A Randomized, Single-blind Trial to Evaluate the Safety and Efficacy of Apraglutide in Subjects With Grade II to IV (MAGIC) Steroid Refractory Gastrointestinal (GI) Acute Graft Versus Host Disease on Best Available Therapy
Phase: PHASE2
Conditions: GVHD
Sponsor: VectivBio AG

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 1 of 132
Clinical Trial Protocol
A randomized, single-blind trial to evaluate the safety and efficacy of 
apraglutide in subjects with Grade II to IV (MAGIC) steroid refractory 
gastrointestinal (GI) acute graft versus host disease on best available 
therapy
Short Protocol Title: Proof-of-concept trial of apraglutide in GVHD
Trial Type:
Phase 2
EudraCT:
2021-004588-29
IND:
IND 156438
NCT:
NCT 05415410
Trial Identifier:
TA799-101
Sponsor:
VectivBio AG,
Aeschenvorstadt 36, 
4051 Basel, 
Switzerland
Investigational Medicinal 
Product:
Apraglutide (TA799) 
Protocol Version and Date:
5.0, FINAL, 27/Mar/2023
CONFIDENTIAL
“The information contained in this document is confidential and the property of 
VectivBio. The information may not - in full or in part - be transmitted, reproduced, 
published, or disclosed to others than the applicable Competent Ethics Committee(s) 
and Regulatory Authority(ies) without prior written authorization from VectivBio except to 
the extent necessary to obtain informed consent from those who will participate in the 
trial.”

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 2 of 132
Sponsor Signature Page 
Trial number
Protocol number TA799-101
Protocol Title
A randomized, single-blind trial to evaluate the safety and 
efficacy of apraglutide in subjects with Grade II to IV 
(MAGIC) steroid refractory gastrointestinal (GI) acute graft 
versus host disease on best available therapy
The Sponsor has approved the current protocol and confirms hereby to conduct the trial 
as set out in this protocol, the current version of the World Medical Association 
Declaration of Helsinki, the recent International Council on Harmonisation harmonized 
tripartite guideline regarding Good Clinical Practice (E6 R2, November 2016) and the 
local legally applicable requirements, and the following as applicable: 
European Union Regulation No 536/2014
United States Food and Drug Administration Title 21 Code of Federal 
Regulations
Any amendments to these regulations 
Local laws and regulations
Sponsor Representative and Medical Expert
Printed name of Sponsor Representative: 
Omar Khwaja
Chief Medical Officer
VectivBio AG,
Aeschenvorstadt 36, 
4051 Basel, 
Switzerland
+41 61 551 3030
Date
Signature
Statistician
Printed name of Statistician:
Carrie Li
Program statistician
VectivBio AG,
Aeschenvorstadt 36, 
4051 Basel, 
Switzerland
+41 61 551 3030
Date
Signature

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 3 of 132
International Coordinating Investigator 
I have read and understood this trial protocol and agree to conduct the trial as set out in 
this trial protocol, the current version of the World Medical Association Declaration of 
Helsinki, the recent International Council on Harmonisation harmonized tripartite 
guideline regarding Good Clinical Practice (E6 R2, November 2016) and the local 
legally applicable requirements, and the following: 
European Union Regulation No 536/2014 
United States Food and Drug Administration Title 21 Code of Federal 
Regulations 
Any amendments to these regulations 
Local laws and regulations
Since the information in this protocol is confidential, I understand that its disclosure to 
any third parties, other than those involved in approval, supervision, or conduct of the 
registry is prohibited. I will ensure that the necessary precautions are taken to protect 
such information from loss, inadvertent disclosure, or access by third parties.
Prof. Dr. Robert Zeiser
Leiter der Abteilung für Tumorimmunologie und Immunregulation 
Klinik für Innere Medizin I (Schwerpunkt Hämatologie, Onkologie und 
Stammzelltransplantation)
Universitätsklinikum Freiburg
Hugstetter Str. 55,
79106 Freiburg,
Germany
Tel.: 0761 270 34580,
Fax.: 0761 270 36580,
robert.zeiser@uniklinik-freiburg.de
Date
Signature

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 4 of 132
Investigator Signature Page*:
Trial number
Protocol number: TA799-101
Protocol Title
A randomized, single-blind trial to evaluate the safety and 
efficacy of apraglutide in subjects with Grade II to IV 
(MAGIC) steroid refractory gastrointestinal (GI) acute graft 
versus host disease on best available therapy
I have read and understood this trial protocol and agree to conduct the trial as set out in 
this protocol, the current version of the World Medical Association Declaration of 
Helsinki, the recent International Council on Harmonisation harmonized tripartite 
guideline regarding Good Clinical Practice (E6 R2, November 2016) and the local 
legally applicable requirements, and the following as applicable: 
European Union Regulation No 536/2014
United States Food and Drug Administration Title 21 Code of Federal 
Regulations
Any amendments to these regulations 
Local laws and regulations
Since the information in this protocol is confidential, I understand that its disclosure to 
any third parties, other than those involved in approval, supervision, or conduct of the 
registry is prohibited. I will ensure that the necessary precautions are taken to protect 
such information from loss, inadvertent disclosure, or access by third parties.
Date (DD/MMM/YYYY)
Signature
Principal Investigator Name
and title
Printed Name
Site ID
Phone number
Address
*NOTE: This page must be individually signed by each participating Principal 
Investigator.

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 5 of 132
TABLE OF CONTENTS
TABLE OF CONTENTS.......................................................................................................... 5
ABBREVIATIONS................................................................................................................. 10
TRIAL SYNOPSIS................................................................................................................. 13
TRIAL SCHEDULE ............................................................................................................... 32
1
INTRODUCTION............................................................................................................. 39
1.1
Background and Rationale ............................................................................................39
1.2
Investigational Medicinal Product and Indication...........................................................41
1.3
Non-clinical Evidence ....................................................................................................41
1.4
Clinical Evidence ...........................................................................................................41
1.5
Trial Objectives, Endpoints, and Rationale ...................................................................42
1.5.1 Trial Objectives.......................................................................................................42
1.5.2 Trial Endpoints........................................................................................................43
1.6
Dose Rationale..............................................................................................................46
1.7
Rationale of Trial Population Studied ............................................................................48
1.8
Risk/Benefit Considerations ..........................................................................................49
1.8.1 Known Risks with Use of Glucagon-like Peptide Analogs......................................49
1.8.2 Assessment of Known and Potential Risks and Benefits .......................................49
1.8.3 Summary of Clinical Safety with Apraglutide Reported During Phase 1 and Phase 2 
Trials.......................................................................................................................50
1.9
Rationale for Choice of Control .....................................................................................50
2
TRIAL DESIGN............................................................................................................... 52
2.1
Rationale for the Trial Design........................................................................................52
2.1.1 Rationale for the Independent Safety Review Committee......................................52
2.2
Overall Design...............................................................................................................52
2.2.1 Screening Period....................................................................................................54
2.2.2 Treatment, Optional Treatment, and Lower GI-aGVHD flare Treatment................55
2.2.3 Follow-up Period.....................................................................................................56
2.2.4 Phone Calls ............................................................................................................56
2.2.5 Subject Treatment after End of Trial.......................................................................56
2.2.6 Early Treatment Discontinuation ............................................................................56
2.2.7 Early Trial Discontinuation......................................................................................57
2.2.8 Screen Failures ......................................................................................................58
2.3
End of Trial Definition ....................................................................................................59
3
TRIAL POPULATION..................................................................................................... 60
3.1
Number of Subjects.......................................................................................................60
3.2
Eligibility Criteria............................................................................................................60
3.2.1 Inclusion Criteria.....................................................................................................60
3.2.2 Exclusion Criteria....................................................................................................62

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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3.3
Lifestyle Considerations ................................................................................................63
4
TRIAL INTERVENTION/MEDICATION.......................................................................... 64
4.1
Description of Investigational Medicinal Products .........................................................64
4.1.1 Packaging, Labeling, and Supply (Re-supply)........................................................64
4.1.2 Storage Conditions.................................................................................................64
4.2
Administration of Experimental and Control Interventions.............................................65
4.2.1 Experimental Intervention.......................................................................................65
4.2.2 Ruxolitinib and Steroid Medications .......................................................................68
4.2.3 Prior and Concomitant Treatments.........................................................................68
4.3
Investigational Medicinal Product Handling...................................................................70
4.3.1 Reconstitution.........................................................................................................70
4.3.2 Documentation and Compliance ............................................................................71
4.3.3 Investigational Medicinal Product Accountability....................................................71
4.3.4 Return or Destruction of Investigational Medicinal Product....................................71
4.4
Randomization and Blinding..........................................................................................71
5
TRIAL SCHEDULE AND TRIAL ASSESSMENTS ........................................................ 72
5.1
Screening/Baseline Assessments .................................................................................72
5.1.1 Demography...........................................................................................................72
5.1.2 Medical, Surgical, and Disease History..................................................................72
5.2
Reporting of Prior and Concomitant Treatment.............................................................72
5.3
Quality of Life Questionnaires .......................................................................................73
5.3.1 EuroQol-5 Dimension – 5 Level Survey .................................................................73
5.3.2 Functional Assessment of Cancer Therapy – Bone Marrow Transplantation ........73
5.4
Global Assessments......................................................................................................73
5.4.1 Patient Global Assessment of Severity ..................................................................73
5.4.2 Patient Global Assessment of Change...................................................................73
5.4.3 Physician Global Assessment of Disease ..............................................................74
5.5
MAGIC Grade Assessment, Survival, and Disease Progression ..................................74
5.6
Parenteral Support ........................................................................................................75
5.7
Gastrointestinal Regeneration and Barrier Function .....................................................75
5.8
Safety Parameters.........................................................................................................75
5.8.1 Colonoscopy, Computed Tomography Colonography, or Magnetic Resonance 
Enterography..........................................................................................................75
5.8.2 Physical Examination .............................................................................................75
5.8.3 Body Weight and Height.........................................................................................75
5.8.4 Vital Signs...............................................................................................................76
5.8.5 Twelve-lead Electrocardiogram..............................................................................76
5.8.6 Adverse Events ......................................................................................................76
5.8.7 Adverse Events of Special Interest.........................................................................77
5.9
Laboratory Analysis.......................................................................................................77
5.9.1 Local Laboratory Parameters .................................................................................77

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 7 of 132
5.9.2 Central Laboratory Parameters ..............................................................................79
6
SAFETY.......................................................................................................................... 81
6.1
Safety Data Reporting ...................................................................................................81
6.2
Definition and Assessment of (Serious) Adverse Events and Other Safety Related Events
......................................................................................................................................81
6.2.1 Events that Do Not Meet the Definition of a Serious Adverse Event......................82
6.2.2 Adverse Events of Special Interest.........................................................................82
6.2.3 Assessment of Causality ........................................................................................84
6.2.4 Unexpected Adverse Drug Reaction ......................................................................85
6.2.5 Suspected Unexpected Serious Adverse Reactions..............................................85
6.2.6 Assessment of Severity..........................................................................................85
6.3
Reporting of Serious Adverse Events and Other Safety Related Events......................86
6.3.1 Reporting of Adverse Events..................................................................................86
6.3.2 Reporting of Serious Adverse Events.....................................................................86
6.3.3 Reporting of Suspected, Unexpected, Serious Adverse Reactions .......................87
6.3.4 Reporting of Safety Signals....................................................................................87
6.3.5 Reporting and Handling of Pregnancies.................................................................87
6.3.6 Periodic Reporting of Safety...................................................................................87
6.4
Follow-up of Serious Adverse Events ...........................................................................87
6.5
Abnormal Laboratory Findings and Other Abnormal Investigational Findings ..............88
6.6
Trial Specific Safety Considerations..............................................................................88
6.6.1 Overdose................................................................................................................88
6.6.2 Considerations on Investigational Medicinal Product Dose Reduction and Temporary 
Discontinuation.......................................................................................................88
6.6.3 Trial Holding/Stopping Criteria................................................................................88
7
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ........................................ 90
7.1
General Considerations.................................................................................................90
7.2
Interim analysis .............................................................................................................90
7.3
Missing, Unused, and Spurious Data ............................................................................90
7.4
Determination of Sample Size.......................................................................................90
7.5
Definition of Analysis Sets.............................................................................................91
7.5.1 Full Analysis Set.....................................................................................................91
7.5.2 Low Body Weight Analysis Set...............................................................................91
7.5.3 Safety Analysis Set 1..............................................................................................91
7.5.4 Safety Analysis Set 2..............................................................................................91
7.6
Statistical Evaluation of Safety ......................................................................................92
7.6.1 Adverse Events ......................................................................................................92
7.6.2 Adverse Events of Special Interest.........................................................................92
7.6.3 Laboratory Results .................................................................................................93
7.6.4 Vital Signs...............................................................................................................93
7.6.5 Physical Examination .............................................................................................93

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 8 of 132
7.6.6 Twelve-Lead Electrocardiogram.............................................................................93
7.6.7 Anti-Drug Antibodies...............................................................................................93
7.7
Pharmacokinetic Statistical Analysis .............................................................................93
7.7.1 Population Pharmacokinetic Analysis.....................................................................93
7.8
Statistical Evaluation of Efficacy....................................................................................94
7.8.1 Lower GI-aGVHD Response at Day 56..................................................................94
7.8.2 Other Secondary Endpoints ...................................................................................95
7.8.3 Exploratory Endpoints ............................................................................................95
7.9
Reporting Deviations from the Statistical Plan ..............................................................95
8
INDEPENDENT SAFETY REVIEW COMMITTEE ......................................................... 96
9
TRIAL CONDUCT........................................................................................................... 97
9.1
Ethical Conduct of the Trial ...........................................................................................97
9.2
Sponsor and Investigator Responsibilities ....................................................................97
9.2.1 Ethical Considerations............................................................................................98
9.2.2 Investigator Delegation Responsibilities.................................................................98
9.2.3 Competent Authorities and Regulatory Considerations..........................................99
9.2.4 Financial Disclosure ...............................................................................................99
9.2.5 Subject Information and Informed Consent............................................................99
9.2.6 Subject Privacy and Confidentiality ......................................................................100
9.3
Trial Documents ..........................................................................................................101
9.4
Early Termination of the Trial ......................................................................................101
9.5
Trial Site Closure.........................................................................................................102
9.6
Protocol Amendments .................................................................................................102
9.7
Contingency Measures................................................................................................102
9.7.1 Clinical and Ancillary Supply Provisioning............................................................102
10 DATA HANDLING AND RECORD KEEPING/ARCHIVING ........................................ 103
10.1 Confidentiality and Access to Source Data .................................................................103
10.2 Record Keeping/Archiving...........................................................................................103
10.2.1Storage of Biological Material and Related Health Data......................................103
10.3 Case Report Forms .....................................................................................................103
10.4 Specification of Source Documents ............................................................................105
11 QUALITY ASSURANCE AND QUALITY CONTROL .................................................. 106
11.1 Audits and Inspections ................................................................................................106
11.2 Monitoring....................................................................................................................106
12 PUBLICATION AND DISSEMINATION POLICY......................................................... 108
13 INSURANCE................................................................................................................. 110
14 FUNDING AND SUPPORT........................................................................................... 111
15 REFERENCES ............................................................................................................. 112
16 APPENDICES............................................................................................................... 115
16.1 Appendix: Scales and Assessments ...........................................................................115
16.1.1EuroQol-5 Dimension – 5 Level Survey (EQ-5D-5L) ...........................................115

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 9 of 132
16.1.2Functional Assessment of Cancer therapy – Bone Marrow Transplantation (FACT-
BMT).....................................................................................................................118
16.1.3Patient Global Assessment of Severity................................................................121
16.1.4Patient Global Assessment of Change ................................................................122
16.1.5Physician Global Assessment of Disease............................................................123
16.2 Appendix: Definitions of Terms ...................................................................................124
16.3 Appendix: Mount Sinai Acute Graft Versus Host Disease International Consortium 
(MAGIC) Grading Scale [Harris, 2016Harris, 2016]....................................................126
16.4 Appendix: Summary of Changes to Previous Protocol Versions ................................127

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 10 of 132
ABBREVIATIONS
ADA
Anti-Drug Antibodies
AE
Adverse Event 
AESI
Adverse Event of Special Interest
aGVHD
Acute Graft Versus Host Disease
alloSCT
Allogeneic Hematopoietic Stem Cell Transplantation
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase
AUC
Area Under the Curve
BAT
Best Available Therapy
BSA
Body Surface Area
BSL
Baseline
CA
Competent Authority
CFR
Code of Federal Regulations
cGVHD
Chronic Graft Versus Host Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration Equation
CL/F
Apparent Clearance
CNI
Calcineurin Inhibitor
CR
Complete Response
CRA
Clinical Research Associate
CRO
Contract Research Organization
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Event
CTR
Clinical Trial Report
DILI
Drug-induced Liver Injury
ECG
Electrocardiogram
eCRF
Electronic Case Report Form 
eGFR
Estimated Glomerular Filtration Rate
EOT 
End of Trial 
EQ-5D-5L
EuroQol-5 Dimension – 5 Level Survey
EU
European Union
EUPI
European Union Prescribing Information
FACT-BMT
Functional Assessment of Cancer Therapy – Bone Marrow 
Transplantation
FAS
Full Analysis Set
FDA
Food and Drug Administration
FFS
Failure-free Survival

TMP no.:
TMP-CD-04_1
Version no.:
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TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 11 of 132
GCP
Good Clinical Practice 
GCS
Glucocorticosteroid
GLP
Glucagon-like Peptide 
GI
Gastrointestinal
GVHD
Graft Versus Host Disease
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HV
Healthy Volunteers
ICF
Informed Consent Form
ICH
International Council on Harmonisation
ID
Identification
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ISR
Injection Site Reaction
iSRC
Independent Safety Review Committee
ka
Absorption Rate Constant
LBW
Low Body Weight
LFT
Liver Function Test
MAGIC
Mount Sinai Acute Graft Versus Host Disease International 
Consortium
MAP
MAGIC Algorithm Probability
MedDRA
Medical Dictionary for Regulatory Activities
MH
Medical History
MP
Methylprednisolone
MR
Magnetic Resonance
NCI
National Cancer Institute
NOAEL
No-Observed-Adverse-Effects Level
NRM
Non-Relapse Mortality
OS
Overall Survival
PD
Pharmacodynamic
PK
Pharmacokinetic
POC
Proof-of-concept
PR
Partial Response
PT
Preferred Term
QTcF
QT Interval corrected according to Fridericia’s formula
Regenerating Islet-Derived Protein 3 Alpha

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 12 of 132
RUX
Ruxolitinib
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SARS-
COV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SAS
Safety Analysis Set
SBS
Short Bowel Syndrome
SBS-IF
Short Bowel Syndrome with Intestinal Failure
SC
Subcutaneous
SIV
Site Initiation Visit
SmPC
Summary of Medicinal Product Characteristics
SMQs
Standardized MedDRA Queries
SOC
System Organ Class
SOP
Standard Operating Procedure
SR
Steroid Refractory
SS
Systemic Steroids
ST2
Suppression of Tumorigenicity 2
sTM
Soluble Thrombomodulin
SUSAR
Suspected Unexpected Serious Adverse Reaction 
TA799
Apraglutide
TEAE
Treatment-emergent Adverse Event
ULN
Upper Limit of Normal
US
United States
USPI
United States Prescribing Information
VAS
Visual Analog Scale
VEGF
Vascular Endothelial Growth Factor
Vz/F
Apparent Volume of Distribution

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 13 of 132
TRIAL SYNOPSIS
Sponsor
VectivBio AG
Protocol title:
A randomized, single-blind trial to evaluate the safety and 
efficacy of apraglutide in subjects with Grade II to IV 
(MAGIC) steroid refractory gastrointestinal (GI) acute graft 
versus host disease on best available therapy
Trial ID:
TA799-101
Protocol version and 
date:
Version 5.0, FINAL, 27/MAR/2023
EudraCT number:
2021-004588-29
IND number:
IND 156438
NCT Number:
NCT 05415410
Clinical phase:
Phase 2
Background and 
rationale:
Graft versus host disease (GVHD) develops in 50–70% of 
patients who undergo allogeneic hematopoietic stem cell 
transplantation (alloSCT). Graft versus host disease is an 
inflammatory disorder that leads to tissue damage and 
ultimately organ failure and is categorized as either acute 
GVHD (aGVHD) or chronic GVHD (cGVHD).
Acute GVHD is most frequent within the first 100 days 
after transplantation and is the leading cause of non-
relapse mortality (NRM) following alloSCT. Acute GVHD 
most typically affects the skin, gastrointestinal (GI) tract, 
and liver. The incidence of GI-aGVHD is reported to be 
between 40% and 50%. Treatment of GI-aGVHD remains 
unsuccessful in most cases, and the GI tract is involved in 
virtually all fatal cases of aGVHD.
Ruxolitinib (RUX) was approved by the United States 
Food and Drug Administration (FDA) and European 
Medicines Agency (EMA) for the treatment of patients 
aged 12 years and older with aGVHD or cGVHD who 
have inadequate response to corticosteroids or other 
systemic therapies. Despite this improvement in treatment 
options, there is still considerable unmet medical need in 
this population, as a significant number of patients either 
do not respond to RUX (30–40%) or lose the initial 
response over time.
Apraglutide is a potent glucagon-like peptide (GLP)-2 
receptor agonist and acts through a GI targeted 
regenerative approach that is intestinotrophic with a mode 

TMP no.:
TMP-CD-04_1
Version no.:
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TA799-101, Version 5.0, FINAL, 27/Mar/2023
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of action that improves absorption and enhances gut 
barrier function. 
In animal models of chemotherapy-induced intestinal 
mucosal injury, where the intestinal mucosa was severely 
injured by cytotoxic agents such as cytarabine or 
melphalan, apraglutide promotes mucosal healing and 
preserves the physical integrity and barrier function of the 
small intestine. Clinically, such pharmacological activity 
translates to animals in attenuating body weight loss and 
reducing mortality without interfering with the anticancer 
efficacy of the chemotherapy or with the efficacy of stem 
cell transplantation. 
In total body irradiation animal models of aGVHD, 
treatment with apraglutide improved animal survival and 
histopathological examination of intestinal segments 
showed less severe morphological effects through the 
entire intestine (including the colon) suggesting that this 
GLP-2 analog has a potential protective effect against the 
mucosal damage induced by the transplantation. 
The pharmacological properties of apraglutide suggest 
this peptide could have a therapeutic benefit in clinical 
conditions where the intestine is damaged by aggressive 
anticancer treatments or aGVHD. This view is further 
supported by evidence in humans with steroid refractory 
(SR) GVHD of the GI tract: a cohort of six subjects with 
SR aGVHD, having failed multiple therapies, were given 
teduglutide (another GLP-2 analog) at a dosage of 
0.05 mg/kg body weight once daily for 10 days. Clinical 
signs of intestinal GVHD improved in all six subjects with 
a decline in diarrhea frequency. These findings suggest 
that GLP-2 may be effective in subjects with SR-GVHD, 
leading to an improvement in clinical symptoms by 
improving the GI barrier function. Based on this 
background, apraglutide could open a new avenue of SR 
GI-aGVHD treatment by using a novel regenerative and 
non-immunosuppressive approach through GLP-2 
signaling, a signaling cascade that may modulate the 
regeneration of lost enterocyte mass secondary to 
inflammation by GVHD together with the repair of 
impaired intestinal barrier function, resulting in improved 
intestinal absorption. 
The aim of this randomized, single-blind, proof-of-concept 
trial is to evaluate safety, tolerability, efficacy, durable 
overall response, and clinical outcomes of apraglutide in 
subjects with SR lower GI-aGVHD of the lower GI tract 
being treated with systemic steroids (SS) and RUX 
(defined as best available therapy [BAT]). The data will be 
compared with a historical control.

