Clinical trial NCT04150250: Cholera Anti-Secretory Treatment Trial
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cholera
Lead sponsor: PATH
Sponsor class: OTHER
Collaborators: name: University of Maryland, Baltimore
name: Pharmaron
First posted: 2019-11-04
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 44
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Willing and able to understand and provide written informed consent
2. 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
3. All women must have a negative serum pregnancy test at screening and one day prior to challenge.
4. Agreement by participants to use an adequate method of contraception\* during the study and for 4 weeks before and after the challenge.
5. 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.
6. 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:

1. Clinically significant history of immunodeficiency, cardiovascular disease, respiratory disease, endocrine disorder, liver disease, renal disease, gastrointestinal disease, anal or rectal disorders, neurologic disease,
2. Current nicotine use or drug, alcohol abuse within the past 6 months
3. Recipient of bone marrow or solid organ transplant
4. Use of systemic chemotherapy in the past 5 years
5. Has a malignancy (excluding localized non-melanoma skin cancers) or lymphoproliferative disorders diagnosed or treated within the past 5 years
6. 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
7. 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
8. Have an elevated blood pressure, systolic ≥ 150 mmHg or diastolic ≥ 90 mmHg, before challenge
9. 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
10. History of Guillain-Barré Syndrome
11. Too low or too high a body mass index (BMI \< 18.5 or \> 39)
12. 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
13. Has regularly used laxatives in the past 6 months
14. Has a history of eating disorders (e.g. anorexia or bulimia) within the past 10 years
15. Known allergy or previous severe adverse effect to all of the following antibiotics: ciprofloxacin (or quinolones), azithromycin and doxycycline.
16. Previously received a licensed or investigational cholera vaccine, within 10 years
17. History of cholera or enterotoxigenic Escherichia coli (ETEC) infection (lab-confirmed natural infection or experimental challenge), within 10 years
18. Travel to a cholera-endemic area in the past 5 years
19. Pregnant or nursing
20. Positive serology for human immunodeficiency virus (HIV), hepatitis B antigen, or hepatitis C antibody
21. 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
22. 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
23. Has poor venous access, defined as the inability to obtain screening blood tests after three attempts
24. Currently on, or plans to be on, antibiotics (e.g., doxycycline) within 14 days prior to challenge and through 28 days after challenge
25. Presence of an acute illness or fever (\> 100.4°F) within 72 hours of admission to the inpatient Clinical Research Unit
26. 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
27. 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
28. 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
29. Lack of ability to fully understand the informed consent
30. 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

Primary outcomes:
measure: Diarrheal Stool Output Rate
timeFrame: Day 1 - Day 5 (up to first dose of antibiotic therapy)
measure: Diarrheal Stool Output Rate Including Participants With Symptom Onset After 48 Hours
timeFrame: Day 1 - Day 5 (up to first dose of antibiotic therapy)
measure: Number of Participants With Treatment-emergent Serious Adverse Events
timeFrame: Day 1 - Day 180
Secondary outcomes:
measure: Percentage of Participants With Moderate to Severe Diarrhea With Onset Within 48 Hours Following Cholera Challenge
timeFrame: Day 1 - Day 5 (up to first dose of antibiotic therapy)
measure: Attack Rate of Any Diarrhea Following Cholera Challenge
timeFrame: Day 1 - Day 5 (up to first dose of antibiotic therapy)
measure: Area Under the Curve (AUC) of Diarrheal Stool Volume Between Challenge Dose and Initiation of Antibiotics
timeFrame: Day 1 to Day 5 (prior to first dose of antibiotic)
measure: Peak Shedding of Cholera Organisms
timeFrame: Day 1 to Day 5 (prior to first dose of antibiotic)
measure: Duration of Diarrheal Episodes
timeFrame: Day 1 to Day 5 (prior to first dose of antibiotics)
measure: Total Number of Loose (Grade 3-5) Stools
timeFrame: Day 1 to Day 5 (prior to first dose of antibiotic therapy)
measure: Percentage of Participants With Fever Following Cholera Challenge
timeFrame: Day 1 to Day 5, prior to first dose of antibiotics
measure: Percentage of Participants With Vomiting Following Cholera Challenge
timeFrame: Day 1 to Day 5, prior to first dose of antibiotics
measure: Number of Participants With Solicited Adverse Effects
timeFrame: Day 1 - Day 8
measure: Number of Participants With Unsolicited Treatment-emergent Adverse Events (TEAE)
timeFrame: From first dose of study drug up to Day 29
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Pharmaron
state: Maryland
Study officials:
References:
citation: Erdem R, Ambler G, Al-Ibrahim M, Fraczek K, Dong SD, Gast C, Mercer LD, Raine M, Tennant SM, Chen WH, de Hostos EL, Choy RKM. 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. PLoS Negl Trop Dis. 2021 Nov 18;15(11):e0009969. doi: 10.1371/journal.pntd.0009969. eCollection 2021 Nov.