Clinical trial NCT04046328
Conditions: Short Bowel Syndrome
Sponsor: Pharmascience Inc.
Start date: 2019-10-15; Completion date: 2021-12-22
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A new Enteric-Coated Cholestyramine (ECC) capsule has been developed to manage diarrhea associated with Short Bowel Syndrome (SBS) in adults. The formulation is expected to release cholestyramine in the remaining segment of the small intestine in SBS patients, thus binding bile acids after fat digestion, but before induction of diarrhea in the colon. The delayed-release profile is also expected to help reduce the potential for drug-drug interactions occurring in the proximal small intestine. Two doses of ECC will be studied for efficacy, safety and tolerability in this Phase IIa trial.

Detailed description:
A new Enteric-Coated Cholestyramine (ECC) capsule has been developed to manage diarrhea associated with Short Bowel Syndrome (SBS). SBS is usually caused by the significant resection or loss of function of the ileum, leading to reduced reabsorption of bile acids and subsequent osmotic diarrhea. The new ECC formulation could release cholestyramine in the remaining segment of the small intestine in SBS patients, delivering and binding bile acids before they induce diarrhea in the colon. The proposed advantages of this formulation are: a) to prevent drug-drug interactions in the proximal GI tract, b) to preserve the fat digestive properties of bile acids in the duodenum and 3) to offer a more palatable dosage form to patients. Moreover, since distal delivery of cholestyramine is expected to be more effective in diarrhea prevention/reduction in SBS, lower doses than the ones used with non-enteric coated cholestyramine may be sufficient. Two doses of ECC will be studied for efficacy, safety and tolerability in well-defined non fully-colectomized, adult SBS patients suffering from diarrhea.

Arms: arm 1: ECC at the 1.7 g daily dose, administered BID (twice daily) as 2 capsules of ECC, plus 3 capsules of placebo, at least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before evening meal. arm 2: ECC at the 4.25 g daily dose, administered BID (twice daily) as 5 capsules of ECC at least 30 minutes before breakfast and 5 capsules of ECC at least 30 minutes before evening meal.
Interventions: intervention 1: Enteric-Coated Cholestyramine (ECC) Capsule intervention 2: Placebo
Intervention descriptions: intervention 1: Enteric-Coated Delayed Release Cholestyramine Capsules intervention 2: Enteric-Coated Delayed Release Placebo Capsules

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL TRIAL PROTOCOL 
PROTOCOL TITLE:  A Phase IIa, Proof of Concept, Randomized, Double-Blind, Dose-
Finding, Cross-Over Study of the Efficacy, Safety and Tolerability of a New Enteric-
Coated Cholestyramine Capsule in Adult Short Bowel Syndrome Patients 
PROTOCOL NUMBER: 
PMS-2018-002 
STUDY PHASE:  
IIa 
SPONSOR: 
Pharmascience Inc. 
6111 Royalmount Ave,  
Montréal (Quebec) H4P 2T4 
CANADA 
PROTOCOL DATE:   
February 16, 2021 
PROTOCOL HISTORY: 
Version 
Date 
3.0 (Amendment 04) 
February 16, 2021 
2.0 (Amendment 03) 
November 6, 2019 
1.2 (Administrative Amendment 02) 
September 10, 2019 
1.1 (Administrative Amendment 01) 
August 15, 2019 
1.0 (Original) 
March 06, 2019 
COMPLIANCE 
The study will be conducted in accordance with standards of Good Clinical Practice, as defined by the 
International Conference on Harmonisation and all applicable federal and local regulations. 
CONFIDENTIALITY STATEMENT 
The information provided in this document is strictly confidential and is available for review to 
investigator(s) and to the appropriate Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB). It may not be used, divulged, published or otherwise disclosed without the written 
authorization from JSS Medical Research or the Sponsor. 
NCT04046328


 
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PROTOCOL AMENDMENT 04 
 
Acknowledgment of Review  
 
I have reviewed the clinical study protocol including the below-mentioned revisions, and I agree with the 
completeness and accuracy of its content. 
 
 
__________________________________ 
 
____________________________ 
 
 
Date (dd/mm/yyyy) 
Protocol Amendment Author 
Pharmascience Inc. 
 
__________________________________ 
 
____________________________ 
 
 
Date (dd/mm/yyyy) 
Sponsor’s Representative 
Pharmascience Inc. 
 
 
Rationale for Revisions Implemented in Protocol Amendment 04 (February 16, 2021): 
 
The following substantial and minor revisions are to be submitted to the central ethics committee and national 
regulatory authority for approval prior to implementation: 
 
1) Revision of Inclusion Criteria #5 to better reflect the patient population at the sites. 
 
2) Replacement of section “Protocol Administrative Amendment 03” with section “Protocol Amendment 
04” to document revisions in this version. 
 
 
 
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Text of Revisions: 
 
1) Synopsis, p. 10, Changed Inclusion Criteria #5 from: 
 
Partial, Home Parenteral Nutrition and/or parenteral fluids are allowed, at a maximum frequency of 4 
times a week throughout the trial 
 
To: 
 
Partial, Home Parenteral Nutrition and/or parenteral fluids are allowed, at a maximum frequency of 6 
times a week throughout the trial, as long as the regimen has been stable for at least 2 weeks prior to 
screening and is expected to remain unchanged during the study 
 
 
2) Section 8.1 Inclusion Criteria, p. 32, Changed Inclusion Criteria #5 from: 
 
Partial, Home Parenteral Nutrition and/or parenteral fluids are allowed, at a maximum frequency of 4 
times a week throughout the trial   
 
To: 
 
Partial, Home Parenteral Nutrition and/or parenteral fluids are allowed, at a maximum frequency of 6 
times a week throughout the trial, as long as the regimen has been stable for at least 2 weeks prior to 
screening and is expected to remain unchanged during the study  
 
 
 
 


 
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STUDY PERSONNEL AND SITES 
 
SPONSOR REPRESENTATIVE 
 
 Pharmascience Inc. 
6111 Royalmount Avenue 
Montreal, Quebec, H4P 2T4, Canada  
Tel: 
   
Email: 
 
 
MEDICAL MONITOR 
 
Neox Clinical Research 
V Jámě 1, 110 00 Praha 1,  
Czech Republic 
Tel: 
 
Fax: 
 
Email: 
 
 
CLINICAL RESEARCH MANAGEMENT  
 
JSS Medical Research Europe Sp. z.o.o.  
ul. Belwederska 26/30 
00-585 Warsaw, Poland  
Tel: 
 
 Email: 
 
 
PRINCIPAL INVESTIGATOR AND  
COUNTRY COORDINATOR 
Konrad Matysiak, MD, PhD 
Solumed Centrum Medyczne 
ul. Dąbrowskiego 77a, 60-529 
Poznań, Poland 
Tel: 
 
Email: 
     
 
PROTOCOL AUTHOR AND  
SPONSOR’S CLINICAL ADVISOR 
 
PCC Inc. 
140 Alexandre de Prouville 
Carignan, Quebec, J3L 6X2, Canada 
Tel: 
 
Email: 
  
 
SPONSOR’S MEDICAL EXPERT  
 
 
Pharmascience Inc. 
6111 Royalmount Avenue 
Montreal, Quebec, H4P 2T4, Canada  
Tel: 
   
Email: 
 
 
 
 
 
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PROJECT MANAGEMENT CONTACT 
 
 
 
 
 
 
DATA MANAGEMENT AND BIOSTATISTICS 
 
 
JSS Medical Research Inc. 
9400 West Henri-Bourassa Boulevard 
St. Laurent, Quebec, H4S 1N8, Canada 
Tel: 
 
Email:
 
 
JSS Medical Research Inc. 
9400 West Henri-Bourassa Boulevard 
St. Laurent, Quebec, H4S 1N8, Canada 
Tel: 
 
 
 
 
 
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SPONSOR SIGNATURE PAGE  
 
 
PRODUCT:   
 
 
Enteric-coated cholestyramine 425 mg capsules (ECC) 
PROTOCOL NUMBER:   
PMS-2018-002 
PROTOCOL DATE:  
 
February 16, 2021 
PROTOCOL VERSION:   
3.0 
 
A Phase IIa, Proof of Concept, Randomized, Double-Blind, Dose-Finding, Cross-Over Study of the Efficacy, 
Safety and Tolerability of a New Enteric-Coated Cholestyramine Capsule in Adult Short Bowel Syndrome 
Patients 
 
I have reviewed the above-mentioned clinical study protocol and I agree with the completeness and accuracy of 
its content.  On behalf of the Sponsor, I agree to comply with all of the procedures contained within this protocol.  
 
 
 
 
 
 
 
____________________________________________ 
 
____________________________ 
 
 
Date (dd/mm/yyyy) 
 
Sponsor’s Representative 
Pharmascience Inc. 
 
 
 
 
 
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INVESTIGATOR SIGNATURE PAGE  
 
 
PRODUCT:   
 
 
Enteric-coated cholestyramine 425 mg capsules (ECC) 
PROTOCOL NUMBER:   
PMS-2018-002 
PROTOCOL DATE:  
 
February 16, 2021 
PROTOCOL VERSION:   
3.0 
 
A Phase IIa, Proof of Concept, Randomized, Double-Blind, Dose-Finding, Cross-Over Study of the Efficacy, 
Safety and Tolerability of a New Enteric-Coated Cholestyramine Capsule in Adult Short Bowel Syndrome 
Patients 
 
I have read the protocol and by my signature below, I agree that it contains all necessary information required 
to conduct this trial.  I agree to conduct the study in accordance with all stipulations of the protocol and in 
accordance with all applicable regulatory requirements, the current International Council for Harmonization of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP), and 
with the principles of the most recent version of the Declaration of Helsinki. 
 
I agree to ensure the confidentiality of my subjects; however, I agree to make available to the Contract Research 
Organization (CRO), the Sponsor of this clinical study or relevant regulatory authorities those sections of my 
subjects ‘medical records which directly concern this study.  I understand that the study may be terminated, or 
enrolment suspended at any time by Pharmascience Inc., or by me if it becomes necessary to protect the best 
interests of the study subjects. 
 
 
 
 
 
___________________________________________ 
__________________________ 
Principal Investigator 
 
 
 
 
 
 
Date (dd/mm/yyyy) 
 
 
 


 
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1. SYNOPSIS 
 
 
Name of Sponsor 
Pharmascience Inc. 
Name of Investigational  
Product 
Enteric-coated Cholestyramine (ECC) Capsules, 425 mg 
Study Title 
 
A Phase IIa Proof of Concept, Randomized, Double-Blind, Dose 
Finding, Cross-Over Study of the Efficacy, Safety and Tolerability of a 
New Enteric-Coated Cholestyramine Capsule in Adult Short Bowel 
Syndrome Patients  
Rationale 
A new enteric-coated cholestyramine (ECC) capsule has been 
developed to manage diarrhea associated with Short Bowel 
Syndrome (SBS). SBS is usually caused by the significant resection or 
loss of function of the ileum, leading to reduced reabsorption of bile 
acids and subsequent osmotic diarrhea. The new ECC formulation 
could release cholestyramine in the remaining segment of the small 
intestine in SBS patients, delivering and binding bile acids before they 
induce diarrhea in the colon. The proposed advantages of this 
formulation are: a) to prevent drug-drug interactions in the proximal 
GI tract, b) to preserve the fat digestive properties of bile acids in the 
duodenum and 3) to offer a more palatable dosage form to patients. 
Moreover, since distal delivery of cholestyramine is expected to be 
more effective in diarrhea preventing/reduction in SBS, lower doses 
than the ones used with non-enteric coated cholestyramine may be 
sufficient.  Two doses of ECC will be studied for efficacy, safety and 
tolerability in well-defined non colectomized, adult SBS patients 
suffering from diarrhea. 
Phase of Development 
Phase IIa 
Objectives 
The primary objective of this study is to investigate the clinical 
efficacy of new ECC capsules and select the most effective dose in 
adult patients with SBS. 
The secondary objectives of this study are to evaluate the safety and 
tolerability of new ECC capsules in adult patients with SBS, and to 
evaluate the patients’ experience of related symptoms using a 11-
point Visual Analog Scale (VAS). 
Primary Efficacy Endpoint 
Change in the weekly frequency of bowel movements measured 
between baseline and the second week of treatment (i.e. Days 8 to 
14, and Days 36 to 42).  
Secondary Endpoints 
- 
Total number of bowel movements per week, after the first 
week of treatment (i.e. Days 1 to 7, and Days 29 to 35) 
- 
Total number of bowel movements for the whole 2-week 
treatment period (i.e. Days 1 to 14 and Days 29 to 42)  


 
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- 
Mean daily stool form score according to the Bristol Stool Form   
Scale (BSFS), measured during the first week of treatment (i.e. 
Days 1 to 7, and Days 29 to 35) 
- 
Mean daily stool form score according to the BSFS, measured 
during the second week of treatment (i.e. Days 8-14, and Days 
36-42) 
- 
Mean daily stool form score according to the BSFS, measured 
during the whole 2-week treatment period (i.e. i.e. Days 1 to 
14 and Days 29 to 42) 
- 
Total number of bowel movements with a BSFS score ≥ 6 during 
the first week of treatment (i.e. Days 1 to 7, and Days 29 to 35) 
- 
Total number of bowel movements with a BSFS score ≥ 6 during 
the whole 2-week treatment period (i.e. Days 1 to 14 and Days 
29 to 42) 
- 
Mean daily dose of loperamide in mg, if used, during the 
second week of treatment (i.e. Days 8-14, and Days 36-42) 
- 
Mean Diarrhea Composite Index ([weekly bowel movement 
frequency X mean daily BSFS score] + loperamide use [weekly 
mg X 3]) during the second week of treatment (i.e. Days 8-14, 
and Days 36-42) 
- 
Safety (to be evaluated through the assessment of adverse 
events (AE), laboratory tests, vital signs, ECG and physical 
examination) 
- 
Tolerability (to be evaluated through assessment of TEAEs and 
TESAEs) 
- 
Evaluation of severity of diarrhea, abdominal pain, urgency and 
bloating using an 11-point Visual Analog Scale (VAS) made on 
Days 0 (baseline), 15, 28 and 43 
Study Design and 
Procedures 
Multiple-center, randomized, double-blind, double dummy, 2-
period, 2-sequence cross-over design. Eligible patients will be 
randomized to one of the following sequences: 
 
Period 1 
Period 2 
Sequence AB (n=9) 
Treatment A 
Treatment B 
Sequence BA (n=9) 
Treatment B 
Treatment A 
- 
A 14-day washout period will separate the 2 periods. All 
subjects will first be enrolled in a 15-day screening phase 
during which SBS diagnosis will be confirmed and full study 
eligibility will be established. Daily number of bowel 
movements and daily BSFS scores will be measured during the 
last 14 days of the 15-day screening period (Day -14 to Day -1).  
Baseline safety parameters will also be assessed during 
screening. Treatment duration with ECC will be 14 consecutive 
days. The total number of bowel movements will be measured 


 
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during each of the 2 weeks of ECC treatment. The BSFS will be 
used daily during the whole study period, including the 
washout period. Patients’ overall experience with related 
symptoms (abdominal pain, diarrhea, bloating, urgency) will be 
assessed using an 11-point VAS at the start and end of each 
period. Finally, safety will be assessed regularly during the trial, 
through physical exams, ECG, AEs, and adequate biochemical 
and hematological lab tests. 
Study Population 
Inclusion Criteria:  
1. Adult, ambulatory male and female subjects 
2. Provision of signed and dated informed consent form (ICF) 
3. Age ≥ 18 years and ≤ 80 years 
4. Stable SBS of: 
a. Non-surgical origin; OR 
b. Surgical origin where the last surgical ileal resection 
was performed at least 6 months prior to enrolment  
5. Partial, Home Parenteral Nutrition and/or parenteral fluids are 
allowed, at a maximum frequency of 6 times a week 
throughout the trial, as long as the regimen has been stable for 
at least 2 weeks prior to screening and is expected to remain 
unchanged during the study 
6. At least 50 % of the colon being intact 
7. Intact duodenum  
8. BMI ≥ 18 
9. Presence of stable chronic diarrhea for at least 3 months prior 
to enrolment as evidenced by medical history 
10. Presence of stable chronic diarrhea during the 2-week 
screening diary period before randomization, as evidenced by 
completion of a screening diary demonstrating:  
a. Mean daily production of at least 3 soft or watery 
stools (BSFS scores 6 or 7); or  
b. More than 3 bowel movements per day on average 
with >25% of them being BSFS type 6 or 7 
11. Stated willingness and ability to comply with all study 
procedures, including daily recording of bowel movements and 
BSFS in the patient diaries, and availability for the duration of 
the study 
12. Clinical laboratory values within the laboratory's stated normal 
range; if not within this range, they must be without clinical 
significance, as determined by the investigator 
13. Female subjects must meet one of the following criteria: 
a) Participant is of childbearing potential and agrees to use 
one of the accepted contraceptive regimens from at least 