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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Trial objectives:
Primary Objective
To assess safety and tolerability of apraglutide in 
subjects with SR lower GI-aGVHD Grade II to IV 
Mount Sinai aGVHD International Consortium 
(MAGIC) who are treated with SS and RUX
Secondary Objectives
To evaluate the overall response rate (partial 
response [PR] and complete response [CR]) at 
Day 56, on the lower GI tract MAGIC score, in 
subjects with SR lower GI-aGVHD Grade II to IV 
MAGIC that are treated with apraglutide, SS, and 
RUX compared to SS and RUX alone (BAT)
To evaluate the overall response rate (PR and CR) at 
Days 14, 28, 91, 119, 147, and 182 on the lower GI-
tract MAGIC score
To evaluate the overall response rate (PR and CR) at 
Days 14, 28, 56, 91, 119, 147, and 182 on the total 
MAGIC score 
To evaluate the rate of durable overall response rate 
from Day 28 to Day 56
To evaluate duration of response from Day 56 on the 
total MAGIC score
To assess the individual durations of lower GI 
response (according to the MAGIC score)
To assess the individual durations of lower GI 
response (according to the MAGIC score) in subjects 
that were re-treated with apraglutide because of a 
lower GI-aGVHD flare
To assess the time to partial lower GI-aGVHD 
response as defined by the MAGIC score
To assess the time to complete lower GI-aGVHD 
response as defined by the MAGIC score
To assess best overall response 
Assessment of failure-free survival (FFS1) 
To assess NRM2
1 The time from the date of randomization/Day 0 to the date of hematologic disease relapse/progression, 
non-relapse mortality, or addition of new systemic aGVHD treatment
2 The time from date of randomization/Day 0 to the date of death not preceded by hematologic disease 
relapse/progression

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
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To assess overall survival (OS3)
To assess the incidence of malignancy relapse4
To assess failure of the transplantation (graft failure5) 
To assess cumulative SS and RUX doses used
To assess the incidence of infections and sepsis 
To assess the effect of the two dose ranges on safety, 
tolerability, and efficacy 
Exploratory Objectives 
To assess pharmacokinetics (PK) of apraglutide in 
subjects with SR lower GI-aGVHD who are taking SS 
and RUX with a population PK approach
To assess changes from baseline in subject Quality of 
Life questionnaires
To assess changes from baseline in global 
assessments questionnaires
To assess changes from baseline in nutrition status 
(body weight and parenteral support)
To assess changes from baseline in GI regeneration 
and barrier function
To assess cumulative need for blood transfusions per 
subject
To explore biomarker expression changes from 
baseline related to GI-aGVHD
To assess the constitution of the stool microbiome 
from baseline
To assess exposure–response relationships for 
selected safety and secondary endpoints
To assess health economics figures (time to 
3 The time from the date of randomization/Day 0 to the date of death due to any cause
4 The time from date of randomization/Day 0 to hematologic disease relapse/progression
5 Primary graft failure:
Absolute neutrophil count <0.5 × 109/L by Day 28
Hemoglobin <80 g/L and platelets <20 × 109/L
Reduced intensity conditioning: Confirmation of donor cell origin is required
Cord blood transplant: Up to Day 42
Secondary graft failure:
Absolute neutrophil count <0.5 × 109/L after initial engraftment not related to relapse, infection, or drug 
toxicity
Reduced intensity conditioning: Loss of donor hematopoiesis to <5%

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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discharge from hospital, number of readmissions to 
inpatient settings, and duration of readmissions)
Trial endpoints:
Safety Endpoints 
Adverse events (AEs; System Organ Class [SOC], 
frequency, and severity)
Incidence of AEs of special interest (AESIs):
o
Injection site reactions
o
Gastrointestinal obstructions 
o
Gallbladder, biliary, and pancreatic disease 
o
Fluid overload 
o
Colorectal polyps 
o
New malignancies 
o
Systemic hypersensitivity
Occurrence of clinically significant changes from 
baseline in clinical chemistry (including liver function 
tests), hematology, hemostasis, and urinalysis
Occurrence of clinically significant changes from 
baseline in vital signs (blood pressure, heart rate)
Occurrence of clinically significant changes from 
baseline in electrocardiogram (ECG) measurements 
(intervals and rhythm)
Occurrence and titer of anti-drug antibodies (ADAs) 
Secondary Endpoints
Overall response rate (PR and CR) at Day 56 on the 
lower GI tract MAGIC score
Overall response rate (PR and CR) at Days 14, 28, 
91, 119, 147, and 182 on the lower GI tract MAGIC 
score 
Overall response rate (PR and CR) at Days 14, 28, 
56, 91, 119, 147, and 182 by organ system (skin, 
lower and upper GI tract, and liver) on the total 
MAGIC score
Proportion of all subjects who achieve a CR or PR at 
Day 28 and maintain a CR or PR at Day 56
Duration of response from Day 56 (median and range) 
on the total MAGIC score where duration of response 
is defined as the interval from the Day 56 response 
(PR and CR) to death or new systemic therapy for 
aGVHD (including an increase in steroids 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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>2 mg/kg/day methylprednisolone [MP] equivalent), 
whichever occurs first, with at least 182 days of follow-
up
Duration of response from Day 28 (median and range) 
on the total MAGIC score where duration of response 
is defined as the interval from the Day 28 response 
(PR and CR) to death or new systemic therapy for 
aGVHD (including an increase in steroids 
>2 mg/kg/day MP equivalent), whichever occurs first, 
with at least 182 days of follow-up
Individual duration of lower GI response (according to 
the MAGIC score) counted from the first response to 
return to baseline or worse
Individual duration of lower GI response (according to 
the MAGIC score) in subjects that were re-treated with 
apraglutide because of a lower GI-aGVHD flare, 
counted from the first response after apraglutide 
restart to return to baseline or worse
Time to partial lower GI-aGVHD response (median 
and range) as defined by the MAGIC score
Time to complete lower GI-aGVHD response (median 
and range) as defined by the MAGIC score
Best overall response defined as overall response 
(PR or CR) at any time point up to and including 
Day 91 and before the start of additional systemic 
therapy for lower GI-aGVHD
Failure-free survival up to 2 years post-first dose of 
apraglutide
Non-relapse mortality up to 2 years post-first dose of 
apraglutide
Incidence of malignancy relapse up to 2 years 
post-first dose of apraglutide
Overall survival up to 2 years post-first dose of 
apraglutide
Incidence of graft failure up to 2 years post-first dose 
of apraglutide
Incidence of lower GI-aGVHD flare up to Day 182 
after the first apraglutide dose following earlier 
cessation due to complete lower GI-aGVHD response
Cumulative SS and RUX doses from start of the RUX 
treatment up to Day 91 after the first dose of 
apraglutide 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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Incidence of infections and sepsis from baseline to 
Day 91 after the first dose of apraglutide
Effect of the two dose groups on safety/tolerability and 
efficacy
Exploratory Endpoints 
Pharmacokinetics of apraglutide assessed with a 
population PK approach. Absorption rate constant 
(ka), apparent clearance (CL/F), and apparent volume 
of distribution (Vz/F) with their intra- and inter-
individual variability derived using a nonlinear mixed 
effects modeling approach, from sparse samples
Quality of life and changes in subject-reported 
outcomes from baseline (EuroQol-5 dimensions-5 
levels [EQ-5D-5L], Functional Assessment of Cancer 
Therapy – Bone Marrow Transplantation 
[FACT-BMT])
Global assessment questionnaires (Physician Global 
Assessment of Disease, Patient Global Assessment 
of Severity, and Patient Global Assessment of 
Change)
Body weight and parenteral support (volume and 
caloric content) at Days 14, 28, 56, 91, 119, 147, and 
182 compared with baseline
Individual need for blood transfusions (cumulative 
bags per subject) assessed from baseline to Day 91
Biomarker expression, clinical chemistry parameters, 
and lower GI histology (when available) related to GI-
aGVHD, GI regeneration, and GI barrier function as
assessed at baseline and at times indicated in the 
schedule of assessments:
o
Citrulline (measure of intestinal repair and 
regeneration) in serum
o
Regenerating islet-derived protein 3 alpha 
o
Suppression of tumorigenicity 2 (ST2) in serum
o
MAGIC algorithm probability (MAP) score 
o
Angiopoetin-1 and -2 in serum
o
Soluble thrombomodulin (sTM) in serum
o
Vascular endothelial growth factor (VEGF) in 
serum

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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o
Albumin in serum
o
Bilirubin in serum
o
Presence of intestinal cell lines (L-cells, Paneth 
cells, intestinal stem cells) and status of 
mucosal architecture (crypts, villi) from histology 
slides of lower GI biopsies before apraglutide 
treatment and at the Day 56 visit (when biopsy 
data are available)
o
Calprotectin in stool
o Microbial constitution of the stool microbiome
Time to discharge from hospital, number of 
readmissions to an inpatient setting and duration of 
readmissions up to Week 26
Trial design:
This is a randomized, single-blind, proof-of-concept trial to 
evaluate the safety, tolerability, and preliminary efficacy of 
apraglutide in subjects with Grade II to IV SR lower 
GI-aGVHD who are taking BAT.
Screening/Baseline
The screening process can start any time after clinical 
diagnosis of lower GI-aGVHD and SS initiation. The 
subject should sign the ICF before any other trial 
procedure.
This period will last at maximum 12 weeks (Days -84 to 
Day -1). Subjects will be randomized (Day 0/Week 0) and
receive the first dose of apraglutide only if they developed 
SR lower GI-aGVHD and have started treatment with RUX
Thirty subjects, weighing 50.0 kg, will be randomized to 
two treatment arms (high dose or low dose of apraglutide) 
based on their body weight at baseline (three body weight 
ranges: 50.0<60.0 kg, 60.0 80.0 kg, and >80.0 kg). In 
addition to the 30 subjects, a separate, non-randomized 
cohort of up to four subjects with body weights from 40.0
to <50.0 kg will be assigned to receive 2.5 mg of 
apraglutide (low body weight [LBW] dose). 
Treatment
Up to 34 subjects will receive apraglutide on a background 
of RUX and SS. Apraglutide will be administered 
subcutaneously once weekly for 8 weeks (Week 0 to 
Week 7, inclusive). Treatment can be continued up to 
13 weeks (Week 8 to Week 12, inclusive) if no complete 
lower GI-aGVHD response is achieved at Week 8. 
Optional Treatment

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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Optional treatment for additional 13 weeks (Week 13 to 
Week 25, inclusive) is allowed if no complete lower GI-
aGVHD response is achieved at Week 13. Optional 
treatment can only be started if additional apraglutide 
treatment would benefit the subject based on the 
Investigator’s judgement.
Lower GI-aGVHD Flare Treatment
Lower GI-aGVHD flare treatment can start as per the 
protocol if a subject develops a lower GI-aGVHD flare 
between Weeks 9 and 25, and if treatment with 
apraglutide was previously stopped when lower GI-
aGVHD CR was achieved at Day 56 (or when PR or CR 
was achieved at Day 91). Only one event of a lower GI-
aGVHD flare can be treated with apraglutide until no later 
than Week 25. 
Follow-up
Follow-up will start at the following occasions: 
At Week 8 (if a complete lower GI-aGVHD response is 
achieved at Week 8). Visits at Weeks 8, 13, 17, 21, 
26, 52, and 104/end of trial (EOT) should be 
performed
At Week 13 (if complete lower GI-aGVHD response is 
achieved at Week 13). Visits at Weeks 13, 17, 21, 26, 
52, and 104/EOT should be performed
Once CR is achieved during the optional treatment or 
lower GI-aGVHD flare treatment. The visits to be 
performed will depend on when the subject achieve a 
lower GI-aGVHD CR
After early treatment discontinuation, the subject will 
perform an early treatment discontinuation visit 
approximately 4 weeks (+1 week) from the last 
apraglutide dose and subsequently transition to 
follow-up visits at Weeks 26, 52, and 104/EOT
The follow-up period will last up to 2 years from the first 
apraglutide dose. 
Early Treatment Discontinuation
In case of early treatment discontinuation, the subject will 
be asked to return for an early treatment discontinuation 
visit approximately 4 weeks (+1 week) from the last 
apraglutide administration. The subject will then transition 
to follow-up visits at Weeks 26, 52, and 104/EOT.
Early Trial Discontinuation  
In case of early trial discontinuation, the subject will be 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
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TA799-101, Version 5.0, FINAL, 27/Mar/2023
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asked to return to the site approximately 4 weeks
(+1 week) from the date of early trial discontinuation. All 
the assessments foreseen at the EOT visit will be 
performed. After this visit, there will be no further visits.
Independent Safety Review Committee
Following the randomization of the first subject, an 
independent Safety Review Committee (iSRC) will 
convene approximately every 4 weeks. 
The iSRC will review the data and provide independent 
safety and trial conduct oversight of the first six 
randomized subjects (all iSRC details such as the 
constitution, meeting frequency, and decision rules are 
detailed in the iSRC charter). Assuming no issues are 
identified during the ongoing iSRC reviews then 24 
additional subjects, weighing 50.0 kg will be randomized
to the two treatment arms. Randomization of these 
additional subjects can occur while iSRC monitoring is 
ongoing.
Inclusion/exclusion 
criteria:
Inclusion Criteria:
1. Signed informed consent for this trial prior to any trial 
specific assessment. A signed assent form will also 
be required for all subjects under the age of 18 years
2. Male or female subjects aged 12 years or above at
the time of consent and who weigh a minimum of 
40.0 kg. Only subjects aged 18 years and above will 
be included in Germany and France
3. Have undergone allogeneic hematopoietic stem cell 
transplantation (alloSCT) from any donor source
(matched unrelated donor, sibling, haplo-identical)
using bone marrow, peripheral blood stem cells, or
cord blood. Recipients of non-myeloablative,
myeloablative, and reduced intensity conditioning are
eligible
4. Evident myeloid and platelet engraftment confirmed
prior to trial medication start:
a. Absolute neutrophil count >1000/mm
3  
and 
b. Platelets
3
Use of growth factor supplementation (granulocyte-
colony stimulating factor and granulocyte-
macrophage colony-stimulating factor) and
transfusion support is allowed
5. Clinical diagnosis of lower GI-aGVHD, MAGIC 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
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TA799-101, Version 5.0, FINAL, 27/Mar/2023
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Stage 1–4 prior to randomization. Suitable 
diagnostic procedures should be implemented to 
exclude alternative reasons for diarrhea; these 
include (but not limited to) fecal cultures and lower 
gut biopsy with histological assessment for infectious 
diseases  
6. Clinically confirmed SR lower GI-aGVHD defined as
subjects administered SS, given alone, or combined
with calcineurin inhibitors (CNIs) and either:
a. Disease progression based on organ assessment 
after 3 days of systemic MP
mg/kg/day6 ([or 
prednisone dose 2.5 mg/kg/day] or equivalent)
±CNIs 
or
b. Did not improve after 7 days of treatment with 
systemic MP 2 mg/kg/day6 ([or prednisone dose 
2.5 mg/kg/day] or equivalent)
or
c. Progressed to a new organ after treatment with 
systemic MP 2 mg/kg/day6 ([or prednisone dose 
2.5 mg/kg/day] or equivalent) for skin and upper 
GI-aGVHD
or
d. Recurred during or after a steroid taper. Initial 
dose should be 
mg/kg/day6 systemic MP ([or 
prednisone dose 2.5 mg/kg/day] or equivalent) 
7. Treatment with SS plus RUX (RUX started
concomitantly to apraglutide or a maximum of
72 hours before apraglutide initiation)  
8. Women of childbearing potential must agree to use a 
highly effective method of contraception and refrain 
from donating eggs during the trial and for 4 weeks 
after the EOT visit. Effective contraceptive methods 
include combined (estrogen and progestogen 
containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, 
transdermal); progestogen-only hormonal 
contraception associated with inhibition of ovulation 
(oral, injectable, implantable); intrauterine device; 
intrauterine hormone-releasing system; bilateral 
6 The SS dose should be calculated based on the subject’s actual weight, within the maximum lower 
margin of 15% from the calculated dose.

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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tubal occlusion; vasectomized partner. In Germany, 
oral methods of hormonal contraception are to be 
combined with another accepted method of 
contraception. 
To be considered sterilized or infertile, females must 
have undergone surgical sterilization (bilateral 
tubectomy, hysterectomy or bilateral ovariectomy) or 
be post-menopausal (defined as at least 12 months 
amenorrhea without an alternative medical cause, 
may be confirmed with follicle-stimulating hormone 
test in case of doubt). Women who do not engage in 
heterosexual intercourse will be allowed to join the 
trial without contraception following a thorough 
discussion with the Investigator to determine if this is 
feasible for the subject. The following methods are 
not considered acceptable methods of contraception: 
calendar, ovulation, symptothermal, post-ovulation 
methods, withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea
method
9. Male subjects with a female partner of childbearing 
potential must commit to practice methods of 
contraception and abstain from sperm donation 
during the trial and for 2 weeks after the EOT visit. 
Nevertheless, if their partners are women of 
childbearing potential, they must agree to practice 
contraception and use a highly effective method of 
contraception during the trial and for 4 weeks after 
the EOT visit. Such methods include combined 
(estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation 
(oral, intravaginal, transdermal); progestogen-only 
hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable); intrauterine 
device; intrauterine hormone-releasing system; 
bilateral tubal occlusion
Exclusion Criteria:
1. Treatment with any systemic GVHD therapy (other 
than SS and RUX) including methotrexate and 
mycophenolate mofetil at the time of 
randomization/Day 0. Graft versus host disease
prophylaxis (ciclosporin A, tacrolimus, sirolimus, 
everolimus, or anti-thymocyte globulin) is allowed
2. Concomitant treatment with Janus kinase inhibitor 
therapy other than RUX at the time of randomization
3. Failed alloSCT due to relapse of underlying 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
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TA799-101, Version 5.0, FINAL, 27/Mar/2023
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malignant disease
4. Presence of SR GI-aGVHD occurring after donor 
lymphocyte infusion for pre-emptive treatment of 
malignancy recurrence
5. Ongoing participation in an interventional trial or 
administration of any investigational drug in less than 
its five half-lives prior to randomization/Day 0. 
Participation in observational or interventional trials 
involving supportive care such as probiotics or 
antiemetics, graft manipulation or transplant 
procedures, new combinations or new dosing of 
approved therapies for conditioning, prophylaxis7,
pre- or post-alloSCT and treatment of the underlying 
malignant disease are allowed after consultation with 
the Sponsor
6. Known or suspected hypersensitivity to GLP-1 or 
GLP-2 analogs or apraglutide excipients 
7. Any use of enteral glutamine or growth factors such 
as native GLP-2, GLP-1, or GLP-2 and GLP-1 
analogs, or known ADA, within 6 months prior to 
randomization/Day 0
8. Inability to understand or unwillingness to adhere to 
the trial visit schedules and other protocol 
requirements including those subjects not willing to 
comply owing to drug or alcohol abuse or any 
condition that would, in the Investigator’s judgment, 
interfere with full participation in the trial, including 
administration of trial medication and attending 
required trial visits, pose a significant risk to the 
subject, or interfere with interpretation of trial data 
9. Less than 2 weeks anticipated survival at screening 
10.Evidence of chronic renal disease as demonstrated 
by inadequate renal function, which is defined as 
estimated glomerular filtration rate (eGFR) 
<20 mL/min/1.73 m2 (using the Chronic Kidney 
Disease Epidemiology [CKD-EPI] formula) and is 
confirmed within 48 hours before randomization/
Day 0
11.Presence of decompensated liver cirrhosis Child 
Pugh Classes B and C
12.Clinically significant or uncontrolled cardiac disease 
including acute myocardial infarction within 6 months 
7 Except methotrexate and mycophenolate mofetil

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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prior to randomization/Day 0 uncontrolled 
hypertension, congestive heart failure New York 
Heart Association Class III or IV
13.Requirement for vasopressor or inotropic support 
within 30 days prior to randomization/Day 0
14.Presence of uncontrolled cholestatic disorders or 
unresolved sinusoidal obstructive syndrome/veno-
occlusive disease of the liver (defined as persistent 
bilirubin abnormalities not attributable to aGVHD and 
ongoing organ dysfunction) 
15.Presence of relapsed primary malignancy or 
treatment for relapse after alloSCT
16.Requirement for unplanned immune suppression 
withdrawal as treatment of early malignancy relapse
or low donor chimerism. Unclear remission states 
will be discussed with the Sponsor
17.Presence of newly diagnosed malignancies at 
screening or prior to randomization/Day 0
18.History of chronic gall bladder or bile duct 
inflammation or biliary obstruction, unless a 
cholecystectomy was performed before screening
19.Presence or history of GI tumors (including the 
hepatobiliary system and pancreas) within the last 
five years before randomization; presence of colonic 
polyps that are not removed
20.Subjects that present or have a history of familial 
adenomatous polyposis
21.Presence of an active clinically uncontrolled infection
or evidence of active tuberculosis (clinical diagnosis 
per local practice). Cytomegalovirus reactivation is 
permitted as long as no evidence of pulmonary 
disease is present
22.Central venous catheter sepsis requiring systemic 
antibiotics within the previous 7 days prior to 
randomization/Day 0
23.Known cGVHD
24.Known active GI inflammation not related to 
GI-aGVHD (e.g., active inflammatory bowel disease 
such as Crohn’s and ulcerative colitis)
25.History of progressive multifocal leuko-
encephalopathy 
26.Known pregnant or nursing (lactating) women 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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27.Known major abdominal surgery in the last 6 months 
prior to randomization/Day 0 (surgical feeding tube 
placement or other minimally invasive surgery is 
allowed)
28.History of clinically significant intestinal adhesions 
increasing the risk of GI obstruction or GI contrast 
examination findings suggesting subacute intestinal 
obstruction or stricture within 6 months prior to 
randomization/Day 0
29.Liver enzymes meeting any of the following criteria 
within 48 hours prior to trial medication start: 
a. Alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >8 x upper limit of 
normal (ULN)
b. Alanine aminotransferase or AST >5 x ULN AND 
international normalized ratio >3
Background therapy
Apraglutide will be given as an add-on-therapy to RUX 
and SS. Systemic steroid dose adjustments are allowed at 
the Investigator’s discretion, and topical steroids may be 
added as needed. 
Ruxolitinib should be administered as per national 
guidelines (including dose adjustments). Apraglutide
should be administered concomitantly to RUX. In 
exceptional cases where concomitant administration is not 
possible, RUX should be administered at maximum 
72 hours before apraglutide initiation. 
Should a worsening of a subject's lower GI-aGVHD
symptoms occur early after starting apraglutide, it is 
recommended to adjust SS/RUX, but to stay on the same
CNI (dose and type) used before baseline.
Allowed/prohibited 
medications 
Allowed Medications
Concomitant medications/therapies for prophylaxis 
(e.g., ciclosporin A, tacrolimus, sirolimus, everolimus, 
or anti-thymocyte globulin) and treatment of SR lower 
GI-aGVHD, except the drugs/classes mentioned as 
prohibited 
Treatment with SS, RUX, and CNIs. These treatments 
should be tapered according to institutional guidelines 
based on the Investigator’s judgement. However, it is 
recommended to stay on the same CNI (dose and 
type) used before baseline
Supportive care, pain control drugs, antibiotics, 
antiemetics, and transfusions 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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Growth factor supplementation (granulocyte-colony 
stimulating factor and granulocyte-macrophage-colony 
stimulating factor), donor lymphocyte infusions, and 
transfusion support 
Prohibited Medications
Treatment with any systemic GVHD therapy other 
than SS and RUX including methotrexate and 
mycophenolate mofetil at the time of 
randomization/Day 0 and during the trial  
Concomitant treatment with Janus kinase inhibitor 
therapy (except RUX) at time of randomization/Day 0
and during the trial
Citrulline supplements, any use of growth hormone, 
enteral glutamine or growth factors such as native 
GLP2, GLP1, or GLP-2 and GLP-1 analogs other than 
the investigational medicinal product under 
investigation within 6 months before 
randomization/Day 0 and during the trial 
Any investigational drug with the exception of the 
investigational drugs allowed as per exclusion 
criterion number 5
Trial 
product/intervention: 
Apraglutide 2.5 mg, 4.0 mg, 5.0 mg, 7.5 mg, or 10.0 mg 
subcutaneous (SC) once weekly
Control intervention:
Historical comparison
Trial duration:
Up to 116 weeks. After the screening period (up to 
12 weeks), subjects will be involved in the trial for 
approximately 24 months (8 or 13 weeks of treatment 
period and a follow-up period lasting up to 2 years after 
the first dose)
Principal 
Investigator:
Prof. Robert Zeiser, Universitaetsklinikum Freiburg, 
Germany
Trial centers:
Approximately 30 sites in Europe and North America
Statistical 
considerations:
General
The principal statistical goal of this trial is to estimate the 
likelihood of efficacy of apraglutide as an add-on to BAT in 
treating subjects with SR lower GI-aGVHD after alloSCT. 
As such, the statistical analysis will not focus upon p-value 
generation but rather estimation and quantification of 
uncertainty. It is planned to randomize 30 subjects on a 
1:1 basis to either a low or high dose of apraglutide. 
The efficacy analyses will be performed using Bayesian 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
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methods comparing the observed results in each 
treatment arm with a historical control dataset.
Analysis
An interim analysis will be performed when 17 subjects 
have either reached Day 56 or withdrawn from the trial. All 
available data points by the data cut-off date will be 
included in the analysis. 
The final analysis will be done in two steps. The primary 
analysis of safety and efficacy will be performed once all 
subjects have either completed Day 91 or withdrawn from 
the trial. Additional analyses will be done once all the 
subjects have either completed the EOT visit or withdrawn 
from the trial. A Clinical Trial Report (CTR) will be issued 
after the primary analysis. An addendum to the CTR will 
cover the follow-up period until 2 years after the first 
apraglutide dose. 
Sample Size
Up to 34 subjects with SR lower GI-aGVHD who are 
taking BAT will be randomized in this trial. The sample 
size justification was based on a selected secondary 
endpoint (Day 56 GI response). Observed response rates 
of 5/7 (71%) subjects at the interim analyses will lead to a 
high probability (>88%) of effectiveness comparing 
apraglutide and BAT with a historical Day 56 response 
rate derived from the previous trial, REACH2, including a 
10% penalty. 
Analysis Sets
The Full Analysis Set (FAS) comprises all enrolled 
subjects (randomized and non-randomized LBWs). All 
efficacy evaluations will be conducted using the FAS 
according to the planned dose (high dose, low dose, LBW 
dose) and in total. 
The LBW Analysis Set comprises all subjects with a body 
weight ranging from 40.0 to <50.0 kg assigned to receive 
2.5 mg apraglutide who actually received at least one 
dose of therapy and who have provided at least one 
post-baseline assessment for any endpoint. All endpoints 
will be analyzed for this set separately. 
Safety Analysis Set 1 (SAS1) comprises all randomized 
subjects exposed to either of the two randomized 
apraglutide dose levels. All principal safety analyses will 
be carried out on the SAS1 according to the dose of 
apraglutide received.
Safety Analysis Set 2 (SAS2) comprises all randomized 
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dose. Supportive safety analyses will be carried out on the 
SAS2 according to the dose of apraglutide received.
Analysis of Secondary Endpoints
Day 56 lower GI-aGVHD responses will be summarized 
and analyzed formally using Bayesian methods. In the 
Bayesian analyses, the response rates will be modelled 
by Beta distributions presenting the mean of the Beta 
distributions-associated with 90% credible intervals. The 
differences in response rates will be taken as the 
difference in mean response rates of the distributions on 
apraglutide with respect to BAT. The associated 90% 
credible interval will be computed using simulations of the 
respective distributions. 
Secondary endpoints measured as response/non-
response will be analyzed in the same fashion as 
described above. If prior data for BAT is not available for a 
given time point, then only the apraglutide data will be 
presented.
Secondary endpoints measured as time-to-event will be 
summarized using Kaplan-Meier analysis. Where there 
are competing risks, time-to-event data will also be 
summarized using cumulative incidence. The median 
time-to-event will be presented where possible, along with 
the associated 90% confidence interval. For comparison 
to BAT where prior data exist, the distribution of time-to-
event will be modelled via the inverse gamma distribution, 
and thus compared on a Bayesian basis. 
Secondary endpoints will be summarized descriptively in 
the LBW Analysis Set. 
Exploratory Endpoints
These endpoints will also be summarized descriptively in 
both the FAS and the LBW Analysis Sets.
Analysis of Safety Endpoints 
All safety data will be summarized by apraglutide dose
level for both SAS1 and SAS2.
Adverse Events
All AESIs, treatment-emergent AEs (TEAEs), serious AEs, 
AEs leading to discontinuation, AEs leading to death, and 
laboratory abnormalities will be summarized by 
apraglutide dose level, severity, and relationship to 
treatment. Adverse event data will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) 
and presented by SOC and Preferred Term (PT).

