Clinical trial NCT04763564
Conditions: Pouchitis Irritable Pouch Syndrome
Sponsor: University of North Carolina, Chapel Hill
Start date: 2022-03-22; Completion date: 2023-10-16
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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.

Arms: arm 1: Participants will be randomly assigned to 6-week Liraglutide treatment. Then after a 5-day washout, treatment will continue with 6 weeks of placebo. arm 2: Participants will be randomly assigned to 6-week placebo treatment. Then after a 5-day washout, treatment will continue with 6 weeks of Liraglutide.
Interventions: intervention 1: Liraglutide Pen Injector intervention 2: Placebo Pen Injector
Intervention descriptions: intervention 1: 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. intervention 2: Matching placebo pens used to administer normal saline in the same fashion as for liraglutide

Protocol documents:
Prot_SAP_000.pdf: 
Efficacy of liraglutide therapy in patients with an ileal -pouch 
anal anastomosis (IPAA) and chronic high bowel frequency 
Investigator-sponsored Study  
Universal Trial Number (UTN):  U1111-1252-6589 
NCT 04763564 
 
Sponsor-
investigator/Principal 
Investigator:  
 
 
 
 
 
Hans H. Herfarth, MD, PhD 
Division of Gastroenterology and Hepatology 
University of North Carolina 
Phone:919-966-6806 
Fax: 919-966-7592 
email: hherf@med.unc.edu 
 
Co-Investigators 
Edward Barnes, MD, MPH 
Division of Gastroenterology and Hepatology 
University of North Carolina 
 
Millie Long, MD, MPH 
 
Division of Gastroenterology and Hepatology 
University of North Carolina 
 
John Buse, MD, PhD 
Chief, Division of Endocrinology 
Verne S. Caviness Distinguished Professor 
Director, Diabetes Center 
Director, NC Translational and Clinical Sciences Institute 
University of North Carolina 
 
 


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TABLE OF CONTENTS 
 
BACKGROUND ................................................................................................................................. 4 
POUCH PATIENTS AND THE PROBLEM OF BOWEL FREQUENCY ................................................................................ 4 
EFFECTS OF GUCAGON -LIKE PEPTIDES (GLP’S) ON GASTROINTESTINAL TRANSIT TIME AND BOWEL FREQUENCY .. 5 
RATIONAL FOR STUDY POPULATION .............................................................................................. 6 
STUDY HYPOTHESIS ........................................................................................................................................................ 7 
STUDY AIMS .............................................................................................................................................................. 7 
STUDY DESIGN ............................................................................................................................................................... 7 
STUDY DRUG, SUPPLY OF STUDY DRUG AND RECRUITMENT PLAN ............................................... 8 
RECRUITMENT PLAN................................................................................................................................................. 10 
STUDY MILESTONES ...................................................................................................................... 10 
INCLUSION AND EXCLUSION CRITERIA ......................................................................................... 10 
INCLUSION CRITERIA ..................................................................................................................................................... 10 
EXCLUSION CRITERIA ..................................................................................................................................................... 10 
ALLOWED CONCOMITANT MEDICATIONS .............................................................................................................. 11 
STUDY OUTCOMES ........................................................................................................................ 12 
PRIMARY OUTCOME ..................................................................................................................................................... 12 
SECONDARY OUTCOME ................................................................................................................................................. 12 
EXPLORATORY OUTCOMES ............................................................................................................................................. 12 
ASSESSMENTS/INDICES ................................................................................................................. 13 
OVERVIEW OF TRIAL SEQUENCE ................................................................................................... 13 
STUDY VISITS ................................................................................................................................. 16 
SCREENING VISIT .......................................................................................................................................................... 16 
VISIT WEEK 0 .............................................................................................................................................................. 17 
VISITS PERIOD 1 WEEK 1 AND 2 (PHONE VISIT; +/- 1 DAY).................................................................................................... 18 
VISIT PERIOD 1 WEEK 4: (SITE VISIT; =/- 3 DAYS) ................................................................................................................ 18 
VISIT PERIOD 1 WEEK 6: (SITE VISIT; =/- 3 DAYS) ................................................................................................................ 19 
VISITS PERIOD 2: WEEK 7 AND 8  (PHONE VISIT; +/- 1 DAY) ................................................................................................. 20 
VISIT PERIOD 2 WEEK 10: (SITE VISIT; =/- 3 DAYS) .............................................................................................................. 20 
VISIT PERIOD 2 WEEK 12: (SITE VISIT; =/- 3 DAYS) ............................................................................................................. 21 
VISITS PERIOD 2 WEEK 14 (PHONE VISIT; +/- 3 DAYS) ......................................................................................................... 22 
MEASUREMENT OF COMPLIANCE .................................................................................................................................... 22 
LABORATORY PARAMETERS AND POUCHOSCOPY ................................................................................................................ 22 
ETHICS ....................................................................................................................................................................... 23 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ...................................................................... 23 
DEFINITIONS ............................................................................................................................................................... 23 
ADVERSE EVENT ........................................................................................................................................................... 23 
SERIOUS ADVERSE EVENT .............................................................................................................................................. 23 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION ......................................................................................................... 24 
UNEXPECTED ADVERSE DRUG REACTIONS ......................................................................................................................... 24 


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EXPECTED ADVERSE DRUG REACTIONS ............................................................................................................................. 24 
HYPOGLYCEMIA MONITORING, HYPOGLYCEMIC PROTOCOL AND REPORTING FORM ................................................................... 25 
DOCUMENTATION AND REPORTING OF ADVERSE EVENTS .................................................................................................... 27 
DOCUMENTATION AND REPORTING OF SERIOUS ADVERSE EVENTS ........................................................................................ 29 
ABNORMAL LABORATORY RESULTS .................................................................................................................................. 29 
WITHDRAWAL OR STOP OF STUDY DRUG CRITERIA ............................................................................................................. 30 
CRITERIA FOR THE TERMINATION OF THE WHOLE STUDY ....................................................................................................... 31 
LIABILITY AND SUBJECT INSURANCE .................................................................................................................................. 32 
RANDOMIZATION, DATA MANAGEMENT AND DATA MONITORING ........................................... 32 
DATA ANALYSIS ............................................................................................................................. 33 
SAMPLE SIZE CALCULATION .................................................................................................................................... 34 
FUTURE PERSPECTIVE ................................................................................................................... 35 
PUBLICATION PLAN ....................................................................................................................... 35 
TABLE STUDY VISITS AND ASSESSMENTS ..................................................................................... 36 
REFERENCES .................................................................................................................................. 38 
APPENDICES .................................................................................................................................. 42 
APPENDIX A: MODIFIED POUCHITIS DISEASE ACTIVITY INDEX (MPDAI) ..................................................................... 42 
APPENDIX B: SF-36 ..................................................................................................................................................... 43 
APPENDIX C: PROMIS MEASURE INCONTINENCE .............................................................................................................. 49 
APPENDIX D: PROBE SCORE ......................................................................................................................................... 50 
APPENDIX E: SUBJECT DIARY FOR POUCHITIS ..................................................................................................................... 51 
APPENDIX F: ADVERSE EVENT DIARY ................................................................................................................................ 52 
APPENDIX G: DAILY GLUCOSE DIARY ................................................................................................................................ 54 
APPENDIX H: HYPOGLYCEMIC PROTOCOL AND REPORTING FORM ........................................................................................... 55 
 
 


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BACKGROUND 
Ulcerative colitis (UC) is a chronic inflammatory gastrointestinal disorder, which is limited to the 
colon and characterized by the involvement of the mucosa only (in contrast to the transmural 
inflammation seen in CD). UC affects approximately 500.000 Americans, most of them being 
primarily young adults (20 - 40 years) but the disease may present at a 
very early age (5-10 years) or later in life (>60 years).1-3 The inflammatory 
process in UC is primarily localized to the rectum (proctitis) or can extend 
proximally in a contiguous manner involving the mucosa up to the splenic 
flexure (left sided colitis) or involving the entire colon (extensive colitis). 
The key clinical feature is bloody diarrhea. Approximately 20-35% of 
patients with UC eventually undergo colectomy, which is most 
frequently performed in conjunction with ileal pouch-anal anastomosis 
(IPAA, Figure 1) due to a refractory course of UC or histological proven 
dysplasia.4-6 The ileal pouch serves as a reservoir for the stool and 
improves functional outcomes following IPAA. While colectomy is often 
depicted as a curative surgery for UC,7 multiple short- and long-term complications can occur, 
including pouchitis, which occurs in 40% of patients within the first year after IPAA creation.8 Up 
to 80% of patients will report pouchitis symptoms at some point after IPAA,9 with 19% of patients 
developing a recurrent form of pouchitis.10 Despite a preoperative diagnosis of UC or 
indeterminate colitis (IC), an estimated 10% of patients will be diagnosed with a Crohn’s-like 
disease (CLD) of the pouch after IPAA.11 Epidemiologic studies to better define the pouch 
population are currently underway (headed by Edward Barnes at the University of North 
Carolina). It is estimated that approximately 50.000 – 100.000 patients live with a pouch in the 
US and 100.000-150.000 in Europe. Thus, the pouch and its associated medical problems, 
according to the FDA, can be defined as an orphan disease.  
 
POUCH PATIENTS AND THE PROBLEM OF BOWEL FREQUENCY 
Increased bowel frequency interfering with daily activities presents a significant clinical problem 
for many pouch patients. Patients with a pouch typically have 4-8 bowel movements over 24 
hours.12, 13 However, a group of patients have a higher baseline bowel frequency in the range of 
8-14 or higher bowel movements in a 24 hour period including increased nightly bowel 
frequency, incontinence and leakage, which significantly impacts their work and social life due to 
impaired sleep and need to alter the mealtimes.14, 15 The reasons for a higher bowel frequency in 
patients with an otherwise not significantly inflamed pouch are thought to be due to 
hypermotility or pouch dysmotility. Thus far, no unique pathomechanism has been identified. 
Many patients report bowel movements which occur shortly after even small meals or especially 
after meals with a higher fat content. Currently, there are very limited medical options such as 
loperamide or anticholinergic drugs (dicyclomine) to control frequent bowel movements. 
Figure 1: 


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However, many patients do not respond to even extremely high doses of these medications or 
experience intolerable side effects (such as dry mouth or heart palpitations) while being on 
anticholinergic medications. 
 
EFFECTS OF GUCAGON -LIKE PEPTIDES (GLP’S) ON GASTROINTESTINAL TRANSIT TIME 
AND BOWEL FREQUENCY  
GLP-1 and GLP-2 belong to the group of incretins and are pleiotropic hormones that not only 
affect glucose metabolism (GLP-1) but also play a role in the regulation of gastrointestinal motility 
(GLP-1, GLP-2) and intestinal regeneration (GLP-2).16, 17 Other effects on intestinal biology such 
as impact on bile acid metabolism, anti-inflammatory properties or effects on the intestinal 
microbiome are currently debated.18-20 GLP-1 prolongs gastric duodenal emptying and decreases 
gastrointestinal motility, whereas GLP-2 exerts a potential effect in intestinal weight gain, 
mucosal development, and intestinal integrity.18, 21 GLP- 1 and GLP-2 are simultaneously 
produced via posttranslational processing of proglucagon and are secreted by intestinal 
enteroendocrine L-cells after contact with ingested 
nutrients. Additionally, GLP-1 secretion occurs by  cells 
in the pancreas. L-cells are predominantly located in the 
distal ileum and colon. Absence or a decrease of these 
enteroendocrine cells leads to lower GLP-1 levels as well 
as lower levels of other incretins such as GLP-2 as shown 
in patients, who underwent colectomy and had a pouch 
or an ileo- or jeunostomys.22-24 GLP-1 plasma levels 
increase especially after high fat meals in healthy 
volunteers, but only partially increase in patients with 
ileostomy with less than 5 cm of terminal ileum resected (see Figure 2 from paper by Robertson 
et al. Journal of Endocrinology 1999)23.  
 