 
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30 days prior to the first study treatment administration 
through to at least 30 days after the last dose of the study 
treatment. An acceptable method of contraception 
includes one of the following: 
a. Abstinence from heterosexual intercourse 
b. Systemic contraceptives (combined birth control 
pills, injectable/implant/insertable hormonal birth 
control products, transdermal patch) 
c. Intrauterine device (with or without hormones) 
d. Condom with spermicide  
b)  Participants of non-childbearing potential, defined as 
surgically sterile (i.e. has undergone complete hysterectomy, 
or bilateral oophorectomy) or is in a menopausal state (i.e. at 
least 1 year without menses prior to the first study drug 
administration) are eligible 
Exclusion Criteria:  
1. Patients with known or suspected intestinal strictures of 
clinical relevance as judged by the Investigator 
2. Active inflammatory bowel disease (IBD) or fistula during 
the screening period as judged by the Investigator 
3. Crohn's disease patients not being in clinical remission for 
the last 12 weeks prior to randomization 
4. Diarrhea caused by other causes than SBS 
5. Presence of clinically significant steatorrhea, requiring 
pancreatic enzymes supplementation 
6. Presence of complete biliary obstruction 
7. Presence of active cancer (except resected cutaneous basal 
or squamous cell carcinoma and except in situ cervical 
cancer) and/or need to receive chemotherapy or 
radiotherapy during the study  
8. History of allergic reaction to cholestyramine or any 
excipient of the investigational drug product or placebo, or 
packaging components 
9. Females who are lactating at screening 
10. Females who are pregnant according to the pregnancy test 
at screening or prior to the first study treatment 
administration 
11. Significant history (at least 3 consecutive months in the 
year prior to Screening) of drug dependency or alcohol 
abuse (> 3 units of alcohol per day, intake of excessive 
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12. Subjects who took an Investigational Product (IP) in the 30 
days prior to the first study drug administration 
13. Any other clinically significant condition that is considered 
by the principal investigator as being susceptible to put the 
patient at greater safety risk, influence response to study 
product, or interfere with study assessments. 
Number of Sites and 
Patients 
3 clinical sites and 18 patients 
Treatments 
Product: ECC capsules, 425 mg (size 00) 
In order to fully blind the study, the double dummy technique will be 
used, i.e. the lowest dose (1.7 g daily) will be co-administered with 
an ECC matching placebo. 
Treatment A (“low” dose): 1.7 g total daily dose of ECC, BID + placebo 
Treatment B (“high” dose): 4.25 g total daily dose of ECC, BID  
Mode of administration: Oral, capsules taken at least 30 minutes 
before breakfast and the evening meal 
Manufacturer: Pharmascience Inc. 
Concomitant Medications 
Concomitant antidiarrheal drugs, such as loperamide, are allowed as 
long as their dose and dosing regimen remain stable at least 2 weeks 
before and for the total duration of the study. 
Antacid medications, such as H2 antagonists, and OTC products are 
prohibited. PPIs are allowed as long as their dose and dosing regimen 
are stable during the study. IBS-D medications, spasmolytics and any 
drug exerting significant effects of gastrointestinal transit are also 
prohibited. Gut trophic factors such as growth hormone and GLP-2 
are also prohibited. 
Standard of Care, concomitant medications are allowed during the 
study only if judged essential by investigator and with a stable dose 
and dosing regimen for at least 2 months prior to enrolment and 
during the study. However, loperamide dose may be modified by the 
investigator if absolutely necessary. Loperamide doses will be 
recorded in the patient diary, on a daily basis. 
Administration 
In each of the study periods, patients will be instructed to take two 
doses of ECC capsules daily (BID regimen), in the morning, at least 30 
minutes before breakfast and before evening meal, for 14 days.  
Patients randomized to Treatment A (Low dose, 1.7 g daily) will take 
2 x 425 mg ECC capsules + 3 x placebo capsules in the morning and 
repeat in the evening.  
Patients randomized to Treatment B (High dose, 4.25 g daily) will take  
5 x 425 mg ECC capsules in the morning and repeat in the evening.   
Capsules should be taken with water at ambient temperature.  The 
capsules should be swallowed whole and not be chewed or crushed. 


 
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Dose Justification 
Currently, at least 4 g daily is the dose recommended for regular, non-
enteric coated cholestyramine. ECC may be as or more effective at a 
lower dose, i.e. 1.7 g daily. 
Sample Size Justification 
Using an alpha of 0.05 and beta of 0.2, a paired t-test, and assuming 
a standard deviation of 1.265 and a 20% attrition rate; 18 patients 
are required to show a minimal 25% difference between the two 
treatments in the reduction of the weekly number of bowel 
movements after 14 days of treatment (measured during the second 
week of treatment). Moreover, with 18 patients, we will have more 
than 80% power to detect a minimal reduction of 4 weekly bowel 
movements after 14 days of treatment with either 1.7 or 4.25 g of 
ECC per day (pooled data; assuming SD of 2). 
Study Duration 
12 - 16 months 




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1 The latest version of the consent form must be signed prior to subject's inclusion (prior to initiating any protocol procedure). The consent form can be 
signed up to 28 days before screening visit.   
2 Vital signs include pulse, blood pressure (diastolic-systolic) and body temperature. 
3 Clinical Laboratory safety tests include full clinical chemistry and hematology panels. 
4 Urinalysis includes nitrites, urobilinogen, protein, pH, blood, specific gravity, ketones, bilirubin, leukocytes, glucose and appearance. 
5 BSFS: Bristol Stool Form Scale   BM: bowel movement (defecation). Patients will use the 14-day diaries to record the frequency of BMs as well as stool 
morphology, throughout the study (ie. Diaries will be provided for Screening, Period 1, Washout and Period 2). 
6 Telephone contact will be established with patients at Days -8, 7, 21 and 35, to assess safety, report concomitant medication use, promote use of diary, 
and promote compliance. 
7   An 11-point Visual Analog Scale (VAS) will be used to assess the following symptoms: abdominal pain, diarrhea, bloating and urgency 
8 To be recorded as Prior Medication if taken before the first dose of study drug (i.e. during Screening). Only current medications to be reported (i.e. 
treatment ongoing at Day -15). 
9 From screening to the first dose of the study, AEs will be recorded as screening events or as part of the medical history, as applicable. Any serious adverse 
events spontaneously reported by subjects up to 30 days following the last day of dosing will be documented. 
 
 
 
 


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3. TABLE OF CONTENTS 
 
PROTOCOL ADMINISTRATIVE AMENDMENT 02 ..............................................................................................2 
STUDY PERSONNEL AND SITES .........................................................................................................................4 
SPONSOR SIGNATURE PAGE ............................................................................................................................6 
INVESTIGATOR SIGNATURE PAGE ....................................................................................................................7 
1. 
SYNOPSIS ..................................................................................................................................................8 
2. 
SCHEDULE OF ACTIVITIES .......................................................................................................................14 
3. 
TABLE OF CONTENTS ..............................................................................................................................16 
4. 
GLOSSARY OF TERMS AND ABBREVIATIONS ..........................................................................................19 
5.  INTRODUCTION .........................................................................................................................................21 
5.1  Short Bowel Syndrome Overview .......................................................................................................21 
5.2  Epidemiology of SBS ............................................................................................................................21 
5.3  Treatment of Short Bowel Syndrome .................................................................................................22 
5.3.1  Nutritional status maintenance ...................................................................................................22 
5.3.2  Treatment of steatorrhea associated with ileal resection ...........................................................22 
5.3.3  Home parenteral nutrition and complications of SBS .................................................................22 
5.4   SBS Associated Bile Acid Diarrhea ......................................................................................................23 
5.5 Rationale for a New ECC Formulation ..................................................................................................24 
5.6  Safety of Cholestyramine ....................................................................................................................26 
5.7  Study Rationale and Risk/Benefit Assessment ....................................................................................26 
6.  STUDY OBJECTIVES ....................................................................................................................................27 
6.1  Primary Objective ................................................................................................................................27 
6.2  Secondary Objectives ..........................................................................................................................27 
7.  STUDY DESIGN ...........................................................................................................................................27 
7.1  Endpoints .............................................................................................................................................27 
7.1.1  Primary Endpoint..........................................................................................................................27 
7.1.2  Justification for the Primary Endpoint .........................................................................................27 
7.1.3  Secondary Endpoints ....................................................................................................................28 
7.2  Study Overview ...................................................................................................................................29 
7.2.1  Study Design .................................................................................................................................29 
7.2.2.  Study/Treatment Arm Stopping Rule Guideline .........................................................................29 
7.2.3  Individual Patient Stopping Rules ................................................................................................30 
7.2.4  Treatment Arm Dose Reduction Guideline ..................................................................................30 
7.3  Blinding and Randomization ...............................................................................................................30 
7.4  Procedure for Unblinding ....................................................................................................................31 
8.  SELECTION AND WITHDRAWAL OF PATIENTS ...........................................................................................31 
8.1   Inclusion Criteria .................................................................................................................................31 
8.2   Exclusion Criteria ................................................................................................................................32 
8.3  Informed Consent................................................................................................................................33 
8.4  Study Withdrawal of Patients .............................................................................................................33 
8.5  Treatment Discontinuation .................................................................................................................34 
8.6  Replacement of Patients .....................................................................................................................34 


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9.  STUDY CONDUCT .......................................................................................................................................35 
9.1  Timing of Assessments ........................................................................................................................35 
9.2  Study Visits and Procedures ................................................................................................................35 
9.2.1  Screening and Eligibility Assessments (Visit 1, Day -15) ..............................................................35 
9.2.2  Screening Telephone Contact (Phone 1, Day -8) .........................................................................35 
9.2.3  Randomization (Visit 2, Day 0) .....................................................................................................36 
9.2.4  Period 1 Telephone Contact (Phone 2, Day 7) .............................................................................36 
9.2.5  Washout (Visit 3, Day 15) .............................................................................................................36 
9.2.6  Washout Telephone Contact (Phone 3, Day 21) ..........................................................................37 
9.2.7  Washout (Visit 4, Day 28) .............................................................................................................37 
9.2.8  Period 2 Telephone Contact (Phone 4, Day 35) ...........................................................................37 
9.2.9  End-of-Study (Day 43, Visit 5) ......................................................................................................37 
10.  INVESTIGATIONAL PRODUCT MANAGEMENT ........................................................................................38 
10.1  Packaging, Labeling, and Shipping ....................................................................................................38 
10.2  Storage, Dispensing and Compliance Verification of Study Drug .....................................................38 
10.3  Study Drug Accountability .................................................................................................................39 
11.  TREATMENT AND PROTOCOL COMPLIANCE ...........................................................................................39 
11.1  Permitted and Prohibited Concomitant Medications .......................................................................40 
11.2  Permitted Medications ......................................................................................................................40 
11.3  Prohibited Medications .....................................................................................................................40 
12.  EFFICACY ASSESSMENTS .........................................................................................................................41 
12.1  Weekly Number of Bowel Movements .............................................................................................41 
12.2  Bristol Stool Form Scale.....................................................................................................................41 
12.3  Patient Visual Analog Scale (VAS) .....................................................................................................42 
13.         SAFETY ASSESSMENT ........................................................................................................................43 
13.1   Documentation of Adverse Events ...................................................................................................43 
13.2  Adverse Event Severity ......................................................................................................................44 
13.3    Adverse Event Causality ..................................................................................................................45 
13.4    Study Drug Action Taken .................................................................................................................45 
13.5    Adverse Event Outcome ..................................................................................................................46 
13.6    Treatment Administered .................................................................................................................46 
13.7    Clinically Significant Assessments ...................................................................................................46 
13.8  Serious Adverse Events .....................................................................................................................47 
13.9    Serious Adverse Event Reporting ....................................................................................................47 
13.10    Suspected Unexpected Serious Adverse Reactions (SUSAR) ........................................................48 
13.11   Pregnancy .......................................................................................................................................48 
13.12    Clinical Laboratory Assessments ...................................................................................................49 
13.13    Medical History, Vital Signs and Physical Examinations ...............................................................50 
13.14  Electrocardiograms .........................................................................................................................50 
14.   STATISTICAL ANALYSIS ............................................................................................................................50 
14.1   Sample Size Determination ..............................................................................................................51 
14.2  Analysis Populations ..........................................................................................................................52 
14.3  Baseline and Demographic Characteristics .......................................................................................53 
14.4  Study Drug Exposure .........................................................................................................................53 
14.5  Study Drug Compliance .....................................................................................................................53 


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14.6  Efficacy Analysis ................................................................................................................................54 
14.6.1  Analysis of Primary Endpoint .....................................................................................................54 
14.6.2  Analysis of Secondary Efficacy Endpoints ..................................................................................54 
14.7  Safety Analyses ..................................................................................................................................55 
14.7.1  Adverse Events ...........................................................................................................................55 
14.7.2  Clinical Laboratory Assessments ................................................................................................55 
14.7.3  Vital Signs ...................................................................................................................................55 
14.7.4  ECG .............................................................................................................................................56 
15.  DATA HANDLING AND RECORD KEEPING................................................................................................56 
15.1  Case Report Forms ............................................................................................................................56 
15.2  Source Documentation .....................................................................................................................56 
15.3  Record Retention ..............................................................................................................................57 
15.4  Data Management and Processing ...................................................................................................57 
16.  MONITORING ..........................................................................................................................................57 
17.  QUALITY CONTROL AND QUALITY ASSURANCE ......................................................................................57 
18.  COMPLIANCE, PROTOCOL AMENDMENT AND DEVIATION ....................................................................58 
18.1  Compliance ........................................................................................................................................58 
18.2  Protocol Amendment ........................................................................................................................58 
18.3  Protocol Deviation .............................................................................................................................58 
19.  STUDY TERMINATION ..............................................................................................................................59 
20.  ETHICAL CONSIDERATIONS .....................................................................................................................59 
21.  FINANCE AND INSURANCE ......................................................................................................................60 
22.  PUBLICATION POLICY AND CLINICAL STUDY REPORT .............................................................................60 
22.1  Confidentiality and Publication Policy ..............................................................................................60 
22.2  Clinical Study Report .........................................................................................................................61 
23.  REFERENCES ............................................................................................................................................62 
APPENDIX 1: Sample Bowel Movement and BSFS Diary................................................................................64 
 
 
 
LIST OF FIGURES 
 
Figure 1 - Study Design ...................................................................................................................................29 
Figure 2 - Bristol Stool Chart ..........................................................................................................................42 
 
LIST OF TABLES 
 
Table 1 - Randomization ................................................................................................................................30 
Table 2 - Laboratory Tests Panels ..................................................................................................................49 
Table 3 - Sample Size Requirements by Size Effect ........................................................................................52 
 
 


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4. GLOSSARY OF TERMS AND ABBREVIATIONS 
 
AE: Adverse Event 
ALT: Alanine Aminotransferase 
AST: Aspartate Aminotransferase 
AUC: Area Under the Curve 
BAD: Bile Acid Diarrhea 
BAM: Bile Acid Malabsorption  
BID: Bis In Die (Latin), twice daily 
BM: Bowel Movement 
BMI: Body Mass Index 
BSFS: Bristol Stool Form Scale 
BW: Body Weight 
CBC: Complete Blood Count 
CRF: Case Report Form 
CRO: Contract Research Organization 
CV: Curriculum Vitae 
DDI: Drug-drug Interaction 
EC: Ethics Committee 
ECC: Enteric-coated Cholestyramine 
ECG: Electrocardiogram 
GCP: Good Clinical Practice 
GI: Gastrointestinal 
GLP: Glucagon-like Peptide 
GMP: Good Manufacturing Practice 
HCTZ: Hydrochlorothiazide 
HPN: Home Parenteral Nutrition 
ICF: Informed Consent Form 
IRB: Institutional Review Board 
ITT: Intent-to-Treat 
IV: Intravenous 
IWRS: Interactive Web Response System 
MedDRA: Medical Dictionary for Regulatory Activities 
PK: Pharmacokinetic 
PO: per os (Latin), by mouth, orally 
PP: Per Protocol 
PPI: Proton Pump Inhibitors 
QD: Quaque Die (Latin), every day/daily 
QTc: QT corrected for heart rate 


