A Phase 3, International, Multicenter, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of Glepaglutide in Patients With Short Bowel Syndrome (SBS)
Phase: PHASE3
Conditions: Short Bowel Syndrome
Sponsor: Zealand Pharma

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GLEPAGLUTIDE 
CLINICAL TRIAL PROTOCOL ZP1848-17111 
EASE SBS 1 
A PHASE 3, INTERNATIONAL, MULTICENTER, 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
TRIAL TO EVALUATE THE EFFICACY AND SAFETY OF 
GLEPAGLUTIDE IN PATIENTS WITH SHORT BOWEL 
SYNDROME (SBS) 
 
Sponsor 
Zealand Pharma A/S 
Sydmarken 11 
DK-2860 Søborg 
Denmark 
IND Number 
133151 
EudraCT Number 
2017-004394-14 
Development Phase 
3 
Date of Protocol 
27-Jan-2022 
Version 
10.0 
 
Protocol version 
Date 
Protocol version 10 
27-Jan-2022 
Protocol version 9 
03-Mar-2021 
Protocol version 8 
15-Oct-2020 
Protocol version 7 
05-Dec-2019 
Protocol version 6 
12-Nov-2019 
Protocol version 5 
18-Sep-2019 
Protocol version 4 
24-Oct-2018 
Protocol version 3 
21-Aug-2018 
Protocol version 2 
31-Jul-2018 
Protocol version 1 
31-May-2018 
The trial will be conducted according to the protocol and in compliance with Good Clinical 
Practice (GCP), the Declaration of Helsinki and with other applicable regulatory requirements. 
 
The information in this document is confidential and is proprietary to Zealand Pharma. It is understood that 
information in this document shall not be disclosed to any third party, in any form, without prior written approval 
from Zealand Pharma. 

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PROTOCOL APPROVAL / SIGNATURE PAGE 
 
Protocol ZP1848-17111 Version 10.0 Dated: 27-Jan-2022  
EASE SBS 1 
A Phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial to 
evaluate the efficacy and safety of glepaglutide in patients with short bowel syndrome (SBS) 
 
 MD, Ph.D. 
Medical Director 
 
 
Signature Medical Responsible 
 
Date 
 
Ph.D.  
Principal Clinical Trial Manager 
 
 
Signature Principal Clinical Trial Manager  
Date 
 
Ph.D., Statistical Project Director 
 
 
 
Signature Statistical Project Director 
 
Date 
 
Prof., MD, Ph.D. 
 
International Coordinating Investigator 
 
 
Signature International Coordinating Investigator 
Date 
 
 
 

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1 Synopsis 
Title of Trial:  
A Phase 3, international, multicenter, randomized, double-blind, placebo-controlled trial to evaluate 
the efficacy and safety of glepaglutide in patients with short bowel syndrome (SBS) 
Short Title: EASE SBS 1 (Efficacy And Safety Evaluation of Glepaglutide in treatment of SBS) 
Trial center(s): Approximately 33 sites in Europe and North America 
Studied period (years):  
Estimated date first patient enrolled: Q3 2018 
Estimated date last patient completed: Q3 2022 
Phase of development:  
3 
 
Objectives:  
Primary Objective: 
To confirm the efficacy of glepaglutide in reducing parenteral support (PS) volume in SBS patients 
Secondary Objectives: 
 
To evaluate the efficacy of glepaglutide on other efficacy endpoints in patients with SBS  
 
To evaluate the safety and tolerability of glepaglutide in patients with SBS 
Methodology:  
This is a multicenter, placebo-controlled, randomized, parallel-group, double-blind, fixed dose, Phase 
3 trial to demonstrate the superiority of once weekly and twice weekly subcutaneous (SC) injections 
of 10 mg glepaglutide versus placebo in stable SBS patients. 
After providing informed consent and initial confirmation of eligibility during the 2-week Screening 
period, patients will enter a PS Optimization and Stabilization Phase before baseline measurements 
are performed. An individual drinking menu will be defined by the patient and the Investigator during 
the Screening period and until the end of the Optimization Phase. All patients will be equipped with 
an electronic diary (eDiary) for recording of trial relevant data/information.  
Unless otherwise specified, baseline is defined as Day 1, prior to first dosing of trial product. 
Optimization Phase 
During the Optimization Phase, the Investigator may change the PS volume and content if the patient 
is considered unstable or not optimized. Any changes in PS volume or content will be administered 
according to institutional standard practice. The effect of any PS optimizations must be investigated 
after 2 weeks. Prior to an Optimization Phase visit, the patient must measure his/her urine over 
48 hours, while adhering to the pre-defined drinking menu, and report the urine volume and oral fluid 
intake in the eDiary. PS optimization consist of 2 rounds, which limits the Optimization Phase to a 
maximum duration of 4 weeks (± 4 days).). If optimization cannot be shown during the 4-week 
period, a second Optimization Phase of up to 4 weeks (± 4 days) is allowed. The last Optimization 
Phase visit can be combined with the first visit in the Stabilization period if the patient is considered 
optimized.  
Stabilization Phase 
The Stabilization Phase has a minimum duration of 2 weeks and a maximum duration of 4 weeks 
(± 4 days). The last visit of the Optimization Phase can also be the first visit of the Stabilization 
Phase. Prior to the Stabilization Phase visit, the patient must measure his/her urine over 48 hours, 
while adhering to the pre-defined drinking menu, and report the urine volume and oral fluid intake in 
the eDiary. Patients will be evaluated every 2 weeks during the Stabilization Phase and will need to 
fulfill the pre-specified stability criteria before the patient can be randomized. If stability cannot be 
shown during the 4-week period due to unforeseen events such as infections, illness or similar, a 
second Stabilization Phase of up to 4 weeks (± 4 days) is allowed. 

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A patient will be considered stable if all the following criteria are met: 
 
Actual PS usage (volume and content) matches prescribed PS (± 10% deviation in 
volume is acceptable) and 
 
48-hour urine volumes at 2 consecutive visits within a 2-week interval (± 4 days, i.e., 
visits should be 10 to 18 days apart) are similar (a maximum of ± 25% deviation is 
acceptable), while the oral fluid intake is constant (the two 48-hour oral intakes differ less 
than 10%) and maximum 3.5 L per day and 
 
 
The Investigator and Medical Monitor must both agree and approve that the patient has met the 
criteria to be considered stable after completing the Stabilization Phase. 
The baseline PS volume (L/week) will be defined as the actual PS volume received during the 7-day 
period prior to Visit 1 (Day 1). The baseline daily urine volume (L per day) will be defined as the 
average of the last two 48-hour urine volume measures from the Stabilization Phase. For scheduling 
of the 48-hour measurement periods throughout the trial, see Table 4. 
Main trial period: 
Visit 1 is done within 2 weeks after the last Stabilization Phase visit. All eligible patients who 
complete the Optimization and Stabilization Phases will be randomized in a 1:1:1 manner to receive 
either: a) glepaglutide 10 mg twice weekly, b) glepaglutide 10 mg once weekly and placebo once 
weekly, or c) placebo SC twice weekly for the following 24 weeks. 
During the 24-week Treatment Phase, PS need will be evaluated by 48-hour balance periods 
involving urine measurements and during which patients will be required to keep to an individually 
pre-defined drinking menu (timing, volume, and content) and document this in the eDiary. 
The actual volume of PS will be recorded on an ongoing basis in electronic diaries (eDiaries) by the 
patients. The Investigator will record the type, content, and volume of the PS being used. Once trial 
drug treatment is initiated, PS volume can be adjusted at trial visits (at Weeks 1, 2, 4, 8, 12, 16, 20, 
and 24) if the criteria for adjustment are met and according to a predefined algorithm. 
Algorithm for PS volume reduction: 
IF: daily average urine volume of the current visit is at least 10% higher than baseline urine 
volume. 
THEN: New PS volume (weekly) = Current PS volume (weekly)  7 x absolute increase in daily 
urine volume from baseline 
The Investigator may arrange unscheduled visits (preceded by a 48-hour balance period) if he or she 
considers the visits to be needed based on medical judgement to assess PS volume needs. 
It is acknowledged that intake of oral liquids and PS might have to be changed between scheduled 
visits to avoid edema, especially if treatment is effective. In such cases changes to the PS is at the 
discretion of the Investigator and the reason needs to be documented in the eCRF. 
Any changes to the content of PS are left to the discretion of the Investigator and the reason is 
documented in the eCRF. 
After completing the Treatment Phase, all patients (patients in all 3 treatment groups) will be eligible 
to enter an Extension Trial and receive glepaglutide. In addition, patients who were dosed but 
discontinued from trial treatment due to reasons other than an unacceptable adverse event (AE) 
related to the trial product or withdrawal of consent may be invited to enter the Extension Trial when 
completing the 24-week Treatment Phase schedule. For patients not entering the Extension Trial, a 
Follow-up Visit will be conducted 4 weeks after completion of the Treatment Phase. 

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Target Patient Population: 
Key patient inclusion criteria include: 
 
Diagnosis of SBS defined as remaining small bowel in continuity of estimated less than 
200 cm [equal to 79 inches] with the latest intestinal resection being at least 6 months prior to 
Screening and where the patient is considered stable with regard to PS needs. No restorative 
surgery planned in the trial period. 
 
PS requirement of at least 3 days per week as assessed prior to Screening and at the end of the 
Optimization and Stabilization Phases. 
 
Willing to adhere to an individual pre-defined drinking menu and urine measurement during 
the 48-hour measuring intervals. 
 
 
 
At randomization: Maintains a stable PS volume for at least 2 weeks prior to randomization. 
Trial products, dosage and mode of administration: 
Glepaglutide: Provided in single-use vials containing 1 mL (an extractable volume of 0.5 mL) of a 
clear, essentially colorless solution for injection, containing 20 mg/mL glepaglutide. Patients 
randomized to active treatment will inject 10 mg (0.5 mL) glepaglutide either a) twice weekly or 
b) once weekly and placebo once weekly. 
Reference therapy: Placebo is provided in single-use vials containing 1 mL (an extractable volume of 
0.5 mL) of clear, essentially colorless solution for injection. Patients randomized to placebo treatment 
will inject (0.5 mL) placebo solution twice weekly. 
Intervention groups and duration: 
Duration of treatment is 24 weeks across treatment groups. 
 
Glepaglutide twice weekly: 10 mg glepaglutide on Day 1 and on Day 4 or 5 (same days of the 
week every week) 
 
Glepaglutide once weekly: 10 mg glepaglutide or placebo on Days 1 and on Day 4 or 5 (same 
days of the week every week) 
 
Placebo: placebo on Day 1 and on Day 4 or 5 (same days of the week every week) 
Endpoints: 
Primary Endpoint: 
Reduction in weekly PS volume from baseline to Week 24 
Key secondary endpoints: 
 
Clinical response, defined as achieving at least 20% reduction in weekly PS volume from 
baseline to both Weeks 20 and 24 
 
Reductio
 
 
Reduction in weekly PS volume from baseline to Week 12 
 
Reduction in weekly PS volume of 100% (weaned off) at Week 24 
Secondary efficacy endpoints: 
 
Reduction of at least 20% in PS volume from baseline to both Weeks 12 and 24 
 
Change in fluid composite effect (FCE) from baseline to Week 24 
 
Reduction in calculated energy content of parenteral macronutrients from baseline to 
Week 24 
 
Reduction in number of days on PS per week from baseline to Week 24 
 
Reduction of at least 40% in PS volume from baseline to both Weeks 20 and 24 
 
PGIC improvement at Weeks 4, 12, 20, and 24 

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Change in weight from baseline to Week 24 
Other efficacy endpoints: 
 
 
 
Reduction in 
 
 
Reduction in duration of PS infusions per week from baseline 
 
Concentration trough levels of glepaglutide and metabolites 
 
Change in plasma citrulline level from baseline to Week 24 
 
Change in weekly need for parenteral micronutrients (sodium, potassium, magnesium and 
calcium) from baseline to Week 24 
 
Change in patient-reported outcomes (SBS-I and EQ-5D-5L) from baseline to Week 24 
 
Reduction in bowel movements or stoma bag emptying from baseline to Week 24 Safety 
endpoints:  
 
Incidence and types of AEs and serious adverse events (SAEs) 
 
Change in clinical evaluations: 
 
Vital signs 
 
Electrocardiogram (ECG) 
 
Change in safety laboratory assessments: 
 
Hematology 
 
Biochemistry 
 
Urinalysis 
 
Standard bone markers  
 
Immunogenicity 
Statistical methodology: 
Inferential statistical analyses of the primary and secondary efficacy endpoints will be performed. All 
comparisons will be between each glepaglutide treatment group and placebo. No statistical interim 
analysis is planned. 
 Analysis Sets 
The Full Analysis Set (FAS) will consist of all randomized patients, who received at least one 
dose of trial drug (glepaglutide or placebo). All efficacy analyses will be based on the FAS. 
 
The Per-protocol Analysis Set will consist of all FAS patients who do not experience any 
major protocol deviations. Final judgments 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 analyses of the primary and key secondary efficacy endpoints. 
 
The Safety Analysis Set will consist of all randomized patients, who received at least 1 dose 
of trial drug (glepaglutide or placebo). This is the same definition as for the FAS, but the two 
can deviate in special circumstances. All safety analyses will be based on the Safety Analysis 
Set. 
Analysis of primary and key secondary endpoints 
The primary analysis of the primary efficacy endpoint uses a restricted maximum likelihood based 
repeated-measures approach to compare treatment groups with respect to the mean change from 
baseline in weekly PS volume at Week 24. The model will use weekly PS volume assessments at 
Week 1, 2, 4, 8, 12, 16, 20, and 24, and will include the covariates for treatment group, baseline 
weekly PS volume, visit (categorical variable), stratification factor (weekly PS volume requirements 
<12 L/week versus >12 L/week), and visit-by-treatment group interaction. Missing values will be 

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imputed using multiple imputation methods. For the primary analysis, a Copy Reference approach is 
used with placebo treatment as reference, while for sensitivity analyses, a Jump to Reference and a 
Copy Incremental from Reference approaches will be applied. As a supplementary analysis, the 
analysis will be repeated using the Per-protocol Analysis Set. 
The 4 key secondary efficacy endpoints will be analyzed to assess the treatment effect using the FAS. 
Continuous endpoints will be analyzed in a similar manner as the primary efficacy endpoint. The 
binary endpoint of clinical response will be tested using the Cochran-Mantel-Haenszel test with 
stratification on the randomization stratification factor (weekly PS volume requirements <12 L/week 
versus >12 L/week). As a supplementary analysis, the 4 key secondary endpoints analyses will be 
repeated using the Per-protocol Analysis Set. 
Gatekeeping Procedure 
testing the primary endpoint together with the key secondary endpoints between each glepaglutide 
treatment group versus placebo. The twice weekly treatment group and once weekly treatment group 
 
Secondary endpoints 
The secondary efficacy endpoints will be analyzed to assess the treatment effect using the FAS. The 
tests will be non-hierarchical and type I error will not be adjusted for multiple testing. The other 
efficacy endpoints will be summarized to assess the treatment effect using the FAS. Only descriptive 
statistics will be presented for these other efficacy endpoints and no inferential statistics will be 
performed. 
Safety Analysis 
All safety analyses will be conducted using the Safety Analysis Set. No inferential tests of safety data 
will be performed. Descriptive summaries of safety data will be presented. Adverse events (treatment-
emergent unless otherwise specified) will be presented by system organ class (SOC) and preferred 
term (PT) for each treatment group. 
Discontinuations and Data Handling Rules 
The analysis for the primary efficacy endpoint as well as for the continuous key secondary efficacy 
endpoints will handle missing values using a CR-imputed data set generated from the multiple 
imputation approach described for the primary efficacy endpoint. For all responder analyses, patients 
who discontinue for any reason will be considered as non-responders from the time of discontinuation 
onwards. No pooling of sites is planned for the efficacy analyses. 
Number of patients (planned):  
Approximately 108 patients are planned to be randomized into the trial 1:1:1. 
 

