Cholera Anti-Secretory Treatment Trial

NCT ID: NCT04150250

Last Updated: 2021-03-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-11-04
• Study Completion Date: 2020-07-27

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.

Conditions

Cholera

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

iOWH032

Intervention Type: DRUG

Anti-secretory synthetically manufactured small molecule designed to inhibit the cystic fibrosis transmembrane conductance regulator chloride channel.

V. cholerae Challenge

Intervention Type: OTHER

Freshly-harvested, wild-type Vibrio (V.) cholerae El Tor Inaba strain N16961,10\^6 cfu suspended in 30 mL of sodium bicarbonate solution ingested orally.

Antibiotics

Intervention Type: DRUG

Antibiotic therapy may include:

• Ciprofloxacin 500 mg, twice daily;
• Azithromycin 500 mg, once daily (for those persons who are allergic to fluoroquinolones);
• Doxycycline 300 mg, once daily (for those persons who are allergic to fluoroquinolones)

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Oral tablets matching iOWH032 on taste, appearance, dissolution time with the same excipients but no active ingredients.

V. cholerae Challenge

Intervention Type: OTHER

Freshly-harvested, wild-type Vibrio (V.) cholerae El Tor Inaba strain N16961,10\^6 cfu suspended in 30 mL of sodium bicarbonate solution ingested orally.

Antibiotics

Intervention Type: DRUG

Antibiotic therapy may include:

• Ciprofloxacin 500 mg, twice daily;
• Azithromycin 500 mg, once daily (for those persons who are allergic to fluoroquinolones);
• Doxycycline 300 mg, once daily (for those persons who are allergic to fluoroquinolones)

Interventions

iOWH032

Anti-secretory synthetically manufactured small molecule designed to inhibit the cystic fibrosis transmembrane conductance regulator chloride channel.

Intervention Type: DRUG

Placebo

Oral tablets matching iOWH032 on taste, appearance, dissolution time with the same excipients but no active ingredients.

Intervention Type: DRUG

V. cholerae Challenge

Freshly-harvested, wild-type Vibrio (V.) cholerae El Tor Inaba strain N16961,10\^6 cfu suspended in 30 mL of sodium bicarbonate solution ingested orally.

Intervention Type: OTHER

Antibiotics

Antibiotic therapy may include:

• Ciprofloxacin 500 mg, twice daily;
• Azithromycin 500 mg, once daily (for those persons who are allergic to fluoroquinolones);
• Doxycycline 300 mg, once daily (for those persons who are allergic to fluoroquinolones)

Intervention Type: DRUG

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

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 44 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Maryland, Baltimore

OTHER

Sponsor Role: collaborator

Pharmaron

INDUSTRY

Sponsor Role: collaborator

PATH

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Pharmaron

Baltimore, Maryland, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34793441 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

DRG-032-PO-2-01-USA

Identifier Type: -

Identifier Source: org_study_id