Clinical trial NCT04991311
Conditions: Short Bowel Syndrome
Sponsor: Zealand Pharma
Start date: 2021-08-10; Completion date: 2023-09-05
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this trial is to investigate the long-term effect of glepaglutide on the intestinal absorption, nutritional status of participants with Short Bowel Syndrome (SBS). The trial will also investigate whether glepaglutide is safe during long-term use. All participants in the trial will receive glepaglutide injections.

Participants will have 14 visits with the study doctor. At 2 of these, participants will spend 48 hours at the trial site, one visit at the start of the trial and one after 24 weeks of treatment with glepaglutide. At all visits, participants will meet with trial staff and will have blood tests along with other clinical checks and tests done. Participants will be asked about their health and medical history.

Detailed description:

Arms: arm 1: All participants will receive 10 mg of glepaglutide as once-weekly injections under the skin (subcutaneous, s.c.)
Interventions: intervention 1: Glepaglutide
Intervention descriptions: intervention 1: Glepaglutide will be delivered in a single-use autoinjector.

Protocol documents:
Prot_000.pdf: 
Zealand Pharma 
Clinical Trial Protocol 
Glepaglutide 
Confidential 
Page 1 of 79 
V3.0, 02Jul2021 
CLINICAL TRIAL PROTOCOL 
Protocol Title: A Single-Center Phase 3b Trial Investigating the Long-term Effect on Intestinal 
Absorption, Nutritional Status and Long-Term Safety of treatment with Glepaglutide in Patients 
with Short Bowel Syndrome (SBS) 
Protocol Number: ZP1848-20060 
Substance: Glepaglutide 
Trial Phase: 3b 
Short Title: The long-term effect on intestinal absorption and safety of treatment with 
Glepaglutide in patients with short bowel syndrome 
Acronym: EASE SBS 4 
Sponsor Name: Zealand Pharma A/S 
Legal Registered Address: Sydmarken 11, DK-2860 Søborg, Denmark 
Regulatory Agency Identifier Numbers: 
EudraCT Number: 2020-005194-27 
Universal Trial Number: U1111-1260-2961 
Approval Date: 02 Jul 2021 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by 
applicable laws and regulations. In any event, persons to whom the information is disclosed must 
be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you 
which is indicated as privileged or confidential. 




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TABLE OF CONTENTS 
SIGNATORY PAGE .................................................................................................................. 2 
1 
PROTOCOL SUMMARY ........................................................................................ 7 
1.1 
Synopsis ....................................................................................................................... 7 
1.2 
Flow Chart ................................................................................................................. 11 
2 
INTRODUCTION ................................................................................................... 16 
2.1 
Trial Rationale ........................................................................................................... 16 
2.2 
Background................................................................................................................ 16 
2.3 
Benefit/Risk Assessment ........................................................................................... 17 
2.3.1 
Risk Assessment ........................................................................................................ 17 
2.3.2 
Benefit Assessment ................................................................................................... 19 
2.3.3 
Overall Benefit: Risk Conclusion .............................................................................. 20 
3 
OBJECTIVES AND ENDPOINTS ........................................................................ 21 
4 
TRIAL DESIGN ...................................................................................................... 23 
4.1 
Overall Design ........................................................................................................... 23 
4.2 
Scientific Rationale for Trial Design ......................................................................... 24 
4.3 
Justification for Dose ................................................................................................. 25 
4.3.1 
Safety ......................................................................................................................... 25 
4.3.2 
Efficacy...................................................................................................................... 25 
4.4 
End of Trial Definition .............................................................................................. 26 
5 
TRIAL POPULATION ........................................................................................... 27 
5.1 
Inclusion Criteria ....................................................................................................... 27 
5.2 
Exclusion Criteria ...................................................................................................... 27 
5.3 
Lifestyle Consideration ............................................................................................. 28 
5.3.1 
Dietary Restrictions ................................................................................................... 28 
5.3.2 
Smoking ..................................................................................................................... 29 
5.4 
Screen Failures .......................................................................................................... 29 
5.5 
Dosing Criteria .......................................................................................................... 29 
6 
TREATMENTS ....................................................................................................... 30 
6.1 
Treatment Administered ............................................................................................ 30 
6.1.1 
Trial product administration ...................................................................................... 30 
6.2 
Handling/Storage/Accountability .............................................................................. 30 
6.2.1 
Handling and Storage ................................................................................................ 30 
6.2.2 
Accountability ........................................................................................................... 31 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....................................... 31 
6.4 
Treatment Compliance .............................................................................................. 32 
6.4.1 
Drug Treatment Compliance ..................................................................................... 32 
6.4.2 
Compliance with 48-hour Drinking Menu ................................................................ 32 
6.5 
Concomitant Therapy ................................................................................................ 32 
6.6 
Prohibited Medication ............................................................................................... 33 
6.7 
Dose Modification ..................................................................................................... 33 
6.8 
Treatment After the End of the Trial ......................................................................... 33 
7 
DISCONTINUATION OF TRIAL PRODUCT AND PATIENT 
WITHDRAWAL...................................................................................................... 34 
7.1 
Discontinuation of Trial Treatment ........................................................................... 34 


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7.2 
Patient Withdrawal from the Trial ............................................................................. 34 
7.2.1 
Replacement of Patients ............................................................................................ 35 
7.3 
Lost to Follow-up ...................................................................................................... 35 
8 
TRIAL ASSESSMENTS AND PROCEDURES................................................... 36 
8.1 
Demographics and Other Baseline Characteristics ................................................... 36 
8.1.1 
Demographics ............................................................................................................ 36 
8.1.2 
SBS Characteristics and History ............................................................................... 36 
8.1.3 
Body Weight and Height ........................................................................................... 37 
8.1.4 
Medical History/Concomitant Illness ........................................................................ 37 
8.1.5 
Concomitant Medication ........................................................................................... 37 
8.1.6 
Colonoscopy .............................................................................................................. 37 
8.1.7 
COVID-19 Management ........................................................................................... 38 
8.2 
Efficacy Assessments ................................................................................................ 39 
8.2.1 
Metabolic Balance Study ........................................................................................... 39 
8.2.2 
Fixed Fluid Intake...................................................................................................... 40 
8.2.3 
48-hour Urine Volume .............................................................................................. 40 
8.2.4 
Patient Diary .............................................................................................................. 41 
8.2.5 
Absorption of Wet Weight/Fluids ............................................................................. 42 
8.2.6 
Absorption of Energy ................................................................................................ 42 
8.2.7 
Absorption of Macronutrients ................................................................................... 42 
8.2.8 
Absorption of Electrolytes ......................................................................................... 42 
8.2.9 
Weekly PS Volume (SBS-IF Only) ........................................................................... 42 
8.2.10 
Weekly PS Macronutrients and Electrolytes (SBS-IF Only) .................................... 43 
8.2.11 
Body Weight .............................................................................................................. 43 
8.2.12 
Body Composition by DEXA .................................................................................... 43 
8.2.13 
Citrulline .................................................................................................................... 43 
8.2.14 
Aldosterone................................................................................................................ 44 
8.2.15 
Hemoglobin A1c ....................................................................................................... 44 
8.2.16 
eGFR, Creatinine Clearance and Liver Function Tests ............................................. 44 
8.2.17 
Patient Reported Outcomes ....................................................................................... 44 
8.2.18 
Microbiome Composition .......................................................................................... 45 
8.2.19 
Weekly PS Macronutrients and Electrolytes: Change from baseline to Week 52 
(SBS-IF Only) ........................................................................................................... 45 
8.2.20 
Weekly Days on PS (SBS-IF Only) .......................................................................... 45 
8.2.21 
Fluid Composite Effect.............................................................................................. 45 
8.2.22 
Urine Output (SBS-II Only) ...................................................................................... 45 
8.2.23 
Drinking Volume During 48-hour Periods ................................................................ 46 
8.3 
Safety Assessments ................................................................................................... 46 
8.3.1 
Body Weight .............................................................................................................. 46 
8.3.2 
Physical Examinations............................................................................................... 46 
8.3.3 
Vital Signs ................................................................................................................. 46 
8.3.4 
Electrocardiograms .................................................................................................... 47 
8.3.5 
Clinical Safety Laboratory Assessments ................................................................... 47 
8.3.6 
Immunogenicity Assessments ................................................................................... 48 
8.4 
Adverse Events and Serious Adverse Events ............................................................ 48 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ..................... 48 
8.4.2 
Method of Detecting AEs and SAEs ......................................................................... 49 
8.4.3 
Follow-up of AEs and SAEs ..................................................................................... 49 


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8.4.4 
Regulatory Reporting Requirements for SAEs ......................................................... 50 
8.4.5 
Pregnancy .................................................................................................................. 51 
8.4.6 
Adverse Events of Special Interest ............................................................................ 51 
8.4.7 
Other Important Events ............................................................................................. 53 
8.4.8 
Technical Complaints ................................................................................................ 53 
8.4.9 
Precautions ................................................................................................................ 53 
8.5 
Treatment of Overdose .............................................................................................. 53 
8.6 
Pharmacokinetics ....................................................................................................... 54 
8.7 
Pharmacodynamics .................................................................................................... 54 
8.8 
Genetics ..................................................................................................................... 54 
8.9 
Biomarkers ................................................................................................................ 54 
8.10 
Health Economics ...................................................................................................... 54 
8.11 
Unscheduled Visits .................................................................................................... 54 
9 
STATISTICAL CONSIDERATIONS ................................................................... 55 
9.1 
Statistical Hypotheses ................................................................................................ 55 
9.2 
Sample Size Determination ....................................................................................... 55 
9.3 
Analysis Sets ............................................................................................................. 56 
9.4 
Statistical Analyzes ................................................................................................... 56 
9.4.1 
General Considerations ............................................................................................. 56 
9.4.2 
Demographics and Baseline Characteristics ............................................................. 57 
9.4.3 
Primary Endpoint - Absorption of Wet Weight/Fluids ............................................. 57 
9.4.4 
Secondary Endpoints ................................................................................................. 57 
9.4.5 
Exploratory Endpoints ............................................................................................... 58 
9.4.6 
Other Safety Analyzes ............................................................................................... 58 
9.4.7 
Other Analyses .......................................................................................................... 58 
9.5 
Interim Analyzes ....................................................................................................... 58 
9.6 
Data Monitoring Committee (DMC) ......................................................................... 58 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 59 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations ..................... 59 
10.1.1 
Regulatory and Ethical Considerations ..................................................................... 59 
10.1.2 
Financial Disclosure .................................................................................................. 59 
10.1.3 
Liability and Insurance .............................................................................................. 59 
10.1.4 
Informed Consent Process ......................................................................................... 60 
10.1.5 
Data Protection .......................................................................................................... 60 
10.1.6 
Committees Structure ................................................................................................ 61 
10.1.7 
Dissemination of Clinical Trial Data ......................................................................... 61 
10.1.8 
Data Quality Assurance ............................................................................................. 61 
10.1.9 
Source Documents ..................................................................................................... 63 
10.1.10 
Trial and Site Start and Closure ................................................................................. 63 
10.1.11 
Responsibilities.......................................................................................................... 64 
10.1.12 
Publication Policy ...................................................................................................... 65 
10.2 
Appendix 2: Clinical Laboratory Tests ..................................................................... 66 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .......................................................................................... 67 
10.3.1 
Definition of AE ........................................................................................................ 67 
10.3.2 
Definition of SAE ...................................................................................................... 67 


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10.3.3 
Recording and Follow-Up of AE and/or SAE ........................................................... 69 
10.3.4 
Reporting of SAEs ..................................................................................................... 71 
10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information ..... 72 
10.5 
Appendix 5: Abbreviations........................................................................................ 75 
11 
REFERENCES ........................................................................................................ 77 
 
TABLE OF TABLES 
Table 1 
Flowchart.................................................................................................................. 11 
Table 2  Flowchart for 48-hour Metabolic Balance Study ................................................. 14 
Table 3 
Flowchart of PK sampling ...................................................................................... 15 
Table 4 
Objectives and Endpoints. ...................................................................................... 21 
Table 5 
Trial Product ............................................................................................................ 30 
Table 6 
Sample Collection during Metabolic Balance Study ............................................ 39 
Table 7 
Analyzes on Collected Material in Metabolic Balance Study .............................. 40 
Table 8 
Timing of 48-hour periods and balance studies .................................................... 41 
Table 9 
Power calculation of a One-Sample t-test for different effect sizes .................... 56 
Table 10 Analysis Sets ............................................................................................................. 56 
Table 11 Laboratory Assessments ......................................................................................... 66 
 
TABLE OF FIGURES 
Figure 1 
Overall Trial Design .............................................................................................. 23 
Figure 2 
Exposure-Response Curve .................................................................................... 26 
 
 
 
Protocol attachment I: Study Contacts 


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Glepaglutide 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Rationale 
The purpose of the present phase 3b trial is to investigate the long-term effect on the intestinal 
absorption, nutritional status and the long-term safety of treatment with glepaglutide in patients 
with SBS. 
The efficacy assessments in the ongoing phase 3 program are focused on the effects of 
glepaglutide on reduction of parenteral support (PS) volume and content in patients with SBS 
with intestinal failure (SBS-IF) with at least 3 days of PS at baseline. The present phase 3b trial 
serves to investigate the effect of glepaglutide on absorption of fluids, micro- and macro 
nutrients in patients with SBS with intestinal insufficiency (SBS-II) and SBS-IF employing the 
gold standard of metabolic balance studies. 
Trial period 
Estimated date first patient first visit (FPFV): Q3, 2021 
Estimated date last patient last visit (LPLV): Q4, 2023 
Objectives and Endpoints 
Primary Objective 
• To demonstrate the 24-week effect of glepaglutide on the absorption of fluids. 
Secondary Objectives 
• To assess the effects of glepaglutide on absorption of energy, absorption of the individual 
macronutrients and absorption of electrolytes. 
• To evaluate the long-term efficacy of glepaglutide in patients with SBS. 
• To describe the long-term safety of glepaglutide. 
Exploratory Objectives 
• To investigate the effect of treatment with glepaglutide on nutritional status, organ 
function and fluid balance. 
• To investigate the effect of treatment with glepaglutide on patient reported outcomes. 
• To investigate the microbiome composition of patients with SBS. 
• To investigate the pharmacokinetics of glepaglutide. 
Primary Endpoint 
• Absorption of wet weight/fluids: Change from baseline to Week 24 assessed by 48-hour 
metabolic balance studies. 
Secondary Endpoints 
Key Secondary Endpoint 
• Absorption of energy (oral intake minus fecal excretion): Change from baseline to Week 
24 measured by 48-hour metabolic balance studies. Energy absorption is measured by 
bomb calorimetry. 


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Secondary Efficacy Endpoints 
• Absorption of individual macronutrients (carbohydrates, lipids and proteins): Change 
from baseline to Week 24 measured by 48-hour metabolic balance studies. 
• Absorption of electrolytes (sodium, potassium, calcium and magnesium): Change from 
baseline to Week 24 measured by 48-hour metabolic balance studies. 
• For patients with SBS-IF only: 
o Weekly PS volume: Change from baseline to Week 12 and 24. 
o Weekly PS macronutrients (carbohydrates, lipids and proteins) and 
electrolytes (sodium, potassium, calcium, and magnesium): Change from 
baseline to Week 12 and 24. 
Safety Endpoints 
• Treatment-emergent adverse events until follow-up at Week 56. 
• Immunogenicity (anti-glepaglutide antibodies, reactivity to ZP18481-34, cross-reactivity to 
glucagon-like peptide [GLP]-2, glepaglutide neutralizing antibodies) at baseline (W0), 
Week 4, 12, 24, 52, and 56. 
Exploratory Endpoints 
• Body weight: Change from baseline to Week 12, 24 and 52. 
• Body composition (lean body mass, fat mass and bone mineral content) by dual-energy 
X-ray absorptiometry (DEXA): Change from baseline to Week 12, 24 and 52. 
• Citrulline: Change from baseline to Week 12, 24 and 52. 
• Aldosterone: Change from baseline to Week 12, 24 and 52. 
• Estimated glomerular filtration rate (eGFR), creatinine clearance and liver function tests: 
Change from baseline to Week 12, 24 and 52. 
• Hemoglobin A1c (HbA1c): Change from baseline to Week 4, 12, 24 and 52. 
• Patient reported outcome (PRO) (patient’s global impression of change [PGIC]). At 
Week 12, 24 and 52. 
• PRO: SBS -impact scale (SBS-I) and EQ-5D-5L. Change from baseline to Week 12, 24 
and to Week 52. 
• Pharmacokinetic (PK) parameters (t½ and Ctrough). 
• To investigate the luminal- and mucosae-associated microbiota of patients with SBS from 
baseline to Week 24. 
• Urinary excretion of electrolytes (sodium, potassium, calcium, magnesium) and urea: 
Change from baseline to Week 24. 
• Fluid Composite Effect: Change from baseline to Week 12, 24 and 52. 
• Drinking volume during 48-hour periods: Change from Week 24 to 52. 
• For patients with SBS-IF only: 
o Weekly PS volume: Change from baseline to Week 52. 
o Weekly PS macronutrients (carbohydrates, lipids and proteins) and 
electrolytes (sodium, potassium and magnesium): Change from baseline to 
Week 52. 
o Weekly days on PS: Change from baseline to Week 12, 24 and 52. 


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• For patients with SBS-II only: 
o Urine output: Change from baseline to Week 12, 24 and 52. 
Overall Design 
This is a single-center, single-arm, fixed dose, phase 3b trial to investigate the long-term effect 
on intestinal absorption and nutritional status and assess long-term safety of treatment with 
glepaglutide in patients with SBS. 
The main inclusion criteria are: 
• Age ≥ 18 years and ≤ 90 years at screening. 
• Stable condition of SBS either with intestinal failure (IF) or intestinal insufficiency. For 
patients with SBS-IF, a stable condition is defined as < 25% change in PS volume or 
energy content for 4 weeks prior to screening. 
• Stable body weight (<5% change in weight in the 3 months prior to screening). 
• Wet weight of fecal excretion ≥1,500 g/day demonstrated during a hospital stay prior to 
screening. 
The main exclusion criteria are: 
• More than 2 SBS-related or PS-related hospitalizations (e.g., catheter-related 
bacteremia/sepsis, bowel obstruction, severe water-electrolytes disturbances, etc.) within 
6 months prior to screening. 
• Poorly controlled inflammatory bowel disease (IBD) that is moderately or severely active 
or fistula interfering with measurements or examinations required in the trial. 
• Current bowel obstruction. 
• Known radiation enteritis or significant villous atrophy, e.g., due to active celiac disease. 
• Cardiac disease defined as: decompensated heart failure (New York Heart Association 
[NYHA] Class III-IV), unstable angina pectoris, and/or myocardial infarction within the 
last 6 months prior to screening. 
• Any history of colon cancer. History of any other cancers (except margin-free resected 
cutaneous basal or squamous cell carcinoma or adequately treated in situ cervical cancer) 
unless disease-free state for at least 5 years. 
• Use of GLP-1, GLP-2, human growth hormone (HGH), somatostatin, or analogs thereof, 
within 3 months prior to screening. 
Number of Patients 
A minimum of 6 and a maximum of 16 patients are planned to be enrolled in the trial (see 
Section 9.2). Patients with SBS-II and SBS-IF will be included in the trial, with an aim of an 
equal distribution between the 2 groups (see Section 5). A screen failure rate of 10% is expected, 
hence, a maximum of approximately up to 18 patients are expected to be screened. 
Treatment Groups and Duration 
This is a single-arm, fixed dose trial and all patients will receive the same treatment. 
The trial consists of a screening period of up to 3 weeks, a treatment period, during which all 
trial patients will receive treatment of glepaglutide for 52 weeks, and a follow-up period of 4 
weeks. 