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Good Clinical 
Practice statement:
This trial will be conducted in compliance with the 
protocol, current version of the World Medical Association 
Declaration of Helsinki, the recent International Council on 
Harmonisation – Good Clinical Practice guidelines and all 
applicable national and local regulations.

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1
INTRODUCTION
1.1
Background and Rationale
Allogeneic hematopoietic stem cell transplantation (alloSCT) is used to treat 
hematologic malignancies and other nonmalignant hematologic diseases and is a 
potentially curative treatment option. One of the major barriers to a successful 
transplant outcome is graft versus host disease (GVHD), which develops in 50–70% of 
patients who undergo alloSCT. Graft versus host disease is an inflammatory disorder 
which leads to tissue damage and ultimately organ failure and is categorized as either 
acute GVHD (aGVHD) or chronic GVHD (cGVHD).
Acute GVHD is most frequent within the first 100 days after transplantation and is the 
leading cause of non-relapse mortality (NRM) following alloSCT. Acute GVHD most 
typically affects the skin, gastrointestinal (GI) tract, and liver, and organ damage is 
characterized by apoptosis of cells.
Acute GVHD of the skin is generally not life-threatening, as both systemic and topical 
therapies are usually effective. While the incidence of Stage 3–4 liver GVHD is low 
(approximately 2%), the incidence of GI-aGVHD is reported to be between 40–50%. 
Treatment of GI-aGVHD remains unsuccessful in most cases, and the GI tract is 
involved in virtually all fatal cases of aGVHD.
Two distinct phenotypes of GI GVHD can be identified, upper GI (limited to Stage 1) and 
lower GI that differ in presentation, natural history, response to therapy, and risk of 
mortality. The upper GI phenotype generally does not progress to the lower GI 
phenotype. The upper GI phenotype presents with persistent loss of appetite, satiety, 
nausea, vomiting, and weight loss, with variable amounts of diarrhea, usually less than 
500 mL per day. The presentation can be indolent, and therapy with prednisone at 
doses of 1 mg/kg/day plus topical oral corticosteroid is effective.
The lower GI phenotype of GVHD presents with secretory, protein-rich diarrhea and 
abdominal pain resulting from GI distention. In severe cases, the entire small intestine 
and colon are edematous and inflamed, with diarrheal volumes in excess of 1.5 L per 
day and evidence of mucosal ulceration and bleeding. Most patients with severe lower 
GI-aGVHD require prolonged hospitalization for supportive care including total 
parenteral support and pain control. Although outcomes are typically poor, the standard 
for initial therapy is prednisone, with the addition of other immune suppressive therapies 
when treatment with prednisone fails to control the disease.
Long-term survival rates in steroid refractory (SR) patients are poor and range between 
5–30%.
Recently, ruxolitinib (RUX) was approved by the United States (US) Food and Drug 
Administration (FDA) for the treatment of SR-GVHD in 2019 based on the results of the 
REACH 1 trial. In this single arm trial, 54.9% (39 patients) had an overall response, 
including 26.8% (19 patients) with a complete response (CR); moreover, median 
duration of response was 345 days, and the overall survival estimate at 6 months was 
51.0%. Despite this improvement in treatment options, there is still considerable unmet 
medical need in this population, as a significant number of patients either do not 
respond to RUX (30–40%) or lose the initial response over time.
Apraglutide is a potent glucagon-like peptide 2 (GLP-2) receptor agonist, specifically 
designed to have slower absorption, decreased clearance, increased resistance to 

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proteolysis, and increased plasma protein binding compared with the marketed GLP-2 
analog, teduglutide. In addition, once weekly dosing with apraglutide, supported by 
pharmacokinetic (PK) data from previous trials, could substantially reduce the burden of 
therapy, improve subject compliance and adherence, and reduce adverse reactions 
associated with subcutaneous (SC) administration compared with teduglutide daily 
dosing. 
When administered subcutaneously to healthy animals, apraglutide exhibited a trophic 
effect resulting in the increase of the weight of the small intestine (80–180% increase in 
Sprague-Dawley rats and 20–80% increase in minipigs across different dose levels and 
time points), and, to a lesser extent the large intestine as well [Apraglutide Investigator 
Brochure]. In animal models of chemotherapy-induced intestinal mucosal injury, where 
the intestinal mucosa was severely injured by cytotoxic agents such as cytarabine or 
melphalan, apraglutide promoted mucosal healing and preserved the physical integrity 
and barrier function of the small intestine. Clinically, such pharmacological activity 
translates to the animals in attenuation of the body weight loss and in reduced mortality 
(40% of the apraglutide treated mice survived after Day 9 compared with no mice in the 
vehicle treated group; p=0.0134) without interfering with the anticancer efficacy of the 
chemotherapy, or with the efficacy of stem cell transplantation [Apraglutide Investigator 
Brochure]. 
In animals, apraglutide showed some beneficial effect on the bacterial flora (microbiota) 
through the protection of the intestinal mucosa allowing the maintenance of a normal 
equilibrium between the commensal bacterial populations [Norona, 2020]. In animal 
models of aGVHD, treatment with apraglutide improved animal survival and 
histopathological examination of intestinal segments showed less severe morphological 
effects through the entire intestine (including the colon) suggesting that this GLP-2 
analog has a potential protective effect against the mucosal damage induced by the 
transplantation [Apraglutide Investigator Brochure].
The pharmacological properties of apraglutide suggest, therefore, that this peptide could 
have a therapeutic benefit in clinical conditions where the intestine is damaged by 
aggressive anticancer treatments or aGVHD. This view is further supported by evidence 
in humans with SR GVHD of the GI tract: a cohort of six subjects with SR aGVHD 
having failed multiple therapies were given teduglutide (another GLP-2 analog) at a 
dosage of 0.05 mg/kg body weight, once daily for 10 days. Intestinal biopsies taken 
from one subject before and during teduglutide treatment showed an increase in Paneth 
cells after the treatment. In addition to the increase in Paneth cells, clinical signs of 
intestinal GVHD improved in all six subjects with a decline in frequency of diarrhea. 
Serum albumin levels were analyzed in the six subjects and an increase in serum 
albumin was shown 2 weeks after treatment when compared with the day before 
treatment start. During the teduglutide treatment period no additional intravenous 
albumin or fresh frozen plasma was substituted. These findings suggest that GLP-2 
may be effective in patients with SR GI-aGVHD, leading to an improvement in clinical 
symptoms, reduced loss of albumin, and regrowth of Paneth cells that secrete 
antimicrobial peptides, thereby improving the GI barrier function. This is in line with 
previous work showing that GLP-2 can increase nutrient absorption in normal rodents 
and in patients with short bowel syndrome (SBS). 
Based on this background, apraglutide could open a new avenue of SR GI-aGVHD
treatment by using a novel regenerative approach through GLP-2 signaling, a signaling 
cascade that may modulate the regeneration of lost enterocyte mass secondary to 

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inflammation by GVHD together with the repair of the impaired intestinal barrier 
function, resulting in improved intestinal absorption. These clinical features continue to 
be high unmet medical needs that contribute to the morbidity and mortality seen with 
acute SR GI-aGVHD.
The aim of this randomized, single-blind, proof-of-concept (POC) trial is to evaluate 
safety, tolerability, efficacy, durable overall response, and clinical outcomes of 
apraglutide in subjects with SR lower GI-aGVHD being treated with systemic steroids 
(SS) and RUX (current best available therapy [BAT]). The data will be compared with 
historical data from the RUX arm of the REACH2 trial when applicable. If available, 
alternative historical control cohorts will also be applied.
1.2
Investigational Medicinal Product and Indication 
Apraglutide is a peptide analog of GLP-2 under development for treatment of SBS with 
intestinal failure (SBS-IF) and aGVHD, and it acts as a full agonist of the GLP-2 
receptor with in vitro potency and selectivity comparable with native GLP-2 [
2016]. This peptide is designed to have a longer elimination half-life by being resistant 
to cleavage by dipeptidyl peptidase-4, the major GLP-2 peptidase and increased 
plasma protein binding which prevents kidney elimination. The systemic half-life in 
various animal species, as well as in human healthy volunteers, is significantly 
prolonged compared with the native human GLP-2. Apraglutide has, in various animal 
models, shown a trophic effect on the small intestine and maintained the mucosal 
barrier function.
Apraglutide has been administered to 66 healthy volunteers and 16 subjects with SBS 
and has been proven to be safe and well tolerated at single doses ranging from 1.0 mg
to 56.9 mg, and repeated weekly doses ranging from 1.0 mg to 28.4 mg. Further details 
are provided in the Investigator’s Brochure. A Phase 3, placebo-controlled trial 
evaluating the efficacy and safety of apraglutide in subjects with SBS-IF is currently 
ongoing. At the time this protocol was written, 45 subjects have been recruited.
1.3
Non-clinical Evidence 
Non-clinical studies performed with apraglutide showed no off-target toxicity and 
indicated a favorable profile for clinical development. 
In a trial with neonatal piglets with resected ileum and jejuno-colic anastomosis, 
apraglutide significantly increased small-intestinal weight, villus height, crypt depth, and 
intestine length, and reduced fecal fat and energy losses [Slim, 2019].
In rats, apraglutide induced a greater intestinotrophic effect than teduglutide and 
glepaglutide using the same doses and dosing intervals, and it showed an extended 
duration of effect compared with teduglutide [Hargrove, 2020].
A detailed review of non-clinical results is provided in the Investigator’s Brochure.
1.4
Clinical Evidence 
To date, four clinical trials with apraglutide have been completed, including the entry 
into human trial with a single ascending dose phase and a multiple ascending phase 
and one multiple dose Phase 1 trial, both in healthy volunteers and two Phase 2 trials 
designed to assess the safety and tolerability and to demonstrate the POC for 
apraglutide in subjects with SBS (5 mg and 10 mg). In these trials, apraglutide doses of 
up to 56.9 mg once weekly and up to 6 weeks duration (10 mg once weekly) have been 
tested.

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In summary, apraglutide was safe and well tolerated after single and repeated doses 
(up to six weekly doses). In the entry in human Phase 1 trial, one subject showed 
increase in liver function test values at the highest dose (56.9 mg) in the multiple 
ascending dose part which resulted in the withdrawal of this subject. Nevertheless, 
overall, there were no relevant differences in adverse events (AEs) and tolerability 
across doses. Apraglutide was also safe and well tolerated with up to six weekly doses 
of 10 mg in a second Phase I healthy volunteer trial. 
In the Phase 2 studies in SBS patients, the most frequent AEs included nausea, stoma 
output decreased, and stoma complications. Some AEs were related to the expected 
pharmacodynamic (PD) effects of apraglutide such as decreased stoma output, 
polyuria, and decreased thirst. Serious AEs (SAEs) reported in these studies were 
disease complications (device-related sepsis and device malfunction). Only one SAE of 
abdominal pain was assessed as related to apraglutide.
A summary of detailed observations from these studies is contained in the Investigator’s 
Brochure [Apraglutide Investigator Brochure]. 
A Phase 3, placebo-controlled trial evaluating the efficacy and safety of apraglutide in 
subjects with SBS-IF is currently ongoing (Section 1.2). At the time this protocol was 
finalized 45 subjects had been recruited but no results are yet available.
1.5
Trial Objectives, Endpoints, and Rationale
1.5.1 Trial Objectives
1.5.1.1 Primary Objective
To assess safety and tolerability of apraglutide in subjects with SR lower GI-aGVHD 
Grade II to IV Mount Sinai aGVHD International Consortium (MAGIC) who are 
treated with SS and RUX
1.5.1.2 Secondary Objectives
To evaluate the overall response rate (partial response [PR] and CR) at Day 56 on 
the lower GI tract MAGIC score in subjects with SR lower GI-aGVHD Grade II to IV 
MAGIC that are treated with apraglutide, SS, and RUX compared to SS and RUX 
alone (BAT)
To evaluate the overall response rate (PR and CR) at Days 14, 28, 91, 119, 147, 
and 182 on the lower GI-tract MAGIC score
To evaluate the overall response rate (PR and CR) at Days 14, 28, 56, 91, 119, 
147, and 182 on the total MAGIC score 
To evaluate the rate of durable overall response rate from Day 28 to Day 56
To evaluate duration of response from Day 56 on the total MAGIC score
To assess the individual durations of lower GI response (according to the MAGIC 
score)
To assess the individual durations of lower GI response (according to the MAGIC 
score) in subjects that were re-treated with apraglutide because of a lower GI-
aGVHD flare
To assess the time to partial lower GI-aGVHD response as defined by the MAGIC 
score 

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To assess the time to complete lower GI-aGVHD response as defined by the 
MAGIC score
To assess best overall response 
Assessment of FFS1
To assess NRM
To assess overall survival (OS) 
To assess the incidence of malignancy relapse
To assess failure of the transplantation (graft failure)
To assess cumulative SS and RUX doses used
To assess the incidence of infections and sepsis 
To assess the effect of the two dose ranges on safety, tolerability, and efficacy 
1.5.1.3 Exploratory Objectives
To assess PK of apraglutide in subjects with SR lower GI-aGVHD who are taking 
SS and RUX with a population PK approach
To assess changes from baseline in subject Quality of Life questionnaires
To assess changes from baseline in global assessments questionnaires
To assess changes from baseline in nutrition status (body weight and parenteral 
support)
To assess changes from baseline in GI regeneration and barrier function
To assess cumulative need for blood transfusions per subject
To explore biomarker expression changes from baseline related to GI-aGVHD
To assess the constitution of the stool microbiome from baseline
To assess exposure–response relationships for selected safety and secondary 
endpoints
To assess health economics figures (time to discharge from hospital, number of 
readmissions to inpatient settings, and duration of readmissions)
1.5.2 Trial Endpoints
1.5.2.1 Safety Endpoints
Adverse events (AEs; System Organ Class [SOC], frequency, and severity)
Incidence of AEs of special interest (AESIs):
o
Injection site reactions
o
Gastrointestinal obstructions 
o
Gallbladder, biliary, and pancreatic disease 
o
Fluid overload 
o
Colorectal polyps 
1 Definitions of these terms are provided in Appendix 16.2.

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o
New malignancies 
o
Systemic hypersensitivity
Occurrence of clinically significant changes from baseline in clinical chemistry 
(including liver function tests), hematology, hemostasis, and urinalysis 
Occurrence of clinically significant changes from baseline in vital signs (blood 
pressure, heart rate)
Occurrence of clinically significant changes from baseline in electrocardiogram 
(ECG) measurements (intervals and rhythm)
Occurrence and titer of anti-drug antibodies (ADAs) 
1.5.2.2 Secondary Endpoints
Overall response rate (PR and CR) at Day 56 on the lower GI tract MAGIC score
Overall response rate (PR and CR) at Days 14, 28, 91, 119, 147, and 182 on the 
lower GI tract MAGIC score
Overall response rate (PR and CR) at Days 14, 28, 56, 91, 119, 147, and 182 by 
organ system (skin, lower and upper GI tract, and liver) on the total MAGIC score
Proportion of all subjects who achieve a CR or PR at Day 28 and maintain a CR or 
PR at Day 56
Duration of response from Day 56 (median and range) on the total MAGIC score 
where duration of response is defined as the interval from the Day 56 response (PR 
and CR) to death or new systemic therapy for aGVHD (including an increase in 
steroids >2 mg/kg/day methylprednisolone [MP] equivalent), whichever occurs first, 
with at least 182 days of follow-up
Duration of response from Day 28 (median and range) on the total MAGIC score 
where duration of response is defined as the interval from the Day 28 response (PR 
and CR) to death or new systemic therapy for aGVHD (including an increase in 
steroids >2 mg/kg/day MP equivalent), whichever occurs first, with at least 182 days 
of follow-up
Individual duration of lower GI response (according to the MAGIC score) counted 
from the first response to return to baseline or worse
Individual duration of lower GI response (according to the MAGIC score) in subjects 
that were re-treated with apraglutide because of a lower GI-aGVHD flare, counted 
from the first response after apraglutide restart to return to baseline or worse
Time to partial lower GI-aGVHD response (median and range) as defined by the 
MAGIC score
Time to complete lower GI-aGVHD response (median and range) as defined by the 
MAGIC score
Best overall response defined as overall response (PR or CR) at any time point up 
to and including Day 91 and before the start of additional systemic therapy for lower 
GI-aGVHD
Failure-free survival up to 2 years post-first dose of apraglutide
Non-relapse mortality up to 2 years post-first dose of apraglutide
 
Incidence of malignancy relapse up to 2 years post-first dose of apraglutide
Overall survival up to 2 years post-first dose of apraglutide

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Incidence of graft failure up to 2 years post-first dose of apraglutide
Incidence of lower GI-aGVHD flare up to Day 182 after the first apraglutide dose 
following earlier cessation due to complete lower GI-aGVHD response
Cumulative SS and RUX doses from start of the RUX treatment up to Day 91 after 
the first dose of apraglutide 
Incidence of infections and sepsis from baseline to Day 91 after the first dose of 
apraglutide
Effect of the two dose groups on safety/tolerability and efficacy
1.5.2.3 Exploratory Endpoints 
Pharmacokinetics of apraglutide assessed with a population PK approach. 
Absorption rate constant (ka), apparent clearance (CL/F), and apparent volume of 
distribution (Vz/F) with their intra- and inter-individual variability derived using a 
nonlinear mixed effects modeling approach, from sparse samples
Quality of life and changes in subject-reported outcomes from baseline 
(EuroQol-5 dimensions-5 levels [EQ-5D-5L], Functional Assessment of Cancer 
Therapy – Bone Marrow Transplantation [FACT-BMT])
Global assessment questionnaires (Physician Global Assessment of Disease, 
Patient Global Assessment of Severity, and Patient Global Assessment of Change) 
Body weight and parenteral support (volume and caloric content) at Days 14, 28, 
56, 91, 119, 147, and 182 compared with baseline
Individual need for blood transfusions (cumulative bags per subject) assessed from 
baseline to Day 91
Biomarker expression, clinical chemistry parameters, and lower GI histology (when 
available) related to GI-aGVHD, GI regeneration, and GI barrier function as
assessed at baseline and at times indicated in the schedule of assessments:
o
Citrulline (measure of intestinal repair and regeneration) in serum
o
Regenerating islet-
o
Suppression of tumorigenicity 2 (ST2) in serum
o
MAGIC algorithm probability (MAP2
o
Angiopoetin-1 and -2 in serum
o
Soluble thrombomodulin (sTM) in serum
o
Vascular endothelial growth factor (VEGF) in serum
o
Albumin in serum
o
Bilirubin in serum
o
Presence of intestinal cell lines (L-cells, Paneth cells, intestinal stem cells) 
and status of mucosal architecture (crypts, villi) from histology slides of 
lower GI biopsies before apraglutide treatment and at the Day 56 visit 
(when biopsy data are available)
o
Calprotectin in stool
2 The MAP score is calculated using predicted probability (p) of 6-month NRM: log[–log(1–p)] = –11.263 + 
1.844 log10(ST2) + 0.577log10

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o
Microbial constitution of the stool microbiome
Time to discharge from hospital, number of readmissions to an inpatient setting and 
duration of readmissions up to Week 26
1.6
Dose Rationale
It has been identified that plasma citrulline levels correlated with functional GI mucosal 
mass, and these levels were significantly lower in the plasma taken from patients with 
GI-aGVHD compared with healthy subjects as a result of the GI damage in the former 
[Vokurka, 2013]. 
To predict apraglutide doses required to return and maintain citrulline levels that are 
reduced to below 2 µg/mL in subjects with GVHD (red zone in Figure 2) back to normal 
levels of above 5 µg/mL (blue zone in Figure 2), the first approach used the PK/PD 
model developed on plasma apraglutide and plasma citrulline concentrations from 
66 healthy volunteers and 16 subjects with SBS. Simulations of plasma apraglutide and 
plasma citrulline from the PK/PD model in Figure 2 show that apraglutide 5 mg and 
10 mg dosed once weekly can restore and maintain citrulline in a range that is typical 
for healthy volunteers with an undisturbed GI tract.

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Figure 2: Simulations of Plasma Apraglutide and Plasma Citrulline
GvHD=graft versus host disease; HV=healthy volunteers
1.
Vokurka, 2013
2.
Crenn, 2003
The exposure margins for 5 mg and 10 mg doses of apraglutide compared to those at
the NOAELs in the Good Laboratory Practice (GLP) repeat-dose toxicity studies are
well in excess of 200-fold in both rat and minipig studies relative to the exposure at the 
proposed clinical dose of apraglutide (5 mg and 10 mg once weekly via SC injection). 
The exposure margin for the proposed weekly clinical doses of 5 mg and 10 mg are
>40-fold and >20-fold higher, respectively, than the NOAEL of 1 mg/kg/day in the 
13-week GLP mouse toxicity trial. The exposure margins are 17- and 11-fold regarding 
the area under the curve (AUC) at steady state for the doses of 5 mg once weekly and 

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10 mg once weekly, respectively, at the NOAEL in the rabbit embryo fetal trial. 
Therefore, effective contraception will be mandatory during this clinical trial. 
The safety of apraglutide doses used so far in clinical trials is summarized in 
Section 1.8.3. 
The effective dose of apraglutide is not known in subjects with GI-aGVHD. Apraglutide 
has a broad therapeutic range and there is a large toxicity margin for the doses 
proposed in this trial. No differences were seen in the AE and SAE profile in doses up to 
10 mg in both the healthy volunteer studies and to date in subjects with SBS. As this 
dose-finding trial aims to optimize GI stabilization and regeneration in a condition with a 
severely impaired organ system and a high morbidity and mortality rate, testing 
apraglutide at doses up to 10 mg once weekly is justified.
Nevertheless, as apraglutide has shown body weight dependency of AUC, the drug will 
be dosed according to four body weight categories in randomized subjects as 
summarized in Table 3. Subjects will be randomized to either a “high dose” or a “low 
dose” treatment group and will receive a dose according to their body weight range. 
Table 3: Low and High Doses by Body Weight Bands and Respective Estimated 
Mean Exposure
Dose
Estimated Mean AUC
Low
High
Low
High
Min
Max
Min
Max
Group
Weight Range (kg)
2.50
295
420
1 
40–<50
2 
50–<60
2.50
5.00
205
295
412
571
3 
60–<80
4.001
7.50
204
329
377
639
4 
80+
5.00
10.00
121
257
237
497
AUC=area under the curve; Max=maximum; Min=minimum 
NOTE: AUC range based on body weight 80–120 kg
1. 
For operational simplicity a 3.75-mg dose that was obtained in modelling was rounded up to 4.0 mg in the subjects 
weighing between 60 and 80 kg. 
A separate, non-randomized cohort of up to four subjects with body weights ranging 
from 40.0–<50.0 kg will receive the low body weight (LBW) dose of apraglutide
(2.5 mg).
1.7
Rationale of Trial Population Studied
The subject population selected for this trial has SR lower GI-aGVHD and is being 
treated with SS and RUX. Currently, this can be considered BAT for patients with this 
disease; however, a significant number of patients either do not respond to RUX (30–
40%) or lose the initial response over time. 
Amongst the three major organ systems involved in aGVHD (skin, liver, and GI), the GI 
is the key driver of morbidity and mortality in this disease. The addition of apraglutide as 
a treatment, complementary to the underlying immunosuppressive regimen, potentially 
acts via intestinal stabilization and regeneration and is expected to have a clinically 
relevant impact on this patient population with a high unmet medical need.

