Pouchitis, Irritable Pouch Syndrome
Conditions
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.
Interventions
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.
DRUGPlacebo Pen Injector
Matching placebo pens used to administer normal saline in the same fashion as for liraglutide
Sponsors
Novo Nordisk A/S
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, double-blind, 2-period, placebo-controlled, crossover proof of concept study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Due to an interruption in drug supply, the study was terminated after 8 of 10 patients were included.
Participants by arm
| Arm | Count |
|---|---|
| Liraglutide Then Placebo Participants will be randomly assigned to 6-week Liraglutide treatment. Then after a 5-day washout, treatment will continue with 6 weeks of placebo.
Liraglutide Pen Injector: 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 Injector: Matching placebo pens used to administer normal saline in the same fashion as for liraglutide | 3 |
| Placebo Then Liraglutide 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 Pen Injector: 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 Injector: Matching placebo pens used to administer normal saline in the same fashion as for liraglutide | 5 |
| Total | 8 |
Baseline characteristics
| Characteristic | Liraglutide Then Placebo | Placebo Then Liraglutide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 5 Participants | 8 Participants |
| Age, Continuous | 49 years | 52 years | 51 years |
| Daily bowel frequency | 10.9 bowel movements/day STANDARD_DEVIATION 2.1 | 12.8 bowel movements/day STANDARD_DEVIATION 2 | 12.1 bowel movements/day STANDARD_DEVIATION 3.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 8 Participants |
| Region of Enrollment United States | 3 Participants | 5 Participants | 8 Participants |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 8 / 8 | 6 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
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)
Population: Analyses were performed according to treatment with Liraglutide vs Placebo (not according to arm/sequence).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | 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 . | 36.3 percentage reduction of bowel frequency | Standard Deviation 19.8 |
| Placebo | 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 . | 17.3 percentage reduction of bowel frequency | Standard Deviation 15.7 |
Comparison: The 2 treatment modalities, Liraglutide and Placebo, were compared. A repeated-measures mixed model was fitted to the data, with treatment (liraglutide or placebo), period, and treatment sequence as fixed effects and the repeated measures within the subject as a random effect.p-value: <0.03Mixed Models Analysis
Secondary
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)
Population: Analyses were performed according to treatment with Liraglutide vs Placebo (not according to arm/sequence).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Liraglutide | 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 Bowel Frequency Day | 8.8 Bowel movements / day or night | Standard Deviation 2.3 |
| Liraglutide | 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 Bowel Frequency Night | 3.3 Bowel movements / day or night | Standard Deviation 1.7 |
| Liraglutide | Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo | Week 4 Day | 5.3 Bowel movements / day or night | Standard Deviation 2.2 |
| Liraglutide | Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo | Week 4 Night | 2.3 Bowel movements / day or night | Standard Deviation 1.1 |
| Liraglutide | Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo | Week 6 Day | 5.4 Bowel movements / day or night | Standard Deviation 1.9 |
| Liraglutide | Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo | Week 6 Night Placebo week 6 | 2.1 Bowel movements / day or night | Standard Deviation 1 |
| Placebo | Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo | Week 6 Day | 7.0 Bowel movements / day or night | Standard Deviation 2 |
| Placebo | 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 Bowel Frequency Day | 8.8 Bowel movements / day or night | Standard Deviation 2.3 |
| Placebo | Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo | Week 4 Night | 3.1 Bowel movements / day or night | Standard Deviation 1.6 |
| Placebo | 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 Bowel Frequency Night | 8.8 Bowel movements / day or night | Standard Deviation 2.3 |
| Placebo | Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo | Week 6 Night Placebo week 6 | 3.1 Bowel movements / day or night | Standard Deviation 1.8 |
| Placebo | Change in the 7 Day Mean Number of Day and Night Bowel Frequency at Week 4 and 6 vs Baseline on Liraglutide vs Placebo | Week 4 Day | 6.9 Bowel movements / day or night | Standard Deviation 2.2 |
Secondary
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
Population: Analyses were performed according to treatment with Liraglutide vs Placebo (not according to arm/sequence).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Liraglutide | Discontinuation of Therapy in Each Treatment Arm | 0 Participants |
| Placebo | Discontinuation of Therapy in Each Treatment Arm | 0 Participants |
Secondary
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.
Time frame: Baseline, week 6 (treatment period 1) and week 12 (treatment period 2)
Population: Analyses were performed according to treatment with Liraglutide vs Placebo (not according to arm/sequence).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Liraglutide | 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. | 36.8 Percent reduction of bowel frequency | Standard Deviation 18.7 |
| Placebo | 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. | 15.7 Percent reduction of bowel frequency | Standard Deviation 5.3 |
Comparison: The 2 treatment modalities, Liraglutide and Placebo, were compared. A repeated-measures mixed model was fitted to the data, with treatment (liraglutide or placebo), period, and treatment sequence as fixed effects and the repeated measures within the subject as a random effect.p-value: 0.01Mixed Models Analysis