Efficacy of Liraglutide Therapy in Patients With IPAA

Study Overview
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Brief Summary
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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
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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.

Official Title
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Efficacy of Liraglutide Therapy in Patients With an Ileal -Pouch Anal Anastomosis (IPAA) and Chronic High Bowel Frequency

Conditions
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Pouchitis, Irritable Pouch Syndrome

Intervention / Treatment
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* Drug: Liraglutide Pen Injector
* Drug: Placebo Pen Injector


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Interventional Model Description: Randomized, double-blind, 2-period, placebo-controlled, crossover proof of concept study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liraglutide then Placebo<br>Participants will be randomly assigned to 6-week Liraglutide treatment. Then after a 5-day washout, treatment will continue with 6 weeks of placebo. | Drug: Liraglutide Pen Injector<br>* 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.<br>* Other names: Victoza;Drug: Placebo Pen Injector<br>* Matching placebo pens used to administer normal saline in the same fashion as for liraglutide<br>* Other names: Saline;|
| Experimental: Placebo then Liraglutide<br>Participants will be randomly assigned to 6-week placebo treatment. Then after a 5-day washout, treatment will continue with 6 weeks of Liraglutide. | Drug: Liraglutide Pen Injector<br>* 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.<br>* Other names: Victoza;Drug: Placebo Pen Injector<br>* Matching placebo pens used to administer normal saline in the same fashion as for liraglutide<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean 7-Day Bowel Frequency By 30% | Percentage of patients with a 30% reduction of the mean 7-day bowel frequency at week 4 and week 10 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). | week 4, week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the 7 Day Mean Number of Day and Night Bowel Frequency | The bowel frequency during the day and night will be recorded on a daily basis. Change in the number of the 7 days mean number of bowel movements during day (from getting up until bedtime) and during night (during sleep) comparing baseline to week 1, week 2, week 3 and week 4 during active treatment with liraglutide or placebo in period 1 or in period 2 (week 7, 8, 9 and 10). | up to 10 weeks | 
| Change in Clinical Modified Pouch Disease Activity Index (mPDAI) Score | The clinical mPDAI will be measured at baseline, week 4, and week 10. The clinical mPDAI is a composite score of stool frequency, presence of rectal bleeding, fecal urgency/abdominal cramps or fever. The clinical mPDAI score ranges from 0 to 6. Values < 3 are considered as remission, whereas symptoms ≥ 3 are considered as having active pouchitis. | up to 10 weeks | 
| Discontinuation of Liraglutide Therapy | Number of patients discontinuing Liraglutide therapy in treatment and placebo arm | up to 12 weeks |