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1.8
Risk/Benefit Considerations
1.8.1 Known Risks with Use of Glucagon-like Peptide Analogs 
Teduglutide, the only approved and marketed GLP-2 analog, has shown good 
tolerability and safety with once daily administration [Kochar, 2018]. There are 
treatment-related risks reported that are related to the mode of action, such as possible 
risk of acceleration of neoplastic growth and enhancement of colon polyp growth 
[Revestive, SmPC]. 
Recently, a long-term safety update on teduglutide was presented [Allard, 2021] 
(ongoing prospective, observational, multinational SBS-IF registry; data cut-off June 30, 
2020). This analysis compared long-term safety outcomes between adult subjects 
treated with teduglutide ("ever-treated") and those receiving standard of care and never 
exposed to teduglutide ("never-treated"). The per protocol analysis set included 
467 ever-treated and 675 never-treated subjects; 306 subjects and 461 subjects, 
respectively, were included in the primary outcome analysis set. The authors reported 
incidences of benign polyposis that are well in line with the current knowledge on 
GLP-2. No malignancies were reported.
The most commonly reported adverse reactions in the teduglutide clinical trials were 
abdominal pain and distension (45%), respiratory tract infections (28%; including 
nasopharyngitis, influenza, upper respiratory tract infection, and lower respiratory tract 
infection), nausea (26%), infected site reactions (ISRs; 26%), headache (16%), and 
vomiting (14%). Approximately 38% of the treated subjects with a stoma experienced GI 
stoma complications. The majority of these reactions were mild or moderate [Revestive, 
SmPC]. Also, due to increased absorption there is a risk of fluid overload and of 
overdose with concomitant medications that have a narrow therapeutic window (Section 
4.2.3.2).
The Sponsor has sufficient pre-clinical safety information to support the planned 
duration of treatment with apraglutide. This assessment is based upon the following: a 
completed (and reported in Investigational New Drug application 143'011) 26-week 
Good Laboratory Practice repeated dose toxicity trial with apraglutide in rats and a 39-
week Good Laboratory Practice repeat-dose toxicity trial in minipigs that showed only 
the expected intestinotrophic pharmacological effect and no evidence of intestinal 
tumors or other adverse effects of apraglutide. Two-year carcinogenicity studies in rats 
and mice with apraglutide are ongoing. For further details, please refer to the 
Investigator’s Brochure.
1.8.2 Assessment of Known and Potential Risks and Benefits
Several precautions are in place to increase the safety of participating subjects with SR 
lower GI-aGVHD in this trial:
Subjects with a current or history of GI disease that might be at risk to develop 
GLP-2 typical adverse effects will be excluded from trial participation
Subjects with known GI polyps will have their polyps removed before the start of the 
apraglutide treatment
Mid- and longer-term follow-up investigations will be in place to check for newly 
emerging polyps
A Sponsor-independent Safety Review Committee (iSRC) is in place to closely 
supervise subject safety during the trial and to make recommendations to the 
Sponsor with regards to the safe conduct of the trial

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The overall assessment of the Sponsor’s own safety data on apraglutide, as well as 
published data on the GLP-2 teduglutide and the anticipated benefit in the target 
population with high unmet medical need, concludes that the anticipated benefit of 
apraglutide treatment outweighs the individual risk for the participating subjects.
1.8.3 Summary of Clinical Safety with Apraglutide Reported During Phase 
1 and Phase 2 Trials
Apraglutide has generally been safe and well tolerated in the clinical trials conducted to 
date as demonstrated by the following:
A dose relationship was not seen for any AE in any of the trials
Doses up to 56.9 mg were safe and well tolerated in the single-ascending dose and 
multiple-ascending dose parts of the Phase 1 trial GYM-P3-698 in healthy 
volunteers
Apraglutide 10 mg was well tolerated in healthy volunteers who received up to 
six weekly doses in trial TA799-002
The most frequent AEs included nausea, GI stoma output decreased, and stoma 
complications
Frequent AEs were primarily related to the expected efficacy effects of apraglutide, 
including decreased stoma output or stoma output abnormal, polyuria, and 
decreased thirst
Serious AEs have primarily been disease complications that are common in 
subjects with SBS, including device-related sepsis and device malfunction. Two 
subjects had a total of three treatment emergent SAEs. All the SAEs resolved and 
only one SAE, abdominal pain, was assessed by the Investigator as related to 
apraglutide
For each hematology, coagulation, and chemistry parameter, mean and median 
change from baseline were not clinically significant. Isolated occurrences of 
clinically significant out of range laboratory parameters were reported as AEs, but 
there was no consistent pattern with the occurrence of these events
No QT interval corrected according to Fridericia’s formula (QTcF) prolongation 
greater than 500 msec was seen in any of the clinical trials. In GLY-311-2017 and in 
GLY-321-2017
all subjects at all time points, except for one subject at the end of trial (EOT) visit 
and in another subject at pre-dose of Period 3
Low-titer ADAs were seen in five subjects out of 64 treated (none in GYMP3698, 
one in TA799-002, three in GLY-311-2017, and one in GLY-311-2017). The ADAs 
had no apparent effect on either the PD or PK of apraglutide
In summary, the safety and tolerability profile of once weekly administration with 
apraglutide derived from clinical trials conducted so far confirms the expected mode of 
action-related safety effects. These should be anticipated to also occur with apraglutide 
in the current trial.
1.9
Rationale for Choice of Control
Published data from REACH2 was chosen to provide an approximate sample size 
estimation based on a selected secondary endpoint (Day 56 GI response). 

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During the trial, the Sponsor will pursue the option of establishing one or more 
alternative historical control cohorts better matched to the current trial population and 
the selected secondary endpoint.

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2 
TRIAL DESIGN 
2.1
Rationale for the Trial Design
This POC trial is designed as a single-blind trial and aimed at assessing the safety and 
tolerability of three dose groups of apraglutide in subjects with SR lower GI-aGVHD 
receiving SS and RUX as underlying immunosuppressive therapy (BAT). Within the 
dose levels studied, subjects will receive an apraglutide dose according to their body 
weight at baseline.
This POC trial will also provide a preliminary assessment of the efficacy of apraglutide 
as a GI-regenerative approach on top of BAT in order to study a novel, complementary 
mode of action in a therapeutic setting that is historically dominated by 
immunosuppression.
Published randomized control trial data on BAT from REACH2 [Zeiser, 2020a] were 
initially chosen to derive a historical control. 
As an increased use of RUX in combination with SS is used in standard of care, during 
the trial, the Sponsor will pursue the option of establishing one or more alternative 
historical control cohorts better matched to the current trial population and the selected 
secondary endpoint.
2.1.1 Rationale for the Independent Safety Review Committee
As this is the first time apraglutide will be administered to this population, intensive 
safety monitoring will occur. The iSRC will oversee the safety of trial participants and 
will make recommendations to the Sponsor as to the safe conduct of the trial. Further 
details are reported in Section 8. The iSRC charter describes the composition, 
objectives, structure, and responsibilities of the iSRC and the procedures the committee 
will follow. 
2.2
Overall Design
This is a randomized, single-blind, POC trial to evaluate the safety, tolerability, and 
preliminary efficacy of apraglutide in subjects with SR lower GI-aGVHD Stage 1–4 who 
are taking BAT. The overall trial design is presented in Figure 1. 
Screening will start any time after clinical diagnosis of lower GI-aGVHD and SS 
initiation, and the period will last a maximum of 12 weeks. Subjects will be 
randomized/dosed on Day 0 only if they develop SR lower GI-aGVHD and have started 
RUX. Overall, subjects will attend a screening visit, a baseline/first dosing visit, up to 
12 treatment visits, up to an additional 13 treatment visits in case of optional or lower 
GI-aGVHD flare treatment, and up to seven follow-up visits depending on when the 
subject transitions from the treatment to follow-up period. 
Thirty subjects will be randomized to receive a low or high dose of apraglutide. Subjects
weighing 50.0 kg, will be randomized to two treatment arms (low or high dose of 
apraglutide) based on their body weight at baseline (three body weight ranges: 
50.0<60.0 kg, 60.0 80.0 kg, and >80.0 kg). In addition to the 30 subjects, a separate, 
non-randomized cohort of up to 4 subjects with body weights from 40.0 to <50.0 kg will 
be assigned to receive 2.5 mg of apraglutide (LBW dose). 
Apraglutide will be administered subcutaneously once weekly from Week 0 to Week 7
inclusive. 

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In case of no complete lower GI-aGVHD response at Week 8, subjects will continue 
treatment from Week 8 to Week 12 inclusive.
Subjects with no complete lower GI-aGVHD response at Week 13 can optionally
continue apraglutide for a maximum of 13 additional weeks (if the Investigator 
concludes that the subject is still benefitting from apraglutide treatment).
Treatment can be re-started in case of lower GI-aGVHD flare (e.g., if flare during Week 
17, treatment will be performed once weekly between Week 17 and Week 25). Only one 
event of flare can be treated with apraglutide.
Follow-up will start at Week 8 (if complete lower GI-aGVHD response occurs by Week 8
inclusive), Week 13 (if complete lower GI-aGVHD response occurs between Week 9 
and Week 13 inclusive), anytime once a complete lower GI-aGVHD response is 
achieved during the optional treatment or lower GI-aGVHD flare treatment, and after 
early treatment discontinuation. Follow-up will continue up to 2 years after the first dose 
of apraglutide.
Assessments scheduled during screening, baseline, treatment, lower GI-aGVHD flare
and optional treatment periods are listed in Table 1. Assessments scheduled during the 
follow-up are presented in Table 2.
Treatment course and subject transition through the trial periods is presented in
Figure 3.
Figure 3: Subject Flow Diagram
aGVHD=acute graft versus host disease; FU=follow-up; GI=gastrointestinal; GVHD=graft versus host disease; W=week
1.
Subject to continue treatment up to Week 7 inclusive, even if complete lower GI-aGVHD response is achieved before 
Week 7 inclusive
2.
Subject to continue treatment up to Week 12 inclusive, even if complete lower GI-aGVHD response is achieved between 
Week 8 and Week 12 inclusive
3.
Lower GI-aGVHD flare treatment can be started after occurrence of a lower GI-aGVHD flare between Week 9 and Week 
25 (e.g., if lower GI-aGVHD flare occurs during Week 17, treatment will be performed once weekly between Weeks 18–
25). Only one episode of lower GI-aGVHD flare can be treated with apraglutide for a maximum of 13 weeks, no later than 
Day 176
4.
Optional apraglutide treatment can be started if the Investigator concludes that the subject is still benefitting from 
apraglutide treatment at Week 13
5.
Apraglutide dosing should be stopped once CR is achieved

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6. 
Perform only the follow-up visits after complete lower GI-aGVHD response is achieved (e.g., if complete lower GI-aGVHD
response was achieved at Week 20, perform follow-up visits at Weeks 21, 26, 52, and 104) 
Following randomization of the first subject, an iSRC will convene approximately every 
4 weeks. The iSRC will review the data and provide independent safety and trial
conduct oversight of the first six randomized subjects. Assuming no issues are identified 
during the ongoing iSRC reviews then 24 additional subjects, weighing 50.0 kg, will be 
randomized to the two treatment arms. Randomization of these additional subjects can 
occur while iSRC monitoring is ongoing. The iSRC will continue the safety supervision 
of the trial.
An interim analysis will be performed when 17 subjects have either reached Day 56 or 
withdrawn from trial. All available data points by the data cut-off date will be included in 
the analysis. 
The final analysis will be done in two steps. The primary analysis of safety and efficacy 
will be performed once all subjects have either completed Day 91 or withdrawn from the 
trial. Additional analyses will be done once all the subjects have either completed the 
EOT visit or withdrawn from the trial. A Clinical Trial Report (CTR) will be issued after 
the primary analysis. An addendum to the CTR will cover the follow-up period until 
2 years after the first apraglutide dose. 
2.2.1 Screening Period
Recruitment will be competitive across sites and countries.
Only after obtaining written informed consent can protocol assessments start to 
determine subject eligibility (see Section 3.2). All eligibility criteria must be met for the 
subject to be allowed to be randomized at the Day 0 visit. 
The screening process can start any time after lower GI-aGVHD diagnosis and SS 
initiation, and screening will continue for a maximum of 12 weeks until the subject 
becomes SR. Subjects will be considered eligible if they fulfil all eligibility criteria and 
after having developed SR lower GI-aGVHD started RUX. 
Ruxolitinib should be administered as per national guidelines (including dose 
adjustments). Apraglutide should be administered concomitantly to RUX. In exceptional 
cases where concomitant administration is not possible, RUX should be administered at 
maximum 72 hours before apraglutide initiation.
A schematic graph of the screening period is illustrated in Figure 4. 
Figure 4: Screening Period
aGvHD=acute graft versus host disease; D=day; GI=gastrointestinal; RUX=ruxolitinib 

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Screening activities may occur on more than one day after informed consent is signed. 
A colonoscopy is required to exclude presence of polyps at screening. A computed 
tomography (CT) colonography (where allowed) or magnetic resonance (MR) 
enterography can be used as an alternative to colonoscopy at the Investigator’s
discretion depending on the subject’s medical condition. Historical data if obtained 
within 6 months prior to screening are allowed. A subject is eligible if no polyps are 
detected. In case polyps detected during screening, these should be removed prior to 
randomization/Day 0.
The screening period cannot be extended beyond 12 weeks as aGVHD may have 
transitioned into cGVHD, in which case the subject will be classified as a screen failure.
If needed, screening can be performed on the same day as baseline, as long as all 
assessments required at screening and baseline are performed and the results are 
available prior to randomization as per the Schedule of Assessments (Table 1).
If the same assessment is foreseen at screening and baseline, and screening and 
baseline are performed on the same day, then the assessment does not need to be 
repeated at baseline.
2.2.2 Treatment, Optional Treatment, and Lower GI-aGVHD flare 
Treatment 
arms (low dose or high dose in one of the three weight bands). The exact dose they 
receive at each visit will depend upon the weight band they fall into at baseline (in the 
range from 2.5 mg to 10 mg, see Table 4). Further details are provided in 
Section 4.2.1.1. Subjects who weigh 40.0–<50.0 kg will not be randomized but assigned 
to receive apraglutide 2.5 mg SC once weekly (LBW dose).
Subjects will receive their first dose of apraglutide concomitantly with RUX. In 
exceptional cases where concomitant administration is not possible, RUX should be 
administered at maximum 72 hours before apraglutide initiation.
Apraglutide will be administered via SC injection weekly for either 8 or 13 weeks. 
Subjects will be dosed weekly from Week 0 to Week 7 inclusive. 
Apraglutide should be given at least until Week 8 unless the Investigator sees 
intolerable AEs that are clearly attributable to apraglutide. This will ensure that 
apraglutide is given enough time to fully establish its GI stabilization and regeneration 
effects. Should a worsening of a subject's GI-related symptoms occur shortly after 
starting apraglutide, adjustment of SS/RUX is the first recommended step.
If there is no complete lower GI-aGVHD response at Week 8, subjects will continue 
treatment from Week 8 to Week 12 inclusive. Treatment between Weeks 0 and 7 or 
between Weeks 8 and 12 should be continued even if a complete lower GI-aGVHD 
response is achieved. If the Investigator concludes that a subject is still benefitting from 
apraglutide treatment and a subject has no complete lower GI-aGVHD response at 
Week 13, apraglutide can be optionally continued for a maximum of 13 additional weeks 
(until Week 25, inclusive) or until a complete lower GI-aGVHD response is achieved, 
whichever comes first. 
Lower GI-aGVHD flare treatment can start as per the protocol if a subject develops a 
lower GI-aGVHD flare between Weeks 9 and 25, and if treatment with apraglutide was 
previously stopped when lower GI-aGVHD CR was achieved at Day 56 (or when PR or 
CR was achieved at Day 91). The definition of a lower GI-aGVHD flare is given in 
Appendix 16.2.

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Only one event of a lower GI-aGVHD flare can be treated with apraglutide until no later 
than Week 25. Apraglutide can be restarted at the same dose received at 
randomization.
Treatment can continue for a maximum 13 weeks (until Week 25, inclusive) or until a 
complete lower GI-aGVHD response is achieved, whichever comes first. 
If the lower GI-aGVHD flare continues after Week 25, standard aGVHD therapies 
should be introduced to control the lower GI-aGVHD flare.
If the lower GI-aGVHD flare is determined to be cGVHD with overlap syndrome, 
standard treatment of cGVHD with immunosuppressive therapy should be initiated.
2.2.3 Follow-up Period 
The follow-up period will last up approximately 2 years from the first investigational 
medicinal product (IMP) administration and will start at different time points during the 
trial:
If a complete lower GI-aGVHD response is achieved by Week 8 inclusive, the 
subject will transition to follow-up at Week 8. Follow-up visits at Weeks 8, 13, 17, 
21, 26, 52, and 104/EOT should be performed 
If a complete lower GI-aGVHD response is achieved from Week 9 to Week 13
inclusive, the subject will transition to follow-up at Week 13. Follow-up visits at 
Weeks 13, 17, 21, 26, 52, and 104/EOT should be performed 
If a complete lower GI-aGVHD response is achieved during the optional 
treatment or lower GI-aGVHD flare treatment, the subject will transition to follow-
up.E.g., if a complete lower GI-aGVHD response is achieved at Week 20, only 
the visits at Weeks 21, 26, 52, and 104/EOT should be performed
In case of early treatment discontinuation, the subject will attend an early 
treatment discontinuation visit approximately 4 weeks (+1 week) from the last 
IMP dose and subsequently transition to follow-up visits at Weeks 26, 52, and 
104/EOT
2.2.4 Phone Calls
Between Week 26 and Week 104/EOT, the site will contact the subject approximately 
every 4 weeks via telephone. Phone calls will not be made in the same week that a trial 
visit is scheduled. Unscheduled calls can be performed at the discretion of the 
Investigator. 
2.2.5 Subject Treatment after End of Trial
A long-term extension trial is not planned. 
2.2.6 Early Treatment Discontinuation 
A subject who discontinues treatment early is NOT considered to be withdrawn from the 
trial, but rather the subject will be followed up until the planned Week 104/EOT visit, 
provided that the subject’s consent has not been withdrawn. 
An early treatment discontinuation visit should be scheduled approximately 4 weeks 
(+1 week) from the last IMP dose. The subject will then transition to follow-up visits at 
Weeks 26, 52, and 104/EOT. The same visit should be completed also in case of early 
treatment discontinuation during the optional treatment period. 
The decision for early treatment discontinuation can be made by the subject, the 
Investigator, or Sponsor personnel. A subject has the right to prematurely discontinue 

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trial medication at any time, without any justification, by withdrawal from trial medication 
only or by withdrawal from any further participation in the trial (i.e., early trial
discontinuation [see Section 2.2.7]).
Although a subject is not obliged to give his/her reason for prematurely withdrawing 
from the treatment or the trial, it is recommended that the Investigator makes a 
reasonable effort to ascertain the reason(s), while fully respecting the subject’s rights.
The Investigator must discontinue trial medication for a given subject if, on balance, 
he/she believes that continued administration would be contrary to the best interests of 
the subject.
A subject who discontinues treatment early and withdraws consent to participate in any 
further trial assessments is considered as withdrawn from the trial and no further 
assessment will be collected after informed consent withdrawal.
Apraglutide should be permanently stopped under the following conditions:
New malignancy is identified during the trial (subjects must be treated and followed 
up as per local guidelines and practices for those malignancies)
In case of an elevation of laboratory parameters as reported in Table 6
The subject is pregnant
In case of unacceptable toxicities associated (definitely, probably, possibly related) 
with apraglutide
For further considerations on IMP dose reduction and temporary discontinuation, see 
Section 6.6.2.
The Investigator must discontinue trial medication for a given subject if, on balance, 
he/she believes that continued administration would be contrary to the best interests of 
the subject.
A subject who discontinues treatment early and withdraws consent to participate in any 
further trial assessments is considered as withdrawn from the trial and no further 
assessment will be collected after informed consent withdrawal. 
Guidance on stopping rules and follow-up medical care of subjects requiring dose 
adjustment are described in Section 4.2.1.2.
2.2.7 Early Trial Discontinuation 
If a subject is withdrawn from the trial, the Sponsor will be informed immediately, and 
the subject will be considered an early-termination subject. 
If there is a medical reason for withdrawal, the subject will remain under the supervision 
of the Investigator at least until the medical situation has resolved.
Regardless of the reason for withdrawal, the subject will be asked to return to the site 
approximately 4 weeks (+1 week) from the date of early trial discontinuation. After this 
visit, no further visits will occur.
In cases where further site visits are not possible, subjects should be asked if they 
would allow the Investigator to continue contacting them and reporting their safety data 
for 4 weeks after early trial discontinuation. 
Reason for withdrawal and the date of discontinuation from the trial should be 
documented under the following categories:
1.
The subject chooses to withdraw

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2.
The Investigator judges it necessary due to non-compliance with trial 
procedures (including if the subject loses the ability to give consent)
3.
The Investigator judges it necessary to protect the subject’s best interest 
4.
Medical considerations have emerged including difficulties with obtaining or 
completing required protocol assessments that, in the opinion of the 
Investigator, potentially affect the safety of the subject. For example, this may 
include inability to obtain blood samples for safety assessments
5.
The subject is pregnant
6.
The clinical trial is terminated by the Sponsor
7.
The iSRC has recommended it
Subjects who discontinue the trial prematurely will be asked to have ADA samples 
drawn at 4 (±2) and 8 (±2) weeks after an Early Trial Discontinuation visit (refer to 
Table 2 and Section 5.9.2).
2.2.7.1 Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A subject is considered lost to follow-up when the Investigator cannot reach the subject. 
If contact details are available and permission has been obtained, the subject’s relatives 
should be contacted by phone to obtain a reason for the subject not attending a visit 
(e.g., an AE). If at least three phone calls or other contact efforts (e.g., e-mails, text 
messages) at different times during a course of 3 weeks are not answered, a registered 
letter should be sent to the subject. All contact attempts should be documented in the 
subject’s source documents. If the subject decides to withdraw early for the trial, the 
Investigator should encourage the subject to continue with follow-up safety 
assessments. If the subject returns to the site at a later time point, the Sponsor should 
be informed to discuss further steps. 
2.2.7.2 Replacement of Subjects
Subjects that discontinue/withdraw after enrollment/randomization will not be replaced. 
2.2.8 Screen Failures
The following data will be collected and entered into the electronic Case Report Form 
(eCRF) for all subjects that are screen failures:
Date of informed consent form (ICF) and screening visit date
Underlying disease history, GI-aGVHD history, history of transplant
Demographics
Eligibility criteria
Screen failure reason and date
 
Serious AEs, trial procedures-related AEs
 
Concomitant medications/procedures related to AEs
If the subject does not meet the eligibility criteria, the subject will be considered a 
screen failure.
Subjects that failed screening may be rescreened once at a later stage if the reason for 
screen failure has changed over time (e.g., out of range laboratory values have 
resolved). Re-screening should occur at least 2 weeks after the time of screen failure 
and require (i) re-consenting and (ii) Sponsor approval. Subjects who are re-screened 
will receive a new subject number. 

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All screening assessments (except colonoscopy/CT colonography/MR enterography) 
will need to be repeated for the re-screened subject. In Germany, only colonoscopies 
or MR enterographies (not colonographies) can be performed.
2.3
End of Trial Definition
The end of the trial is defined as the last subject’s last visit.
The Sponsor may terminate the trial early according to certain circumstances, for 
example, but not restricted to:
Ethical concerns
Insufficient recruitment
When the safety of the subjects is doubtful or at risk
Alterations in accepted clinical practice that make the continuation of a clinical trial 
unwise
Early evidence of benefit or harm of the experimental intervention

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3
TRIAL POPULATION
3.1
Number of Subjects
This trial will include approximately 34 adult and pediatric subjects (12 years or older on 
the day of screening) who have SR lower GI-aGVHD. In Germany and France, only 
subjects 18 years old and above will be included in this trial. 
Sufficient subjects will be screened to allow randomization of approximately 30 subjects 
to one of two treatment arms (low dose or high dose based on three body weight 
bands). Up to a further four subjects with a weight of 40.0–<50.0 kg will be treated with 
apraglutide 2.5 mg (LBW dose). 
3.2
Eligibility Criteria
3.2.1 Inclusion Criteria
1.
Signed informed consent for this trial prior to any trial specific assessment. A
signed assent form will also be required for all subjects under the age of 18 
years
2.
Male or female subjects aged 12 years or above at the time of consent and 
who weigh a minimum of 40.0 kg. Only subjects aged 18 years and above will 
be included in Germany and France
3.
Have undergone alloSCT from any donor source (matched unrelated donor, 
sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or 
cord blood. Recipients of non-myeloablative, myeloablative, and reduced 
intensity conditioning are eligible
4.
Evident myeloid and platelet engraftment confirmed prior to trial medication 
start:
a. Absolute neutrophil count >1000/mm
3
and
b. Platelets
3
Use of growth factor supplementation (granulocyte-colony stimulating factor 
and granulocyte-macrophage-colony stimulating factor) and transfusion 
support is allowed
5.
Clinical diagnosis of lower GI-aGVHD, MAGIC Stage 1–4 prior to 
randomization. Suitable diagnostic procedures should be implemented to 
exclude alternative reasons for diarrhea; these include (but not limited to)
fecal cultures and lower gut biopsy with histological assessment for infectious 
diseases 
6.
Clinically confirmed SR lower GI-aGVHD defined as subjects administered 
SS, given alone, or combined with CNIs and either:
a. Disease progression based on organ assessment after 3 days of systemic 
mg/kg/day3
mg/kg/day] or equivalent) 
±CNIs
3 The SS dose should be calculated based on the subject’s actual weight, within the maximum lower 
margin of 15% from the calculated dose

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TMP-CD-04_1
Version no.:
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10-Oct-2019
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or
b. Did not improve after 7 days of treatme
mg/kg/day3
mg/kg/day] or equivalent)
or
c. Progressed to a new organ after treatment with systemic MP 
2 mg/kg/day3 ([or prednisone dose 2.5 mg/kg/day] or equivalent) for 
skin and upper GI-aGVHD
or
d. Recurred during or after a steroid taper. Initial dose should be 
mg/kg/day3 MP (or equivalent) systemic MP ([or prednisone dose 
mg/kg/day] or equivalent)
7.
Treatment with SS plus RUX (RUX started concomitantly to apraglutide or a 
maximum of 72 hours before apraglutide initiation)
8.
Women of childbearing potential must agree to use a highly effective method 
of contraception and refrain from donating eggs during the trial and for 
4 weeks after the EOT visit. Effective contraceptive methods include 
combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, transdermal); 
progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, implantable); intrauterine device; intrauterine 
hormone-releasing system; bilateral tubal occlusion; vasectomized partner. In 
Germany, oral methods of hormonal contraception are to be combined with 
another accepted method of contraception.
To be considered sterilized or infertile, females must have undergone surgical 
sterilization (bilateral tubectomy, hysterectomy, or bilateral ovariectomy) or be 
post-menopausal (defined as at least 12 months amenorrhea without an 
alternative medical cause, may be confirmed with follicle-stimulating hormone 
test in case of doubt). Women who do not engage in heterosexual intercourse 
will be allowed to join the trial without contraception following a thorough 
discussion with the Investigator to determine if this is feasible for the subject. 
The following methods are not considered acceptable methods of 
contraception: calendar, ovulation, symptothermal, post-ovulation methods, 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method
9.
Male subjects with a female partner of childbearing potential must commit to 
practice methods of contraception and abstain from sperm donation during 
the trial and for 2 weeks after the EOT visit. Nevertheless, if their partners are 
women of childbearing potential, they must agree to practice contraception 
and use a highly effective method of contraception during the trial and for 
4 weeks after the EOT visit. Such methods include combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal); progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, 
implantable); intrauterine device; intrauterine hormone-releasing system; 
bilateral tubal occlusion