CLINICAL DATA 
So far no threshold for sufficient postprandial GLP-1 levels have been described, but low levels 
of GLP-1 are associated with rapid small bowel transit in patients with a jejunostomy suggesting 
a defective neuro-endocrine “ileo-colonic brake” after removal of parts of ileum and/or colon.25 
Application of GLP-1 or GLP-2 restores the transit time and decreases diarrhea and fecal 
excretions.25 Whereas the therapeutic efficacy of GLP-2 receptor agonist therapy e.g. with 
teduglutide for patients with short bowel syndrome is well established, two small studies in 
patients with ileostomies or short gut syndrome also suggest a clinical beneficial effect of a GLP-
1 receptor agonist therapy.17, 26, 27 The GLP-1 receptor agonist liraglutide significantly reduced 
ileostomy output in a small group of 8 patients with high ileostomy output.27 In this study 
liraglutide reduced ostomy wet weight output by 474 ± 563 g/d from 3249 ± 1352 to 2775 ± 1187 


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g/d. Interestingly the effects were immediately evident in 3 patients after the start of therapy, 
whereas 2 patients were even after prolonged therapy non-responders explaining the high 
standard variation. Exenatide, a short acting 
GLP-1 receptor agonist, successfully reduced 
bowel frequency in 5 patients  and even 
enabled 3 patients to discontinue total 
parenteral 
nutrition.26 
Again 
similar 
to 
liraglutide the authors of this study report 
theta the beneficial effects of the exenatide 
occurred immediately after start of therapy 
(Table 1 adapted from Kunkel et al. 
Neurogastroenterol Motil 2011).26 In addition, 
a recently published translational study 
demonstrated the beneficial effects of liraglutide therapy in 2 patients with bile acid 
malabsorption syndrome.19 Due to decreased small bowel motility and increased bile acid 
absorption the bowel frequency normalized to 1-2 bowel movements daily in both patients.  
Taken together, the data strongly suggest that patients with either increased small intestinal 
motility due to low GLP-1 levels after removal of the colon or patients with impaired small 
intestinal absorption of bile acids can be successfully treated by GLP-1 receptor agonists. 
 
RATIONAL FOR STUDY POPULATION 
UNMET NEEDS IN POUCH PATIENTS AND RATIONALE FOR A GLP-1 RECEPTOR AGONIST STUDY 
Treatment of diarrhea in patients with inflammatory bowel diseases including pouch patients is 
one of the top 10 research questions for patients and clinicians.28 The average daily bowel 
frequency for a pouch patient is around 6 and 1-2 bowel movements during the night.13 However, 
frequently patients have > 8 bowel movements in 24 hours in the absence of significant pouch 
inflammation. This high bowel frequency in many pouch patients may be due to low GLP-1 and 
GLP-2 levels leading to postprandial accelerated gastric emptying and increased small bowel 
motility as shown in ileostomy patients.22-24, 29 The fact that most patients report that they 
experience urgency and need for immediate evacuation of the pouch 10-20 min after meals point 
towards the absence of the in the literature described neuroendocrine ileocolonic brake 
mediated by GLP-1. As outlined above, patients with ileostomies or a pouch have low GLP-1 and 
GLP-2 levels and GLP-1 as well as GLP-2 receptor agonist therapy can decrease gastric and small 
intestinal motility as well as stool wet weight output by increasing intestinal absorption.21, 25-27 
The only available GLP-2 receptor agonist teduglutide is exclusively approved for patients with 
short gut syndrome depending on parenteral support.30 Currently a therapy with teduglutide 
outside of this indication would be cost prohibitive due to a price tag > $300.000/year. Given the 
Table 1: Effects of exenatide in patients with SBS 


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overall accepted safety profile and affordability of a GLP-1 receptor agonist, this therapy has the 
potential to re-establish the neuro-endocrine "brake mechanism", which was abolished due to 
colectomy. By slowing down the stomach-pouch transit time, increasing wet weight absorption 
of intestinal contents and decreasing irritant effects of bile acids in the pouch GLP-1 receptor 
agonist therapy would lead to a higher quality of life for pouch patients with high bowel 
frequency. 
 
STUDY HYPOTHESIS 
Liraglutide is a safe and effective therapy to decrease the number of daily bowel movements in 
pouch patient with higher than usual bowel frequency. 
 
STUDY AIMS  
1. To evaluate the effects of liraglutide on bowel frequency in patients with an ileo-anal pouch 
anastomosis (IPAA) and abnormal high bowel frequency and no signs of endoscopically 
moderate-severe inflammation (pouchitis). Increased bowel frequency is defined as an 
increased average > 8 bowel daily over a 7-day time period. 
2. To study safety, tolerability and quality of life in the trial period of liraglutide vs placebo 
application 
3. To collect first data about the efficacy of a liraglutide therapy in patients with an ileo-anal 
pouch anastomosis (IPAA) and abnormal high bowel frequency in the absence of inflammation 
for planning a larger phase 3 study in this orphan status patient population 
 
STUDY DESIGN 
Randomized, double-blind, 2-period, placebo- controlled, crossover proof of concept study.  
Ten patients with increased bowel frequency is defined as > 8 bowel daily/week without 
significant pouchitis* 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). 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.26, 27 
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.  


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Figure 3: Study design 
Randomization: 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. 
 
* While there is an ongoing debate about potential anti-inflammatory effects of GLP-1 receptor agonists 
(reviewed in 18), we prefer to have a well-defined patient population with endoscopically low inflammatory 
load (endoscopic pouch disease activity index < 4 in pre-pouch and pouch, only mild cuffitis). However, we will 
monitor intestinal inflammation using calprotectin levels. We anticipate that some patients will have higher 
calprotectin levels but still low endoscopic inflammation and potential effects of GLP-1 receptor agonist 
therapy on inflammation will be captured with this biomarker. 
 
STUDY DRUG, SUPPLY OF STUDY DRUG AND RECRUITMENT PLAN 
Hvistendahl et al. described a significant decrease of fecal wet weight in ileostomy patients 
treated with liraglutide.27 Based on this study and the fact that a longer acting GLP-1 receptor 
agonist such as semaglutide would also have a longer washout period in the setting of a crossover 
study, we have chosen the short acting liraglutide (Victoza®). A washout period between the two-
treatment periods is required in crossover trials and a prolonged crossover period without any 
treatment intervention makes such a study design in a patient population with a significant 
clinical burden (high bowel frequency, incontinence) not feasible. Liraglutide has half-life of 11-
12 hours compared to e.g. semaglutide with a half-life of 165 hours. With a washout period of at 
least 5 days between treatments, we do not expect any carry over effects. 
 


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Liraglutide (Victoza®) or placebo will be supplied by Novo Nordisk A/S and dispensed by the UNC 
investigational pharmacy. The liraglutide or placebo solution for subcutaneous injection will be 
delivered as blinded pre-filled, multi-dose pens that deliver doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 
mg/mL, 3 mL cartridge). In order to blind the product, a clinic variant of the marketed product is 
supplied. The clinic variant of the 3 ml cartridge is produced with an army green closure cap 
compared to a light blue closure cap in the marketed Victoza® product. The push button and 
cartridge holder are light brown, while the marketed pen-injector has a light blue push button 
and cartridge holder. Neither closure cap nor the pen is in contact with the product and the 
differences in colors have no impact on the stability of the product. The investigator will ensure 
the availability of proper storage conditions, and record and evaluate the temperature. The dose 
escalation and administration of liraglutide therapy will be performed according to the current 
FDA approved prescribing information to improve glycemic control in adults with type 2 diabetes. 
A Directions for Use (DFU) for the device will be provided by Novo Nordisk A/S. It will be handed 
out to subject at first dispensing visit and the subject must be trained according to DFU. 
Liraglutide will be administered once daily independently of meal. The patient will choose the 
optimal administration time (morning, midday, evening) and will continue with this timing 
throughout the study. Liraglutide will be injected subcutaneously in the abdomen, thigh or upper 
arm according to the DFU. The patient will be instructed by the investigator how to use the pen 
using the DFU provided by Novo Nordisk A/S. 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 start of drug until week 6 (or week 8-12 in period 
2 depending on randomization) 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. 
 
 
LIRAGLUTIDE AND TACHYPHYLAXIS 
So far extent of tachyphylaxis of the effects of liraglutide on gastric emptying are inconclusive or 
not well defined. Liraglutide (1·2 mg, 1·8 mg, or 3·0 mg daily) delays 1-h gastric emptying, as 
measured by the plasma acetaminophen method (which reflects predominantly the gastric 
emptying of liquids, not solids) compared with placebo.31-34 However, tachyphylaxis of the delay 
of gastric emptying seems to occur over time but the extent is not clear. For liraglutide 3.0 mg 
daily one study reports complete tachyphylaxis for delay in gastric emptying based on the plasma 
acetaminophen method after 5 weeks whereas another study, using a scintigraphy method for 
gastric emptying which includes the emptying of solid food describes partial tachyphylaxis but 
still significant efficacy compared to placebo after 16 weeks of therapy.32, 34 All studies so far have 
been performed in patients with an intact GI-tract. The question remains if tachyphylaxis occur 
in patients with low GLP-1 levels and potentially upregulated GLP-1 receptors in the absence of 


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a colon. In the only available 2 studies analyzing the effects of liraglutide or exenatide on  
jejunostomy output no tachyphylaxis was reported after 8 weeks(liraglutide) or 1 year 
(exenatide) of therapy.26, 27  
 
RECRUITMENT PLAN 
We estimate to screen 20 - 25 pouch patients/month and randomize 1 patient/month. We 
expect that all patients will complete the study after randomization. Under the direction of Dr. 
Hans Herfarth, the University of North Carolina has a Multidisciplinary Pouch Clinic that 
involves gastroenterology and surgery care for pouch-related disorders. We follow 
approximately 450 patients from throughout the southeast region of the United States that 
are treated regularly in our clinic.  
 
STUDY MILESTONES 
Months 
1-4 
4-16 
16-22 
Activities 
Start-up of 
trial 
IRB 
IND/FDA 
Recruitment 
Follow-up last 
patients 
Analysis of 
clinical data 
 
 
INCLUSION AND EXCLUSION CRITERIA 
 
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 clinically significant obstructive stricture of the ileo-anal anastomosis or afferent 
limb  
• 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 


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• 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 (GFR < 30)) 
• Clinically significant decompensated liver disease defined as elevation of AST, ALT or 
bilirubin > 2-fold the upper limit of normal (Primary Sclerosing Cholangitis with LFT’s 
<1.5 upper limit 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-1RA 
• 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. NOTE:  this 
includes two forms of barrier contraception (e.g. condoms and foam; e.g. condoms and 
diaphragm); long-acting reversible contraception (e.g. subdermal contraceptive implant, 
intrauterine device, contraceptive injections), and oral contraceptive pills 
NOTE:  Non-childbearing potential is defined as postmenopausal for at least 1 year or 
surgically sterile, meaning your ovaries and/or uterus have been removed (bilateral 
oophorectomy and/or hysterectomy) 
• 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. 
 
ALLOWED CONCOMITANT MEDICATIONS 
• Biologics to treat Crohn’s disease like disease of the pouch 
• Antibiotics to treat antibiotic dependent pouchitis (Antibiotics should be stable 2 weeks 
before start of study medication and kept stable or can be stopped and if needed be 
restarted at the same dose or lower during the study) 
• Anti-diarrheal medication (e.g. loperamide) should be kept stable. Changes in the 
dosage will be documented in patient’s diary. 
 
Following drug groups are not permitted as concomitant medication: 
• New start of biologics, antibiotics, steroids, anti-motility therapies (e.g. hyoscyamine, 
loperamide, atropine)  


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• Non - steroidal anti-inflammatories (NSAIDs) as long-term treatment, defined as use for at 
least 4 days a week each month 
 
 
STUDY OUTCOMES 
 
PRIMARY OUTCOME 
• 
Reduction of the mean of the 7-daily bowel frequency by 30% in week 4 and week 10. 
 
SECONDARY OUTCOME 
• Safety and Tolerability of GLP-1 
o Number of study patients, who discontinued therapy 
o Adverse events grouped by body system  
o Changes in laboratory values 
o Changes in nausea, appetite, abdominal pain and well being 
• Change in bowel frequency during day (patient is awake from morning until bedtime) and 
during night (patient is asleep and has to get up because he has a bowel movement) 
comparing screening period 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). 
• Change in clinical PDAI week 0 and week 4 and week 10 
 
EXPLORATORY OUTCOMES 
• Change in stool calprotectin from baseline 
• Change in SF-36 
• Change in PROMIS measures 
• Change in PROBE score 
• Change in body weight and experience of nausea, decreased appetite or increased 
abdominal pain 
• Change in PDAI at week 6 or week 12 in patients responding to liraglutide therapy 
• Change in bowel frequency during day (patient is awake from morning until bedtime) 
and during night (patient is asleep and has to get up because he has a bowel movement) 
comparing screening period to week 5 and 6 in period 1 or 11 or week 11 and 12 in 
period 2. 
 
 


Liraglutide therapy in patients with IPAA and chronic high bowel frequency 
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ASSESSMENTS/INDICES 
In regard to when the assessments are performed please also refer to study visits and table 
study visits and assessments. 
 