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The trial treatment is provided in single-use autoinjector containing 0.5 mL of a clear, 
essentially colorless solution for injection, containing 20 mg/mL glepaglutide. Patients will 
receive 10 mg glepaglutide once-weekly as a subcutaneous injection. 
Data Monitoring Committee 
No Data Monitoring Committee will be established in this trial. 
 


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1.2 
Flow Chart 
Table 1 
Flowchart 
Procedure 
Screening 
Treatment Period 
EoT 
Follow-
up 
Visit 
SCR 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
FU 
Visit day or week 
 
Day -3 to 
day 1 
(W0) 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W32 
W40 
W52 
W56 
Time window (days) 
Up to 21 days 
before V1. 
 
±2 
±3 
±5 
±5 
±5 
±7 
±7 
±7 
±14 
±14 
±14 
±14 
Visit type: Site (S), In-house (I) 
S 
I 
S 
S 
S 
S 
S 
S 
S 
I 
S 
S 
S 
S 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
SBS characteristics and history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and BMI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/concomitant  
illness3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG (12 lead)  
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Vital signs4 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Physical examination5 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
Colonoscopy 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory parameters 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting requirement 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
HIV, Hepatitis B and C screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                 
1 Informed consent must be signed before any other trial-related activities. 
2 Eligibility criteria to be checked prior to initiating 48-hour Metabolic Balance Study. 
3 Also includes patient history of drug and/or alcohol abuse, information on smoking and current alcohol consumption. Concomitant illness to be divided into SBS-related or not. 
4 Pulse rate, blood pressure and body temperature. 
5 Full physical examination at Screening. At the other visits, an abbreviated examination will be performed driven by SBS. 
6 Patients with a remnant colon are required to have a colonoscopy as part of the screening procedures and the follow-up visit (Week 56). Colonoscopy results must be available for Visit 1. 
Colonoscopies performed up to 6 months prior to screening are acceptable. If a remnant colon is present, but a colonoscopy may not be appropriate, a computerized tomography (CT) scan, 
colon capsule endoscopy (CCE) or magnetic resonance imaging (MRI) will suffice at the discretion of the Investigator. 


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Procedure 
Screening 
Treatment Period 
EoT 
Follow-
up 
Visit 
SCR 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
FU 
Visit day or week 
 
Day -3 to 
day 1 
(W0) 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W32 
W40 
W52 
W56 
Time window (days) 
Up to 21 days 
before V1. 
 
±2 
±3 
±5 
±5 
±5 
±7 
±7 
±7 
±14 
±14 
±14 
±14 
Visit type: Site (S), In-house (I) 
S 
I 
S 
S 
S 
S 
S 
S 
S 
I 
S 
S 
S 
S 
Serum pregnancy test (hCG) 
(WOCBP only)  
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FSH7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine dipstick test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Hematology, biochemistry8  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Citrulline9 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Aldosterone 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Cholesterol and triglyceride 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
ADA10 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
HbA1c 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
PK, See Table 3 
 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Metabolic balance study 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection and measurement of urine, 
fecal output and food and liquids for 
analysis, see Table 2 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Efficacy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PS regimen (patients with SBS-IF 
only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Set drinking menu for 48-hour periods 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Registration of drinking and urine 
volumes during 48-hour periods11 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DEXA scan 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Microbiome composition12 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
Trial materials and reminders 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensing of trial product 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
                                                 
7 As needed in women of non-childbearing potential only. See additional information in Section 10.4. 
8 Magnesium and zinc should be measured at visit 1, 9 and 12 only.  
9 Blood samples for citrulline will be collected after a 10-hour (±1 hour) overnight fast (since app. 22:00h); water ad libitum is allowed. Smoking is not permitted the last 2 hours prior to blood 
sampling. 
10 ADA samples to be taken before dosing (if the dosing is on the day of site visit). A baseline sample must be taken pre-dose at day 1. 
11 48-hour period assessments should be performed within 7 days before each visit, except for V1 and V9. 
12 Samples to be taken as soon as possible, but after 12:00 on day of admission, prior to the 48h balance study. 


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Procedure 
Screening 
Treatment Period 
EoT 
Follow-
up 
Visit 
SCR 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
FU 
Visit day or week 
 
Day -3 to 
day 1 
(W0) 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W24 
W32 
W40 
W52 
W56 
Time window (days) 
Up to 21 days 
before V1. 
 
±2 
±3 
±5 
±5 
±5 
±7 
±7 
±7 
±14 
±14 
±14 
±14 
Visit type: Site (S), In-house (I) 
S 
I 
S 
S 
S 
S 
S 
S 
S 
I 
S 
S 
S 
S 
Dispensing of instructions for use13 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
 
Administration of trial product 
 
X 
 
 
 
 
 
 
 
X14 
 
 
 
 
Return of trial product 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
Handout of diaries and urine 
measuring cups 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Collection of diaries  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Handout of patient card 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGIC15 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
SBS-I15 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
EQ-5D-5L15 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
End of treatment 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
End of trial 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ADA = anti-drug antibodies; AE = adverse event; BMI = body mass index; DEXA = dual-energy x-ray absorptiometry; ECG = electrocardiogram; EoT = End of Treatment; FSH = follicle-
stimulating hormone; HbA1c = hemoglobin A1c; HIV = human immunodeficiency virus; in-house = hospital admission at site; PGIC = patient’s global impression of change; PK = 
pharmacokinetics; PS = parenteral support; SBS = short bowel syndrome; SBS-I = SBS impact scale; SBS-IF = SBS with intestinal failure; WOCBP = women of childbearing potential
                                                 
13 Patients to receive instructions orally and in writing. 
14 Trial product administration at visit 9 according to treatment schedule. 
15 Questionnaires must be completed at site visits prior to any other trial related assessment. It is recommended that the PGIC is completed first, followed by the SBS-I, then the EQ-5D 5L. All 
PROs are to be completed during treatment as indicated in the flowchart. 


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Table 2  Flowchart for 48-hour Metabolic Balance Study 
 
48-hour metabolic balance study (Visit 1 and Visit 9) 
Procedures 
Day 1 
Day 2 
Day 3 
Day 4 
Admission to hospital 
X 
(≥ 16 hours prior to 
metabolic balance samples 
collection start) 
 
 
 
Confirmation of eligibility 
X (Visit 1 only) 
 
 
 
Adverse events 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
ECG (12-lead) 
X 
 
 
 
Vital signs (blood pressure, pulse 
rate, temperature)1 
X 
X 
X 
X 
Body weight1 
X 
X 
X 
X 
Biochemistry 
X 
 
 
 
Hematology 
X 
 
 
 
Urinalysis 
X 
 
 
 
Serum pregnancy test (WOCBP 
only) 
X 
 
 
 
Citrulline 
X 
 
 
 
PK, see Table 3 
X 
X (Visit 9 only) 
X (Visit 9 only) 
X (Visit 9 only) 
Aldosterone 
X 
 
 
 
Cholesterol and triglyceride 
X 
 
 
 
ADA2 
X 
 
 
 
Fasting requirement (PS regimen 
allowed) 
X 
(start 22:00h ±30min) 
X 
(until start of MBS3 
collections) 
 
 
Urinate/ defecate/ empty stoma bag 
– prior to MBS collection start 
 
X (-15 min) 
 
 
Urinate/ defecate/ empty stoma bag 
– end of study 
 
 
 
X (-15 min) 
Start of balance study collection 
 
X 
 
 
Collection of urine 
 
X 
X 
X 
Collection of feces 
 
X 
X 
X 
Collection of duplicate food and 
liquids 
 
X 
X 
X 
End of collection 
 
 
 
X 
(48h from start ±1 
hour) 
Confirm drinking menu 
X (Visit 1 only) 
 
 
 
Fixed oral fluid intake 
 
X 
X 
X 
Define baseline PS type, volume, 
content4 
X (Visit 1 only) 
 
 
 
DEXA scan5 
 
X 
 
 
PGIC 
 
X (Visit 9 only) 
 
 
SBS-I 
 
X 
 
 
EQ-5D-5L 
 
X 
 
 
Luminal- and mucosa-associated 
microbiota6 
X 
 
 
 
Adjustment of PS (at visit 9 only, if 
applicable) 
 
 
 
X 
Trial product administration 
 
 
 
X (Visit 1) 7 
Trial product dispensing 
 
 
 
X 
Hospital discharge 
 
 
 
X 
                                                 
1 Body weight and vital signs will be performed at the same time point each day, in the morning prior to breakfast and by 
08:00 (±2 hour). 
2 ADA sample should be taken pre-dose at visit 1. At visit 9 the ADA sample should be taken as long time after last dose as 
possible and before next dosing during the admission. 
3 Metabolic Balance Study (MBS). 
4 Based on current weekly average PS volume. 
5 DEXA scan may be done on Day 2 or Day 3 to allow for study site flexibility. 
6 To be collected after 12:00 – preferably as close to 12:00 as possible. To be frozen at -80◦C as fast as possible. 
7 Trial product administration at visit 9 according to treatment schedule. 


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Table 3 
Flowchart of PK sampling 
Sample 
Sampling time 
V1 
V4 
V6 
V9 
V12 
EoT 
FU 
Day 1 Day 2 Day 3 Day 4 
PK 
Prior to administration 
1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Minimum 6 hours 
between samples on 
Visit 9, day 2 and day 3 
 
 
 
 
X 
X 
 
 
 
                                                 
1 To be collected prior to trial product administration if dosing occurs on the visit day. 


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2 
INTRODUCTION 
2.1 
Trial Rationale 
The purpose of the present phase 3b trial is to investigate the long-term effect on intestinal 
absorption, nutritional status and the long-term safety of treatment with glepaglutide in patients 
with SBS. 
The efficacy assessments in the ongoing phase 3 program are focused on the effects of 
glepaglutide on reduction of PS volume and content in patients with SBS with intestinal failure 
(SBS-IF) with at least 3 days of PS at baseline. The present phase 3b trial serves to investigate 
the long-term effect of glepaglutide on absorption of fluids, nutrients, electrolytes, and trace 
elements in patients with SBS with intestinal insufficiency (SBS-II) and SBS-IF employing the 
gold standard of metabolic balance studies. 
2.2 
Background 
Patients with SBS are characterized by reduced intestinal absorptive surface area due to 
extensive surgical bowel resection or congenital diseases, such as recurrent Crohn’s disease or 
mesenteric vascular disease (1,2,3,4), resulting in decreased absorptive capacity of the gut (5). 
This causes a reduced uptake of nutrients, fluids, electrolytes, vitamins, and trace elements, 
leading to difficulties with maintaining metabolic balances when receiving a conventional diet 
(6). The malabsorption can lead to dehydration, malnutrition, and weight loss if left untreated 
(7). 
Less severely affected SBS patients are able to compensate for their malabsorption by increasing 
oral intake (hyperphagia) and adapt metabolically or pharmacologically. These patients suffer 
from intestinal insufficiency (SBS-II). More severely affected patients with intestinal failure 
(SBS-IF) depend upon the safe and well-adjusted provision of PS of nutrients, fluids, 
electrolytes, vitamins, and trace elements to maintain body function, growth, homeostasis, and 
health (8). For those dependent on PS, it is life-sustaining but at the same time associated with 
life-threatening complications. Among those are catheter-related blood stream infections or 
sepsis (9), central vein thrombosis, liver damage (10), and renal impairment (11). In addition, the 
treatment burden of PS is substantial. Often 10-28 liters of PS per week are required. In addition 
to 10- to 12-hour overnight PS infusions in such patients, additional hours during daytime may 
be required to compensate for losses. While liberating patients during daytime, night-time 
infusions disturb sleep and exacerbate the need for nocturnal urination. Adding to the treatment 
burden, patients on PS often need frequent follow-up checks at the hospital, and for many there 
is a need for help from a homecare nurse. 
Glucagon-like peptide (GLP)-2 is a specific pro-adaptive factor that plays a role in enhancing 
small intestinal mucosal morphology, function, and integrity both under normal as well as 
pathophysiological conditions. Exogenous GLP-2 induces significant growth of the small 
intestinal mucosal epithelium via the stimulation of stem cell proliferation in the crypts and 
inhibition of apoptosis on the villi (12). This trophic effect of GLP-2 has been observed in 
numerous species, including humans (13). Additional effects of GLP-2 include inhibition of 
gastric emptying and gastric acid secretion, stimulation of nutrient absorption, enhancement of 
intestinal barrier function, and increase in intestinal blood flow (13,14,15,16,17,18,19). The short 
half-life of native GLP-2 of 5-7 minutes in circulation is a major drawback for its use in a 
therapeutic setting, and with the approval of teduglutide (US: Gattex®, EU: Revestive®) for the 


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treatment of adult patients with SBS to improve intestinal absorption of fluids and nutrients, the 
therapeutic relevance of a GLP-2 analog in SBS has been established. 
Glepaglutide is a potent, long-acting GLP-2 analog comprised of 39 L-amino acids, all of which 
are naturally occurring. Glepaglutide has 9 amino acid substitutions compared with native GLP-2 
and a C-terminal structure inducing probe tail consisting of 6 lysines. The sequence similarity of 
the backbone is about 64% compared with native GLP-2. 
When glepaglutide is injected into the subcutaneous (SC) compartment, 2 well-described and 
functionally active metabolites are formed (ZP18481-34 and ZP18481-35). Under steady-state 
conditions, the majority of the functional effect on the GLP-2 receptor derives from the main 
metabolite ZP18481-34, which accumulates during continued use. Thus, the pharmacokinetic (PK) 
profile and the pharmacological effects of glepaglutide are described and should be understood 
as a composite effect of the drug substance and its 2 metabolites. 
Glepaglutide shows significantly protracted PK. The half-life after SC injection has been shown 
to differ for glepaglutide and its 2 main metabolites, with the longest half-life observed for the 
main metabolite ZP18481-34. This suggests that a SC depot is formed and that release of 
glepaglutide and metabolites from the depot into the systemic circulation is the rate-limiting step 
that governs the plasma half-life. 
The efficacy of 3 weeks of treatment with glepaglutide was demonstrated in a phase 2 trial (trial 
ZP1848-15073) in a small number of stable SBS patients, where glepaglutide was shown to 
significantly improve fluid absorption and showed tendencies to improve absorption of 
macronutrients. 
This phase 3b trial is being conducted to confirm the findings from the phase 2 trial, but after 
long-term treatment and investigate the safety and efficacy of glepaglutide on the amount of PS 
needed for patients to maintain a satisfactory hydration level. 
Based on data from the phase 2 trial (ZP1848-15173) and the PK data from the phase 1 PK trial 
(ZP1848-16182), one dosing regimen of glepaglutide, 10 mg once-weekly, will be investigated 
(see Section 4.3 for the rationale for these doses). 
For more information on glepaglutide, please refer to the Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment 
Main benefits and risks are described in the below sections. More detailed information about the 
known and expected benefits and risks and reasonably expected adverse events (AEs) of 
glepaglutide may be found in the Investigator’s Brochure. 
2.3.1 
Risk Assessment 
Overall Risk Profile 
The results from clinical and non-clinical studies and the safety profile described to date do not 
give rise to specific safety concerns. 
Specifically, the completed non-clinical chronic toxicity program raises no concerns in relation 
to the extended treatment period of the present trial. The evaluation of chronic toxicity included 
a study in rats receiving up to 1, 3, and 10 mg/kg/day glepaglutide for 26 weeks and a study in 
Beagle dogs receiving 0.25, 1, and 5 mg/kg/day glepaglutide for 39 weeks. In both studies, 
glepaglutide caused a range of findings in the intestinal tract that were attributable to its 
pharmacological action. In the study in rats, changes occurred in the liver and kidney, which 


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were likely physiological adaptations to high dose levels of the test material. The systemic no-
observed-adverse-effect-level (NOAEL) in this study was therefore determined to 10 mg/kg/day. 
In the study in Beagle dogs, reduced weight gain was noted in females receiving the highest dose 
level of 5 mg/kg/day glepaglutide, and the systemic NOAEL in this study was therefore 
determined to 5 mg/kg/day in males and 1 mg/kg/day in females. Local irritation at the injection 
sites occurred at all dose levels in both studies. The identified NOAEL exposure level in rats and 
dogs is ≥86 and ≥48 times higher, respectively, than the expected maximum exposure level in 
this trial. The carcinogenic potential of glepaglutide has been tested in a mouse and a rat 
carcinogenicity study. Subcutaneous administration of glepaglutide to CD-1 mice for up to 104 
weeks at doses up to 1.0 mg/kg/day, caused a range of findings in the intestinal tract that were 
attributable to its pharmacological action. There were no neoplastic findings due to treatment 
demonstrating that ZP1848 was not carcinogenic to the CD-1 mouse. Subcutaneous 
administration of glepaglutide to Wistar rats at doses up to 2.0 mg/kg/day for 104 weeks caused 
a range of findings in the intestinal tract that were attributable to its pharmacological action. 
Mucosal hypertrophy/hyperplasia is considered part of the continuum leading to adenoma and 
adenocarcinoma formation, and this was considered the cause for the presence of such tumors in 
the duodenum in a few males given 2.0 mg/kg/day (at exposure approx. 25 times higher than the 
expected maximum exposure level in this trial. Chronic inflammatory changes at the injection 
sites seen in both the mouse and the rat carcinogenicity study, resulting from repeated daily 
subcutaneous injection, occurred at all dose levels and led to an increased incidence of cutaneous 
pleomorphic fibrosarcomas in males. Pleomorphic fibrosarcomas are considered a group of 
largely undifferentiated or primitive sarcomas and are the most common type induced in rodents 
by repeated subcutaneous injection of agents not considered carcinogens (solutions of glucose 
and other sugars, sodium chloride, certain water-soluble food colourings and surfactants, 
carboxymethycellulose and macromolecular dextrans (20,21). 
Glepaglutide was well tolerated at daily doses of up to 10 mg in the phase 2 trial ZP1848-15073 
conducted in SBS patients. Consistent with the clinical setting, the most frequently reported AEs 
(reported in >20% of patients) in the phase 2 trial were nausea, abdominal pain, abdominal 
distension, vomiting, stoma complication, fatigue, dizziness, polyuria, decreased appetite, 
peripheral edema and cough. Treatment-emergent serious adverse events (SAEs) comprised 
8 events, with no dose dependency or clustering of events being observed. Injection site 
reactions were dose dependent, mild to moderate in severity and transient by nature. The most 
frequently reported symptoms were itching and redness. No deaths were reported in this or any 
other trials with glepaglutide. 
No specific safety issues were raised from the phase 1 clinical trial program; for further details 
please see the Investigator’s Brochure. 
In addition to the gastrointestinal tract, there are also GLP-2 receptors in the lung, brain, and 
hypothalamus (22). So far, clinically significant off-intestinal targeted effects resulting from 
these additional receptor sites have not been seen. 
Experiences with native GLP-2 and teduglutide suggest that expected common AEs for this class 
of compounds include abdominal pain and distension, injection site reactions, nausea, headache, 
upper respiratory tract infection, and (in some studies) vomiting, and fluid overload (23). 
Immunogenicity 
Based on the current non-clinical and clinical knowledge of glepaglutide, the risk of 
immunogenicity (development of anti-drug antibodies [ADAs]) following administration of 
glepaglutide is considered high. However, longer-term clinical treatment is required to 