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2 Table of Contents 
1 
SYNOPSIS ...................................................................................................................3 
2 
TABLE OF CONTENTS ...........................................................................................12 
LIST OF TABLES .........................................................................................................................17 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18 
4 
INTRODUCTION ......................................................................................................20 
4.1 
Background .................................................................................................................20 
4.2 
Key Characteristics of Glepaglutide ...........................................................................20 
4.3 
Risk-Benefit Assessment ............................................................................................21 
4.3.1 
Benefits .......................................................................................................................21 
4.3.2 
Risks ...........................................................................................................................22 
4.3.3 
Overall Benefit-risk Conclusion for the Trial .............................................................23 
5 
TRIAL OBJECTIVES ................................................................................................23 
5.1 
Primary Objective .......................................................................................................23 
5.2 
Secondary Objectives .................................................................................................23 
5.3 
Estimand .....................................................................................................................24 
6 
INVESTIGATIONAL PLAN .....................................................................................24 
6.1 
Trial Design Rationale ................................................................................................24 
6.1.1 
Glepaglutide Dose Rationale ......................................................................................25 
6.2 
Overall Trial Design ...................................................................................................26 
6.3 
Trial Endpoints ...........................................................................................................28 
6.3.1 
Primary Endpoint ........................................................................................................28 
6.3.2 
Key Secondary Endpoints ...........................................................................................28 
6.3.3 
Reduction in weekly PS volume of 100% (weaned off) at Week 
24Secondary Efficacy Endpoints ................................................................................28 
6.3.4 
Other Efficacy Endpoints ...........................................................................................29 
6.3.5 
Safety Endpoints .........................................................................................................29 
6.4 
End of Trial Definition ...............................................................................................29 
6.5 
Criteria for Premature Termination of the Trial and/or Trial Site ..............................29 
7 
TRIAL PATIENTS .....................................................................................................30 
7.1 
Number of Patients .....................................................................................................30 
7.2 
Inclusion Criteria ........................................................................................................30 

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7.3 
Exclusion Criteria .......................................................................................................31 
7.4 
Randomization Criteria ...............................................................................................32 
7.5 
Patient Withdrawal or Discontinuation from Trial Treatment ...................................33 
7.6 
Trial Drug Pausation ...................................................................................................34 
7.7 
Patient Replacement ...................................................................................................35 
8 
TREATMENT OF PATIENTS ..................................................................................35 
8.1 
Treatment Assignment and Randomization ................................................................35 
8.2 
Trial Drug Administration ..........................................................................................36 
8.3 
Missed Doses of Trial Drug ........................................................................................37 
8.4 
Treatment Compliance ................................................................................................37 
8.5 
Concomitant Medications ...........................................................................................37 
8.6 
Prohibited Medications ...............................................................................................37 
8.7 
Parenteral Support ......................................................................................................37 
8.7.1 
Algorithm for Parenteral Support Adjustments during the Optimization 
Phase ...........................................................................................................................38 
8.7.2 
Parenteral Support during Stabilization Phase ...........................................................38 
8.7.3 
Algorithm for Parenteral Support Adjustments during Trial Drug Treatment ...........38 
8.7.4 
Parenteral Support Volume Adjustments due to Clinical Signs .................................39 
8.7.5 
Parenteral Support Volume Adjustments during Unscheduled Visits ........................39 
9 
INVESTIGATIONAL MEDICINAL PRODUCT .....................................................40 
9.1 
Trial Drug ...................................................................................................................40 
9.1.1 
Glepaglutide ................................................................................................................40 
9.1.2 
Placebo ........................................................................................................................40 
9.2 
Blinding and Breaking the Blind ................................................................................40 
9.3 
Trial Drug Packaging, Labeling and Storage .............................................................40 
9.4 
Accessory Supplies .....................................................................................................41 
9.5 
Trial Drug Supply and Handling ................................................................................41 
9.6 
Trial Drug Accountability ...........................................................................................42 
10 
TRIAL PROCEDURES BY VISIT ............................................................................42 
10.1 
Screening ....................................................................................................................42 
10.2 
Optimization Phase .....................................................................................................44 
10.3 
Stabilization Phase ......................................................................................................44 
10.4 
Treatment Phase (Up to 24 Weeks) ............................................................................45 

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10.4.1 
Visit 1 (Day 1) ............................................................................................................45 
10.4.2 
Visit 2 (Day 3 ± 1 day) ...............................................................................................46 
10.4.3 
Visit 3 (Week 1/Day 8 ± 2 days) ................................................................................47 
10.4.4 
Visit 4 (Week 2/Day 15 ± 3 days) ..............................................................................47 
10.4.5 
Visit 5 (Week 4/Day 29 ± 5 days) ..............................................................................48 
10.4.6 
Visit 6 (Week 8/Day 57 ± 5 days) ..............................................................................49 
10.4.7 
Visit 7 (Week 12/Day 85 ± 5 days) ............................................................................50 
10.4.8 
Visit 8 (Week 16/Day 113 ± 7 days) ..........................................................................51 
10.4.9 
Visit 9 (Week 20/Day 141 ± 7 days) ..........................................................................51 
10.4.10 
Visit 10 (End of Treatment; Week 24/Day 169 ± 7 days) ..........................................52 
10.5 
Follow-up/Final Visit..................................................................................................54 
10.5.1 
Follow-up Visit (Week 28/Day 197 ± 7 days) ............................................................54 
10.6 
Unscheduled Visits .....................................................................................................54 
11 
TRIAL ASSESSMENTS ............................................................................................55 
11.1 
General Assessments ..................................................................................................55 
11.1.1 
Demographics and Medical History ...........................................................................55 
11.1.2 
SBS Characteristics and Disease History ...................................................................55 
11.1.3 
Concomitant Medications ...........................................................................................56 
11.1.4 
Drinking Menu ............................................................................................................56 
11.2 
Assessments of Efficacy .............................................................................................56 
11.2.1 
Patient Diaries .............................................................................................................56 
11.2.2 
Parenteral Support Use and Volume ...........................................................................56 
11.2.3 
Parenteral Calories and Nutrients ...............................................................................56 
11.2.4 
48-hour Urine Volume ................................................................................................56 
11.2.5 
Plasma Citrulline Levels .............................................................................................57 
11.2.6 
Patient-Reported Outcomes ........................................................................................58 
11.2.7 
Health Economic Assessments ...................................................................................58 
11.2.8 
Exit interview ..............................................................................................................58 
11.3 
Assessment of Safety ..................................................................................................59 
11.3.1 
Safety Parameters .......................................................................................................59 
11.3.2 
Vital Signs ..................................................................................................................59 
11.3.3 
Weight and Height ......................................................................................................59 
11.3.4 
Physical Examination .................................................................................................59 

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11.3.5 
Electrocardiogram (ECG) ...........................................................................................59 
11.3.6 
Laboratory Assessments .............................................................................................60 
11.3.6.1 
Hematology .................................................................................................................60 
11.3.6.2 
Biochemistry ...............................................................................................................60 
11.3.6.3 
Bone Markers ..............................................................................................................60 
11.3.6.4 
Urinalysis ....................................................................................................................61 
11.3.6.5 
Pregnancy Screen ........................................................................................................61 
11.3.6.6 
Immunogenicity ..........................................................................................................61 
11.3.6.7 
Pharmacokinetics ........................................................................................................61 
11.3.6.8 
HIV, Hepatitis B, and Hepatitis C ..............................................................................61 
11.4 
Adverse and Serious Adverse Events .........................................................................62 
11.4.1 
Definitions ..................................................................................................................62 
11.4.1.1 
Adverse Events ...........................................................................................................62 
11.4.1.2 
Adverse Events of Special Interest (AESI) ................................................................63 
11.4.1.3 
Serious Adverse Event ................................................................................................65 
11.4.1.4 
Other Important Adverse Events ................................................................................65 
11.4.1.5 
Non-serious Adverse Event ........................................................................................65 
11.4.1.6 
Suspected Unexpected Serious Adverse Reactions ....................................................65 
11.4.2 
Collection, Recording and Reporting of Adverse Events ...........................................66 
11.4.3 
Follow-up of Adverse Events .....................................................................................67 
11.4.4 
Pregnancy ...................................................................................................................68 
11.4.5 
Precautions ..................................................................................................................69 
11.4.6 
Safety Committee .......................................................................................................69 
12 
STATISTICS ..............................................................................................................69 
12.1 
General Considerations for Data Analysis .................................................................69 
12.2 
Analysis Sets ...............................................................................................................70 
12.3 
Efficacy Analysis ........................................................................................................70 
12.3.1 
Primary Efficacy Endpoint .........................................................................................70 
12.3.2 
Key Secondary Endpoints ...........................................................................................71 
12.3.3 
Gatekeeping Procedure ...............................................................................................72 
12.3.4 
Secondary Efficacy Endpoints ....................................................................................73 
12.3.5 
Other Efficacy Endpoints ...........................................................................................74 
12.4 
Safety Analysis ...........................................................................................................75 

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12.5 
Demographic and Baseline Characteristics ................................................................76 
12.6 
Interim Analysis .......................................................... Error! Bookmark not defined. 
12.7 
Discontinuations and Data Handling Rules ................................................................76 
12.8 
Sample Size and Power Considerations .....................................................................78 
13 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................78 
13.1 
Trial Monitoring .........................................................................................................78 
13.2 
Audits and Inspections ................................................................................................79 
13.3 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..................79 
14 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................80 
14.1 
Electronic Case Report Forms ....................................................................................80 
14.2 
Patient Electronic Diaries (eDiaries) ..........................................................................80 
14.3 
Data Processing ..........................................................................................................80 
15 
ETHICS ......................................................................................................................80 
15.1 
Ethics Review .............................................................................................................80 
15.2 
Ethical Conduct of the Trial .......................................................................................81 
15.3 
Written Informed Consent ..........................................................................................81 
15.4 
Confidentiality ............................................................................................................81 
15.5 
Liability and Insurance ...............................................................................................81 
16 
DATA HANDLING AND RECORD KEEPING ......................................................82 
16.1 
Records .......................................................................................................................82 
16.2 
Retention of Records ..................................................................................................82 
17 
CLINICAL TRIAL REPORT AND PUBLICATION POLICY ................................82 
17.1 
Final Clinical Trial Report ..........................................................................................82 
17.2 
Publication Policy .......................................................................................................82 
18 
LIST OF REFERENCES ............................................................................................83 
19 
APPENDICES ............................................................................................................85 
19.1 
Clinical Classification of Patients based on PS Volume ............................................85 
 

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LIST OF TABLES 
Table 1: 
Schedule of Assessments ..............................................................................................9 
Table 2: 
Abbreviations and Specialist Terms ...........................................................................18 
Table 3: 
Dosing Regimen .........................................................................................................36 
Table 4: 
Timing of 48-hour Measurements ..............................................................................57 
Table 5:  
Power considerations ..................................................................................................78 
 
 
List of Figures 
Figure 1: 
Trial Design ..................................................................................................................8 
Figure 2: 
Exposure-Response Curve ..........................................................................................26 
Figure 3: 
Testing Hierarchy .......................................................................................................73 
 
  
 

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3 List of Abbreviations and Definitions of Terms 
The following abbreviations and specialist terms are used in this trial protocol. 
Table 2: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist Term 
Explanation 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
Cavg 
Average steady-state plasma concentration in the dosing interval 
CiC 
Colon-in-continuity 
CLCr 
Clearance creatinine 
CMH 
Cochran-Mantel-Haenszel 
CT 
Computerized tomography 
DILI 
Drug-induced liver injury 
DPP-4 
Dipeptidyl peptidase-4 
DUN 
Dispensing Unit Number 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eDiary(ies) 
Electronic diary(ies) 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
EQ-5D-5L 
European Quality of Life-5 Dimension 5 Level 
ESPEN 
European Society for Clinical Nutrition and Metabolism 
FAS 
Full Analysis Set 
FCE 
Fluid Composite Effect 
FDA 
Food and Drug Administration 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GLP 
Glucagon-like peptide 
HGH 
Human growth hormone 

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Abbreviation or Specialist Term 
Explanation 
hCG 
Human chorionic gonadotropin 
HRQoL 
Health Related Quality of Life 
IBD 
Inflammatory bowel disease 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
IWRS 
Interactive web Response System 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NOAEL 
No observed adverse effect level 
NYHA 
New York Heart Association 
PGIC 
Patient Global Impression of Change scale 
PK 
Pharmacokinetic 
PRO 
Patient-reported outcome 
PS 
Parenteral support 
QTc 
Corrected QT interval 
QTcF 
 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBS 
Short bowel syndrome 
SBS-I 
SBS-Impact Scale. A disease specific patient reported outcome 
questionnaire developed by Zealand Pharma 
SC 
Subcutaneous 
SD 
Standard deviation 
SUSAR 
Suspected unexpected serious adverse reaction 
TNF-  
Tumor necrosis factor-alpha 
ULN 
Upper limit of normal 

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4 Introduction 
4.1 
Background 
Patients with short bowel syndrome (SBS) are characterized by reduced intestinal absorptive 
surface area due to extensive surgical bowel resection or congenital diseases, such as recurrent 
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 
Whereas less severely affected SBS patients are able to compensate for their malabsorption by 
increasing oral intake (hyperphagia) and adapt metabolically or pharmacologically, more 
severely affected patients depend upon the safe and well-adjusted provision of parenteral support 
of nutrients, fluids, electrolytes, vitamins, and trace elements to maintain body function, growth, 
homeostasis, and health.8 For those dependent on parenteral support (PS), it is life-sustaining but 
at the same time associated with life-threatening complications. Among those are blood stream 
infections or sepsis,9 central vein thrombosis, liver damage10, and renal impairment.11 In 
addition, the treatment burden of parenteral support is substantial. Often 10-18 liters of 
parenteral support per week are required. In addition to 10- to 12-hour over-night parenteral 
support 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 parenteral support 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 intestinal growth 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 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. 
4.2 
Key Characteristics of Glepaglutide 
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 structural inducing probe (SIP) tail consisting of 6 lysines. The sequence 
similarity of the back bone 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 

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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. 
This Phase 3 trial is being conducted to confirm the findings from the Phase 2 trial and to 
compare the safety and efficacy of glepaglutide versus placebo 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), 2 dosing regimens of glepaglutide  10 mg once weekly and 10 mg twice 
weekly  will be investigated in order to find the optimal dosing regimen. See Section 6.1.1 for 
the rationale for these doses. 
4.3 
Risk-Benefit Assessment 
4.3.1 Benefits 
For the conducted dose-finding trial ZP1848-15073 testing glepaglutide in SBS patients with or 
without the need of parenteral support, the primary endpoint of change in wet weight of 
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 
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 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 
 
Patients receiving glepaglutide treatment in the present Phase 3 trial are likely to experience 
similar improvements in intestinal function, with reduced dependence on parenteral support as 
result. Trial patients completing the trial period (including those receiving placebo and patients 
who were dosed but discontinued from trial treatment due to reasons other than an AE related to 
the trial product or withdrawal of consent) will receive the opportunity to receive long-term 
glepaglutide treatment in an Extension Trial to the present trial. 

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4.3.2 Risks 
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 
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 
this trial. 
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 
adverse events (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 Investigato
 
In addition to in the gastrointestinal tract, there are also GLP-2 receptors in the lung, brain, and 
hypothalamus22. 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 [ADA]) following administration of 
glepaglutide is considered high. However, longer-term clinical treatment is required to 
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-

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glepaglutide response are so far considered of minor criticality. Glepaglutide ADA will be 
monitored in this trial, including their glepaglutide neutralizing potential and cross-reactivity to 
the main glepaglutide metabolite (ZP18481-34) as well as to 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 FDA in April 2018. 
Patients with severe and acute cardiac disease are excluded from trial participation (see 
Section 7.3). 
Neoplasms 
GLP-2 stimulates development of colonic adenomas in rodent models.20,21 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 colonoscopy has been 
suggested for patients taking GLP-2 analogs who have residual colons.20 Therefore a screening 
colonoscopy (within 6 months prior to screening) 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. These are considered adequate precautionary 
measures. Neoplasms (malignant and benign) are defined as AEs of special interest (AESIs) for 
the trial. 
Risk of underdosing 
The PK results and exposure-response analyses for glepaglutide substantiates that both once 
weekly and twice-weekly dosing of 10 mg glepaglutide result 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. 
4.3.3 Overall Benefit-risk Conclusion for the Trial 
In conclusion, the benefit-risk ratio for the proposed glepaglutide treatment regimens is 
considered favorable for the intended trial population, and potential risks are considered 
appropriately handled and mitigated. 
5 Trial Objectives  
5.1 
Primary Objective 
To confirm the efficacy of glepaglutide in reducing PS volume in SBS patients. 
5.2 
Secondary Objectives 
To evaluate the efficacy of glepaglutide on other efficacy endpoints in patients with SBS. 
To evaluate the safety and tolerability of glepaglutide in patients with SBS. 

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5.3 
Estimand 
Translating the trial objective into a precise description of the treatment effect to be estimated, 
leads to four components that together define the estimand of interest: 
1. The population is defined as patients with SBS randomized into the trial and having 
received treatment 
2. The endpoint is the reduction from baseline in actual weekly PS volume after 24 weeks 
3. The effect of twice weekly and once weekly glepaglutide 10 mg, regardless of 
discontinuing treatment or not, is of interest 
4. The summary measure is the difference in endpoint means between active (twice weekly 
and once weekly glepaglutide 10 mg) and placebo 
Estimand: Difference between mean reduction from baseline in actual weekly PS volume at 
24 weeks in the SBS population regardless of whether treatment is discontinued. 
The estimand is constructed based on the treatment policy strategy (ICH E9 (R1) addendum). 
It is required to collect data after treatment discontinuation to get a reliable estimate of this 
estimand. 
6 Investigational Plan 
6.1 
Trial Design Rationale 
A double-blind, randomized trial design permits the unbiased assessment of the safety and 
efficacy of glepaglutide compared with placebo. Placebo was chosen as the comparator for this 
trial to allow for a direct comparison of glepaglutide with local standard of care for PS. 
A 3-treatment, parallel-group design with a 1:1:1 randomization scheme (2 active treatment 
groups [once and twice weekly] and placebo) was chosen to compare the dosing regimen. The 
trial design is presented in Figure 1.  
Originally, the trial was designed with a fixed samples size of 129 SBS patients (43 patients 
planned for each of the three treatment groups) without any interim analysis. Because the 
recruitment of new patients into the phase 3 trial ZP1848-17111 is impacted by COVID-19, the 
trial design has been amended to a reduced fixed sample size of approximately 108 SBS patients 
(36 patients planned for each of the three treatment groups). 
A reduction of the weekly PS volume is the primary aim of the treatment to be confirmed in the 
present trial. The primary comparison to placebo will be made using the actual weekly PS 
reduction in L/week, which is a direct assessment of the decrease in burden for the patients. A 
reduction of at least 20% in the weekly need for PS volume is considered a clinically meaningful 
endpoint in the SBS patients and is included as a key secondary endpoint. This 20% reduction 
has previously been used in the teduglutide development program as the primary endpoint. A 
reduction in the need for parenteral support may further result in clinically meaningful benefits 
such as an increase in the number of days off of PS per week, decreased nocturia and less 
interrupted sleep, reduced infusion time per day, decreased stomal output or diarrhea, and 
reduced costs and resources associated with managing patients dependent on PS. 

