Study of EXE-346 Live Biotherapeutic to Reduce High Bowel Movement Frequency in Subjects With an IPAA (PROF)

Study Overview
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Brief Summary
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The aim of this study is to assess the safety and preliminary efficacy of treatment with EXE-346, a live biotherapeutic, which may reduce bowel movement frequency in patients with an ileal pouch-anal anastomosis (IPAA) and lead to a higher quality of life.

Detailed Description
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The aim of this study is to assess the safety and preliminary efficacy of treatment with EXE-346 which may reduce bowel movement frequency in patients with an IPAA and lead to a higher quality of life. EXE-346 is a live biotherapeutic product containing a fixed proportion mixture of 8 individual bacterial strains. The Phase 1b part of the study is an open label (OL), single-arm study to assess the safety of EXE-346 administered orally for up to 4 weeks. The Phase 2 part of the study is a randomized, double-blinded study to assess the safety and efficacy of the same dose of EXE-346 administered orally for up to 8 weeks, compared with placebo. Subjects who complete the Phase 2 double-blinded part of the study will be eligible to participate in an optional open label extension phase to receive EXE-346 for up to 8 weeks.

Official Title
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A Phase 1b/2 Study to Demonstrate the Safety and Efficacy of EXE-346 Live Biotherapeutic to Reduce High Bowel Movement Frequency in Subjects With an Ileal Pouch-Anal Anastomosis (PROF). The PROF Study.