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RBC: Red Blood Cells 
SAE: Serious Adverse Event 
SAP: Statistical Analysis Plan 
SD: Standard Deviation 
SUSAR: Suspected Unexpected Serious Adverse Reactions 
TEAE: Treatment Emergent Adverse Event 
TMF: Trial Master File 
TPN: Total Parenteral Nutrition 
VAS: Visual Analog Scale 
 
 


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5.  INTRODUCTION 
5.1  Short Bowel Syndrome Overview  
Short Bowel Syndrome (SBS) is a malabsorptive condition most often caused by significant resection of the small 
intestine.  In patients with SBS, the small intestine absorptive surface area is insufficient and leads to malabsorption 
of nutrients and bile acids, diarrhea, steatorrhea, malnutrition, and electrolyte abnormalities.  Some common causes 
of SBS in adults include Crohn’s disease, radiation enteritis, trauma, mesenteric vascular accidents and recurrent 
intestinal obstruction.  In the pediatric population, necrotizing enterocolitis, intestinal atresia, and intestinal volvulus 
are the most common etiologic factors (1).   
The most important consequence of extensive intestinal resection is loss of absorptive surface area, which results in 
malabsorption of macro and micronutrients, electrolytes and water (2). Most macronutrients are absorbed in the 
proximal 100–150 cm of intestine. SBS almost always occurs when there is less than 200 cm of bowel remaining. SBS 
patients exposed to the greatest nutritional risk generally have a duodenostomy or a jejunoileal anastomosis with 
less than 35 cm of residual small intestine, jejunocolic or ileocoloic anastomosis with less than 60 cm of residual small 
intestine, or an end jejunostomy with less than 115 cm of residual small intestine (3).  
Permanent total parenteral nutrition (TPN) support is usually needed in patients with less than 120 cm of intestine 
without colon in continuity and less than 60 cm with colonic continuity (4). Besides, malabsorption of macro- and 
micronutrients with a loss of intestinal absorptive surface area results in water and electrolyte malabsorption, which 
manifests as voluminous diarrhea, hypovolemia, hyponatremia and hypokalemia (5). 
Gastrin, cholecystokinin, secretin, gastric inhibitory polypeptide and motilin are produced by endocrine cells in 
proximal gastrointestinal tract. In SBS, the status of these hormones remains intact. On the other hand, glucagon-
like peptide (GLP) 1 and 2, neurotensin, and peptide YY are produced in ileum and proximal colon. In SBS, deficiency 
of these hormones is common, and this results in rapid gastric emptying, shortened intestinal transit and 
hypergastrinemia (6,7). 
The small intestine is able to adapt to compensate for the reduction in absorptive surface area caused by intestinal 
resection. This process occurs in the first few years following resection. This progressive adaptive response results 
from changes in the intestinal structure, motility and function (8). The mechanism of intestinal adaptation is not 
entirely understood. The degree of intestinal adaptation is related to the extent and site of intestinal resection (9). 
Complete intestinal adaptation can be achieved in only several months if minimal small intestine resection is present, 
such as 100-150 cm. 
5.2  Epidemiology of SBS 
Challenges to estimating the prevalence of SBS include its multifactorial etiology, varying definitions, and difficulty in 
estimating intestinal length.  Therefore, estimates of the incidence and prevalence of SBS are usually based on data 
from registries of patients on home parenteral nutrition (HPN), for which SBS is the most common indication.  SBS 
occurs in about 15% of adult patients who undergo intestinal resection, with 3/4th of these cases resulting from 
massive intestinal resection and 1/4th from multiple sequential resections. About 70% of patients in whom SBS 
develops are discharged from the hospital and a similar percentage remain alive a year later. This improved survival 
rate has been achieved primarily by the ability to deliver long-term nutritional support (5). 
 


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The annual prevalence of HPN in the United States is approximately 120 per million population, of whom about 
25%have SBS; this amounted to about 10,000 individuals (10). 
5.3  Treatment of Short Bowel Syndrome 
The early management of a patient with SBS is that of a critically ill surgical patient who has recently undergone 
intestinal resection and other concomitant procedures. Thus, control of sepsis, maintenance of fluid and electrolyte 
balance and initiation of nutritional support are important in the early management of these patients. For patients 
who have survived this early phase, the primary goals of management are to maintain adequate nutritional status 
and prevent development of complications related to both underlying pathophysiology and nutritional therapy. 
5.3.1  Nutritional status maintenance 
This is the primary goal in the management of SBS. Fluid and electrolyte losses from the gastrointestinal tract may 
be significant in the early postoperative period and must be monitored and replaced. TPN will be required in the 
early postoperative period and enteral nutrition should be initiated as soon as possible. 
Patients with limited ileal resection (less than 100 cm) with or without right hemicolectomy can resume intake of 
solid food in late postoperative phase. These patients may develop diarrhea or steatorrhea with consumption of a 
regular diet due to fat malabsorption, which in turn can lead to deficiencies of fat soluble vitamins, vitamin B12, 
calcium and magnesium. Maintenance of nutritional status becomes all the more important in the setting of diarrhea, 
which is quite common in SBS and may be due to gastric acid hypersecretion, rapid intestinal transit time, fat 
malabsorption and poor water reabsorption. H2 blockers, antidiarrheals, cholestyramine and octreotide have all 
been used to control diarrhea.  
5.3.2  Treatment of steatorrhea associated with ileal resection 
Fat maldigestion due to bile salt malabsorption frequently occurs when more than 100 to 150 cm of terminal ileum 
has been resected. Various therapeutic options have been suggested for the treatment of the resulting steatorrhea. 
Use of bile salt replacement therapy with ox bile or a synthetic conjugated bile acid (cholesarcosine) has been 
reported (11). These patients may be put on low-fat high-carbohydrate diet. Low fat may decrease steatorrhea, but 
it also results in decreased energy intake which may worsen patient’s energy balance. However, a high fat intake is 
associated with malabsorption of divalent cations, delayed gastric emptying, early satiety and increased water loss 
from colon.  
Pharmacologic therapy for SBS is a rapidly expanding area of investigation. Recent evidence suggests that provision 
of appropriate diet, nutritional supplements such as glutamine and growth factors such as growth hormone improves 
intestinal absorption and perhaps modifies the adaptive response in patients with established SBS (5, 12,13). 
Currently GLP-2 appear to have the most promising results. 
5.3.3  Home parenteral nutrition and complications of SBS 
Home parenteral nutrition (HPN) is an option for patients who require long-term TPN. To prepare the patient for 
HPN, the regime should be compressed gradually in 2 to 4 h daily increments so that the total volume can be infused 
over a 10–12 h period, typically over night. The HPN infusion is generally tapered off over a 30–60 min period to 


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avoid hypoglycemia. Gastric hypersecretion can be a serious problem in SBS and is due to parietal cell hyperplasia 
and hypergastrinemia. In addition to malabsorption and diarrhea, gastric hypersecretion can cause or flare up peptic 
ulcer disease. H2 receptor antagonists or PPI can be tried with good results (14,15).  
5.4   SBS Associated Bile Acid Diarrhea 
During normal digestion, bile acids are secreted into the intestines and are then re-absorbed from the intestinal tract 
and returned to the liver via the enterohepatic circulation.  In SBS and other medical conditions, bile acids are 
insufficiently re-absorbed from the intestinal tract and make their way to the colon, giving rise to bile acid diarrhea 
(BAD).  For instance, patients with an ileal resection of 30 cm or more may develop malabsorption of bile acids, 
resulting in their increased passage into the colon, where dihydroxy bile acid induces the secretion of salt and water 
and hence diarrhea (15,16).  
A small proportion of the secreted bile acids are not reabsorbed in the ileum and reach the colon. Here bacterial 
action results in deconjugation (removal of the taurine or glycine) and   dehydroxylation (removal of the 7-hydroxy 
group), producing the secondary bile acids, deoxycholate and lithocholate. Bile acids in the colon, in particular the 
dihydroxylated bile acids chenodeoxycholate and deoxycholate, stimulate electrolyte and water secretion (15). This 
condition is now better understood and has also been called bile salt or bile acid malabsorption (BAM). The usually 
effective enterohepatic circulation of bile salts is most obviously disturbed in ileal disease. Following ileal resection, 
typically for Crohn’s disease, bile acids are not absorbed efficiently, resulting  in clear-cut BAM. This was called 
cholegenic diarrhoea or cholerheic enteropathy when first described by Alan Hofmann in 1967 (15). 
 
Cholestyramine is a quarternary ammonium anion exchange resin with a polystyrene polymer skeleton. As the 
chloride salt, it binds bile acids both in vitro and in vivo, exchanging chloride for bile acid. During normal digestion, 
bile acids are secreted into the intestines. A major portion of the bile acids is absorbed from the intestinal tract and 
returned to the liver via the enterohepatic circulation. Only very small amounts of bile acids are found in normal 
serum. Cholestyramine resin absorbs and combines with the bile acids in the intestine to form an insoluble complex 
which is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation by 
preventing their absorption. The increased fecal loss of bile acids due to cholestyramine resin administration leads 
to an increased oxidation of cholesterol to bile acids, a decrease in beta lipoprotein or low density lipoprotein plasma 
levels and a decrease in serum cholesterol levels. Although in man cholestyramine resin produces an increase in 
hepatic synthesis of cholesterol, plasma cholesterol levels fall (17,18). 
Cholestyramine is indicated as adjunctive therapy to diet and exercise for the reduction of elevated serum cholesterol 
in patients with primary hypercholesterolemia. Cholestyramine may also be useful in lowering elevated cholesterol 
in patients with combined hypercholesterolemia and hypertriglyceridemia but it is not indicated where 
hypertriglyceridemia is the abnormality of most concern. In Canada, cholestyramine is also indicated as a 
symptomatic control of bile acid induced diarrhea due to SBS and for the relief of pruritus associated with partial 
biliary obstruction (19). The recommended adult dose is 4 g of cholestyramine resin, one to six times daily.  
Management of SBS associated BAD generally relies on binding (or sequestering) excess bile salts in order to prevent 
their secretory actions.  Because of its proven bile acids binding capacity, cholestyramine has been given for many 
years for diarrhea in patients with ileal resection (20). The principle for its use in diarrhea has been to prevent free 
bile acids from stimulating secretion in the colon.  They are effective and most patients with abnormal SeHCAT values 
will respond.  Subjects with lower SeHCAT values (less than 5%) are more likely to respond than those with higher 


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values (below 15%) (21). Another bile acid sequestrant, colesevelam, available in a tablet form, has been used initially 
for hyperlipidaemia (22). Colesevelam was shown to be effective at doses between 1.25 and 3.75 g/day and was well-
tolerated (21).  
 
The efficacy of cholestyramine as a treatment for diarrhea in patients with ileal resection was examined by inpatient 
and outpatient trials as early as in 1969, by Hofmann et al. Ten (10) of 12 patients having less than 100 cm of distal 
ileum resected and some remaining ascending colon responded to cholestyramine, 16 g/day, by a significant 
decrease in fecal frequency or fecal weight or both. By contrast, none of eight patients having resections of more 
than 100 cm of ileum responded. The degree of steatorrhea was also of predictive value since all eight patients with 
fecal fat excretion less than 20 g/day responded, whereas none of five patients with greater steatorrhea responded. 
Cholestyramine is useful in the symptomatic treatment of diarrhea in patients with small ileal resections and mild 
steatorrhea (16). 
 
Cholestyramine may be of particular benefit in a select group of patients with ileal resection less than 150 cm and 
colon in continuity. Since bile salts are absorbed primarily in the distal ileum, these patients may experience spillover 
of bile salts into the colon, where they are metabolized by bacteria to lithocholic acid and deoxycholic acid and induce 
a secretory diarrhea. Bile acid-binding resins form insoluble complexes with bile salts and reduce diarrhea in these 
patients. However, more extensive ileal resection is more common. As noted above, patients with extensive ileal 
resection experience a decrease in bile acid pool and use of a conventional bile acid-binding resin may worsen fat 
malabsorption. Therefore, conventional cholestyramine should be used with caution in patients with SBS and 
clinicians and patients should monitor for steatorrhea, fat-soluble vitamin deficiencies, and decreased efficacy of 
concomitant medications that result from impaired absorption (13,14,16,23).  
 
As an anion exchanging resin, cholestyramine may also bind other drugs that are administered concurrently. 
Cholestyramine resin may delay or reduce the absorption of concomitant oral medications such as thyroid and 
thyroxine preparations, warfarin, hydrochlorothiazide (acidic), phenylbutazone, phenobarbital, tetracycline, 
penicillin G, and digitalis, as well as therapeutic bile acids such as ursodiol and obeticholic acid.  These medications 
are mostly absorbed in the proximal portion of the small intestine, such as the duodenum and the proximal jejunum. 
This is where a complexation with cholestyramine may occur. Thus, patients are recommended to take other drugs 
either one hour before, or 4-6 hours after, taking cholestyramine which is an inconvenience for most patients (13, 
19, 20). 
5.5 Rationale for a New ECC Formulation 
Although treatment with conventional bile acid binding resins such as cholestyramine is effective in 75-88% of SBS 
patients, there are several physiological disadvantages.  Firstly, the jejunal concentration of non-sequestered bile 
acids is below the optimum for sufficient solubilization of the lipolytic products after meals and thus the result is 
malabsorption of fat, steatorrhea, and diarrhea induced by fatty acids.  Secondly, malabsorption of bile acids is 
increased because sequestered bile acids are not available for small intestinal absorption. Moreover, the reduced 
reabsorption of bile acids leads to a decreased bile acids pool and synthesis.  Recent studies have shown that 
cholestyramine can lower FGF19 levels, through binding of bile acids in the small bowel, which potentially decreases 
the ability of bile acids to bind to the ileal nuclear receptor Farnesoid X Receptor that controls transcription of FGF19. 
Lundasen et al. showed that administration of cholestyramine to healthy volunteers reduced FGF19 by 87% and 
increased C4 18-fold (24). Since FGF19 has beneficial effects on bile acid metabolism as well as hepatic 


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gluconeogenesis and lipid storage, the lowering of FGF19 by bile acid sequestrants may be undesirable. Therefore, it 
might be an advantage to deliver cholestyramine in a more distal portion of the small intestine, beyond the segments 
involved in fat digestion and concomitant drugs absorption. Consequently, administering a delayed-release capsule 
dosage form that releases the active substance in the terminal ileum or proximal colon, would represent a 
therapeutic advantage. Such a formulation would not influence the fat digestive properties of bile acids but would 
still prevent their osmotic, laxative effects.  
 
In fact, this concept had originally been proposed by Jacobsen et al. (25) , who conducted a small study comprising 
14 patients who had undergone ileal resection of 40-150 cm for Crohn's disease.  This double-blind cross-over trial 
was performed with placebo and cholestyramine enterocoated with cellulose acetate phthalate. During treatment 
with cholestyramine the daily fecal output decreased, the number of defecations each week decreased, and the 
intestinal transit time increased. Acceptability of the tablets was high, in contrast with general clinical experience 
with cholestyramine powder.  No change was observed in the total fecal output of bile acids or fat. Cholestyramine 
tablets caused a reduction in diarrhea without noticeably interfering with the metabolism of fat or bile acid. 
 
Another main concern with the use of conventional resins (sequestrants) is poor tolerance, with discontinuation rates 
of over 40%. Many of these effects are due to palatability or upper abdominal symptoms.  In addition, conventional 
sequestrants may interact with other drugs including fat soluble vitamins (6,12,19). As such, a novel formulation that 
could deliver cholestyramine to the lower intestine and colon may have several advantages including a more 
favourable patient acceptance profile, fewer drug interactions, no or minimal effect on FGF19 and a better 
tolerability.   
 