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The target population consists of SBS patients with a stable need for PS at least 3 days per week. 
The exclusion criteria ensure that randomized patients are not put at any undue risk and that there 
are no concomitant diseases, conditions, or treatments that potentially could interfere with the 
interpretation of the data and results. 
Key clinical safety risks include the potential for acceleration of neoplastic growth and enhanced 
growth of colorectal polyps, intestinal obstruction/stenosis, cholecystitis, pancreatitis, fluid 
overload, and immunogenicity. Patients will be screened to exclude those recently hospitalized 
due to SBS, those with uncontrolled inflammatory bowel disease, those with a history of cancer 
(except resected cutaneous basal or squamous cell carcinoma and in situ cervical cancer) unless 
it can be 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 be entered. 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 before start of the stabilization phase. If the patient 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 
computerized tomography (CT) scan or magnetic resonance imaging (MRI) (if standard of care 
at site) will suffice at the discretion of the Investigator to document the absence of concerns 
regarding malignancy. During treatment with trial drug, 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 
. In the event that a patient discontinues early, the patient will be asked to come 
for a site visit for ADA sampling at EOT (End of Treatment) and approximately four weeks after 
treatment discontinuation, so that a potential ADA response can be characterized and results 
related to the clinical picture. Additionally, an internal Safety Committee will routinely review 
blinded safety data to monitor and ensure patient safety. 
6.1.1 Glepaglutide Dose Rationale 
The selected doses for Phase 3 are 10 mg, once- or twice-weekly. The selected doses are 
considered supported with respect to both safety and efficacy, as described below. 
Safety 
The safety of the proposed doses is supported by the outcome of the completed clinical trials, 
which showed that SC administrations of 10 mg (or 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 phase 3. From a safety perspective, once- or twice-weekly SC injection of 10 mg 
glepaglutide is therefore considered to be appropriate dose levels for testing in Phase 3. 
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) as well as for 
twice-weekly dosing (based on estimated data). These average plasma concentrations and 
associated 90% prediction intervals are shown superimposed on the exposure-response curve 

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established for the Phase 2 primary endpoint in supporting that both once-weekly and twice-
weekly dosing of 10 mg glepaglutide result in glepaglutide concentrations within the 
therapeutically effective dose range (see Figure 2). 
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. 
In conclusion for dose selection, the PK results and exposure-response analyses for glepaglutide 
substantiates that both once-weekly and twice-weekly dosing of 10 mg glepaglutide result in 
glepaglutide concentrations within the therapeutically effective dose range. To establish the 
optimal dosing interval, both a 10 mg once-weekly glepaglutide arm and a 10 mg twice-weekly 
glepaglutide arm are tested in this trial. 
6.2 
Overall Trial Design 
After providing informed consent, and initial confirmation of eligibility during the 2-week 
Screening period, patients will enter a PS Optimization and Stabilization Phase before baseline 
measurements are performed. An individual drinking menu will be defined by the patient and the 
Investigator during the Screening Period and until the end of the Optimization Phase. All patients 
will be equipped with an electronic diary (eDiary) for recording trial relevant data/information. 
Unless otherwise specified, baseline is defined as Day 1, prior to first dosing of trial product. PS 
optimization consist of 2 rounds, which limits the Optimization Phase to a maximum duration of 
4 weeks (± 4 days). If optimization cannot be shown during the 4-week period, a second 
Optimization Phase of up to 4 weeks (± 4 days) is allowed. The last Optimization Phase visit can 
be combined with the first visit in the Stabilization Phase if the patient is considered optimized. 
During the Optimization Phase, the Investigator and the patient may redefine and optimize the 
individual drinking menu to best fit th

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the end of the Optimization Phase, no additional modification to the drinking menu will be 
allowed and the patient will be required to adhere to the drinking menu during the 48-hour 
balance periods throughout the remainder of the trial. 
Stabilization Phase 
The Stabilization Phase has a minimum duration of 2 weeks and a maximum duration of 4 weeks 
(± 4 days). The last visit of the Optimization Phase can also be the first visit of the Stabilization 
Phase. Prior to the Stabilization Phase visit, the patient must measure his/her urine volume over 
48 hours while adhering to the pre-defined drinking menu and report the urine volume and oral 
fluid intake in the eDiary. Patients will be evaluated every 2 weeks (± 4 days) during the 
Stabilization Phase and will need to fulfill the stability criteria (see below) before the patient can 
be randomized. If stability cannot be shown during the 4-week period due to unforeseen events 
such as infections, illness or similar, a second Stabilization Phase of up to 4 weeks (± 4 days) is 
allowed. 
The baseline value for urine volume (L per day) will be defined as the average of the last two 48-
hour urine volumes from the Stabilization Phase (e.g., visits St1 and St2 or visits St2 and St3). 
The baseline PS volume (L/week) will be defined as the actual PS volume received during the 7-
day period prior to Visit 1 (Day 1). No changes in the prescribed weekly PS volume or schedule 
is allowed during the Stabilization phase. 
A patient will be considered stable if all of the following criteria are met: 
 Actual PS usage (volume and content) matches prescribed PS (± 10% deviation in total 
volume is acceptable) and 
 48-hour urine volumes at 2 consecutive visits within a 2-week interval (± 4 days, i.e., 
visits should be 10 to 18 days apart) are similar (a maximum of ± 25% deviation is 
acceptable), while the oral fluid intake is constant (the two 48-hour oral intakes differ less 
than 10%) and maximum 3.5 L per day, and 
 Urine volume is on average 
 
The Investigator and Medical Monitor must both agree and approve that the patient has met the 
criteria to be considered stable after completing the Stabilization Phase. See Section 8.7 for more 
details. 
Main Trial Period 
Visit 1 is done within 2 weeks after the last Stabilization Phase visit. If done on the same day, 
Visit 1 lab samples should be drawn. All eligible patients who complete the Optimization and 
Stabilization Phases will be randomized in a 1:1:1 manner to receive 2 SC injections weekly of 
either: a) glepaglutide 10 mg twice weekly, b) glepaglutide 10 mg once weekly and placebo once 
weekly, or c) placebo twice weekly for the following 24 weeks. 
During the 24-week Treatment Phase, PS need will be evaluated based on the 48-hour balance 
periods with a fixed drinking menu (individually pre-defined during the Optimization Phase) and 
measurements of urine volume done prior to each trial visit (except for Visit 2-phone 
assessment). 

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The actual volume of PS will be recorded on an ongoing basis in the eDiaries by the patients. 
The Investigator will record in the eCRF the type, content, and volume of the PS being used. 
Once trial drug treatment is initiated, PS volume can be adjusted at trial visits (at Weeks 1, 2, 4, 
8, 12, 16, 20, and 24) if the criteria for adjustment are met and according to a predefined 
algorithm (Section 8.7.4). 
The Investigator may arrange unscheduled visits (preceded by a 48-hour balance period) if he or 
she considers the visits to be needed based on medical judgement to assess PS volume needs. 
It is acknowledged that intake of oral liquids and PS might have to be changed between 
scheduled visits to avoid edema, especially if treatment is effective. In such cases changes to the 
PS is at the discretion of the Investigator and the reason needs to be documented in the eCRF. 
Any changes to the content of PS are left to the discretion of the Investigator and the reason 
documented in the eCRF. 
After completing the Treatment Phase, all patients (patients in all 3 treatment groups) will be 
eligible to enter an Extension Trial and receive glepaglutide. In addition, patients who were 
dosed but discontinued from trial treatment due to reason other than an AE related to trial 
product or withdrawal of consent may be invited to enter the Extension Trial when completing 
the 24-week Treatment Phase schedule. 
For patients not entering the Extension Trial, a Follow-up Visit will be conducted 4 weeks after 
completion of the Treatment Phase. Any post-treatment Follow-up Visit will be considered 
redundant if the patient is enrolled in the Extension Trial at the time of the Follow-up Visit. 
6.3 
Trial Endpoints 
6.3.1 Primary Endpoint 
Reduction in weekly PS volume from baseline to Week 24 
6.3.2 Key Secondary Endpoints 
 Clinical response, defined as achieving at least 20% reduction in weekly PS volume from 
baseline to both Weeks 20 and 24 
 
 day/week from baseline to Week 24 
 Reduction in weekly PS volume from baseline to Week 12 
6.3.3 Reduction in weekly PS volume of 100% (weaned off) at Week 24Secondary 
Efficacy Endpoints 
 Reduction of at least 20% in PS volume from baseline to both Weeks 12 and 24 
 Change in fluid composite effect (FCE) from baseline to Week 24 
 Reduction in calculated energy content of parenteral macronutrients from baseline to 
Week 24 
 Reduction in number of days on PS per week from baseline to Week 24 
 Reduction of at least 40% in PS volume from baseline to both Weeks 20 and 24 
 PGIC improvement at Weeks 4, 12, 20, and 24 

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 Change in weight from baseline to Week 24  
6.3.4 Other Efficacy Endpoints 
 
 
 
 
 Reduction in duration of PS infusions per week from baseline 
 Concentration trough levels of glepaglutide and metabolites 
 Change in plasma citrulline level from baseline to Week 24 
 Change in weekly need for parenteral micronutrients (sodium, potassium, magnesium, 
and calcium) from baseline to Week 24 
 Change in patient-reported outcomes (SBS-I and EQ-5D-5L) from baseline to Week 24 
 Reduction in bowel movements or stoma bag emptying from baseline to Week 24 
6.3.5 Safety Endpoints  
 Incidence and type of AEs and SAEs 
 Changes in clinical evaluations: 
- 
Vital signs 
- 
Electrocardiogram (ECG) 
 Changes in safety laboratory assessments: 
- 
Hematology 
- 
Biochemistry 
- 
Urinalysis 
- 
Standard bone markers 
 Immunogenicity 
 
6.4 
End of Trial Definition 
A patient will be considered as having completed the trial when: 
 Patient completed EOT visit and exit interview, if consented (Danish, French, German, 
UK and US, sites only) and will continue participation in Extension Trial. 
 Patient completed Follow-up (FU)/Final Visit and exit interview, if consented (Danish, 
French, German, UK, and US, sites only) and will not enter the Extension Trial. 
6.5 
Criteria for Premature Termination of the Trial and/or Trial Site 
The Sponsor, the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs), or 
a Regulatory Authority may decide to stop the trial, part of the trial, or a trial site at any time. 
The trial will be prematurely terminated overall or at a particular trial site at any time in the 
emergence of any safety information that could significantly affect continuation of the trial, i.e. 

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adverse events or other safety information that are considered unacceptable taken the indication 
into account and resulting in an unacceptable benefit-risk ratio. Guidance for when the Safety 
Committee will take action is provided in Section 11.4.6. 
If the trial is suspended or prematurely terminated, the Investigator must inform the patients 
promptly and ensure appropriate therapy and follow-up. The Investigator and/or Sponsor must 
also promptly inform the Regulatory Authorities and IRBs/IECs and provide a detailed written 
explanation. 
If, after the termination of the trial, the benefit-risk analysis changes, the new evaluation must be 
provided to the IRBs/IECs 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. 
7 Trial Patients 
7.1 
Number of Patients 
A total of approximately 108 patients are planned to be randomized into the trial; approximately 
72 to the glepaglutide treatment groups (36 in each of the 2 active treatment groups) and 
approximately 36 to the placebo treatment group, after the PS Stabilization Phase is completed. 
A screen failure rate of 15% is expected, hence, approximately 152 patients may need to be 
screened. 
7.2 
Inclusion Criteria 
The patient must meet all of the following inclusion criteria: 
1. Informed consent obtained before any trial-related activity. 
2. 
0 years at Screening. 
3. Diagnosis of SBS defined as remaining small bowel in continuity of estimated less than 
200 cm [equal to 79 inches] and with the latest intestinal resection being at least 6 months 
prior to Screening and considered stable with regard to PS need. No restorative surgery 
planned in the trial period. 
4. Requiring PS at least 3 days per week. 
5. Willing to adhere to an individual pre-defined drinking menu during 48-hours measuring 
intervals. 
6. Willing to maintain a stable weight (± 5%) for the duration of the trial (24 weeks). 
7. Having: 
a. A stoma Or 
b. Colon-in-Continuity (CiC) with documented colonoscopy performed during 
Screening and which does not give rise to any safety concerns.  
1. Note: A colonoscopy performed within 6 months prior to Screening and not giving 
rise to any safety concerns is accepted. For patients with a remnant colon, which is 
not connected to the passage of foods and is thereby dormant, a computerized 

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tomography (CT) scan or magnetic resonance imaging (MRI) (if standard of care at 
site) will suffice at the discretion of the investigator.  
8. Having a) a stoma Or b) colon-in-continuity (CiC) and able to separate stool and urine 
during the 48 hours measuring intervals. 
7.3 
Exclusion Criteria 
The patient must be excluded from the trial if he or she meets any of the following criteria: 
1. 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. 
2. Poorly controlled inflammatory bowel disease (IBD) that is moderately or severely active 
or fistula interfering with measurements or examinations required in the trial. 
3. Bowel obstruction. 
4. Known radiation enteritis or significant villous atrophy, e.g., due to active celiac disease. 
5. 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. 
6. Clinically significant abnormal ECG as judged by the Investigator. 
7. Repeated (2 or more consecutive measurements separated by at least 15 minutes) systolic 
blood pressure measurements > 180 mm Hg. 
8. HIV (human immunodeficiency virus) positive, acute liver disease, or unstable chronic 
liver disease. 
9. 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. 
10. Estimated creatinine clearance (CLcr; by the Cockcroft-Gault formula) < 30 mL/min. 
11. Hepatic impairment defined as: 
a. 
 × the upper limit of normal (ULN), or 
b. 
 × ULN, or 
c. 
 ULN 
12. Use of GLP-1, GLP-2, human growth hormone (HGH), somatostatin, or analogs thereof, 
within 3 months prior to Screening. 
13. Use of dipeptidyl peptidase (DPP)-4 inhibitors within 3 months prior to Screening. 
14. Systemic immunosuppressive therapy that has been introduced or has been unstable 
within 3 months prior to Screening. 
15. Unstable biological therapy (e.g. anti-TNF-
Screening, including significant changes in doses or switch of drug. 

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16. Females of childbearing potential, who are pregnant, breast-feeding, intend to become 
pregnant or are not using highly effective contraceptive methods. Highly effective 
contraception methods and definition of child-bearing potential are described in 
Section 11.4.4. 
17. Known or suspected hypersensitivity to glepaglutide or related products. 
18. Previous exposure to glepaglutide. 
19. Previous participation (randomization) in this trial. 
20. Current, or within 30 days prior to Screening, participation in another interventional 
clinical trial that includes administration of an active compound. 
21. Mental incapacity or language barriers which preclude adequate understanding or 
cooperation, or unwillingness to comply with trial requirements. 
22. Any condition or disease or circumstance that in the Investigator's opinion would put the 
patient at any undue risk, prevent completion of the trial, or interfere with the analysis of 
the trial results. 
23. Committed to an institution by virtue of an order issued either by the judicial or the 
administrative authorities. 
24. An employee of the sponsor or Investigator or otherwise dependent on them. 
7.4 
Randomization Criteria 
The patient must meet all of the following criteria at the time of randomization: 
2. Requiring PS at least 3 days per week and maintains a stable PS volume for at least 
2 weeks. PS volume is considered stable if all of the criteria below are fulfilled: 
o Actual PS usage (volume and content) matches prescribed PS (± 10% deviation in 
volume is acceptable) and 
o 48-hour urine volumes at 2 consecutive visits within a 2-week interval (± 4 days, 
i.e., visits should be 10 to 18 days apart) are similar (a maximum of ± 25% 
deviation is acceptable), while the oral fluid intake is constant (the two 48-hour 
oral intakes differ less than 10%) and maximum 3.5 L per day and 
o 
 
3. No SBS-related hospitalizations within 30 days prior to randomization. Note: 
Hospitalizations related to trial procedures are allowed. 
4. Since Screening, no poorly controlled IBD that is moderately or severely active or fistula 
interfering with measurements or examinations required in the trial. 
5. No bowel obstruction since Screening. 
6. No cardiac disease defined as: decompensated heart failure (New York Heart Association 
[NYHA] Class III-IV), unstable angina pectoris, and/or myocardial infarction since 
Screening. 
7. No clinically significant abnormal ECG as judged by the Investigator. 