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investigate whether such a response will be transient or persistent. As no acute or non-acute AEs 
or effects on PK or pharmacodynamics have been linked to the immune response towards 
glepaglutide in the completed clinical trials, the effects and potential consequences of the anti- 
glepaglutide response are so far considered of minor criticality. Glepaglutide ADAs will be 
monitored in this trial, including their glepaglutide neutralizing potential and reactivity to the 
main glepaglutide metabolite (ZP18481-34), as well as cross-reaction with native GLP-2. 
Cardiovascular Safety 
No cardiovascular safety issues have been identified for glepaglutide. A concentration-response 
analysis of the potential of glepaglutide to cause QT prolongation ruled out any clinically 
concerning effect at the intended dose level, on which grounds a waiver for a dedicated TQT 
study was granted by the US Food and Drug Administration (FDA) in April 2018. 
Patients with severe and acute cardiac disease are excluded from trial participation (see Section 
5.2). 
Neoplasms 
GLP-2 stimulates development of colonic adenomas in rodent models (24,25,26). Increases in 
plasma citrulline concentrations as seen with GLP-2 analog treatment might promote growth of 
existing tumors in patients during long-term treatment. Although the risk of malignancy is 
hypothetical in humans and colonoscopy can be difficult in these patients, a baseline and a 
follow-up colonoscopy has been suggested for patients taking GLP-2 analogs who have residual 
colons (24,25,26). Therefore a screening colonoscopy (within 6 months prior to screening) and a 
Week 56 colonoscopy is a requirement for patients in the present trial, and patients with a pre-
existing recent history of cancer (except for select, treated, and highly curable in situ cancers) are 
excluded from the trial. If a remnant colon is present, but a colonoscopy may not be appropriate, 
a computerized tomography (CT) scan, colon capsule endoscopy (CCE) or magnetic resonance 
imaging (MRI) will suffice at the discretion of the Investigator. 
If a remnant colon is present, but not connected to the passage of foods and thereby dormant, a 
colonoscopy may not be appropriate and in this case a CT scan or MRI (if standard of care at 
site) will suffice at the discretion of the Investigator to document the absence of concerns 
regarding malignancy. These are considered adequate precautionary measures. Neoplasms 
(malignant and benign) are defined as adverse events of special interest (AESIs) for the trial. 
Risk of Underdosing 
The PK results and exposure-response analyzes for glepaglutide substantiates that once-weekly 
dosing of 10 mg glepaglutide results in glepaglutide concentrations within the therapeutically 
effective dose range. Regardless, a risk of inadequate dosing in individual patients receiving 10 
mg glepaglutide once-weekly cannot be excluded. 
2.3.2 
Benefit Assessment 
For the conducted dose-finding trial ZP1848-15073 testing glepaglutide in SBS patients with or 
without the need of PS, the primary endpoint of change in wet weight of ostomy/diarrhea output 
(‘wet weight output’) was chosen as the most direct measure of the impact of glepaglutide on 
intestinal absorption. The trial met its primary efficacy endpoint by showing statistically 
significant and clinically relevant reductions in wet weight of ostomy/diarrhea output (‘wet 
weight output’) with glepaglutide dosed 1 mg/day (estimated reduction of 592 g/day; p=0.002) 
and 10 mg/day (estimated reduction of 833 g/day; p=0.0002). Results for wet weight absorption 


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and urine weight supported the results for the primary endpoint, with statistically significant 
improvements demonstrated for 1 mg/day and 10 mg/day glepaglutide. In addition, absorption of 
macronutrients increased in the combined 1+10 mg and 1 mg dose groups, and improvements 
were observed for absolute absorption of sodium and potassium at the higher glepaglutide dose 
levels. In conclusion, the phase 2, dose-finding trial of glepaglutide in SBS patients showed 
consistent and clinically relevant benefit for 1 mg/day and 10 mg/day glepaglutide in improving 
intestinal function. For further efficacy results please see the Investigator’s Brochure for 
glepaglutide. 
Patients receiving glepaglutide treatment in the present phase 3b trial are likely to experience 
similar or better improvements in intestinal function. 
2.3.3 
Overall Benefit: Risk Conclusion 
In conclusion, the benefit-risk ratio for the proposed glepaglutide treatment regimen is 
considered favorable for the intended trial population, and potential risks are considered 
appropriately handled and mitigated. 


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3 
OBJECTIVES AND ENDPOINTS 
Table 4 
Objectives and Endpoints. 
Objectives 
Endpoints 
Primary 
 
1. To demonstrate the 24-week effect 
of glepaglutide on the absorption of 
fluids. 
1. Absorption of wet weight/fluids: Change from baseline to 
Week 24 assessed by 48-hour metabolic balance studies. 
Secondary 
 
Secondary Objectives 
1. To assess the effects of 
glepaglutide on absorption of energy, 
absorption of the individual 
macronutrients and absorption of 
electrolytes. 
2. To evaluate the long-term 
efficacy of glepaglutide in patients 
with SBS. 
3. To describe the long-term safety 
of glepaglutide. 
Key Secondary endpoint: 
1. Absorption of energy (oral intake minus fecal excretion): 
Change from baseline to Week 24 measured by 48-hour 
metabolic balance studies. Energy absorption is measured by 
bomb calorimetry. 
Secondary efficacy endpoints: 
2. Absorption of individual macronutrients (carbohydrates, 
lipids and proteins): Change from baseline to Week 24 
measured by 48-hour metabolic balance studies. 
3. Absorption of electrolytes (sodium, potassium, calcium 
and magnesium): Change from baseline to Week 24 
measured by 48-hour metabolic balance studies. 
For patients with SBS-IF only: 
4. Weekly PS volume: Change from baseline to Week 12 and 
24. 
5. Weekly PS macronutrients (carbohydrates, lipids and 
proteins) and electrolytes (sodium, potassium and 
magnesium): Change from baseline to Week 12 and 24. 
Safety endpoints: 
6. Treatment-emergent AEs until follow-up at Week 56. 
7. Immunogenicity (anti-glepaglutide antibodies, reactivity to 
ZP18481-34, cross-reactivity to glucagon-like peptide [GLP]-
2, glepaglutide neutralizing antibodies) at baseline (W0), 
Week 4, 12, 24, 52, and 56. 
Explorative 
 
 Exploratory objectives 
1. To investigate the effect of 
treatment with glepaglutide on 
nutritional status, organ function and 
fluid balance. 
2. To investigate the effect of 
treatment with glepaglutide on patient 
reported outcomes. 
Exploratory endpoints 
1. Body weight: Change from baseline to Week 12, 24 and 52. 
2. Body composition (lean body mass, fat mass and bone 
mineral content) by DEXA: Change from baseline to Week 12, 
24 and 52. 
3. Citrulline: Change from baseline to Week 12, 24 and 52. 
4. Aldosterone: Change from baseline to Week 12, 24 and 52. 


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3. To investigate the microbiome 
composition of subjects with SBS. 
4. To investigate the pharmacokinetics 
of glepaglutide. 
5. Estimated glomerular filtration rate (eGFR), creatinine 
clearance and liver function tests: Change from baseline to 
Week 12, 24 and 52. 
6. HbA1c: Change from baseline to Week 4, 12, 24 and 52. 
7. PRO: patient’s global impression of change (PGIC). At 
Week 12, 24 and 52. 
8. PRO: SBS -impact scale (SBS-I) and EQ-5D-5L. Change 
from baseline to Week 12, 24 and to Week 52. 
9. Pharmacokinetic (PK) parameters (t½ and Ctrough). 
10. To investigate the luminal- and mucosae-associated 
microbiota of patients with SBS from baseline to Week 24. 
11. Urinary excretion of electrolytes (sodium, potassium, 
calcium, magnesium) and urea: Change from baseline to Week 
24. 
12. Fluid Composite Effect: Change from baseline to Week 11, 
24 and 52. 
13. Drinking volume during 48-hour periods: Change from 
Week 24 to 52. 
For patients with SBS-IF only: 
14. Weekly PS volume: Change from baseline to Week 52. 
15. Weekly PS macronutrients (carbohydrates, lipids and 
proteins) and electrolytes (sodium, potassium and magnesium): 
Change from baseline to Week 52. 
16. Weekly days on PS: Change from baseline to Week 12, 24 
and 52. 
For patients with SBS-II only: 
17. Urine output: Change from baseline to Week 12, 24 and 
52. 


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4 
TRIAL DESIGN 
4.1 
Overall Design 
This is a single-center phase 3b trial investigating the long-term effect on intestinal absorption 
and nutritional status and long-term safety of treatment with glepaglutide in patients with SBS. 
It is planned to enroll a minimum of 6 and a maximum of 16 patients for the trial, where 
enrollment is defined as receiving trial product.  
The overall trial design is presented in Figure 1. 
 
The orange circles represent 48-hour in-house metabolic balance studies. Visits are indicated with lines and the week number from 
Visit 1 is indicated. 
Figure 1 Overall Trial Design 
The trial consists of a screening period, a treatment period and a follow-up period. 
After signing informed consent, patients will be screened for initial confirmation of eligibility. 
The screening procedures should be performed within 3 weeks prior to Visit 1 (baseline). 
At Visit 1, eligible patients will complete a 48-hour in-house (admission to the hospital, at site) 
baseline metabolic balance study as well as other baseline assessments, where after they will 
start treatment with glepaglutide 10 mg once-weekly for 52 weeks. The treatment period covers 
12 visits at the week numbers indicated in Figure 1. 
All patients will have in-house stays for 48-hour metabolic balance studies at baseline and at 
Visit 9; see Figure 1. During the in-house periods, they must follow an individual drinking menu, 
but may vary the food intake according to their own choice. 
All patients will have a 48-hour period scheduled before each Visit (except Visit 1 and 9 where 
balance studies are done), during which they must record their fluid intake and urine output. 
During the screening phase, all patients need to construct an individual fixed drinking menu to 
be kept during all 48-hour “pre-visit” periods until Visit 9. The same individual drinking menu 
will be followed during both scheduled in-house 48-hour metabolic balance studies (at Visit 1 
and 9). After Visit 9, the patients are no longer restricted to a fixed drinking menu during the 48-
hour periods, but they should instead drink an amount that reflects their preferred or habitual 
fluid intake. They must only drink the same fluid items as in the drinking menu and must record 
their intake as well as their urine output. Patients receiving PS (patients with SBS-IF) will have 
their PS adjusted based on an algorithm which will be used at each visit (see section 8.2.9). 
A follow-up visit will be performed 4 weeks after end of treatment. 
For each patient the trial period will be a maximum of 59 weeks. 


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4.2 
Scientific Rationale for Trial Design 
The purpose of the present phase 3b trial is to investigate the long-term effect on the intestinal 
absorption, nutritional status and the long-term safety of treatment with glepaglutide in patients 
with SBS. 
The efficacy assessments in the ongoing phase 3 program are focused on the effects of 
glepaglutide on reduction of PS volume and content in patients with SBS-IF with at least 3 days 
of PS at baseline. The present phase 3b trial serves to investigate the direct effect of glepaglutide 
on absorption of fluids, nutrients, electrolytes, and trace elements in patients with SBS-II and 
SBS-IF. 
Balance studies quantify weight, volume, as well as the content of energy, macronutrients and 
electrolytes of oral intake (i.e. food and fluid intake) and of the output (i.e. ostomy output, 
diarrhea and urine production). Balance studies are acknowledged as the “gold standard” to 
measure intestinal function and the methods used have been published (27). Metabolic balance 
study is a comprehensive method, and the laboratory of the Department of Gastroenterology and 
Hepatology at Rigshospitalet is one of the few centers of excellence in the world holding the 
equipment and expertise to perform these metabolic balance studies. The trial site has become 
internationally recognized for its pioneering role and its significant contribution to evidence-
based treatment options within the field of intestinal failure. In a patient group as SBS, having a 
severe compromised intestinal absorption that may require PS, the ability to quantify intestinal 
absorptive function of wet weight, energy, macronutrients (carbohydrate, fat, protein), and 
electrolytes (sodium, potassium, calcium and magnesium), provides the clinician with options to 
tailor an individual nutritional and medical strategy for patients. Implementing the metabolic 
balance study in a clinical trial setup is a unique opportunity to test the efficacy of a medical 
therapy on the intestinal function. The principle of this clinical trial is to perform a “baseline” 
metabolic balance study leading up to the first administration of trial product. The “treatment” 
metabolic balance study is then repeated after a period of treatment. In this trial, the primary and 
key secondary endpoints will be captured after 24 weeks of treatment with glepaglutide 10 mg 
once-weekly. 
Intestinal wet weight absorption is an important clinical outcome for patients with SBS. Efficacy 
on intestinal wet weight absorption and nutritional status of GLP-2 and its analogs has until this 
trial been limited to short-term clinical trials of 3-4 weeks treatment periods (28,29). For the first 
time, this trial will investigate the effect of long-term treatment with a GLP-2 analog on 
intestinal absorption, nutritional status and long-term safety in patients with SBS. The primary 
objective of the trial has therefore been chosen as the 24-week effect of glepaglutide on the 
absorption of fluids. Key secondary endpoint of this trial was chosen as the intestinal absorption 
of energy (oral intake minus fecal excretion) measured at Week 24 of treatment with 
glepaglutide. 
The documentation of glepaglutide’s effects on intestinal energy absorption obtained in this 
glepaglutide single-center, single-arm, fixed dose, phase 3b trial is expected to directly 
contribute to the regulatory filing and support the medical communication both pre- and post-
launch of the product. During glepaglutide treatment, patients with SBS-IF will have less need of 
PS and micronutrients. The long-term effects of the reduced amount of PS on body equilibrium, 
body weight, body composition and other organ functions are unknown. 
Patients will be screened to exclude those recently hospitalized more than twice due to SBS or 
related to PS, those with uncontrolled IBD, those with a history of cancer (except resected 
cutaneous basal or squamous cell carcinoma and in situ cervical cancer) unless it can be 


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documented that the patient has been in a disease-free state for at least 5 years and other 
disorders that may put the patient at an increased risk. Patients with any history of colon cancer 
are not allowed to enter the trial. Additionally, patients with a remnant colon are required to have 
a colonoscopy according to local standard practice performed as part of the screening 
procedures, and at the follow-up visit. If patients had a colonoscopy performed within the last 6 
months prior to screening as part of the standard of care of the disease, results from this will be 
acceptable. If a remnant colon is present, but not connected to the passage of foods and thereby 
dormant, a colonoscopy may not be appropriate and in this case a CT scan, CCE or MRI will 
suffice at the discretion of the Investigator to document the absence of concerns regarding 
malignancy. 
During treatment with trial product, patients will be carefully monitored for AEs, vital signs, and 
laboratory abnormalities. As no acute or non-acute AEs have been linked to the immune 
response to glepaglutide so far, samples for ADA will be analyzed following the last patient’s 
last visit. Additionally, an internal Safety Committee (see Section 10.1.6) will routinely review 
safety data to monitor and ensure patient safety. 
4.3 
Justification for Dose 
The selected dose for this trial is 10 mg glepaglutide once-weekly for 52 weeks. The selected 
dose is considered supported with respect to both safety and efficacy, as described below. 
4.3.1 
Safety 
The safety of the proposed dose is supported by the outcome of the completed clinical trials, 
which showed that single SC administrations up to 20 mg and total weekly doses of 10 mg, 
70 mg or 140 mg all appeared well tolerated. No safety issues were raised in these trials, which 
included maximum plasma concentration (Cmax) and overall exposure levels well above those 
proposed for this phase 3b trial. From a safety perspective, once-weekly SC injections of 10 mg 
glepaglutide is therefore considered to be an appropriate dose level for testing in phase 3b. 
4.3.2 
Efficacy 
Using the data from the glepaglutide PK trial ZP1848-16182, the average steady-state plasma 
concentration in the dosing interval (Cavg) and the associated 90% prediction interval can be 
calculated for 10 mg glepaglutide dosed once-weekly (based on observed data). These average 
plasma concentrations and associated 90% prediction intervals are shown superimposed on the 
exposure-response curve established for the phase 2 primary endpoint in supporting that once-
weekly dosing of 10 mg glepaglutide results in glepaglutide concentrations within the 
therapeutically effective dose range (see Figure 2). 


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Figure 2 Exposure-Response Curve 
Investigating the assumption that a minimum plasma concentration is needed to drive efficacy, 
the analysis predicts that a once-weekly dosing regimen of 10 mg glepaglutide would result in 
plasma concentrations within the therapeutically effective range for several days after dosing, but 
possibly falling below the therapeutically effective level during the latter phase of each weekly 
dosing interval. This dosing regimen is expected to result in a therapeutically relevant overall 
effect based on the current knowledge of biological activities related to GLP-2 receptor 
activation. 
4.4 
End of Trial Definition 
A patient is considered to have completed the trial when he or she has completed trial product 
treatment for 52 weeks and completed both metabolic balance study periods (at Visit 1 and 9) as 
well as the final safety assessments at Visit 12 and completed the follow-up visit (week 56). 
The end of the trial is defined as the date of the last visit (follow-up visit) of the last patient in the 
trial. 