• Patient diary (performed daily): Bowel frequency during the day (6 am-6 pm) and night 
(6 pm -6 am) and recording of bowel movement consistency (liquid, pasty or formed)14 
• Patient diary (performed daily): Timing of bowel movement in relation to meals (within 
15 min, 30 min or >30 min) 
• Modified pouch disease activity index (mPDAI)35 
The Pouchitis Disease Activity Index (PDAI) was developed by Sandborn et al for diagnosing active pouchitis 
and quantifying the severity of pouchitis 36. Shen et al. later on modified the index (mPDAI) and showed 
that similar outcomes can be measured after omitting the evaluation of histology, thus omitting the biopsy 
and histology costs.35 The PDAI or the modified PDAI has been used in a number of clinical studies where it 
appears quite useful in discriminating between subjects with and without pouchitis and in quantifying the 
severity of pouchitis 37-45 The mPDAI will be evaluated based at screening, week0,2,4,6,7,8,10,12. 
• Stool calprotectin (assessment of pouch inflammation over time) 
Calprotectin, a member of the S100 family of calcium-binding proteins is abundant in the stool and its 
level correlates with the endoscopic degree of intestinal inflammation in patients with ulcerative colitis 
and pouchitis. 46, 47 Calprotectin can be quantified in feces using enzyme-linked immunosorbent assay 
(ELISA) or an immunoassay. We will collect stool samples for the measurement of calprotectin at the 
screening visit and on weeks 2,4,6,8,10,12. 
• 36-Item Short Form Health Survey (SF-36)  
The SF-36 will be evaluated at screening, week 2,4,6,8,10 and 12.  
• PROMIS measures for incontinence48 
The GI-PROMIS scales belong to the PROMIS system, which was created by the National Institutes of 
Health (NIH) to allow efficient, online measurements of patient reported outcomes and correlate with 
other established quality of life measures.48, 49 The PROMIS scale for incontinence will be evaluated at 
screening, week 2,4,6,8,10 and 12. 
• PROBE score50 
PROBE assesses the psychosocial burden of IBD and has been recently validated.50 PROBE will be 
evaluated at screening, week 2,4,6,8,10 and 12. 
• Body weight and visual analogue scales for nausea, appetite, abdominal pain and well 
being25 Body weight will be evaluated at screening and on weeks 4,6,10,12.  
OVERVIEW OF TRIAL SEQUENCE 
Screening visit (site visit): The trial will begin with the screening visit (days -14 to -10). The 
investigator will ask patients who are interested in participating in the study after a careful 
explanation, to sign an informed consent form prior to study specific examinations. The study 
patient will receive a copy of the consent form, which outlines the sequence of events in brief 
and summarizes the advantages and disadvantages of participation in the study. 


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After the patient has given his/her written consent, the screening examination will be performed 
to evaluate whether the patient is probably eligible for the study. 
The coordinator and PI will take a complete history will be taken including concomitant 
medication and demographic data will be collected. If subject is a woman of child-bearing 
potential, a reliably and highly effective contraceptive method will be confirmed.  A physical 
examination will be performed, and vital signs will be documented. Blood samples (max. 20 ml) 
will be taken from the study patient (all study patients: Haematology, serum chemistry, 
creatinine, CRP (female study patients: urine samples for pregnancy test). Also the study patient 
will be provided with a stool collection kit to provide a stool sample, which should be collected 
at this visit or before the week 0 visit. This stool kit will also contain a sample kit for C. difficile 
toxin. The study patient will also be provided with an access password to a web based a diary, 
which he/she will be asked to complete the diary every day in the evening during the trial.  The 
study patient will also undergo a pouchoscopy as standard of care for evaluation of the pouch 
inflammation as the reason for the high bowel frequency and to rule out complications in the 
pouch structure (e.g. strictures, isolated cuffitis, which would lead to exclusion of the trial). 
After the screening visit the patient will also start a daily electronic diary to assess the average 
weekly bowel frequency. Before week 0 at least 7 days of bowel frequency data need to be 
available to assess baseline bowel frequency.  
 
Visit week 0 (site visit): The study patient will have a physical exam and a urine pregnancy test.  If 
subject is a woman of child-bearing potential, a reliably and highly effective contraceptive 
method will be confirmed.  The patient’s AE and symptom diary will be reviewed and the clinically 
modified PDAI calculated. The patient’s concomitant medications will be reviewed. If the study 
patient fulfils all inclusion criteria and does not have an exclusion criterion the study patient will 
be randomized to either the placebo or the liraglutide group and a unique study ID number will 
be assigned, which will appear on all medication packs, which will be containing treatment until 
week 6 period 1.  A glucometer, supplies, and instructions for use will be provided as well as a 
review of signs and symptoms of hypoglycemia, plus a review of hypoglycemic protocol and 
reporting form. 
 
Visits week 1 and 2 (phone visits): The coordinator will ask the study patient if adverse events 
occurred and will review the adverse event diary with the study patient. The coordinator will also 
evaluate the web registered clinical components of the mPDAI of the last 3 days before the phone 
call (stool frequency, rectal bleeding, fecal urgency/ abdominal cramping, fever) as well as the 
concomitant medications. At visit week 1 and 2 the patient will be asked to collect/send in a stool 
sample for the next (in person or as mail in collected days -2 - +2 around the visit date).  There 
will also be a review of glucose diary and hypoglycemic protocol and reporting form.  If subject is 
a woman of child-bearing potential, a reliably and highly effective contraceptive method will be 
confirmed.   
 


Liraglutide therapy in patients with IPAA and chronic high bowel frequency 
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Visit week 4 (site visit): The coordinator will review the adverse events, which occurred since the 
previous visit. A physical exam and blood tests will be performed and the mPDAI will be 
calculated.  The concomitant medications will be assessed.  If subject is a woman of child-bearing 
potential, a reliably and highly effective contraceptive method will be confirmed.  A stool sample 
will be collected from the patient either at visit or days -2 - +2 around the study visit or as mail 
in. Instructions to either mail in or provide in person stool sample at visit week 6 period 1. In case 
of early crossover female patients will provide urine samples for pregnancy test at week 4.  There 
will also be a review of glucose diary and hypoglycemic protocol and reporting form. 
If at visit week 4 the bowel frequency of the patient did not respond to treatment (at least a 15% 
decrease compared to baseline the patient can proceed to early crossover. The patient will be 
given study drug (either the placebo or the liraglutide group) in medication packs with his unique 
study ID medication packs, which will be containing treatment until week 12 and be instructed 
to bring back the study medication from study period 1 at the final visit of period 2 (week 12). He 
will be instructed to start injections on day 6 after 5 days of washout. The day he starts will be 
defined as week 6 period 2.  
 
Visit week 6 period 1 (site visit): If the patient did not qualify for early crossover, he will come to 
visit week 6 period 1 the coordinator will review the adverse events, which occurred since the 
previous visit. A physical exam and blood tests will be performed and the mPDAI will be 
calculated.  The concomitant medications will be assessed.  If subject is a woman of child-bearing 
potential, a reliably and highly effective contraceptive method will be confirmed.   A stool sample 
will be collected from the patient either at visit or days -2 - +2 around the study visit as mail in. 
Female patients will provide urine samples for pregnancy test at week 6 period 1. The patient 
will be given either the placebo or the liraglutide group with his unique study ID for period 2 and 
will be instructed to start injections on day 6 after 5 days of washout. The day he starts will be 
defined as week 6 period 2. The patients will be also be instructed to bring back the study 
medication from study period 1 at the final visit of period 2 (week 12).  There will also be a review 
of glucose diary and hypoglycemic protocol and reporting form. 
 
Visits week 7 and 8 (phone visits): The coordinator will ask the study patient if adverse events 
occurred and will review the adverse event diary with the study patient. The coordinator will also 
evaluate the web registered clinical components of the mPDAI of the last 3 days before the phone 
call (stool frequency, rectal bleeding, fecal urgency/ abdominal cramping, fever) as well as the 
concomitant medications. At visit week 7 and 8 the patient will be asked to send in a stool sample 
for visit week the next visit (in person or as mail in collected days -2 - +2 around the visit date).  
There will also be a review of glucose diary and hypoglycemic protocol and reporting form.  If 
subject is a woman of child-bearing potential, a reliably and highly effective contraceptive 
method will be confirmed.   
 
Visit week 10 (site visit): The coordinator will review the adverse events, which occurred since 
the previous visit. A physical exam and blood tests will be performed and the mPDAI will be 


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calculated. The concomitant medications will be assessed.  If subject is a woman of child-bearing 
potential, a reliable and highly effective contraceptive method will be confirmed and they will 
provide urine samples for pregnancy test at week 10.  A stool sample will be collected from the 
patient either at visit or days -2 - +2 around the study visit or as mail in. Instructions to either mail 
in or provide in person stool sample at visit week 12.  There will also be a review of glucose diary 
and hypoglycemic protocol and reporting form. 
If at visit week 10 the bowel frequency of the patient did not respond to treatment (at least a 
15% decrease compared to baseline this visit will be classified as end of treatment (week 12). If 
the patient meets the criteria of non-response, he/she will be instructed to bring back all 
medication of study period 1 and 2 to a follow-up visit at week 12. The patients who were 
responders at week 10 and finished the trial at week 12 will be informed about follow-up visit 2 
weeks later (week 14). 
Visit week 12 (site visit): the coordinator will review the adverse events, which occurred since the 
previous visit. A physical exam and blood tests will be performed and the mPDAI will be 
calculated. The concomitant medications will be assessed.  If subject is a woman of child-bearing 
potential, a reliable and highly effective contraceptive method will be confirmed and they will 
provide urine samples for pregnancy test at Week 12.  A stool sample will be collected from the 
patient either at visit or days -2 - +2 around the study visit or as mail in. All study medications 
from period 1 will be collected to assess compliance. All patients who completed visit week 12 
and the full treatment period 2 patient will be informed about follow- up visit 2 weeks later (week 
14). There will also be a review of glucose diary and hypoglycemic protocol and reporting form. 
For all non-responders at week 10, week 12 will be the final follow-up visit in person to collect all 
study medications from period 1 and 2 to assess compliance. 
Week 14 (phone visit): The coordinator will call the patients, who finished the trial at week 12 
(responders week 10) and will assess changes in concomitant medication and occurrence of new 
adverse events since last week. 
 
STUDY VISITS 
 
SCREENING VISIT 
 
Data to be recorded: 
- 
General parameters: 
- 
Initials 
- 
Date of birth 
- 
Sex 
- 
Smoker (yes/no/ex-smoker) 
- 
Race (NIH categories) 
- 
Ethnicity (NIH categories) 
Case history 


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- 
Date of confirmation of the diagnosis 
- 
Classification of UC before IPAA (proctitis, left sided colitis, pancolitis) 
- 
Type of extraintestinal symptoms 
- 
Specific therapies for pouchitis within the last year 
- 
Type of medication 
- 
Specific therapies for pouchitis within the last 4 weeks 
- 
Type of medication 
Examinations 
- 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), calculation of 
BMI, temperature 
- 
Height (cm) 
- 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
Blood sampling and measurement of laboratory parameters 
- 
Labs 
- 
Urine pregnancy test (female) 
- 
Stool sample for C. difficile toxin 
- 
Pouchoscopy (standard of care): Evaluation of endoscopic PDAI. 
Formal aspects: 
- 
Informed consent procedure 
- 
Verification of inclusion / exclusion criteria (eligibility check) 
- 
Confirm reliable and highly effective contraceptive method if subject is a woman of 
child-bearing potential  
- 
Dispense stool collection kit for stool sample period 1 
- 
Explain and distribute stool diary to study patient (at least 7 days of daily bowel 
frequency are necessary to calculate baseline weekly bowel frequency)  
 
VISIT WEEK 0 
 
Examinations 
- 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), temperature 
- 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 


Liraglutide therapy in patients with IPAA and chronic high bowel frequency 
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- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
Blood sampling and measurement of laboratory parameters 
- 
Urine pregnancy test (female patients) 
- 
If no GLP-1 baseline yet at screening, if possible fasting GLP-1 baseline blood draw 
- 
Dispense stool collection kits for stool samples  
Formal Aspects: 
- 
Review diary data and calculation of the mPDAI  
- 
Confirm reliable and highly effective contraceptive method if subject is a woman of child-
bearing potential  
- 
Verification of inclusion / exclusion criteria (eligibility check) 
- 
Randomization 
- 
Dispensation of glucometer including auxiliary supplies as well as instructions for 
use, review of glucose diary, review of signs and symptoms of hypoglycemia, 
review of hypoglycemic protocol and reporting form 
 
VISITS PERIOD 1 WEEK 1 AND 2 (PHONE VISIT; +/- 1 DAY) 
 
Blood sampling and measurement of laboratory parameters 
- 
Check if stool sample was received (Period 1 week 2) 
 
Formal aspects: 
- 
Adverse events (review adverse events diary) 
- 
Review of glucose diary and hypoglycemic protocol and reporting form 
- 
Concomitant medication 
- 
Calculation of clinical mPDAI  
- 
Remind of stool sample collection at Period 1 week 1 for Period 1 week 2 and Period 
1 week 2 for Period 1 week 4.  
- 
Confirm reliable and highly effective contraceptive method if subject is a woman of 
child-bearing potential  
 
 
VISIT PERIOD 1 WEEK 4: (SITE VISIT; =/- 3 DAYS) 
 
Examinations 
- 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), temperature 
- 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 


Liraglutide therapy in patients with IPAA and chronic high bowel frequency 
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- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
Blood sampling and measurement of laboratory parameters 
- 
Labs 
- 
Check if stool sample was received 
- 
In case of early crossover:  
o Urine pregnancy test (female) 
o Dispense stool collection kits for stool samples Period 2 
 
Formal aspects: 
- 
Adverse events (review adverse events diary) 
- 
Confirm reliable and highly effective contraceptive method if subject is a woman of 
child-bearing potential  
- 
Review of glucose diary and hypoglycemic protocol and reporting form 
- 
Concomitant medication 
- 
Calculation of clinical mPDAI and assess if patient is responder or not (early 
crossover) 
- 
If patient continues reminder stool Period 1 week 6.  
- 
Early crossover: Dispense study medication for Period 2. Instruct patient to restart 
study medication on day 6. Instruct to keep study medication from Period 1 and 
bring back at last visit of Period 2 (week 12) or Period 2 week 10. 
 