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8. Repeated (2 or more consecutive measurements separated by at least 15 minutes) systolic 
 
9. No use of GLP-1, GLP-2, human growth hormone (HGH), somatostatin, or analogs 
thereof since Screening. 
10. No use of dipeptidyl peptidase (DPP)-4 inhibitors since Screening. 
11. No systemic immunosuppressive therapy that has been introduced or has been unstable 
since Screening. 
12. No unstable biological therapy (e.g. anti-TNF-
including significant changes in doses or switch of drug. 
13. No unstable doses (including as needed use) within 2 weeks prior to randomization:  
 Antimotility drugs, e.g., loperamide, diphenoxylate, codeine or other opiates 
 H2 antagonists 
 Anti-diarrheal agents 
 Bile acid sequestering agents 
 Oral glutamine 
 Proton pump inhibitors 
 Diuretics 
 Systemic antibiotics or antibiotics affecting the gastrointestinal tract 
 Oral rehydration fluids 
14. Females of childbearing potential, using highly effective contraceptive methods and who 
are not pregnant, breast-feeding, or intend to become pregnant. 
7.5 
Patient Withdrawal or Discontinuation from Trial Treatment 
withdraw from the trial must always be respected. 
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 
 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. 
For patients who permanently discontinue from trial treatment (i.e. there is no plan to resume 
trial treatment or to enter the Extension Trial) every efforts must be made to ensure patients 
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 
of actual PS volume in Week 24 (primary endpoint). 

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Patients who permanently discontinue from trial treatment and the trial (without withdrawal of 
consent) should be asked to come to the site for an EOT visit during which all general, safety, 
and laboratory assessments should be performed as detailed in the schedule of assessments. 
During this visit, the Investigator should also discuss further treatment options for SBS with the 
patient. Note: if a patient is discontinued during a trial visit, efforts should be made to complete 
all trial-related assessments for the EOT Visit. If not participating in the Extension Trial, the 
patient should attend the FU/Final visit. 
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 unacceptab
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 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 8.6). 
Patients can be discontinued from trial treatment if: 
1. A patient was randomized despite it was later identified as having violated any of the 
inclusion, exclusion, or randomization criteria. The Investigator must discuss with the 
 
If a patient prematurely discontinues trial treatment, the primary reason must be specified in the 
eCRF and the Investigator must undertake procedures similar to those for the relevant visits as 
soon as possible. 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 trial visits not having been performed must be documented. 
7.6 
Trial Drug Pausation 
If a patient experiences an AE, which is considered related to trial drug and which according to 
the Investigator requires dose pausation, the investigator may decide that the patient should skip 
 doses in total); i.e. the dose interval is increased; however, the 
injected dose remains the same. In that case, both the doses in the week need to be skipped in 
order to keep the blind.  
If the AE does not abate and it continues to be considered related to trial product, the investigator 
may decide that the patient should continue to pause treatment but always so that both doses in a 
week are skipped. If the AE has not abated and the AE continues to be considered related to trial 
product and is not acceptable based on an overall assessment of benefit and risks, the patient 

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should be discontinued from the trial treatment but should, to the extent possible, adhere to the 
planned visit schedule. 
The patient may resume treatment if the AE resolves and the Investigator deems it safe and in the 
Vial 1, followed by Vial 2. 
If the same type of AE reappears with re-challenge and the nature of the event is not considered 
acceptable, the dosing should be stopped, but the patient should, to the extent possible, adhere to 
the planned visit schedule. 
An accumulated maximum of 4 weeks of treatment pausation can be allowed. Hereafter, trial 
treatment should be discontinued (discontinuation due to adverse event) for the remainder of the 
trial, but patients should be encouraged to attend all remaining visit and complete all required 
assessments. 
7.7 
Patient Replacement 
Randomized patients who have subsequently withdrawn consent or who have been discontinued 
from trial treatment will not be replaced. 
Rescreening is allowed and can take place after a patient has failed the Optimization and 
Stabilization Phases (prior to randomization) if the Investigator judges that the patient is 
clinically stable. 
8 Treatment of Patients 
8.1 
Treatment Assignment and Randomization 
Eligible patients will be randomized in a double-blind fashion to 1 of 3 treatment groups in a 
ratio of 1:1:1: 
 Glepaglutide 20 mg per week, administered as 10 mg SC injections twice weekly  
 Glepaglutide 10 mg per week, administered as 10 mg SC injection once weekly and 
placebo SC injection once weekly 
 Placebo, administered as SC injections twice weekly 
All 3 treatment arms involve twice-weekly dosing (glepaglutide and/or placebo) to maintain the 
blind. The first dose is taken on Day 1 and the second dose should be taken on either Day 4 or 
Day 5 of each treatment week (interval chosen at the randomization visit and adhered to 
throughout the trial period). Please see Table 3 for a schematic overview. 

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Table 3: 
Dosing Regimen 
Second Dosing 3 Days after Visit 1 
Day 
1 
4 
8 
11 
15 
18 
22 
 
Dispensing unit 
1 
2 
3 
4 
Twice weekly DB 
treatment 
Vial 1 
Vial 2 
Vial 1 
Vial 2 
Vial 1 
Vial 2 
Vial 1 
 
Second Dosing 4 Days after Visit 1 
Day 
1 
5 
8 
12 
15 
19 
22 
... 
Dispensing unit 
1 
2 
3 
4 
Twice weekly DB 
treatment 
Vial 1 
Vial 2 
Vial 1 
Vial 2 
Vial 1 
Vial 2 
Vial 1 
 
Abbreviations: DB=double-blind 
 
The choice of dosing days will be recorded. Both the patient and Investigator will be blinded to 
the actual content of each vial (active or placebo); therefore, it is important that the patient 
selects the correct vial for each administration. Randomization will be performed using a block 
randomization scheme stratified by 
 12 L/week). 
The randomization scheme will be generated prior to the initiation of the trial by an independent 
statistician/programmer who will not be a member of the trial team; Investigators will not be 
aware of the block size of the randomization scheme. 
Patients will be randomly assigned to trial treatments using an automatic, interactive web 
response system (IWRS), which is integrated into the electronic data capture system (EDC) and 
has been validated for the intended use under Title 21 of the US Code of Federal Regulations 
(CFR) Part 11 (FDA regulation for Electronic Records and Electronic Signatures) and the 
International Council for Harmonisation (ICH) Guidance E6 for Industry on Good Clinical 
Practice. 
8.2 
Trial Drug Administration 
Glepaglutide and placebo are delivered as ready-to use liquid formulation in vials. Patients will 
use single-use syringes, provided by Zealand Pharma, to withdraw 0.5 mL solution from a vial of 
drug product and inject it SC. 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 1 thigh or both thighs during the Treatment Phase. 
The initial dose of trial drug will be administered by a trial staff member at the first visit (Day 1). 
The patient will be instructed by trial staff on the preparation, administration, storage, and return 
of trial drug at the Day 1 visit. Patients will be instructed to report the DUN (Dispensing Unit 
Number) and date and time of the day of trial drug administration. If dosing is on the same day 
as the visits (and in the morning), the trial drug should not be administered at home before 

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visiting the site as the trial drug is taken at the trial site shortly after the PK and ADA and other 
lab sampling and assessments. 
8.3 
Missed Doses of Trial Drug 
Patients should not omit planned doses. Patients who miss a scheduled dose of trial drug should 
be instructed to administer the missed dose as soon as they become aware of the mistake; 
however, two doses should not be administered the same day. 
8.4 
Treatment Compliance 
Treatment compliance is encouraged by patients receiving reminders from their eDiary for trial 
drug administrations. Patients are requested to enter details regarding trial drug administration 
(including date and time of the day as well as DUN) and injection site area used (i.e., abdomen, 
thigh) in the eDiary. Patients are to record PS use (including bag name, volume, infusion date, 
and duration) in the eDiary on an ongoing basis. 
8.5 
Concomitant Medications 
Since the mechanism of action of glepaglutide may increase absorption of orally administered 
drugs (e.g., motility medications, warfarin, benzodiazepines, phenothiazines, and thyroid 
medications), consideration is advised when modifying concomitant oral medication regimens. 
Down-titration of concomitant medications should be considered when drugs, including those 
with a narrow therapeutic range or those requiring titration, are given at dosages that are higher 
than usual. Investigators should monitor all patients carefully, since some of the patients have not 
previously been treated with a GLP-2 analog. 
8.6 
Prohibited Medications 
GLP-1, 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 Medical Monitor be informed on the indication for the change. Any 
changes to concomitant medications must be documented in the eCRF. 
8.7 
Parenteral Support 
Actual volume of PS will be recorded on an ongoing basis in the eDiaries by the patients. Type 
and content of the prescribed PS will be recorded in the eCRF by the Investigator. The PS 
volume and content should always be according to prescription. Patients will develop a personal 
drinking menu together with the Investigator before initiation of the Optimization Phase. During 
the Optimization Phase, the Investigator and patient will be allowed to redefine or optimize the 
drinking menu. Thereafter, no further changes to the drinking menu will be allowed and the 
patient will be required to adhere to the personal drinking menu for the remainder of the trial 
during the 48-hour balances periods. Thus, patients must follow this personal drinking menu 
during all subsequent 48-hour urine measurement days performed during the trial. 
Once trial drug treatment is initiated, PS volume can be adjusted at trial visits if the criteria for 
adjustment are met and according to the algorithm described in Section 8.7.3. However, intake of 
oral liquids and PS might have to be changed to avoid edema, especially if treatment is effective. 

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The patient should discuss any changes with the Investigator, as requirement for changes in PS 
records and the eCRF. 
8.7.1 Algorithm for Parenteral Support Adjustments during the Optimization Phase 
A patient is considered stable if: 
 Actual PS usage (volume and content) matches prescribed PS (± 10% deviation in 
volume is acceptable) and 
 48-hour urine volumes at 2 consecutive visits within a 2-week interval (± 4 days, i.e., 
visits should be 10 to 18 days apart) are similar (a maximum of ± 25% deviation is 
acceptable), while the oral fluid intake is constant (the two 48-hour oral intakes differ less 
than 10%) and maximum 3.5 L per day, and 
 
 
During the Optimization Phase, the Investigator may change the PS volume and content if the 
patient is considered unstable or not optimized. Any changes in PS volume or content should be 
done according to institutional standard practice. The effect of any PS optimizations must be 
investigated after 2 weeks (± 4 days). Prior to an Optimization Phase visit, the patient must 
measure the volume of his/her urine over 48 hours, while adhering to the 48-hour pre-defined 
drinking menu. No more than 2 rounds of PS optimization are allowed to be performed, which 
limits the Optimization Phase to a maximum duration of 4 weeks (± 4 days). If optimization 
cannot be shown during the 4-week period, a second Optimization Phase of up to 4 weeks 
(± 4 days) is allowed.  
8.7.2 Parenteral Support during Stabilization Phase 
The Stabilization Phase has a minimum duration of 2 weeks and a maximum duration of 
4 weeks. The last visit of the Optimization Phase can also be the first visit of the Stabilization 
Phase. Patients will be evaluated every 2 weeks (± 4 days) during the Stabilization Phase and 
will need to fulfill the stability criteria as listed in Section 8.7.1 before the patient can be 
randomized. It must be documented that the stability criteria are fulfilled, before a patient can be 
randomized. If stability cannot be shown during the 4-week period due to unforeseen events such 
as infections, illness, or similar, a second Stabilization Phase of up to 4 weeks is allowed. The 
baseline values for urine production will be the average values for 48-hour urine volume 
measured at the last 2 Stabilization Phase visits. 
8.7.3 Algorithm for Parenteral Support Adjustments during Trial Drug Treatment 
In general, patients should remain well hydrated during the trial. The urine production should 
stay above 1 L per day for all patients and the targeted daily urine production should be close to 
the baseline urine production for the individual patient. 
Changes to the content of PS are left to the discretion of the Investigator. Once trial drug 
treatment is initiated, PS volume can be adjusted at Weeks 1, 2, 4, 8, 12, 16, 20, and 24 if the 
criteria for adjustment are met and according to the pre-defined algorithm below. Unscheduled 
visits (preceded by a 48-hour measurement period) may be considered by the Investigator as 
medically appropriate to adjust PS. 
Prerequisite for PS volume reduction: 

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IF: daily average urine volume of the current visit is at least 10% higher than baseline urine 
volume. 
THEN: New PS volume (weekly) = Current PS volume (weekly)  7 × absolute increase in 
daily urine volume from baseline. 
Algorithm 
New PS volume (weekly) =  
Current PS volume (weekly)  7 x (daily current urine volume  daily baseline urine 
volume) 
Note: The current PS volume is defined as the latest prescribed PS volume, i.e. the PS 
volume that the patient should be following prior to the visit. 
Example: 
Patient receives 10 L of PS per week. The urine volume has increased from 1.3 L per day to 
1.5 L per day. Hence, the urine volume has increased by more than 10% and PS volume 
should be reduced. The new weekly PS volume should be 8.6 L (detailed as 10 L  7 × 
0.2 L). 
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. 
8.7.4 Parenteral Support Volume Adjustments due to Clinical Signs 
Especially in the beginning of the trial drug Treatment Phase, the Investigator must be in 
frequent contact with the patient. If the patient presents with clear adverse clinical signs of fluid 
overload, PS volume may be reduced without 48-hour urine measurements being available. 
During the next scheduled 48-hour measurement period however, further PS volume adjustments 
might have to be considered based on the results of the 48-hour urine measurement. 
8.7.5 Parenteral Support Volume Adjustments during Unscheduled Visits 
PS volume adjustments are allowed during unscheduled visits if the patient has performed a 
48-hour urine volume measurement. In these cases, PS volume should be adjusted according to 
the algorithm described in Section 8.7.3. 

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9 Investigational Medicinal Product 
9.1 
Trial Drug 
The investigational medicinal products to be used comprise 1 active dose strength of 
glepaglutide (10 mg) and a placebo formulation. 
9.1.1 Glepaglutide 
Glepaglutide is provided in a single-use vial containing 1 mL (an extractable volume of 0.5 mL) 
of a clear, essentially colorless solution for injection, containing 20 mg/mL glepaglutide. 
9.1.2 Placebo 
Placebo for glepaglutide is provided in a single-use vial containing 1 mL (an extractable volume 
of 0.5 mL) of clear, essentially colorless solution for injection. 
9.2 
Blinding and Breaking the Blind 
Each unique dispensing unit will be labelled such that treatment blinding is ensured. It will not 
be possible to conclude from the appearance of the dispensing unit (box containing 2 vials) the 
treatment sequence allocated. 
The Investigator, all site research personnel, trial patients, Sponsor, and Contract Research 
Organization (CRO) will be blinded to the allocated trial treatments until database lock 
For pharmacokinetic and immunogenicity analyses the randomization codes will be supplied to 
the bioanalytical teams at Charles River (PK analyses) and Syrinx (ADA analyses). Blinding of 
samples are secured throughout the trial conduct until database lock. All PK and ADA samples 
are shipped from the central laboratory to the bioanalytical lab, regardless if the patient has been 
on placebo or active treatment. The randomization list is sent to the bioanalytical teams by an 
unblinded, trial independent, data system designer at the CRO.  
Un-blinded results will only be shared with the Sponsor and the CRO after database lock.  
In case of an emergency, where the knowledge of the trial drug treatment is important for the 
further treatment course, treatment assignment will be available in the IWRS set up within EDC 
to the blinded personnel. The Investigator may unblind immediately without any restrictions. 
However, unblinding should only be performed when the knowledge of the actual treatment 
administered will influence decisions on the future treatment of the patient. Date, reason for code 
break, and randomization number must be documented in the medical records. However, the 
Investigator should NOT reveal the actual treatment identification to sponsor or sponsor 
representatives. The Medical Monitor should be contacted immediately after the blind is broken. 
An automated notification will be sent to designated personnel at Zealand Pharma and Pharm-
Olam if the blind is broken for a patient. 
9.3 
Trial Drug Packaging, Labeling and Storage 
Trial drug vials will be packed and labeled into a treatment box containing two vials (unique 
dispensing unit), as appropriate according to the 3 treatment groups. The dispensing unit 
configuration will support administration of trial drug on Day 1 and Day 4/5, see Section 8.1. 
Sponsor (or designee) will package and label the trial drug. The trial drug label will describe the 
storage conditions for the trial drug. The labels will supply no information about the patients. 

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Each dispensing unit will have a unique DUN for drug allocation, drug accountability, and 
traceability purposes. 
Drug labels will be printed in local language and labeling will be performed according to 
Annex 13 of the Good Manufacturing Practice guidelines of the European Commission, ICH 
Good Clinical Practice (GCP) guidelines, local laws, and regulations. 
For further information, refer to the Trial Material Manual. 
The Investigator must ensure the availability of proper storage conditions. All drug supplies 
provided for this trial will be stored in a secure area with restricted access at the trial site. 
The temperature should be monitored by recording the actual, minimum, and maximum 
temperatures using a calibrated thermometer or thermocouple, or by continuous recording using 
a qualified temperature monitoring system. The temperature should be evaluated and 
documented at least on working days on a temperature log. This log must be included in the 
Investigator Site File upon trial termination. 
The Investigator (or designee) must inform Zealand Pharma or designee and the monitor 
immediately if any trial product has been stored outside the defined conditions (e.g., outside the 
temperature range). 
Trial drug should be stored at 2°C to 8°C 
 
Patients will be instructed to store the trial drug refrigerated at 2 t
they are not required to monitor the storage temperature. 
The vials should be maintained in the outer packaging (dispensing carton box) until immediately 
prior to trial drug use. 
9.4 
Accessory Supplies 
Besides the trial products, patients will be provided with syringes, needles, swabs for 
disinfection, a safety bin for safe disposal of used syringes. For further details, see the Trial 
Material Manual. 
9.5 
Trial Drug Supply and Handling 
The Sponsor will provide trial drug to each site for each patient for the duration of his/her 
participation in the trial. The Investigator, or designee will dispense trial drug at each dispensing 
visit. A sufficient quantity of trial drug will be dispensed to assure that the patient has sufficient 
drug supply to last at least until the next scheduled drug dispensing visit. No trial product may be 
dispensed to any person not enrolled in the trial. 
Patients will be instructed to report in the eDiary the administration of the trial drug (DUN and 
date and time of the day) as well as injection site (abdomen or thigh). 
Patients will be familiarized with the handling and use of vials and syringes prior to the first 
administration of trial drug, and as needed at the site. The Investigator must maintain an accurate 
record of the shipment and dispensing of trial drug as described in Section 9.6. 
In case the Investigator, the site staff, or the monitor suspect that the trial drug is defective or 
potentially defective, Zealand Pharma should be contacted immediately. 