A new enteric-coated cholestyramine capsule (ECC) has been developed to manage diarrhea associated with SBS in 
patients who still have their transverse and descending colon. SBS is usually caused by the significant resection or 
loss of function of the terminal ileum, leading to reduced reabsorption of bile acids and subsequent osmotic diarrhea. 
The new ECC capsule can release cholestyramine in a more distal segment of the intestinal tract, downstream to the 
duodenum, in order to bind excess bile acids before they induce diarrhea. Moreover, non-enteric coated 
cholestyramine can interact with several drugs such as hydrochlorothiazide in the duodenum, leading to decreased 
bioavailability and therapeutic response of hydrochlorothiazide (26,27). It is then hypothesized that delivering 
cholestyramine in a more distal intestinal segment will prevent such interaction. 
Gastrointestinal Behavior of New ECC Formulation  
The anatomical site of release of cholestyramine is of paramount importance for the proposed indication, since the 
drug must be available for non-reabsorbed bile acids binding prior to their passage into the colon.  At the same time, 
a too proximal delivery of the resin should be avoided to prevent any potential drug interaction in the duodenum 
and to preserve the lipolytic activity of bile acids.   
In this context, an open-label, single center, single-dose, non-randomized scintigraphy study evaluating 
gastrointestinal transit, site of disintegration, site of dispersion, and associated variability of a new ECC formulation 
was conducted in 8 healthy, adult male volunteers (28). Safety evaluations included assessment of physical 
examination, ECG, adverse events (AEs) and periodic monitoring of vital signs (heart rate, blood pressure) and clinical 
laboratory tests (including hematology, serum chemistry, and urinalysis).  The dosing period was about 24 hours in 


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duration post-dose of the cholestyramine capsules.  Follow-up procedures were performed within 14 days of the 
dosing period inclusive of the final day of the dosing period. 
 
A study-specific batch of ECC capsules was manufactured for PMS-2017-001, incorporating non-radioactive 
samarium oxide as a surrogate marker in the cholestyramine blend prior to encapsulation.  The non-radioactive 
isotope samarium-152 (Sm-152) was subsequently converted to the radioactive isotope Sm-153.  
 
Previous in vitro disintegration studies had shown that ECC remains intact at acidic pH, with capsule burst at pH 
.  
The Phase I study results demonstrated proof of concept that the enteric-coating of ECC functionally resists 
disintegration under acidic pH conditions in vivo and enables successful targeting and delayed-release of 
cholestyramine prior to and in the ileum. The formulation was considered robust with a high degree predictability of 
release into the mid- to distal small intestine.  
 
Drug-Drug Interaction Study with New ECC Formulation 
A second Phase I, single-dose, cross-over, drug-drug interaction (DDI) study was conducted to investigate the effect 
of ECC on plasma kinetics of hydrochlorothiazide (HCTZ), used as a victim drug, in healthy volunteers.  Cholestyramine 
powder is known to substantially reduce bioavailability of HCTZ as measured by plasma levels and urinary excretion 
of HCTZ. The effects of this DDI have been shown to be time-dependent and heightened by multiple dosing.  Results 
of the study showed that both formulations of cholestyramine (ECC capsule and powder) exhibit an effect on the 
fasting pharmacokinetics of HCTZ. However, the impact of ECC is notably lower than the impact of the cholestyramine 
powder on HCTZ and is therefore expected to be of minor clinical significance compared to that of the non-enteric-
coated powder formulation.  The results suggest that the delivery of cholestyramine in a more distal intestinal 
segment via an enteric-coated capsule, successfully reduces the magnitude of DDIs.  Overall, ECC was generally safe 
and well-tolerated by the subjects in this study.  
5.6  Safety of Cholestyramine 
The adverse events (AEs) and safety profile of cholestyramine powder is very well known since it has been used for 
many decades globally (20).  The most frequent AE is constipation.  Predisposing factors for most complaints of 
constipation are high dose and increased age (more than 60 years old).  Most instances of constipation are mild, 
transient, and controlled with conventional therapy.  Some patients require a temporary decrease in dosage or 
discontinuation of therapy. 
 
Less frequent AEs include: abdominal discomfort and/or pain, flatulence, nausea, vomiting, diarrhea, heartburn, 
anorexia, dyspepsia and steatorrhea, bleeding tendencies due to hypoprothrombinemia (Vitamin K deficiency) as 
well as Vitamin A (one case of night blindness has been reported) and D deficiencies, hyperchloremic acidosis in 
children, osteoporosis, rash and irritation of the skin, tongue and perianal area. 
5.7  Study Rationale and Risk/Benefit Assessment 
The new ECC capsule has been developed to manage diarrhea associated with SBS. The formulation is expected to 
release cholestyramine in the remaining segment of the small intestine in SBS patients (mid-jejunum to terminal 
ileum), thus binding bile acids after fat digestion, but before induction of diarrhea in the colon. The delayed-release 
profile is also expected to help reduce the potential for DDIs occurring in the proximal small intestine. 
 
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Since delayed distal delivery of cholestyramine is expected to be more effective in prevention and reduction of 
diarrhea in SBS, compared to non-enteric coated cholestyramine powder, lower doses may be sufficient.  The 
recommended adult dose of cholestyramine powder is 4 g, one to six times daily. Consequently, 2 doses of ECC were 
selected for this dose-finding study.  The "high” dose will be 4.25 g (10 capsules) daily corresponding approximately 
to the recommended dose of cholestyramine powder.  The “low” dose will be 1.7 g (4 capsules) daily.  These doses 
will be evaluated for efficacy, safety, and tolerability in well-defined non fully colectomized SBS patients suffering 
from diarrhea. 
 
To avoid any carry-over effect, a washout of 14 calendar days is planned between periods. Washout periods of a 7-
14 day duration have been used in previous, published trials on cholestyramine and/or treatment of BAD. 
 
The doses of ECC administered in this study are not anticipated to induce any potential risks to the patients and are 
well below the maximum doses of cholestyramine typically administered for other indications.  The safety monitoring 
practices employed by this protocol (i.e. physical examination, vital signs, clinical laboratory assessments, and AE 
questioning) are adequate to protect the patients’ safety and should detect all expected treatment-emergent AEs 
(TEAEs).  The potential medical benefit from participation in this trial would be the expected reduction of diarrhea or 
bowel movements following treatment with “high” dose ECC, and potentially treatment with “low” dose ECC as well. 
 
6.  STUDY OBJECTIVES 
6.1  Primary Objective  
The primary objective of this study is to investigate the clinical efficacy of new ECC capsules and select the most 
effective dose in adult patients with SBS. 
6.2  Secondary Objectives  
The secondary objectives of this study are to evaluate the safety and tolerability of new ECC capsules in adult patients 
with SBS, and to evaluate patients’ overall experience with related symptoms via an 11-point Visual Analog Scale 
(VAS). 
7.  STUDY DESIGN 
7.1  Endpoints 
7.1.1  Primary Endpoint 
The primary endpoint will be the change in the weekly frequency of bowel movements, measured between baseline 
and the second week of treatment (ie. Days 8 to 14 and Days 36 to 42). Efficacy will be assessed as the overall 
difference vs baseline as well as the difference between the two treatment doses. 
7.1.2  Justification for the Primary Endpoint 
Several efficacy endpoints have been used in the study of the use of cholestyramine or other bile acids sequestrants 
in the management of bile acid diarrhea (BAD). These included fecal weight, fecal volume, weekly frequency of bowel 
movement (typically called ‘ number of stools’ in the literature), mean stool type according to the Bristol Stool Form 
Scale (BSFS), loperamide use, etc. In a clinical trial in primary and secondary BAD, Walters et al. used an innovative 


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index taking into consideration the weekly stool frequency, the mean BSFS, as well as loperamide use (29). This index 
was: (weekly stool frequency X mean BSFS) + loperamide use. This index, while non-validated per se, was justified by 
the variable nature of BAD symptoms. All components of this index were influenced by the study treatment, 
obeticholic acid, in BAD patients. 
 
Weekly stools (bowel movement [BM] frequency) is an objective endpoint that can be easily measured by patients, 
using a diary. BSFS can be more difficult to assess by study subjects, since it implies a visual evaluation of the stools 
and is consequently more subjective. Fecal weight and volume require regular stool collection, which is cumbersome.  
 
In light of these considerations, the weekly number of bowel movements is proposed as the study primary efficacy 
endpoint. This endpoint is clinically relevant to the symptom of diarrhea, and an increased frequency translates to a 
decreased water reabsorption as well as an accelerated GI transit, both important pathogenic components of SBS. 
The data obtained from Walters and other authors show that bowel movement frequency (stool frequency) is a 
sensitive index for pharmacological intervention in SBS. While significant variability can be observed with this 
parameter, weekly bowel movement frequency can be greatly reduced by antidiarrheal drugs and bile acids 
modulating agents (e.g. obeticholic acid). Moreover, the second week of treatment with ECC will be used for this 
purpose, in order to reach an expected maximum and stable effect at each dose of the drug studied. 
7.1.3  Secondary Endpoints 
- 
Total number of bowel movements per week, after the first week of treatment (i.e. Days 1 to 7, and Days 29 
to 35) 
- 
Total number of bowel movements for the whole 2-week treatment period (i.e. Days 1 to 14 and Days 29 to 
42)  
- 
Mean daily stool form score according to the BSFS, measured during the first week of treatment (i.e. Days 1 to 
7, and Days 29 to 35) 
- 
Mean daily stool form score according to the Bristol Stool Form Scale (BSFS), measured during the second week 
of treatment (i.e. Days 8-14, and Days 36-42) 
- 
Mean daily stool form score according to the BSFS, measured during the whole 2-week treatment period (i.e. 
i.e. Days 1 to 14 and Days 29 to 42) 
- 
Total number of bowel movements with a BSFS score ≥ 6 during the first week of treatment (i.e. Days 1 to 7, 
and Days 29 to 35) 
- 
Total number of bowel movements with a BSFS score ≥ 6 during the whole 2-week treatment period (i.e. Days 
1 to 14 and Days 29 to 42) 
- 
Mean daily dose of loperamide in mg, if used, during the second week of treatment (i.e. Days 8-14, and Days 
36-42) 
- 
Mean Diarrhea Composite Index ([weekly BM frequency X mean daily BSFS score] + loperamide use [weekly 
mg X 3]) during the second week of treatment (i.e. Days 8-14, and Days 36-42) 
- 
Safety (to be evaluated through the assessment of AE, laboratory tests, vital signs, ECG and physical 
examination) 
- 
Tolerability (to be evaluated through assessment of TEAEs and TESAEs) 
 
Overall evaluation of diarrhea, abdominal pain, urgency and bloating using an 11-point Visual Analog Scale (VAS) 
made on Days 0 (baseline), 15, 28 and 43 


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7.2  Study Overview 
7.2.1  Study Design 
This is a multiple center, randomized, double-blind, double dummy, 2-period, 2-sequence cross-over study design 
(Figure 1).  The study will be conducted across three study centers. A total of 18 patients will be selected to participate 
in the study.  All 18 patients will receive treatment with ECC during each study period.  Patients will be randomized 
to either “low” dose ECC (1.7 g with matching placebo BID), or “high” dose ECC (4.25 g BID) daily for 14 days, followed 
by a 14-day washout, and then allocated to the other treatment for the second period. 
 
Figure 1 - Study Design 
 
A: ECC 1.7 g BID 
B: ECC 4.25 g BID 
D: Day 
Screening: 15-day duration 
 
The duration of the clinical portion of this study (excluding the screening period) is expected to be approximately 43 
days. The actual overall study duration may vary. 
 
The end of the study is defined as completion of the last visit or study procedure, as shown in the schedule of 
activities) for the trial, globally. 
7.2.2.  Study/Treatment Arm Stopping Rule Guideline 
The following recommendations are proposed for stopping the enrolment and/or further drug administration in a 
given treatment arm. An agreement will be reached with the Study Medical Monitor and the Sponsor on making such 
decisions. The following guidelines will be followed:  
 
• 
Occurrence of any case of death that may be attributed to ECC (in such a case, the blind will have to be broken 
and allocated treatment dose identified); 


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• 
Occurrence of a significant number of unexpected SAEs that could be attributable to the drug (at least probable 
causality relationship) and that raise Investigators/Sponsor concerns about patients’ safety; 
• 
Increased frequency and/or severity of expected cholestyramine-related AEs, that in the judgment of the 
Investigators/Sponsor, will result in the advice to discontinue ECC treatment. 
7.2.3  Individual Patient Stopping Rules 
The following should be used as a guide for the Investigator to determine if the study drug administration is to be 
interrupted: 
 
• 
A subject develops a medical condition that requires prolonged concomitant therapy with a prohibited 
medication or prolonged interruption of the study drug (more than 2 consecutive days) 
• 
Occurrence of an AE or SAE that could be attributable to the drug (at least probably causality relationship) or not, 
and causes discontinuation of study drug for more than 2 days; 
• 
High and unexpected frequency and/or severity of AEs (at least probably causality relationship), serious or not, 
that in the judgment of the Investigator, requires withdrawal of the patient from the study. 
7.2.4  Treatment Arm Dose Reduction Guideline 
No ECC treatment dose reduction will be permitted during the study, within each treatment arm. 
7.3  Blinding and Randomization 
This study will be fully blinded, using the double dummy technique (combination of active ECC capsules and matching 
placebo in the low dose treatment arm). Subjects will be randomized to one of the following 2 treatments per period 
(Table 1):  
 
• 
Treatment A: ECC at the 1.7 g daily dose, administered BID as 2 capsules of ECC, plus 3 capsules of placebo, at 
least 30 minutes before breakfast and 2 capsules of ECC, plus 3 capsules of placebo at least 30 minutes before 
evening meal.  
• 
Treatment B: ECC at the 4.25 g daily dose, administered BID as 5 capsules of ECC at least 30 minutes before 
breakfast and 5 capsules of ECC at least 30 minutes before evening meal. 
 
The capsules should be swallowed whole and not be chewed or crushed.  All 18 patients will receive both ECC doses 
by the end of the study. 
 
If the patient misses the morning dose, they should take the dose at least 30 minutes before lunch. If the patient 
misses the evening dose, they should skip that dose. Doses should not be doubled. Patients should note the times 
that they take the study medication on their bowel movement diaries.  
 
Table 1 - Randomization 
 
Period 1 
Period 2 
Sequence AB (n=9) 
Treatment A 
Treatment B 


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Sequence BA (n=9) 
Treatment B 
Treatment A 
 
JSS Medical Research will develop the computer-generated randomization sequences to be programmed into the 
Interactive Web Response System (IWRS), according to the study design, the number of subjects and the sequence 
of treatment administration.  The IWRS will assign a randomization number to each patient.  The random allocation 
of each sequence of drug administration to each subject is done in such a way that the study is balanced. Once 
generated, the randomization code will be final and will not be modified. 
7.4  Procedure for Unblinding 
This is a double-blind study. Patients, investigators and site staff, Sponsor and CRO personnel, and data managers 
will be kept blinded to treatment assignments until the end of the study, except for emergency unblinding as 
described below. 
  
Only the Packaging/Distribution provider’s unblinded staff and CRO staff administering the IWRS or performing the 
statistical analyses will be knowledgeable of individual treatment assignments. As well, in the case of emergency 
unblinding as described below, some additional people will become aware of treatment assignment for specific 
patient(s). 
  
The study blind may be broken for an individual patient or several patients in the event of an emergency in which 
knowledge of the treatment assignment is needed for the safety of the patient(s) and/or for medical decision-making 
or as required by local regulatory authority. Unless the event for which the blind needs breaking is life-threatening, 
the investigator must first contact the study’s medical monitor (or designee) prior to breaking the blind. The 
investigator will obtain unblinding information from the staff administering the IWRS. The reason and justification 
for breaking the blind must be fully documented in the source documentation and captured on the patient(s) 
electronic case report form (e-CRF).  
 
8.  SELECTION AND WITHDRAWAL OF PATIENTS 
 
Subjects who meet all the inclusion criteria and none of the exclusion criteria at the screening visit will be eligible for 
participation in this study. Continued eligibility will be assessed upon baseline visit at start of Period 1, prior to the 
first study drug administration. 
 
