Efficacy of Liraglutide Therapy in Patients With IPAA

Phase 2

Terminated

• Conditions: Pouchitis; Irritable Pouch Syndrome
• Interventions: Drug: Liraglutide Pen Injector; Drug: Placebo Pen Injector

• Registration Number: NCT04763564
• Lead Sponsor: University of North Carolina, Chapel Hill

Brief Summary

Patients with an ileal pouch-anal anastomosis(IPAA; pouch) due to refractory inflammatory bowel disease and increased bowel frequency in the absence of significant pouch inflammation will be randomized to liraglutide or placebo in a prospective cross over study.

Detailed Description

Randomized, double-blind, 2-period, placebo- controlled, crossover proof of concept study.

Ten patients with increased bowel frequency defined as bowel frequency \> 8 bowel movements in 24 hours on at least 4 of 7 days/week and presence of high bowel frequency \> 4 weeks despite adequate therapy for acute pouchitis or Crohn's like disease of the pouch will be randomized to either liraglutide or placebo treatment for 6 weeks (Period 1). Subjects will be randomized 1:1 to 1 of 2 treatment sequences, liraglutide-placebo or placebo-liraglutide, and receive either liraglutide or volume-matched placebo. After a wash-out period of at least 5 days (the half-life of liraglutide is 11-12 hours, thus the minimal washout period of 5 days is equal to 10 half-life's) patients will be crossed over to the other treatment arm (Period 2). Since high bowel frequency can result in significant malaise and dehydration, patients not responding to the respective therapies in period 1 may be crossed over after 4 weeks of therapy or in period 2 can be terminated early at week 4. The rationale behind the early termination is based on 2 open-label cohorts reporting the efficacy of liraglutide or exenatide in patients with high output ileostomies (the patient group the most comparable to the pouch patient population). Glucagon-like peptide- 1 (GLP-1) receptor agonist therapy even at the lowest dose showed an almost immediate effect reducing the ostomy output after 1-3 days in most patients.Thus, patients not responding to a 4-week therapy with a GLP-1receptor agonist are highly unlikely to respond if the therapy would be continued.

Study Timeline

• Study First Submitted: 2021-02-16
• Study First Submitted QC: 2021-02-16
• Study First Posted: 2021-02-21
• Study Start: 2022-03-22
• Status Verified: 2023-10
• Primary Completion: 2023-10-16
• Study Completion: 2023-10-16
• Results First Submitted: 2024-06-04
• Results First Submitted QC: 2024-06-28
• Last Update Submitted: 2024-06-28
• Results First Posted: 2024-07-23
• Last Update Posted: 2024-07-23

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 8

Inclusion Criteria

• Informed consent will be obtained before any trial-related procedures
• Age > 18 years
• Patients with IPAA and bowel frequency > 8 bowel movements in 24 hours on at least 4 of 7 days/week and presence of high bowel frequency > 4 weeks despite adequate therapy for acute pouchitis or Crohn's like disease of the pouch

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Exclusion Criteria

• Significant pouch inflammation defined as an endoscopic pouch disease activity index (PDAI ) ≥ 4
• Known stricture of the ileo-anal anastomosis or afferent limb stricture
• New onset of high bowel frequency in the setting of acute pouchitis
• IPAA since < 6 months
• Known Clostridium difficile pouchitis
• Known clinically significant chronic nausea and/or vomiting in the past
• Known type 1 or type 2 diabetes
• History of or active neoplasia
• Personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2
• Renal impairment defined as glomerular filtration rate (glomerular filtration rate < 30)
• Clinically significant decompensated liver disease defined as elevation of aspartate aminotransferase , alanine transaminase or bilirubin > 2-fold the upper limits of normal (Primary Sclerosing Cholangitis with liver function tests (LFT's) <1.5 upper limits of normal can be included)
• New York Heart Association class 3 or greater heart failure or recent (within 6 months) cardiovascular event
• Prior history of pancreatitis
• Prior treatment with a GLP-1receptor agonist
• Known hypersensitivity to liraglutide or any product components
• Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method.
• Participation in any clinical trial of an approved or non-approved investigational medicinal product within 30 days before screening.
• Any disorder, which in the investigator's opinion might jeopardize patient's safety or compliance with the protocol.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Liraglutide then Placebo	Placebo Pen Injector	Participants will be randomly assigned to 6-week Liraglutide treatment. Then after a 5-day washout, treatment will continue with 6 weeks of placebo.
Placebo then Liraglutide	Liraglutide Pen Injector	Participants will be randomly assigned to 6-week placebo treatment. Then after a 5-day washout, treatment will continue with 6 weeks of Liraglutide.
Placebo then Liraglutide	Placebo Pen Injector	Participants will be randomly assigned to 6-week placebo treatment. Then after a 5-day washout, treatment will continue with 6 weeks of Liraglutide.
Liraglutide then Placebo	Liraglutide Pen Injector	Participants will be randomly assigned to 6-week Liraglutide treatment. Then after a 5-day washout, treatment will continue with 6 weeks of placebo.

Primary Outcome Measures

Name	Time	Method
Mean % Reduction of Bowel Frequency in Percent of the Mean 7-day Bowel Frequency After 4 Weeks of Therapy on Liraglutide vs Placebo Compared to Baseline .	Baseline, Week 4 (treatment period 1) and week 10 (treatment period 2)	Mean percentage reduction of 7-day bowel frequency after 4 weeks of therapy on Liraglutide vs placebo compared to baseline (baseline is defined as the mean 7-day bowel frequency in a 7-day period during the screening period before week 0).; Due to the cross-over design, the outcome is reported depending on randomization in treatment period 1 at week 4 and treatment period 2 at week 10 vs baseline.

Secondary Outcome Measures

Name	Time	Method
Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo	Baseline, Week 4 and week 6 (treatment period 1) and week 10 and week 12 (treatment period 2)	Bowel frequency during the day and night was recorded on a daily basis. The 7-day mean number of bowel movements during the day (from getting up until bedtime) and during the night (during sleep) at baseline and at weeks 4 and 6 on liraglutide or placebo therapy is depicted.; Baseline, week 4 and week 6 (treatment period 1) and week 10 and week 12 (treatment period 2)
Discontinuation of Therapy in Each Treatment Arm	treatment period 1 before week 6 or treatment period 2 before week 12	Number of patients discontinuing Liraglutide therapy in treatment or placebo arm due to intolerance in treatment period 1 before week 6 or treatment period 2 before week 12
Mean % Reduction of Bowel Frequency in Percent of the Mean 7-day Bowel Frequency After 6 Weeks of Therapy on Liraglutide vs Placebo Compared to Baseline.	Baseline, week 6 (treatment period 1) and week 12 (treatment period 2)	Mean percentage reduction of 7-day bowel frequency after 6 weeks of therapy on Liraglutide vs placebo compared to baseline (baseline is defined as the mean 7-day bowel frequency in a 7-day period during the screening period before week 0).; Due to the cross-over design, the outcome is reported depending on randomization in treatment period 1 at week 6 or treatment period 2 at week 12 vs baseline.

Trial Locations

Locations (1)

University of North Carolina; 🇺🇸 Chapel Hill, North Carolina, United States