Conditions
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Ileal Pouch

Intervention / Treatment
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* Biological: EXE-346
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA [Phase 1b only] Subject is a male or female and is between the age of 18 to 65 years, inclusive, at screening. [Phase 1b only] Subject has had a documented pouchoscopy within 12 months prior to screening. [Phase 2 only] Subject is a male or female and is aged 18 years or older at screening. Subject or the subject's legally acceptable representative is willing and able to provide written informed consent prior to the initiation of any study-related procedures. Subject has had an IPAA for at least 6 months prior to screening. Subject has an average daily bowel movement frequency of at least 10 bowel movements recorded during screening and has correctly completed at least 7 days of electronic diary (eDiary) entries during the screening period. Female subjects of childbearing potential must have a negative serum pregnancy test result at screening and must not be lactating and/or breastfeeding. Female subjects of childbearing potential and male subjects with partners of childbearing potential must agree to use proper contraceptive methods to avoid pregnancy during the study. [Phase 2 OL extension only] Subject must have completed the Phase 2 double-blinded part of the study and be willing to participate in the optional open-label extension phase. [Phase 2 OL extension only] Subject must understand the study procedures, the risks involved, and be willing to continue to adhere to the study visit/protocol schedule. EXCLUSION CRITERIA [Phase 1b only] Subject has Crohn's-like disease of the pouch, as indicated by their most recent pouchoscopy during the 12 months prior to screening. [Phase 1b only] Subject has a stricture of the IPAA or afferent limb stricture, as indicated by their most recent pouchoscopy during the 12 months prior to screening. [Phase 2 only] Subject has Crohn's-like disease of the pouch, as indicated by the pouchoscopy conducted during study screening. [Phase 2 only] Subject has isolated severe cuffitis without pouch inflammation (endoscopic modified Pouch Disease Activity Index (mPDAI) score of 2 or lower). [Phase 2 only] Subject has a stricture of the IPAA or afferent limb stricture as indicated by the pouchoscopy conducted during study screening. Subject has enterocutaneous or recto- or pouch-vaginal fistula. Subject has active Clostridium difficile infection. Subject has known or suspected active cytomegalovirus (CMV) infection. Subject initiated a new treatment with antibiotics or antimotility therapies within the 2 weeks prior to screening or plans to start a new or change doses of a current treatment during the study period. Subject has taken biologics, azathioprine, or methotrexate within the 12 weeks prior to screening or systemic steroids within 4 weeks of screening. Subject is taking NSAIDs as a long-term treatment (i.e., consistent use for at least 4 days/week each month). Subject has a known history or positive test during screening for HIV, HIV-1, HIV-2, or active hepatitis B virus (HBV) or hepatitis C virus (HCV). Subject has a positive reverse transcriptase-polymerase chain reaction (PCR) diagnostic test for SARS-CoV-2 (COVID-19) within the 14 days prior to screening. Subject has a history of malignancy within the 5 years prior to screening, with the exception of nonmelanoma skin cancer that has been treated with no evidence of recurrence, treated cervical dysplasia, or treated in situ grade 1 cervical cancer. Subject has estimated glomerular filtration rate <30 mL/min/1.73 m^2 at screening. Subject has uncontrolled hypertension at screening. Subject has known hypersensitivity to EXE-346 or any product components. Female subject is pregnant or lactating and/or breastfeeding. Subject has participated in any clinical study of an approved or unapproved investigational medicinal product within the 30 days prior to screening. Subject has any disorder that, in the investigator's opinion, might jeopardize the subject's safety or compliance with the protocol, including but not limited to: Decompensated liver disease Elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin >2 × upper limit of normal (ULN) Primary sclerosing cholangitis with elevated transaminases [Phase 2 OL extension only] Subject has developed any medical or psychologic condition excluded in the Phase 2 double-blinded part of the study or which, in the investigator's opinion, might create undue risk to the subject, interfere with the subject's ability to comply with the protocol requirements, or interfere with the subject's ability to complete the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b Open Label<br>EXE-346 live biotherapeutic product, 1500x10^9 colony forming units (CFU) twice daily (BID), 4 weeks | Biological: EXE-346<br>* EXE-346 contains a proprietary, fixed-dose, lyophilized blend of 8 strains of gram positive, lactic acid bacteria. EXE-346 excipients are maltose and silicon dioxide.<br>|
| Experimental: Phase 2: Active Arm<br>EXE-346 live biotherapeutic product, 1500x10^9 CFU BID, 8 weeks | Biological: EXE-346<br>* EXE-346 contains a proprietary, fixed-dose, lyophilized blend of 8 strains of gram positive, lactic acid bacteria. EXE-346 excipients are maltose and silicon dioxide.<br>|
| Placebo Comparator: Phase 2: Placebo Arm<br>Powder containing same inactive ingredients as EXE-346 but none of the active ingredients, BID, 8 weeks | Other: Placebo<br>* Placebo contains excipients maltose and silicon dioxide.<br>|