An effort will be made to include similar proportions of males and females in the study. 
8.1   Inclusion Criteria 
1.    Adult, ambulatory male and female subjects 
2. Provision of signed and dated informed consent form (ICF) 
3. Age ≥ 18 years and ≤ 80 years 
4. Stable SBS, of: 
a. Non-surgical origin; OR 
b. Surgical origin where the last surgical ileal resection was performed at least 6 months prior to 
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5. Partial, Home Parenteral Nutrition and/or parenteral fluids are allowed, at a maximum frequency of 6 times a 
week throughout the trial, as long as the regimen has been stable for at least 2 weeks prior to screening and is 
expected to remain unchanged during the study 
6. At least 50 % of the colon being intact 
7. Intact duodenum  
8. BMI ≥ 18 
9. Presence of stable chronic diarrhea for at least 3 months prior to enrolment as evidenced by medical history 
10. Presence of stable chronic diarrhea during the 2-week screening diary period before randomization, as 
evidenced by completion of a screening diary demonstrating: 
a. Mean daily production of at least 3 soft or watery stools (BSFS scores 6 or 7); or 
b. More than 3 bowel movements per day on average with >25% of them being BSFS type 6 or 7 
 
11. Stated willingness to comply with all study procedures and availability for the duration of the study 
12. Clinical laboratory values within the laboratory's stated normal range; if not within this range, they must be 
without clinical significance, as determined by the investigator 
13. Female subject must meet one of the following criteria: 
      a) Participant is of childbearing potential and agrees to use one of the accepted contraceptive regimens 
 
from at least 30 days prior to the first study treatment administration through to at least 30 days after the 
 
last dose of the study treatment. An acceptable method of contraception includes one of the following: 
 
 
a) Abstinence from heterosexual intercourse 
 
b) Systemic contraceptives (combined birth control pills, injectable/implant/insertable hormonal   
birth control products, transdermal patch) 
 
 
c)Intrauterine device (with or without hormones) 
 
 
d) Condom with spermicide 
b)  Participants of non-childbearing potential, defined as surgically sterile (i.e. has undergone complete 
hysterectomy or bilateral oophorectomy) or is in a menopausal state (i.e. at least 1 year without menses 
prior to the first study drug administration) are eligible 
8.2   Exclusion Criteria 
1. Patients with known or suspected intestinal strictures of clinical relevance as judged by the Investigator 
2. Active inflammatory bowel disease (IBD) or fistula during the screening period as judged by the Investigator 
3. Crohn's disease patients not being in clinical remission for the last 12 weeks prior to randomization 
4. Diarrhea caused by other causes than SBS 
5. Presence of clinically significant steatorrhea, requiring pancreatic enzymes supplementation 
6. Presence of complete biliary obstruction 
7. Presence of active cancer (except resected cutaneous basal or squamous cell carcinoma and except in situ 
cervical cancer) and/or the need to receive chemotherapy or radiotherapy during the study  
8. History of allergic reaction to cholestyramine or any excipient of the investigational drug product or placebo such 
as lactose, or packaging components. 
9. Females who are lactating at screening 


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10. Females who are pregnant according to the pregnancy test at screening or prior to the first study treatment 
administration 
11. Significant history (at least 3 consecutive months in the year prior to Screening) of drug dependency or alcohol 
abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) 
12. Subjects who took an Investigational Product (IP) in the 30 days prior to the first study drug administration 
13. Any other clinically significant condition that is considered by the principal investigator as being susceptible to 
put the patient at greater safety risk, influence response to study product, or interfere with study assessments. 
8.3  Informed Consent 
Subjects are required to provide written informed consent prior to commencement of any protocol procedure. The 
consent form can be signed up to 28 days before screening visit. When a suitable subject presents with SBS, the 
Investigator or designee will explain the nature, purpose, risks and benefits associated with the study to the subject 
and ensure that the subject is given full and adequate written information.  Subjects must be informed that they are 
free to discontinue from the study at any time.  The subject should be given opportunity to ask questions and allowed 
time to consider the information provided.  If the subject agrees to participate in the study, the Informed Consent 
Form (ICF) must be signed by the subject or his/her legal representative to indicate that the subject understands all 
aspects of the study.  The subject’s signed and dated informed consent must be obtained before any study 
procedures are performed.  The Investigator will provide the subject with a copy of the ICF. 
8.4  Study Withdrawal of Patients 
A subject may withdraw from the study at any time at his/her own request without prejudice to further treatment 
or clinical care.  In addition, subjects may be withdrawn at the discretion of the Investigator for safety, behavioral, 
compliance or administrative reasons.  Patients should be withdrawn from the study in the event of any of the 
following:  
1. If a patient does not continue to meet eligibility criteria at baseline, the patient will be withdrawn prior to 
randomization.  
2. Safety issues as described in the Study/Treatment Arm or Individual Patient Stopping Rules.   
3. If a patient withdraws consent during the treatment period, and more specifically consent to contribute 
additional outcome information, the patient shall be withdrawn from the study (although it is recommended that 
the investigator attempts to perform a Treatment Discontinuation Visit Evaluation). If the patient withdrawing 
consent to further treatment agrees to contribute additional outcome information, then the regular schedule of 
visits could be maintained, for safety and relevant outcome measures of efficacy.  
4. If a patient is serially and persistently noncompliant with study procedures and/or visit schedules, the 
investigator or the Sponsor may withdraw the patient from the study. 
5. A patient's treatment is unblinded by the Investigator.  
6. If a female patient or a female partner of a male patient has a confirmed pregnancy (with the exception of a 
pregnancy resulting from in-vitro fertilization), this should be immediately reported to the Medical Monitor and 
the Sponsor (within 1 working day of discovery) and the female patient shall be withdrawn. The male patient 
would continue in the study. 
 
The reason for patient withdrawal from the study will be noted on the e-CRF, reported to the Sponsor, and 
documented in the clinical study report. The investigator should attempt to follow patients withdrawn after first 


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dosing until resolution of any AEs, or at least 4 weeks after the last dose of study agent, or until completion of 
pregnancy. Upon withdrawal, no further dosing should be performed for these patients. Investigators shall make 
reasonable attempts to contact lost-to-follow-up patients for evaluation. 
8.5  Treatment Discontinuation 
Patients should discontinue treatment but remain in the study for adequate follow-up, for any of the following 
reasons:  
• 
Patients may discontinue study drug treatment at any time if the patient, Investigator, or the Sponsor determines 
that it is not in the best interest of the subject to continue treatment. 
• 
Unacceptable toxicity associated with treatment (see Study Treatment Arm Stopping Rule section for details). 
• 
Clinically significant lab abnormalities or AEs that, in the Investigator’s judgment, would preclude continued 
treatment.  
 
The reason for treatment discontinuation will be noted on the e-CRF, reported to the Sponsor, and documented in 
the clinical study report.  
 
If a patient discontinues treatment due to unacceptable toxicity or any other safety reason, that patient should 
continue to be assessed according to the planned visit schedule for safety, or at the minimum, attend a Treatment 
Discontinuation Visit four (4) weeks after having received the last dose of study drug. 
 
A clear distinction should be made between study withdrawal and treatment discontinuation.   
8.6  Replacement of Patients 
A subject who withdraws during the pretrial evaluations but before receiving the treatment will not be considered 
as a drop-out and will not be included in the final statistical analysis. 
 
Standbys should be recruited and available to replace any subject who withdraws prior to the first treatment 
administration.  
  
Patients who are withdrawn or lost to follow-up during the study may be replaced in order to achieve the number of 
evaluable patients required, per the sample size calculations, to address the primary objective. 
 
 
 
 
 


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9.  STUDY CONDUCT 
9.1  Timing of Assessments 
All scheduled clinic visits allow a +/- 1 day window. See Section 2 for the Schedule of Activities. The latest version of 
the consent form must be signed prior to subject's inclusion (prior to initiating any protocol procedure). 
9.2  Study Visits and Procedures 
Prior to any study specific screening activities, all potential patients will sign the Study Informed Consent Form 
(ICF). The consent forms will comply with all applicable regulations governing the protection of human subjects. An 
ICF, approved by the Sponsor and the site's institutional review board (IRB) or Ethics Committee (EC), must be used. 
The consent form can be signed up to 28 days before screening visit. 
9.2.1  Screening and Eligibility Assessments (Visit 1, Day -15) 
On Day -15 prior to randomization, interested SBS patients will undergo a screening session, Visit 1. Patients will 
arrive in the fasted state (i.e. fast for 4 hours before visit). This visit is comprised of the following elements: 
 
1. Verification of identity and demographics (age, gender, race); 
2. Confirmation of the SBS diagnosis will be obtained, with proper medical history data; 
3. Description of the type and extent of intestinal surgical resection will be provided (if applicable); 
4. Verification of all inclusion and exclusion criteria; 
5. Collection of medical history including history of intestinal surgical resection or other possible cause of SBS, all 
current medications and therapies, non-prescription drug intake, and HPN if still administered. Particular 
attention will be paid to obtaining the history of diarrhea in the 3 months prior to screening, as well as prohibited 
drugs; 
6. Measurement of body weight and height, and calculation of BMI; 
7. Measurement of vital signs including heart rate, blood pressure and body temperature; 
8. Complete physical examination; 
9. An ECG will be performed; 
10. All safety laboratory tests including hematology, serum chemistry, pregnancy test (if applicable) and urinalysis 
(dipstick). Screening laboratory results must be available and reviewed by the Investigator before randomization. 
11. Patients will be given a bowel movement (BM) and BSFS diary, in which they will need to record daily the number 
of stools and their form, using the BSFS. Proper instructions will be provided for the use of the BSFS. Patients will 
be instructed to start recording in this Screening diary at Day -14 and to fill it out daily until Day -1 inclusive, in 
order to establish a baseline and confirm patients’ eligibility. 
12. All screening results must be available prior to Day 0 randomization so that the study Investigator can determine 
eligibility. 
13. From screening to the first dose of the study, AEs will be recorded as screening events or as part of the medical 
history, as applicable. 
9.2.2  Screening Telephone Contact (Phone 1, Day -8) 
Each patient will be contacted by phone by the study coordinator, to inquire about the occurrence of AEs, any 
changes in medications, and use of the BM and BSFS screening diary. 


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9.2.3  Randomization (Visit 2, Day 0) 
Eligible SBS patients will be invited to the study site for the selected baseline procedures.  
1. Verification of completion of the BM and BSFS screening diary and review of eligibility criteria to decide if patient 
can continue to be randomized into the study.  If yes:  
2. Vital signs will be measured (heart rate, blood pressure and body temperature). 
3. A urine pregnancy test will be performed if applicable. This test must be negative to dispense study medication. 
4. Randomized patients will receive a 14-day supply of study treatment. Patients will be instructed to start taking 
their study medication the next day in the morning, i.e. on Day 1, and for 14 consecutive days, until Day 14 
inclusive. 
5. Patients will be given a new BM and BSFS diary for Period 1, in which they will need to record daily the number 
of stools and their form, using the BSFS, for Days 1 to 14 inclusive. Proper instructions will be provided for the 
use of the BSFS.  They will also be provided the BM/BSFS diary for the Washout period, to be completed during 
Days 15 to 28. 
6. Patients will be given a VAS questionnaire to complete on site. The four 11-point VAS scales (from 0 to 10), will 
be used by the patients to make an overall assessment of diarrhea, abdominal pain, bloating and urgency 
experienced during the last 24 hours. Zero will mean no symptom at all, and 10: very severe. The VAS assessments 
will be made at Days 0, 15, 28 and 43, but not during screening. 
9.2.4  Period 1 Telephone Contact (Phone 2, Day 7)   
Each patient will be contacted by phone by the study coordinator, to inquire about the occurrence of AEs, 
concomitant medications, compliance to study treatment and use of the BM and BSFS diary. 
9.2.5  Washout (Visit 3, Day 15) 
On the first day of the Washout period (Day 15), patients will return to the clinic with their BM and BSFS diaries, and 
the remaining study medication.  Patients will arrive in the fasted state (i.e. fast for 4 hours before visit). The following 
assessments and procedures will be performed:  
 
1. Complete physical examination; 
2. Measurement of vital signs including heart rate, blood pressure and body temperature; 
3. Measurement of body weight, and calculation of BMI; 
4. All safety laboratory tests, including: urinalysis (dipstick), hematology, serum chemistry; 
5. Recording of concomitant medications; 
6. Study drug compliance check – patients will return all study medication from Period 1 to the study coordinator. 
Drug accountability will be performed. 
7. Verification of completion of the BM and BSFS diary for Period 1, and start of diary for Washout. Patients will 
return the Period 1 diary and will be reminded to complete the Washout diary daily during Days 15 to 28. 
8. The VAS symptoms questionnaire will be completed by the patient on site. 
9. Recording of AEs and concomitant medications. 
 
During the Washout period (Days 15 – 28), patients will not be taking any study medication, for 14 consecutive days. 
Other concomitant medications can be maintained as long as their dose and doing regimen remain unchanged (See 


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Permitted Medications section for details). Patients will be instructed to keep using their BM/BSFS diary during the 
washout period to report the daily number of bowel movements as well as stool form using the BSFS. 
9.2.6  Washout Telephone Contact (Phone 3, Day 21)   
Each patient will be contacted by phone by the study coordinator, to inquire about the occurrence of AEs, 
concomitant medications, compliance to study treatment and use of the BM and BSFS diary. 
9.2.7  Washout (Visit 4, Day 28)   
On the last day of the Washout period (Day 28), patients will return to the clinical with their BM/BSFS diary. Patients 
will arrive in the fasted state (i.e. fast for 4 hours before visit). The following assessments and procedures will be 
performed: 
 
1. Complete physical examination; 
2. Measurement of vital signs including heart rate, blood pressure and body temperature; 
3. Measurement of body weight, and calculation of BMI; 
4. All safety laboratory tests, including at a minimum: urinalysis (dipstick), hematology, serum chemistry;  
5. A urine pregnancy test will be performed if applicable. This test must be negative to dispense study medication 
for Period 2. 
6. Recording of concomitant medications; 
7. Verification of the BM and BSFS Washout diary. The Washout diary will be given back to the patient and they will 
be instructed to continue using the diary for Day 28.  The patient will also be provided a new diary for Period 2. 
8. The VAS symptoms questionnaire will be completed by the patient on site. 
9. Recording of AEs; 
10. Study medication for Period 2 will be supplied at the end of the visit, with instructions to begin dosing on Day 29. 
9.2.8  Period 2 Telephone Contact (Phone 4, Day 35)   
Each patient will be contacted by phone by the study coordinator, to inquire about the occurrence of AEs, 
concomitant medications, compliance to study treatment and use of the BM/BSFS diary. 
9.2.9  End-of-Study (Day 43, Visit 5) 
At Day 43, the final clinic visit, all patients will return to the clinic with their BM and BSFS diaries, and the remaining 
study medication. Patients will arrive in the fasted state (i.e. fast for 4 hours before visit). The following assessments 
and procedures will be performed: 
 
1. Complete physical examination; 
2. Measurement of vital signs including heart rate, blood pressure and body temperature; 
3. Measurement of body weight, and calculation of BMI; 
4. A 12-lead ECG; 
5. All safety laboratory tests, including at a minimum: urinalysis (dipstick), hematology, serum chemistry; 
6. A urine pregnancy test will be performed if applicable;  
7. Recording of concomitant medications; 


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8. Study drug compliance check - patients will return all study medication from Period 2 to the study coordinator. 
Drug accountability will be performed.  
9. Verification of completion of the BM and BSFS diaries for Washout and for Period 2. The diaries will be given back 
to the study coordinator. 
10. The VAS symptoms questionnaire will be completed by the patient on site. 
11. Recording of AEs. 
 
AEs still ongoing at the time of the visit will be assessed and evaluated for further follow-up as necessary. SAEs 
occurring during the 30-day period following the End-of-Study, Day 43 visit, should be reported to the medical 
monitor. (See Serious Adverse Event Reporting section for details) 
10.  INVESTIGATIONAL PRODUCT MANAGEMENT  
10.1  Packaging, Labeling, and Shipping 
The Sponsor will be responsible for ensuring the Test and Placebo investigational products are manufactured in 
accordance with Good Manufacturing Practice (GMP); the labeling should also comply with applicable regulatory 
requirement(s). 
 
Study medication will be provided in patient kits containing enough medication for one period (14 days). Each patient 
kit consists of 2 labeled bottles packed inside a labeled carton. Patients randomized to “high” dose will receive 2 
bottles of ECC, and patients randomized to “low” dose will receive 1 bottle of ECC and 1 bottle of matching placebo. 
Study medication will be specifically identified and will bear instructions to ensure proper order of intake at all times. 
Each bottle and carton label will bear a unique number linked to a randomized medication list to identify the kit 
contents (i.e. high dose or low dose treatment). Both bottles contained within one kit will have the same number as 
the outer carton. The randomized medication list will be linked to the patient randomization schedule at the IWRS 
level. 
 
Each bottle and patient kit box will bear a label that conforms to the appropriate local regulations.  
 
Shipments of patient kits to the clinical sites will be done using a Sponsor-defined courier. A temperature data logger 
will accompany the shipment to ensure an adequate chain of custody. Excursions outside of 15oC to 30oC will be 
promptly reported to the Sponsor. 
10.2  Storage, Dispensing and Compliance Verification of Study Drug 
All patient kits will be shipped from the Sponsor or Sponsor resources to the clinical sites. 
Patient kits will be provided to study subjects only. 
 