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5 
TRIAL POPULATION 
The patient population selected for this trial must have SBS with intestinal insufficiency or 
intestinal failure. Since patients with SBS-II compensate with an increased oral intake of fluid 
and food, they can have as large fecal output as patients with SBS-IF. Thus, fecal output is 
important to assess in both patients with SBS-II and SBS-IF. 
The impact of SBS on quality of life seems to depend on the degree of malabsorption and thus 
the need for PS: the higher the need for PS, the greater negative impact of SBS on quality of life. 
Hence, for the population of patients with SBS-IF there exists an unmet need for medical 
treatment to reduce the burden of malabsorption and PS. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Patients are eligible to be included in the trial only if all of the following criteria apply: 
1. Informed consent obtained before any trial-related activities. Trial-related activities are any 
procedures that are carried out as part of the trial, including activities to determine suitability 
for the trial. 
2. Age ≥ 18 years and ≤ 90 years at screening. 
3. Willing to comply with trial procedures, including 2 in-house visits with urine and fecal 
output collection. 
4. Stable condition of SBS either with intestinal failure (IF) or intestinal insufficiency. For 
patients with SBS-IF a stable condition is defined as < 25% change in PS volume or energy 
content for 4 weeks prior to screening. 
5. Stable body weight (<5% change in weight in the 3 months prior to screening). 
6. Wet weight of fecal excretion ≥1,500 g/day demonstrated during a hospital stay prior to 
screening*. 
*If inclusion criteria #6 cannot be met, a visit may be scheduled where fecal output collected at 
home by the patient or during a hospital stay can be assessed. If the wet weight of fecal excretion 
≥1,500 g/day can be demonstrated, the criterion #6 is met. 
5.2 
Exclusion Criteria 
Patients are excluded from the trial if any of the following criteria apply: 
General 
1. Current, or within 30 days prior to screening, participation in another interventional clinical 
trial that includes administration of an active compound. 
2. Mental incapacity or language barriers which preclude adequate understanding or 
cooperation, or unwillingness to comply with trial requirements. 
3. Previous participation in this trial. Participation is defined as having received trial product. 
4. Females of childbearing potential, who are pregnant, breast-feeding, intend to become 
pregnant or are not using highly effective contraceptive methods. Male patients with female 
partners, who intend to become pregnant. 


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Medical history and concomitant diseases 
5. More than 2 SBS-related or PS-related hospitalizations (e.g., catheter-related 
bacteremia/sepsis, bowel obstruction, severe water-electrolytes disturbances, etc.) within 
6 months prior to screening. 
6. Poorly controlled inflammatory bowel disease (IBD) that is moderately or severely active or 
fistula interfering with measurements or examinations required in the trial. 
7. Current bowel obstruction. 
8. Known radiation enteritis or significant villous atrophy, e.g., due to active celiac disease. 
9. Cardiac disease defined as: decompensated heart failure (New York Heart Association 
[NYHA] Class III-IV), unstable angina pectoris, and/or myocardial infarction within the last 
6 months prior to screening. 
10. Clinically significant abnormal electrocardiogram (ECG) as judged by the Investigator. 
11. Human immunodeficiency virus (HIV) positive, acute liver disease including positive results 
for Hepatitis B antigens (HBsAg) and Hepatitis C (HCV), or unstable chronic liver disease. 
12. Any history of colon cancer. History of any other cancers (except margin-free resected 
cutaneous basal or squamous cell carcinoma or adequately treated in situ cervical cancer) 
unless disease-free state for at least 5 years. 
13. Hepatic impairment defined as: 
 
a. Total bilirubin ≥ 2 × the upper limit of normal (ULN), or 
 
b. Aspartate aminotransferase (AST) ≥ 5 × ULN, or 
 
c. Alanine aminotransferase (ALT) ≥ 5× ULN 
14. Use of GLP-1, GLP-2, human growth hormone (HGH), somatostatin, or analogs thereof, 
within 3 months prior to screening. 
15. Known or suspected hypersensitivity to glepaglutide, its components or related products. 
16. Use of dipeptidyl peptidase (DPP)-4 inhibitors within 3 months prior to screening. 
17. Surgical resection of gut tissue within 6 months prior to screening. 
18. Systemic immunosuppressive therapy for treatment of the gastrointestinal tract that has been 
introduced or has been unstable within 3 months prior to screening. 
19. Unstable biological therapy (e.g. anti-TNF-α, natalizumab, etc.) within 6 months prior to 
screening, including significant changes in doses or switch of drug. 
5.3 
Lifestyle Consideration 
5.3.1 
Dietary Restrictions 
The patients must follow an individual ‘drinking menu’ (which will be set during the screening 
phase) on the days of the metabolic balance study during hospital admissions (Visit 1 and Visit 
9) as well as on the days of 48-hour urine collection at home prior to each visit up to and 
including Visit 9. The drinking menu starts on the same day as the 48-hour pre-visit urine 
collection, and lasts for a total of 48 hours (see Section 8.2.2). 
Fasting is required for blood sampling for citrulline, cholesterol and triglycerides (see Section 
8.2.13). Fasting is defined as no intake of food or drinks, except water, for at least 10 hours (±1 
hour) (since app. 22:00h) the day before the blood sampling. PS administration is allowed. 
For other laboratory tests, fasting is optional. 


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5.3.2 
Smoking 
Smoking is not permitted the last 2 hours prior to blood sampling for citrulline (see Section 
8.2.13). 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to trial intervention. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure reason(s), 
eligibility criteria, and any SAE. A screen failure rate of 10% is expected. 
Individuals who do not meet the criteria for participation in this trial (screen failure) may be 
rescreened. Rescreened participants should be assigned a new participant number for every 
screening/rescreening event. 
5.5 
Dosing Criteria 
The first dose of trial product must only be administered after the baseline metabolic balance 
study as well as all other baseline assessments are completed at Visit 1. 
To be eligible for dosing, all inclusion criteria must be met and none of the exclusion criteria. 
Re-sampling is not allowed if the patient has failed any of dosing criteria related to laboratory 
parameters. However, in case of technical issues (e.g. hemolysed or lost), re-sampling is allowed 
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6 
TREATMENTS 
6.1 
Treatment Administered 
The trial product for the trial is described in Table 5. 
Table 5 
Trial Product 
Trial Product Name 
Glepaglutide 20 mg/mL 
Dose Formulation 
Solution for injection 
Unit Dose Strength 
10 mg/0.5mL 
Dosage Level 
10 mg once-weekly 
Route of Administration 
SC injection 
Sourcing 
By Sponsor 
Packaging and Labeling 
Trial product will be provided in single-use autoinjectors 
containing 0.5 mL of 20 mg/mL glepaglutide (clear, essentially 
colorless solution). Each autoinjector and box will be labeled in 
accordance with Annex 13, country and trial requirements.  
Storage  
Store in refrigerator between 2°C – 8°C. 
Protect from light 
Additional details regarding the trial product can be found in the trial materials manual. 
Each dispensing unit/pen is uniquely numbered with a dispensing unit number. 
6.1.1 
Trial product administration 
Patients must choose their preferred injection site area; either on their abdomen or their thigh(s). 
Unless otherwise agreed with the Investigator, patients must use this selected injection site area 
during the entire trial. The specific injection site must be rotated for each weekly injection such 
that the injections are administered at least 5 cm away from the last injection administered, and 
still within the same injection site area, i.e., abdomen or thigh. It is acceptable to inject in one 
thigh or both thighs during the treatment period. Only patients eligible for treatment must use 
trial product and only delegated site staff must dispense or administer trial product. No trial 
product may be dispensed to any person not enrolled in the trial. 
6.2 
Handling/Storage/Accountability 
6.2.1 
Handling and Storage 
The Sponsor will provide trial product for each patient for the duration of his/her participation in 
the trial. The Investigator, or designee will dispense trial product at each dispensing visit. A 
sufficient quantity of trial product will be dispensed to assure that the patient has sufficient trial 
product supply to last at least until the next scheduled drug dispensing visit. The Investigator, or 
designee must ensure that no patient uses expired trial product at any time. 
Patients will be familiarized with the handling and use of the autoinjector prior to the first 
administration of trial product, and as needed at the site. The Investigator must document that 
Instructions for use are given to the patient verbally, and in writing at all dispensing visits (as 
specified in the flowchart). 


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The Investigator must maintain an accurate record of the shipment and dispensing of trial 
product. 
The Investigator or designee must instruct the patient in what to return at next visit to the clinic. 
All returned (used and unused), expired or damaged trial products (for technical complaint 
samples, see section 8.4.8) must be stored separately from non-allocated trial products and can 
be done at room temperature. No temperature monitoring is required. 
In case the Investigator, the site staff, or the monitor suspect that the trial drug is defective or 
potentially defective, the Sponsor should be contacted immediately. 
6.2.2 
Accountability 
The Investigator must ensure that a designated person receives trial product deliveries from the 
Sponsor or designee and that all such deliveries are: 
• Recorded 
• Handled and stored safely and properly 
• Returned to sponsor or designee, as required 
The Investigator or designee must keep drug inventory and accountability logs of which a copy 
must be given to the Sponsor at the end of the trial. An accurate record of the date and amount of 
trial product dispensed to and returned from each patient must be available for inspection at any 
time. The inventory log will include details of the trial product received and dispensed to the 
patient. All used and unused autoinjectors and the dispensing cartons must be kept and returned 
to the monitor who will perform reconciliation of delivery records and accountability logs. 
Discrepancies between the amount of trial drug received, dispensed and returned will be verified. 
Patients should be instructed to bring all their trial product including the dispensing cartons to 
each scheduled trial visit. Investigator or delegated staff must perform drug accountability with 
the patient at every visit to the clinic. Returned trial product (used or unused autoinjectors and 
the dispensing cartons) must be stored separately from non-allocated trial product. 
The Investigator must not destroy any used or unused trial product supplies. At the conclusion of 
the trial (or by agreement with Sponsor during the trial if storage capacity at site is limited) the 
Investigator will return all used and unused trial drug and the dispensing cartons to the Sponsor. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This is a single-arm, fixed dose trial and all patients will receive the same treatment. No 
randomization and blinding will be performed. 
The primary and key secondary endpoints are addressing the absorptive capacity of the intestines 
and are thus objective. They are derived from laboratory measurements of the input and output 
during the balance studies. To minimize bias on the wet weight absorption, fluid intake during 
the balance study is restricted to a drinking menu. 
Adjustment of PS for patients with SBS-IF, will be done according to an algorithm that takes the 
urine output at baseline and during the 48h periods along with the current PS into account. This 
will limit the bias of the open-label design. 


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6.4 
Treatment Compliance 
6.4.1 
Drug Treatment Compliance 
Throughout the trial, the Investigator will remind the patients to follow the trial procedures and 
requirements to encourage patient compliance. 
During the trial, patients will mainly self-administer trial product at home. The first dose will be 
administered at the trial site. 
Patients are requested to enter details regarding trial product administration (including date and 
time of the day as well as dispensing unit number) and injection site area used (i.e., abdomen, 
thigh) in the diary and transcribed to the eCRF. 
Patients are to record PS use (including bag name, volume and infusion date) in the diary on an 
ongoing basis, and must be checked and transcribed into the eCRF at every visit by the 
Investigator. 
When patients self-administer trial product at home, compliance with trial product administration 
will be assessed and documented in source documents at each visit where information is 
available. If any suspicion of non-compliance arises, the site must start a dialogue with the 
patient, re-emphasizing the importance of compliance, uncover barriers to compliance, and re-
train the patient, if needed. This dialogue must be documented. Compliance will be assessed by 
cross-checking the following sources and comparing these to the expected use: 
• Drug accountability information; visual inspection of returned autoinjectors 
• Review of patient diaries 
The Investigator must ensure that patients who temporarily discontinue treatment with trial 
product due to safety concerns, e.g. admission to hospital, are resuming treatment safely to avoid 
dehydration. 
Missed Doses of Trial Drug 
Patients should not omit planned doses. Patients who miss a scheduled dose of trial product 
should be instructed to administer the missed dose as soon as they become aware of the mistake; 
however, 2 doses should not be administered the same day. 
6.4.2 
Compliance with 48-hour Drinking Menu 
Compliance to the drinking menu in association with the at-home 48-hour urine collection prior 
to each visit (up to and including Visit 9) will be assessed by review of patient diaries, where the 
patients will record their fluid intake (see Section 8.2.2). 
6.5 
Concomitant Therapy 
Medications commonly used to treat SBS symptoms including anti-diarrhea agents are allowed 
during trial participation; however, changes (start, stop, new brands, or dose changes) should be 
kept to a minimum and the Medical Monitor be informed on the indication for the change via 
reporting in the eCRF. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
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prior to and including the screening visit, or receives during the trial must be recorded along 
with: 
• Trade name or generic name 
• Indication 
• Dates of administration including start and stop dates 
• Dose (total daily), unit and route of administration 
Changes in concomitant medication must be recorded at each visit. If a change is due to an AE, 
then this must be reported according to Section 8.4. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
6.6 
Prohibited Medication 
GLP-1 analogs, GLP-2 analogs (teduglutide), HGH, DPP-4 inhibitors, and somatostatins are not 
allowed to be used by patients during the course of the trial. 
Medications commonly used to treat SBS symptoms including anti-diarrhea agents are allowed 
during trial participation; however, changes (start, stop, new brands, or dose changes) should be 
kept to a minimum and the reason for the change should be recorded in in eCRF. Any changes to 
concomitant medications must be documented in the eCRF. 
6.7 
Dose Modification 
Not applicable. 
6.8 
Treatment After the End of the Trial 
When discontinuing trial product (Visit 12), the patient should be treated according to the 
standard of care at the discretion of the Investigator or treating physician. 


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7 
DISCONTINUATION OF TRIAL PRODUCT AND PATIENT WITHDRAWAL 
7.1 
Discontinuation of Trial Treatment 
Treatment of a patient may be discontinued at any time during the trial at the discretion of the 
Investigator for safety reasons. However, the patient can still continue, and should be encouraged 
to stay in the trial if assessed safe according to the Investigator. 
Efforts must be made so that patients continue to attend and complete all scheduled visit 
procedures to the extent possible. Patients should stay in the trial regardless of compliance with 
trial drug, assessments, or visit schedule. The Investigators should make a special effort to ensure 
that all patients complete the assessment for the primary and key secondary endpoints. 
Patients must be educated about the continued scientific importance of their data, even if they 
discontinue trial product. 
 A patient must be discontinued from trial treatment if: 
1. Any safety concerns or AEs that in the opinion of the Investigator might place the patient at 
unacceptable risk, including any deterioration of a patient’s health state, especially in terms 
of the frequency and volume of total PS. 
2. Any malignancy. 
3. Increased liver values, defined as: 
a. ALT or AST >3 times baseline value lasting more than 2 weeks*, or 
b. ALT or AST >5 × ULN and total bilirubin >2 x ULN*, or 
c. ALT or AST >5 × ULN and international normalized ratio (INR) >1.5*, or 
d. ALT or AST >5 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)* 
* where no other etiology exists. 
4. Pregnancy or intention to become pregnant. 
5. The patient requires treatment with prohibited medications (see Section 6.6). 
Patients can be discontinued from trial treatment if: 
• A patient was enrolled despite it was later identified that some of the inclusion or 
exclusion criteria were violated. The Investigator must discuss with the Sponsor’s Medical 
Monitor if it is safe for the patient to continue the trial treatment. If a patient prematurely 
discontinues trial treatment, the primary reason must be specified in the eCRF. If the 
patient continues in the trial without trial treatment, the intent should be to follow the 
patient to the extent possible according to the planned visit schedule and assessments with 
the purpose of following the safety and efficacy of the patients. Reason for visits not 
having been performed must be documented. 
7.2 
Patient Withdrawal from the Trial 
A patient may withdraw from the trial at any time at his/her own request (withdrawal of 
consent). The patient’s request to withdraw from the trial must always be respected. A patient 
may be withdrawn at any time at the discretion of the Investigator for safety reasons. 


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A patient must be withdrawn if any of the following applies: 
• Withdrawal of informed consent 
• Safety concerns or AEs that in the opinion of the Investigator might place the patient at 
unacceptable risk for further participation in this trial or would likely make the patient 
unable to carry out the full trial 
• Sponsor closure of the trial 
• Pregnancy or intention of becoming pregnant 
IMPORTANT: Efforts must be made to have the patients to attend the Week 52 end of treatment 
visit (EoT) and the Week 56 follow-up visit (FU) where all general, safety, and laboratory 
assessments should be performed as detailed in the flowchart (see section 1.2). 
Final drug accountability must be performed even if the patient is not able to come to the site. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such withdrawal. 
If a patient withdraws from the trial, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site trial records. 
Although a patient is not obliged to give his/her reason(s) for withdrawing, the Investigator must 
make a reasonable effort to ascertain the reason(s), while fully respecting the patient's rights. 
Where the reasons are obtained, the primary reason for withdrawal must be specified in the ‘end 
of trial’ form in the eCRF. 
All data collected from a withdrawn patient prior to withdrawal and during the final visit will be 
included in the analyses of the trial data. Although a patient is not obliged to give his/her 
reason(s) for withdrawing consent, the Investigator must make a reasonable effort to ascertain 
the reason(s), while fully respecting the patient’s rights. An end of trial form must be completed 
and final drug accountability done even when patients are not able to come for a trial visit. Only 
patients who withdraw their consent will be considered as withdrawn from the trial. 
7.2.1 
Replacement of Patients 
Patients who discontinue trial product or withdraw from the trial will not be replaced. 
7.3 
Lost to Follow-up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the trial site. 