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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3.2.2 Exclusion Criteria
1.
Treatment with any systemic GVHD therapy other than SS and RUX including 
methotrexate and mycophenolate mofetil at the time of randomization/Day 0. 
Graft versus host disease prophylaxis (ciclosporin A, tacrolimus, sirolimus, 
everolimus, or anti-thymocyte globulin) is allowed
2.
Concomitant treatment with Janus kinase inhibitor therapy other than RUX at 
the time of randomization
3.
Failed alloSCT due to relapse of underlying malignant disease
4.
Presence of SR GI-aGVHD occurring after donor lymphocyte infusion for pre-
emptive treatment of malignancy recurrence 
5.
Ongoing participation in an interventional trial or administration of any 
investigational drug in less than its five half-lives prior to randomization/Day 0. 
Participation in observational or interventional trials involving supportive care 
such as probiotics or antiemetics, graft manipulation or transplant procedures, 
new combinations or new dosing of approved therapies for conditioning, 
prophylaxis4, pre- or post-alloSCT and treatment of the underlying malignant 
disease are allowed after consultation with the Sponsor
6.
Known or suspected hypersensitivity to GLP-1 or GLP-2 analogs or 
apraglutide excipients
7.
Any use of enteral glutamine or growth factors such as native GLP-2, GLP-1,
GLP-2 and GLP-1 analogs, or known ADA within 6 months prior to 
randomization/Day 0
8.
Inability to understand or unwillingness to adhere to the trial visit schedules 
and other protocol requirements including those subjects not willing to comply 
owing to drug or alcohol abuse or any condition that would, in the 
Investigator’s judgment, interfere with full participation in the trial, including 
administration of trial medication and attending required trial visits, pose a 
significant risk to the subject, or interfere with interpretation of trial data
9.
Less than 2 weeks anticipated survival at screening
10.
Evidence of chronic renal disease as demonstrated by inadequate renal 
function, which is defined as estimated glomerular filtration rate (eGFR) 
<20 mL/min/1.73 m2 (using the Chronic Kidney Disease Epidemiology [CKD-
EPI] formula) and is confirmed within 48 hours before randomization/Day 0
11.
Presence of decompensated liver cirrhosis Child Pugh Classes B and C
12.
Clinically significant or uncontrolled cardiac disease including acute 
myocardial infarction within 6 months prior to randomization/Day 0, 
uncontrolled hypertension, congestive heart failure New York Heart 
Association Class III or IV 
13.
Requirement for vasopressor or inotropic support within 30 days prior to 
randomization/Day 0
14.
Presence of uncontrolled cholestatic disorders or unresolved sinusoidal 
obstructive syndrome/veno-occlusive disease of the liver (defined as 
4 Except methotrexate and mycophenolate mofetil

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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persistent bilirubin abnormalities not attributable to aGVHD and ongoing 
organ dysfunction)
15.
Presence of relapsed primary malignancy or treatment for relapse after 
alloSCT
16.
Requirement for unplanned immune suppression withdrawal as treatment of 
early malignancy relapse or low donor chimerism. Unclear remission states 
will be discussed with the Sponsor
17.
Presence of newly diagnosed malignancies at screening or prior to 
randomization/Day 0
18.
History of chronic gall bladder or bile duct inflammation or biliary obstruction 
unless a cholecystectomy was performed before screening
19.
Presence or history of GI tumors (including the hepatobiliary system and 
pancreas) within the last five years before randomization; presence of colonic 
polyps that are not removed 
20.
Subjects that present or have a history of familial adenomatous polyposis
21.
Presence of an active clinically uncontrolled infection or evidence of active 
tuberculosis (clinical diagnosis per local practice). Cytomegalovirus 
reactivation is permitted as long as no evidence of pulmonary disease is 
present. 
22.
Central venous catheter sepsis requiring systemic antibiotics within the 
previous 7 days prior to randomization/Day 0
23.
Known cGVHD
24.
Known active GI inflammation not related to GI-aGVHD (e.g., active 
inflammatory bowel disease such as Crohn’s and ulcerative colitis)
25.
History of progressive multifocal leuko-encephalopathy
26.
Known pregnant or nursing (lactating) women 
27.
Known major abdominal surgery in the last 6 months prior to 
randomization/Day 0 (surgical feeding tube placement or other minimally 
invasive surgery is allowed)
28.
History of clinically significant intestinal adhesions increasing the risk of GI 
obstruction or GI contrast examination findings suggesting subacute intestinal 
obstruction or stricture within 6 months prior to randomization/Day 0
29.
Liver enzymes meeting any of the following criteria within 48 hours prior to 
trial medication start: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>8 x upper limit of normal (ULN)
b. Alanine aminotransferase or AST >5 x ULN AND international normalized 
ratio >3
3.3
Lifestyle Considerations
Subjects will observe the contraception requirements laid out in inclusion criteria 
numbers 8 (female subjects) and 9 (male subjects).
Subjects should not use any drugs of abuse from screening until the EOT visit unless 
they have been prescribed (e.g., benzodiazepines).

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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4
TRIAL INTERVENTION/MEDICATION
4.1
Description of Investigational Medicinal Products
The IMP tested in this trial is apraglutide, a GLP-2 analog composed of 33 amino acids, 
containing natural and unnatural amino acids from non-animal origin. Apraglutide is 
manufactured by solid-phase peptide synthesis using 9-fluorenylmethyloxycarbonyl as 
an amine-protecting group. The formulation of apraglutide- is an aseptically 
manufactured freeze-dried powder for reconstitution with commercially available sterile 
water for injection. The IMP also contains the following excipients: glycine, L-histidine, 
mannitol, and sodium hydroxide. The pH of the reconstituted solution is approximately 
8.3.
Apraglutide will be supplied in vials with 10 mg freeze-dried powder for reconstitution in 
sterile water prior to SC injection. Further details are provided in the Investigator’s 
Brochure.
4.1.1 Packaging, Labeling, and Supply (Re-supply) 
Packaging and labeling of the IMP is performed by the Clinical Trial Supplies vendor in 
accordance with Good Manufacturing Practice and applicable regulatory requirements.
The freeze-dried apraglutide powder is filled in 2-mL vials and sealed with rubber 
stoppers and aluminum caps. The subject boxes and individual vials will be labeled 
according to Annex 13, EudraLex Volume 4 [EudraLex Vol. 4, 2010] and national 
regulatory requirements. 
All dosing will occur at the trial sites. Details are included in the Pharmacy Manual.
4.1.2 Storage Conditions 
The Investigator must ensure that the IMP is stored between 2–8°C in a secure location 
with controlled access when at the site. At the site, the temperature will be monitored as 
described in the Pharmacy Manual and recorded in a temperature log as per the 
policies and guidelines of the site and prior to IMP dispensation. Any IMP experiencing 
temperature deviations outside the allowed range must be placed in quarantine 
(between 2–8°C) reported and evaluated prior to releasing it back into stock for use in 
the trial. Details are provided to the site in the Pharmacy Manual.

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 65 of 132
4.2
Administration of Experimental and Control Interventions
4.2.1 Experimental Intervention
4.2.1.1 Administration of Apraglutide
The dose to be administered to the subject at each time point depends on the treatment 
arm to which the subject is randomized and the subject’s weight at baseline, as 
presented in Table 4. Non-randomized subjects with LBWs will only receive 2.5 mg of 
apraglutide.
Table 4: Dose of Investigational Medicinal Product Based on Treatment Arm and 
Weight
Treatment Arm
Weight Band (based on Baseline Weight)
40.0–<50.0 kg1
50.0–<60.0 kg
60.0–80.0 kg
>80.0 kg
Low dose (mg)
2.5
2.5
4 
5 
High dose (mg)
5 
7.5
10
1. 
A non-randomized cohort of up to four subjects 
The SC injection will be administered in the abdominal area or in the thigh. The injection 
site must be rotated such that an injection is administered at least 5 cm away from 
where the last injection was administered. 
The IMP must be administered weekly as per scheduled (Table 1 and Table 2). Detailed 
instructions will be provided in the Pharmacy Manual for the site. 
The Investigator is ultimately responsible for the appropriate preparation and 
administration of the IMP by assigning the appropriate site personnel and ensuring they 
are well-trained. The dose assigned through IRT will need to remain blinded to the 
subjects. Investigational medicinal product will not be administered to any person not 
enrolled in this trial.
4.2.1.2 Apraglutide Dose Adjustments, Interruptions and Stopping Rules 
For subjects who do not tolerate the protocol dosing schedule, dose adjustments, or 
interruptions are mandated to allow the subjects to continue the trial medication and 
maintain apraglutide dosing for optimal treatment of aGVHD. The objective of these 
dose adjustment rules is to optimize response for each individual subject while avoiding 
clinically relevant toxicities attributed to apraglutide. 
Dose reductions should be undertaken as outlined in Table 5. 
Table 5: Dose Reduction Steps for Apraglutide
Original dose (mg)
2.5
4 
5 
7.5
10
New dose (mg)
0 
2.5
4 
5 
7.5
Deviations to the recommended dose reductions, temporary interruptions, or permanent 
interruptions will need to be documented. 
Subjects who are receiving multiple oncological treatments, or are dependent on 
parenteral support, develop abnormal liver function tests. In both cases bilirubin, ALT, 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 66 of 132
and/or AST may be elevated at baseline; therefore, the stopping rules for these subjects 
will use the increase from baseline instead of values from the ULN.
Table 6 depicts the dose adjustments for apraglutide dose in case of deviations of 
clinical safety parameters starting from Week 1. 
Table 6: Apraglutide Dose Adjustments—Holding and Stopping Rules
Total bilirubin elevated (adapted from MAGIC)
Use x ULN if normal at baseline (BSL) or x BSL if elevated at BSL
>1.5–3.0 x ULN or BSL
Recommendation: Maintain dose level
>3.0–5.0 x ULN or BSL
Mandatory: reduce by 1 dose level 
Monitor LFTs weekly, or more frequently if clinically indicated, 
x ULN/BSL:
If resolved in >14 days, then maintain the dose level 
minus 1
>5.0–10.0 x ULN or BSL
Mandatory: Hold dosing
Monitor LFTs weekly, or more frequently if clinically indicated, 
If resolved in >14 days, then resume at dose level 
minus 1
>10.0 x ULN or BSL
Mandatory: Hold dosing
Monitor LFTs weekly, or more frequently if clinically indicated, 
minus 1
If resolved in >14 days, then STOP dosing 
The subject should be further monitored weekly (including LFTs), 
or more frequently if clinically indicated, until total bilirubin has 
resolved to baseline or stabilization over 4 weeks
AST or ALT elevated (normal BSL)
>5.0–<8.0 x ULN for more 
than 2 weeks
Mandatory: Hold dosing
Repeat LFTs as soon as possible, preferably within 48–72 hours 
from awareness of the abnormal results; monitor LFTs weekly, or 
× ULN.
Then:
weeks of 
elevation), then resume at initial dose level
If resolved in >14 days (which start after 2 weeks of 
elevation), wait for resolution to ULN then resume at 
dose level minus 1

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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–
x ULN 
Mandatory: Hold dosing
Repeat LFTs as soon as possible, preferably within 48–72 hours 
from awareness of the abnormal results; monitor LFTs weekly, or 
Then resume at dose level minus 1
>20.0 x ULN 
Mandatory: STOP dosing
AST or ALT elevated (elevated at BSL)
>3.0 –<5.0 x BSL 
Mandatory: Hold dosing
Repeat LFTs as soon as possible, preferably within 48–72 hours 
from awareness of the abnormal results; monitor LFTs weekly, or 
more frequently if clinically indicated, until resolved to 
.
Then:
If resolved in >14 days, wait for resolution to BSL then 
resume at dose level minus 1
–
Mandatory: Hold dosing
Repeat LFTs as soon as possible, preferably within 48–72 hours 
from awareness of the abnormal results; monitor LFTs weekly, or 
Then resume at dose level minus 1.
>20.0 x BSL 
Mandatory: STOP dosing
Combined AST/ALT and bilirubin elevation
Use x ULN if normal at BSL or x BSL if elevated at BSL
ALT/AST >3.0 × ULN/BSL 
and total bilirubin >2.0 × 
ULN/BSL 
Mandatory: Hold dosing
Assess causality of the investigational compound:
If relationship to apraglutide is suspected (definitely, 
probably, possibly related) Stop dosing
If another cause is identified manage with institutional 
guidance and restart treatment
Asymptomatic amylase and/or lipase elevation
>1.0–1.5 x ULN
Recommendation: Maintain dose level
>1.5–2.0 x ULN
Recommendation: Maintain dose level
>2.0–5.0 x ULN
Recommendation: Hold dosing until resolved to Grade
then:
If resolved in >7 days, then resume at dose level minus 
1
>5.0 x ULN 
Recommendation: Stop dosing
Pancreatitis

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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Grade 2
Recommendation: Maintain dose level
Mandatory: Stop dosing
New onset of abdominal pain or worsening from BSL
Mandatory: Stop dosing
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BSL=baseline; LFT=liver function test; MAGIC=Mount Sinai 
Acute Graft Versus Host Disease International Consortium; ULN=upper limit of normal  
Additional visits for unscheduled laboratory samplings or for safety reasons can be 
arranged as per the Investigator’s judgment. In case of abnormal laboratory results of 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher 
assessed at a subject’s local doctor, a re-assessment should be scheduled at the site.
4.2.2 Ruxolitinib and Steroid Medications
4.2.2.1 Ruxolitinib Dose Adjustments
Dose reductions and temporary interruptions of RUX treatment may be needed in SR 
lower GI-aGVHD subjects with thrombocytopenia, neutropenia, or elevated total bilirubin 
after standard supportive therapy, including growth-factors, anti-infective therapies, and 
transfusions. Dose adjustment recommendations for RUX should be followed according 
to the current regional recommendations (the European Union Prescribing Information
[EUPI] and United States Prescribing Information [USPI]).  
Dose adjustments of RUX should be documented in the source documentation and in 
the relevant eCRF page.
4.2.2.2 Steroids Dose Adjustments
The dose of SS administered may be changed at the Investigator’s discretion based on 
the subject’s aGVHD symptoms and clinical parameters such as white blood cell and 
thrombocyte counts; furthermore, topical steroids may be added at the discretion of the 
Investigator. 
4.2.3 Prior and Concomitant Treatments
4.2.3.1 Prior Medication/Therapy
Prior treatment includes previous medications or interventions received in the past
which are no longer ongoing at screening. Details of following medications from the 
start of conditioning are to be recorded in the source documents and entered in the 
eCRF: 
Any systemic aGVHD prophylaxis or therapy including methotrexate and 
mycophenolate mofetil, ciclosporin A, tacrolimus, sirolimus, everolimus, or anti-
thymocyte globulin
Janus kinase inhibitor therapy
Any investigational drug including supportive care such as probiotics or 
antiemetics, graft manipulation or transplant procedures, new combinations or
new dosing of approved therapies for conditioning, prophylaxis, pre- or post-
alloSCT, and treatment of the underlying malignant disease  

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 69 of 132
4.2.3.2 Concomitant Medication/Therapy
Concomitant treatment is any medication or therapeutic intervention ongoing at 
screening and any new medication received during the trial. 
At every visit, the Investigator or a qualified designee will ask the subject about 
concomitant medication.
No clinical drug-drug interaction trials have been performed with apraglutide, but 
experimental settings revealed that apraglutide is not an inhibitor nor an inducer of the 
most common cytochromes tested, in line with apraglutide being a peptide. 
Experimental investigations revealed furthermore that apraglutide has only a minimal 
likelihood of causing clinically relevant transporter interactions (see the Investigator’s 
Brochure for details).
Based upon the PD effect of apraglutide, there is a potential for increased enteral 
absorption of medicinal products. Subjects receiving oral concomitant medicinal 
products requiring titration or with a narrow therapeutic index (e.g., opioids, 
aminoglycosides, ciclosporin, carbamazepine, digoxin, digitoxin, flecainide, lithium, 
phenytoin, phenobarbital, rifampicin, theophylline, warfarin, or others) should be 
monitored closely, with therapeutic drug monitoring or other suitable clinical parameters 
at the discretion of the Investigator.
In case of pain, it is recommended that non-opioid therapies are tried and optimized 
before prescribing immediate-release opioids, rather than extended-release/long-acting 
opioids. It is also recommended to prescribe the lowest effective dosage, below 
50.0 morphine milligram equivalent per day, and to evaluate benefits and harms with 
the subject within 1–4 weeks of starting opioid therapy or of dose escalation.
Subjects should be advised to consult the Investigator or designee prior to taking any 
prescribed or over-the-counter medications. 
Concomitant treatments are to be recorded in the source documents and entered in the 
eCRF. In particular, the exact dose of SS and RUX taken throughout the trial must be 
clearly recorded in the eCRF including any dose adjustments.
Routine vaccinations (flu, tetanus, etc.) are allowed during the trial but must be entered 
into the eCRF. Vaccination for SARS-COV-2 is allowed but each vaccine administration 
and the type of vaccine must be entered into the eCRF. All AEs attributed to vaccination 
e.g., soreness at injection site, must be recorded in the eCRF.
4.2.3.3 Prohibited Medication/Therapy
Treatment with any systemic GVHD therapy other than SS and RUX including 
methotrexate and mycophenolate mofetil at the time of randomization/Day 0 and 
during the trial  
Concomitant treatment with Janus kinase inhibitor therapy (except RUX) at time of 
randomization/Day 0 and during the trial
Citrulline supplements, any use of growth hormone, enteral glutamine or growth 
factors such as native GLP2, GLP1, or GLP-2 and GLP-1 analogs other than the 
IMP under investigation within 6 months before randomization/Day 0 and during the 
trial
Any investigational drug with the exception of the investigational drugs allowed as 
per exclusion criterion number 5 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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4.2.3.4 Allowed Medication/Therapy
Concomitant medications/therapies for prophylaxis (e.g., ciclosporin A, tacrolimus, 
sirolimus, everolimus, or anti-thymocyte globulin) and treatment of SR lower 
GI-aGVHD, except the drugs/classes mentioned in Section 4.2.3.3
Treatment with SS, RUX, and CNIs. These treatments should be tapered according 
to institutional guidelines based on the Investigator’s judgement. However, it is 
recommended to stay on the same CNI (dose and type) used before baseline.
Supportive care, pain control drugs, antibiotics, antiemetics, and transfusions
 
Growth factor supplementation (granulocyte-colony stimulating factor and
granulocyte-macrophage-colony stimulating factor), donor lymphocyte infusions, 
and transfusion support 
4.3
Investigational Medicinal Product Handling
4.3.1 Reconstitution
Reconstitution and preparation of the solution for SC administration will be performed 
using aseptic techniques following all applicable local guidelines. Guidelines detailing 
specific instructions for IMP handling will be made available in a Pharmacy Manual that 
will be provided to the site.
For reconstitution, sterile water will be injected into the vial to obtain a sterile solution 
(Table 7). The vial will be gently swirled until its contents are completely dissolved and 
the contents of the vial verified to be free of foreign particles.
Table 7: Reconstitution of Investigational Medicinal Product 
2.5 mg IMP
4 mg IMP 
5.0 mg IMP
7.5 mg IMP
10.0 mg MP
Vial content 
(apraglutide)
10 mg
10 mg
10 mg
10 mg
10 mg
Number of vials 
used
1 
1 
1 
2 
2 
Reconstitution with 
water for injection 
per vial
0.4 mL
0.4 mL
0.4 mL
0.4 mL
0.4 mL
Total volume 
administered 
0.1 mL
0.16 mL
0.2 mL
0.3 mL
0.4 mL
Concentration of 
reconstituted 
solution
25 mg/mL
25 mg/mL
25 mg/mL
25 mg/mL
25 mg/mL
IMP=investigational medicinal product 
After reconstitution, the IMP must be injected within a maximum of 2 hours from 
completing reconstitution to ensure sterility is maintained.
The solution can be drawn up into the syringe immediately following reconstitution and 
kept at room temperature until administration within 2 hours of reconstitution, or the 
syringe can be drawn up just before administration. The required amount of 
reconstituted apraglutide (0.1 mL for 2.5 mg, 0.16 mL for 4 mg, 0.2 mL for 5 mg, 0.3 mL 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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for 7.5 mg, and 0.4 mL for 10 mg) will be drawn from the vial into the syringe for SC 
injection. Two reconstituted vials are to be used to draw 0.3 mL and 0.4 mL for the 
7.5 mg and 10 mg doses, respectively. After drawing up the syringe, it will be inspected 
for foreign particles and used if judged acceptable for administration.
4.3.2 Documentation and Compliance
The IMP administration time and site of administration (injection) performed at the site 
will be documented in the subject’s medical record. 
Compliance will be assessed by recording the injected volume in the IMP and 
accountability log and, unless restricted by the site standard operating procedures 
(SOPs), will be verified by a monitor during the trial against used vials. Compliance will 
also be assessed during IMP accountability (see Section 4.3.3).
4.3.3 Investigational Medicinal Product Accountability 
The Investigator is responsible for maintaining records of all IMP vials and sterile water
for injection ampoules received and administered to subjects (IMP accountability). The 
amount of unused IMP at site will be verified by a monitor during the trial against used 
vials and interactive response technology (IRT) data. If the Monitor’s verification against 
used vials is restricted by site SOPs, then this verification will be performed by the 
Monitor using site records in accordance to site-specific IMP destruction policies. 
Any discrepancies between the amount of IMP (including sterile water) received and 
administered must be documented. 
4.3.4 Return or Destruction of Investigational Medicinal Product 
All used IMP vials and water for injection ampoules are to be accounted for and kept at 
site for final reconciliation by the Monitor before being returned to the Clinical Trials 
Supplies vendor for destruction according to local site policy/procedures. If such final 
reconciliation by the Monitor is restricted by site SOPs, then this reconciliation will be 
performed in accordance with site-specific IMP destruction policies. Details are 
described in the Pharmacy Manual.
4.4
Randomization and Blinding
This trial is designed as single-blind trial (only subjects will be blinded regarding the 
apraglutide dose level received). 
A single-blind trial design does not represent a bias in the interpretation of results given 
that the main efficacy measure is an objective measurement (i.e., MAGIC score) of the 
disease progression based on symptoms and laboratory results.

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
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5
TRIAL SCHEDULE AND TRIAL ASSESSMENTS
The trial visits shall be conducted according to the Schedule of Assessments (Table 1
and Table 2). Subjects who are inpatients may be visited on the ward by site staff.
5.1
Screening/Baseline Assessments
5.1.1 Demography
Demographic and baseline characteristics include:
Age and birth year
Sex
Race and ethnicity
These details will be recorded in the subject’s medical chart and entered in the eCRF. 
Collection of this information will be highlighted in the ICF. 
5.1.2 Medical, Surgical, and Disease History
Relevant medical and surgical history will be recorded in the eCRF only for eligible 
subjects (not for screen failures), as judged by the Investigator. The information 
collected for medical and surgical history must include: 
Diagnosis and baseline severity of ongoing diseases
Date of onset
Date of resolution (if not ongoing)
Additionally, at screening, any drug or alcohol abuse within the last 12 months prior to 
screening will be documented as medical history (MH).
The MH will be obtained by asking the subject and/or by inspecting his/her medical 
records. 
For the documentation of the subject’s SR lower GI-aGVHD type and disease history, 
the subject will be asked, and/or his/her medical records will be inspected for 
information on:
Details of the initial malignancy 
Date of transplant and type of donor
Conditioning scheme received
Date of onset of aGVHD
Symptoms of aGVHD
Treatment to date for aGVHD and when SR developed
For documentation of eligibility the source documents should include details on the MH, 
prior treatment, imagistic or endoscopic assessments results as applicable, to 
sufficiently document for each criterion the eligibility of the subject. 
5.2
Reporting of Prior and Concomitant Treatment
Prior and concomitant treatment as defined in Section 4.2.3 will be entered into the 
eCRF only for eligible subjects (not for screen failures). For screened subjects and 
screen failures prior and concomitant treatment will be collected in eCRF only if linked 
to an AE.

