Efficacy of Liraglutide Therapy in Patients With IPAA

Phase 2TerminatedNCT04763564

University of North Carolina, Chapel Hill8 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Pouchitis Irritable Pouch Syndrome

Interventions

Liraglutide Pen InjectorDRUG

Treatment will be initiated at 0.6 mg per day for one week. The patient will be instructed to increase the dose to 1.2/day and 1.8 mg /day in week 2 and in week 3, respectively. From week 3 after the start of the drug until week 6 the patient will apply 1.8 mg/day liraglutide. In case of intolerance (e.g. occurrence of refractory nausea) at a higher dose (e.g. 1.8 mg daily, the highest dose in this trial) liraglutide can be reduced to the previous level.

Placebo Pen InjectorDRUG

Matching placebo pens used to administer normal saline in the same fashion as for liraglutide

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 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.

Locations (1)

University of North Carolina

Chapel Hill, North Carolina, United States

Outcomes

Primary Outcomes

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 .

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.

Time frame: Baseline, Week 4 (treatment period 1) and week 10 (treatment period 2)

Secondary Outcomes

Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo

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)

Time frame: 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

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

Time frame: 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.

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.

Data from ClinicalTrials.gov

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