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8 
TRIAL ASSESSMENTS AND PROCEDURES 
• The following sections describe the trial assessments and procedures, while their timing 
is summarized in the flowchart (see Section 1.2). 
• Informed consent must be obtained before any trial-related activity, see Section 10.1.4. 
• All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all inclusion criteria and none of the exclusion criteria. 
• The Investigator will maintain a screening log to record details of all patients screened 
and to confirm eligibility or record reason for screen failure, as applicable. 
• At screening, patients will be provided with a patient card stating that they are 
participating in a trial and giving contact details of relevant site staff that can be 
contacted in case of emergency. 
• Adherence to the trial design requirements, including those specified in the flowchart, is 
essential and required for trial conduct. 
• Patients will be provided with patient diaries to register administrations of trial product, 
PS use (SBS-IF only) as well as fluid intake and urinary output during 48-hour periods 
prior to site visits. 
• Review of patient diaries, PRO questionnaires, ECG, laboratory reports etc. must be 
documented either on the documents or in the patient's source documents. If clarification 
of entries or discrepancies in the patient diary or PRO questionnaires is needed, the 
patient must be questioned, and a conclusion made in the patient's source documents. 
Care must be taken not to bias the patient. 
• During the trial, blood samples will be collected from all patients for efficacy, safety, PK 
and ADA assessments. The total blood volume drawn per patient amounts to a maximum 
of approximately 530 mL, including all assessments described in Sections 8.2 and 8.3. 
The samples are collected over a period of approximately 59 weeks (1 year and 1.5 
months). 
• Repeat samples may be taken for technical issues and unscheduled samples or 
assessments may be taken for safety reasons. Please refer to Appendix 2 (see section 
10.2) for further details on laboratory samples. 
8.1 
Demographics and Other Baseline Characteristics 
8.1.1 
Demographics 
Demographic information to be collected includes date of birth, gender, race, and ethnicity. 
8.1.2 
SBS Characteristics and History 
Information about the patient’s SBS includes the following characteristics: 
• The underlying cause of SBS 
• Date of diagnosis of underlying disease 
• Date of SBS diagnosis 


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• Remaining bowel sections [30]; whether patient has a colon-in-continuity (jejuno-colic 
anastomosis/SBS anatomical group 2, jejuno-ileo-colic anastomosis/SBS anatomical 
group 3, or other), an end-jejunostomy/SBS anatomical group 1, ileostomy/SBS 
anatomical group 1, or colostomy, presence of ileocecal valve, the surgery dates and 
reason(s) for resection, this includes the most recent resection 
• Bowel lengths; length of the remnant small bowel, the remnant colon in percent 
(according to Cummings classification [31]) 
• Severity of SBS based on the ESPEN Functional and Clinical Classification of Chronic 
Intestinal Failure (8) 
• Date that the patient started PS, if applicable 
8.1.3 
Body Weight and Height 
Body weight (kg with 1 decimal accuracy) will be measured at all visits. Height (cm) will be 
measured at screening only. 
Weight will be measured on a calibrated scale. Patients should wear light clothing and no shoes. 
Stoma bags should be emptied prior to the measurement. 
Patients should be encouraged to measure their body weight at home weekly to detect potential 
signs of fluid retention early (before edema becomes readily visible). If the weight changes, 
patients should be instructed to call the site for guidance. 
8.1.4 
Medical History/Concomitant Illness 
Medical history information to be collected includes all ongoing conditions and 
relevant/significant medical history (including all major hospitalizations and surgeries). 
Details of whether the patient suffered from any of the following will be recorded: 
Encephalopathy, ascites, cholestasis, steatosis, and/or cirrhosis. If yes, the outcome / 
histopathologic diagnosis and date of histopathologic diagnosis will be recorded. 
Concomitant illness must also be captured and noted as to relatedness to SBS. 
The patient’s history of drug and/or alcohol abuse, information on tobacco smoking (never 
smoker (<100 cigarettes or equivalent /lifetime), current smoker, or former smoker) and current 
alcohol use will also be captured. 
8.1.5 
Concomitant Medication 
All prescription and non-prescription medications taken within 7 days prior to and including the 
screening visit will be recorded in the eCRF. Any changes to concomitant medications that occur 
throughout the trial will be recorded (see Section 6.5). 
All relevant previous treatments, including treatment with teduglutide, any other GLP-2 analogs 
or native GLP-2 are recorded in the eCRF. 
8.1.6 
Colonoscopy 
Patients with a remnant colon are required to have a colonoscopy as part of the screening 
procedures and the follow-up visit (Week 56). Colonoscopy results must be available for Visit 1. 
Colonoscopies performed up to 6 months prior to screening are acceptable. If a remnant colon is 


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present, but a colonoscopy may not be appropriate, a CT scan, CCE or MRI will suffice at the 
discretion of the Investigator. 
8.1.7 
COVID-19 Management 
The COVID-19 pandemic is expected to exist during the conduct of the trial. In case the situation 
worsens, the following mitigating actions may be implemented, as applicable: 
• Site visits (Visit 2 and forward) can be converted to phone/video calls to obtain and record 
information about: 
o AEs 
o Body weight (patient´s home scale is acceptable) 
o Procedures and changes to concomitant medication 
o Urine and blood samples for safety assessments (may be collected at a local 
community laboratory, patient´s general practitioner or by a home nurse at the 
Investigator´s discretion) 
o Pregnancy, planned pregnancy and missed menstruation, if any. For females of 
childbearing potential a pregnancy urine dipstick kit will be shipped to patient’s 
home from the site. 
o Adherence to PS regimen in the diary (see Section 6.4.1) as per standard practice 
(including volume, and content) and modify weekly PS volume and schedule in 
accordance with section 8.2.9 in the protocol. 
• PROs: 
o Copies of PGIC, SBS-I and EQ-5D-5L questionnaires can be sent to the patients 
for completion, including the standard instructions for how to complete, date, and 
sign. The instructions include among other things the following notes; It is 
important the SBS-I is completed by the patient without assistance of family 
members. 
o Patients should: 
 Fill in the PROs and complete the questionnaires on the same day as the 
remote visit is scheduled, but prior to the site visit call. 
 Send a copy of completed PROs to site for review and entry into eCRF. 
 Bring original documents to site at next possible visit. These documents 
will be source data to be verified at that point. If source data is lost, then 
copies received will suffice. 
• Trial product can be sent directly from the site to the patient’s home 
• Visit 9 can be postponed, until on-site visit is possible again. After 24 weeks of treatment, the 
patient will be in a stable treatment, and postponing the visits is not expected to affect the 
assessments 
• The EoT visit can be postponed (time window can be extended up to + 8 weeks) 


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Deviations from the protocol caused by circumstances related to the pandemic will be 
documented. Handling of data affected by the pandemic situation will, if applicable, be 
addressed in the statistical analysis plan. 
8.2 
Efficacy Assessments 
Planned time points for all efficacy assessments are provided in the flowchart (Section 1.2). 
Assessment of the primary and key secondary endpoints will be based on metabolic balance 
studies, described in Section 8.2.1. During the metabolic balance studies, as well as before trial 
visits, the patients will adhere to an individual fixed drinking menu, described in Section 8.2.2, 
associated with measurements of urine volume, described in Section 8.2.3. 
8.2.1 
Metabolic Balance Study 
The metabolic balance study measures the total intake and output of energy, macronutrients 
(lipids, carbohydrates, proteins [nitrogen as a marker]) and micronutrients. The oral diet intake 
(i.e. food and fluids) are assessed by duplicate meals and liquids by quantification of weight, 
volume, as well as the content of energy, macronutrients and electrolytes. During the metabolic 
balance study, the patients will collect duplicate portions of all intake solid and liquid in buckets 
covering 24-hour periods. Likewise, all output (i.e. ostomy output, diarrhea and urine 
production) will be collected and quantified. The content of the buckets will be weighed, 
processed into dry matter by laboratory techniques and subsequently analyzed at the site’s local 
laboratory. 
Before the metabolic balance study is started, a fixed drinking menu will be set which will be 
followed for the metabolic balance study at Visits 1 and 9 (see Section 8.2.2). 
The 48-hour metabolic balance study will start at 8:00 in the morning. If the patient receives PS 
at baseline, the 48 hours should preferably cover a day on PS (first day) and a day off PS. 
The procedure for the metabolic balance study is listed below: 
• The laboratory technician will inform the patient about collection of diet and liquid 
intake, urine and feces and hand out bottles and buckets that will be used for the 
collection. 
• The collection will be performed for 48 hours. 
• The patient will collect oral diet intake corresponding to the type and amount ingested. 
Wrapping paper, plum stones, chicken bones and similar will not be collected. 
• Each day, bottles and buckets will be picked up by the laboratory technician. 
Table 6 specifies the samples collected. 
Table 6 
Sample Collection during Metabolic Balance Study 
Sample 
To be collected in 
Handling and storage 
Urine 
Bottle 
No special handling or precautions 
Feces 
Bucket 
Feces will be stored in a freezer 
Oral liquid intake 
Bottle 
No special handling or precautions 
Oral food intake 
Bucket 
No special handling or precautions 
The content of the bottles/buckets will be weighed, processed into dry matter by laboratory 
techniques and subsequently analyzed at the laboratory. Details of the techniques used are 
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The analyses performed on the collected material are presented in Table 7. 
Table 7 
Analyzes on Collected Material in Metabolic Balance Study 
Analysis 
Samples 
Method 
Weight/volume 
Urine, feces, food an liquid 
Weight/measuring cylinder 
Energy content  
Feces, food and liquid 
Bomb calorimetry 
Fat (aliphatic compounds)  
Feces, food and liquid 
Titration 
Carbohydrates  
Feces,  food and liquid 
Englyst’s method (33) 
Nitrogen (as a marker of protein)  
Urine, feces, food and liquid 
Kjeldahl’s method (34) 
Sodium and potassium 
Feces,  food and liquid 
Flame photometry 
Calcium and magnesium 
Feces, food and liquid 
Atomic absorptiometry 
Sodium, potassium, calcium, 
magnesium, urea, creatinine 
Urine 
• Sodium (potentiometri) 
• Potassium (potentiometri) 
• Calcium (calculated as a product of the 
urine calcium concentration and 24h 
urine volume) 
• Magnesium (calculated as a product of 
the urine magnesium concentration and 
24h urine volume) 
• Urea (calculated as a product of the urine 
carbamide concentration and 24h urine 
volume) 
• Creatinine (absorption photometry) 
8.2.2 
Fixed Fluid Intake 
The oral liquid intake should be kept constant during the metabolic balance study, ensuring that 
potential changes in any output measurements are not caused by changes in liquid intake. 
Therefore, during the screening phase, patients will be instructed to in detail documenting their 
24-hour fluid intake, specifying sort (water, tea, milk, coffee etc.), amount (mL) and time of 
intake. 
The patients must follow their drinking menu on metabolic balance study days during hospital 
admissions (Visit 1 and Visit 9) and during the 48-hour pre-visit urine collection periods at home 
prior to each visit, excluding Visit 1 and 9. As stated above, the drinking menu starts on the same 
day/time as the 48-hour pre-visit urine collection, and lasts for a total of 48 hours. After Visit 9, 
the patients are no longer restricted to a fixed drinking menu during the 48-hour periods, but they 
should instead drink an amount that reflects their preferred or habitual fluid intake. They must 
only drink the same fluid items as in the drinking menu and must record their intake as well as 
their urine output. 
Solid oral food intake is unrestricted and may be varied according to the patients’ own choice. 
8.2.3 
48-hour Urine Volume 
Urine volume will be recorded by the patient in his or her patient diary during the defined 48-
hour measurement periods prior to a trial visit and transcribed to the eCRF. During this time the 
patient must adhere to the individually predefined drinking menu (up to Visit 9, see Section 
8.2.2). The patient will be provided with urine measuring cups. 
The 48-hour urine volume measurements should occur as close as possible to and within 7 days 
of the coming site visit. For patients with SBS-IF the measurements should be timed with the PS 
schedule. Patients on PS 7 days weekly must perform the 48-hour measurement on 2 consecutive 


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days on PS. Patients on PS 1-6 days weekly must record the 48-hour measurement at 1 day on 
PS and 1 day off starting on the day on PS. 
See Table 8 for further clarity. The grey boxes indicate the possible 48-hour urine measurement 
periods. If more than 1 interval is available anyone of them can be chosen. 
The patient should perform the 48-hour measurement on the same days of the week during each 
period as long as the PS regimen remains the same. The selected days will be recorded in the 
patient diary. If the PS regimen changes during the trial, a new schedule for 48-hour 
measurement can be chosen. 
Table 8 
Timing of 48-hour periods and balance studies 
PS days/ Week 
48-hour measurement 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
7 days 
2 days on PS 
1 
2 
3 
4 
5 
6 
7 
6 days 
1 day on PS + 1 day off PS 
1 
2 
3 
4 
5 
 
6 
5 days 
1 day on PS + 1 day off PS 
1 
 
2 
3 
4 
 
5 
4 days 
1 day on PS + 1 day off PS 
1 
 
2 
 
3 
4 
 
3 days 
1 day on PS + 1 day off PS 
1 
 
2 
 
3 
 
 
2 days 
1 day on PS + 1 day off PS 
1 
 
 
 
2 
 
 
1 day 
1 day on PS + 1 day off PS 
1 
 
 
 
 
 
 
0 days 
2 days off PS 
 
 
 
 
 
 
 
8.2.4 
Patient Diary 
Patients will be required to complete diaries throughout the course of the trial. Patients will 
record the following: 
• Details regarding trial product administration, including date and time of the day as well 
as injection site area used, i.e. abdomen or thigh 
• PS use (SBS-IF only) including bag name, volume and infusion date on an ongoing basis 
• Urine volume and oral fluid intake will be recorded by the patient during the defined 48-
hour periods prior to a trial visit 
o The patient should perform the 48-hour measurement on the same days of the 
week during each period as long as the PS regimen remains the same. The 
selected days will be recorded in the patient diary. 
• If the PS regimen changes during the trial, a new schedule for 48-hour measurement can 
be chosen and recorded in the patient diary 
The Investigator (or designee) must review the patient´s diary entries routinely throughout the 
entire trial period. If clarification of entries or discrepancies in the diary is needed, the patient 
must be questioned, and a conclusion made in the patient's medical record and in the diary. Care 
must be taken not to bias the patient. 


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8.2.5 
Absorption of Wet Weight/Fluids 
During both 48-hour metabolic balance studies (Visit 1 and Visit 9), the duplicate meal and 
liquid intake and the total excretion of stomal output and/or diarrhea will be collected and 
weighed. Absorption of wet weight/fluids is calculated as oral intake (liquid and solid) minus 
fecal output. Absolute intestinal wet weight absorption (g/day) = oral wet weight intake (liquid 
and solid) – fecal wet weight output. Changes from baseline to Week 24 (Visit 9) will be 
measured. 
8.2.6 
Absorption of Energy 
During both 48-hour metabolic balance studies (Visit 1 and Visit 9) the processed dry matter for 
the duplicate meal and all liquid intake and the fecal output will be analyzed for energy content 
by bomb calorimetry. Absorption of energy is measured as oral intake (liquid and solid) minus 
fecal output. Changes from baseline to Week 24 (Visit 9) will be measured. 
8.2.7 
Absorption of Macronutrients 
During both 48-hour metabolic balance studies (Visit 1 and Visit 9), the processed dry matter for 
the duplicate meal and all liquid intake and the fecal output will be analyzed for macronutrients: 
fat by titration, carbohydrate by Englyst’s method (33) and nitrogen by Kjeldahl’s method (34). 
Energy will be assessed by bomb calorimetry. Absorption of macronutrients is measured as oral 
intake (liquid and solid) minus fecal output. Changes from baseline to Week 24 (Visit 9) will be 
measured. 
8.2.8 
Absorption of Electrolytes 
During both 48-hour metabolic balance studies (Visit 1 and Visit 9), the homogenized wet 
weight of the duplicate meal and all liquid intake and the fecal output will be analyzed for 
electrolytes. Absorption of electrolytes is measured as oral intake (liquid and solid) minus fecal 
output. Changes from baseline to Week 24 (Visit 9) will be measured. 
8.2.9 
Weekly PS Volume (SBS-IF Only) 
During the trial, PS volume and content will be regulated according to changes in urine output, 
weight change and clinical symptoms of fluid overload. During the second part of the trial, this 
will be based on a 48-hour measurement without a fixed drinking menu. Changes from baseline 
to Week 12 (Visit 6), Week 24 (Visit 9) and Week 52 (Visit 12) will be measured. 
Requirement for PS volume reduction: 
 
IF: daily urine volume of the current visit is at least 10% higher than baseline urine volume. 
Quantity of PS volume reduction: 
 
THEN: New PS volume (weekly) = Current PS volume (weekly) – 7 x absolute increase in 
daily urine volume. 
Example: 
Patient received so far 10 L of PS per week. The urine output has increased from 1300 mL per 
day to 1500 mL per day. Hence, the urine output has increased by more than 10% and PS 
volume should be reduced. The new weekly PS volume should be 8.6 L (10 L – 7 x 200 mL). 


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PS volume and content may be changed for safety reasons, e.g. if clinical signs of laboratory 
values support this or in case of clinical signs of fluid overload, as judged by the Investigator. 
In cases where a patient may not have been fully compliant with the adherence to the prescribed 
PS volume, the drinking menu, and/or may have missed a urine measurement (e.g., in case the 
patient has missed to report a urine measurement during the 48-hour measurement period), the 
Investigator may still perform adjustments to the new PS volume at the Investigators discretion, 
in order to best match the needs of the patient and in adherence with the algorithm stated above. 
In that case, the reason for the change must be documented in the eCRF. 
The patients should be instructed to contact the clinical site in case urine production falls below 
normal and if their clinical status changes. 
Increasing PS volume: 
Increasing PS volume should be considered if laboratory parameters indicate safety concerns. If 
the average urine production falls below 1 L per day, the Investigator should consider increasing 
PS volume. 
If PS is not adjusted according to the algorithm (within ±200mL/day) a reason for not adhering 
to the algorithm must be provided in the eCRF. 
8.2.10 
Weekly PS Macronutrients and Electrolytes (SBS-IF Only) 
Changes to the content of PS are left to the discretion of the Investigator and the reason is 
documented in the eCRF. Changes from baseline to Week 12 (Visit 6) and Week 24 (Visit 9) 
will be measured. This only applies for patients with SBS-IF. 
8.2.11 
Body Weight 
For both 48-hour metabolic balance studies an average of the two 24-hour days will be 
calculated. Changes from baseline to Week 12 (Visit 6), Week 24 (Visit 9) and Week 52 (Visit 
12) will be measured. See also Section 8.1.3. 
8.2.12 
Body Composition by DEXA 
A DEXA scan shows the distribution of total body fat, lean body mass and bone mineral content 
and thus, also contributes as a safety assessment to determine if patients accumulate fluid as 
edema. DEXA is a low dose x-ray assessment equivalent to 1/10 of the dose of a regular x-ray 
examination of the thorax. Patients are exposed to less than 0.0005 mSv per scan. During the 
whole trial (4 DEXA-scans), the radiation dose is comparable to one day of natural background 
radiation (35). The radiation a patient is exposed to is considered low and is not associated with 
any known risk. A full DEXA scan takes approximately 20 minutes. 
The total lean body mass, total fat mass, fat percent, total bone mineral content, bone mineral 
density as well as the T-score and Z-score will be measured using DEXA scan. 
Changes from baseline to Week 12 (Visit 6), Week 24 (Visit 9) and Week 52 (Visit 12) will be 
measured. 
8.2.13 
Citrulline 
Samples for measurement of Lith-Hep plasma citrulline should be taken in the morning after at 
least 10 hours (±1 hour) of oral fasting. Smoking is not permitted the last 2 hours prior to blood 
sampling. Samples will be taken prior to first dose of trial product at Visit 1 and prior to 


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administration of trial product at other visits (if dosing occurs on the visit day). Details are 
provided in the laboratory manual. The samples will be stored at the trial site until shipment for 
analysis by special laboratory Klinische Chemisch Laboratorium, Nijmegen, Holland. Samples 
will be destroyed after analysis. 
Changes from baseline to Week 12 (Visit 6), Week 24 (Visit 9) and Week 52 (Visit 12) will be 
measured. 
8.2.14 
Aldosterone 
Blood samples for measurement of plasma aldosterone will be drawn prior to first dose of trial 
product at Visit 1 and prior to administration of trial product at other visits (if dosing occurs on 
the visit day). Details are provided in the laboratory manual. Analysis will be performed at the 
local laboratory at the trial site. Samples will be destroyed after analysis. 
Changes from baseline to Week 12 (Visit 6), Week 24 (Visit 9) and Week 52 (Visit 12) will be 
measured. 
8.2.15 
Hemoglobin A1c 
Blood samples for measurement of hemoglobin A1c (HbA1c) will be drawn prior to first dose of 
trial product at Visit 1 and prior to administration of trial product at other visits (if dosing occurs 
on the visit day).1 Details are provided in the laboratory manual. Analysis will be performed at 
the local laboratory at the trial site. Samples will be destroyed after analysis. 
Changes from baseline to Week 4 (Visit 4), Week 12 (Visit 6), Week 24 (Visit 9) and Week 52 
(Visit 12) will be measured.  
8.2.16 
eGFR, Creatinine Clearance and Liver Function Tests 
eGFR will be calculated by modification of diet in renal disease (MDRD) formula based on the 
patient’s creatinine level, age, body size and gender. Creatinine levels are measured as part of the 
safety laboratory tests (see Section 8.3.5). 
Liver function will be assessed based on levels of ALT, AST, alkaline phosphatase (ALP), 
albumin and bilirubin. Levels are measured as part of the safety laboratory tests (see Section 
8.3.5). 
Changes from baseline to Week 12 (Visit 6) and Week 24 (Visit 9) and Week 52 (Visit 12) will 
be measured. 
8.2.17 
Patient Reported Outcomes 
The PGIC, SBS-I and EQ-5D-5L (36). PROs will be used to investigate the effects of treatment 
on health-related quality of life. 
Questionnaires must be completed in paper format at site visits, see Table 1, prior to any other 
trial-related assessment. The PROs will be completed by the patient without assistance of site 
personnel. 
• When all 3 questionnaires are to be completed at a visit, patients are recommended to 
first complete the PGIC followed by the SBS-I and the EQ-SD-5L. 
                                                 
1 Blood samples for analyses of HbA1c will only be collected for patients who reach Week 4 after protocol 
amendment #2 has become effective. 