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At every visit the Investigator or a qualified designee will ask the subject about 
concomitant medication.
Blood transfusions should be recorded as a concomitant procedure in the eCRF.
The subject should be advised to consult the Investigator or designee before taking any 
prescribed or over-the-counter medications. Any new medication use needs to be 
documented with the reason stated.
5.3
Quality of Life Questionnaires
Quality of life questionnaires will be completed at the times outlined in the Schedule of 
Assessments (Table 1 and Table 2). They are recommended to be completed at the 
beginning of the visit prior to other procedures being performed.
5.3.1 EuroQol-5 Dimension – 5 Level Survey
The EQ-5D-5L is a descriptive system that combines five dimensions (mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression) and the EuroQol 
visual analog scale (VAS) to characterize the participant’s health on the day [EuroQol 
Group, 1990; Brooks, 1996; Rabin, 2001; Herdman, 2011]. A copy of this questionnaire 
is presented in Appendix 16.1.1.
Each dimension has five levels or response options, with Level 1 representing best 
health, and Level 5 representing worst health. The single digit for each dimension is 
then combined to create a five-digit value that describes the participant’s health today. 
The EuroQol VAS assesses “how good or bad” the participant’s health is today using a 
vertical VAS ranging from 0 (worst health you can imagine) to 100 (best health you can 
imagine). Participants choose a location on the vertical line, and the number associated 
with that location is recorded as their rating of health today.
5.3.2 Functional Assessment of Cancer Therapy – Bone Marrow 
Transplantation 
The FACT-BMT is a 50-item questionnaire covering five areas: physical well-being, 
social/family well-being, emotional well-being, functional well-being, and additional 
concerns. Each item is marked on a five-point Likert scale (not at all, a little bit, 
somewhat, quite a bit, very much) in relation to the previous 7 days. A copy of this 
questionnaire is presented in Appendix 16.1.2.
The FACT-BMT will only be completed by subjects aged 18 years old.
5.4
Global Assessments
The Global Assessments will be completed at the times outlined in Table 1 and Table 2. 
They are recommended to be completed at the beginning of the visit prior to other 
procedures being performed.
5.4.1 Patient Global Assessment of Severity
The Patient Global Assessment of Severity is a single-item questionnaire using a 
seven-point verbal response scale to assess the current status of the subject’s 
condition. Response options range from 0=absent to 4=extremely severe 
(Appendix 16.1.3).
5.4.2 Patient Global Assessment of Change
The Patient Global Assessment of Change is a single-item questionnaire using a 
seven-point verbal response scale, to assess overall change in the subject’s status 

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since taking the IMP. Response options range from 2=a lot better to -2=a lot worse 
(Appendix 16.1.4).
5.4.3 Physician Global Assessment of Disease
The Physician Global Assessment of Disease is a single-item questionnaire using a 
five-point verbal response scale to assess the current status of the subject’s condition. 
Response options range from 0=no sign of disease to 4=extremely severe 
(Appendix 16.1.5).
5.5
MAGIC Grade Assessment, Survival, and Disease Progression
The Investigator or designee will assess the subject’s aGVHD using the MAGIC grading 
scale (Section 1.5.2.3 and Appendix 16.3) at the times outlined in the Schedule of 
Assessments (Table 1 and Table 2). 
If RUX and apraglutide do not start on the same day, MAGIC assessment should be 
done at screening and at RUX initiation. Historical data is allowed, if available, if RUX 
was started before the subject consented. 
The four target organs (skin, liver, upper GI, and lower GI) will be assigned a Stage 
(between 0 and 4) and the four Stages combined to assign the subject’s disease as 
being Grade 0–IV. 
Stool volume is converted in the equivalent number of episodes in the MAGIC score 
grading scale (i.e., on average 200 mL of diarrhea corresponds to one episode in 
adults). Formed or mostly-formed stools should not be quantified or counted towards 
the diarrhea volume. If the subject has diarrhea, the Investigator should assess whether 
the diarrhea is due to GVHD or to other confounding effects such as infections or 
medications. 
The blood draw for bilirubin analysis should be performed the same day as the MAGIC 
assessment, except for the baseline measurement where sample collection is permitted 
within 48 hours before the randomization.
Both the Stage of each target organ and the overall grade will be documented in the 
eCRF to track disease progression. 
Severe abdominal pain, ileus, and/or grossly bloody stool should be documented when 
present because Stage 4 lower GI-aGVHD is staged based upon the presence of these 
symptoms and is independent of volume of diarrhea. Streaks of blood in the stool due to 
hemorrhoids or anal fissures, or transient hematochezia following endoscopic biopsies 
are not considered when making this determination. The definition of severe abdominal 
pain remains a judgment call on the part of the treating clinician, but it is suggest only 
considering pain attributed to GVHD that requires the initiation of high doses of narcotic 
pain medication or a significant increase in on-going narcotic use, and the abdominal 
pain significantly impacts a subject’s performance status as determined by the treating 
clinician [Harris, 2016].
As part of the analysis, MAP will be calculated. The exact date of recurrence of aGVHD 
and organ staging will be recorded in the eCRF.
Survival and disease progression (graft failure, FFS, NRM, OS, malignancy relapse and 
progression, GVHD response, and relapse) as well as GVHD relapse will be monitored 
throughout the trial. Date(s) of discharge, any readmissions, and hospital stays will be 
recorded. Where the status of the subject is unknown, and the subject fails to attend for 
a visit, attempts will be made to determine survival status including contacting the 

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subject’s treating physician and (where contact details are available, and permission 
has been obtained) next of kin. 
5.6
Parenteral Support
The average daily volume and caloric content of parenteral support used in the previous 
7 days will be recorded in the eCRF.
5.7
Gastrointestinal Regeneration and Barrier Function
Gastrointestinal regeneration and barrier function will be assessed through plasma 
citrulline levels, mucosal cell population regrowth from biopsies, serum albumin, and 
incidence of systemic infections of likely GI origin.
5.8
Safety Parameters
5.8.1 Colonoscopy, Computed Tomography Colonography, or Magnetic 
Resonance Enterography
A colonoscopy must be performed at the screening, 1-year, and 2-year visits after 
apraglutide treatment to detect colonic polyps (Table 1 and Table 2). In general, a 
colonoscopy is the gold standard for polyp detection. Therefore, this should be the 
endoscopic procedure of choice whenever possible. Subjects with a low platelet count 
may receive a platelet transfusion prior to this procedure. 
The population in this trial includes subjects with lower GI-aGVHD. These subjects have 
highly inflamed, friable, ulcerated, and denuded GI mucosa, with large volumes, 
frequently bloody, osmotic, and bile acid diarrhea. This places GI-aGVHD subjects at a 
higher risk of bleeding or perforation during a colonoscopy [Schwartz, 2001; Lohsiriwat, 
2010]. Therefore, in this trial, the Investigator can, based on his/her judgment, perform a 
CT colonography (where allowed) or MR enterography as an alternative method for 
polyp detection. In Germany, only colonoscopies or MR enterography (not CT 
colonographies) can be performed.
At screening, historical data may be used if obtained within 6 months prior to the 
screening visit. Any polyps identified in the screening assessment should be removed. 
Histopathology assessment of any removed polyps must be documented in the source 
documents and in the eCRF. Subjects who do not want to have their polyps 
removed or whose histology reports show malignancy cannot be randomized and 
dosed with apraglutide.
5.8.2 Physical Examination
A general physical examination will be completed at the times outlined in the Schedule 
of Assessments (Table 1 and Table 2). Additional physical examination should be 
performed at any time during treatment, if clinically indicated.
This examination serves to detect obvious and severe abnormalities and will be 
documented in the source documents and eCRF. 
5.8.3 Body Weight and Height
Body height will be recorded at screening to the nearest 0.5 cm. Subjects should be 
measured without footwear.
Body weight will be measured at each visit using the standard scales at the site, using 
the same scale at each assessment for a subject as far as possible and recorded in 

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local standard metrics. During weighing, the subject should wear light clothing and no 
shoes.
5.8.4 Vital Signs
Vital signs including systolic and diastolic blood pressure, heart rate, and temperature 
will be measured before apraglutide administration at the times outlined in Table 1 and 
Table 2.
Vital signs will be measured in a sitting or supine position after 5 minutes rest and blood 
pressure will be recorded in millimeters of mercury (mmHg). Temperature will be 
recorded in either degrees centigrade or degrees Fahrenheit.
Measures will be collected in the source documents and eCRF.
5.8.5 Twelve-lead Electrocardiogram
A 12-lead ECG will be recorded at rest at the times outlined in Table 1 and Table 2
using the standard equipment and procedure at the site. Additional ECG monitoring 
should be performed at any time during the treatment, if clinically indicated. All ECG 
parameters, including heart rate, pulse rate, QRS, and QT will be recorded. The QTcF 
will be calculated in the eCRF. 
If screening and randomization occur on the same day, historical ECG results obtained 
within 48 hours can be used. 
If randomization occurs within 48 hours from screening, the ECG does not need to be 
repeated.
Additionally, an overall clinical assessment of the ECG will be made and recorded as 
“normal,” “abnormal not clinically significant,” or “abnormal clinically significant.”
Abnormal clinically significant findings after signing of the ICF which meet the definition 
of an AE must be recorded in the eCRF (see Section 6.5). 
5.8.6 Adverse Events 
Adverse events will be recorded in the AE pages of the eCRF for all eligible subjects. 
During screening only SAEs or trial related AEs will be reported. Once eligibility is 
confirmed all AEs will be reported in the ECRF. Adverse events will be reported using a 
recognized medical term or diagnosis that accurately reflects the event. Adverse events
will be assessed by the Investigator for severity, relationship to the investigational 
product or a protocol requirement, possible etiologies, and whether the event meets 
criteria as an SAE and therefore requires immediate notification of the Sponsor. See 
Section 6.2 for the definition of SAEs, and Section 6.2.6 and Section 6.2.3 for guidelines 
for assessment of severity and relationship, respectively. If the event has not recovered 
to baseline or Grade 1 at the end of the trial reporting period, it will be documented as 
ongoing for all events that are at least possibly related to apraglutide. If an AE evolves 
into a condition which becomes “serious” it will be reported as an SAE.
Any laboratory abnormality will be considered an AE if it is judged to be clinically
significant by the Investigator.
Infections (local as well as systemic) and sepsis events will be captured in the eCRF 
together with the severity and any interventions taken; they will be coded according to 
the version of the Medical Dictionary for Regulatory Activities (MedDRA) in use in the 
trial at the time. 

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5.8.7 Adverse Events of Special Interest
The handling and further clarification of AESIs are described in detail in Section 6.2.2; 
special reporting requirements apply (refer to Section 6.3.4). When documenting an AE 
as per the section above, the Investigator will assess if the AE is an AESI. 
In this trial, AESIs are:
Injection site reactions 
Gastrointestinal obstructions
Gallbladder, biliary and pancreatic disease 
Fluid overload 
Colorectal polyps 
New malignancies 
Systemic hypersensitivity
5.9
Laboratory Analysis
The total blood volume to be collected in this trial will not exceed 550 mL for each 
subject. For subjects with a positive historical serology result post-transplantation for 
cytomegalovirus, Epstein-Barr virus, SARS-COV-2 virus, HIV, hepatitis B virus, or
hepatitis C virus an additional volume, up to a maximum of 4 mL will be drawn for viral 
load assessment. 
Information of the clinical laboratories involved in the trial will be available in the 
Laboratory Manual and Site File.
5.9.1 Local Laboratory Parameters
Blood samples for clinical chemistry, including liver enzymes, hematology, and 
hemostasis, and urine samples for urinalysis will be collected at the times outlined in 
Table 1 and Table 2.
Blood and urine samples will be processed at the site in accordance with local 
procedures. Local laboratory ranges for each site must be provided to the Sponsor prior 
to site initiation for the trial.
All local laboratory reports will be reviewed by the Investigator and parameters out of 
normal range assessed as “clinically significant” or “not clinically significant.” Clinically 
significant abnormal results during the trial will be appropriately followed up by the 
Investigator and recorded as an AE (see Section 6.5).
The following clinical chemistry parameters will be collected
Total HCO3-(bicarbonate)
Calcium
Phosphate
Sodium
Chloride
Ferritin
Glucose
Blood urea nitrogen and/or urea
Creatinine and estimated glomerular filtration rate (eGFR) calculated using the 
CKD-EPI formula

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Note: The CKD-EPI formula employs serum creatinine measurements and a 
subject’s age, sex, and race to estimate the glomerular filtration rate.
An online calculator is available at: [https://www.merckmanuals.com/medical-
calculators/GFR_CKD_EPI.htm].  
The formula is: eGFR = 141 x 
 x max (serum 
creati
-1.209 x 0.993Age x 1.018[if female] x 1.159[if black]
The eGFR is expressed as mL/min/1.73 m2
(females) or 0.9 (males); 
-0.329 (females) or -0.411 (males); min = indicates 
the minimum of serum 
This formula expects creatinine to be measured 
in mg/dL. 
Uric acid
Bilirubin (total, conjugated [direct] and, if possible, unconjugated [indirect]) 
Lactate dehydrogenase
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Albumin
 
C-reactive protein
Gamma-glutamyl transferase
Total amylase and, if possible, pancreas type [pancreatic amylase]
Triacyl glycerol lipase (lipase)
The following hematology parameters will be collected:
Erythrocytes
Hematocrit
Hemoglobin
Leukocytes, including differential counts (% and/or absolute values. However, to 
confirm inclusion criterion 4 absolute neutrophil count is required) 
Thrombocytes (platelets)
International normalized ratio
Hemostasis
Prothrombin time and, if possible, activated partial thromboplastin time
The following urinalysis parameters will be collected:
pH
Leukocytes or leukocyte esterase
Nitrite
Protein
Glucose
Ketones

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Hemoglobin (blood)
Specific gravity
Urinalysis parameters will be measured via dipstick or site-specific procedures.
5.9.1.1 Assessment of Viral Load
For subjects with a positive historical serology result post-transplantation for Epstein-
Barr virus, cytomegalovirus, SARS-COV-2 virus, HIV, hepatitis B virus, or hepatitis C 
virus, viral load will be assessed by polymerase chain reaction. 
A sample must be collected within 7 days prior to randomization/Day 0. 
5.9.1.2 Pregnancy Test
Pregnancy tests (serum at screening and baseline, urine test thereafter) will be 
performed for all female subjects of childbearing potential at the times outlined in 
Table 1 and Table 2. A positive urine pregnancy test should be confirmed using a serum 
pregnancy test prior to deciding on subject discontinuation of trial medication or 
participation. 
To be considered sterilized or infertile, women must have undergone surgical 
sterilization (bilateral tubectomy, hysterectomy, or bilateral ovariectomy) or be 
post-menopausal (defined as at least 12 months amenorrhea without an alternative 
medical cause; this may be confirmed with a follicle-stimulating hormone test if there is 
doubt). Any pregnancies should be reported as described in Section 6.3.5. 
5.9.2 Central Laboratory Parameters
Anti-Drug Antibodies 
A blood sample for analysis of anti-apraglutide antibodies that may include neutralizing 
antibodies and cross-reactivity to endogenous GLP-2 (collectively ADA) will be collected 
prior to dosing, at the times outlined in Table 1 and Table 2. 
At Weeks 21, 52, and 104, samples will not be collected if treatment was stopped 
before the previous sample collection date and the previous sample result was negative 
(if these results are available). In addition, unscheduled samples should be collected in 
the case of an AE judged relevant by the Investigator, such as hypersensitivity.
Subjects who discontinue the trial prematurely will be asked to have ADA samples 
drawn at 4 (±2) and 8 (±2) weeks after an early trial discontinuation visit. The Sponsor 
will inform the Principal Investigator of these results once available.
Stool Sample Collection
Stool sample collection can be done within 24 hours prior to the visit. 
Subjects will be asked to bring a stool sample to each visit outlined in Table 1 and 
Table 2, and samples will be frozen prior to shipment to the central laboratory for 
analysis of calprotectin and microbiome. Collection pots and instructions will be 
provided to subjects by site staff. Sample processing, storage, and shipment details will 
be outlined in the Laboratory Manual.
Biomarkers
Blood samples for analysis of biomarkers (including but not limited to albumin, citrulline, 
-1 and -2, sTM, and VEGF) will be collected at the times 
outlined in Table 1 and Table 2. Different biomarkers may be tested at different time 
points.  

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Details on blood volume, stool samples, handling, storage, and shipment of the samples 
to the central laboratory will be provided in a trial-specific Laboratory Manual. 
Lower GI Biopsy  
The screening and Day 56 lower GI biopsy samples are optional and should be 
obtained only if the subject is medically suitable for the procedure. Historical lower GI 
biopsies collected at clinical diagnosis of lower GI-aGVHD are allowed to confirm
eligibility (if a biopsy is needed to rule out other reasons for diarrhea) and further trial 
analysis. 
If lower GI biopsy was not obtained at screening, the Day 56 lower GI biopsy is not 
required.  
A less invasive sigmoidoscopy may be used for taking lower GI biopsies instead of 
full colonoscopy.  
The analysis for mucosal cell regrowth assessment will be done at a central laboratory.
Further details on the processing of biopsy samples are described in the Laboratory 
Manual.
Pharmacokinetics
Pre-dose Pharmacokinetic Samples
Blood samples for analysis of the plasma concentration of apraglutide will be collected 
at the times outlined in Table 1 and Table 2. Pre-dose PK samples must always be 
drawn within 2 hours before administration of apraglutide on Weeks 1, 2, 3, 4, 6, and 8.
The exact time of PK sampling and subsequent apraglutide administration must be 
captured.
If the dose is not given, e.g., for safety reasons, the sample should however be 
collected at any time of the visit, and the actual time should be documented.  
In cases where the apraglutide was not administered during the previous week, e.g., for 
safety reasons, the pre-dose PK sample at the current visit can be skipped.
Post-dose Pharmacokinetic Samples
Post-dose PK samples should be collected at Week 0 and Week 4 (or if not possible at 
Week 4, then PK sampling should be performed at Week 5 or Week 6 or Week 7 or 
Week 8). 
The following post-dose PK samples are required at: 
6 hours
30 hours
72 hours
120 hours
168 hours (this sample is not to be collected if a pre-dose sample is collected for 
the subsequent IMP administration)
All post-dose PK samples must be collected within ±2 hours window, except for the 
6-hour post-dose sample where only ±1 hour window is permitted.  
It is recommended to administer the IMP in the morning to avoid performing PK sample 
collection during the night.
Details on blood volume, handling, storage, and shipment of the samples to the central 
laboratory will be provided in a trial-specific Laboratory Manual. It is important to 
document the exact time of IMP administration and PK sampling.

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6
SAFETY
All AEs regardless of relationship to IMP will be collected, fully investigated, and
documented in the source documents from ICF signature until EOT visit. For screen 
failures, AEs reporting is described in Section 2.2.8. The region-specific emergency 
contact details for the Sponsor can be found in the Investigator Site File (ISF).
After the Week 104/EOT visit, only SAEs that are judged as related to apraglutide will 
be reported.
In case of early trial discontinuation, AEs should be collected until 4 weeks after the 
early trial discontinuation date. 
Adverse events that occur prior to first dosing will be captured as pre-treatment AEs. 
6.1
Safety Data Reporting
The Investigator must monitor the condition of the subject throughout the trial from the 
time of obtaining informed consent until the last protocol-specific procedure, whether it 
is the EOT visit, or during the safety follow-up period.
If an Investigator becomes aware of an SAE after the subject’s last visit (this includes 
withdrawn subjects), and he/she assesses the SAE to have a reasonable possible 
causality to the IMP, the case will have to be reported to the Sponsor via the Contract 
Research Organization (CRO) using the contact information, regardless of the length of 
time that has elapsed since the end of the trial.
6.2
Definition and Assessment of (Serious) Adverse Events and Other Safety 
Related Events
An AE is any untoward medical occurrence in a subject or a clinical investigation subject 
administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with the trial procedure. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether 
related to the medicinal (investigational) product or not International Council on 
Harmonisation ICH E6(R2) [ICH E6 (R2), 2016].
The sources of AEs include:
The subject’s response to questions about his/her health (a standard non-leading 
question such as “How have you been feeling since your last visit?” is asked at 
each visit)
Symptoms spontaneously reported by the subject
Investigations and examinations with findings that are assessed by the Investigator 
to be clinically significant
Other information relating to the subject’s health becoming known to the 
Investigator
Medical conditions present prior to signing the ICF are defined as MH and are not to be 
considered AEs.
If an AE or MH event worsens in severity or frequency during the trial, then a new AE is 
to be registered with the date of the worsening as the start date.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure 
is considered as the AE rather than the procedure itself.

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An SAE is classified as any untoward medical occurrence that:
Results in death
Is life-threatening
Requires inpatient hospitalization or prolongation of existing hospitalization
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
IMP (also applies if father was exposed to IMP)
Is a clinically significant event in the Investigator’s judgment (e.g., may jeopardize 
the subject or may require medical/surgical intervention to prevent one of the 
outcomes listed above) [ICH E2A, 1995]
6.2.1 Events that Do Not Meet the Definition of a Serious Adverse Event
Elective hospitalizations to administer or to simplify trial treatment or trial procedures are 
not considered SAEs. However, all events leading to unplanned hospitalizations or 
unplanned prolongation of an elective hospitalization (for example, undesirable effects 
of any administered treatment) must be documented and reported as SAEs.
Events that do not meet the definition of an SAE:
1.
Hospitalization or prolongation of hospitalization as part of a routine 
procedure 
2.
Hospitalization for a survey visit, annual physicals or social reasons
3.
Hospitalization that does not include an overnight stay
4.
Elective hospitalizations for pre-existing conditions documented in the MH 
that have not worsened
In case of doubt, an event should be reported within timelines.
6.2.2 Adverse Events of Special Interest
An AESI (serious or non-serious) is an AE of scientific and medical concern specific to 
the Sponsor’s product or program, for which ongoing monitoring, additional information, 
and rapid communication by the Investigator to the Sponsor is appropriate. Depending 
on the nature of the event, rapid communication by the trial Sponsor to other parties 
(e.g., regulators) might also be warranted in line with Council for International 
Organizations of Medical Sciences standards and local regulations.
Once the clinical database containing all AEs is available, potential AESIs will be 
identified using the following algorithmic standardized MedDRA queries (including 
Standardized MedDRA Queries [SMQs]):
Standardized MedDRA Queries—functional, inflammatory- and gallstone-related 
biliary disorders
Standardized MedDRA Queries—GI perforation, ulceration, hemorrhage, or 
obstruction
Standardized MedDRA Queries—malignancies
In the absence of related SMQs, custom queries will be set up from the Sponsor-
defined list of Preferred Terms (PTs) as listed in the Statistical Analysis Plan (SAP).
These standardized searches will occur prior to each iSRC meeting.
The following are considered AESIs for this trial and should be communicated by the 
Investigator to the Sponsor within 2 weeks following the event:

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Injection Site Reactions
given at site, during a trial visit at the site, or longer (i.e., until the reaction stops or the 
subject leaves the site), as necessary. The individual symptoms of the ISR should be 
reported as AEs. 
Data on local tolerability will be collected as an AESI. The following characteristics of 
ISRs will be documented:
Pain
Erythema
Induration
Pruritus
Bruising
Severity and duration of these features of the ISR will be collected by the site by direct 
observation when IMP is administered on site. 
Table 8: Grading of Severity is based on National Cancer Institute – Common 
Terminology Criteria for Adverse Events 5.0 in line with Other Adverse Events in 
this Trial
Pain
Grade 1
Mild pain
Grade 2
Moderate pain; limiting instrumental activities of daily living
Grade 3
Severe pain; limiting self-care activities of daily living
Pruritus
Grade 1
Mild, localized reaction with only topical intervention
Grade 2
Moderate with noticeable skin change from scratching (e.g., excoriation); oral 
therapy indicated
Grade 3
Widespread and resulting in treatment interruption
Induration
Grade 1
Mild induration with skin able to slide and pinch up
Grade 2
Unable to pinch up skin but still slides
Grade 3
Severe, unable to slide or pinch, potentially limiting activity of daily living, and 
consideration of treatment interruption
Erythema
Grade 1
Mild, <2.5 cm
Grade 2
Moderate, 2.5–5 cm
Grade 3
>5 cm
Bruising
Grade 1
Mild, <2.5 cm
Grade 2
Moderate, 2.5–5 cm
Grade 3
>5 cm
Gastrointestinal Obstruction
Any GI obstructions will be treated by the Investigator according to the Investigator’s 
judgement and carefully followed up. 

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Gallbladder, Biliary, and Pancreatic Disease
These should be monitored by symptoms, liver enzymes (ALT, AST, and alkaline 
phosphatase), bilirubin, lipase, and amylase, and subjects should be treated according 
to the Investigator’s judgement.
Fluid Overload
Subjects will be monitored closely for signs and symptoms related to fluid overload, 
(e.g., edema, due to increased absorption). The Investigator will document cases of 
substantial fluid overload and manage as per clinical practice for the subject 
accordingly.
Colorectal Polyps
Colonoscopies or colonographies (where allowed) or MR enterographies will be 
performed during the trial (Table 1 and Table 2). Any polyps found during colonoscopies 
must be removed, and the histology documented in the source documents and eCRF. 
In Germany, only a colonoscopy or MR enterography (not colonography) can be 
performed.
New Malignancies
For any subject with a malignancy identified during the trial, a thorough MH will be taken 
and documented (e.g., smoking history for lung cancer). Information on type of 
malignancy, histological type, and grading will be collected. The IMP treatment will be 
discontinued, and the subject will be closely followed up by the Investigator (subjects 
must be treated and followed up as per local guidelines and practices for those 
malignancies). 
Systemic Hypersensitivity
Hypersensitivity and anaphylaxis (narrow SMQs) will be collected as AESIs.
6.2.3 Assessment of Causality
Both the Investigator and Sponsor will assess the causality of the event in relation to the 
IMP, based on the criteria listed in the International Council on Harmonisation ICH 
E6(R2) guidelines [ICH E6 (R2), 2016]. 
Investigators must also systematically assess the causal relationship of AEs to 
IMP(s)/trial treatment (including any other non-IMPs, radiation therapy, etc.) using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE 
to the IMP include, but may not be limited to, temporal relationship between the AE and 
the IMP, known side effects of IMP, MH, concomitant medication, course of the 
underlying disease, and trial procedures.

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Table 9: Assessment of Causality of Adverse Events
Assessment of Causality
Definitely
Probably
Possibly
Unlikely
Unrelated
Clearly due to 
extraneous causes
N
N
N
N
Y
Reasonable temporal 
association with drug 
administration
Y
Y
Y/N
N
N
May be produced by 
subject clinical state, 
etc.
N
N
Y
Y
Y
Known response pattern 
to IMP
Y/N
Y/N
N
N
N
Disappears or 
decreases on cessation 
or reduction in dose
Y
Y/N
N
N
N
Reappears on re-
challenge (if possible)
Y
N
N
N
N
IMP=investigational medicinal product; Y=yes; N=no
Not related: Not reasonably related to the IMP. The AE could not medically 
(pharmacologically/clinically) be attributed to the IMP under trial in this clinical trial 
protocol. A reasonable alternative explanation must be available. Adverse events 
reported as “unlikely” related and “unrelated” will be considered unrelated for reporting 
purposes.
Related: Reasonably related to the IMP. The AE could medically (pharmacologically/ 
clinically) be attributed to the IMP under trial in this clinical trial protocol. Table 9 can be 
used to differentiate between the AEs related to the IMP. Adverse events reported as 
definitely, probably, and possibly related will be considered as “related” for reporting 
purposes.
6.2.4 Unexpected Adverse Drug Reaction
An “unexpected” adverse drug reaction is an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information (e.g., Investigator’s 
Brochure for drugs that are not yet approved and Product Information for approved 
drugs, respectively) [ICH E2A, 1995].
6.2.5 Suspected Unexpected Serious Adverse Reactions
The Sponsor will evaluate any SAE that has been reported regarding seriousness, 
causality, and expectedness. If the event is related to the IMP and is both serious and 
unexpected, it is classified as a suspected unexpected serious adverse reaction 
(SUSAR). 
6.2.6 Assessment of Severity
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the National Cancer Institute (NCI)–CTCAE [NCI-CTCAE, 
2017], version 5 (publication date: 27 November 2017), a descriptive terminology that 
can be used for AE reporting.