 
VISIT PERIOD 1 WEEK 6: (SITE VISIT; =/- 3 DAYS) 
 
Examinations 
- 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), temperature 
- 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
 
Blood sampling and measurement of laboratory parameters 
- 
Labs 


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- 
Check if stool sample was received 
- 
Urine pregnancy test (female) 
 
Formal aspects: 
- 
Adverse events (review adverse events diary) 
- 
Confirm reliable and highly effective contraceptive method if subject is a woman of 
child-bearing potential  
- 
Review of glucose diary and hypoglycemic protocol and reporting form 
- 
Concomitant medication 
- 
Calculation of clinical mPDAI  
- 
Crossover: collect all study medication and dispense study medication for period 2. 
Instruct patient to restart study medication on day 6.  
 
VISITS PERIOD 2: WEEK 7 AND 8 (PHONE VISIT; +/- 1 DAY) 
 
Blood sampling and measurement of laboratory parameters 
- 
Check if stool sample was received (week 8) 
 
Formal aspects: 
- 
Adverse events (review adverse events diary) 
- 
Review of glucose diary and hypoglycemic protocol and reporting form 
- 
Concomitant medication 
- 
Calculation of clinical mPDAI  
- 
Remind of stool sample collection at Period 2 week 7 for Period 2 week 8 and at Period 2 
week 8 for Period 2 week 10 
- 
Confirm reliable and highly effective contraceptive method if subject is a woman of 
child-bearing potential  
VISIT PERIOD 2 WEEK 10: (SITE VISIT; =/- 3 DAYS) 
 
Examinations 
- 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), temperature 
- 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
Blood sampling and measurement of laboratory parameters 


Liraglutide therapy in patients with IPAA and chronic high bowel frequency 
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- 
Labs 
- 
Urine pregnancy test (female) 
- 
Check if stool sample was received 
 
Formal aspects: 
- 
Adverse events (review adverse events diary) 
- 
Confirm reliable and highly effective contraceptive method if subject is a woman of 
child-bearing potential  
- 
Review of glucose diary and hypoglycemic protocol and reporting form 
- 
Concomitant medication 
- 
Calculation of clinical mPDAI and assess if patient is responder or not (early 
termination in case of non-responder). If non-responder, patient should stop 
medication and will be considered early termination 
- 
If patient continues reminder stool week 12.  
- 
Early termination: Remind patient to come to final visit at Period 2 week 12 and 
bring all study medication of ( if not done already from Period 1 and complete from 
Period 2). For this patient group at visit Period 2 week 12 only adverse events 
(review adverse events diary) and concomitant medication will be assessed. An 
alternative approach is a phone visit Period 2 week 12 and patient returns all study 
medication 2 before Period 2 week 12.  
 
VISIT PERIOD 2 WEEK 12: (SITE VISIT; =/- 3 DAYS) 
 
Examinations 
Vital signs: blood pressure (mm Hg), heart rate (min-1), weight (kg), temperature 
Physical examination:  
- Head (including ENT and eyes) 
- Gastrointestinal tract, liver, spleen 
- Lymphatic system 
- Urogenital system 
- Endocrine system 
- Nervous system 
- Lungs and respiratory tract 
- Muscular and skeletal system 
- Peripheral vascular system 
- Skin and connective tissue 
- Cardiovascular system 
- Other 
 
each: actual status: Present finding / normal condition / not examined 
 
Blood sampling and measurement of laboratory parameters 
- 
Labs 
- 
Urine pregnancy test (female) 
- 
Check if stool sample was received 
 
Formal aspects: 
- 
Adverse events (review adverse events diary) 


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- 
Review of glucose diary and hypoglycemic protocol and reporting form 
- 
Concomitant medication 
- 
Calculation of clinical mPDAI .  
- 
Collect all study medication (Period 1 and 2). 
- 
Confirm reliable and highly effective contraceptive method if subject is a woman of 
child-bearing potential  
 
For non-responders at Period 2 Week 10  use assessment as outline in Period 2 Week 14, since 
patient is off study drug for 2 weeks now (only assessment of adverse event and concomitant 
medication assessment as well as collect all study). Also collect all study medication (period 1 and 
2). 
 
VISITS PERIOD 2 WEEK 14 (PHONE VISIT; +/- 3 DAYS) 
 
Formal aspects: 
- 
Adverse events (review adverse events diary) 
- 
Concomitant medication 
- 
Confirm reliable and highly effective contraceptive method if subject is a woman of 
child-bearing potential  
 
MEASUREMENT OF COMPLIANCE 
Compliance will be assessed at the end of period 1 and period 2 by checking the study 
medication (pens) returned at the follow-up visits and the final visit by the investigator.  
During the Induction and Maintenance Period all returned pens will be counted by the 
investigator and the number will be documented in the electronic CRF.  
 
LABORATORY PARAMETERS AND POUCHOSCOPY 
All laboratory analyses will be carried out in a central laboratory.  
 
Acute phase reactants (nonspecific inflammatory markers) 
• 
C-reactive protein (CRP) 
Hematology: 
• 
Blood count (erythrocytes, hemoglobin, hematocrit, leukocytes, platelets and 
differential WBC) 
Serum chemistry: 
• 
Kidney function: serum urea and creatinine 
• 
Liver function (alanine aminotransferase {ALT}, aspartate aminotransferase {AST}, 
alkaline phosphatase, bilirubin), albumin 
• 
Other serum parameters (total protein, Na+, K+) 
 


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Stool sample for C. diff .toxin  
 
POUCHOSCOPY (SCREENING) 
Pouchoscopy will be performed to evaluate the pouch, prepouch ileal segment and the cuff. The 
pouch and prepouch inflammation will be graded according mPDAI (see attachment). If a 
pouchoscopy describing prepouch pouch and cuff is available and this pouchoscopy was 
performed in 6 months previous to screening and a PDAI can be calculated based on the report, 
no additional pouchoscopy is necessary.  
 
ETHICS 
IRB approval for the study will be obtained after the study is funded. The study protocol will be 
submitted 
to 
the 
UNC 
IRB 
and 
the 
office 
of 
Human 
research 
ethics 
(https://research.unc.edu/human-research-ethics). The study will be conducted in accordance 
with the Declaration of Helsinki, the ICH GCP guidelines. This study will comply with all applicable 
regulatory and legal requirements, ICH GCP guidelines and the Declaration of Helsinki in 
obtaining and documenting the informed consent. 
 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
DEFINITIONS 
ADVERSE EVENT  
An adverse reaction is an adverse event for which the causal relationship between the product 
and the adverse event is suspected i.e. e.g.: 
 
• 
any new diagnosis 
• 
any symptom that requires medical clarification or leads to in-patient admission (surgery 
or accident) 
• 
any suspected adverse drug reaction (ADR) 
• 
any symptom that appears on the patient’s medical records 
• 
any event related in time with the application of the study medication and affecting the 
health of the patient (including laboratory value changes) 
Adverse events (AEs) will be recorded at each regular scheduled study visit or study phone 
contact in the patient record (source document) as well as on a specific AE form on the 
electronic CRF. 
 
SERIOUS ADVERSE EVENT 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
results in death 


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• 
is life-threatening 
• 
requires inpatient hospitalization or prolongation of existing hospitalization  
• 
results in persistent or significant disability/incapacity 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an Serious Adverse Event when, based upon appropriate 
medical judgement, they may jeopardize the patient or subject or require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Suspicion of transmission of 
infectious agents must always be considered an SAE. 
 
Non-serious adverse events are all AEs that do not fall into any of the above categories. 
 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION  
A suspected unexpected serious adverse reaction (SUSAR) is an SAE which is unexpected and 
regarded as possibly or probably related to the trial/study product by the investigator 
 
UNEXPECTED ADVERSE DRUG REACTIONS  
An unexpected adverse drug reaction (ADR) is an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. 
 
EXPECTED ADVERSE DRUG REACTIONS 
Liraglutide (Victoza®)is a FDA approved drug for treatment of diabetes and obesity. The protocol 
uses the current version of US/FDA approved Prescribing Information or any updates hereof for 
assessment of expectedness. Diarrhea, nausea or vomiting, the more frequent ADR have not 
been reported to be severe in the available studies in patients treated with a GLP-1 receptor 
agonist for diarrhea or high ileostomy output. This may be due to pre-existing low GLP-1 levels in 
this patient population or in case of diarrhea the lack of the colon (ileostomy patients).19, 26, 27 
 
Common ADRs caused by liraglutide include the following: 
• nausea 
• diarrhea 
• constipation 
• vomiting 
• headache 
• dyspepsia 
• fatigue 
• dizziness 
• abdominal pain 


Liraglutide therapy in patients with IPAA and chronic high bowel frequency 
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• abdominal distension/flatulence 
• GERD 
• gastroenteritis 
• eructation 
• UTI 
• cholelithiasis 
• lipase increase 
• injection site reaction 
• insomnia 
• xerostomia 
• asthenia 
• anxiety 
• tachycardia 
HYPOGLYCEMIA MONITORING, HYPOGLYCEMIC PROTOCOL AND REPORTING FORM 
Hypoglycemia can occur in patients without concomitant treatment with a sulfonylurea drug or 
other drugs used to treat diabetes. There is currently no requirement to measure glucose levels 
in non-diabetic patients while being treated with liraglutide therapy for weight loss. Previous 
single center series in patients with ileostomy have not revealed an increased risk of 
hypoglycemia while treated with drugs like liraglutide. However, since this type of drug has not 
yet been evaluated in patients with an ileo- pouch anal anastomosis, patients will measure daily 
glucose levels before breakfast.  
All study patients will be provided with a blood glucose (BG) meter including auxiliary supplies as 
well as instructions for use. The subjects will be instructed in to measure blood glucose fasting 
before breakfast daily, how to use the device and how to fill out the daily glucose protocol. The 
glucose diary will be reviewed at every study visit.  
 
HYPOGLYCEMIC PROTOCOL AND REPORTING FORM 
 
At randomization, all study patients will be instructed in symptom recognition and handling of 
hypoglycemia. Symptoms of hypoglycemia will be explained which may be hunger, shakiness, 
nervousness, sweating, dizziness or light-headedness, sleepiness, confusion, difficulty speaking, 
anxiety, weakness. 
 


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 If one of these symptoms occur study patients will be instructed to measure plasma glucose level 
and record these in the hypoglycemic protocol and reporting form. Study patients will report all 
plasma glucose values: 
≤ 3.9 mmol/L (70 mg/dL)  
or 
> 3.9 mmol/L (70 mg/dL) occurring in conjunction with hypoglycemic symptoms.  
 
Upon onset of a hypoglycemic episode with a plasma glucose of ≤ 3.9 mmol (70 mg/dl) the subject 
is recommended to measure plasma glucose every 15 minutes until the self-measured plasma 
glucose value is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved in accordance to 
current guidelines. Repeated self-measured plasma glucose measurements and/or symptoms, 
occurring within a period of 60 min after onset on a hypoglycemic episode, will by default be 
considered as one hypoglycemic episode until a succeeding self-measured plasma glucose value 
is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved and should be reported on one 
hypoglycemic episode form. Self-measured plasma glucose measurements ≤ 3.9 mmol/L (70 
mg/dL) or hypoglycemic symptoms after the 60 min period shall trigger the reporting of a new 
hypoglycemia episode and prompt the subject to fill out a new hypoglycemic episode form until 
a succeeding measurement is > 3.9 mmol/L (70 mg/dL) and/or symptoms have been resolved.  
 