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• When only the SBS-I and EQ-5D-5L are to be completed at a visit, it is recommended 
that the SBS-I is completed first. 
The PROs must not be completed at home before the patient attends the visit (however, see also 
COVID-19 Management, section 8.1.7). Patients will be instructed to complete the PROs in a 
private area without influence from site personnel or accompanied by family or friends. No one 
is allowed to answer or interpret items for the patient. The Investigator or a delegated site 
personnel is allowed to read items/answers options to the patient aloud if the patient is unable to 
read. The Investigator or delegated site personnel will instruct the patient to complete every item 
in the PROs and explain that there are no right or wrong answers. The Investigator or a delegated 
site personnel will instruct the patient to give the best answer they can and explain that all 
responses will remain confidential. 
Immediately after completion, the PROs will be reviewed by the Investigator (or designee) for 
completeness and potential AEs. When reviewing the PROs for AEs the Investigator should not 
influence nor question the patient on the content of their response to PRO questions. Review of 
the PROs must be documented. If entries are missing in the PROs, the patient should be asked to 
answer all questions. Care should be taken not to bias the patient. 
The Investigator and/or delegated site personnel will receive training and instruction in 
completion of the PROs prior to the conduct of the trial. 
8.2.18 
Microbiome Composition 
Fecal samples may be analyzed for microbe abundance using 16 rDNA sequencing. Absolute 
abundance, using spike-in bacteria, will allow for absolute values that will be compared between 
patients at baseline and after 24 weeks of treatment. Samples will be analyzed at Clinical 
Microbiomics, Copenhagen. 
8.2.19 
Weekly PS Macronutrients and Electrolytes: Change from baseline to Week 52 
(SBS-IF Only) 
Changes to the content of PS are left to the discretion of the Investigator and the reason is 
documented in the eCRF. Changes from baseline to Week 52 will be measured. This only applies 
for patients with SBS-IF. 
8.2.20 
Weekly Days on PS (SBS-IF Only) 
The changes from baseline of weekly days on PS and the weekly average administration time to 
Week 12, 24 and 52 will be measured. This only applies for patients with SBS-IF. 
8.2.21 
Fluid Composite Effect 
The fluid composite effect has been defined as parenteral volume + oral fluid volume - urine 
volume. Changes from baseline to Week 12 (Visit 6), Week 24 (Visit 9) and Week 52 (Visit 12) 
will be measured. 
8.2.22 
Urine Output (SBS-II Only) 
During the baseline and treatment metabolic balance study (Visit 1 and Visit 9), and at home 
before V2-V8 and V10-V12, the total urinary output for 48 hours will be measured. This will be 
performed under a fixed drinking menu (see Section 8.2.2). Changes from baseline to Week 12 
(Visit 6) and Week 24 (Visit 9) will be calculated. Likewise, changes in 48-hour urine output 


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from Week 24 (Visit 9) to Week 52 (Visit 12) will be measured. This will be performed without 
a fixed drinking menu (see Section 8.2.2). This only applies for patients with SBS-II. 
8.2.23 
Drinking Volume During 48-hour Periods 
The drinking volume during the 48-hour periods will be recorded. Changes from Week 24 (Visit 
9) to Week 52 (Visit 12) will be measured. 
8.3 
Safety Assessments 
Planned time points for all safety assessments are provided in the flowchart (see Section 1.2). 
Safety will be assessed by the following parameters: 
• Body weight 
• Physical examination 
• Vital signs 
• ECGs 
• Clinical laboratory tests (hematology, biochemistry and urinalysis) 
• Immunogenicity 
• AEs 
8.3.1 
Body Weight 
Body weight (kg) will be measured at every visit (see Section 8.1.3 and 8.2.11). 
8.3.2 
Physical Examinations 
At screening, patients will undergo a full physical examination, consisting of the following: 
General Appearance, Skin and mucosae, Head, Ears, Eyes, Nose and Throat incl. thyroid gland, 
Heart, Lung, Chest (incl. breast), Abdomen (incl. genitourinary system), Nervous System, 
Lymph Nodes, and Musculoskeletal. Abnormalities on physical examination will be recorded in 
the patient’s medical notes and in the eCRF. Clinically significant changes from baseline 
examination that are noted during follow-up will be recorded as an AE. 
During the treatment phase, an abbreviated physical examination, driven by SBS (e.g. edema), 
will be performed. The body systems included in these exams will be based on Investigator 
judgment and/or patient symptoms. 
8.3.3 
Vital Signs 
The following vital signs will be collected: body temperature (ºC) (measured according to the 
site’s usual procedure), pulse rate (beats/min), and seated diastolic and systolic blood pressure 
(mm Hg). During the treatment period visits, vital signs will be collected prior to injection of 
trial product, if the visit is scheduled on a dosing day. 
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest for 
the patient in a quiet setting without distractions. Blood pressure and pulse rate measurements 
will be performed with a completely automated device. Manual techniques must be used only if 
an automated device is not available. Clinically significant changes from baseline examination 
that are noted during follow-up will be recorded as an AE. 


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8.3.4 
Electrocardiograms 
A 12-lead ECG will be performed. During the treatment phase, ECG will be obtained prior to 
dosing of trial product if trial product is administered on the same day. 
ECG parameters (heart rate, PR, QRS, QT, QTcF, RR) and any abnormality will be recorded and 
described in the eCRF including the Investigator’s assessment of clinical significance 
(‘abnormal, not clinically significant’ or ‘abnormal, clinically significant’). Any clinically 
significant deterioration of a pre-existing condition as well as any new clinically significant 
findings will be recorded as AEs. 
Additional ECGs will be performed for cause as needed to evaluate AEs. 
8.3.5 
Clinical Safety Laboratory Assessments 
All laboratory assessments, as defined in Appendix 2: Clinical Laboratory Tests, must be 
conducted in accordance with the laboratory manual and the protocol flowchart. 
All samples should be taken prior to dosing of trial product if trial product is administered on the 
same day. 
Safety laboratory tests include hematology, biochemistry and urinalysis. All parameters assessed 
are listed in Appendix 2: Clinical Laboratory Tests. 
Urinalysis will be performed during the Metabolic Balance Study (Visit 1 and 9), see Table 2 
and Table 7, and at every trial visit by urine dipstick, see Appendix 2: Clinical Laboratory Tests. 
In addition, screening tests will be performed to confirm the HIV, Hepatitis B and C status (if 
positivity is confirmed, the patient will be excluded from participation in the trial). 
Serum pregnancy tests (human chorionic gonadotropin [hCG]) will be performed at screening, 
Visit 1 and  Visit 4 to Visit 12 and the FU visit for women of childbearing potential, and follicle-
stimulating hormone (FSH) will be assessed at screening as needed in women of non-
childbearing potential (to confirm menopause). 
The Investigator must review the laboratory reports, document this review, and record any 
clinically relevant changes occurring during the trial as the AEs. The laboratory reports must be 
filed with the source documents. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the trial should be repeated until the values return to normal or baseline, or are no longer 
considered clinically significant by the Investigator or Medical Monitor. 
In case of suspected liver injury based on increased ALT, AST, ALP, or total bilirubin, the tests 
should be repeated at 48-72 hours for evaluation of the event course/confirmation (see Section 
8.4.6). When drug-induced liver injury (DILI) is suspected based on the transferases values, the 
liver functionality needs to be evaluated by the bilirubin and INR for confirmation/information 
of DILI. 
IMPORTANT: If a generalized hypersensitivity reaction is suspected and assessed as possibly or 
probably related to IMP dosing, additional blood samples should be taken to further characterize 
the reaction. If possible, blood samples should be taken within 4 hours after the event for the 
measurement of tryptase and ADA, and again approximately 2-4 weeks later (or at next planned 
visit) to determine tryptase baseline levels. In addition, samples should be taken for ADA 
according to trial protocol: In case of treatment discontinuation, at the EOT and FU visits. If 


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treatment is continued/re-initiated, an ADA sample should be taken pre-dose 2-4 weeks after the 
reaction (or at the next planned visit). 
8.3.6 
Immunogenicity Assessments 
Serum samples will be obtained to determine the presence of ADA and the ADA titer. Samples 
will be taken before initiation of the first 48-hour metabolic balance study, prior to first dose of 
trial product at Visit 1 (Week 0) and prior to administration of trial product (if dosing occurs on 
the visit day) at other selected visits, i.e. Week 4, 12, 24, 52, and Week 56 at follow-up. Details 
are provided in the laboratory manual. 
In the event that a patient permanently discontinues treatment early, the patient will be asked to 
come for a site visit for ADA sampling at end of treatment and approximately 4 weeks after 
treatment discontinuation, so that a potential ADA response can be characterized and results 
related to the clinical picture. 
The serum samples will be analyzed using a tiered approach (screening, confirmation, and 
titration of confirmed anti-glepaglutide-antibody positive samples), followed by characterization 
of ADA-positive samples for in vitro glepaglutide-neutralizing potential and reactivity to the 
major metabolite (ZP18481-34), and cross-reaction with GLP-2.  
All ADA samples will be retained at the special laboratory Syrinx Bioanalytics Oy, Finland, or 
long-term storage facility at MLM Medical Labs GmbH, Germany, until drug approval by FDA 
and/or the European Medicines Agency (EMA) or 15 years after end of trial at maximum. The 
retained ADA samples may be used for further confirmation and characterization of detected 
ADAs if required by health authorities or for safety reasons. 
8.4 
Adverse Events and Serious Adverse Events 
Timely, accurate, and complete reporting and analysis of safety information from clinical trials 
are crucial for the protection of patients. Investigator and Sponsor are mandated by regulatory 
agencies worldwide to report the safety information. 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the trial intervention or trial procedures, or that 
caused the patient to discontinue the trial (see Section 7). 
See further guidance in Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting. 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs, whether serious or non-serious, must be collected from the time a signed and dated 
informed consent form is obtained until the follow-up visit. 
Patients will be observed for any signs or symptoms and asked about their condition by open 
questions, such as “How have you been feeling since you were last asked?” at each contact with 
the trial site. Patients will also be encouraged to spontaneously inform the Investigator of any 
signs or symptoms occurring at any other time during the trial. 
All AEs, regardless of seriousness, severity, or presumed relationship to trial product, must be 
recorded and evaluated by the Investigator. Whenever possible, diagnoses should be given when 
signs and symptoms are due to a common etiology. If no diagnosis can be made, the Investigator 


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should record each sign and symptom as individual AEs. Investigators must record their opinion 
concerning the relationship of the AE to the trial product. All measures required for AE 
management must be recorded in the source document and reported according to Sponsor 
instructions. 
• All AEs will be reported in the eCRF. 
• AE information should as a minimum include the following: 
o Date and time of onset. 
o Date and time of Investigators first information about the AE. 
o Seriousness. 
o Severity. 
o Causal relationship with trial product. 
o Measures taken due to AE. 
o Interruption or discontinuation of treatment with trial product. 
o Date of resolution and final outcome. 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).1 
All SAEs will be recorded and reported to Pharmalex immediately and under no circumstance 
should this exceed 24 hours, as indicated in Appendix 3: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting. The Investigator will submit 
any updated information on SAEs to Pharmalex within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the trial 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a patient has been discharged from the trial, and he/she considers the event to be reasonably 
related to the trial intervention or trial participation, the Investigator must promptly notify the 
Sponsor. 
8.4.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Section 10.3 (Appendix 3). 
Care should be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.4.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs including AESIs (as defined in Section 8.4.6) will be 
followed up until resolution, stabilization, the event is otherwise explained, or the subject is lost 
to follow-up (as defined in Section 7.3). As the case for initial AEs/SAEs, follow-up information 
is reported in the eCRF. Follow-up questions to Investigators regarding SAEs are queried 
directly by Pharmalex to the Investigator. Further information on follow-up procedures is 
provided in Section 10.3 (Appendix 3). 
Follow-up information must be reported according to the following: 
                                                 
1 The most current version at the beginning of the trial. 


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• SAEs: All SAEs must be followed until the outcome of the events is 
“recovered/resolved”, “recovered/resolved with sequelae”, or “fatal”, and until all queries 
have been resolved. Cases of chronic conditions, cancer, or AEs ongoing at time of death 
(where death is due to another AE) may be closed with the outcome 
“recovering/resolving” or “not recovered/not resolved”. Cases can be closed with the 
outcome of “recovering/resolving” when the patient has completed the follow-up period 
and is expected by the Investigator to recover. 
The SAE follow-up information should only include new (e.g., corrections or additional) 
information and must be reported within 24 hours of the Investigator’s first knowledge of the 
information. This is also the case for previous non-serious AEs which subsequently become 
SAEs. 
• Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
“recovering/resolving”, “recovered/resolved”, or “recovered/resolved with sequelae” or 
until the end of the follow-up period stated in the protocol, whichever comes first, and 
until all queries related to these AEs have been resolved. Cases of chronic conditions, 
cancer, or AEs ongoing at time of death (where death is due to another AE) may be 
closed with the outcome of “recovering/resolving” or “not recovered/not resolved”. Cases 
can be closed with the outcome of “recovering/resolving” when patient has completed the 
follow-up period and is expected by the Investigator to recover. 
 
The Investigator must ensure that the worst-case severity and seriousness of an event is kept 
throughout the trial, i.e. if the severity of an AE changes over time then it should be reported as a 
single AE with worst-case severity. A worsening of an unresolved AE must be reported as 
follow-up with re-assessment of severity and/or seriousness of the event. 
If an AE is resolved and re-appears later then it should be reported as a new AE. 
Queries or follow-up requests must be responded within 14 calendar days from the date of 
receipt of the request, unless otherwise specified in the follow-up request. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a trial 
intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a trial intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Independent Ethics Committees (IEC), and Investigators. 
For all trials, except those utilizing medical devices, Investigator safety reports must be prepared 
for suspected unexpected serious adverse reactions (SUSAR) according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file 


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it along with the Investigator’s Brochure and will notify the IEC, if appropriate according to 
local requirements. 
8.4.5 
Pregnancy 
Pregnancy during the trial should be avoided and the patients must be instructed in highly 
effective contraception as per local guidelines (see Contraception Guidance in Appendix 4: 
Contraceptive Guidance and Collection of Pregnancy Information), and to use this throughout 
the trial through 4 weeks after receiving the last dose of trial product. 
Pregnancy information for female patients and female partners of male patients will be collected 
after the start of trial treatment and until the follow-up visit. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Section 10.4 (Appendix 
4). 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
If a patient becomes pregnant during the trial, the patient should be withdrawn from trial (see 
Section 7.2). 
8.4.6 
Adverse Events of Special Interest 
In this trial the following events are to be regarded as AESIs, should they occur: 
• Neoplasms (malignant and benign) 
• Suspicion of liver injury 
• Pancreatitis 
• Cholecystitis 
If the event is reported as an SAE, the timelines for SAE reporting apply. If the event is reported 
as a non-serious AE, it should be reported in the dedicated eCRF page within 2 working days (if 
at all possible) of Investigator’s first knowledge. 
The event-specific information that needs to be captured in addition to the standard AE 
information is presented below: 
Neoplasms: 
Information on histopathology (date of examination and results), imaging (if imaging is 
performed), TNM staging, history of cancer (the patient’s and family), treatment received for 
this event, and an event narrative. Copies of images (if performed) should be stored at site. A 
retrospective imaging review may be performed if deemed necessary. 
Suspicion of Liver Injury: 
Suspicion of liver injury* is defined as: 
• ALT or AST increasing more than 3 times from baseline value, or 
• ALT or AST > 5 × ULN and total bilirubin > 2 x ULN, or 
• ALT or AST > 5 × ULN and INR > 1.5. 
* In that case, the tests should be repeated at 48-72 hours for evaluation of the event 
course/confirmation. Furthermore, additional information needs to be provided by the site, e.g. 


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physical examination, information on alcohol consumption, concomitant therapy (including 
herbals). 
Narrative of the event should include: 
• Clinical signs and symptoms and how they developed over time. Aspects like e.g. 
abdominal pain, nausea, vomiting, jaundice, fever, rash, abdominal tenderness, 
hepatomegaly, splenomegaly, blood pressure, peripheral edema, jugular venous 
distension, signs of ascites, recent weight gain should be considered and described. 
• Information on relevant medical history, alcohol consumption, and relevant concomitant 
therapy (including herbals). 
• Lab tests (at local lab, if needed): as a minimum ALT, AST, Bilirubin (direct and total) 
and INR. Other tests may be warranted as clinically indicated. 
• Imaging diagnostic (ultrasound/CT scan/MRI/Other imaging modality). Copies of images 
(if performed) should be stored at site. 
• Biopsy results (if performed). 
Pancreatitis: 
Narrative of the event should include: 
• Clinical signs and symptoms and how they developed over time. Aspects like pain 
(character of the pain including the anatomical region (e.g. sudden and in center 
abdomen) +/- irradiating pain in the back), tenderness of the abdomen, diarrhea, 
indigestion, fever, jaundice) should be considered and described. 
• Information on relevant medical history, alcohol consumption, and relevant concomitant 
therapy (including herbals). 
• Lab tests (at local lab, if needed): pancreatic and liver function tests, including lipase, 
amylase, ALT, AST, bilirubin, and ALP. Other tests may be warranted as clinically 
indicated. 
• Imaging diagnostic (ultrasound/CT scan/MRI/Other imaging modality). Copies of images 
(if performed) should be stored at site. 
• Biopsy results (if performed). 
Cholecystitis: 
Narrative of the event should include: 
• Clinical signs and symptoms and how they developed over time. Aspects like pain 
(character of the pain including the anatomical region (e.g. sudden, after a large meal, in 
upper right or center abdomen) +/- irradiating pain to right shoulder or back), tenderness 
of the abdomen, nausea, vomiting, and fever should be considered and described. 
• Information on relevant medical history, alcohol consumption, and relevant concomitant 
therapy (including herbals). 
• Lab tests (at local lab, if needed): liver function tests, including ALT, AST, bilirubin, and 
ALP. Other tests may be warranted as clinically indicated. 
• Imaging diagnostic (ultrasound/X-Ray/CT scan/MRI/Other imaging modality). Details 
like presence of gall bladder stones and common bile duct diameter should be reported, if 
available. 