Upon receipt of the patient kit shipper container, the pharmacy site staff should record the receipt, date, time, and 
temperature of the product based on inspection or on the temperature logger reading. Any study drug that arrives 
in improper storage conditions or is damaged in any way must be reported to the Sponsor as soon as possible and 
shall not be administered until instructed otherwise. Each clinical site will maintain an inventory record of the patient 
kits received, stored (in a secure restricted area), and dispensed. 
 


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At the clinical sites, patient kits are to be stored under labeled storage conditions in a secure location with limited 
access. Any temperature excursions outside of 15oC to 30oC will be promptly reported to the Sponsor.  
 
Upon instructions from the IWRS, the pharmacy site staff will, at the time of dispensing, formally identify and remove 
the assigned Patient Kit box(es) from storage and will cross-check the expiry date on the labels on the Patient Kit 
box(es) with the target dates of use, at a minimum. The necessary Patient Kits will be sent to the site staff actually 
dispensing the study drug to the patients. 
10.3  Study Drug Accountability 
At Visit 2, the patient will receive one Patient Kit box which will contain sufficient study drug for Period 1. At Visit 3, 
the patient will return to the site the Patient Kit box containing all the remaining study drug from Period 1.  The next 
dispensing visit is Visit 4 where the patient will receive another Patient Kit box which will contain sufficient study 
drug for Period 2. At the End-of-Study visit, the patient will return to the site the Patient Kit box containing all the 
remaining study drug from Period 2.  If a patient withdraws or discontinues from the trial, they will be requested to 
return all study supplies promptly.  
 
Complete and accurate records regarding the receipt, dispensing, and return or destruction of study drug for each 
patient in the study will be kept. Any used study drug containers, as well as any unused containers or unused portions 
of containers, or patient kits must be maintained until accounted for by the study monitor. Drug accountability will 
be performed at the end of each period to confirm that the required amount of study drug has been consumed.  If 
the amount of study drug is not as expected, the patient will be contacted for clarification. After drug accountability 
by the monitor and approval from the Sponsor, the study drug and containers should be destroyed per the CRO’s 
procedures. 
11.  TREATMENT AND PROTOCOL COMPLIANCE 
Patients are expected to self-administer oral daily doses based on the protocol schedule and have all procedures 
done within the allowable time windows (detailed in the Schedule of Activities).  
 
Regardless of allowable visit windows, each period or study drug treatment cycle should always be 14 calendar days. 
Investigational drug will then be supplied for this 14 consecutive days period. A 14-day treatment-free period 
(Washout) will be included between the 2 dosing periods. 
In the event a patient misses a scheduled assessment visit, this should be rescheduled for the earliest possible date, 
no more than 2 days later. Patients who are persistently noncompliant may be withdrawn from the study at the 
investigator’s or the Sponsor’s discretion. 
 
The following measures will be employed to ensure treatment and protocol compliance: 
 
• 
Patients will be given clear instructions prior to study drug dispensing on how to self-administer the study drugs. 
• 
Patients will be given clear instructions and reminders during each visit and telephone contact on how to use the 
BSFS and BM diary.  
• 
Patients will be contacted by telephone on Days -8, 7, 21 and 35 to confirm continued compliance with the dosing 
regimen, use of concomitant medication, and use of BM/BSFS diaries. 
• 
BM/BSFS diaries will be checked for compliance at each visit. 


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11.1  Permitted and Prohibited Concomitant Medications  
The standard of care for patients with SBS includes several medications, nutritional recommendations and 
procedures destined to improve their quality of life, treat symptoms and prevent complications. This section outlines 
the general study-specific requirements in terms of concomitant medications, vitamin supplements and potential 
drug interactions.  
11.2  Permitted Medications 
All standard of care drugs will be permitted, unless they are listed in the Prohibited Medications List section. 
However, dose and dosing regimen of permitted drugs must remain constant during the whole study duration, until 
Day 42. 
11.3  Prohibited Medications 
After consulting the protocol, in case of doubt about a patient’s concomitant medication, study personnel should 
consult with the Sponsor before enrolling/pursuing participation of a patient on study. If a medication other than 
those specified in the protocol (including OTC) is used after the first treatment administration or at any time before 
the end of the study, the Sponsor will decide whether the subject will be permitted to remain in the study, depending 
on the drug used, the time of drug intake, etc. The drug and dose taken will be noted. 
Prohibited medications include: 
• 
H2 receptors antagonists: cimetidine, famotidine, ranitidine and nizatidine (should be stopped at least 72 hours 
prior to Day 0 visit) 
• 
Pancrelipase supplements  
• 
Prostaglandin E drugs, such as misoprostol (should be stopped at least 24 hours prior to Day 0 visit) 
• 
Over the counter antacid medications, containing:  bismuth salts, aluminium and magnesium hydroxide, sodium 
alginate, sodium bicarbonate, etc. (should be stopped at least 24 hours prior to Day 0 visit) 
• 
Drugs used to treat Diarrhea Predominant Irritable Bowel Syndrome (IBS-D), such as: alosetron (Lotronex), 
eluxadoline (Viberzi), rifaximin (Xifaxan), lubiprostone (Amitiza), linaclotide (Linzess) and trimebutine (Modulon) 
(should be stopped at least 72 hours prior to Day 0 visit) 
• 
Antispasmodic drugs, such as dicyclomine (should be stopped at least 24 hours prior to Day 0 visit) 
• 
Prokinetic drugs, such as: domperidone and metoclopramide (should be stopped at least 48 hours prior to Day 0 
visit) 
• 
Any kind of pre-, and probiotics (should be stopped at least 72 hours prior to Day 0 visit) 
• 
Bile acids sequestrants, such as regular cholestyramine, colestipol and colesevelam (should be stopped at least 
72 hours prior to Day 0 visit) 
• 
Any kind of orally administered antibiotics, unless judged absolutely necessary by the investigators (should be 
stopped at least 72 hours prior to Day 0 visit) 
• 
Gut trophic factors such as growth hormone and GLP-2 are also prohibited (should be stopped at least 48 hours 
prior to Day 0 visit) 
• 
Products containing cannabinoids. 
 


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12.  EFFICACY ASSESSMENTS 
12.1  Weekly Number of Bowel Movements  
The total number of bowel movements (defecations) occurring during the second week of ECC treatment (Days 8 to 
14) compared those occurring during screening in the week prior to randomization, will be used to assess the primary 
endpoint. Use of loperamide will also be recorded. Bowel movements will be recorded by the patients on a daily 
basis, as follows: 
 
- each day of the last 14 days of the screening period, prior to randomization, to establish the first baseline and 
confirm subject eligibility 
- each day of the first 14-day treatment period 
- each day of the 14-day washout period 
- each day of the second 14-day treatment period 
 
In summary, this implies that occurrences of bowel movements will be recorded daily by the patient, in the diary, 
from Day -14 (screening) up to Day 42, i.e. the last dosing day of the study.  
12.2  Bristol Stool Form Scale 
The Bristol Stool Form Scale (BSFS) is a diagnostic medical tool designed to categorize and score the form of human 
stools into seven categories (30,31). It is used mostly in clinical research. It is sometimes also referred to as the Bristol 
stool chart (BSC), Bristol stool form scale, or BSF scale.  
 
It was developed at the Bristol Royal Infirmary as a clinical assessment tool in 1997, and is widely used as a research 
tool to evaluate the effectiveness of treatments for various diseases of the bowel, especially Irritable Bowel 
Syndrome and chronic constipation. BSFS scores of 6 or 7 indicate diarrhea.  
 
 




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13.         SAFETY ASSESSMENT 
Safety evaluations will include reporting of Adverse Events (AEs), clinical laboratory assessments (clinical chemistry, 
hematology and urinalysis), ECGs, and clinical evaluation of vital signs and physical examinations performed at 
regular intervals during the study. 
 
All AEs will be assessed, documented, and reported in accordance with ICH GCP guidelines. 
13.1   Documentation of Adverse Events 
AEs will be collected from the time of informed consent signing until the last scheduled study follow-up. From 
screening to the first dose of the study, AEs will be recorded as screening events or as part of the medical history, as 
applicable. An AE is any untoward medical occurrence (which does not necessarily have a causal relationship with 
the treatment). An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of an investigational product, whether or not 
related to the study drug. This includes any occurrence that was new in onset or aggravated in severity or frequency 
from the baseline condition. Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was screened in the study are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the study (e.g. surgery was performed earlier than planned).   
 
Abnormal results of diagnostic procedures, including laboratory test abnormalities, are considered AEs if they result 
in any one of the following:   
• 
Discontinuation of study treatment; 
• 
Require treatment or any other therapeutic intervention; 
• 
The necessity for further diagnostic evaluation (excluding a repetition of the same procedure to confirm the 
abnormality); 
• 
Association with clinical signs or symptoms that may have a significant clinical impact, as determined by the 
Investigator.  
 
Patients are encouraged to report AEs spontaneously or in response to general, non-directed questioning. All AEs are 
to be followed until resolution or until a stable clinical endpoint is reached. The investigator should question patients 
about AEs and changes in pre-existing illnesses since their last visit and must record the information in the patients’ 
medical records. The onset and end dates, severity, relationship to study agent, action taken, and outcome must be 
recorded for each AE. All AEs are to be recorded on the appropriate e-CRF and in detail on the source documents. 
 
SAEs must be reported immediately to the medical monitor, i.e. no later than 24 hours after they are known.  AEs 
that are ongoing at the end of the study should be marked as ongoing. However, it is the responsibility of the 
Investigator to follow up on these events until resolution, according to standard medical care.  Any SAE that the 
investigator becomes aware of outside of the study period should be reported to the medical monitor, for a period 
up to 30 days post-last investigational drug dose.   
 
Patients who experience AEs will be monitored with relevant clinical assessments and laboratory tests, as determined 
by the Investigator. All AEs and laboratory abnormalities encountered during the study should be followed until 
resolution or stabilization of the event(s). Any action taken and follow-up results must be recorded in the patient’s 


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medical record. Follow-up laboratory results should be filed with the patient’s source documentation and e-CRF. For 
all AEs that require the patient to discontinue treatment, relevant clinical assessments and laboratory tests should 
be repeated on at least a monthly basis until final resolution or stabilization of the event(s). These assessments should 
be captured in the source data and SAE forms but will not be entered in the e-CRF. 
 
All AEs for randomized patients will be recorded in the e-CRF and the patient's source documents. AEs for patients 
who are screened but not subsequently randomized in the study will be recorded only in the patient's source 
documents. The following data should be documented for each AE:  
• 
Description of the event; 
• 
Classification of "serious" or "not serious"; 
• 
Date of first occurrence and date of resolution (if applicable); 
• 
Severity; 
• 
Causal relationship to study drug(s); 
• 
Action taken; 
• 
Outcome; 
• 
Concomitant medication or other treatment given.   
13.2  Adverse Event Severity 
The severity of an AE should be determined according to the definitions below. Clinically significant laboratory tests 
should be recorded as AEs in the patient's source documents and e-CRF.  
 
Severity will be assessed according to the following criteria: 
Classification 
Definition 
Mild (Grade 1) 
Mild level of discomfort and does not interfere with regular 
activities 
Moderate (Grade 2) 
Moderate level of discomfort and significantly interferes with 
regular activities 
Severe (Grade 3) 
Significant level of discomfort and prevents regular activities 
Life-threatening (Grade 4) 
Any adverse drug experience that places the patient, in the view 
of the investigator, at immediate risk of death 
 
 
 


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13.3    Adverse Event Causality 
Causality will be assessed according to the following criteria: 
Classification 
Definition 
Definitely Related 
Reasonable temporal relationship to study drug administration 
Follows a known response pattern (i.e., drug is known to cause 
this AE) 
There is no alternative etiology 
Probably Related 
Reasonable temporal relationship 
Follows a suspected response pattern (i.e., based on similar 
drugs) 
Little or no evidence for a more likely alternative etiology 
Possibly Related  
Reasonable temporal relationship 
Some evidence for a more likely alternative etiology 
Unrelated 
Does not have a temporal relationship. Or, 
Definitely due to alternative etiology 
 
ICH guidelines (March, 1995) clarify “reasonable causal relationship” to mean “that there are facts [evidence] or 
arguments to suggest a causal relationship.” 
 
The causality assessment must be made by the Investigator based on information available at the time that the 
AE/SAE worksheet is completed. The initial causality assessment may be revised as new information becomes 
available. 
13.4    Study Drug Action Taken 
The investigator will classify the study drug action taken with regard to the AE. The action taken should be classified 
according to the categories shown below: 
 
Classification 
Definition 
Dose Not Changed 
Study drug dose not changed in response to an AE; 
Drug Withdrawn 
Study drug administration permanently discontinued in response 
to an AE; 
Not Applicable 
Action taken regarding study drug administration does not apply. 
"Not applicable" should be used in circumstances such as when 
the investigational treatment had been completed before the AE 
began and no opportunity to decide whether to continue, or 
withdraw treatment is possible. 
 
 
 


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13.5    Adverse Event Outcome 
An AE should be followed until the investigator has determined and provided the final outcome. The outcome should 
be classified according to the categories shown below: 
 
Classification 
Definition 
Recovered/Resolved 
Resolution of an AE with no residual signs or symptoms 
Recovered/Resolved with 
Sequelae 
Resolution of an AE with residual signs or symptoms 
Not Recovered/Resolved 
(Continuing) 
Either incomplete improvement or no improvement of an AE, 
such that it remains ongoing 
Fatal 
Outcome of an AE is death. "Fatal" should be used when death is 
at least possibly related to the AE 
Unknown 
Outcome of an AE is not known (e.g., a patient lost to follow-up) 
13.6    Treatment Administered 
The Investigator will ensure adequate medical care is provided to patients for any AEs, including clinically significant 
laboratory values related to study drug. In addition, the Investigator will describe whether any treatment was 
administered for the AE. "Yes" is used if any treatment was administered in response to an AE and may include 
treatments such as other medications, hospitalization, surgery, or physical therapy. "No" indicates the absence of 
any kind of treatment for an AE. 
13.7    Clinically Significant Assessments 
Study assessments including safety laboratory tests, ECGs, and vital signs should be assessed and those deemed a 
clinically significant worsening from baseline documented as an AE. When possible, a clinical diagnosis for the study 
assessment should be provided rather than the abnormal test result alone (e.g. urinary tract infection, anemia). In 
the absence of a diagnosis, the abnormal study assessment itself should be listed as the AE (e.g. bacteria in urine or 
decreased hemoglobin).  
 
An abnormal study assessment is considered clinically significant if the patient has one or more of the following: 
• 
Concomitant signs or symptoms related to the abnormal study assessment; 
• 
Further diagnostic testing or medical/surgical intervention; 
• 
Discontinuation from study drug treatment.  
 
Repeat testing to determine whether the result is abnormal, in the absence of any of the above criteria, does not 
necessarily meet clinically significant criteria. The determination of whether the study assessment results are 
clinically significant must be made by the Investigator. A laboratory abnormality judged to be Grade 4, in itself, may 
not constitute a SAE unless the clinical status of the patient indicates a life-threatening AE. 
 
 


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13.8  Serious Adverse Events 
SAEs are generally any AEs that result in one or more of the following:   
• 
Fatal (death, regardless of cause, that occurs during participation in the study or occurs after participation in the 
study but within 30 days post-study, and is suspected of being a delayed toxicity due to administration of the 
study drug); 
• 
Is immediately life-threatening (i.e., presents an immediate risk of death at the time of the AE, not an AE that 
hypothetically might have caused death if it were more severe);  
• 
Requires or prolongs inpatient hospitalization; 
• 
Causes persistent or significant disability/incapacity; 
• 
Is a congenital anomaly/birth defect; 
• 
Other important medical events that may jeopardize the patient and/or require medical or surgical intervention 
to prevent one of the outcomes listed above. 
 
Definition of Inpatient Hospitalization: 
An inpatient hospitalization is defined as an admission for any length of time. A hospitalization for administration of 
study drug, for routine or planned clinical procedures, or for “social” reasons (not the result of any adverse change 
in the patient’s condition) should not be considered an AE and should not be reported as a SAE. If the patient 
experiences any adverse change in condition during hospitalization, the condition must be reported as an AE or SAE 
according to the above definitions. 
 