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A general grading (severity/intensity; hereafter referred to as severity) scale is provided 
at the beginning of the above referenced document, and specific event grades are also 
provided.
If a particular AE’s severity is not specifically graded by the guidance document, the 
Investigator is to use the general NCI-CTCAE definitions of Grade 1 through to Grade 5 
following his or her best medical judgment [NCI-CTCAE, 2017].
The five general grades are:
Grade 1 or Mild
Grade 2 or Moderate
Grade 3 or Severe
Grade 4 or Life-threatening
Grade 5 or Death
6.3
Reporting of Serious Adverse Events and Other Safety Related Events 
6.3.1 Reporting of Adverse Events
All AEs must be reported to the CRO and/or Sponsor through the eCRF for all eligible 
subjects and within the data entry timeline defined for this trial and stipulated in the site 
agreement.
6.3.2 Reporting of Serious Adverse Events
This trial will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting) [ICH E2A, 1995].
All SAEs must be reported on both the clinical and safety databases immediately and 
within a maximum of 24 hours to the CRO and/or Sponsor of the trial through the 
eCRF. 
All SAEs occurring after signing of informed consent up to EOT must be reported on AE
pages in the eCRF or on an SAE form (if the eCRF is not available), regardless of the 
Investigator-attributed causal relationship with trial medication or trial-mandated 
procedures.
The CRO/Sponsor will re-evaluate the SAE and queries will be raised in the eCRF and 
returned to the site, requesting clarification or follow-up information if needed. After the 
initial SAE report, the Investigator is required, proactively, to provide further information 
regarding the subject’s condition. All follow-up information for other SAEs must be 
entered into the eCRF as soon as possible, within 24 hours after it becomes available. 
In case eCRF access is not possible, the Investigator must contact the Clinical 
Research Associate (CRA) in charge of the site and/or the medical person allocated to 
the site (contact names are available in the ISF).
Serious AEs resulting in death will be reported to the Independent Ethics Committee 
(IEC) within 7 days or sooner based on local regulations.
The minimum data required for a report is: 
Subject identification (ID)
Trial code/protocol number
Description of SAE or SAE term
Assessment of causality relationship to IMP

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Name and contact details of person reporting the event
6.3.3 Reporting of Suspected, Unexpected, Serious Adverse Reactions
A SUSAR for an event that is life-threatening or fatal needs to be reported to the 
IEC/Institutional Review Board (IRB) (local event via local Investigator) and competent 
authorities (CAs) within 7 calendar days. 
All other SUSARs need to be reported to the IEC/IRB (local event via local Investigator) 
and CAs within 15 calendar days. 
As necessary, the Sponsor must inform the iSRC and all Investigators, IEC/IRBs, and 
CAs participating in the clinical trial of the occurrence of a SUSAR. 
6.3.4 Reporting of Safety Signals
All suspected new risks and relevant new aspects of known adverse reactions that 
require safety-related measures, i.e., so-called safety signals, must be reported to the 
Sponsor within 24 hours. The Sponsor must report the safety signals within 7 days to 
the IEC/IRB (local event via local Investigator) and CAs. 
The Sponsor must immediately inform all participating Investigators about all safety 
signals. The other IECs/IRBs and CAs involved in the trial will be informed about safety 
signals by the Sponsor as necessary.
6.3.5 Reporting and Handling of Pregnancies
Pregnant subjects must immediately be withdrawn from the clinical trial. Any pregnancy, 
in a female subject or female partner of a male subject, identified during the treatment 
phase of the trial and within 90 days after discontinuation of trial medication must be 
reported to the Sponsor within 24 hours (in the case of a female partner of a male 
subject this will be within 24 hours after obtaining written informed consent from the 
pregnant woman). The course and endpoint of the pregnancy should be followed up 
carefully, and any abnormal endpoint regarding the mother or the child should be 
documented and reported.
A female subject must be instructed to stop taking the IMP and immediately inform the 
Investigator if she becomes pregnant. The Investigator will make arrangements for the 
subject and/or partner to be seen by a specialist who can discuss any risks of 
continuing with the pregnancy. Monitoring of the subject and the child should continue 
until 4 weeks after the outcome of the pregnancy is known.
6.3.6 Periodic Reporting of Safety
An annual safety report will be submitted once a year to the local IEC/IRB via the local 
Investigator and to CAs via the Sponsor or CRO.
6.4
Follow-up of Serious Adverse Events
Serious AEs should be followed until resolution or stabilization. Subjects with ongoing 
SAEs at trial termination (including safety visit) will be further followed up until recovery, 
return to baseline status, or stabilization. If after follow-up, return to baseline status or 
stabilization cannot be established, an explanation should be recorded on the eCRF 
SAE form.

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6.5
Abnormal Laboratory Findings and Other Abnormal Investigational 
Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, 
on an ECG trace) should not be reported as AEs unless they are associated with clinical 
signs and symptoms, lead to treatment discontinuation, or are considered otherwise 
clinically significant by the Investigator. If a laboratory abnormality fulfills these criteria, 
the identified medical condition must be reported as the AE rather than the abnormal 
value itself. 
Elevations (or new elevations from baseline) in transaminases or tests of liver function 
will be closely monitored. Laboratory tests (AST, ALT, alkaline phosphatase, gamma 
glutamyl transaminase, total bilirubin, viral serologies) will be used to distinguish other 
causes of liver injury from drug-induced liver injury. Subjects with persistent or new 
deterioration of hepatic function will be followed up.
6.6
Trial Specific Safety Considerations
6.6.1 Overdose
Details of overdose of apraglutide or any concomitant therapy must be recorded in the 
eCRF and on the dedicated paper form to be included into the Safety Database. Any 
overdose that is considered by the Investigator to be clinically significant must be 
reported as an SAE in the eCRF.
6.6.2 Considerations on Investigational Medicinal Product Dose 
Reduction and Temporary Discontinuation 
If the Investigator reduces the dose of the IMP because of documented safety reasons, 
the safety reasons should be documented as an AE. 
Reduction of IMP means reducing the dose by one step (see Table 5) or pausing in 
case of general tolerability issues. The IMP dose can only be reduced by one step 
during the trial. 
For specific dose adjustments of apraglutide in cases of abnormal liver function tests, 
bilirubin, or other clinical chemical parameters, refer to Section 4.2. The Investigator 
should attempt to return to the per protocol dose as soon as the medical 
condition of the subject allows and a new weekly schedule of IMP administration 
may be established. If the subject does not continue to tolerate the per protocol dose 
the Investigator may choose to resume IMP administration at the weekly lower dose. 
Changes and discontinuations must be reported to the CRA in charge of the site and 
discussed with the Medical Monitor. If the subject’s medical condition allows, this 
discussion may occur before any dose change/discontinuation but must occur after if 
not possible (e.g., an AE necessitating an immediate stop to dosing with apraglutide). 
The final decision to reduce or discontinue IMP rests with the Investigator.
Dose changes and the rationale will be documented in the medical records, and in the 
eCRF. Missed doses (scheduled doses that have not been taken) will not be made up 
for, i.e., the treatment period will not be prolonged due to temporary discontinuation. 
Missed doses should be reported as a protocol deviation.
6.6.3 Trial Holding/Stopping Criteria 
The trial will be placed on hold (i.e. screening or randomization of new subjects and 
treatment of existing subjects should be interrupted) if, during the first 182 days after the 
start of apraglutide treatment, a subject experiences:

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Emergence of a new GI or hepatobiliary cancer
or
Undergo major surgical intestinal resection due to a proliferative intestinal 
phenomenon
Subsequently, an ad-hoc iSRC will review the data and make a recommendation to 
either continue or stop the trial.
The following toxicity events have been identified for monitoring:
Apraglutide-related (definitely, probably, possibly) deaths 
Grades 3–4 apraglutide-related (definitely, probably, possibly) organ toxicities
Any apraglutide or/and RUX administration stop or hold due to elevation of 
ALT/AST and/or bilirubin as defined in Section 4.2.1.2 and Section 4.2.2.1
(confirmed Hy’s law cases) 
These events will be monitored in accordance with the Toxicity Guidance Rule outlined 
in Table 10. If the Guidance Rule is met, this will trigger an iSRC review to re-evaluate 
the benefit risk of apraglutide and thus make recommendations on the further conduct 
of the trial as necessary and appropriate. During a triggered iSRC review, apraglutide 
dosing to existing subjects, and the screening/randomization of new subjects into the 
trial, will be suspended until the iSRC has concluded their review.
Table 10: Toxicity Guidance Rule
Number of subjects 
randomized
Number of observed toxicity events triggering 
iSRC meeting
1–6
7–12
13–15
16–21
22–24
25–27
28–30
iSRC=independent safety review committee

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7
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
7.1
General Considerations
All continuous efficacy data will be summarized descriptively by dose group and time 
point including changes from baseline (n, arithmetic mean, standard deviation, 
minimum, lower quartile [Q25], median, upper quartile [Q75], and maximum). 
Categorical variables will be summarized with frequencies and percentages by 
treatment group and time point. 
From an efficacy perspective, the overall statistical aim of the trial is geared toward 
estimation. Thus, efficacy data collected on both the low and high doses will be 
compared to external data on BAT where possible using Bayesian methods to provide 
insight into the likelihood of efficacy vis-à-vis BAT. In this sense, statistical analysis will 
not focus upon p-value generation but rather estimation and quantification of 
uncertainty. 
A SAP will be prepared and finalized prior to the final analysis. The SAP will detail the 
implementation of the planned statistical analyses in accordance with the principal 
features stated in the protocol, and will provide full details of the analyses, data 
displays, and algorithms to be used for data derivation. 
The final analysis will be done in two steps. The primary analysis of safety and efficacy 
will be performed once all subjects have either completed Day 91 or withdrawn from the 
trial. Additional analyses will be done once all the subjects have either completed the 
EOT visit or withdrawn from the trial. A CTR will be issued after the primary analysis. An 
addendum to the CTR will cover the follow-up period until 2 years after the first 
apraglutide dose.
7.2
Interim analysis
An interim analysis will be performed when 17 subjects have either reached Day 56 or 
withdrawn from the trial. All available data points by the data cut-off date will be included 
in the analysis. This interim analysis does not represent a typical interim analysis with 
testing of hypotheses and alpha spend. 
7.3
Missing, Unused, and Spurious Data
Strategies for handling missing, unused, or spurious data will be specified in the SAP.
7.4
Determination of Sample Size
The principal statistical goal of this trial from an efficacy perspective is to estimate the 
likelihood of efficacy of apraglutide therapy in the treatment of subjects with SR lower 
GI-aGVHD after alloSCT. Published, randomized control trial data on BAT in the 
treatment of such subjects [Zeiser, 2020a] provides estimates of overall response rate 
at Day 28 of 62% (96/154) and durable overall response at Day 56 of 40% (61/154). 
Further, the GI-aGVHD response rate at Day 28 of 57% (55/96) is also published 
Zeiser, 2020b]. At the time of trial initiation, this was considered the best matched 
information available for a reasonable sample size determination.
Assuming same degree of decline of GI response from Day 28 to Day 56 as observed 
for an overall response from Day 28 to Day 56, the GI response at Day 56 can be 
estimated as 36% (r=35 responses in n=96 subjects). These data provide a reliable 
-
r+1)=Beta(36,62).”

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In the current trial, it is planned to randomize 30 subjects on a 1:1 basis to high or low 
dose apraglutide. Assuming a non-informative prior for the Day 56 GI response rate with 
apraglutide, 15 subjects per dose will provide a posterior distribution for the true 
-s+1) where s is the 
observed number of successes on any given dose. Using the prior for BAT response, 
-
Considering a penalty on the original assumptions that are based on Day 56 durable 
overall response instead of Day 56 response, one can still detect an effect of 
apraglutide over BAT.
At least five out of seven responders at the interim analysis will be able to detect a 
signal of apraglutide at least 10% greater than the Day 56 durable overall response with 
a probability of 88.2%. 
In case of a sufficiently large response rate in a single treatment arm, the planned 
sample size will allow for reliable conclusions regarding the effectiveness of apraglutide 
relative to BAT for Day 56 response rate in the treatment of subjects with SR lower GI-
aGVHD after alloSCT. Considering a penalty on the original assumptions, we can still 
detect an effect of apraglutide over BAT.
In addition to the N=30 subjects randomized to receive low or high doses of apraglutide 
once weekly for 26 weeks, a separate, non-randomized cohort of up to four subjects 
with body weights ranging from 40.0 to <50.0 kg will be assigned to receive 2.5 mg 
apraglutide (LBW dose). 
7.5
Definition of Analysis Sets
7.5.1 Full Analysis Set
The Full Analysis Set (FAS) comprises all enrolled subjects (randomized and non-
randomized LBWs). All efficacy evaluations will be conducted using the FAS according 
to the planned dose (high dose, low dose, LBW dose) and in total. All subjects will be 
analyzed according to the apraglutide dose assigned by randomization. 
7.5.2 Low Body Weight Analysis Set
The LBW Analysis Set comprises a separate, non-randomized cohort of up to 
four subjects with body weights ranging from 40.0 to <50.0 kg assigned to receive 
2.5 mg apraglutide (LBW dose) who receive at least one dose of therapy and who 
provide at least one post-baseline assessment for any secondary endpoint. 
7.5.3 Safety Analysis Set 1
The Safety Analysis Set (SAS) 1 (SAS1) comprises all randomized subjects exposed to 
both apraglutide dose levels. All principal safety analyses of subjects randomized low or 
high doses of apraglutide will be carried out on the SAS1. Subjects are analyzed 
according to the dose of apraglutide received.
7.5.4 Safety Analysis Set 2
The SAS2 comprises all randomized and non-randomized subjects exposed to both 
apraglutide dose levels. Supportive safety analyses will be carried out on the SAS2. 
Subjects are analyzed according to the dose of apraglutide received.

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7.6
Statistical Evaluation of Safety
Safety data will be summarized by randomized dose separately and combined for both 
SAS1 and SAS2. Safety data on apraglutide 2.5 mg in the non-randomized LBW 
Analysis Set will be listed and presented separately. Safety assessments include AE 
reporting, vital signs, 12-lead ECG, clinical laboratory evaluations, and physical 
examinations.
7.6.1 Adverse Events
All AESIs, treatment-emergent AEs (TEAEs), SAEs, AEs leading to discontinuation, 
AEs leading to death and laboratory abnormalities will be summarized by apraglutide 
dose received. Adverse event data will be coded using the latest version of MedDRA. A 
definition of TEAEs will be presented in the SAP. Treatment-emergent AEs will be 
summarized descriptively by apraglutide dose received, and by the frequency of 
subjects experiencing events corresponding to body systems and MedDRA PT. 
Subjects with multiple occurrences of events will only be counted once at the maximum 
severity/grade to trial therapy for each PT, SOC, and overall. Should the majority of 
subjects experience multiple occurrences of the same event type, individual event rates 
of these events will be evaluated. 
A summary table will be presented for each of the following AE categorizations in terms 
of the number and percentage of subjects experiencing AEs by SOC and PT:
All TEAEs
Serious TEAEs
Treatment-emergent AEs by severity (mild/moderate/severe)
Treatment-emergent AEs leading to withdrawal from the trial
Treatment-emergent AEs leading to discontinuation of randomized treatment
Treatment-emergent AEs leading to death
Furthermore, AEs will be summarized by causality and the maximum intensity. Any 
SAEs and/or AEs that led to withdrawal will be listed. All AEs will also be summarized 
by relatedness to apraglutide therapy. Adverse events that are reported as possibly, 
probably, or definitely related to apraglutide therapy will be counted as related to trial 
therapy. Adverse events with a missing relationship will be considered as “related” for 
this summary.
The SAP will provide detailed descriptions for the analysis of other AE information, such 
as duration, action taken, and clinical outcome. 
7.6.2 Adverse Events of Special Interest
The individual and cumulative incidence of the following groupings AESIs will be 
summarized by dose:
Injection site reactions 
Gastrointestinal obstructions 
Gallbladder, biliary, and pancreatic disease 
Fluid overload
Colorectal polyps
New malignancy
Systemic hypersensitivity

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The specific AE PTs falling into each of these groupings will be determined prior to 
randomization of the first subject and will be captured in the SAP.
7.6.3 Laboratory Results
Hematology and chemistry laboratory data will be summarized by apraglutide dose 
received. Clinical Laboratory evaluation results will be listed and compared to laboratory 
reference ranges, with those values outside of the applicable range flagged as high or 
low. Shift tables will be provided to examine the distribution of changed pre/post receipt 
of apraglutide therapy. Quantitative laboratory data will be summarized using 
descriptive statistics (n, arithmetic mean, median, minimum, and maximum) for each 
parameter by dose and time. 
7.6.4 Vital Signs
Each vital sign and respective change from baseline will be summarized over time by 
apraglutide dose received. Subjects with clinically significant abnormalities in vital signs 
as compared to baseline will be listed.
7.6.5 Physical Examination
A summary table for the shift from pre-/post-trial therapy received in physical 
examination will be summarized over time by apraglutide dose. 
7.6.6 Twelve-Lead Electrocardiogram
The ECG data will be summarized by apraglutide dose received over time using 
descriptive statistics for change-from-baseline values and categorical outliers. Any 
clinically significant changes will be recorded as AEs.
7.6.7 Anti-Drug Antibodies
All immunogenicity analyses will be descriptive and carried out with a special focus on 
neutralizing antibodies, and treatment-induced or treatment-boosted ADA. Impact on 
PK, PD, and safety will be described.
7.7
Pharmacokinetic Statistical Analysis
Apraglutide individual subject concentrations will be summarized in the FAS and the 
LBW Analysis Set. The PK parameters will be obtained as post-hoc estimates based on 
the population PK/PD analysis developed by Lyo-X. They will be reported in a dedicated 
separate report.
7.7.1 Population Pharmacokinetic Analysis
Apraglutide PK parameters: absorption rate constant (ka), apparent clearance (CL/F), 
and apparent volume of distribution (Vz/F) of apraglutide, with their intra- and inter-
individual variability in the subject population, will be derived by population PK data 
analysis using a nonlinear mixed effects modeling approach, based on sparse sampling. 
These parameters will be reported in a dedicated separate report. 
Trough plasma concentrations (Ctrough) will be collected before dosing at Weeks 1, 2, 3, 
4, 6, and 8. At Week 0 and Week 4 (or if not possible at Week 4, then samples should 
be collected at Week 5 or Week 6 or Week 7 or Week 8), samples will be collected at 
6, 30, 72, 120, and 168 hours post-dose. Samples will have to be taken within ±2 hours 
window, except for the 6-hour post-dose sample where samples will have to be taken 
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For every subject, visual inspection of the actual concentrations of apraglutide will be 
compared with a simulated PK profile based on a PK model developed on healthy 
volunteers and SBS patients’ data from Phase I and II clinical studies. The simulated PK 
profile will be constructed based on the dose received and the subject’s body weight. 
This will be performed online for every subject, and this will be used to check if the 
subject is correctly exposed to apraglutide.
7.8
Statistical Evaluation of Efficacy
In general, efficacy data will be summarized by randomized dose separately and 
combined in the FAS. Efficacy data on apraglutide 2.5 mg in the non-randomized LBW 
Analysis Set will be listed and presented separately.
7.8.1 Lower GI-aGVHD Response at Day 56
Overall response rate (PR and CR) at Day 56 on the lower GI tract MAGIC score was 
used for sample size estimation. It will be summarized descriptively and analyzed 
formally using Bayesian methods.
and i will be based on 
the best matched historical control available at the time of analysis. The true response 
-r+1), where n is the number of 
subjects treated with BAT and r is the number of successes observed in the historical 
control. Assuming a non-informative prior for the Day 56 lower GI response rate with 
-s+1) where m is the number of subjects randomized 
to the 5 mg dose and s is the number of successes observed on this dose. A similar 
formulation applies to the 10 mg dose and for the two doses combined. 
tributions and the 
5th and 95th percentiles will provide the associated 90% credible intervals. The 
-
be taken as the difference in mean response rates. The associated 90% credible 
interval will be computed by sampling 100,000 pairs of random deviates from the 
respective Beta distributions, taking the difference of each pair (apraglutide – BAT) and 
extracting the 5th and 95th centiles of the resulting empirical distribution of the 
differences. Similarly, the probability that the true response rate is higher with 
apraglutide than with BAT will be taken as the fraction of differences greater than zero.
Day 56 lower GI response will also be summarized descriptively in the LBW Analysis 
Set using the Beta distribution. The response rate and associated 95% credible interval 
will be estimated and presented. 
Subjects with missing data such that the Day 56 lower GI response cannot be 
determined will be included in the preceding analysis as non-responders consistent with 
intent to treat philosophy. A sensitivity analysis will also be performed based only on 
those subjects with non-missing data being consistent with a missing at random 
assumption.
To evaluate the robustness of the analysis of the Day 56 secondary endpoint, sensitivity 
analyses evaluating alternative response definitions taking account for the potential 
influence of intercurrent events like increase in steroids, development of infectious 
colitis, relapse, and the use of budesonide or other non-absorbable steroids will be 
made. Details of these analyses will be outlined in the SAP.

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7.8.2 Other Secondary Endpoints
Secondary endpoints will be summarized descriptively in the FAS. These endpoints are 
listed in Section 1.5.2.2.
Secondary endpoints assessed as binary responses will be summarized and analyzed 
in the same fashion as outlined above; if prior data for BAT are not available for a given 
time point, then only the apraglutide data will be presented. 
Subjects with missing data such that response cannot be determined will be included in 
the analyses as non-responders. Again, supportive analyses of the secondary 
endpoints will be performed based only on those subjects with non-missing secondary 
endpoint data consistent with a missing at random assumption. 
Secondary endpoints assessed as time-to-event endpoints will be summarized using 
Kaplan-Meier analysis. The median time duration of response will be presented where 
possible, along with the range and the associated 90% confidence interval. For 
comparison to BAT where prior data exist on duration of response, the distribution 
duration of response will be modelled via the inverse gamma distribution and thus 
compared on a Bayesian basis.
Where there are competing risks, time to event data will also be summarized using 
cumulative incidence. For endpoints like graft failure and NRM, subjects who die prior to 
reaching either endpoint will be right censored at the time of death. For comparison to 
BAT where prior data exist, for example for FFS, the distribution of mean time to event 
will be modelled via the inverse gamma distribution and thus compared on a Bayesian 
basis. Similarly, the distribution of event rates will be modelled via a gamma distribution 
and compared on a Bayesian basis.
Further details of these analyses will be outlined in the SAP.
7.8.3 Exploratory Endpoints
Exploratory endpoints will be summarized descriptively in the FAS; full details will be 
provided in the SAP. These endpoints are outlined in Section 1.5.2.3.
7.9
Reporting Deviations from the Statistical Plan
Any deviations from the original statistical plan will be reported in the CTR with a 
rationale for the deviation.

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8
INDEPENDENT SAFETY REVIEW COMMITTEE
Intensive safety monitoring will occur during the dosing of the first six subjects who 
approximately every 4 weeks to review all available data and assess safety and 
tolerability. The iSRC may receive periodic updates between these planned meetings 
for continued monitoring and assessment if more frequent monitoring by the iSRC is 
required. These reviews will continue until the sixth subject has completed Day 56, at 
which 
randomized to the two treatment arms. Randomization of these additional subjects can 
occur while iSRC monitoring is ongoing. Safety data from subjects <50.0 kg will also be 
evaluated by the iSRC as they are enrolled and being treated.
Assuming no issues are identified in the iSRC reviews of the initial six subjects, 
subsequent iSRC reviews are anticipated to occur when approximately 14, 22, and 
30 subjects have completed Day 56 or withdrawn from the trial, whichever comes first. 
Details on the composition, conduct, tasks, and responsibilities of the iSRC will be 
described in a separate iSRC charter.