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8.4.7 
Other Important Events 
The following events must always be reported to Pharmalex according to SAE timelines, 
regardless of whether the event is non-serious or serious: 
• Suspicion of transmission of infectious agents via the trial product. 
• Overdose of the trial product. 
• Medication error involving the trial product. 
• Inadvertent or accidental exposure to the trial product. 
 
Note: Medication errors are defined as all unintended failures (e.g. wrong kit, missing dose, not 
taking the full amount, etc.) to administer the investigational product correctly that either: 
• Lead to harm to the patient 
• Have the potential to lead to harm to the patient 
 
Other important events must be recorded in the eCRF. 
8.4.8 
Technical Complaints 
Technical complaints on trial products and technical issues with the device will be reported by 
the Investigator via the eCRF. 
8.4.9 
Precautions 
Normal precautions taken for a human trial, including the provision of emergency equipment, 
will be taken during this trial. Qualified and well-trained physicians and medical staff will 
instruct the patients. During a patient’s participation in the trial, the Investigator should ensure 
that adequate medical care is provided to the patients for any AEs, including clinically 
significant laboratory values related to the trial. The Investigator should inform the patient when 
medical care is needed for intercurrent illnesses of which the Investigator becomes aware. 
For further information on safety precautions for glepaglutide, refer to the current version of the 
Investigator’s Brochure. 
8.5 
Treatment of Overdose 
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
• Contact the Medical Monitor immediately. 
• Closely monitor the patient for any AE/SAE and laboratory abnormalities for at least 14 
days. In case of AEs/SAEs, these should be followed up until resolution, stabilization or 
until the event is otherwise explained, or the subject is lost to follow-up as described in 
section 8.4.3. 
• Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 


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8.6 
Pharmacokinetics 
PK parameters will be assessed as an exploratory endpoint. 
Blood samples for assessment of PK will be taken according to Table 3 , and prior to 
administration of trial product at other visits (if dosing occurs on the visit day). Details are 
provided in the laboratory manual. The actual date and time of each sample will be recorded. 
The PK sampling schedule is set in order to be able to correlate PK values of glepaglutide to 
ADA data and to obtain sufficient information from the dosing regimen tested. Results will not 
be revealed to the site. PK samples will be shipped for analysis to Charles River Laboratories, 
UK. Samples will be destroyed after completion of the final clinical trial report. 
8.7  
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this trial. 
8.8 
Genetics 
Genetics are not evaluated in this trial. 
8.9 
Biomarkers 
Biomarkers are not evaluated in this trial. 
8.10 
Health Economics 
Health Economics parameters are not evaluated in this trial. 
8.11 
Unscheduled Visits 
If required an unscheduled visits can be performed, including, but not limited to, any of the 
following: 
• PS volume adjustments 
• Lab sampling: In case of suspected liver injury based on increased ALT, AST, ALP, or 
total bilirubin, the tests should be repeated at 48-72 hours for evaluation of the event 
course/confirmation 
• Additional trial product dispensing and/or to replace trial product to ensure that no patient 
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9 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Hypotheses 
The primary statistical null hypothesis 𝐻𝐻0 is defined as 
𝐻𝐻0: 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 24-week change in Wet Weight Absorption = 0 
With the alternative hypothesis being defined as 
𝐻𝐻𝑎𝑎: 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 24-week change in Wet Weight Absorption ≠ 0 
For the key secondary endpoint the corresponding null hypothesis is defined as 
𝐻𝐻0: 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 24-week change in absorption of energy = 0 
With the alternative hypothesis being defined as 
𝐻𝐻𝑎𝑎: 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 24-week change in absorption of energy ≠ 0 
The statistical hypotheses will be tested sequentially in a hierarchical testing procedure, such that 
the rejection of the primary hypothesis leads to the test of the secondary hypothesis, whereas the 
acceptance of the primary hypothesis prevents confirmatory testing of the secondary null 
hypothesis. In addition to the primary and secondary hypotheses, supplementary analyzes will be 
performed that analyze the primary hypotheses for the SBS-II and SBS-IF patients separately. 
The supplementary analyzes will however not be part of the testing strategy. 
9.2 
Sample Size Determination 
Sample size is planned based on both, feasibility considerations and statistical considerations. 
Sample size should be such that there is sufficient power to reject at least the primary null 
hypothesis (primary endpoint). In the phase 2 trial, ZP1848-15073, after three weeks of 
treatment, the pooled 1 and 10 mg/day treatment groups displayed a mean (SD) change from 
baseline in absorption of wet weight fluids of 719 g/day (340 g/day), corresponding to an effect 
size (mean divided by standard deviation) of 2.11. Calculations based on a one-sample t-test 
(alpha= 0,05, two-sided) reveal 90% power for a statistically significant test result of the primary 
null hypothesis, if an effect size of 2.11 can be assumed and 5 patients are analyzed. The effect 
size is the true population mean of the 24 week change in wet weight absorption divided by its 
standard deviation. 
In the same trial, the change from baseline in the intestinal energy absorption was 391 KJ/day 
(1374 KJ/day), corresponding to an effect size of 0.28.While achieving statistical significance for 
the key secondary endpoint in addition to the primary endpoint is aimed for, a sample size 
providing high power for the key secondary endpoint is not considered feasible, should a similar 
variability have to be expected for the present study. It seems, however, reasonable to assume 
that the variability of results for the key secondary endpoint will be lower after 24 weeks 
compared to after 3 weeks. Should the reduced variability lead to an effect size of around 1.15, 
then the below table shows that 90% power can be achieved with 10 patients in the analysis, and 
80% power can be achieved with 8 patients in the analysis. Even a less extensive reduction in 
variability can still lead to a reasonable power with 8 to 10 patients in the analysis. 
 


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Table 9 
Power calculation of a One-Sample t-test for different effect sizes 
Number Of Patients 
Effect Size 
 
Power (%) 
8 
1,156 
 
80 
8 
1,2 
 
82 
8 
1,3 
 
88 
8 
1,342 
 
90 
8 
1,4 
 
92 
 
 
 
 
10 
0,996 
 
80 
10 
1,0 
 
80 
10 
1,1 
 
87 
10 
1,155 
 
90 
10 
1,2 
 
92 
Taken together, the sample size will be as follows: Aiming for at least 8 patients in the full analysis 
set (i.e. patients assigned to trial treatment who received at least one dose), 2 more patients will be 
allocated to treatment. This means patients will be screened until 10 eligible patients (eligible with 
respect to inclusion and exclusion criteria) are enrolled and allocated to treatment. Patients with 
SBS-II and SBS-IF will be included in the trial, with an aim of an equal distribution between the 
two. 
9.3 
Analysis Sets 
The analysis of efficacy will be performed based on the full analysis set (primary confirmatory 
analysis) and based on the per-protocol analysis set (supportive analysis). The analysis of safety 
will be based on the safety analysis set. The analysis are defined in Table 10 : 
Table 10 Analysis Sets 
Analysis Set 
Description 
Full analysis set (FAS) 
The FAS comprises all patients assigned to trial treatment who received at 
least one dose of trial product. 
Per-protocol analysis set 
The per-protocol analysis set comprises all FAS patients without major 
protocol deviations. Criteria for exclusion from the per-protocol analysis set 
will be listed in the statistical analysis plan (SAP). Final judgment on 
exclusion from the per-protocol analysis set will be made prior to database 
lock. The per-protocol analysis set will be used for supplementary analyzes of 
the primary and key secondary efficacy endpoints. 
Safety analysis set (SAS) 
The SAS comprises all patients who received at least one dose of trial product. 
9.4 
Statistical Analyzes 
The statistical analysis plan (SAP) will be finalized prior to database lock, and it will include a 
more technical and detailed description of the statistical analyzes described in this section. This 
section is a summary of the planned statistical analyzes of the most important endpoints 
including primary and key secondary endpoints. Any changes from the methods planned in the 
SAP will be justified in the clinical trial report (CTR). 
9.4.1 
General Considerations 
Statistical analyzes will be performed after end of trial, when the database has been locked. The 
results will be included in the CTR. 


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The primary analysis will be based on observed data, missing data will not be replaced. 
Sensitivity analyses with regard to the handling of missing data may be described in the SAP. 
In general, data will be summarized using descriptive statistics: Continuous data will be 
summarized by presenting the number of non-missing observations, mean, standard deviation 
(SD), median, minimum, and maximum. Categorical data will be summarized by presenting the 
number of patients and percentage for each category. Listings of individual patient data will be 
presented. 
9.4.2 
Demographics and Baseline Characteristics 
Demographic data, SBS history, medical history/concomitant illness and other baseline data will 
be summarized in terms of descriptive statistics. 
9.4.3 
Primary Endpoint - Absorption of Wet Weight/Fluids 
The primary efficacy endpoint is change from baseline to Week 24 for absorption of wet 
weight/fluids assessed by 48-hour metabolic balance studies. 
The primary analysis will use a one-sample t-test (two-sided alpha= 0.05) to analyze the mean 
change from baseline in absorption of wet weight/fluids to Week 24. The null hypothesis to be 
tested is defined in Section 9.1. The primary analysis will include all FAS patients, a descriptive 
analysis will also be provided separately for patient with SBS-II and patient with SBS-IF. 
The primary estimand for the primary endpoint is defined according to the intention-to-treat 
principle as follows: The population will be the FAS DB, the variable will be 24 week change in 
absorption of wet weight/fluids, the population level summary will be the arithmetic mean, and 
intercurrent events will be handled as follows: With regards to intercurrent events like lack of 
compliance with intake of trial product, lack of compliance with instructions concerning intake 
of food, fluids or PS, or use of prohibited concomitant medication the treatment policy strategy 
will be applied, i.e. data will be included in the analysis even if collected after occurrence of 
such an intercurrent event. 
More details will be described in the SAP. This may include definition of an estimand with 
handling of intercurrent events according to the hypothetical strategy. 
9.4.4 
Secondary Endpoints 
The key secondary endpoint change from baseline to Week 24 in absorption of energy (measured 
by bomb calorimetry and based on 48 hour metabolic balance studies) will be analyzed using the 
same approach as for the primary endpoint. According to the hierarchical testing procedure a 
statistical test in the confirmatory sense will only be performed in case the test for the primary 
endpoint was statistically significant. 
The other secondary endpoints (changes from baseline for absorption of individuals 
macronutrients, absorption of electrolytes, weekly PS volume [SBS-IF only], and weekly PS 
macronutrients and electrolytes [SBS-IF only]) will be analyzed descriptively. 
9.4.4.1 
Absorption of Energy (Key Secondary Endpoint) 
Change from baseline to Week 24 measured by 48-hour metabolic balance studies. Energy 
absorption is measured by bomb calorimetry. 


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9.4.4.2 
Absorption of Individual Macronutrients 
Change from baseline to Week 24 measured by 48-hour metabolic balance studies. 
9.4.4.3 
Absorption of Electrolytes 
Absorption of electrolytes (sodium, potassium, calcium and magnesium): Change from baseline 
to Week 24 measured by 48-hour metabolic balance studies. 
9.4.4.4 
Weekly PS Volume (SBS-IF Only) 
Change from baseline to Week 12 and Week 24. 
9.4.4.5 
Weekly PS Macronutrients and Electrolytes (SBS-IF Only) 
Change from baseline to Week 12 and Week 24. 
9.4.5 
Exploratory Endpoints 
For details on analyzes of exploratory endpoints, please refer to the SAP. 
9.4.6 
Other Safety Analyzes 
All safety analyzes will be made on the SAS. The standard safety assessments (AEs [only 
treatment-emergent AEs will be tabulated, whereas non-TE AEs will be listed], safety laboratory 
parameters, vital signs, etc.) will be reported descriptively; including any notable changes of 
clinical interest in laboratory parameters. Treatment-emergent AEs are defined as AEs with onset 
date on or after the day of first administration of trial product. 
9.4.7 
Other Analyses 
No formal statistical interim analysis is planned. Safety data may need to be summarized for 
regulatory purposes while the study is ongoing. 
9.5 
Interim Analyzes 
An interim analysis may be conducted during the course of the trial. 
9.6 
Data Monitoring Committee (DMC) 
No Data Monitoring Committee will be established in this clinical trial. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki (37) and applicable ICH Good Clinical Practice 
Guidelines (38) 
o Applicable laws and regulations 
• The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents must be submitted to an IEC by the Investigator 
and reviewed and approved by the IEC before the trial is initiated. 
• Any amendments to the protocol will require IEC approval before implementation of 
changes made to the trial design, except for changes necessary to eliminate an immediate 
hazard to trial patients. 
• The Investigator will be responsible for the following: 
o Providing written summaries of the status of the trial to the IEC annually or more 
frequently in accordance with the requirements, policies, and procedures 
established by the IEC 
o Notifying the IEC of SAEs or other significant safety findings as required by IEC 
procedures 
o Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IEC, European regulation 536/2014 
for clinical studies, and all other applicable local regulations 
10.1.2 
Financial Disclosure 
The Investigator and Sub-Investigators will provide Sponsor with sufficient, accurate financial 
information as requested to allow Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the trial and 1 year after 
completion of the trial. 
10.1.3 
Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance coverage in accordance with 
all legal requirements. The civil liability of the Investigator, the person instructed by him or her 
and the hospital, practice, or institute in which they are employees and the liability of the Sponsor 
with respect to financial loss due to personal injury and other damage that may arise as a result of 
carrying out this trial are governed by the applicable law. The Sponsor will arrange for liability 
insurance if trial patients should be injured due to the participation in the trial and will provide that 
Sponsor is legally liable for that. Excluded from the insurance cover are injuries to health and 
deteriorations of illnesses already in existence which would have occurred or continued to exist 
even if the trial patient had not taken part in the clinical trial. 


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The insurance cover is jeopardized if the trial patient fails to report immediately to the Investigator 
or responsible physician any injury to health, which might have resulted from participation in the 
clinical trial, or if he/she undergoes any other medical treatment without their consent before the 
clinical trial has been completely finished insofar as the individual trial patient is concerned. Any 
injury to health, which might have occurred as a result of participation in the clinical trial, must be 
reported by the trial patient to the Investigator without delay. The Investigator is obliged to make 
such a report in any case. 
10.1.4 
Informed Consent Process 
• The Investigator or his representative will explain the nature of the trial to the patient and 
answer all questions regarding the trial. 
• The Investigator must ensure the patient ample time to come to a decision whether or not 
to participate in the trial. 
• Patients must be informed that their participation is voluntary and that the patient may 
withdraw from the trial at any time and for any reason. 
• Patients must be informed about their privacy rights. 
• Patients will be required to sign and date a statement of informed consent that meets the 
requirements of local regulations, Declaration of Helsinki (37), ICH guidelines (38), and 
the IEC or site. 
• The medical record must include a statement that written informed consent was obtained 
before any trial-related activity and the date when the written consent was obtained. The 
authorized person obtaining the informed consent must also sign and date the ICF before 
any trial-related activity. 
• The responsibility of seeking informed consent must remain with the Investigator, but the 
Investigator may delegate the task to a medically qualified person, in accordance with 
local requirements. 
• Patients must be re-consented to the most current version of the ICF during their 
participation in the trial. 
• A copy of the ICF must be provided to the patient. 
10.1.5 
Data Protection 
• Patients will be assigned a unique identifier by the Sponsor. Any patient records or 
datasets that are transferred to the Sponsor will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred. 
• The patient must be informed that his/her personal trial-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the patient who will be required to give consent for their data to be used 
as described in the informed consent. 
• The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IEC members, and by inspectors from regulatory authorities. 


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10.1.6 
Committees Structure 
Internal Safety Committee 
An internal Sponsor Safety Committee is constituted to perform ongoing safety surveillance of 
clinical trials with glepaglutide, including this trial. 
If safety signals or concerns are observed, whether based on reported SAEs, review of all AEs 
and laboratory parameters reported or any other notification of significant findings, the Safety 
Committee will respond appropriately to protect the safety of the patients. 
The Safety Committee meets quarterly and additionally on an ad-hoc basis, as needed, and will 
call upon external expertise when judged needed. 
10.1.7 
Dissemination of Clinical Trial Data 
Information of the trial will be disclosed at clinicaltrials.gov before the first patient enters into 
the trial. It will also be disclosed according to other applicable requirements, such as those of the 
International Committee of Medical Journal Editors (ICMJE) (39), the FDA Amendment Act 
(FDAAA)(40), European Commission Requirements (41,42) and other relevant 
recommendations or regulations. If a patient requests to be included in the trial via a Sponsor e-
mail contact at these web sites, Sponsor disclose the Investigator’s contact details to the patient. 
A CTR describing the conduct of the trial and the results obtained, will be prepared by the 
Sponsor or delegate. A summarizing report will be submitted to the applicable Competent 
Authority (CA) and IEC within 12 months after completion of the trial. 
Trial results (positive, negative or inconclusive) will be reported in the European Clinical Trials 
Database per applicable regulations within 12 months after completion of the trial. Trial 
completion is defined as the date of the last visit (follow-up visit) of the last patient in the trial. 
The primary completion date (PCD) is the last assessment of the primary endpoint, and is for this 
trial last patient first treatment (LPFT) + 24 weeks, corresponding to Visit 9. If the last patient is 
withdrawn early, the PCD is considered the date when the last patient would have completed 
Visit 9. The PCD determines the deadline for results disclosure at clinicaltrials.gov according to 
FDAAA. 
10.1.8 
Data Quality Assurance 
10.1.8.1 Case Report Forms 
• KLIFO A/S is responsible for the data management of this trial including quality 
checking of the data. 
• All patient data relating to the trial will be recorded in an eCRF. The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
• Patients will record data in paper diaries and PROs which subsequently will be 
transferred to the eCRF by the site. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• The following will be provided as paper CRFs: 
o Pregnancy forms. 