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9.6 
Trial Drug 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 
 Only dispensed to trial patients according to the IWRS 
 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 drug 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 vials and the dispensing cartons must be kept and returned to 
Sponsor after reconciliation of delivery records and accountability logs. Discrepancies between 
the amount of trial drug received, dispensed and returned must be reconciled. 
Patients should be instructed to bring all their trial drug supply with them to each scheduled trial 
visit. Investigator or delegated staff must perform drug accountability with the patient at every 
visit to the clinic. This to enforce strict adherence to schedule and amount withdrawn and dosed 
from each vial. Returned trial drug (used or unused vials and the dispensing cartons) must be 
stored separately from non-allocated trial drug. The Investigator must not destroy any used or 
unused drug 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 vials and the dispensing cartons to the Sponsor. Returned drug vials may also be destroyed 
locally according to trial site procedures. However, prior destruction of any vials it has to be 
approved by the sponsor via completion of the trial drug accountability forms. When the drug is 
destroyed the destruction certificate must be provided the sponsor. The Investigator's copy of the 
drug accountability forms must accurately document the return of all trial drug supplies to the 
Sponsor.  
After self-administration, the patient should dispose the used syringe and needle in the container 
provided. 
10 Trial Procedures by Visit 
All trial visits will be performed on-site, except Visit 2, which will occur via a phone call from 
the trial coordinator or Investigator to the patient. 
10.1 Screening 
The Screening visit will occur 0 to 14 days prior to starting the Optimization Phase. 
During the Screening visit, the following assessments will be performed: 
 Obtain informed consent; must be signed before the start of any protocol-related 
assessments 
 Confirm eligibility based on inclusion/exclusion criteria 

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 Document patient demographics 
 Record medical history (including history of drug/alcohol abuse) 
- 
Record current concomitant illnesses and note relatedness to SBS 
- 
Record information on smoking and current use of alcohol 
- 
Record the details of whether the patient suffered from any of the following: 
Encephalopathy, ascites, cholestasis, steatosis, and/or cirrhosis. If yes, the outcome / 
histopathologic diagnosis and date of histopathologic diagnosis is recorded 
 Document SBS characteristics (see Section 11.1.2) 
 Record PS regimen (including weekly schedule, volume, and content) 
 Record all concomitant medications and relevant previous treatments, including treatment 
with teduglutide, any other GLP-2 analogs or native GLP-2 
 Perform a 12-lead ECG 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Measure body weight and height 
 Perform a full physical examination 
 Perform colonoscopy if needed (results from colonoscopy performed within 6 months of 
Screening visit are acceptable). In case of a dormant colon, i.e. a remnant colon is 
present, but not connected to the passage of foods, 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 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) or FSH (to confirm 
menopause) 
- 
Hematology 
- 
Biochemistry 
- 
HIV 
- 
Hepatitis B and C 
 Agree with patient on individually fixed drinking menu for future 48-hours balance 
periods (including volume, content, and approximate time) 
 Provide information and instructions for documentation in eDiary of: 
- 
PS use 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 

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10.2 Optimization Phase 
The first Optimization Phase visit should be scheduled within 2 weeks after the Screening Visit 
and a possible subsequent Optimization Phase visit should occur 2 weeks hereafter (duration 2 to 
4 weeks ± 4 days). Thus the PS optimization consist of 2 rounds, which limits the Optimization 
Phase to a maximum duration of 4 weeks (± 4 days). If optimization cannot be shown during the 
4-week period, a second Optimization Phase of up to 4 weeks (± 4 days) is allowed. The last 
Optimization Phase visit can be combined with the first visit in the Stabilization period if the 
patient is considered optimized.  
During the Optimization Phase visit(s), the following assessments will be performed: 
 Complete patient-reported outcome (PRO) questionnaires (preferably the SBS-I first 
followed by the EQ-5D-5L) at start of optimization phase 
 Record prescribed PS regimen (including weekly schedule, volume, and content) 
 Record body weight 
 Record any procedures and changes to concomitant medications 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 
- 
Biochemistry 
 Review eDiary information for: 
- 
PS use 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
Agree with patient if any changes to the individually fixed drinking menu for future 
48-hours balance periods are needed (including volume, content, and approximate 
time). Hereafter, no further changes will be allowed for the remainder of the trial. 
10.3 Stabilization Phase 
The Stabilization Phase visits should be scheduled approximately 2 to 4 weeks (± 4 days, i.e., 
visits should occur 10 to 18 days apart) after the Optimization Phase visit. The first Stabilization 
Phase visit can be combined with the last Optimization Phase visit if the patient is considered 
optimized. If stability cannot be shown during the 4-week period due to unforeseen events such 
as infections, illness or similar, a second Stabilization Phase (St4, St5, etc.) of up to 4 weeks (± 4 
eDiary information to ensure that the necessary data are available. If the information was not 

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-
hour balance measurements. 
During the Stabilization Phase visit(s), the following assessments will be performed: 
 Complete PRO questionnaires (preferably the SBS-I followed by EQ-5D-5L) at start of 
stabilization phase 
 Record body weight 
 Record any procedures and changes to concomitant medications 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 
- 
Biochemistry 
 Review eDiary information for: 
- 
PS use 
- 
48-hour oral fluid intake 
- 
48-hour urine volume output 
- 
48-hour bowel movements/stoma bag emptying 
 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
drinking menu 
 Instruct patient in eDiary completion of number of bowel movements (CiC patients) 
/number of stoma bags emptied (stoma patients) during the 48-hour balance periods 
10.4 Treatment Phase (Up to 24 Weeks) 
Once the last two Stabilization visits have occurred and both the Medical Monitor and the 
Investigator have reported that the patient is considered stable, the Visit 1 can be scheduled. The 
Visit 1 should be planned to occur within 2 weeks after the last Stabilization Phase visit. 
Note: Prior to 
information to ensure that the necessary data are available. If the information was not entered 
 
10.4.1 Visit 1 (Day 1) 
During Visit 1, the following assessments will be performed: 
 Confirm eligibility based on inclusion/exclusion criteria and that the patient meets the 
stable PS regimen criteria 

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 Complete PRO questionnaires (preferably the SBS-I first followed by EQ-5D-5L) 
 Record any procedures and changes to concomitant medications 
 Perform 12-lead ECG 
 Record body weight 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Obtain urine sample for urinalysis 
 Obtain blood samples prior to dosing for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 
- 
Biochemistry 
- 
Citrulline 
- 
PK 
- 
ADA 
- 
Bone markers 
 Review eDiary information for (if applicable): 
- 
PS use 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
48-hour bowel movements/stoma bag emptying 
 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
drinking menu 
 Upon approval from Medical Monitor of the stabilization criteria, randomize patient into 
treatment group using the IWRS criteria set up within EDC 
 Administer trial drug and review self-administration procedures, clean-up procedures, 
and eDiary assignments with patient 
 Dispense trial product to patient and discuss treatment compliance with the patient 
 Decide on dosing schedule (Day 1 and 4 or Day 1 and 5) (See Table 3) 
10.4.2 Visit 2 (Day 3 ± 1 day) 
Visit 2 will occur via a phone call by the Investigator or designee to the patient on Day 3. 
During Visit 2, the following assessments will be performed: 

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 Record adherence to PS regimen (including weekly schedule, volume, and content) 
 Record AEs 
 Confirm patient is recording the following information in the eDiary: 
- 
PS use 
- 
Trial product administration (including injection site, time of administration) 
 Remind patient of next dose and discuss treatment compliance with the patient 
10.4.3 Visit 3 (Week 1/Day 8 ± 2 days) 
During Visit 3, the following assessments will be performed: 
 Complete SBS-I 
 Record any procedures and changes to concomitant medications 
 Record body weight 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
Hematology 
- 
Biochemistry 
- 
PK (drawn prior to dosing if dosing on same day) 
 Review eDiary information for: 
- 
PS use 
- 
Trial product administration (including injection site, time of administration) 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
48-hour bowel movements/stoma bag emptying 
 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
modify weekly PS volume and schedule in accordance with Section 8.7.3) 
10.4.4 Visit 4 (Week 2/Day 15 ± 3 days) 
During Visit 4, the following assessments will be performed: 
 Complete SBS-I 
 Record any procedures and changes to concomitant medications 

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 Record body weight 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
Hematology  
- 
Biochemistry 
- 
PK (drawn prior to dosing if dosing on same day) 
- 
ADA (drawn prior to dosing if dosing on the same day) 
 Review eDiary information for: 
- 
PS use 
- 
Trial product administration (including, injection site, time of administration) 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
48-hour bowel movements/stoma bag emptying 
 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
modify weekly PS volume and schedule in accordance with Section 8.7.3) 
 Collect and account for returned trial product 
10.4.5 Visit 5 (Week 4/Day 29 ± 5 days) 
During Visit 5, the following assessments will be performed: 
 Complete PGIC and SBS-I 
 Record any procedures and changes to concomitant medications 
 Record body weight 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 

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- 
Biochemistry 
- 
Citrulline (drawn prior to dosing, if dosing on same day) 
- 
PK blood sample (drawn prior to dosing, if dosing on same day) 
- 
ADA (drawn prior to dosing, if dosing on same day) 
 Review eDiary information for: 
- 
PS use 
- 
Trial product administration (including injection site, time of administration) 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
48-hour bowel movements/stoma bag emptying  
 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
modify weekly PS volume and schedule in accordance with Section 8.7.3) 
 Patient to return all used and unused vials and the dispensing cartons. Account for 
returned trial product 
 Dispense trial product to patient 
10.4.6 Visit 6 (Week 8/Day 57 ± 5 days) 
During Visit 6, the following assessments will be performed: 
 Complete SBS-I 
 Record any procedures and changes to concomitant medications 
 Record body weight 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 
- 
Biochemistry 
- 
ADA (drawn prior to dosing, if dosing on same day) 
- 
PK (drawn prior to dosing if dosing on same day) 
 Review eDiary information for: 
- 
PS use 

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- 
Trial product administration (including injection site, time of administration) 
- 
48-hour oral fluid intake 
- 
48-hour urine volume  
- 
48-hour bowel movements/stoma bag emptying 
 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
modify weekly PS volume and schedule in accordance with Section 8.7.3) 
 Patient to return used and unused vials and the dispensing cartons. Account for returned 
trial product 
 Dispense trial product to patient 
10.4.7 Visit 7 (Week 12/Day 85 ± 5 days) 
During Visit 7, the following assessments will be performed: 
 Complete PROs (PGIC, SBS-I, and EQ-5D-5L) 
 Record any procedures and changes to concomitant medications 
 Perform 12-lead ECG 
 Record body weight 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 
- 
Biochemistry 
- 
PK (drawn prior to dosing, if dosing on the same day) 
- 
ADA (drawn prior to dosing if dosing on the same day) 
 Review eDiary information for: 
- 
PS use 
- 
Trial product administration (including injection site, time of administration) 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
48-hour bowel movements/stoma bag emptying 

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 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
modify weekly PS volume and schedule in accordance with Section 8.7.3) 
 Patient to return used and unused vials and the dispensing cartons. Account for returned 
trial product 
 Dispense trial product to patient 
10.4.8 Visit 8 (Week 16/Day 113 ± 7 days) 
During Visit 8, the following assessments will be performed: 
 Complete SBS-I 
 Record any procedures and changes to concomitant medications 
 Record body weight 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 
- 
Biochemistry 
- 
PK (drawn prior to dosing if dosing on the same day) 
 Review eDiary information for: 
- 
PS use 
- 
Trial product administration (including injection site, time of administration) 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
48-hour bowel movements/stoma bag emptying 
 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
modify weekly PS volume and schedule in accordance with Section 8.7.3) 
 Patient to return all used and unused vials and the dispensing cartons. Account for 
returned trial product 
 Dispense trial product to patient 
10.4.9 Visit 9 (Week 20/Day 141 ± 7 days) 
During Visit 9, the following assessments will be performed: 

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 Complete PGIC and SBS-I  
 Record any procedures and changes to concomitant medications 
 Record body weight 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 
- 
Biochemistry 
- 
PK blood sample (drawn prior to dosing, if dosing on the same day) 
 Review eDiary information for: 
- 
PS use 
- 
Trial product administration (including injection site, time of administration) 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
48-hour bowel movements/stoma bag emptying 
 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
modify weekly PS volume and schedule in accordance with Section 8.7.3) 
 Patient to return all used and unused vials and the dispensing cartons. Account for 
returned trial product 
 Dispense trial product to patient 
 Schedule patient Exit Interview in Clinigma patient interview portal, if consented 
(Danish, French, German, UK, and US, sites only), to be conducted no longer than 7 days 
after EOT visit 
10.4.10 Visit 10 (End of Treatment; Week 24/Day 169 ± 7 days) 
During Visit 10, the following assessments will be performed: 
 Complete PROs (PGIC, SBS-I, and EQ-5D-5L) 
 Record any procedures and changes to concomitant medications 
 Perform 12-lead ECG 
 Record body weight 

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 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 
- 
Biochemistry 
- 
Citrulline (drawn prior to dosing, if dosing on the same day) 
- 
PK (drawn prior to dosing, if dosing on the same day) 
- 
ADA (drawn prior to dosing, if dosing on the same day) 
- 
Bone markers 
 Review eDiary information for: 
- 
PS use 
- 
Trial product administration (including injection site, time of administration) 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
48-hour bowel movements/stoma bag emptying 
 Record adherence to PS regimen (including weekly schedule, volume, and content) and 
modify weekly PS volume and schedule in accordance with Section 8.7.3 
 Patient to return all used and unused vials and dispensing cartons. Account for returned 
trial product 
 Decision whether the patient will participate in the Extension Trial or not 
- 
If not participating 
o The patient should resume standard of care and the treating physician is 
advised to pay careful attention to the PS regimen  
o The patient should attend the Follow-up/Final visit 
- 
If the patient agrees to enter the Extension Trial: 
o Complete the end-of-trial form in the eCRF 
- 
Exit Interview (selected countries only) 
o The exit interviews, if consented (Danish, French, German, UK and US sites 
only sites only) will be conducted no longer than 7 days after EOT visit  

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Investigator to review the transcript of exit interview for potential AE reporting 
within 2 days after receiving the transcript. 
10.5 Follow-up/Final Visit 
-up visit t
eDiary information to ensure that the necessary data are available. If the information was not 
-up/Final Visit is 
only applicable for patients who will not enter the Extension Trial. 
10.5.1 Follow-up Visit (Week 28/Day 197 ± 7 days) 
Patients who are not entering the Extension Trial should return the eDiary. During Follow-up 
Visit, the following assessments will be performed: 
 Complete PROs (SBS-I and EQ-5D-5L) 
 Record any procedures and changes to concomitant medications 
 Record body weight 
 Record vital signs (heart rate, systolic and diastolic blood pressure, and body 
temperature) 
 Record AEs 
 Perform short physical examination (driven by SBS symptoms) 
 Collect urine sample for urinalysis 
 Obtain blood samples for: 
- 
hCG pregnancy test (for females of childbearing potential only) 
- 
Hematology 
- 
Biochemistry 
- 
Citrulline 
- 
PK 
- 
ADA 
 Review eDiary information for: 
- 
PS use 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
- 
48-hour bowel movements/stoma bag emptying 
 Complete end-of-trial form in the eCRF 
10.6 Unscheduled Visits 
following as applicable: 

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 Review eDiary information for: 
- 
PS use 
- 
48-hour oral fluid intake 
- 
48-hour urine volume 
 Record PS regimen (including weekly schedule, volume, and content) and modify weekly 
PS volume and schedule in accordance with Section 8.7.3) 
 Lab sampling: In case of suspected liver injury based on increased ALT, AST, alkaline 
phosphatase, or total bilirubin, the tests should be repeated at 48-72 hours for evaluation 
of the event course/confirmation 
11 Trial Assessments 
11.1 General Assessments 
11.1.1 Demographics and Medical History 
Demographic information and medical history will be obtained at Screening. Demographic 
information to be collected includes age, gender, race, and ethnicity (if allowed in the 
participating country). 
Medical history information to be collected includes all ongoing conditions and 
relevant/significant medical history (including all major hospitalizations and surgeries). 
Concomitant illness must also be captured and not
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. 
11.1.2 SBS Characteristics and Disease History 
characteristics: 
 The underlying cause of SBS 
 Date of diagnosis of underlying disease 
 Date of SBS diagnosis 
 Remaining bowel sections28; 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, 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 classification29) 
 Severity of SBS based on the ESPEN Functional and Clinical Classification of Chronic 
Intestinal Failure8 
 Date that the patient started PS 

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11.1.3 Concomitant Medications 
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. 
All relevant previous treatments, including treatment with teduglutide, any other GLP-2 analogs 
or native GLP-2 are recorded in the eCRF. 
11.1.4 Drinking Menu 
An individual fixed drinking menu should be decided upon by the patient and the Investigator 
based on the patien
 
The drinking menu should be followed throughout the 48-hour urine volume measurement 
periods (which means that the 24-hour drinking menu will be repeated twice during the 
48 hours). 
11.2 Assessments of Efficacy 
11.2.1 Patient Diaries 
Patients will be required to complete eDiaries throughout the course of the trial. The patient will 
record the following: 
 Trial drug administration (including date and time of day) and injection site area used 
 PS use 
 During 48-hour measurement periods: 
o Oral fluid intake based on the individually pre-defined drinking menu 
o Urine volume 
o Number of bowel movements resulting in defecation/stoma bags emptied 
 
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. 
11.2.2 Parenteral Support Use and Volume 
Parenteral support use and volume will be assessed based on trial visit records of weekly average 
s daily diary entries. Data will be checked at all 
trial visits. 
11.2.3 Parenteral Calories and Nutrients 
Parenteral calories (macro-nutrients) and micro-nutrients will be assessed based on the 
 daily diary entries of 
patient-reported PS regimen. 
11.2.4 48-hour Urine Volume 
Urine volume will be recorded by the patient in his or her diary during the defined 48-hour 
measurement periods prior to a trial visit. During this time the patient must adhere to the 

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individually pre-defined drinking menu (see Section 11.1.4). 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 and should be timed with the PS schedule. Patients on PS 7 days weekly 
must perform the 48-hour measurement on 2 consecutive 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 4 for further clarity. The grey boxes indicate the possible 48-hour balance periods. 
If more than one interval is available any 1 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 
eDiary. If the PS regimen changes during the trial a new schedule for 48-hour measurement can 
be chosen and recorded in the eDiary. 
Table 4: 
Timing of 48-hour Measurements 
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 
 
 
 
 
 
 
 
* Relative to PS week days 
** < 3 days of PS per week is only allowed after reduction during trial participation. 
 