| Experimental: Phase 2 Open Label Extension (optional)<br>EXE-346 live biotherapeutic product, 1500x10^9 CFU BID, 8 weeks | Biological: EXE-346<br>* EXE-346 contains a proprietary, fixed-dose, lyophilized blend of 8 strains of gram positive, lactic acid bacteria. EXE-346 excipients are maltose and silicon dioxide.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Incidence, Severity, Relatedness, and Frequency of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | To assess the safety of EXE-346 using incidence, severity, relationship to study treatment, and frequency of treatment emergent adverse events (TEAE) and serious adverse events (SAE). | 4 weeks | 
| Phase 1b: Number of Participants with Abnormal Physical Examinations | To assess the safety of EXE-346 using abnormal findings in physical examinations after the start of study treatment that suggest a clinically significant worsening of medical issue. | 4 weeks | 
| Phase 1b: Number of Participants with Abnormal Vital Signs | To assess the safety of EXE-346 using abnormal findings in vital sign readings after the start of study treatment that suggest a clinically significant worsening of medical issue, including blood pressure. | 4 weeks | 
| Phase 1b: Number of Participants with Abnormal Safety Labs | To assess the safety of EXE-346 using markedly abnormal findings in safety labs after the start of study treatment that suggest a clinically significant worsening of medical issue. | 4 weeks | 
| Phase 1b: Study Treatment Discontinuation Due to Treatment Emergent Adverse Events (TEAEs) | To assess the safety of EXE-346 using study treatment discontinuation due to TEAE(s). | 4 weeks | 
| Phase 2: Incidence, Severity, Relatedness, and Frequency of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | To assess the safety of EXE-346 using incidence, severity, relationship to study treatment, and frequency of TEAEs and SAEs. | 8 weeks | 
| Phase 2: Number of Participants with Abnormal Physical Examinations | To assess the safety of EXE-346 using abnormal findings in physical examinations after the start of study treatment that suggest a clinically significant worsening of medical issue. | 8 weeks | 
| Phase 2: Number of Participants with Abnormal Vital Signs | To assess the safety of EXE-346 using abnormal findings in vital sign readings after the start of study treatment that suggest a clinically significant worsening of medical issue, including blood pressure. | 8 weeks | 
| Phase 2: Number of Participants with Abnormal Safety Labs | To assess the safety of EXE-346 using markedly abnormal findings in safety labs after the start of study treatment that suggest a clinically significant worsening of medical issue. | 8 weeks | 
| Phase 2: Study Treatment Discontinuation Due to Treatment Emergent Adverse Events (TEAEs) | To assess the safety of EXE-346 using study treatment discontinuation due to TEAE(s). | 8 weeks | 
| Phase 2: Change in Total Daily Bowel Movement Frequency | To assess the efficacy of EXE-346 to reduce the total daily bowel movement frequency using change in average daily bowel movement frequency from baseline to each post-baseline week | 8 weeks | 
| Phase 2 Open Label: Incidence, Severity, Relatedness, and Frequency of Treatment Emergent Adverse Events (TEAE) and Serious Adverse Events (SAE) | To assess the safety of EXE-346 using incidence, severity, relationship to study treatment, and frequency of TEAEs and SAEs. | 8 weeks | 
| Phase 2 Open Label: Number of Participants with Abnormal Physical Examinations | To assess the safety of EXE-346 using abnormal findings in physical examinations after the start of study treatment that suggest a clinically significant worsening of medical issue. | 8 weeks | 
| Phase 2 Open Label: Number of Participants with Abnormal Vital Signs | To assess the safety of EXE-346 using abnormal findings in vital sign readings after the start of study treatment that suggest a clinically significant worsening of medical issue, including blood pressure. | 8 weeks | 
| Phase 2 Open Label: Number of Participants with Abnormal Safety Labs | To assess the safety of EXE-346 using markedly abnormal findings in safety labs after the start of study treatment that suggest a clinically significant worsening of medical issue. | 8 weeks | 
| Phase 2 Open Label: Study Treatment Discontinuation Due to Treatment Emergent Adverse Events (TEAEs) | To assess the safety of EXE-346 using study treatment discontinuation due to TEAE(s). | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Bowel Movement Frequency | To assess the effect of EXE-346 on bowel movement frequency using change in average daily bowel movement frequency from baseline to each post-baseline week | 4 weeks | 
| Phase 1b: Nighttime Awakening Frequency | To assess the effect of EXE-346 on nighttime awakening frequency using change in average nighttime awakenings for bowel movements from baseline to each post-baseline week | 4 weeks | 
| Phase 1b: Bowel Movement Consistency | To assess the effect of EXE-346 on bowel movement consistency using change in average consistency of daily bowel movements from baseline to each post-baseline week | 4 weeks | 
| Phase 2: Nighttime Awakening Frequency | To assess the effect of EXE 346 on nighttime awakening frequency using change in average nighttime awakenings for bowel movements from baseline to each post-baseline week | 8 weeks | 
| Phase 2: Bowel Movement Consistency | To assess the effect of EXE-346 on bowel movement consistency using change in average consistency of daily bowel movements from baseline to each post-baseline week | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pouchitis, Pouch, Ileal Pouch Anastomosis, IPAA