Definition of Life-Threatening Adverse Experience: 
An adverse experience is life-threatening if the patient was at immediate risk of death from the event as it occurred 
(i.e., it does not include a reaction that, had it occurred in a more serious form, might have caused death). For 
example, drug-induced hepatitis that resolved without evidence of hepatic failure would not be considered life-
threatening, even though drug-induced hepatitis can be fatal. 
 
Definition of Disabling/Incapacitating Experience:  
An adverse experience is incapacitating or disabling if the experience results in a substantial and/or permanent 
disruption of the patient’s baseline ability to carry out normal life functions.  
13.9    Serious Adverse Event Reporting  
Any SAE that occurs during this study, including death from any cause, must be reported by the Investigator (or 
designee) to the medical monitor within 24 hours of awareness of occurrence, regardless of causality or 
expectedness.  The initial notification must contain a description of the observed symptoms and an assessment of 
causality. Initial reports must be followed up by a written detailed report and submitted within 24 hours of the 
occurrence of the SAE.  The designated contact for SAE reporting is the medical monitor: 
 
 
Neox Clinical Research 
V Jámě 1, 110 00 Praha 1, Czech Republic 
Tel: 
 
Fax: 
 
Email: 
  
PI
PI
PI
PI


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It is imperative that the medical monitor be informed (by email) within 24 hours of a SAE so that SAE reporting to the 
applicable health authorities can be met within the required time frame. The medical monitor will be responsible for 
evaluating the reported events for completeness and accuracy and will follow-up with the clinical site for any 
information missing. The medical monitor or designee will also be responsible for expedited reporting to the 
applicable health authorities, regulatory agencies and independent ethics committees (IECs)/institutional review 
boards (IRBs).  The medical monitor or designee will be responsible for notifying the Sponsor of SAEs as specified in 
the safety and communications plans. 
 
Because of the need to report to health authorities all serious adverse reactions in a timely manner, it is vitally 
important that an Investigator report immediately any adverse experiences which would be considered serious, even 
if the Investigator does not consider the adverse experience to be clinically significant or drug related. Should the 
Investigator become aware of a SAE (regardless of relationship to study drug) that occurs within 30 days after the 
last dose of the study drug, the SAE must be reported in accordance with the procedures specified in this protocol.  
 
All SAEs that are not resolved by the end of the study, or that were not resolved upon discontinuation of the patient’s 
participation in the study, are to be followed until the SAE resolves, the SAE stabilizes, the SAE returns to baseline 
values (if a baseline value is available), or it is shown that the SAE is not attributable to the study drug or study 
conduct.  
13.10    Suspected Unexpected Serious Adverse Reactions (SUSAR)  
SUSARs are SAEs that are possibly related or related to the study drug and are unexpected (i.e., not listed in the 
Investigator’s Brochure). SUSARs will be collected and reported expeditiously, by the Investigator (or designee) to 
the medical monitor (i.e. within 24 hours of occurrence) who will then report to the competent authorities and 
independent ethics committees (IECs)/institutional review boards (IRBs) according to regulations, and to the Sponsor 
as per the safety and communications plans. Medical and scientific judgment of the Investigator is to be exercised in 
deciding whether expedited reporting is appropriate in other situations, such as for important medical events that 
are not immediately life-threatening or do not result in death or hospitalization, but jeopardize the patient or the 
patient population.  
13.11   Pregnancy 
Females of childbearing potential who have a negative pregnancy test and are enrolled in the study are to continue 
contraception until 30 days after the last administration of study drug.  If the subject becomes pregnant during the 
study, the study drug should be immediately discontinued, and the Investigator should report the pregnancy to the 
medical monitor immediately.  The Investigator should counsel the subject with regard to the possible untoward 
effects on the fetus.  The subject will be withdrawn from the study and end of study visit performed as soon as 
possible.   The subject should be monitored until the conclusion of the pregnancy.  The outcome of all pregnancies 
must be followed up and documented even if the subject was discontinued from the study.   
 
Pregnancies are considered immediately reportable AEs (within 24 hours).  All reports of congenital 
abnormalities/birth defects are SAEs.  Spontaneous miscarriages should also be reported and handled as SAEs. 
 


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13.12    Clinical Laboratory Assessments 
Blood and urine samples will be collected according to the Schedule of Activities (Section 2) and analyzed at each 
individual clinical site. Specific instructions for the collection, processing, and shipment of samples are presented in 
the Study Laboratory Manual. Laboratory test results that are abnormal and considered clinically significant by the 
Investigator or designee must be reported as AEs. Screening laboratory results must be available and reviewed by 
the Investigator before randomization. The safety laboratory test panels are shown in Table 2 below. 
 
Table 2 - Laboratory Tests Panels 
 
Serum Chemistry 
Hematology 
Urinalysis (dipstick)* 
Albumin 
Hematocrit 
Nitrite 
Creatinine 
Hemoglobin 
Urobilinogen 
Total protein 
Red blood cells 
Protein 
Potassium 
Platelet count 
pH 
Sodium 
Leukocytes 
Blood 
Calcium 
WBC Differential (absolute and %) 
Leukocytes  
Bicarbonate 
Eosinophils 
Density 
Phosphate 
Basophils 
Ketones 
Alkaline phosphatase 
Neutrophils 
Bilirubin 
ALT 
Lymphocytes 
Glucose 
AST 
Monocytes 
 
Total bilirubin 
 
Other (Urine) 
Uric acid 
 
Appearance (clarity and color) 
Glucose 
 
 
Total cholesterol 
 
 
Triglycerides 
 
 
Lipase 
 
 
 
* If dipstick urine is positive for leukocytes, nitrite, urobilinogen, protein, or blood, microscopic examination of urine 
will be performed for further evaluation. 
 
In addition, according to the Schedule of Activities, the following tests are also performed: 
 
• 
Pregnancy (β-human chorionic gonadotropin) tests for females of childbearing potential: Serum or urine samples 
will be obtained as specified in the Schedule of Activities (Section 2) and analyzed at the local labs (serum and 
urine). The urine pregnancy tests on Day 0 and Day 28 must be negative before dispensing of study drug. A 
positive result during the study will result in immediate interruption of study drug. 


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13.13    Medical History, Vital Signs and Physical Examinations 
The medical history at screening will include all queries by the medical and clinical staff related to the subject’s well-
being and history of relevant past medical events/experiences. Medical history will include all demographic data 
(age, gender, race, body weight adjusted for indoor clothing, height, and BMI) and baseline characteristics. Alcohol 
and smoking habits will also be recorded. History of intestinal surgical resection or other possible cause of SBS, all 
recent and current medications and therapies, non-prescription drug intake, and home parenteral nutrition if still 
administered, will be recorded. Particular attention will be paid to obtaining the history of diarrhea in the 3 months 
prior to screening, including estimated weekly bowel movement frequency and stool morphology (using the BSFS). 
This will help in establishing a background diarrhea pattern and confirming patient eligibility for the study. 
 
Vital signs and complete physical examinations will be performed by a medically qualified and licensed individual 
according to the Schedule of Activities (Section 2). 
 
A complete physical examination (review of all body systems) will be performed at screening and Days 15, 28 and 43 
visits.  
A complete physical examination includes a review of the following systems: head/neck/thyroid, 
eyes/ears/nose/throat, respiratory, cardiovascular, lymph nodes, abdomen, skin, musculoskeletal, and neurological. 
Breast, anorectal, and genital examinations will be performed only when medically indicated. Clinically significant 
physical examination findings prior to the first dose of study drug will be recorded as medical history; after first dose, 
any clinically significant abnormal findings in physical examinations should be reported as AEs. 
 
Vital signs include blood pressure (systolic and diastolic), heart rate and body temperature. These will be assessed 
following a 5-minute rest (seated) and before any scheduled blood sample collection.  
13.14  Electrocardiograms 
Standard, digital 12-lead ECGs will be performed twice, i.e. during screening and at the End-of Study, Day 43 visit.  
Sites will use their own ECG equipment.  
 
Performance of all ECGs must adhere to the following guidelines in order to minimize variability and consistent 
assessments of each patient. ECG recording will be read and interpreted by an internal medicine specialist, at each 
participating clinical site. 
 
• 
ECGs will be performed after the patient has been supine for at least 5 minutes; 
• 
The ECG will be performed before any other procedures that may affect heart rate;  
• 
The ECG will be performed during the screening period and on Day 43. 
 
A hard copy of the ECG will be printed and signed by the Investigator at the site.  
 
14.   STATISTICAL ANALYSIS 
A statistical analysis plan (SAP) will provide details of the methods of analysis to address all study objectives. The SAP 
may be amended during the course of the study but will be finalized before the database hard-lock for any analysis.  


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Data summaries by treatment group will be presented. For continuous variables, data will be summarized with the 
number of patients, mean, standard deviation, median, and minimum and maximum values by treatment group. For 
categorical variables, data will be tabulated in frequency tables to display the number and proportion of patients for 
each category by treatment group. Baseline assessments for each outcome variable will be defined as the last 
measurement obtained before the first dose of study drug. 
14.1   Sample Size Determination 
This is a cross-over trial in which patients will be randomized to two different sequences of treatment. 
The primary outcome measure will be the change in the weekly frequency of bowel movements between baseline 
and Week 2 of treatment (ie. Days 8 to 14, and Days 36 to 42).  Efficacy will be assessed as the difference vs. baseline 
as well as the difference between the two treatments.  
 
Given that this is a cross-over study, patient will serve as their own control and the statistical analysis will be based 
on matched comparisons. Depending on the distribution of the difference between the two treatments the 
parametric Paired Student’s t-test, or non – parametric Wilcoxon’s sign rank test will be used. The current sample 
size computation will be based on the parametric test, since this is more conservative and hence demanding of a 
higher sample size. 
 
The following assumptions have been employed: 
i. 
The mean change in the lesser efficacious treatment will be 4 bowel movements per week. 
ii. 
The SD for the change in bowel movements per week will be 2.0 based on extrapolation of results from 
the literature (32). 
iii. 
The correlation of the changes between the two treatments will be 0.80 given that there is a strong 
patient effect on bowel movements. Hence the SD of the difference between treatment groups is 1.265 
assuming an SD of 2.00 for each treatment group. 
iv. 
The significance level will be 0.05. 
v. 
The power of the study will be 80%. 
vi. 
The effect size to be detected will be between 10% and 25%. 
vii. 
Adjustment of 20% has been considered to compensate for attrition. 
 
The following table describes the sample size requirements (number of patients) for the study by different effect 
size.  
 
 
 


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Table 3 - Sample Size Requirements by Size Effect 
 
ECC - A 
ECC - B 
Percent 
Difference (%) 
Absolute 
Difference 
Sample 
Size 
4.00 
4.40 
10 
0.40 
81 
4.00 
4.44 
11 
0.44 
67 
4.00 
4.48 
12 
0.48 
57 
4.00 
4.52 
13 
0.52 
49 
4.00 
4.56 
14 
0.56 
43 
4.00 
4.60 
15 
0.60 
37 
4.00 
4.64 
16 
0.64 
33 
4.00 
4.68 
17 
0.68 
30 
4.00 
4.72 
18 
0.72 
27 
4.00 
4.76 
19 
0.76 
24 
4.00 
4.80 
20 
0.80 
22 
4.00 
4.84 
21 
0.84 
20 
4.00 
4.88 
22 
0.88 
19 
4.00 
4.92 
23 
0.92 
17 
4.00 
4.96 
24 
0.96 
16 
4.00 
5.00 
25 
1.00 
15 
 
Values are the mean change in bowel movement frequency (number of bowel movements per week) between 
baseline and Week 2. Higher values indicate a greater reduction in stool frequency. 
 
Based on the above assumptions and assuming a 25% difference between treatments, a total sample size of 18 
patients is recommended.  It is expected that about 6 patients will be randomized at each of the 3 participating 
clinical sites. 
 
With 18 patients, we will have more than 80% power to detect a minimal reduction in the weekly number of bowel 
movements by 4.  
14.2  Analysis Populations 
• 
The intent-to-treat (ITT) population will include all randomized patients who complete the baseline 
evaluations, including those who are not exposed to study drug. The ITT population will be used for the 
primary analyses of all efficacy endpoints. Analysis will be done by randomized treatment. 
• 
The per-protocol (PP) population will include all randomized patients who (i) are administered all study 
medication, in both study periods, in accordance with the protocol, including receipt of the two study drug 
doses in the randomized sequence, receipt of all dispensed study drug as described in the protocol, and non-
use of medications prohibited by the protocol; (ii) have available information for the assessment of the 
primary endpoint, i.e. available weekly number of bowel movements at baseline and Week 2. The PP 
population will serve as the basis for secondary analyses of all efficacy endpoints. 


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For the purposes of identifying the PP analysis population, the protocol deviations/violations compiled during 
the study will be reviewed prior to database lock and, based on the PP definition above, will be classified as 
major vs. minor. Review of the relevant data available in the database will also be conducted to identify the 
patients to be included in the PP population. 
• 
The safety population will include all randomized patients who received at least one dose of study drug 
treatment. This population will serve as the basis for analyses of all safety endpoints. Analysis will be done 
by actual treatment received. 
14.3  Baseline and Demographic Characteristics 
Demographic and baseline data will be summarized by treatment group using descriptive statistics. Demographics 
will include, among others, age, gender, ethnicity, weight, height, body mass index. Childbearing status and 
pregnancy test results will be summarized descriptively for each treatment group.  
 
The demographics and baseline characteristics summary will be presented for the ITT and the PP populations to allow 
review of the characteristics of those included in the efficacy analyses.  
 
Prior and Concomitant Medications 
 
Medications used in this study will be coded by using the World Health Organization Drug Dictionary and categorized 
as follows:  
• 
Prior medication: Any medication that started before the first dose of study drug, independently of when it 
ended. 
• 
Concomitant medication: Medication continued or newly received at or after first dose of study drug to the last 
follow-up. 
 
A given medication can be classified using the above, in one or more categories. If a medication has a missing or 
partial missing start/end date or time and it cannot be determined whether the medication was taken before the 
first dose of study drug or concomitantly, it will be considered as concomitant medication. Prior medications and 
concomitant medications will be summarized descriptively based on the ITT population.  
14.4  Study Drug Exposure 
The duration of study drug exposure is defined as follows: Last dose date minus first dose date plus 1 day, regardless 
of any interruptions in dosing. If the last dose date of study drug is missing, the patient's discontinuation or 
completion date will be used for analysis purpose. Duration of study drug exposure will be summarized descriptively 
as a continuous variable (number, mean, SD, median, minimum, and maximum), by study group, using the safety 
population. 
14.5  Study Drug Compliance 
Study drug compliance will be assessed at the end of each treatment period. Treatment compliance percentages will 
be summarized descriptively as continuous variables (number, mean, SD, median, minimum, and maximum) using 
the ITT and PP populations. The percentage of patients whose compliance is <80% or ≥80% will also be summarized, 
by study group. 


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14.6  Efficacy Analysis  
14.6.1  Analysis of Primary Endpoint  
For the primary objective of the study, descriptive statistics will be produced for the change in weekly frequency of 
bowel movements between baseline and the second week of treatment. A sequential analysis approach will be used 
where: 
a. First, the efficacy of the High ECC dose (4.25 g daily) will be tested using a paired Student’s t-test 
and a null hypothesis of 0. If this comparison shows a statistically significant improvement, then 
the efficacy of the Low ECC dose will be tested.  
b. To assess the efficacy of Low ECC dose (1.7 g daily) a paired Student’s t-test and a null hypothesis 
of 0 will be used, similarly to above. If this comparison shows a statistically significant 
improvement, then the two doses will be compared. 
c. To compare the efficacy of the two doses, the absolute change in weekly frequency of bowel 
movements will be compared using a paired Student’s t-test and a null hypothesis of 0 (δHigh – δ
Low = 0). 
d. Given the sequential design of the analysis correction for multiplicity will not be required.  
 
If the change in weekly frequency of bowel movements between baseline and the second week of treatment does 
not follow the normal distribution the non-parametric Wilcoxon signed rank test will be used.  
 
The primary analysis will be conducted on the ITT population. The PP population will be used in a secondary analysis.  
14.6.2  Analysis of Secondary Efficacy Endpoints 
For all secondary endpoints, no official statistical hypothesis will be tested, and statistical comparisons may be 
conducted for exploratory purposes only. 
 
• 
For the total number of bowel movements per week at week 1 and for the whole week 2 period, similar 
methods to those described for the primary endpoint will be used. 
 
• 
The mean daily stool form score according to BSFS will be summarized over time by treatment dose using 
descriptive statistics. The mean daily score during the first week, second week and during the whole 2-week 
period of treatment will be compared to the baseline score using the paired Student’s t-test or the Wilcoxon 
signed rank test, as appropriate based on the data distribution. 
 