The patient will, if possible, be contacted prior to the scheduled start of the 48-hour measurement 
period and reminded to start measuring complete oral fluid intake and urine volume, and to 
record these measurements in the eDiary. 
11.2.5 Plasma Citrulline Levels 
Plasma citrulline levels will be measured at Visit 1 (prior to first dose of trial drug), Visit 5 
(Day 29/Week 4), Visit 10 (Day 169/Week 24), and at Follow-up Visit (Day 197/Week 28), if 

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applicable. After at least 8 hours of orally fasting, plasma citrulline blood samples will be taken 
in the morning and analyzed at a central laboratory. 
11.2.6 Patient-Reported Outcomes 
The PGIC, SBS-I and EQ-5D-5L24 PROs will be used to investigate the effects of treatment on 
health-related quality of life (HRQoL). 
Questionnaires must be completed in paper format at site visits prior to any other trial related 
assessment. The PROs will be completed by the patient without assistance of site personnel. 
When the PGIC, SBS-I, and the EQ-5D-5L questionnaires are to be completed, patients is 
recommended to complete the PGIC first. When only the SBS-I and EQ-5D-5L are to be 
completed, it is recommended that the SBS-I is completed first. The PROs must not be 
completed at home before the patient attends the visit. Patients will be instructed to complete the 
PRO in a private area without influence from trial team members or accompanied by family or 
friends. No one is allowed to answer or interpret items for the patient. The Investigator or a 
delegated trial team member is allowed to read items/answers options to the patient aloud if the 
patient is unable to read. The Investigator or delegated trial team member 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 trial team member 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 trial team members will receive training and instruction in 
completion of the PROs prior to the conduct of the trial. 
Patients will report in the eDiary their number of bowel movements/stoma bag emptying during 
the 48-hour balance periods. 
11.2.7 Health Economic Assessments 
The health economic assessments will collect the number and duration of hospitalizations due to 
SBS-related issues during the 24- to 28-week trial period (including follow-up if not continuing 
in Extension Trial). Information will include reason for admission, dates and duration of stay and 
medications given and procedures performed. 
11.2.8 Exit interview 
A telephone exit interview will be conducted by an external provider on a subset of patients upon 
completion of the placebo-controlled, double-blind treatment period. The purpose of the exit 
assess the clinical meaningfulness of reducing parenteral support. See the separate Exit Interview 
Manual for full research. 
 

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11.3 Assessment of Safety 
11.3.1 Safety Parameters 
Safety will be assessed by the following parameters: 
 AEs 
 Weight 
 Vital signs 
 ECGs 
 Clinical laboratory tests (hematology, biochemistry, and urinalysis) 
 Immunogenicity 
11.3.2 Vital Signs 
The following vital signs will be collected at every trial visit (except Visit 2-phone assessment): 
(beats/min), and seated diastolic and systolic blood pressure (mm Hg). During treatment period 
visits, vital signs will be collected before trial drug injection. 
11.3.3 Weight and Height 
Body weight (kg or lb) will be measured at Screening, during the Optimization and Stabilization 
Phases, and at every trial visit (except Visit 2-phone assessment). During weight measurements 
patients should wear light clothing and no shoes. Stoma bags should be emptied prior to the 
mass index (BMI) will be calculated. 
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 trial site for guidance. 
11.3.4 Physical Examination 
Patients will undergo a full physical exam at Screening. The physical exam will consist of an 
examination 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 
baseline examination that are noted during follow-up will be recorded as an AE on the 
appropriate eCRF pages. 
For all subsequent site visits during Treatment Phase, an abbreviated physical exam will be 
completed. The body systems included in these exams will be based on Investigator judgment 
and/or patient symptoms. 
11.3.5 Electrocardiogram (ECG) 
A 12-lead ECG will be obtained at Screening and at Visits 1 (Day 1; prior to the start of the first 
trial drug), 7 (Day 85/Week 12; prior to dosing of trial drug in case drug is administered this 

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day), and 10 (Day 169/Week 24). Additional ECGs will be performed for cause as needed to 
evaluate AEs. 
ECG parameters (heart rate, PR, QRS, QT, QTcF, RR) and any abnormality will be recorded and 
described in the eCRF including the In
significant deterioration of a pre-existing condition as well as any new clinically significant 
findings will be recorded as AEs (see Section 11.4). 
11.3.6 Laboratory Assessments 
Safety laboratory tests, including hematology, biochemistry, and bone markers will be performed 
as specified below, and in the Schedule of Assessments (Table 1). Blood samples should be 
obtained prior to trial drug dosing. In total approximately 280 mL blood is drawn. 
Safety laboratory tests are to be performed and reviewed by the Investigator or qualified 
analyzed via central laboratories. 
11.3.6.1 Hematology 
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differential, and platelet count will be measured at Screening, at the Optimization and 
Stabilization Phase visits, and at every trial visit (with the exception of Visit 2-phone 
assessment). 
11.3.6.2 Biochemistry 
The following parameters will be measured (or calculated) at every trial visit (with the exception 
of Visit 2-phone assessment): Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine, CLcr (estimated), glucose, calcium, phosphorous, alkaline phosphatase, ALT, AST, 
international normalized ratio (INR), gamma-glutamyl transferase (GGT), lactic dehydrogenase, 
conjugated bilirubin, total bilirubin, total protein, albumin, amylase, uric acid, and C-reactive 
protein. 
In case of suspected liver injury based on increased ALT, AST, alkaline phosphatase, or total 
bilirubin, the tests should be repeated at 48-72 hours for evaluation of the event 
course/confirmation. 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. 
Cholesterol and triglycerides will be measured orally fasting at Visits 1 (Day 1) and 10 
(Day 169/Week 24). 
Magnesium and zinc will be measured at Visits 1 (Day 1), 7 (Day 85/Week 12), and 10 
(Day 169/Week 24) only. 
11.3.6.3 Bone Markers 
The standard bone markers collected are: 25OH vitamin D, parathyroid hormone (PTH), thyroid 
stimulating hormone (TSH; thyrotropin), P-CTx (collagen I, C-terminal telopeptide-fragments), a 
marker of bone resorption and P-PINP (Pro-collagen, N-terminal pro-peptide) a marker of bone 

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formation. Blood samples for bone markers will be obtained at Visit 1 (Day 1) and Visit 10 (Day 
169/Week 24) only. 
11.3.6.4 Urinalysis 
Urinalysis will be measured at every trial visit (with the exception of Visit 2-phone assessment). 
Urinalysis will include: blood, glucose, leukocytes, pH, osmolality, protein, sodium and 
potassium. 
11.3.6.5 Pregnancy Screen 
A pregnancy test (serum beta-human chorionic gonadotropin [hCG]) will be completed for all 
females of childbearing potential at Screening, at Optimization Phase visit 1 (Op1), Stabilization 
Phase visit 1 (St1), at Visit 1 (Day 1), and from Visit 5 (Day 29/Week 4) to Visit 10 (Day 
169/Week 24). Sterilized or infertile patients, i.e., patients who have undergone surgical 
sterilization (vasectomy/bilateral tubectomy, hysterectomy, and bilateral ovariectomy) or women 
who are postmenopausal, which is defined as > 52 years of age and 12 months or more with no 
menstruation prior to enrollment and/or as FSH level >30 mIU/mL (as measured at site) are not 
regarded as being of childbearing potential. 
11.3.6.6 Immunogenicity 
Serum samples will be obtained prior to dosing (if dosing occurs on the visit day) at Visit 1 
(Day 1), 4 (Day 15/Week 2), 5 (Day 29/Week 4), 6 (Day 57/Week 8), 7 (Day 85/Week 12), 10 
(Day 169/Week 24), and Follow-up Visit (Day 197/Week 28) (if applicable) to determine the 
presence of ADA and the ADA titer. Each ADA sample will contain 5 mL of blood, resulting in 
30 mL (35 mL with Follow-up Visit) of blood drawn for ADA analysis. 
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 ZP1848-neutralizing potential and cross-reactivity to the 
major metabolite (ZP18481-34) and GLP-2. Results will not be revealed to the sites. 
All ADA samples will be retained at the special lab (Syrinx Bioanalytics Oy, Finland) or long-
term storage facility (MLM Medical Labs GmbH, Germany) until drug approval by the US FDA 
and/or 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. 
11.3.6.7 Pharmacokinetics 
A blood sample will be obtained prior to administration of trial drug (if dosing occurs on the visit 
day) at every trial visit during the Treatment Phase (except for Visit 2-phone assessment) and the 
Follow-up Visit (Day 197/Week 28). The PK sampling schedule is set in order to be able to 
correlate PK values to ADA data and to obtain sufficient information from the dosing regimens 
tested. Results will not be revealed to the sites. 
Each PK sample will contain 6 mL of blood, resulting in 60 mL of blood drawn for PK analysis. 
11.3.6.8 HIV, Hepatitis B, and Hepatitis C 
A blood sample will be obtained at screening to confirm the HIV, hepatitis B and C status. If 
positivity is confirmed, the patient will be excluded from participation in the trial. 

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11.4 Adverse and Serious Adverse Events 
Timely, accurate, and complete reporting and analysis of safety information from clinical trials 
are crucial for the protection of patients. Investigators and the Sponsor are mandated by 
regulatory agencies worldwide to report the safety information. 
11.4.1 Definitions 
11.4.1.1 Adverse Events 
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 unfavorable 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. 
When assessing an AE, the following definitions will be used: 
Severity: 
 Mild: 
 
 Moderate: 
 
 Severe: 
finds unacceptable. A severe reaction does not necessarily deem the AE as serious and an 
SAE are not always severe in nature. 
Causality: 
 Probably: Good reason and sufficient documentation to assume a causal relationship 
 Possibly: A causal relationship is conceivable and cannot be dismissed 
 Unlikely: The event is most likely related to etiology other than the product 
 Not related: No relationship to product. 
Outcome: 

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 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 
ith 
as an SAE 
 Unknown: This term is only applicable if the patient is lost to follow-up. 
  
11.4.1.2 Adverse Events of Special Interest (AESI) 
In this trial the following events are to be regarded as AESI, should they occur: neoplasms 
(malignant and benign), suspicion of liver injury, pancreatitis, and cholecystitis. 
If the event is reported as an SAE, the timelines for SAE reporting apply. If the event is reported 
as non-serious AE, it should be reported in the dedicated eCRF page within 2 working days (if at 
 
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 
event, and an event narrative. Copies of images (if performed) should be stored at each 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, 

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e.g. 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 each 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 alkaline phosphatase. 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 each 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). 

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 Lab tests (at local lab, if needed): liver function tests, including ALT, AST, bilirubin, 
and alkaline phosphatase. 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. 
11.4.1.3 Serious Adverse Event 
An SAE is any untoward medical experience that at any dose fulfills any of the following 
criteria: 
 Results in death 
 Is life-threatening 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 
 Is otherwise medically important, that may not result in death, be life threatening or 
require hospitalization may be considered an SAE when (based on appropriate medical 
judgement) it may jeopardize the patient and may require medical or surgical intervention 
to prevent one of the outcomes listed in the definition of SAE. Examples could be 
emergency room or home treatment of allergic bronchospasm or convulsion. 
SAEs must be reported to the appropriate Sponsor contact person(s) within 24 hours after 
obtaining knowledge about the event, followed by a complete SAE form as soon as more 
information is available. 
11.4.1.4 Other Important Adverse Events 
The following events must always be reported to Sponsor 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. 
11.4.1.5 Non-serious Adverse Event 
A non-serious AE is any AE which does not fulfill the definition of an SAE. 
11.4.1.6 Suspected Unexpected Serious Adverse Reactions 
An AE is considered a Suspected Unexpected Serious Adverse Reaction (SUSAR) if the nature 
or severity is not consistent with the applicable product Reference Safety Information (RSI). 
Zealand Pharma or designee will notify the Investigator of SUSARs in accordance with local 
requirements and ICH GCP. 

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11.4.2 Collection, Recording and Reporting of Adverse Events 
All AEs, whether serious or non-serious, will be reported from the time a signed and dated 
Informed Consent Form (ICF) is obtained until the end of the post-treatment follow-up period 
(which may include contacts for follow-up of safety). In addition, patients will be observed for 
ntact with the trial site (visit or 
telephone). Patients will also be encouraged to spontaneously report AEs 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 
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: 
- 
Date and time of onset 
- 
Date and time of Investigators first information about the AE 
- 
Seriousness 
- 
Severity 
- 
Causal relationship with trial product 
- 
Measures taken due to AE 
- 
Interruption or discontinuation of treatment with trial product 
- 
Date and time of resolution and final outcome. 
 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 21.0. 
SAEs, including those spontaneously reported to the Investigator within 30 days after the last 
dose of trial product must be reported to the appropriate Sponsor contact person(s) within 
24 hours after obtaining knowledge about the event, followed by a complete SAE form as soon 
as more information is available. For each SAE, a separate SAE form should be completed in the 
eCRF. 
It is the responsibility of Sponsor (or delegate) to report all SUSARs that occur in this trial to the 
relevant Regulatory Authorities in participating countries and it is the responsibility of the 
designated CRO or Investigator to report to IRBs/IECs in accordance with the local requirements 
in force and ICH guideline for GCP. 
Zealand Pharma has outsourced the processing of SAEs and AESIs from this trial to PharmaLex. 

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Contact information for SAE reporting: 
Company: 
PharmaLex A/S 
Address: 
Agern Allé 24, DK-2970 Hørsholm, Denmark 
Ph.:  
+45 74 44 19 36 (24-hours) 
Email: 
PV-nordic@pharmalex.com  
 
 
11.4.3 Follow-up of Adverse Events 
The Investigator must record follow-up information. Follow-up information is reported by eCRF 
in a similar manner as initial AE/SAEs. Follow-up questions to Investigators regarding SAEs are 
queried directly by safety CRO to the Investigator. 
Follow-up information must be reported according to the following: 
 SAEs: All SAEs must be followed until the outcome of the events is 
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 
-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 
information. This is also the case for AEs initially reported as non-serious which subsequently 
become SAEs. 
 Non-serious AEs: Non-serious AEs must be followed until the outcome of the event is 
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 
follow-up period and is expected by the Investigator to recover. 
IMPORTANTLY: If a potential hypersensitivity reaction is observed, additional blood samples 
are required to further characterize the potential hypersensitivity reaction. If an anaphylactic 
shock is suspected, samples should be taken for the measurement of tryptase. In this case, a 
blood sample should be within 3 to 4 hours after the event and again approximately 2 to 4 weeks 
later to determine tryptase baseline levels. In addition, assessments for elevated histamine levels 
may be considered. Furthermore, a blood sample should be taken 2 to 4 weeks after the event for 
the determination of ADA and characterization of a potential ADA response in order to be able 
to relate this to the clinical picture. 