Hypoglycemic protocol and reporting form will advise the patient how to treat the hypoglycemia 
with either one of the following: 
• 1/2 cup, or 4 ounces, of any fruit juice  
• 1/2 cup, or 4 ounces, of a regular— not diet—soft drink 
• 1 cup, or 8 ounces, of milk 
• 5 or 6 pieces of hard candy 
• 1 tablespoon of sugar or honey 
 
The lowest value measured during the hypoglycemic episode will be reported as the plasma 
glucose value for the episode.  The patient will also report symptoms, the time of the last meal 
and the activity preceding the episode.  
 
If the question "Was the hypoglycemic episode so severe that you could not care for yourself and 
needed help from others?’ which suggests that the hypoglycemic episode is associated with 
severe neuroglycopenia, usually resulting in coma or seizure and requiring parenteral therapy 
(glucagon or intravenous glucose)?" is answered "YES"; the following information will be 
recorded: 
• Who assisted in the treatment of the hypoglycemic episode (i.e., medical person or non-
medical person)? 
• Where the treatment was administered (in clinic/emergency room/hospital or other.  
• Type of treatment provided by other person (i.e., oral carbohydrates, glucagon, IV glucose 
or other) 
• Were symptoms alleviated after administration of treatment? 
 
If the hypoglycemic episode fulfils the criteria for an SAE then an AE form and a safety 


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information form will be completed.   
 
 
DOCUMENTATION AND REPORTING OF ADVERSE EVENTS 
The patients will be instructed to contact the investigator, if any serious or unexpected AE occurs, 
so that appropriate action can be taken. 
Moreover, the investigator must ask at each follow-up visit a generally worded question without 
searching for any special symptoms, e.g. “Has your state of health worsened since we last met?” 
If the answer to this question is “no”, no further questions will be asked. If the answer to the 
question is "yes”, the investigator will document the nature, time, severity, seriousness and 
duration as well as the causality of the AE. For each AE a specific AE documentation form will be 
provided to the investigators. In case of an AE, this should be completed by the physician as an 
initial report. The report must contain a detailed description of the symptoms observed and the 
concomitant treatment administered. Furthermore, the investigator must comment on a 
possible causative relationship between the AE and the trial medication. Each AE must be 
followed until it is resolved or can be explained satisfactory. 
 
The following has to be documented for each AE: 
• Nature of the event 
• Time of onset: date, time 
• Concomitant treatment: product (generic name), indication, dosage, dosage interval, 
presentation, mode of administration, administration regimen 
• Duration of the AE 
• Severity 
• Seriousness 
• Causality 
• Outcome 
 
SEVERITY 
The severity is evaluated as follows: 
1. Mild: 
- event/symptom does not interfere with normal daily activities 
2. Moderate: 
- event/symptom interferes with normal daily activities 
3. Severe: 
- event/symptom prevents normal daily activities 
 
Causality 
The relationship between an AE and the study medication is classified according to the WHO 
classification: 
 
Certain 


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A clinical event, including laboratory test abnormality, is occurring in a plausible time relationship 
to drug administration, and which concurrent disease or other drugs or chemicals cannot explain. 
The response of the patient to withdrawal of the drug should be clinically plausible. The event 
must be definite pharmacologically or phenomenologically, using a satisfactory rechallenge 
procedure if necessary. 
 
Probable/Likely 
A clinical event, including laboratory test abnormality, with a reasonable time sequence to the 
administration of the drug, unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on withdrawal (de challenge). 
Rechallenge information is not required to fulfil this definition. 
 
Possible  
A clinical event, including laboratory test abnormality, with a reasonable time sequence to 
administration of the drug, but which could also be explained by concurrent disease or other 
drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 
 
Unlikely  
A clinical event, including laboratory test abnormality, with a temporal relationship to drug 
administration which makes a causal relationship improbable, and in which other drugs, 
chemicals or underlying disease provide plausible explanations. 
 
Conditional/Unclassified 
A clinical event, including laboratory test abnormality, reported as an adverse reaction, about 
which more data are essential for a proper assessment or the additional data are under 
examination. 
Not assessable / Unclassifiable 
A report suggesting an adverse reaction, which cannot be judged because information is 
insufficient or contradictory, and which cannot be supplemented or verified. 
 
As an alternative to the above-mentioned WHO assessments, the following assessment can be 
made: 
 
Not related 
There is sufficient information available to show that the etiology is unrelated to the study 
medication. 
 
MEASURES AT THE ONSET OF ADVERSE EVENTS  
Measures at the onset of adverse events are classified and described as follows: 
1) 
None, i.e. the study medication was not changed 
2) 
The dose of the study medication was reduced 
3) 
The study medication was withdrawn and/or 
4) 
Other measures (clear text) 
 


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The course and outcome of the adverse event will be commented on as follows: 
1) 
Recovered without sequelae 
2) 
Not yet recovered 
3) 
Recovered with sequelae 
4) 
Fatal 
 
DOCUMENTATION AND REPORTING OF SERIOUS ADVERSE EVENTS 
On enrolment in the study, the patients will be instructed to contact the investigator if a serious 
or unexpected AE occurs, so that appropriate measures can be taken. 
Any SAE (including death, irrespective of the cause) occurring during or for up to 14 days after 
the end of the study will be reported without delay, i.e. within 24 hours, irrespective of its 
relationship with the administration of the study medication (minimum information required: 
investigator’s name/study center, patient number, patient initials, date of first dose, date of 
last dose, date of event, description of event, causality assessment, and countermeasures). 
A specific AE documentation form will be available. In case of an SAE, this will be completed by 
the PI (sponsor-investigator) as an initial report. The report must contain a detailed description 
of the symptoms observed and the concomitant treatment administered. Furthermore, the 
investigator must comment on a possible causative relationship between the AE and the trial 
medication. Each SAE must be followed until it is resolved or can be explained satisfactorily. 
The general procedure for the observation, collection and analysis of drug risks (regulatory 
affairs) in conformity with the appropriate national Drug Law shall apply without qualification. 
In accordance with drug safety and national requirements, the PI of the study (sponsor 
investigator) will inform the Data and IRB of the study and will make sure that the involved 
persons will obtain adequate information.  
The PI of the study (sponsor-investigator) will report to Novo Nordisk all SAEs, SUSARs, and SADRs 
at the same time such events are reported to regulatory authorities or within 15 days from the 
sponsor-investigator becoming aware of such adverse events, whichever comes first. 
 
The sponsor-investigator will collect the following information at minimum for each of these 
events: 
1. Study name 
2. Patient identification (e.g. initials, sex, age) 
3. Event (preferably a diagnosis) 
4. Drug  
5. Reporter identification (e.g. Name, or initials) 
6. Causality 
7. Outcome might be reported, but this is not mandatory. 
 
ABNORMAL LABORATORY RESULTS  
All laboratory values outside of the normal range will be repeated if judged appropriate by the 
investigator to ensure the validity of the abnormal result. The investigator will document all 


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laboratory values on the relevant page of the electronic CRF and will assess the etiology of the 
clinically relevant abnormal laboratory values.  
Clinically relevant abnormal laboratory values are only documented on the AE form of the 
electronic CRF, if the patient is discontinued, hospitalized, or, in the investigator’s opinion, it 
should be considered as an AE. 
Abnormal laboratory results caused by ulcerative colitis should not be reported on the AE form. 
 
Pregnancy 
Pregnancy tests will be performed at the screening visit, week 0, week 4 (in case of early cross 
over), week 6, week 10, and week 12 of the study. Women of child bearing potential will be 
asked about contraception compliance at each study contact.  If there is concern for pregnancy 
during the study, the subject will be asked to immediately come to the site for a pregnancy test.  
The PI (sponsor-investigator) will report to Novo Nordisk any pregnancy occurring during the 
trial period. Reporting of pregnancy by sponsor-investigator should occur within the same 
timelines described above for reporting of serious adverse events.  
 
WITHDRAWAL OR STOP OF STUDY DRUG CRITERIA 
CRITERIA IN INDIVIDUAL CASES 
Any patient can withdraw from the study at any time without personal disadvantages and 
without having to give a reason. The time of withdrawal, the results available up to that time, 
and, if known, the reason for withdrawal must be documented in the CRF. The investigator can 
also discontinue the study after considering the risk-to-benefit ratio, if he/she no longer 
considers the further participation of the patient justifiable. The date of and the primary reason 
for the withdrawal as well as the observations available at the time of withdrawal are to be 
documented on the electronic CRF. 
Reasons leading to the withdrawal of a patient can include the following (primary reason must 
be determined): 
 
• inclusion criterion not fulfilled, or exclusion criterion fulfilled; coming to knowledge after 
recruitment  
• patient’s request 
• technical/logistical reasons (e.g. a change in place of residence, not referred by family 
physician, etc.)  
• withdrawals due to adverse events (including non-serious adverse events leading to 
withdrawal) 
• withdrawal to known adverse drug reaction (ADR as listed above), which is defined as 
severe according to the listed severity criteria (event/symptom prevents normal daily 
activities). 
• Acute gallstone disease confirmed by 
o Signs and symptoms of acute gallstone disease 
o Specific laboratory test supporting a diagnosis of gallstone disease 


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o Imaging performed and consistency with gallstone disease 
 
• New onset of Pancreatitis confirmed if a minimum 2 of 3 criteria ae met: 
o  Severe acute abdominal pain  
o  Blood amylase and/or lipase >3x upper limit of normal (ULN)  
o   Characteristic findings on relevant imaging (e.g., computerized axial 
tomography/magnetic resonance imaging/ultrasound)  
 
• Any medical condition or clinically significant abnormal finding(s) (physical, laboratory, vital 
sign) that may jeopardize the subject’s safety if study drug is continued, in the investigator’s 
and/or sponsor’s opinion; this may include the development of persistent events such as:  
o ALT or AST > 3x ULN and either total bilirubin > 2x ULN or INR > 1.5  
o ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, right upper-
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)  
o Creatinine elevation > 2x above upper limit of normal 
 
• Recurrent hypoglycemia defined as a blood glucose of ≤ 3.9 mmol/L (70 mg/dL)  
 
• other reasons (noting reason) 
 
Reasons leading to the stop of study drug but follow-up according protocol can include the 
following (primary reason must be determined): 
• lack of efficacy of the study medication, e.g. 
- 
need for a prohibited concomitant medication (e.g. need for steroids) 
• lack of patient’s cooperation, e.g. 
- 
patient’s request 
- 
lack of compliance (fails to attend the follow-up visits as agreed)  
- 
existing pregnancy or intended pregnancy* (females), lactation (females) 
In all patients who finish the study prematurely, a withdrawal examination should be carried out 
within 2 weeks after the last application of the study medication. The withdrawal examination 
must be conducted as a final examination and documented in the CRF. 
 
REPLACEMENT OF WITHDRAWN PATIENTS 
Replacement lists will not be provided since it is not planned to replace subjects if they withdraw 
or become ineligible after the first dose of study drug has been given. 
 
CRITERIA FOR THE TERMINATION OF THE WHOLE STUDY 
If safety concerns arise, the PI can terminate or interrupt the study by agreement with Novo-
Nordisk. If new information on the risk-to-benefit ratio of the drug or on the treatment methods 


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used in the study is obtained in the meantime, the PI reserves the right to interrupt or terminate 
the project by agreement with Novo-Nordisk. Premature termination is also possible if patient 
recruitment is insufficient and cannot be expedited by appropriate measures. 
 
LIABILITY AND SUBJECT INSURANCE 
The PI (sponsor-investigator) and his/her institution will provide adequate medical care to the 
study subject for any study-related adverse events, including clinically significant laboratory 
values related to the study. Sponsor-investigator should state that this medical care for study 
subjects will be provided regardless of their insurance status. 
 
The PI (sponsor-investigator) will be responsible for the conduct of the study. The PI (sponsor-
investigator) agrees to defend, indemnify, and hold harmless Novo Nordisk, any of its parent 
companies, affiliates, or subsidiaries, and their respective officers, directors, employees, agents, 
representatives, distributors, salespersons, customers, licensees, and end-users from and against 
any claim, suit, demand, loss, damage, expense or liability imposed by any third party arising from 
or related to: (a) any breach of PI’s (sponsor-investigator's) obligations or representations; or (b) 
PI (sponsor-investigator’s) negligent or grossly negligent use or willful misuse of the study drug, 
the results, or services derived therefrom.  This indemnification shall not apply in the event and 
to the extent that a court of competent jurisdiction or a duly appointed arbiter determines that 
such losses or liability arose as a result of Novo Nordisk’s gross negligence, intentional 
misconduct, or material breach of its responsibilities.  
 