• 
For the total number of bowel movements with a BSFS ≥6 after 1 and 2 weeks of treatment and for the Mean 
Diarrhea Composite Index, descriptive statistics will be used by treatment dose. Within-group comparisons 
with the baseline values and between-group comparisons will be conducted as described in the primary 
endpoint. 
  
• 
The proportion of patients treated with loperamide will be described by treatment dose and among treated 
patients the mean daily dose of loperamide in mg will be summarized. 
 
• 
Overall evaluation of diarrhea, abdominal pain, urgency and bloating will be summarized over time by 
treatment dose using descriptive statistics. Within-group comparisons with the baseline score will be 
conducted using the paired Student’s t-test or the Wilcoxon signed rank test, as appropriate. 
 


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14.7  Safety Analyses  
All safety data will be included in subject data listings. Summary tables will be based on the safety population. No 
statistical comparisons will be conducted. 
14.7.1  Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, version 21.1 or later).  
 
For the purpose of analyses and tabulations, AEs will be classified as pretreatment AEs, TEAEs, or post-treatment 
AEs. More specifically: Pretreatment AE are those that started before the first dose of study drug. TEAE are those 
that increased in severity (compared to pre-treatment) or that appeared at or after the first dose of study drug but 
before the last follow-up of each period. Post-treatment AEs are those that increased in severity or that appeared 
after the last follow-up, planned for 4 weeks after the last dose of study drug. For AEs with missing or incomplete 
start dates, if there is no clear evidence that the AEs started before or after the first dose of study drug, then the AEs 
will be classified as TEAEs.  
 
AE summary tables, including the number and percentage of patients with at least one AE overall and by MedDRA 
system organ class (SOC) and preferred term (PT), will be presented by treatment group for TEAE only and will include 
the following: All TEAEs, TEAEs by relationship, TEAEs by maximal severity, TEAEs leading to treatment 
discontinuation, serious TEAEs and fatal TEAEs. All AEs, including pre-and post-treatment AEs, will be presented in 
individual patient data listings. For these summaries, patients with multiple events will be counted only once per PT. 
For the TEAEs by relationship and TEAEs by maximal severity, at each level of summarization, the event with the 
strongest drug relationship and highest level of severity, respectively, will be presented. 
 
All AEs must be listed. In addition, separate listings will be provided for patients who die, experience a SAE, or 
discontinue the study because of an AE. These listings will include treatment, patient’s age and gender, duration of 
follow-up, amount of ECC received, and time since last intake.  
14.7.2  Clinical Laboratory Assessments 
Safety laboratory variables (e.g., hematology, biochemistry, and urinalysis results) will be presented in the 
International System of units at each time point using descriptive statistics (mean, standard deviation, median, 
minimum, and maximum). Change from baseline values for each variable will also be presented by treatment group. 
The number and percentage of patients with shift changes from baseline (normal, high, and low according to the 
reference range as provided by the laboratories) to post-baseline will be tabulated by treatment group. 
14.7.3  Vital Signs 
 
Vital signs (blood pressure, temperature and heart rate) will be presented at each time point using descriptive 
statistics (mean, standard deviation, median, minimum, and maximum). Change from baseline values for each 
variable will also be presented by treatment group.  
 
The number and percentage of patients with shift changes from baseline to post-baseline based on abnormal criteria 
will be presented by treatment group.  


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14.7.4  ECG 
For ECG measurements, a summary of raw values at baseline and end of study and change from baseline values will 
be provided for the following standard digital ECG measurements: PR, QT, and QT corrected for heart rate (QTc) 
intervals, QRS duration, and HR. The number and percentage of patients with shift changes from baseline (normal, 
not clinically significant, and potentially clinically significant according to overall ECG evaluation as provided by the 
laboratories) to end of study will be tabulated.  
 
In addition, the number and percentage of patients with QT/QTc intervals values of ≤500msec and >500msec, as well 
with changes from baseline in the value of QT/QTc intervals by >30msec will also be tabulated. 
15.  DATA HANDLING AND RECORD KEEPING 
15.1  Case Report Forms  
All patient data generated by the study will be recorded in each patient’s e-CRFs. Data reported on the e-CRFs that 
are derived from source documents should be consistent with the source documents or the discrepancies should be 
explained. e-CRFs will be considered complete when all missing and/or incorrect data have been resolved and all 
safety data have been recorded. 
 
The Investigator, or designated representative, should complete the e-CRF as soon as possible after information is 
collected. e-CRFs must be completed only by persons designated by the Investigator. The e-CRF system should enable 
an audit trail that will provide the user's identification information and the date and time of any entry/correction. 
The completed e-CRF will be reviewed by the Sponsor, study monitor or Sponsor’s designees on a routine basis. 
 
The Investigator must approve formally (via signature) all the information in the e-CRFs for the patients for whom 
he/she is responsible. 
 
A copy of the e-CRFs will be provided to the Sponsor with the final report. 
 
Subjects who do not meet protocol criteria will be entered on a screening/enrolment log and no e-CRF will be 
completed. 
15.2  Source Documentation 
Source documents are considered to be all information in original records and certified copies of original records of 
clinical findings, observations, data, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study. The Investigator and designees agree to maintain accurate e-CRFs and source documentation 
as part of the case histories. Source documents are the originals of any documents used by the Investigator, sub-
Investigator, or hospital/institution that will allow verification of the existence of the patient and substantiate the 
integrity of the data collected during the trial. All data entered into the e-CRF also must be available in the source 
documents. The Investigator will allow designated representatives of the Sponsor and regulatory bodies to have 
direct access to the source documents to verify the data reported in the e-CRFs in the course of trial-related 
monitoring, audits, IRB/IEC review and regulatory inspections. 


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15.3  Record Retention  
Study records and source documents must be retained for at least 25 years after the completion or discontinuation 
of/withdrawal from the study, or 2 years after the last approval of a marketing application in an International 
Conference on Harmonization (ICH) region, whichever is the longest time period.  If it becomes necessary for the 
Sponsor to review any documentation relating to the study, the Investigator must permit access to such records.   
 
The Investigator should contact the Sponsor before destroying any records pertaining to the study to ensure they no 
longer need to be kept. 
15.4  Data Management and Processing 
Data management activities will be performed using the Omnicomm Trial Master electronic data capture (EDC) 
software in accordance with the data management facility’s SOPs. 
Data entered will be checked for accuracy through QC checks. When the database is declared to be complete and 
accurate, it will be locked. 
16.  MONITORING 
In accordance with current applicable regulations, Good Clinical Practice (GCP), and the Sponsor’s Standard 
Operational Procedures, monitors from the CRO will contact the site before the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and Sponsor 
requirements. When reviewing procedures for data collection, the discussion will include identification, agreement, 
and documentation of data items which will be recorded in each patient’s e-CRF. 
 
The study will be monitored to ensure the following: 
• 
Data are authentic, accurate, and complete; 
• 
The safety and rights of patients are being protected; 
• 
The study is being conducted in accordance with the currently approved protocol, any other study agreements, 
GCP, and all applicable regulatory requirements.  
 
The Investigator and the head of the medical institution (where applicable) agree to allow the monitor direct access 
to all relevant documents. 
17.  QUALITY CONTROL AND QUALITY ASSURANCE 
The Sponsor’s designee will perform the quality assurance and quality control activities of this study. Designated 
personnel from the quality assurance unit(s) of the clinical facility will be responsible for maintaining QA systems to 
ensure that the trial is conducted and that clinical data is generated, documented and reported in compliance with 
the protocol and ICH Guideline E6 for GCP. 
 
Designated personnel from the corresponding operation unit (usually of the clinical and statistical facilities) will be 
responsible to maintain and assure the quality control (QC) of all data generated and documented in compliance with 
the protocol.  However, responsibility for the accuracy, completeness, and reliability of the study data presented to 
the Sponsor lies with the principal or qualified Investigator generating the data. 
 


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The Sponsor or its designated representative will conduct a study site visit to verify the qualifications of the principal 
Investigator and sub-Investigators, inspect clinical site facilities as needed, and inform the Investigator of 
responsibilities and procedures for ensuring adequate and correct study documentation. 
 
Study data for randomized patients will be entered into an e-CRF by clinical site staff using a secure, validated web-
based electronic data capture (EDC) application. Select data for patients not randomized will also be collected in e-
CRFs.  
 
Instances of missing, discrepant, or uninterpretable data will be queried with the Investigator for resolution. Any 
changes to study data will be enacted in the e-CRF and documented in an audit trail, which will be maintained within 
the clinical database. 
 
18.  COMPLIANCE, PROTOCOL AMENDMENT AND DEVIATION 
18.1  Compliance 
An application dossier for the commencement of a clinical trial, must be submitted to the national competent 
authorities of Poland and the Ethics Committees, prior to the start of the study.  The authorization to conduct the 
clinical trial must be obtained prior to initiation of any screening activities, including ICF signature. 
 
It is very important that no modifications to the protocol be made without prior approval from the Sponsor. Changes 
that significantly affect the safety of the patients, the nature, the scope and the scientific integrity of the study will 
require IRB/IEC notification/approval before their implementation. Exceptions are cases where the modification is 
necessary to abrogate an apparent immediate risk to the patients. The Sponsor’s designee will submit all protocol 
modifications to IRB/IEC and the required regulatory authorities. When there is a need for immediate deviation from 
procedures enunciated in the protocol, the Investigator will contact the Sponsor to discuss the course of action and 
possible alternatives, if at all possible, before any implementation of changes. Any deviation from protocol must be 
fully documented in the source documentation and in the study documentation on protocol deviations. 
18.2  Protocol Amendment  
Administrative amendments to the protocol will be classified as amendments of typographical errors, clarifications 
of confusing wording, name changes, and minor modifications that have no impact on the safety of the patients or 
the science of the study. Administrative amendments will be submitted to the IRB/IEC for information only. JSS 
Medical Research will ensure that acknowledgement is received and filed. Any other amendment will be classified as 
a substantial amendment and will be submitted by the Sponsor’s designee to the appropriate regulatory authorities 
and the IRBs/IECs for approval. 
18.3  Protocol Deviation 
Should a protocol deviation occur, the Sponsor must be informed as soon as possible. Important protocol deviations 
and their reasons will be summarized in the clinical study report. In accordance with applicable regulatory authority 
mandates, the Investigator is responsible for reporting protocol deviations to the IRB/IEC.  


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19.  STUDY TERMINATION 
At any time, the Sponsor may terminate this study in its entirety or at a specific clinical site. In addition, for reasonable 
cause, the IRB/IEC and/or the Investigator at a clinical site may terminate the study at their center.  In such cases, 
the Sponsor should be informed immediately and if at all possible, before implementation. 
 
Conditions that may lead to reasonable cause and warrant termination include, but are not limited to:  
• 
Investigator noncompliance and/or lack of adherence to protocol procedures; 
• 
Unsatisfactory patient enrollment; 
• 
Lack of evaluable and/or complete data; 
• 
Potentially unacceptable risk to patients;  
• 
Changes in the Sponsor’s drug development plans; 
• 
Decision by regulatory authorities. 
 
The reason(s) for clinical study termination must be properly documented. If the trial is prematurely terminated or 
suspended for any reason, the clinical site or the qualified investigator (or delegate) should promptly inform the trial 
subjects, should assure appropriate therapy and follow-up for the subjects and should inform the regulatory 
authority(ies) when required. 
20.  ETHICAL CONSIDERATIONS 
This study will be conducted in compliance with the study protocol, the ethical principles that have their origins in 
the Declaration of Helsinki, ICH Guideline E6 for Good Clinical Practice (GCP), the FDA GCP Code of Federal 
Regulations (CFR) Title 21 (part 56), the European regulation EU 536/2014, the Tri-Council Policy Statement (Canada) 
and Division 5 part C section of Health Canada. 
 
IRB/EC committees will review and approve this protocol and informed consent forms.  Substantial amendments to 
the protocol and ICF will be submitted to the IRB/EC and written approval will be obtained prior to implementation.  
All patients must provide signed informed consent where applicable, before participation in the study. Before 
screening activities commence, each subject will be given a copy of the ICF to read, as well as a full explanation of 
the purpose of the study, the procedures to be carried out, and the potential AE(s). Once this essential information 
is provided to the subject and the physician in charge or delegate has the conviction the subject understands the 
implications of participating in the study, and if the subject chooses to continue the screening process, they will be 
requested to sign and date a properly executed ICF. Subjects will be assured they may withdraw from the study at 
any time without jeopardizing their medical care or future study participation (for which they qualify). Subjects will 
be given a signed copy of the ICF. If an amended or revised ICF is introduced during the study, each subject’s further 
consent must be obtained. 
 
This study will be performed by qualified clinical investigators and in accordance with GCP. The study specifically 
incorporates all of the following features:  
• 
Multicenter, randomized study design; 
• 
Prospectively stated objectives and analytical plan; 
• 
Accepted, pre-specified outcome measures for safety and efficacy; 
• 
A detailed protocol to promote consistency across sites; 


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• 
Compliance with current GCP, with assessment via regular monitoring; 
• 
Quality assurance procedures performed at study sites and during data management to ensure that safety and 
efficacy data are adequate and well documented. 
 
This protocol and the ICF will be submitted to an Institutional Review Board (IRB) (or Independent Ethics Committee 
(IEC)) prior to initiation of the study and the study will not start until the Board has approved the documents. 
Notification of the Board’s approval will be appended to the final report.  The study will only be conducted at sites 
where IRB/IEC approval has been obtained. The protocol, Investigator's Brochure, sample ICF, advertisements (if 
applicable), written information given to the patients, safety updates, annual progress reports, and any revisions to 
these documents will be provided to the IRB/IEC by the Sponsor’s designee, as allowable by local applicable laws and 
regulations. 
 
The investigators and the Sponsor will preserve the confidentiality of all subjects taking part in the study, in 
accordance with GCP and local regulations. Subjects should be identified by a unique subject identifier on all study 
documents provided to the sponsor. In compliance with local regulations/ICH GCP Guidelines, it is required the 
investigator and institution permit authorized representatives of the company, of the regulatory agency(s), and IRB 
access to review the subject’s original medical records for verification of study-related procedures and data. The 
investigator is obligated to inform the subject that his/her study-related records will be reviewed by the above-
named representatives without violating the subject’s confidentiality. 
21.  FINANCE AND INSURANCE 
Financial aspects of the study are addressed in a separate clinical study agreement.  
 
The Investigator/institution is required to have adequate current insurance to cover claims for negligence and/or 
malpractice according to national regulations. The Sponsor’s designee will provide insurance coverage for the clinical 
study as required by national regulations.  This should include sufficient insurance coverage should any serious events 
or deaths result, either directly or indirectly, from the execution of the present protocol. 
 
The present article is not to be interpreted as engaging the Sponsor’s responsibility in the event of fault or negligence 
of the subjects, investigators, or any persons or employees under the control of the clinical site. 
22.  PUBLICATION POLICY AND CLINICAL STUDY REPORT 
22.1  Confidentiality and Publication Policy 
Both the use of data and the publication policy are detailed within the clinical study agreement. 
Any and all scientific, commercial, and technical information disclosed by the Sponsor in this protocol or any other 
documents and communications should be considered the confidential and proprietary property of the Sponsor. The 
Investigator shall hold such information in confidence and shall not disclose the information to any third party except 
to the Investigator's staff on a “need to know” basis, as long as the said staff has been made aware that the 
information is confidential and who are bound to treat it as such.  
 
The Investigator shall not use any and all information for any purpose other than determining interest in performing 
the study and, if the parties decide to proceed with the study, for the purpose of conducting the study. The 


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Investigator understands that the information developed from this clinical study will be used by the Sponsor for the 
development of the study drug and therefore may be disclosed as required to other clinical Investigators, potential 
and current business partners and associates, Health Canada, the FDA, and possibly other regulatory agencies. The 
Investigator also understands that, to allow for the use of the information derived from the clinical study, he/she has 
the obligation to provide the Sponsor with complete results and accompanying data developed in the study. 
 
No publication or disclosure of study results will be permitted except under the terms and conditions of a separate 
written agreement between the Sponsor and the Investigator and/or the Investigator's institution. 
22.2  Clinical Study Report 
A full clinical study report, written in accordance with the ICH E3 Guideline, will be submitted in accordance with 
local regulations.  
 
 


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APPENDIX 1: Sample Bowel Movement and BSFS Diary