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For a comprehensive safety evaluation, the treatment-emergent adverse events are a key 
parameter. 
For an adverse event with onset before the first administration of the trial drug, which worsens in 
severity/seriousness in the period after the trial drug initiation, the worsening should be recorded 
as a separate adverse event with the onset date stated as the date of the severity and/or 
seriousness upgrade. 
For an adverse event with onset after the first administration of the trial drug, which worsens 
over time, the worsening must be recorded as follow-up information to the initial event (with re-
assessment of severity and/or seriousness) with no change to the initial onset date. The 
Investigator must ensure that the worst-case severity/seriousness of the event is recorded and 
kept throughout the trial. 
If an AE is resolved and recurs, then the later event needs to be reported as a new AE. 
Queries or follow-up request must be responded within 14 calendar days from the date of receipt 
of the request, unless otherwise specified in the follow-up request. 
11.4.4 Pregnancy 
Pregnancy during the trial should be avoided and the patients must be instructed in highly 
effective contraception as per local guidelines and to use this throughout the trial through 4 
weeks after receiving the last trial drug dose. 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 the 
Sponsor by the trial site personnel within 24 hours of knowledge of the event using the 
appropriate pregnancy form. Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal 
death, stillbirth, congenital anomalies, and ectopic pregnancy) are considered SAEs and must be 
reported using the SAE form. If a patient becomes pregnant during the trial, the patient should be 
discontinued from trial treatment (see Section 7.5). 
Highly effective contraception is defined as: 
a. Having a male partner who is sterile (vasectomized or orchiectomized) prior to the 
 
b. Use of intra-uterine devices 
c. Use of intrauterine hormone-releasing system 
d. Bilateral tubal occlusion 
e. Use of hormonal contraceptives containing combined estrogen and progestogen 
associated with inhibition of ovulation (intravaginal, transdermal) 
f. Use of progestogen-only hormonal contraception associated with inhibition of ovulation 
(injectable, implantable) 
g. 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 who are not sterilized or infertile must use condom throughout the trial through 4 
weeks after receiving the last trial drug dose. If their partner is a female of childbearing potential, 

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she must use highly effective contraception (as detailed above) throughout the trial through 4 
weeks after last dose. 
Because the effect of the trial product on sperm is unknown, pregnancies in partners of male 
patients must be reported by the trial site personnel within 24 hours of their knowledge of the 
event using the appropriate pregnancy form. Male patients must be instructed to notify the 
Investigator immediately if his partner becomes pregnant or suspects to be pregnant. 
The Investigator must follow the pregnancy until the pregnancy outcome is known and the 
newborn infant is 1 month of age. The Investigator must report information about the pregnancy, 
pregnancy outcome, and health of the newborn infant(s), as well as AEs in connection with the 
pregnancy, and AEs in the fetus and newborn infant. 
11.4.5 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 
d 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 
 
11.4.6 Safety Committee 
An internal Zealand Pharma Safety Committee is constituted to perform ongoing blinded 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. 
12 Statistics  
12.1 General Considerations for Data Analysis 
This is a multicenter, placebo-controlled, randomized, parallel-group, double-blind, fixed-dose, 
Phase 3 trial to demonstrate the superiority of glepaglutide 10 mg given twice weekly and once 
weekly SC versus placebo in stable SBS patients.  
A detailed Statistical Analysis Plan (SAP) will be written specifying all analyses that will be 
performed and completed prior to database lock and analysis. The SAP will contain any 
modifications to the analysis plan described below, and thus serves as the overriding document 
dictating the statistical analyses to be performed. Any changes from the SAP will be explained in 
the Clinical Trial Report (CTR). 
In general, all data will be summarized with descriptive statistics for each treatment group. 
Unless otherwise specified, continuous data will be summarized by presenting the number of 

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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. 
Baseline is defined as Visit 1 (Day 1) for efficacy analyses, and defined as the last available 
value prior to or on Visit 1 (Day 1) for safety analyses. 
Inferential statistical analyses of the primary and secondary efficacy endpoints will be performed 
as described below. All comparisons will be between each ZP1848-17111 treatment group and 
placebo. Listings of individual patient data will be presented. 
12.2 Analysis Sets 
The following analysis sets will be defined: 
 The Full Analysis Set (FAS) will consist of all randomized patients, who received at least 
one dose of trial drug (glepaglutide or placebo). All efficacy analyses will be based on the 
FAS. 
 The Per-protocol Analysis Set will consist of all FAS patients who do not experience any 
major protocol deviations. Specific criteria for exclusion from the Per-protocol Analysis 
Set will be listed in the SAP. Final judgments 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 analyses of the primary and key secondary efficacy endpoints. 
 The Safety Analysis Set will consist of all randomized patients who received at least 
1 dose of trial drug (glepaglutide or placebo). This is the same definition as for the FAS, 
but the two can deviate in special circumstances. All safety analyses will be based on the 
Safety Analysis Set. 
Because of the extensive PS optimization and stabilization phases conducted between enrollment 
and randomization, safety data will be summarized for the period after enrollment, but before 
treatment with trial drug, i.e. separate from the Safety Analysis Set. 
12.3 Efficacy Analysis 
The primary efficacy analysis will be conducted using the FAS. The twice weekly treatment 
group 
 the key secondary 
endpoints between each glepaglutide treatment group versus placebo. No adjustments for 
multiplicity will be performed for testing secondary endpoints. 
12.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the actual reduction in weekly PS volume from baseline to 
Week 24. Baseline weekly PS volume is defined as the PS volume received during the 7-day 
period prior to Visit 1 (Day 1), i.e. during the stabilization phase. The Week 1, 2, 4, 8, 12, 16, 20, 
and 24 weekly PS volume is defined as the PS volume received during the 7-day period prior to 
these visits. 
The primary analysis uses a restricted maximum likelihood (REML) based repeated-measures 
approach to compare treatment groups with respect to the mean change from baseline in weekly 

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PS volume at Week 24. The model will use weekly PS volume assessments at Week 1, 2, 4, 8, 
12, 16, 20, and 24, and will include the covariates for treatment group, baseline weekly PS 
volume, visit (categorical variable), stratification factor (weekly PS volume requirements <12 
L/week versus >12 L/week), and visit-by-treatment group interaction. Variance estimation is 
based on an unstructured covariance matrix, which does not presume a particular correlation 
structure for repeated weekly PS volume measurements within patients over time. The primary 
comparison is the difference in the reduction in weekly PS volume from baseline to Week 24 
between each glepaglutide treatment group versus placebo. 
Following the Treatment Policy estimand strategy, missing values will be imputed using multiple 
imputation methods. For the primary analysis, a Copy Reference (CR) approach is used with 
placebo treatment as reference, while for sensitivity analyses, a Jump to Reference (J2R) and a 
Copy Incremental from Reference (CIR) approaches will be applied. Details are described in 
Section 12.6 and in the SAP. 
The Copy Reference approach is justified as the trophic effects on the intestines mediated by 
glepaglutide would take weeks to abate after treatment withdrawal. A longitudinal growth of the 
remaining intestines could also have occurred after prolonged therapy and such modifications 
would not be expected to return fully to the baseline condition. Other effects of GLP-2 agonism, 
like reduced fluid secretion from the upper part of the GI tract and effects on reducing motility 
would however be expected to return to the baseline conditions when treatment is withdrawn. 
As a supplementary analysis, the analysis will be repeated using the Per-protocol Analysis Set. 
when testing the primary endpoint together with the key secondary endpoints between each 
glepaglutide treatment group versus placebo. See Section 12.3.3 for details. 
12.3.2 Key Secondary Endpoints  
The following 4 key secondary efficacy endpoints will be analyzed to assess the treatment effect 
using the FAS. 
Clinical response, defined as achieving at least 20% reduction in weekly PS volume from 
baseline to both Weeks 20 and 24 
The difference in clinical response between each glepaglutide treated group and the placebo 
treated group will be tested using the Cochran-Mantel-Haenszel (CMH) test with stratification on 
the randomization stratification factor. Missing values for the clinical response will be imputed 
as no clinical response. As a sensitivity analysis, missing values will be derived from the CR-
imputed data sets generated from the multiple imputation approach described for the primary 
efficacy endpoint. 
 
-day/week from baseline to Week 24 
between each glepaglutide treatment group versus placebo will be analyzed using a CMH test 
stratified on the randomization stratification factor. Missing values for this endpoint will be 
imputed as no response. As a sensitivity analysis, missing values will be derived from the CR-
imputed data set generated from the multiple imputation approach described for the primary 
efficacy endpoint. 

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Reduction in weekly PS volume from baseline to Week 12 
The reduction in weekly PS volume from baseline to Week 12 between each glepaglutide 
treatment group versus placebo will be analyzed in the same model as the primary efficacy 
analysis. The comparison is the difference in the reduction in weekly PS volume from baseline to 
Week 12 between each glepaglutide treatment group versus placebo in the mixed effects model 
for repeated measures (MMRM) described for the primary endpoint. A Copy Reference (CR) 
approach is used for this analysis, while for sensitivity analyses, a Jump to Reference (J2R) and a 
Copy Incremental from Reference (CIR) approaches will be applied. This follows the same 
multiple imputation approach described for the primary efficacy endpoint. 
Reduction in weekly PS volume of 100% (weaned off) at Week 24 
The difference in response in reduction in weekly PS volume of 100% (weaned off) at Week 24 
between each glepaglutide treatment group comparison to placebo will be analyzed using a CMH 
test stratified on the randomization stratification factor. Missing values for this endpoint will be 
imputed as no response. As a sensitivity analysis, missing values will be derived from the CR-
imputed data set generated from the multiple imputation approach described for the primary 
efficacy endpoint. 
12.3.3 Gatekeeping Procedure 
when testing the primary endpoint together with the key secondary endpoints between each 
glepaglutide treatment group versus placebo. The twice weekly treatment group and once weekly 
. 
The gatekeeping procedure starts by identifying the smallest maximum p-value of the first three 
tests (primary efficacy endpoint, 1st key secondary endpoint, and 2nd key secondary endpoint), 
among the two dosing regimens, once- and twice-weekly. For this regimen, the primary efficacy 
endpoint, 1st key secondary endpoint, and 2nd key secondary endpoint are evaluated at an 
 
significance level sequentially, only continuing to the next evaluation if the preceding test is 
statistically significant. If all of the first three tests result in p-values less than or equal to 
, the 
procedure continues at an  level for the other regimen. If, on the other hand, one of the first 
three tests result in a p-value greater than 
, the procedure stops for this regimen, and the 
procedure continues at an 
 level for the other regimen. 
Depending upon the results for the first three endpoints in the regimen where the procedure 
begins, the significance level is specified for the other regimen at 
 or at  The sequential test 
procedure then continues for the first three endpoints in the other regimen. If all six hypotheses 
(three first endpoints from both regimens) are significant, the last two key secondary endpoints 
are evaluated sequentially at the  significance level, only continuing to the next evaluation if the 
preceding is statistically significant. 
The parallel gatekeeping procedure is displayed in Figure 3 below. 

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Figure 3:
Testing Hierarchy
12.3.4 Secondary Efficacy Endpoints
The following secondary efficacy endpoints will additionally be analyzed to assess the 
treatment effect using the FAS. The tests will be non-hierarchical and type I error will not be 
adjusted for multiple testing:
Reduction of at least 20% in PS volume from baseline to both Weeks 12 and 24
The dif
and 24 between each glepaglutide treatment group versus placebo will be analyzed in a similar 
manner as the first key secondary efficacy endpoint.
Change in FCE from baseline to Week 24
The absolute change of FCE25, as defined by a reduction in PS volume (L/week), plus reduction 
in oral fluid intake volume (L/week), plus increase in urine volume (L/week) of the Stabilization 
Phase and at every trial visit (with the exception of Visit 2-phone assessment) will be analyzed. 
The difference in change in FCE from baseline to Week 24 between each glepaglutide treatment 
group versus placebo will be analyzed in a similar manner as the primary efficacy endpoint using 
a MMRM, but without multiple imputation.

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Reduction in calculated energy content of parenteral macronutrients from baseline to Week 24 
The difference in reduction in calculated energy content of parenteral macronutrients from 
baseline to Week 24 between each glepaglutide treatment group comparison to placebo will be 
analyzed in a similar manner as the primary efficacy endpoint using a MMRM, but without 
multiple imputation. 
Reduction in number of days on PS per week from baseline to Week 24 
The difference in reduction in number of days/week on PS from baseline to Week 24 between 
each glepaglutide treatment group comparison to placebo will be analyzed in a similar manner as 
the primary efficacy endpoint. 
Reduction of at least 40% in PS volume from baseline to both Weeks 20 and 24 
The difference in response in reduction of at least 40% in PS volume from baseline to both 
Weeks 20 and 24 between each glepaglutide treatment group comparison to placebo will be 
tested using the CMH test with stratification on the randomization stratification factor. 
PGIC improvement at Weeks 4, 12, 20, and 24 
7-point Likert Scale for each of the weeks 4, 12, 20, and 24. Improvement between each 
glepaglutide treatment regimen compared to placebo will be tested using the CMH test with 
stratification on the randomization stratification factor. 
Change in weight from baseline to Week 24  
The change in body weight (kg) from baseline to Week 24 will be presented descriptively in 
patients who are (1) below ideal weight at the start of the treatment period (BMI < 18.5 kg/m2 at 
baseline), and (2) maintaining an ideal/acceptable weight at the start of the treatment period 
(18 
aseline). The change in body weight (kg) from baseline to Week 24 
will also be categorized into three groups of less than 5% change, 5% to 10% change, and greater 
than 10% change. In addition will the proportion of patients in each treatment group who are 
(BMI > 25 kg/m2) will be presented descriptively in patients who are (1) below ideal weight at 
the start of the treatment period (BMI < 18.5 kg/m2 at baseline), and (2) maintaining an 
Descriptive statistics will include the number of non-missing observations, mean, SD, median, 
minimum, and maximum values. 
12.3.5 Other Efficacy Endpoints 
The following other efficacy endpoints will be summarized to assess the treatment effect using 
the FAS. Only descriptive statistics will be presented for these other efficacy endpoints and no 
inferential statistics will be performed. 
Reduction in 
 
baseline to Week 24 will be presented for each glepaglutide treatment group and placebo. 

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Reduction in days o
 
baseline to Week 24 will be presented for each glepaglutide treatment group and placebo. 
Reduction in duration of PS infusions per week from baseline.  
The reduction will be presented descriptively and include the number of non-missing 
observations, mean, SD, median, minimum, and maximum values. 
Concentration trough levels of glepaglutide and metabolites 
Concentration trough levels of glepaglutide and metabolites will be summarized descriptively. 
The number of non-missing observations, mean, SD, median, minimum, and maximum values 
will be presented by visit. 
Change in plasma citrulline levels from baseline to Week 24 
The change in plasma citrulline levels from baseline to Week 24 will be presented descriptively 
and include the number of non-missing observations, mean, SD, median, minimum, and 
maximum values. 
Change in weekly need for parenteral micronutrients (sodium, potassium, magnesium, and 
calcium) from baseline to Week 24 
The change in weekly need for parenteral micronutrients from baseline to Week 24 will be 
summarized using number of non-missing observations, mean, SD, median, minimum, and 
maximum values for sodium, potassium, magnesium, and calcium. 
Change in PROs (SBS-I and EQ-5D-5L) from baseline to Week 24 
The change in patient-reported outcome scores (SBS-I and EQ-5D-5L) from baseline to Week 24 
will be presented descriptively and include the number of non-missing observations, mean, SD, 
median, minimum, and maximum values. 
Reduction in bowel movements or stoma bag emptying from baseline to Week 24 
The reduction in bowel movements or stoma bag emptying will be presented descriptively by 
displaying the mean and the 95% confidence interval of the by treatment across the trial period. 
12.4 Safety Analysis 
Safety endpoints are: 
 Incidence and type of AEs and SAEs 
 Change in clinical evaluations: 
- 
Vital signs 
- 
ECG 
 Change in laboratory assessments: 
- 
Hematology 
- 
Biochemistry 
- 
Urinalysis 
- 
Standard bone markers 

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 Immunogenicity 
All safety analyses will be conducted using the Safety Analysis Set. No inferential tests of safety 
data will be performed. Descriptive summaries of safety data will be presented and for each 
AESI, a time to event analysis will be performed. This will be detailed in the SAP. Adverse 
events (treatment-emergent unless otherwise specified) will be presented by system organ class 
(SOC) and preferred term (PT) for each treatment group. 
Treatment-emergent AEs are defined as AEs with onset date on or after the first day of exposure 
to randomized treatment up through the last day prior to the start day of the Extension Trial or to 
the Week 28 (for patients not entering the Extension Trial). 
Immunogenicity endpoints will be associated with PK, efficacy, and safety endpoints as 
appropriate and described in detail in the SAP. 
Standard bone markers will be assessed as an exploratory endpoint. 
12.5 Demographic and Baseline Characteristics 
The number and percentage of patients who were screened, randomized, discontinued (with 
reason for discontinuation), and completed the trial will be summarized descriptively for all 
screened patients. 
Prior and concomitant medications as well as medical history will be summarized descriptively 
for the FAS. 
12.6 Discontinuations and Data Handling Rules 
The estimand of interest is the effectiveness of the assigned treatment in all randomized, treated 
participants, the treatment policy estimand (often called the intention-to-treat or de facto 
estimand). A placebo-based multiple imputation approach, Copy Reference (CR), will be used as 
the primary analysis to consider a missing-not-at-random (MNAR) mechanism for monotone 
missing data. Mean changes from baseline in actual PS volume will be analyzed based on data 
observed while the patient remains on trial as well as data imputed using multiple imputation 
(MI) methodology for time points at which no value is observed. The placebo arm is used as 
reference, as opposed to treatment-discontinuation patients, as it is expected that few patients on 
active treatment will discontinue treatment. This expectation is based on the drop-out rate seen in 
the teduglutide Phase 3 trial. 
Imputation of values in the placebo (control) arm will assume missing-at-random (MAR). 
Imputation of values in the glepaglutide arms will be done as if the patient had been a member of 
the placebo arm. Imputed values in the glepaglutide arms will be sampled using the imputation 
model of the placebo arm, i.e., conditional on patient values observed at time points prior to 
discontinuation relative to the mean of the model for the placebo arm. This approach does not 
assume a sustained benefit of glepaglutide treatment after discontinuation and limits a post-
discontinuation effect to that of placebo drug and trial effect as reflected in estimated correlations 
between time points in the placebo arm.  
Intermittent (non-monotone) missing data will be imputed first based on the MAR assumption 
and a multivariate joint Gaussian imputation model using Markov chain Monte Carlo (MCMC) 
method within each treatment arm. The MCMC method will be used with a single chain, 