 
RANDOMIZATION, DATA MANAGEMENT AND DATA MONITORING 
The randomization sequence of the patients and the processing and analysis of the data will be 
carried out by the Biostatistics core of the Center for Gastrointestinal Biology and Disease at UNC 
Chapel Hill. The randomization sequence will be established by the CGIBD Biostatistics core and 
communicated with the investigational drug services of UNC.  
 
Study data for this study will be collected and stored using electronic records.  Data captured will 
be entered in real time using web forms developed to replicate paper case report forms.  All data 
will be created, modified, maintained, archived, retrieved and distributed by a computer system.  
The use of electronic records will increase the speed of data collection and exchange and 
facilitates daily reporting of patient reported outcomes. This will reduce the manpower necessary 
to perform double-data entry from paper forms and transcription error. In addition, electronic 
records permit economical storage of study data and ease of accessibility and analysis. Data 
management and data quality systems will be built into the system.  
Data quality using electronic records will ensure that data are attributable, legible, 
contemporaneous and original.   
The Data Management Center (DMC) at the CGIBD at the University of North Carolina will track 
the data collection, provide data security, control for confidentiality of study data, maintain 


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computer backups to protect data until study closure and archive study data according to FDA 
requirements (21 CFR 11).  Electronic signatures will be linked to each entry.   
All computer systems and programs will be password protected, and all electronic 
communications of study and other confidential information will be encrypted. Personnel at the 
CGIBD have extensive training and experience using electronic data systems.  Good computer 
security practice (restricting physical access to machines, prohibition of password sharing, and 
logging off computers after work hours or when away from the machine) will be required of all 
study personnel.  
Standard Operating Procedures exist for users of the DMC.  Only authorized persons are 
authorized for data entry and access. Data security systems require password protected 
identification codes for data entry and provide protection against data manipulation.  The 
database is located on a server protected by firewalls.  Access to the database server will not be 
allowed by users on computers outside of the firewall-protected zone.  Virus protection software 
is installed on each study machine.  System access to computer systems will be audited.  
Redundant backups and off-site backup storage will allow for quick restoration of data in the 
unlikely event that a hardware failure, disaster, or security breach should occur.  Servers and 
backups will be located in a secured location with access limited to authorized personnel. 
 
Data cleaning will include range and edit checks, cross form edit checks, query generating and 
tracking and periodic data status reports.  Any data errors or inconsistencies detected after data 
entry will be automatically tracked, communicated and resolved using a web-based application.  
An audit trail of all data changes over the life of the study will be maintained.  All study raw data, 
forms, documents, software programs, software applications and computer data files will be 
indexed and archived routinely.  Strict version control of documents and software applications 
will be instituted.  Retention of study documentation after study completion will conform to FDA 
and NIH requirements. 
Standardized study management reports will be generated monthly during the recruitment 
phase of the study. These reports will be used to track study progress including patient 
enrollment, randomization, compliance, patient status changes, and study events.   
 
DATA ANALYSIS 
Efficacy analyses will primarily be based on a modified intent-to-treat {mITT} analysis set, which 
includes all randomized patients, who took at least one dose of the investigational product. 
Statistical tests will be 2-sided and performed at the 0.05 level of significance. Missing data will 
be imputed for the mITT population using the last observation carried forward (LOCF) method. 
Baseline observations will not be carried forward if all subsequent measurements are missing.  
 
 
Primary analyses 
The primary outcome is the reduction of the mean 7-day bowel frequency of 30% 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). A crossover trial will be performed. Subjects with a history of 
averaging > 8 bowel movements per day over a 7-day span will be entered into the study and the 


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order in which they receive treatments (liraglutide or placebo) will be randomized. At the end of 
each week, the average number of bowel movements the subject had during that week will be 
computed. A repeated measure mixed model will be fit to the data with treatment (liraglutide or 
placebo), period and treatment sequence as fixed effects and the repeated measures within 
subject as a random effect. After the model is run, any non-significant effects for period or 
treatment sequence will be removed from the model. The treatment effect will remain in the 
model and is the outcome of interest. P-value less than 0.05 will be considered statistically 
significant. In a sensitivity analysis the same model will be run without removing any effects. P-
value less than 0.05 will be considered statistically significant. 
 
Secondary analyses 
Continuous secondary outcomes (stool frequency, clinical PDAI) will be summarized using 
descriptive statistics (mean, median, standard deviation, minimum, and maximum) of the values 
at each assessment and the change from baseline to each assessment. A repeated measure 
mixed model will be fit to the data with treatment (liraglutide or placebo), period and treatment 
sequence as fixed effects and the repeated measures within subject as a random effect. After the 
model is run, any non-significant effects for period or treatment sequence will be removed from 
the model. The treatment effect will remain in the model and is the outcome of interest. P-value 
less than 0.05 will be considered statistically significant.  
 
Safety analyses 
The safety analyses will comprise all included patients, who got at least one dose of the 
investigational product. 
 
– 
Number of study patients, who discontinued therapy 
– 
Adverse events grouped by body system  
– 
Changes in laboratory values 
 
Exploratory analyses 
We will perform exploratory analyses using descriptive statistics (mean, median, standard 
deviation, minimum, and maximum) and bivariate analyses of the values at each assessment and 
the change from baseline to each assessment. In the evaluation of the PROMIS measure for 
incontinence, PROMIS measures utilize a T-score metric where a score of 50 is the mean of a 
relevant reference population and 10 is the standard deviation. Additionally, a clinically minimally 
important difference is reflected by a change of 2.  
 
Missing data 
Due to short and intensive period of follow-up for the primary outcome, we do not anticipate 
significant missing data. 
 
SAMPLE SIZE CALCULATION 
The analysis will be based on the within-subject difference between two one-week averages of 
the number of bowel movements per day (BMPD). A one-sample t-test will be used to test the 


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null hypothesis that the mean difference is zero. With a sample size of 10 subjects and Type-I 
0.05 (2-sided), the power is 0.80 against a difference of 1 standard deviation (SD) of the 
difference (not SD of the individual outcomes). The first average within each patient, by design, 
will be greater than 8 BMPD, and the range is most likely to be 8-11. The standard deviation (SD) 
of such an outcome can't (mathematically) exceed 1.5, and this will be used in the sample size 
calculations as the SD of each weekly average (control and treatment). Additionally, the SD of the 
difference depends on the correlation between the two weekly averages. Taking that into 
account, the power is 0.80 against a difference of 2.1 BMPD if the correlation is 0, 1.8 BMPD if 
the correlation is 0.25, 1.5 BMPD if the correlation is 0.50, 1.1 BMPD if the correlation is 0.75. 
Assuming a baseline average of 10 BMPD, the design has good power against relative changes of 
21% or higher if the within-subject correlation is zero. The power increases with increasing 
positive correlation and, naturally, is higher against larger effects. If patients drop out during the 
study the power will decrease, however patents will be carefully selected and thus dropouts are 
unlikely to occur.  
FUTURE PERSPECTIVE 
If this proof-of-concept study does not reveal any safety concerns and suggests efficacy of a 
GLP-1 receptor agonist therapy, we propose to conduct a multicenter phase 2, double blind, 
parallel group, randomized, placebo-controlled trial. Financial support for such a trial could be 
obtained by the investigators in the setting of a NIH funded collaborative trial. Given the 
orphan disease status of the pouch population, such a trial could be also conducted in advisory 
collaboration with the FDA. The applicants of this project have profound experience in 
successfully conducting NIH funded multi-center studies in the US. 51-53 Eight academic US 
centers collaborate already in the setting of the Crohn’s and Colitis Foundation supported 
multicenter registry (THE PROP-RD Study: A Prospective Registry for the Study of Outcomes 
and Predictors in Pouchitis and Pouch-Related Disorders). Additional centers can be easily 
recruited through the Clinical Research Alliance (CRA) of the Crohn’s and Colitis 
Foundation (Millie Long is currently chair of the CRA, which comprises 72 centers, Hans 
Herfarth was chair of the CRA between 2010 and 2018).  
 
PUBLICATION PLAN 
The trial will be registered at ClinicalTrials.gov. The applicants will present and discuss all clinical 
trial data with the sponsor. All relevant trial data will be posted on ClinicalTrals.gov following 
the discussion of the results. The applicants plan to submit a final paper of the results of this 
trial to a peer-reviewed gastroenterology journal.  
 


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TABLE STUDY VISITS AND ASSESSMENTS 
 
Study periods 
 
Period 1 
Period 2 
 
Screening & 
randomization 
 
Cross 
overf 
 
Follow-
up 
Visits 
Screen 
10-14 days 
before 
week 0 
Week 0 
Week  
1d 
± 1 day 
Week  
2d 
± 1 day 
Week  
4 
± 3 days 
Week  
6 
± 3 days 
Week  
7d 
± 1 day 
Week  
8d 
± 1 day 
Week  
10 
± 3 days 
Week  
12 k 
± 3 days 
Week  
14k 
± 3 days 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
PDAI scorea 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam (including body 
weight) 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
Blood Testsb 
X 
 
 
 
X 
X 
 
 
X 
X 
 
C. diff stool test 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
 
 
Xg 
X 
 
 
X 
X 
 
Confirm contraceptive 
method if applicable 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Stool calprotectin 
X 
X 
 
Xd 
X 
X 
 
Xd 
X 
X 
 
Pouchoscopy with endoscopic 
PDAI (standard of care) 
X 
 
 
 
 
 
 
 
 
 
 
Pouch biopsies (standard of 
care) 
X 
 
 
 
 
 
 
 
 
 
 
Review Subject Diaryc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Review of glucose diary and 
hypoglycemic protocol and 
reporting form 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assessment of responseh  
 
 
 
 
X 
 
 
 
X 
 
 
PROMIS questionnaires, SF36, 
PROBE 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
Study drug dispensation 
 
X 
 
 
Xi 
X 
 
 
 
 
 
Study drug collection 
 
 
 
 
 
 
 
 
 
Xj 
 


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a Clinical PDAI excluding pouchoscopy 
bCBC, AST, ALT, AP, Bilirubin, Creatinine, CRP. Serum samples for GLP-1 baseline fasting if possible (Screening or week 0). 
c Subject diary will be maintained electronically and completed daily reporting stool frequency, rectal bleeding, fecal urgency or abdominal cramps, and/or 
fever. The patient will complete this diary each day, beginning with the screening visit and ending at the visit. The average 7-day bowel frequency will be 
calculated for each 7-day period. For the clinical PDAI scores the last three days of diary entries before each visit will be used to calculate stool frequency and 
fecal urgency/abdominal pain scores. 
d Phone visit only with review of diaries and dose increase of study drug if tolerated. Patient will mail stool sample calprotectin or bring in person. 
f Crossover occurs after at least 5 days of washout after the last study dose 
g Pregnancy test at week 4 in case of early crossover 
h Assessment of response: If average weekly bowel frequency of patient did not decrease by at least 15% compared to baseline the patient can proceed to 
early crossover (Period 1 week 4) or early termination (Period 2 week 10). 
i Non-responder at Period 1 week 4 receive study drug for period 2 to start 5 days after the last study dose of period 1 
j Collection of study drug from non-responders in Period 2 week4 and all patients who were responding at Period 2 week 10 and completed study at Period 2 
week 12.  
k For non-responders at Period 2 week 10 the safety outcomes below will be assessed at Period 2 week 12. For this patient group at Period 2 week 12 only 
adverse events (review adverse events diary) and concomitant medication will be assessed at Period 2 week 12. An alternative approach is a phone visit at 
Period 2 week 12 (similar to the final visit at Period 2 week 14) and patient returns all study medication from period 1 and 2 before Period 2 week 12.  
 


