools; Moderate: \> 3 liters loose stools; Severe: \> 5 liters loose stools.
Number of Participants With Unsolicited Treatment-emergent Adverse Events (TEAE)	From first dose of study drug up to Day 29	Unsolicited AEs include any AEs reported spontaneously by the participant, observed by the study personnel during study visits or those identified during review of medical records or source documents. Investigators assigned causality of unsolicited AEs to either the study drug, cholera infection, or an alternate etiology.
Total Number of Loose (Grade 3-5) Stools	Day 1 to Day 5 (prior to first dose of antibiotic therapy)	Total number of loose stools (Grade 3 and above) per participant during the interval immediately following challenge and prior to initiation of antibiotic therapy.