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2000 tuning units and a minimum number of 4 tuning cycles, a burn-in of 1000, and a thinning of 
100 and non-informative priors for all parameters. 
The remaining, monotone missing data for all patients who discontinue the trial prematurely will 
be imputed using sequential regression multiple imputation model estimated based on data from 
the placebo arm only. Each sequential regression model (i.e., for imputation of values at a given 
time point) will include explanatory variables (treatment group, visit (categorical variable), 
stratification factor (weekly PS volume requirements <12 L/week versus >12 L/week)), and all 
previous (Baseline weekly PS volume, Visit at Weeks 1, 2, 4, 8, 12, 16, 20, and 24) values of 
actual PS volume. Missing values at a given time point in placebo and glepaglutide arms will be 
imputed from the same imputation model, conditional on patient values observed or imputed at 
previous time points. No rounding or range restrictions will be applied to imputed continuous 
values. 
Imputed data will consist of 1000 imputed datasets. A different and separate random seed 
number will be used for the partial imputation with the MCMC method, and for the sequential 
regression multiple imputation. Those random seed numbers will be specified in the SAP. 
Each of the 1000 imputed datasets will be analyzed using the following analysis method. Change 
in actual PS volume from baseline to each post-baseline visit will be calculated based on 
observed and imputed data. Treatment group comparison at Week 24 will be based on the least 
squares mean (LSM) difference between glepaglutide groups and placebo in change from 
baseline in actual PS volume estimated by the analysis model in each of the imputed datasets. 
Results from analysis of each imputed dataset, i.e., LSM treatment differences and their standard 
errors, will be 
treatment difference, its 95% confidence interval, and a pooled p-value for the test of null 
hypothesis of no treatment effect. 
The Copy Reference (CR) and Jump to Reference (J2R) approaches multiply impute missing 
data using estimated means in the control group. This is justifiable scientifically under the 
assumption that patients who stop taking the therapy will no longer benefit from it in the future, 
and thus will tend to have outcomes similar to those in the control group. The difference in the 
two methods is that the Copy Reference approach presumes patients who withdraw from the 
active arm were on the control (rather than the active) treatment before dropout; the resulting 
positive residuals before withdrawal leads to imputed values that slowly (rather than quickly) 
trend toward the estimated mean on the control arm. The Copy Reference is used in the primary 
analysis and the Jump to Reference will be applied as a sensitivity analysis. As a second 
sensitivity analysis, the Copy Increments from Reference will be used. This scenario provides a 
contrast to the extreme effect of J2R by assuming that in the future a dropout continues from 
their established position, but the subsequent changes in mean profile follow that of the reference 
arm. 
For all binary responder analyses, patients who discontinue for any reason will be considered as 
non-responders from the time of discontinuation onwards. 
Imputation rules for the handling of missing data for PROs and health economic assessments will 
be described in the SAP. 
No pooling of sites is planned for the efficacy analyses. 

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12.7 Sample Size and Power Considerations 
The sample size calculation for this trial is based on the effect achieved in the teduglutide Phase 
3 trial and that the PS vol, changes from baseline after 24 weeks of treatment (primary endpoint) 
are expected to be -4.5L/week and -4.3L/week with twice-weekly and once-weekly dosing, 
respectively, and -2.3L/week for placebo. The standard deviation of the treatment effect (once-
weekly or twice-weekly versus placebo) is assumed to be 2.62.  
A total of approximately 108 SBS patients are planned for inclusion, with 33-36 patients planned 
for each of the three treatment groups. The trial size will result in 93-95% power for detecting 
the assumed difference with either once-weekly or twice-weekly for the primary endpoint. The 
assumed effects include imputed effects for patients with missing data. The power calculations 
are shown in Table 5 including the scenario where once-weekly and twice-weekly dosing are 
assumed to be slightly worse. 
Table 5:  
Power considerations 
Power (%) to show superiority of either once-weekly or twice-weekly compared to placebo with respect to 
the primary endpoint 
Assumptions: 
 PS vol, change from baseline (L/week) 
Number of patients (total) 
Twice-weekly 
One-weekly 
Placebo 
99 
108 
117 
129 
-4.5 
-4.3 
-2.3 
93 
95 
96 
98 
-4.3 
-4.1 
-2.3 
88 
91 
93 
95 
The two comparisons, once-weekly vs placebo and twice-weekly vs placebo are tested two-sided in parallel at 
  
13 Direct Access to Source Data/Documents 
During the course of the trial, a Monitor will make site visits to review protocol compliance, 
that the trial is being conducted according to pertinent regulatory requirements. 
Checking of the eCRFs for completeness and clarity, and cross-checking with source documents, 
are required to monitor the progress of the trial. Moreover, Regulatory Authorities of certain 
countries, IRBs/IECs, and/or the Sponsor may wish to carry out such source data checks and/or 
on-site audits or inspections. Direct access to source data are required for these inspections and 
audits; they are to be carried out giving due consideration to data protection and medical 
confidentiality. 
13.1 Trial Monitoring 
Before an investigational site can begin enrolling patients into the trial, a representative of 
Zealand Pharma will visit the investigational trial site to: 
 Determine the adequacy of the facilities 

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 Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of Zealand Pharma or its representatives. 
This will be documented in a Clinical Trial Agreement between Zealand Pharma and the 
Investigator. 
During the trial, a Monitor from Zealand Pharma or representative will have regular contact with 
the investigational site, for the following: 
 Provide information and support to the Investigator(s). 
 Confirm that facilities remain acceptable. 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed. 
 Perform source data verification. This includes a comparison of the data in the case report 
 medical records at the hospital or practice, and other records 
relevant to the trial. This will require direct access to all original records for each patient 
(e.g., clinic charts). 
 Record and report any protocol deviations to Zealand Pharma. 
 Confirm AEs and SAEs have been properly documented on the eCRFs and confirm any 
SAEs have been forwarded to Zealand Pharma and those SAEs that met criteria for 
reporting have been forwarded to the IRB/IEC. 
The Monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
In addition to the above, medical monitors will be reviewing the clinically relevant data points to 
provide independent medical and safety oversight to protect the safety of the trial patients and 
the integrity of data, for more detailed procedures please refer to the Medical Monitoring Plan.  
13.2 Audits and Inspections 
Authorized representatives of Zealand Pharma or designee, a Regulatory Authority, IRB/ an IEC 
may visit the site to perform audits or inspections, including source data verification. The 
purpose of a Zealand Pharma audit or inspection is to systematically and independently examine 
all trial-related activities and documents to determine whether these activities were conducted, 
and data were recorded, analyzed, and accurately reported according to the protocol, ICH GCP 
guidelines, and any applicable regulatory requirements. The Investigator should contact Zealand 
Pharma immediately if contacted by a Regulatory Agency about an inspection. 
13.3 Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
The Principal Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC 
informed consent form and recruitment materials must be maintained by the Investigator and 
made available for inspection. 

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14 Quality Control and Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, Zealand Pharma or 
designee may conduct quality assurance audit(s). 
14.1 Electronic Case Report Forms 
Electronic case report forms will be used for data collection. Following training, trial staff will 
be given access to the CRF. Access to the database is restricted to staff participating in the trial 
 
The trial participants will be identified in the database by patient numbers. The Investigator or 
delegate will enter patient data into the eCRF within 2 working days (if at all possible). All data 
are to be entered in English. Data recorded in the eCRFs will be accessible to the trial staff 
throughout the trial. 
After data entry, systematic data validation will be performed, and data entry discrepancies will 
be presented electronically directly to the site staff. Queries for discrepant data may be generated 
automatically by the software upon entry and/or generated manually by the monitor or the trial 
data manager. All queries, whether generated by the system or by trial staff, will be in electronic 
format. 
All sections of the eCRF are to be electronically approved by the Investigator after the data have 
been entered and all queries have been resolved. Changes to any eCRF page subsequent to the 
approval require a new approval signature. 
All queries and changes/corrections to the data are documented in the eCRF. 
14.2 Patient Electronic Diaries (eDiaries) 
Patients will use eDiaries to record PS volume, number of bowel movements/stoma bags 
emptying, 48-hour oral fluid intake according to drinking menu and urine volume, date, time and 
 
14.3 Data Processing 
The trial is run as an EDC trial, i.e. all relevant data are entered by the site directly into the 
clinical database. The database and application are set up and managed by Pharm-Olam 
International. The eCRF is designed to capture all required information in compliance with GCP 
standards. Site staff will be provided with eCRF guidelines for this trial. 
The General Data Protection Regulation 2016/679 applies for the processing of data regarding 
the trial patients. 
15 Ethics 
15.1 Ethics Review 
The final trial protocol, including the final version of the ICF and patient facing material, must 
be approved or given a favorable opinion in writing by an IRB/IEC as appropriate. The 
Investigator must submit written approval from the IRB/IEC to Zealand Pharma or designee 
before he or she can enroll any patient into the trial. 

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Any changes to the protocol must be made in the form of an amendment that has the prior 
written approval of Zealand Pharma. The Investigator is responsible for informing the IRB/IEC 
of any amendment to the protocol in accordance with local requirements. In addition, the 
IRB/IEC must approve all advertising used to recruit patients for the trial. The protocol must be 
re-approved by the IRB/IEC upon receipt of amendments and annually, as local regulations 
require. 
The Investigator is also responsible for providing the IRB/IEC with reports of any reportable 
serious adverse drug reactions from any other trial conducted with the investigational product. 
Zealand Pharma or designee will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB/IEC according to local regulations and guidelines. 
15.2 Ethical Conduct of the Trial 
The trial will be performed according to the current protocol and in accordance with the 
Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, 
adopted by the General Assembly of the World Medical Association (1996)26, ICH GCP27 and 
other applicable regulatory requirements. 
15.3 Written Informed Consent 
The Investigator(s) at each center will ensure that the patient is given full and adequate oral and 
written information about the nature, purpose, possible risk and benefit of the trial. Patients must 
also be notified that they are free to discontinue from the trial at any time without any impact on 
their future care. The patient should be given the opportunity to ask questions and allowed time 
to consider the information provided. 
st be obtained before conducting any trial 
procedures. 
The Investigator(s) must maintain the original, signed ICF. A copy of the signed ICF must be 
given to the patient. 
15.4 Confidentiality 
All trial findings and documents will be regarded as confidential. The Investigator and members 
of his/her research team must not disclose such information without prior written approval from 
the Sponsor. 
The anonymity of participating patients must be maintained. Patients will be identified on eCRFs 
by their patient and/or randomization number. On the SAE reports and all other source 
documents, the patient will be identified via patient and/or randomization number and age. 
Documents that identify the patient (e.g., the signed informed consent) must be maintained 
confidentially by the Investigator. 
15.5 Liability and Insurance 
The Sponsor will take out reasonable third-party liability insurance coverage in accordance with 
all local legal requirements. The civil liability of the Investigator, the persons instructed by him 
or her and the hospital, practice, or institute in which they are employed and the liability of the 

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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 provided 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. 
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. 
16 Data Handling and Record Keeping 
16.1 Records 
The Investigator or delegate will enter patient data into the eCRF within 2 working days of the 
trial visit (if at all possible). 
16.2 Retention of Records 
The Investigator must maintain all documentation relating to the trial for a period of 2 years after 
the last marketing application approval, or if not approved 2 years following the discontinuance 
of the test article for investigation. If it becomes necessary for Zealand Pharma or a Regulatory 
Authority to review any documentation relating to the trial, the Investigator must permit access 
to such records. 
The Sponsor will maintain all documentation relating to the trial for a period of 25 years after 
completion or termination of the trial. 
17 Clinical Trial Report and Publication Policy 
17.1 Final Clinical Trial Report 
Zealand will retain ownership of the data. 
The final clinical trial report will be prepared and reviewed in cooperation with the coordinating 
Investigator. The coordinating Investigator will be appointed by Zealand Pharma to review and 
sign the clinical trial report on behalf of all participating Investigators. This report will include a 
summary of the trial results based on a statistical evaluation and clinical assessment of the 
protocol-defined endpoints. 
17.2 Publication Policy 
The information obtained during the conduct of this trial is considered confidential and may be 
used by Zealand Pharma for regulatory purposes and for the general development of the trial 

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product. No confidential information provided by Zealand Pharma in connection with the 
conduct of this trial shall be disclosed to others without prior written consent from Zealand 
Pharma. The Investigator will be provided with the randomization code once the clinical trial 
report has been finalized and signed. 
At the end of the trial, 1 or more public disclosures are intended to be prepared collaboratively 
by the Investigators and Zealand Pharma. Results from the trial will be made publicly available 
irrespective of whether the outcome of the trial is positive, negative, or inconclusive. Zealand 
Pharma reserves the right to postpone publication and/or communication for up to 3 months after 
data base lock to protect intellectual property. Public disclosure includes publication of a paper 
in a scientific journal, abstract submission with a subsequent poster, or oral presentation at a 
scientific meeting, or disclosure by other means. All publications conform to the Vancouver 
guidelines for sound scientific publications. Additional publications may be proposed by the 
Investigators and prepared in collaboration with Zealand Pharma. 
Zealand Pharma reserves the right to defer the release of data until specified milestones are 
reached, for example when the clinical trial report is available. All authors will be given the 
relevant statistical tables, figures, and reports needed to support the planned publication. The trial 
results will be reported in an objective, accurate, balanced, and complete manner, with a 
discussion of the strengths and limitations. In the event of any disagreement on the content of 
any publication, both the opinion of the Investigators and the opinion of Zealand Pharma will be 
fairly and sufficiently represented in the publication. 
Authors of the primary publication must fulfil the criteria defined by the International Committee 
of Medical Journal Editors. 
This clinical trial will also be registered on clinicaltrials.gov prior to initiation. It will also be 
available on the EMA Clinical Trial Register on https://www.clinicaltrialsregister.eu/, and other 
national or international web sites. 
18 List of References 
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glucagon-like peptide 2. Proc Natl Acad Sci U S A 1996; 93(15): 7911-6. 
13. Wallis K, Walters JR, Forbes A. Review article: glucagon-like peptide 2--current 
applications and future directions. Aliment Pharmacol Ther 2007; 25(4): 365-72. 
14. Meier JJ, Nauck MA, Pott A, et al. Glucagon-like peptide 2 stimulates glucagon secretion, 
enhances lipid absorption, and inhibits gastric acid secretion in humans. Gastroenterology 
2006; 130(1): 44-54. 
15. Benjamin MA. Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both 
transcellular and paracellular pathways in the mouse. Gut 2000; 47(1): 112-9. 
16. Wojdemann M, Wettergren A, Hartmann B, Hilsted L, Holst JJ. Inhibition of sham feeding-
stimulated human gastric acid secretion by glucagon-like peptide-2. J Clin Endocrinol Metab 
1999; 84(7): 2513-7. 
17. Au A, Gupta A, Schembri P, Cheeseman CI. Rapid insertion of GLUT2 into the rat jejunal 
brush-border membrane promoted by glucagon-like peptide 2. Biochem J 2002; 367(Pt 1): 
247-54. 
18. Cheeseman CI. Upregulation of SGLT-1 transport activity in rat jejunum induced by GLP-2 
infusion in vivo. Am J Physiol 1997; 273(6 Pt 2): R1965-71. 
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glucose uptake is nitric oxide-dependent in TPN-fed piglets 1 1This work is a publication of 
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20. Buchman AL. Teduglutide and short bowel syndrome: every night without parenteral fluids 
is a good night. Gastroenterology 2012; 143(6): 1416-20. 
21. Thulesen J, Hartmann B, Hare KJ, et al. Glucagon-like peptide 2 (GLP-2) accelerates the 
growth of colonic neoplasms in mice. Gut 2004; 53(8): 1145-50. 
22. Yusta B, Huang L, Munroe D, et al. Enteroendocrine localization of GLP-2 receptor 
expression in humans and rodents. Gastroenterology 2000; 119(3): 744-55. 
23. NPS. GATTEX (teduglutide [rDNA origin]), for injection, for subcutaneous use. Package 
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27. International Conference on Harmonisation. ICH Harmonised Tripartite Guideline: Guideline 
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19 Appendices 
19.1 Clinical Classification of Patients based on PS Volume 
On the basis of the energy and volume of the required PS, the patients are categorized into 16 
combinations (adapted from Pironi et al (2016)8): 
IV Energy 
Supplementation b 
(kcal/kg body weight) 
Volume of IV Supplementation a (L)  
 1 [1] 
>1-2 [2] 
>2-3 [3] 
> 3 [4] 
0 (A) 
A1 
A2 
A3 
A4 
1-10 (B) 
B1 
B2 
B3 
B4 
11-20 (C) 
C1 
C2 
C3 
C4 
> 20 (D) 
D1 
D2 
D3 
D4 
IV=intravenous 
a 
Calculated as daily mean of the total volume infused per week = (volume per day of infusion × number of 
infusions per week)/7. 
b 
Calculated as daily mean of the total energy infused per week = (energy per day of infusion × number of 
infusions per week)/7/kg.