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REFERENCES 
1. 
Kappelman MD, Rifas-Shiman SL, Kleinman K, et al. The prevalence and geographic 
distribution of Crohn's disease and ulcerative colitis in the United States. Clin 
Gastroenterol Hepatol 2007;5:1424-9. 
2. 
Herrinton LJ, Liu L, Lewis JD, et al. Incidence and prevalence of inflammatory bowel 
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Gastroenterol 2008;103:1998-2006. 
3. 
Loftus CG, Loftus EV, Jr., Harmsen WS, et al. Update on the incidence and prevalence of 
Crohn's disease and ulcerative colitis in Olmsted County, Minnesota, 1940-2000. 
Inflamm Bowel Dis 2007;13:254-61. 
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Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The natural history of 
pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol 
2009;104:2080-8. 
5. 
Allison J, Herrinton LJ, Liu L, et al. Natural history of severe ulcerative colitis in a 
community-based health plan. Clin Gastroenterol Hepatol 2008;6:999-1003. 
6. 
Langholz E, Munkholm P, Davidsen M, et al. Course of ulcerative colitis: analysis of 
changes in disease activity over years. Gastroenterology 1994;107:3-11. 
7. 
Devaraj B, Kaiser AM. Surgical management of ulcerative colitis in the era of biologicals. 
Inflamm Bowel Dis 2015;21:208-20. 
8. 
Shen B. Acute and chronic pouchitis--pathogenesis, diagnosis and treatment. Nat Rev 
Gastroenterol Hepatol 2012;9:323-33. 
9. 
Barnes EL, Herfarth HH, Sandler RS, et al. Pouch-Related Symptoms and Quality of Life in 
Patients with Ileal Pouch-Anal Anastomosis. Inflamm Bowel Dis 2017;23:1218-1224. 
10. 
Madiba T, Bartolo D. Pouchitis following restorative proctocolectomy for ulcerative 
colitis: incidence and therapeutic outcome. J R Coll Surg Edinb 2001;46:334-7. 
11. 
Barnes EL, Kochar B, Jessup HR, et al. The Incidence and Definition of Crohn's Disease of 
the Pouch: A Systematic Review and Meta-analysis. Inflamm Bowel Dis 2019;25:1474-
1480. 
12. 
Hahnloser D, Pemberton JH, Wolff BG, et al. Results at up to 20 years after ileal pouch-
anal anastomosis for chronic ulcerative colitis. Br J Surg 2007;94:333-40. 
13. 
Lightner AL, Mathis KL, Dozois EJ, et al. Results at Up to 30 Years After Ileal Pouch-Anal 
Anastomosis for Chronic Ulcerative Colitis. Inflamm Bowel Dis 2017;  
10.1097/MIB.0000000000001061; epub. 
14. 
Michelassi F, Lee J, Rubin M, et al. Long-term functional results after ileal pouch anal 
restorative proctocolectomy for ulcerative colitis: a prospective observational study. 
Ann Surg 2003;238:433-41; discussion 442-5. 
15. 
Farouk R, Pemberton JH, Wolff BG, et al. Functional outcomes after ileal pouch-anal 
anastomosis for chronic ulcerative colitis. Ann Surg 2000;231:919-26. 
16. 
Thazhath SS, Marathe CS, Wu T, et al. The Glucagon-Like Peptide 1 Receptor Agonist 
Exenatide Inhibits Small Intestinal Motility, Flow, Transit, and Absorption of Glucose in 
Healthy Subjects and Patients With Type 2 Diabetes: A Randomized Controlled Trial. 
Diabetes 2016;65:269-75. 


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17. 
Jeppesen PB. Gut hormones in the treatment of short-bowel syndrome and intestinal 
failure. Curr Opin Endocrinol Diabetes Obes 2015;22:14-20. 
18. 
Zatorski H, Salaga M, Fichna J. Role of glucagon-like peptides in inflammatory bowel 
diseases-current knowledge and future perspectives. Naunyn Schmiedebergs Arch 
Pharmacol 2019;392:1321-1330. 
19. 
Karhus ML, Bronden A, Roder ME, et al. Remission of Bile Acid Malabsorption Symptoms 
Following Treatment With the Glucagon-Like Peptide 1 Receptor Agonist Liraglutide. 
Gastroenterology 2019;  10.1053/j.gastro.2019.04.002; epub 2019/04/10. 
20. 
Karhus ML, Bronden A, Sonne DP, et al. Evidence connecting old, new and neglected 
glucose-lowering drugs to bile acid-induced GLP-1 secretion: A review. Diabetes Obes 
Metab 2017;19:1214-1222. 
21. 
Nakatani Y, Maeda M, Matsumura M, et al. Effect of GLP-1 receptor agonist on 
gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy. 
Diabetes Metab 2017;43:430-437. 
22. 
Palnaes Hansen C, Andreasen JJ, Holst JJ. The release of gastric inhibitory peptide, 
glucagon-like peptide-I, and insulin after oral glucose test in colectomized subjects. 
Scand J Gastroenterol 1997;32:473-7. 
23. 
Robertson MD, Livesey G, Morgan LM, et al. The influence of the colon on postprandial 
glucagon-like peptide 1 (7-36) amide concentration in man. J Endocrinol 1999;161:25-
31. 
24. 
Jeppesen PB, Hartmann B, Hansen BS, et al. Impaired meal stimulated glucagon-like 
peptide 2 response in ileal resected short bowel patients with intestinal failure. Gut 
1999;45:559-63. 
25. 
Madsen KB, Askov-Hansen C, Naimi RM, et al. Acute effects of continuous infusions of 
glucagon-like peptide (GLP)-1, GLP-2 and the combination (GLP-1+GLP-2) on intestinal 
absorption in short bowel syndrome (SBS) patients. A placebo-controlled study. Regul 
Pept 2013;184:30-9. 
26. 
Kunkel D, Basseri B, Low K, et al. Efficacy of the glucagon-like peptide-1 agonist 
exenatide in the treatment of short bowel syndrome. Neurogastroenterol Motil 
2011;23:739-e328. 
27. 
Hvistendahl M, Brandt CF, Tribler S, et al. Effect of Liraglutide Treatment on Jejunostomy 
Output in Patients With Short Bowel Syndrome: An Open-Label Pilot Study. JPEN J 
Parenter Enteral Nutr 2018;42:112-121. 
28. 
Hart AL, Lomer M, Verjee A, et al. What Are the Top 10 Research Questions in the 
Treatment of Inflammatory Bowel Disease? A Priority Setting Partnership with the 
James Lind Alliance. J Crohns Colitis 2017;11:204-211. 
29. 
Nightingale JM, Kamm MA, van der Sijp JR, et al. Disturbed gastric emptying in the short 
bowel syndrome. Evidence for a 'colonic brake'. Gut 1993;34:1171-6. 
30. 
Kochar B, Herfarth HH. Teduglutide for the treatment of short bowel syndrome - a 
safety evaluation. Expert Opin Drug Saf 2018;17:733-739. 
31. 
Frandsen CS, Dejgaard TF, Andersen HU, et al. Liraglutide as adjunct to insulin treatment 
in type 1 diabetes does not interfere with glycaemic recovery or gastric emptying rate 
during hypoglycaemia: A randomized, placebo-controlled, double-blind, parallel-group 
study. Diabetes Obes Metab 2017;19:773-782. 


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32. 
Halawi H, Khemani D, Eckert D, et al. Effects of liraglutide on weight, satiation, and 
gastric functions in obesity: a randomised, placebo-controlled pilot trial. Lancet 
Gastroenterol Hepatol 2017;2:890-899. 
33. 
Horowitz M, Flint A, Jones KL, et al. Effect of the once-daily human GLP-1 analogue 
liraglutide on appetite, energy intake, energy expenditure and gastric emptying in type 2 
diabetes. Diabetes Res Clin Pract 2012;97:258-66. 
34. 
van Can J, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide on 
gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-
diabetic adults. Int J Obes (Lond) 2014;38:784-93. 
35. 
Shen B, Achkar JP, Connor JT, et al. Modified pouchitis disease activity index: a simplified 
approach to the diagnosis of pouchitis. Dis Colon Rectum 2003;46:748-53. 
36. 
Sandborn WJ, Tremaine WJ, Batts KP, et al. Pouchitis after ileal pouch-anal anastomosis: 
a Pouchitis Disease Activity Index. Mayo Clin Proc 1994;69:409-15. 
37. 
Isaacs KL, Sandler RS, Abreu M, et al. Rifaximin for the treatment of active pouchitis: a 
randomized, double-blind, placebo-controlled pilot study. Inflamm Bowel Dis 
2007;13:1250-5. 
38. 
Gionchetti P, Morselli C, Rizzello F, et al. Infliximab in the treatment of refractory 
pouchitis. Gastroenterology 2005;128:A578-A578. 
39. 
Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic 
therapy: a double-blind, placebo-controlled trial. Gastroenterology 2003;124:1202-9. 
40. 
Gionchetti P, Rizzello F, Morselli C, et al. High-dose probiotics for the treatment of active 
pouchitis. Dis Colon Rectum 2007;50:2075-2082. 
41. 
Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment 
in patients with chronic pouchitis: a double-blind, placebo-controlled trial. 
Gastroenterology 2000;119:305-9. 
42. 
Gionchetti P, Rizzello F, Venturi A, et al. Antibiotic combination therapy in patients with 
chronic, treatment-resistant pouchitis. Aliment Pharmacol Ther 1999;13:713-8. 
43. 
Kuhbacher T, Ott SJ, Helwig U, et al. Bacterial and fungal microbiota in relation to 
probiotic therapy (VSL#3) in pouchitis. Gut 2006;55:833-41. 
44. 
Mimura T, Rizzello F, Helwig U, et al. Once daily high dose probiotic therapy (VSL#3) for 
maintaining remission in recurrent or refractory pouchitis. Gut 2004;53:108-14. 
45. 
Shen B, Remzi FH, Lopez AR, et al. Rifaximin for maintenance therapy in antibiotic-
dependent pouchitis. BMC Gastroenterol 2008;8:26. 
46. 
Yamamoto T, Shimoyama T, Bamba T, et al. Consecutive Monitoring of Fecal 
Calprotectin and Lactoferrin for the Early Diagnosis and Prediction of Pouchitis after 
Restorative Proctocolectomy for Ulcerative Colitis. Am J Gastroenterol 2015;  
10.1038/ajg.2015.129; epub. 
47. 
Lin JF, Chen JM, Zuo JH, et al. Meta-analysis: fecal calprotectin for assessment of 
inflammatory bowel disease activity. Inflamm Bowel Dis 2014;20:1407-15. 
48. 
Kochar B, Martin CF, Kappelman MD, et al. Evaluation of Gastrointestinal Patient 
Reported Outcomes Measurement Information System (GI-PROMIS) Symptom Scales in 
Subjects With Inflammatory Bowel Diseases. Am J Gastroenterol 2018;113:72-79. 


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49. 
Almario CV, Chey WD, Khanna D, et al. Impact of National Institutes of Health 
Gastrointestinal PROMIS Measures in Clinical Practice: Results of a Multicenter 
Controlled Trial. Am J Gastroenterol 2016;111:1546-1556. 
50. 
Barnes EL, Kappelman MD, Long MD, et al. A Novel Patient-Reported Outcome-Based 
Evaluation (PROBE) of Quality of Life in Patients With Inflammatory Bowel Disease. Am J 
Gastroenterol 2019;114:640-647. 
51. 
Herfarth HH, Katz JA, Hanauer SB, et al. Ciprofloxacin for the Prevention of 
Postoperative Recurrence in Patients with Crohn's Disease: A Randomized, Double-
blind, Placebo-controlled Pilot Study. Inflamm Bowel Dis 2013;19:1073-1079. 
52. 
Herfarth HH, Jackson S, Schliebe BG, et al. Investigator-Initiated IBD Trials in the United 
States: Facts, Obstacles, and Answers. Inflamm Bowel Dis 2017;23:14-22. 
53. 
Herfarth H, Barnes EL, Valentine JF, et al. Methotrexate Is Not Superior to Placebo in 
Maintaining Steroid-Free Response or Remission in Ulcerative Colitis. Gastroenterology 
2018;155:1098-1108 e9. 
 
 
 


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APPENDICES 
APPENDIX A: MODIFIED POUCHITIS DISEASE ACTIVITY INDEX (MPDAI) 
According to Shen et al.; 2003 35 
 
Clinical Criteria 
 
 
 
Score 
Stool Frequency 
Usual post-op stool frequency  
 
0 
1-2 stools/day > post-op usual  
 
1 
3 or more stools/day > post-op usual  
2 
  
Rectal Bleeding 
None or rare  
 
 
 
0 
Present daily  
 
 
 
1 
  
Fecal Urgency / Abdominal Cramps 
None  
 
 
 
 
0 
Occasional 
 
 
 
 
1 
Usual  
 
 
 
 
2 
 
Fever (temperature> 100oF)  
Absent  
 
 
 
 
0 
Present 
 
 
 
 
1 
 
Endoscopic Criteria  
 
Edema  
 
 
 
 
1 
Granularity 
 
 
 
 
1 
Friability 
 
 
 
 
1 
Loss of vascular pattern 
 
 
1 
Mucus exudate 
 
 
 
1 
Ulceration 
 
 
 
 
1 
 
 


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APPENDIX B: SF-36 
 
 
 
 
Choose one option for each questionnaire item.
1. In general, would you say your health is:
 1 - Excellent
 2 - Very good
 3 - Good
 4 - Fair
 5 - Poor
2. Compared to one year ago, how would you rate your health in general now?
 1 - Much better now than one year ago
 2 - Somewhat better now than one year ago
 3 - About the same
 4 - Somewhat worse now than one year ago
 5 - Much worse now than one year ago


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The following items are about activities you might do during a typical day. Does your
health now limit you in these activities? If so, how much?
 
