Cholera Anti-Secretory Treatment Trial

NCT04150250 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: DRG-032-PO-2-01-USA
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 1

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.

Conditions

Cholera

Outcome Measures

Primary Outcomes (3)

• Diarrheal Stool Output Rate

  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.

  Day 1 - Day 5 (up to first dose of antibiotic therapy)

• Diarrheal Stool Output Rate Including Participants With Symptom Onset After 48 Hours

  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.

  Day 1 - Day 5 (up to first dose of antibiotic therapy)

• Number of Participants With Treatment-emergent Serious Adverse Events

  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.

  Day 1 - Day 180

Secondary Outcomes (10)

• 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)

• Attack Rate of Any Diarrhea Following Cholera Challenge

  Day 1 - Day 5 (up to first dose of antibiotic therapy)

• 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)

• Peak Shedding of Cholera Organisms

  Day 1 to Day 5 (prior to first dose of antibiotic)

• Duration of Diarrheal Episodes

  Day 1 to Day 5 (prior to first dose of antibiotics)

Study Arms (2)

iOWH032

EXPERIMENTAL

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.

Drug: iOWH032; Other: V. cholerae Challenge; Drug: Antibiotics

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo; Other: V. cholerae Challenge; Drug: Antibiotics

Interventions

iOWH032 DRUG

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

iOWH032

Placebo DRUG

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

Placebo

V. cholerae Challenge 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.

Placebo; iOWH032

Antibiotics 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; iOWH032

Eligibility Criteria

• Age: 18 Years - 44 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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 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

Sponsors & Collaborators

• PATH: lead
• University of Maryland, Baltimore: collaborator
• Pharmaron: collaborator

Study Sites (1)

Pharmaron

Baltimore, Maryland, 21201, United States

Location

Related Publications (1)

• 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.

  PMID: 34793441 DERIVED

MeSH Terms

Conditions

Cholera

Interventions

IOWH-032; Anti-Bacterial Agents

Condition Hierarchy (Ancestors)

Vibrio Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Anti-Infective Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Results Point of Contact

• Title: Gwen Ambler
• Organization: PATH

gambler@path.org

206-285-3500

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2019
• First Posted: November 4, 2019
• Study Start: November 4, 2019
• Primary Completion: July 27, 2020
• Study Completion: July 27, 2020
• Last Updated: March 25, 2021
• Results First Posted: March 25, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)