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• The following will be provided as paper CRFs to be used when access to the CRF is 
revoked or the CRF is temporarily unavailable: 
o SAE forms 
o Technical complaint forms (also to be used to report complaints on trial product 
not yet allocated to a patient) 
• Corrections to the eCRF data may be made by the Investigator or the Investigator’s 
delegated staff. An audit trail will be maintained in the eCRF application containing as a 
minimum: the old and the new data, identification of the person entering the data, date 
and time of the entry and reason for the correction. If corrections are made by the 
Investigator’s delegated staff after the date when the Investigator signed the eCRF, the 
eCRF must be signed and dated again by the Investigator. 
• The Investigator must ensure that data is recorded in the eCRF as soon as possible, 
preferably within 5 working days after the visit. Once data has been entered, it will be 
available to Sponsor for data verification and validation purposes. 
10.1.8.2 Monitoring 
The Investigator must permit trial-related monitoring, Audits, IEC review, and Regulatory 
Agency Inspections, be available during Audits and Inspections for Interviews and provide direct 
access to source data documents (original documents), data and records. Direct access includes 
permission to examine, analyze, verify and reproduce any record(s) and report(s) that are 
important to the evaluation of the trial. If the electronic medical record does not have a visible 
audit trail, the Investigator must provide the monitor with signed and dated printouts. In addition, 
the relevant site staff should be available for discussions at monitoring visits and between 
monitoring visits (e.g. by telephone). 
Trial monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; to monitor drug 
accountability, and that the trial is being conducted in accordance with the currently approved 
protocol and any other trial agreements, ICH GCP (E6 R2) (38), and all applicable regulatory 
requirements. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Monitoring 
Plan and Medical Monitoring Plan. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial must be 
retained by the Investigator according to relevant legislation after the completion of the trial, and 
no less than 25 years after trial completion. No records may be destroyed during the retention 
period without the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor. 
The Sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 


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10.1.8.3 Protocol Compliance 
Deviations from the protocol should be avoided. If deviations do occur, the Investigator must 
inform the monitor without delay and the implications of the deviation must be reviewed and 
discussed. 
Deviations must be documented and explained in a protocol deviation by stating the reason, date, 
and the action(s) taken. Some deviations, for which corrections are not possible, can be 
acknowledged and confirmed via edit checks in the eCRF or via listings from the trial database. 
10.1.9 
Source Documents 
• All data entered in the eCRF must be verifiable in source documentation other than the 
eCRF. 
• The originals of the completed diaries and PROs must not be removed from the site. 
• Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the site. 
• Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents, or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records. Also, current medical 
records must be available. 
• It must be possible to verify the patient’s medical history in source documents, such as 
the patient’s medical record. 
• The Investigator must document any attempt to obtain external medical information by 
noting the date(s) when information was requested, and who was contacted. 
• Definition of what constitutes source data can be found in a source document agreement 
at the site. There will only be one source document defined at any time for any data 
element. 
10.1.10 
Trial and Site Start and Closure 
The trial start date is the date on which the clinical trial will be open for recruitment of patients. 
The Sponsor designee reserves the right to close the trial site or terminate the trial at any time for 
any reason at the sole discretion of the Sponsor. The trial site will be closed upon trial 
completion. The trial site is considered closed when all required documents and trial supplies 
have been collected and a trial site closure visit has been performed. 
The Investigator may initiate trial site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the Sponsor or Investigator may include but are not 
limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of patients by the Investigator 
• Discontinuation of further trial intervention development 
If the trial is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigator, the IEC, the regulatory authorities, and any contract research organization(s) used 


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in the trial of the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the patients and should assure appropriate 
patient therapy and/or follow-up. 
The trial will be prematurely terminated at any time in the emergence of any safety information 
that could significantly affect continuation of the trial, i.e. AEs or other safety information that 
are considered unacceptable taken the indication into account and resulting in an unacceptable 
benefit-risk ratio. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IEC in case it has an impact on the planned follow-up of patients who have 
participated in the trial. If it has an impact, the actions needed to inform and protect the patients 
should be described. 
10.1.11 
Responsibilities 
The Investigator is accountable for the conduct of the trial at his/her site and must ensure 
adequate supervision of the conduct of the trial at the site. If any tasks are delegated, the 
Investigator is responsible for supervising any individual or party to whom the Investigator 
delegates trial-related duties and functions conducted at the trial site. The Investigator must 
maintain a log of appropriately qualified persons to whom he has delegated specified trial-related 
duties and should implement procedures to ensure the integrity of the trial-related duties and 
functions performed and any data generated. The Investigator must ensure that there is adequate 
and documented training for all staff participating in the conduct of the trial. It is the 
Investigator’s responsibility to supervise the conduct of the trial and to protect the rights, safety, 
and well-being of the patients. 
A qualified physician, who is an Investigator or a sub-Investigator for the trial, must be 
responsible for all trial-related medical decisions. 
The Investigator is responsible for filing essential documents (i.e. those documents which 
individually and collectively permit evaluation of the conduct of a trial and the quality of the 
data produced) in the Investigator trial master file. The documents, including the patient 
identification code list must be kept in a secure locked facility so that no unauthorized persons 
can get access to the data. 
The Investigator will take all necessary technical and organizational safety measures to prevent 
accidental or wrongful destruction, loss or deterioration of data. The Investigator will prevent 
any unauthorized access to data or any other processing of data against applicable law. The 
Investigator must be able to provide the necessary information or otherwise demonstrate to 
Sponsor that such technical and organizational safety measures have been taken. 
During any period of unavailability, the Investigator must delegate responsibility for medical 
care of patients to a specific qualified physician who will be readily available to patients during 
that time. 
If the Investigator is no longer able to fulfill the role as Investigator (e.g. if he moves or retires), 
a new Investigator will be appointed in consultation with the Sponsor. 
The Investigator and other site personnel must have sufficient English skills according to their 
assigned task(s). 


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10.1.12 
Publication Policy 
The site (Institution) reserves the right to publish all findings related to the project; provided, 
however, that Institution, Institution or Investigator shall notify Zealand Pharma of any such 
publication at least 30 day prior to submission for publication to allow Zealand Pharma to ensure 
against inadvertent disclosure of unprotected trial drug discoveries or confidential information. 
Zealand Pharma shall be entitled to receive in any such publication an acknowledgement of its 
contribution to the project. In addition, Institution, or Investigator shall delay any such 
publication, at the request of Zealand Pharma, for up to 90 days to permit Zealand Pharma to 
prepare and file one or more patent applications relating to the subject matter of such 
publication. 
Institution shall undertake to use its best efforts to ensure that the findings of the project are 
made public through publications in scientific journals or scientific conferences. Institution shall 
undertake to use its best efforts to ensure that each publication that it seeks to publish in 
connection with the project complies with applicable international standards, including the 
requirements for financial disclosures, if applicable. 
Upon Institution’s publication of any findings relating to project, Zealand Pharma shall have the 
right to use the published information without any restrictions; provided that Zealand Pharma 
shall do so only with appropriate references. Upon publication Zealand Pharma shall not be 
liable to pay any royalties for the use or re-publication of this information. 
The Sponsor will comply with the requirements for publication of trial results. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
No confidential information shall be disclosed to others without prior written consent from 
Sponsor. Such information shall not be used except in the performance of this trial. 
 
 


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10.2 
Appendix 2: Clinical Laboratory Tests 
• The analyses detailed in Table 11 will be performed at a local laboratory at the trial site. 
• Samples for the safety laboratory assessments* will be destroyed after analyzes. 
• The Investigator must review all laboratory results for concomitant illnesses and AEs. 
Table 11 Laboratory Assessments 
Laboratory Assessments 
Parameters 
Time For Assessment 
Hematology* 
• 
Hemoglobin 
• 
Hematocrit 
• 
Red blood cell count 
• 
White blood cell count with Differential: 
o 
Neutrophils 
o 
Lymphocytes 
o 
Monocytes 
o 
Eosinophils 
o 
Basophils 
• 
Platelet Count 
All trial visits (screening, 
Visit 1-12 and follow-up) 
Biochemistry* 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Blood Urea Nitrogen 
• 
Creatinine 
• 
Creatinine Clearance (estimated) 
• 
Glucose 
• 
Calcium 
• 
Phosphorous 
• 
ALP 
• 
ALT 
• 
AST 
• 
INR 
• 
Gamma-glutamyl transferase (GGT) 
• 
Lactic dehydrogenase 
• 
Conjugated bilirubin 
• 
Unconjugated bilirubin 
• 
Total bilirubin 
• 
Total protein 
• 
Albumin 
• 
Amylase 
• 
Uric acid 
• 
C-reactive protein 
All trial visits (screening, 
Visit 1-12 and follow-up) 
• 
HbA1c 
Visits 1, 4, 6, 9, 12 and 
follow-up 
• 
Cholesterol, measured orally fasting 
• 
Triglycerides, measured orally fasting 
• 
Magnesium 
• 
Zinc 
Visits 1, 9 and 12 only 
Other analyses 
• 
Aldosterone 
• 
Citrulline 
• 
ADA 
Visits 1, 4, 6, 9, 12 and 
follow-up 
• 
PK 
See Table 3 
Urinalysis 
(by dipstick)* 
• 
Blood 
• 
Glucose 
• 
Leukocytes 
• 
pH 
• 
Protein 
All trial visits (screening, 
Visit 1-12 and follow-up) 
Urinalysis* 
• 
Sodium 
Visit 1 and 9 MBS only 


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• 
Potassium 
• 
Calcium 
• 
Magnesium 
• 
Urea 
• 
Creatinine 
Pregnancy testing 
• 
Serum human chorionic gonadotropin (hCG) pregnancy 
test (women of childbearing potential only) 
Screening and visits 1, 4, 
5, 6, 7, 8, 9, 10, 11, 12 and 
follow-up  
Screening tests 
• 
FSH; as needed in women of non-childbearing potential 
to confirm menopause 
• 
HIV type 1 and 2 antibodies 
• 
Hepatitis B surface antigen (HBsAg) 
• 
Hepatitis C virus antibody (HCV) 
Screening only 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a clinical trial patient administered a 
medicinal (investigational or non-investigational) product and which does not 
necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporarily associated with the use of a product, whether or not 
related to the product. 
AEs include: 
• A clinically significant worsening of a concomitant illness. 
• A clinical laboratory AE: a clinical abnormality which is clinically significant, i.e., any 
abnormality that suggests a disease and/or organ toxicity and is of a severity that 
requires active management. Active management includes active treatment or further 
investigations, e.g., change of dose or more frequent follow-up due to the abnormality. 
The following should not be considered as AEs: 
• Pre-existing conditions, including those found as a result of screening procedures (pre-
existing conditions should be reported as medical history or concomitant illness). 
• 
Pre-planned procedure, unless the condition for which the procedure was planned has 
worsened from the first trial-related activity after the patient has signed the informed 
consent. 
10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose fulfills any of 
the following criteria: 


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a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Otherwise medically important: 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 


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10.3.3 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The Investigator will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the Investigator to send photocopies of the patient’s medical 
records to Pharmalex in lieu of completion of the AE/SAE eCRF page. All SAEs will 
be recorded and reported to Pharmalex immediately and under no circumstance should 
this exceed 24 hours. Sponsor is informed by Pharmalex. 
• There may be instances when copies of medical records for certain cases are requested 
by Pharmalex. In this case, all patient identifiers, with the exception of the patient 
number, will be redacted on the copies of the medical records before submission to 
Pharmalex. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Severity 
The Investigator will assess severity for each event reported during the trial and assign it to 
one of the following categories: 
• Mild: No or transient symptoms, no interference with the patient’s daily activities. 
• Moderate: Marked symptoms, moderate interference with the patient’s daily activities. 
• Severe: Considerable interference with the patient’s daily activities, which the patient 
finds unacceptable. A severe reaction does not necessarily deem the AE as serious and 
an SAE are not always severe in nature. 
 


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Assessment of Causality 
• The Investigator is obligated to assess the relationship between trial intervention and 
each occurrence of each AE/SAE according to the following definitions: 
o Probably: Good reason and sufficient documentation to assume a causal 
relationship. 
o Possibly: A causal relationship is conceivable and cannot be dismissed. 
o Unlikely: The event is most likely related to etiology other than the product. 
o Not related: No relationship to product. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to trial intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure in his assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred, and the Investigator has 
minimal information to include in the initial report to Pharmalex. However, it is very 
important that the Investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to Pharmalex. 
• The Investigator may change his opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
 
Assessment of Outcome 
The Investigator must judge outcome of the AE by the following terms: 
• Recovered/resolved: The patient has fully recovered, or by medical or surgical 
treatment, the condition has returned to the level observed at the first trial-related 
activity after the patient signed the informed consent. 
• Recovering/resolving: The condition is improving and the patient is expected to 
recover from the event. This term is only applicable if the patient has completed the 
trial or has died from another AE. 
• Recovered/resolved with sequelae: The patient has recovered from the condition, but 
with lasting effect due to a disease, injury, treatment, or procedure. If a sequela meets 
an SAE criterion, the AE must be reported as an SAE. 
• Not recovered/not resolved: The condition of the patient has not improved and the 
symptoms are unchanged, or the outcome is not known. 
• Fatal: This term is only applicable if the patient died from a condition related to the 
reported AE. Outcomes of other reported AEs in a patient before he/she died should be 
assessed as “recovered/resolved”, “recovering/resolving”, “recovered/resolved with 
sequelae”, or “not recovered/not resolved”. An AE with fatal outcome must be 
reported as an SAE. 
• Unknown: This term is only applicable if the patient is lost to follow-up.  


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Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Pharmalex 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. The SAE follow-up information 
should only include new (e.g., corrections or additional) information and must be 
reported to Pharmalex within 24 hours of the Investigator’s first knowledge of the 
information. This is also the case for previous non-serious AEs which subsequently 
become SAEs. 
• If a patient dies during participation in the trial or during a recognized follow-up 
period, the Investigator will provide Pharmalex with a copy of any post-mortem 
findings including histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
10.3.4 
Reporting of SAEs 
SAE Reporting to Pharmalex via the eCRF  
• The primary mechanism for reporting an SAE to Pharmalex will be the eCRF. 
• If the electronic system is unavailable, then the site will use the SAE paper form (see 
below) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• After the trial is completed, the eCRF will be taken off-line to prevent the entry of new 
data or changes to existing data. 
• If the trial site receives a report of a new SAE from a trial patient or receives updated 
data on a previously reported SAE after the eCRF has been taken off-line, then the site 
can report this information on a paper SAE form (see next section). 
Reporting to Pharmalex via Paper CRF (in case of eCRF unavailability). 
• SAE paper forms must be forwarded to Pharmalex. 
• Email transmission of the SAE paper form is the preferred method to transmit this 
information to Pharmalex. 
• Contact details for Pharmalex are: 
Phone: +45 74 44 19 36 
Email: PV-nordic@pharmalex.com 
 
 


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10.4 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of trial intervention, additional evaluation should be considered. 
Females in the Following Categories Are Not Considered WOCBP 
1. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Females with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Müllerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining trial entry. 
Note: Documentation can come from the site personnel’s: review of the patient’s medical 
records, medical examination, or medical history interview. 
2. Postmenopausal female 
• A postmenopausal state is defined as amenorrhea for 12 months without an alternative 
medical cause. 
• A high FSH level (>25,8 IU/L) in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with more than one FSH measurement is required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the trial. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before trial enrollment. 
Contraception Guidance: 
Female patients: 
Highly effective contraception is defined as: 
• 
Having a male partner who is sterile (vasectomized or orchiectomized) prior to the 
female patient’s entry into the trial and is the sole sexual partner for that female patient. 
• 
Use of intrauterine devices. 
• 
Use of intrauterine hormone-releasing system. 
• 
Bilateral tubal occlusion. 
• 
Use of hormonal contraceptives containing combined estrogen and progestogen 
associated with inhibition of ovulation (intravaginal, transdermal). 


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• 
Use of progestogen-only hormonal contraception associated with inhibition of ovulation 
(injectable, implantable). 
• 
True abstinence: When this is in line with the preferred and usual lifestyle of the patient 
(period abstinence [e.g. calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable methods of contraception). 
Male patients: 
Male patients who are not sterilized or infertile must use condom throughout the trial through 
4 weeks after receiving the last trial product dose. If their partner is a female of childbearing 
potential, she must use highly effective contraception (as detailed above) throughout the trial 
through 4 weeks after last dose. 
Collection of Pregnancy Information 
Female patients who become pregnant 
• 
The Investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this trial. 
• 
Female patients must be instructed to notify the Investigator immediately if she becomes 
pregnant or if she suspects she might be pregnant during the trial. 
• 
All initial reports of pregnancy in female patients must be reported to PharmaLex by the 
trial site personnel within 24 hours of knowledge of the event using the appropriate 
pregnancy form. 
• 
The initial information will be recorded on the appropriate form and submitted to the 
Sponsor within 24-hours of learning of a patient's pregnancy. 
• 
The patient will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the patient and the neonate, and the information 
will be forwarded to the Sponsor. Follow-up will not be required for longer than 1 month 
beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be reported 
as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g. spontaneous abortion [occurring at <22 weeks 
gestational age], stillbirth [occurring at >22 weeks gestational age], fetal death, 
congenital anomalies, and ectopic pregnancy) are considered SAEs and must be reported 
using the SAE form. 
• 
Any post-trial pregnancy related SAE considered reasonably related to the trial 
intervention by the Investigator will be reported to the Sponsor as described in Section 
8.4.1. While the Investigator is not obligated to actively seek this information in former 
trial patients, he or she may learn of an SAE through spontaneous reporting. 
• 
Any female patient who becomes pregnant while participating in the trial will discontinue 
trial intervention. 


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Male patients with partners who become pregnant 
• 
Because the effect of the trial product on sperm is unknown, the Investigator will attempt 
to collect pregnancy information on any male patient’s female partner who becomes 
pregnant while the male patient is in this trial. This information will include medical 
history in relation to previous pregnancy(ies) and birth(s), if applicable, relevant medical 
history, and information on present pregnancy. 
• 
Male patients must be instructed to notify the Investigator immediately if his partner 
becomes pregnant or suspects to be pregnant. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to PharmaLex within 24-hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 1 month following the estimated delivery 
date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
 
 


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10.5 
Appendix 5: Abbreviations 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BMI 
body mass index 
CA 
competent authority 
CCE 
colon capsule endoscopy 
CLcr 
creatinine clearance 
Cmax 
maximum plasma concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
case report form 
CT 
computerized tomography 
CTR 
clinical trial report 
DEXA 
dual-energy x-ray absorptiometry 
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 
DPP 
dipeptidyl peptidase 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency  
EoT 
end of treatment 
FAS 
full analysis set 
FDA 
US Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FSH 
follicle-stimulating hormone 
FU 
follow-up 
GGT 
gamma-glutamyl transferase 


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GLP-2 
glucagon-like peptide 2 
HbA1c 
hemoglobin A1c 
HGH 
human growth hormone 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
IBD 
inflammatory bowel disease 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NOAEL 
no observed adverse-effect level 
NYHA 
New York Heart Association 
PCD 
primary completion date 
PGIC  
patient’s global impression of change 
PK 
pharmacokinetics 
PRO 
patient reported outcome 
PS 
parenteral support 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SBS 
short bowel syndrome 
SBS-I 
SBS impact scale (a disease specific PRO questionnaire developed by Sponsor)  
SBS-IF 
short bowel syndrome with intestinal failure 
SBS-II 
short bowel syndrome with intestinal insufficiency 
SC 
subcutaneous 
SD 
standard deviation 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
 


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11 
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