Yes,
limited a
lot
Yes,
limited a
little
No, not
limited at
all
3. Vigorous activities, such as running, lifting heavy objects,
participating in strenuous sports
 1
 2
 3
4. Moderate activities, such as moving a table, pushing a
vacuum cleaner, bowling, or playing golf
 1
 2
 3
5. Lifting or carrying groceries
 1
 2
 3
6. Climbing several flights of stairs
 1
 2
 3
7. Climbing one flight of stairs
 1
 2
 3
8. Bending, kneeling, or stooping
 1
 2
 3
9. Walking more than a mile
 1
 2
 3
10. Walking several blocks
 1
 2
 3
11. Walking one block
 1
 2
 3
12. Bathing or dressing yourself
 1
 2
 3


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During the past 4 weeks, have you had any of the following problems with your work or
other regular daily activities as a result of your physical health?
 
Yes
No
13. Cut down the amount of time you spent on work or other activities
1
2
14. Accomplished less than you would like
1
2
15. Were limited in the kind of work or other activities
1
2
16. Had difficulty performing the work or other activities (for example, it took extra
effort)
1
2
During the past 4 weeks, have you had any of the following problems with your work or
other regular daily activities as a result of any emotional problems (such as feeling
depressed or anxious)?
 
Yes
No
17. Cut down the amount of time you spent on work or other activities
 1
 2
18. Accomplished less than you would like
 1
 2
19. Didn't do work or other activities as carefully as usual
 1
 2
20. During the past 4 weeks, to what extent has your physical health or emotional
problems interfered with your normal social activities with family, friends, neighbors, or
groups?
 1 - Not at all
 2 - Slightly
 3 - Moderately
 4 - Quite a bit
 5 - Extremely


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21. How much bodily pain have you had during the past 4 weeks?
 1 - None
 2 - Very mild
 3 - Mild
 4 - Moderate
 5 - Severe
 6 - Very severe
22. During the past 4 weeks, how much did pain interfere with your normal work
(including both work outside the home and housework)?
 1 - Not at all
 2 - A little bit
 3 - Moderately
 4 - Quite a bit
 5 - Extremely


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These questions are about how you feel and how things have been with you during the
past 4 weeks. For each question, please give the one answer that comes closest to the way
you have been feeling.
How much of the time during the past 4 weeks...
 
All of
the
time
Most
of the
time
A good
bit of the
time
Some
of the
time
A little
of the
time
None
of the
time
23. Did you feel full of pep?
 1
 2
 3
 4
 5
 6
24. Have you been a very nervous
person?
 1
 2
 3
 4
 5
 6
25. Have you felt so down in the
dumps that nothing could cheer you
up?
 1
 2
 3
 4
 5
 6
26. Have you felt calm and peaceful?
 1
 2
 3
 4
 5
 6
27. Did you have a lot of energy?
 1
 2
 3
 4
 5
 6
28. Have you felt downhearted and
blue?
 1
 2
 3
 4
 5
 6
29. Did you feel worn out?
 1
 2
 3
 4
 5
 6
30. Have you been a happy person?
 1
 2
 3
 4
 5
 6
31. Did you feel tired?
 1
 2
 3
 4
 5
 6
32. During the past 4 weeks, how much of the time has your physical health or emotional
problems interfered with your social activities (like visiting with friends, relatives, etc.)?
 1 - All of the time
 2 - Most of the time
 3 - Some of the time
 4 - A little of the time
 5 - None of the time


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How TRUE or FALSE is each of the following statements for you.
 
Definitely
true
Mostly
true
Don't
know
Mostly
false
Definitely
false
33. I seem to get sick a little easier than
other people
 1
 2
 3
 4
 5
34. I am as healthy as anybody I know
 1
 2
 3
 4
 5
35. I expect my health to get worse
 1
 2
 3
 4
 5
36. My health is excellent
 1
 2
 3
 4
 5


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APPENDIX C: PROMIS MEASURE INCONTINENCE 
 
According to Kochar et al.48  
In the past 7 days... 
  
1 = No 
days 
2 = 1 day 
3 = 2-3 
days 
4 = 4-5 
days 
5 = 6-7 
days 
31611 - How often did you have 
bowel incontinence—that is, have 
an accident because you could not 
make it to the bathroom in time? 
 
 
 
 
 
31621 - How often did you soil or 
dirty your underwear before getting 
to a bathroom? 
 
 
 
 
 
31631 - How often did you leak stool 
or soil your underwear? 
 
 
 
 
 
 
 
  
1 = Never 
2 = 
Rarely 
3 = 
Sometimes 4 = Often 
5 = 
Always 
31641 - How often did you think you 
were going to pass gas, but stool or 
liquid came out instead? 
 
 
 
 
 
 
 
 


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APPENDIX D: PROBE SCORE 
 
PROBE, a 6-question measure of quality of life among patients with inflammatory bowel 
disease50 
 
 
In the past 7 days… 
I found it hard to focus on anything other than my anxiety 
(5)  Never 
(4)  Rarely 
(3)  Sometimes 
(2)  Often 
(1)  Always 
I felt hopeless 
(5)  Never 
(4)  Rarely 
(3)  Sometimes 
(2)  Often 
(1)  Always 
How fatigued were you on average 
(5)  Not at all 
(4)  A little bit 
(3)  Somewhat 
(2)  Quite a bit 
(1)  Very much 
I am satisfied with my ability to meet the needs of my friends 
(1)  Not at all 
(2)  A little bit 
(3)  Somewhat 
(4)  Quite a bit 
(5)  Very much 
How much did pain interfere with work around the home? 
(5)  Not at all 
(4)  A little bit 
(3)  Somewhat 
(2)  Quite a bit 
(1)  Very much 
How would you rate your IBD activity? 
(5)  Remission 
(4)  Minimal symptoms 
(3)  Mildly active 
(2)  Moderately active 
(1)  Severely active 
Note: Scores for each response to an individual question are listed in parentheses 
 
 


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APPENDIX E: SUBJECT DIARY FOR POUCHITIS 
Instructions:  
Begin recording in your diary each night. You should record before going to bed and the answers 
should describe the preceding 24 hours. 
Date 
During the past 24 hours 
how many bowel 
movements did you 
have? 
(Please provide number) 
During the past 24 
hours how many of 
your bowel 
movements 
contained blood? 
(Please provide 
number) 
How many of 
these bowel 
movements 
were liquid 
(BL; number), 
pasty (BP; 
number) or 
formed (BF 
number) 
During the 
past 24 hours 
how many of 
your bowel 
movements 
were 
preceeded by 
abdominal 
cramps or an 
urgent need 
to go to the 
bathroom? 
(Please 
provide 
number) 
During the 
past 24 hours 
did you 
experience 
fever higher 
than 37.8C 
(100.0F)? 
(Please mark 
“yes” or “No”) 
 
Day 
8 am-22 
pm 
Night 
22pm-8 am 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
Yes 
No 
 
 
 
 
 
 
Yes 
No 


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APPENDIX F: ADVERSE EVENT DIARY 
Front pages of diary 
Efficacy of GLP-1 receptor agonist therapy in patients with an ileal -pouch anal anastomosis 
(IPAA) and chronic high bowel frequency 
 
Record of Side Effects 
 
This diary is one way researchers will get information from you regarding any possible problems 
or side effects in this study. 
 
❖ What you are going to do is simple.  Just keep a record of any unpleasant thing that 
happens to you while you are in the study, before, during, and after we started the study 
therapy.  We even want you to record things that do not seem to be part of the study 
therapy, at all. 
❖ When do you start?  When do you end? You will complete one entry per day starting 
with the first day of study treatment time as well as daily until the last phone visit of the 
trial is completed.  
❖ What do you look for?  What do you report?  Any symptom or problem whether or not 
it may be from the medicine, stool therapy.  This could include: fever, abdominal pain, a 
big belly, lots of gas, diarrhea, nosebleeds, and anything else you know is not quite right. 
❖ What will you do? Starting with the first day of the study medication, you will report some 
of the specific things that have bothered you by checking the boxes in the diary (see 
below).  You can also write any other problems that you may have had during that time.   
   
 
How will you record it?  Like this… 
EVENT 
DATE OF 
ONSET 
INTENSITY 
ACTION 
TAKEN 
MEDICATION 
DATE 
RESOLVED 
Fever 
3/1/12 
3 
Missed 2 
days of 
school 
Tylenol-200mg 
3/3/12 
Sore throat 
3/5/12 
1 
None 
None 
3/6/12 
 
OTHER SYMPTOMS 
Record each symptom at its worst level for each day. 
For example, a sore throat that starts at ‘Grade 1” but increases to ‘Grade 2’ should be 
recorded as ‘Grade 2”. 
 
Examples of Grades: 
Grade 1 – Mild: I noticed the symptom.  It did not keep me from doing my normal activities. 
Grade 2 – Moderate: I noticed the symptom and it kept me from doing some of my normal 
activities. 
Grade 3 – Severe: I really noticed the symptom and it kept me from doing activities that I 
wanted or needed to do. 


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Grade 4 – Very severe: The symptom made me unable to perform basic self-care functions such 
as washing myself OR medical or surgical intervention was needed to prevent serious 
consequences. 
-------------------------------------------------------------------------------------------------------------------------------------------- 
Daily diary page day 0 (start of trial therapy) 
Day after start: _____________ 
 
Subject ID:_____________________ 
 
Date:____/____/______ 
              Check here is no side effects present:                   
Highest temperature of the day:____oF    
 
Check if 
symptom 
present 
Event 
Date of 
Onset 
Intensity 
Action 
taken 
Medications 
Date 
Resolved 
 
 
Fever 
 
 
 
 
 
 
 
Abdominal Pain 
 
 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
 
Nausea/Vomiting 
 
 
 
 
 
 
 
Blood in Stool 
 
 
 
 
 
 
 
Other 1 
 
 
 
 
 
 
 
Other 2 
 
 
 
 
 
 
 
Other 3 
 
 
 
 
 
 
Other 4  
 
 
 
 
 
 
Grade 1 – Mild: I noticed the symptom.  It did not keep me from doing my normal activities. 
Grade 2 – Moderate: I noticed the symptom and it kept me from doing some of my normal activities. 
Grade 3 – Severe: I really noticed the symptom and it kept me from doing activities that I wanted or needed to do. 
Grade 4 – Very severe: The symptom made me unable to perform basic self-care functions such as washing myself OR medical or 
surgical intervention was needed to prevent serious consequences. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Completed by: ____________________ 
 


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APPENDIX G: DAILY GLUCOSE DIARY 
 
Daily Glucose Diary 
 
Week 1  2  3  4  5  6 (please circle) 
 
Please measure glucose daily first thing in the morning before eating or 
drinking anything but water. 
 
Day (date) 
Time  
Glucose level 
1. 
 
 
2. 
 
 
3. 
 
 
4. 
 
 
5. 
 
 
6. 
 
 
7. 
 
 
 
 
If you measure a glucose level below 3.9 mmol/L (70 mg/dL) , please 
start measuring your glucose values every 15 minutes and follow the 
hypoglycemic protocol


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APPENDIX H: HYPOGLYCEMIC PROTOCOL AND REPORTING FORM 
 
Hypoglycemic protocol and reporting form 
 
 
Please measure your blood glucose anytime if you feel symptoms of hypoglycemia, which can be hunger, 
shakiness, nervousness, sweating, dizziness or light-headedness, sleepiness, confusion, difficulty 
speaking, anxiety, weakness. 
 
 If you have a plasma glucose level < 3.9 mml/L (70- mg/dl) one of these quick-fix foods should be 
consumed right away to raise blood glucose:  
 
• 1/2 cup, or 4 ounces, of any fruit juice  
• 1/2 cup, or 4 ounces, of a regular— not diet—soft drink 
• 1 cup, or 8 ounces, of milk 
• 5 or 6 pieces of hard candy 
• 1 tablespoon of sugar or honey 
 
You should continue to measure your glucose level every 15 min until it is > 3.9 mmol/L (70 mg/dL) and 
fill the values in the hypoglycemia reporting form. Please fill out a new form for each event if > 60 
minutes apart.  


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Hypoglycemia reporting form 
 
Day 
(date) 
Time  
Glucose 
level 
Symptoms 
What did you eat/drink 
when after you measured a 
plasma glucose level < 3.9 
mml/L (70- mg/dl)   
Last meal/snack before 
hypoglycemia episode (what 
did you eat/snack and when 
did you eat it?) 
Activity preceding 
hypoglycemic episode 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Was the hypoglycemic episode so severe that you could not care for yourself and needed help from 
others?   
 
    0   Yes    0   No 
 
 
 
If yes: 
 
Who assisted in the treatment of the hypoglycemic episode (i.e., medical person or non-medical 
person)? 
 
 
Where was the treatment administered (in clinic/emergency room/hospital or other)? 
 
 
What type of treatment was provided by other person (i.e., oral carbohydrates, glucagon, IV glucose or 
other)? 
 
 
Were symptoms alleviated after administration of treatment?