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9
TRIAL CONDUCT
Written approval will be obtained from the IEC/IRB/CA concerning the conduct of the 
trial by the Sponsor before the trial commences. The clinical trial can only begin once 
approval from all required authorities has been received. 
Steps to ensure the accuracy and reliability of data include the selection of qualified
Investigators and appropriate trial sites, review, and training of protocol procedures with 
the Investigator and associated personnel before the trial, periodic monitoring visits, and 
thorough data management review.
9.1
Ethical Conduct of the Trial
This clinical trial will be conducted in compliance with this protocol and with the 
following:
The ethical principles stated in the locally valid version of the Declaration of Helsinki
All applicable laws and regulations of the country where the trial is conducted
Applicable Good Clinical Practice (GCP) Guidelines (April 1996 ICH Guidance for 
Industry E6 GCP (including archiving of essential trial documents) and the 
Integrated Addendum to ICH E6(R2)
The US FDA guidelines along with applicable laws and regulations including the 
FDA GCP Code of Federal Regulations (CFR) Title 21 [21 CFR]
Clinical trial regulatory framework in the EU
Any update to these regulations which occur during the conduct of the trial
9.2
Sponsor and Investigator Responsibilities
This trial will be conducted under a Clinical Trial Agreement between VectivBio 
(“Sponsor”) and the institution(s) representing the investigational trial site(s) 
(“Authority”). Financial support to the investigational site(s) will be detailed in the Clinical 
Trial Agreement. The Clinical Trial Agreement must be signed before the 
commencement of the trial and will clearly delineate the responsibilities and obligations 
of Investigator and VectivBio (“Sponsor”) and will form the contractual basis under 
which the clinical trial will be conducted.
The Sponsor is obligated to conduct the trial in accordance with strict ethical principles 
(Section 9.1). The Sponsor reserves the right to withdraw a subject from the trial 
(Section 2.2.6), to terminate participation of a trial site at any time, and/or to discontinue 
the trial early (Section 2.3).
The Sponsor agrees to provide the Investigator with sufficient material and support to 
permit the Investigator to conduct the trial according to the trial protocol.
By signing the Investigator Signature Page (found at the start of this protocol), the 
Investigator indicates that he or she has read the protocol carefully, fully understands 
the requirements and agrees to conduct the trial in accordance with the procedures and 
requirements described in this protocol.
The Investigator also agrees to conduct this trial in accordance with the laws, 
regulations, and guidelines outlined in Section 9.1. While delegation of certain aspects 
of the trial to sub-Investigators and trial coordinators is appropriate, the Investigator will 
remain personally accountable for overseeing the trial closely and for ensuring 
compliance with the protocol and all applicable regulations and guidelines. The 
Investigator is responsible for maintaining a list of all persons that are/have been 

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delegated trial-related responsibilities (e.g., sub-Investigators and trial coordinators) and 
their specific trial-related duties.
9.2.1 Ethical Considerations
Before trial initiation, this protocol, the proposed subject information and ICF, as well as 
other documents required by current regulations will be submitted to an IEC/IRB 
responsible for providing approval for the site. 
A signed and dated statement that this protocol and the ICF have been approved by the 
IEC/IRB must be filed in the ISF and the Trial Master File. In accordance with GCP and 
applicable regulatory requirements, the trial will not start at a site before receival of the 
respective IEC/IRB approval that must be signed and dated. 
Investigators are responsible for promptly informing the IEC/IRB and the authorities of 
all protocol amendments, serious adverse reactions, and SUSARs occurring during the 
trial that are likely to affect the safety of the subjects or the conduct of the trial. 
Information on pregnancies occurring during the trial and pregnancy outcomes 
qualifying as serious are also to be reported to the IEC/IRB. In the case that a 
vulnerable subject enters the trial, the Investigator is encouraged to consult their local 
IEC/IRB for guidance.
The protocol may not be modified without written approval from the Sponsor. Protocol 
modifications or changes may not be initiated without prior written IEC/IRB/CA approval 
except when necessary to eliminate immediate hazards to the subjects or when the 
change(s) involves only logistical or administrative aspects of the trial. Such 
modifications will be submitted to the IEC/IRB and written verification that the 
modification was submitted should be obtained, as per local regulations.
Substantial Amendments are those considered ‘substantial’ to the conduct of the clinical 
trial and are likely to have a significant impact on e.g., the safety or physical or mental 
integrity of the subjects, the scientific value of the trial, the conduct or management of 
the trial or the quality or safety of the IMP used in the trial. Documentation of IEC/IRB 
approval must be sent to the Sponsor immediately upon receipt.
The constitution of the IEC/IRB must meet the requirements of the participating 
countries and ICH E6(R2). A list of the IEC/IRB members with names and qualifications 
plus a statement that it is organized according to ICH-GCP (R2) and the applicable laws 
must be provided to the Investigator and to the CRO for filing and archiving as per 
applicable local law.
9.2.2 Investigator Delegation Responsibilities
While delegation of certain aspects of the trial is appropriate, the Investigator will remain 
personally accountable for overseeing the trial closely and for ensuring compliance with 
the protocol and all applicable regulations and guidelines. The Investigator is 
responsible for maintaining a list of all persons that are and/or have been delegated 
trial-related responsibilities (e.g., sub-Investigators and trial coordinators) and their 
specific trial-related duties.
If the Investigator will delegate all trial site related medical decisions to another qualified 
physician, their contact information will be available in the Site File.
Investigators should ensure that all persons who are delegated trial-related 
responsibilities are adequately qualified and informed about the protocol and their 
specific duties within the context of the trial. Investigators are responsible for providing 
the Sponsor with documentation of the qualifications, GCP training, and research 

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experience for themselves and their staff as required by the Sponsor and IEC/IRB/CA. 
The Investigators are responsible for keeping an up-to-date ISF, which includes all 
required and relevant trial documents. 
9.2.3 Competent Authorities and Regulatory Considerations
The clinical trial protocol and related documents will need CA approval or notification, as 
required by local regulations and requirements prior to the initiation of the trial, i.e., 
screening or enrollment/randomization of a subject. No changes will be made to the 
protocol or related documents without prior approval by the CA, except for 
non-substantial amendments which may be implemented with notification only. Annual 
reporting will be done, and early or planned trial end as well as the CTR will be 
submitted to the CA as required within the appropriate timeframe (e.g., early termination 
of the trial within 15 days and CTR within 1 year after last subject’s last visit, 
respectively).
9.2.4 Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information, as requested, to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate 
CA/IECs/IRBs. Investigators are responsible for providing information on financial 
interests during the trial and for 1 year after completion of the trial or for a longer period 
of time if required by local legislation.
9.2.5 Subject Information and Informed Consent 
The Investigators will explain to each subject the nature of the trial, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits, and any 
discomfort it may entail. Each subject will be informed that their participation in the trial 
is voluntary and that he/she may withdraw from the trial at any time and that withdrawal 
of consent will not affect his/her subsequent medical assistance and treatment. 
The subject must be informed that his/her medical records may be examined by 
authorized individuals other than their treating physician.
All subjects for the trial will be provided a subject information sheet and a consent form 
(this will be in the form of a paper ICF or an electronic consent form) describing the trial 
and providing sufficient information for subject to make an informed decision about their 
participation in the trial. Enough time needs to be given to the subject to ask questions 
and to decide whether to participate or not. 
The formal consent process with a subject, using the current approved consent form, 
must be obtained before any trial specific procedures are conducted on the subject. 
The written informed consent and assent documents should be prepared in the 
language(s) of the potential subject population, based on an English version provided 
by the Sponsor and should be easy to understand. Before a minor subject’s 
participation in the trial, the Investigator is responsible for obtaining written informed 
consent from the parent or legal guardian and, in cases where institutional guidelines 
and the subject’s age dictate, informed assent from the subject, after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the trial 
and before any protocol specific screening procedures or any trial drugs are 
administered. Sufficient time must be given to consider whether to participate in the trial. 
The acquisition of informed consent/assent and the parent/legal guardian’s/subject’s 
agreement or refusal should be documented in the subject’s medical records, and the 

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informed consent/assent form(s) should be signed and personally dated by the 
parent/legal guardian/subject and by the trial person who conducted the informed 
consent/assent discussion. In general, permission should be obtained from both parents 
before a minor is enrolled. Permission must be obtained from both parents, unless one 
parent is deceased, unknown, incompetent, or not reasonably available, or when only 
one parent has legal responsibility for the care and custody of the child. The original 
signed informed consent/assent form(s) should be retained in the ISF and in any other 
locations required by institutional policy, and a copy of the signed consent/assent 
form(s) should be provided to the parent or guardian.
The subject should read and consider the statement before signing and dating the ICF 
that meets the requirements of 21 CFR Part 50 [21 CFR], local regulations, ICH 
guidelines, requirements of the Health Insurance Portability and Accountability Act of 
1996 (HIPAA), where applicable, and the IEC/IRB or trial site requirements, and should 
be given a copy of the signed document. The consent form must also be signed and 
dated by the Investigator (or their designee) at the same time as the subject signs, and 
it will be retained by the Investigator as part of the trial records.
The Investigator must document the informed consent process in the subject’s source 
documents (medical chart). 
In the event of substantial changes to the trial or to the risk-benefit ratio, the Investigator 
will obtain the signed informed consent of subjects for continued participation in the trial 
using an IEC/IRB approved amendment to the ICF.
Subjects who are re-screened will undergo the consenting processes again and sign a 
new ICF prior to the re-screening procedures beginning.
9.2.6 Subject Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this trial must, 
where applicable, comply with HIPAA. A US-based site that is not a Covered Entity as 
defined by HIPAA must provide documentation of this fact to the CRO/the Sponsor.
VectivBio, as Data Controller, ensures that all processing activities involving personal 
data performed in the scope of this trial are compliant with, but not limited to, the 
requirements set by EU General Data Protection Regulation (GDPR 679/2016), its 
subsequent amendments, and any additional national laws on Data Protection, 
recommendations, and guidelines as applicable.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. The subject’s 
confidentiality and privacy are to be strictly held in trust by the participating sites, 
Investigators, their staff, the Sponsor(s) and its designees involved in the trial. This 
confidentiality is extended to testing of biological samples, including biomarker testing, 
and any future testing in addition to the clinical information relating to the subject. The 
subject’s contact information will be securely stored at each clinical site for internal use 
during the trial.
After subjects have consented to take part in the trial, the Sponsor and/or its 
representative will review their medical records and data collected during the trial. 
These records and data may, in addition, be reviewed by others including the following: 
monitors and independent auditors who validate the data on behalf of the Sponsor; third 
parties with whom the Sponsor may develop, register, or market apraglutide; national or 
local regulatory authorities; and the IEC(s)/IRB(s) which gave approval for the trial to 
proceed. The Sponsor and/or its representatives accessing the records and data will 

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take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subject research data, which is for purposes of statistical analysis and scientific 
reporting, will be entered in the eCRF by the trial staff at each site and then transmitted 
to and stored at the Sponsor or its designee. This will not include the subject’s contact 
or identifying information. Rather, individual subjects and their research data will be 
identified by a unique trial identification number (unique identifier). The key between the 
personal data and the unique identifier (subject trial number) will be kept at each clinical 
site and this information will never leave the respective clinical site. The trial data entry 
and trial management systems used by clinical sites will be secured and password 
protected. At the end of the trial, all trial databases will be archived by the Sponsor or its 
designee for a minimal period of 25 years. 
Even though subjects are assigned a unique identifying number; age, sex, and birth 
year may also be collected and used to assist the Sponsor to verify the accuracy of the 
data, for example, to confirm that laboratory results have been assigned to the correct 
subject.
The results of trials—containing subjects’ unique identifying number, relevant medical 
records, and age and birth year—will be recorded. Subject to adequate safeguards, 
they may be transferred to, and used in, other countries that may not afford the same 
level of protection that applies within the countries where this trial is conducted. The 
purpose of any such transfer would include, but not be limited to, to support regulatory 
submissions, to conduct new data analyses to publish or present the trial results, to 
answer questions asked by regulatory or health authorities, or for activities that are 
otherwise connected to the trial.
9.3
Trial Documents
All documentation and materials provided by Sponsor for this trial are to be retained in a 
secure location and treated as confidential material.
9.4
Early Termination of the Trial
The Sponsor may terminate the trial early according to certain circumstances, for 
example:
Ethical concerns
Insufficient subject recruitment
When the safety of the subjects is at risk (refer to both Individual subject stopping 
rules and trial stopping criteria are described in Section 4.2.1.2 and Section 6.6.3, 
respectively)
Alterations in accepted clinical practice that make the continuation of a clinical trial 
unwise 
Early evidence of benefit or harm of the experimental intervention
At the time of early termination of the trial, all subjects (regardless of their response to 
apraglutide) will receive GVHD treatment according to the established local standard of 
care. 

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9.5
Trial Site Closure
At the end of the trial, all trial sites will be closed. Sponsor may terminate participation of 
a trial site at any time. Examples of conditions that may require early termination of a 
trial site include, but are not limited to, the following:
Non-compliance with the protocol and/or applicable regulations and guidelines
Inadequate subject enrollment/randomization
Discontinuation of the trial, as decided by the Sponsor 
Institution and/or Investigator breaches the Clinical Trial Agreement, or the 
agreement is terminated
Trial is not initiated or suspended at the institution for any reason
9.6
Protocol Amendments
The protocol may not be modified without written approval from the Sponsor. Protocol 
modifications or changes may not be initiated without prior written IEC/IRB/CA approval 
except when necessary to eliminate immediate hazards to subjects or when the 
changes involve only logistical or administrative aspects of the trial. Such modifications 
will be submitted to the IECs/IRBs/CA and written verification that the modification was 
submitted should be obtained.
If an amendment to this protocol is required, it will be classified into one of the following 
categories:
Substantial Amendments are those considered “substantial” to the conduct of the 
clinical trial and are likely to have a significant impact on, e.g., the safety or physical 
or mental integrity of the subjects, the scientific value of the trial, the conduct or 
management of the trial or the quality or safety of the IMP used in the trial
Non-substantial Amendments are amendments that are not considered to meet the 
definition of substantial 
Investigators are responsible for promptly informing the IECs/IRBs of any amendments 
(substantial only in the EU) to the protocol. 
Documentation of IEC/IRB/CA approval must be sent to the Sponsor immediately upon 
receipt.
All instances where the requirements of the trial protocol were not complied with will be 
tracked. Corresponding subjects may be withdrawn from the trial at the discretion of the 
Investigator and/or Sponsor. Trial protocol deviations arise when subjects who have 
been entered in the trial deviate from the IEC/IRB-approved trial protocol.
If a major protocol deviation (i.e., a deviation that could have a significant effect on the 
subject’s safety, rights, or welfare and/or on the integrity of the trial data) occurs, the 
Investigator must notify the Sponsor and the appropriate IRB/IEC as soon as possible 
or as per local requirements.
9.7
Contingency Measures
9.7.1 Clinical and Ancillary Supply Provisioning
Subjects will have drug administered exclusively during trial visits (details are described 
in the pharmacy manual).

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10 DATA HANDLING AND RECORD KEEPING/ARCHIVING
10.1 Confidentiality and Access to Source Data
All documentation and materials provided by Sponsor to the investigational site for this 
trial are to be retained in an ISF, which should be stored in a secured location and 
treated as confidential material.
All local legal requirements regarding protection of personal data must be adhered to. 
The trial protocol, documentation, data, and all other information generated during the 
trial will be held in strict confidence. No information concerning the trial, or the data will 
be released to any unauthorized third party without prior written approval of the 
Sponsor. 
10.2 Record Keeping/Archiving
Each clinical site will retain in a secured location, trial records, and documents 
pertaining to the conduct of this trial and the distribution of IMP, including eCRFs, ICFs, 
laboratory test results, and medication inventory records, for at least 25 years after 
completion or discontinuation of the trial, or for the length of time required by relevant 
national or local health authorities, whichever is longer. Additionally, record retention 
may be dependent on the reviewing IRB/IEC, institutional policies, respective country 
legislation, specifications in trial contract, or Sponsor requirements. 
The Sponsor is to be informed about any re-location of documents. After the 25-year 
archiving period, the documents may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of VectivBio. Written 
notification should be provided to VectivBio prior to transferring any records to another 
party or moving them to another location.
10.2.1 Storage of Biological Material and Related Health Data
Pharmacokinetics, ADA, neutralizing antibodies, and citrulline samples will be kept for a 
maximum of 15 years after the completion of the bioanalytical report to use later for 
refinement and optimization of the bioanalytical methods or for additional research 
involving apraglutide, GLP-1/2 biology and gastroenterology to make informed decisions 
as applicable to optimize product use and further development. Future analyses will not 
include any genetic testing but may include additional evaluation of biomarkers related 
to the trial population or antibody responses induced by apraglutide.
Tissue slides and blocks will be kept for a maximum of 3 months after completing the
bioanalytical report. The tissue blocks will be either destroyed or returned to the sites.
No future analysis is planned.
10.3 Case Report Forms 
All subject data relating to the trial will be recorded using an eCRF (conforming to 
21 CFR Part 11 requirements [21 CFR]) unless transmitted to the Sponsor or designee 
electronically (e.g., laboratory data). 
The subjects screened into the trial will be identified in a clinical trial database by a 
subject number. The Investigator or delegate will enter subject data from the source 
documents into the eCRF.
Access to the eCRF is restricted to staff participating in the trial and the extent of access 
will depend on the subjects’ user role in the trial. Following training, the trial staff will be 

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given access to the eCRF and be able to enter data. The eCRF is designed to capture 
all required information in compliance with applicable ICH-GCP standards.
The clinical database will be designed based on the final protocol, system configuration, 
and consistency check specifications. 
A complete electronic audit trail will be maintained.
Medidata Rave will be used as an eCRF.
All eCRF data is to be entered in English. Data recorded in the eCRFs will be 
accessible to the trial staff throughout the trial.
All sections of the eCRF are to be electronically approved by the Investigator or 
designee (i.e., to confirm the accuracy of the data recorded) using an electronic 
signature [21 CFR] after the data has been entered and all queries have been resolved, 
signifying that the data entered in the eCRF is complete and accurate. Any subsequent 
changes to any eCRF page require a new approval signature.
Data Collection
The Investigator or delegate is responsible for ensuring the accuracy, completeness, 
and timeliness of the data reported. A trial monitor will visit each site in accordance with 
the monitoring plan and review the eCRF data against the source data for completeness 
and accuracy. Data entry, corrections, and addressing of discrepancies will be made by 
qualified site personnel. 
Subject screening and randomization data will be completed for all subjects (i.e., eligible 
and non-eligible) through the IRT system and eCRF. 
For each subject enrolled/randomized, regardless of trial medication initiation, an eCRF 
must be completed and signed by the Investigator/delegate. This also applies to those 
subjects who fail to complete the trial. If a subject withdraws from the trial, the reason 
must be reported on the eCRF.
Clinical Data Management
Data are to be entered in the eCRF database in a timely manner of the subject’s visit in 
accordance with the trial specific data management plan and according to the 
agreement between the Sponsor/CRO and the clinical trial site. Quality Control and data 
validation procedures are applied to ensure the validity and accuracy of the clinical data. 
The Investigators will have access to the site eCRF data until the database is locked. 
Thereafter, they will have read-only access until sites receive the subjects’ CRFs in PDF 
format via electronic means.  
The eCRF must be kept current to reflect subject status at any time point during the 
trial.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. While entering the data, the 
Investigator or delegate will be instantly alerted to data queries by validated 
programmed checks. Additional data review will be performed by the Sponsor, by the 
CRA, or other CRO personnel on an ongoing basis to look for unexpected patterns in 
data and for trial monitoring. If discrepant data are detected, a query specifying the 
problem and requesting clarification will be issued and visible to the Investigator or
delegate via the eCRF. All electronic queries visible in the system either require a data 
correction (when applicable) and a response from the Investigator or delegate to clarify 
the queried data directly in the eCRF, or simply a data correction in the eCRF.
This process will continue until database lock.

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The Investigator or delegate must, on request, supply the Sponsor with any required 
background data from the trial documentation or clinical records. This is particularly 
important when errors in data transcription are suspected. In the event of CA queries, it 
is also necessary to have access to the complete trial records, provided that subject 
confidentiality is protected.
All AEs will be coded according to the latest version of MedDRA used by the Sponsor. 
After the database has been declared complete and accurate, the database will be 
locked. Any changes to the database after that time may only be made as described in 
the appropriate CRO Quality System documents. After database lock, the Investigator 
will receive the eCRFs of the subjects of his/her site (including the audit trail) on 
electronic media.
10.4 Specification of Source Documents 
Source documents provide evidence for the existence of the participating subject and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s trial site.
Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents and the discrepancies must be explained. The 
Investigator may need to request medical records from other healthcare professionals, if 
appropriate. Also, current medical records must be available. The use of electronic 
source data is described in FDA Guidance for Industry [FDA, 2013].
All entries into the eCRF performed by site personnel must be verifiable by source 
documents. Additionally, the following data entered in the eCRF should be verifiable by 
source documents in the subject’s medical record, or other records, at the trial site, as 
applicable:
Details of trial participation (Trial ID and unique identifier)
Date(s) of subject’s informed consent 
Date of each trial visit including signature and/or initials of person(s) conducting the 
trial visit
Results of blood tests and other examinations 
Information recorded in the eCRF system should be supported by corresponding source 
documentation, which is attributable, legible, contemporaneous, original, accurate, and 
complete. Changes to source data should be traceable, should not obscure the original 
entry which must remain readable, and should be explained if necessary (e.g., via an 
audit trail). Examples of acceptable source documentation include, but are not limited 
to, hospital records, paper diary, clinic and office charts, laboratory notes, and recorded 
data from automated instruments, and memoranda.
Clinical laboratory data required by the protocol will be electronically transferred from 
the central laboratory. Any other clinical laboratory data received from a local laboratory 
for entry into the eCRF will be considered as source documentation.
Entries into the eCRF will be verified with source documentation by the Monitor for 
which a risk-based approach will be taken. The location of source data for all pertinent 
data will be defined in the relevant source data location form prior to the start of the trial.

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11 QUALITY ASSURANCE AND QUALITY CONTROL 
This trial will be performed in compliance with the Clinical Trial Protocol, the Declaration 
of Helsinki, ICH E6(R2), and applicable regulatory requirements.
The accuracy, consistency, completeness, and reliability of the trial data produced 
under this protocol will be assured through quality assurance and quality control 
activities performed in accordance with the SOPs of the Sponsor or of the Sponsor 
representative (CRO). The Investigator agrees, when signing this protocol, to fully 
cooperate with compliance checks by allowing direct access to all clinical trial-related
documentation by authorized individuals. 
11.1 Audits and Inspections 
The trial may be subject to audit by the Sponsor or its designee, IEC/IRB, and/or CA 
inspections. Audits may be performed to check compliance with ICH E6(R2) guidelines 
and other applicable regulations, and may include:
Site audits
(Electronic) Trial Master File/ISF audits
Database audits
Document audits 
The Sponsor or its designee may conduct additional audits on a selection of trial sites, 
which may require access to subject’s notes/medical records, trial documentation, and 
facilities or laboratories used for the trial.
The trial site, facilities, all data (including source data), and documentation will be made 
available for audit by quality assurance auditors and for IEC/IRB/CA inspections 
according to ICH E6 (R2) guidelines. The Investigator agrees to cooperate with the 
auditor during the visit and will be available to supply the auditor with eCRF or other 
files necessary to conduct that audit. Any findings will be strictly confidential. Serious 
breaches or other significant findings will be reported to Health Authorities and/or Ethics 
Committees/Independent Review Boards as required by applicable laws and 
regulations.
If a CA informs the Investigator that it intends to conduct an inspection, the Investigator 
shall notify the Sponsor immediately.
11.2 Monitoring 
The Sponsor and/or its representatives will conduct on-site monitoring visits to assess 
site qualifications and its appropriateness for inclusion in the trial, at the site initiation 
visit (SIV), and to monitor the trial to ensure compliance with the protocol, GCP, and 
applicable regulations and guidelines. Remote monitoring may be done, if needed. The 
frequency of the monitoring visits will be based on subject recruitment rate, data quality 
performance of site, and critical data-collection times. There will be a Clinical Monitoring 
Plan that will provide details to identify the Monitor of the trial and guidelines for Clinical 
Research Associates concerning how to monitor the trial.
Before trial start, a SIV will be performed after the site is approved for inclusion in the 
trial by the Sponsor and essential approvals and documents are in place. The Principal 
Investigator must ensure that all site personnel involved in the trial are present during 
the SIV and will dedicate time for training. The SIV must be completed before the site 
can begin screening trial subjects. 

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To check compliance and verify the completeness, consistency and accuracy of the 
data being entered in the eCRFs and other protocol-related documents, monitoring
visits will be performed to review source data versus the eCRFs. The assigned monitor 
will visit the Investigator and trial site at periodic intervals and maintain periodic 
communication. The Investigator agrees to allow the Monitor(s) and other authorized 
Sponsor personnel access to trial facilities and all source documents, as and when 
needed. 
The Sponsor’s monitoring standards require full verification that informed consent has 
been provided, verification of adherence to the inclusion/exclusion criteria, 
documentation and proper reporting of SAEs, and the recording of the trial endpoints. 
Additional checks will be performed according to the trial monitoring guidelines. The 
Monitor(s) will maintain knowledge of the trial through observation, review of trial 
records and source documentation, and discussion of the conduct of the trial with the 
Investigator and site staff. 
While on site, the Monitor(s) will review the following documents, and the Investigator 
must ensure these documents are available for review by the Monitor: 
Source documents, in order to directly compare entries in the eCRF with the source 
documents
Consenting procedures and documents
Investigator Site File [ICH E6 (R2)]
Other documentation verifying the activities conducted for the trial
The Monitor will ask for clarification and/or correction of any noted inconsistencies 
(procedures for correcting eCRFs are described in the eCRF completion guideline). The 
Investigator agrees to cooperate with the CRA(s) to ensure that any issues detected 
during these monitoring visits are resolved. As representatives of the Sponsor, monitors 
are responsible for notifying project management of any noted protocol deviations.
In compliance with ICH guidelines, the Investigator, or person designated by the 
Investigator, should document and explain any deviation from the approved protocol. 
The CRA should be informed of all deviations relating to trial inclusion/exclusion criteria, 
conduct of the trial, subject management, or subject assessment and ensure this is 
described and recorded in the relevant pages in the eCRF.
All laboratory data from biomarkers samples and from future analyses of the residuals 
of the biomarker samples will be available only to the Sponsor. 
By signing the Investigator’s Agreement (found at the start of this protocol), the 
Investigator agrees to meet with the Monitor during trial site visits, to ensure that trial 
staff are available to the Monitor as needed; and to provide the Monitor with access to 
all trial documentation as described above, if requested. Further, the Investigator agrees 
to allow the Sponsor to assist inspectors and/or auditors in their duties, if requested. 
A close-out visit will be performed for any initiated site when there are no more active 
subjects and after all follow-up issues have been resolved. If a site does not enroll any 
subjects, the close-out visit may be performed before trial database closure at the 
discretion of the Sponsor.

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12 PUBLICATION AND DISSEMINATION POLICY 
Data will be reported in a CTR in compliance with the requirements of the current 
version of ICH E3: “Structure and Content of Clinical Study Reports” [ICH E3, 1995].  
The CTR will be issued within 12 months after the primary analysis the end of the trial
and distributed as required by local regulations. 
The addendum to the CTR will be completed within 12 months after the end of the trial 
and distributed as required by local regulations. 
A description of this clinical trial is available on clinical trial registries such as 
ClinicalTrials.gov and the EU Clinical Trials Register (www.clinicaltrialsregister.eu). A 
summary of the results, whether positive, negative, or inconclusive, will be published on 
ClinicalTrials.gov and the EU Clinical Trials Database.
The trial results may be published and presented to the public and/or used for 
educational purposes. The Sponsor shall have the sole and exclusive right to the first 
publication of the results of the trial, which is intended to be a multi-center publication of 
the trial results, collected from all Investigators and institutions participating in the trial. 
Information that could identify subjects will not be used in any publication or 
presentation.
All information concerning the Sponsor’s operations, patent applications, basic scientific 
data, and information supplied by the Sponsor or its designee to the Investigator and 
not previously published, is considered confidential and remains the sole property of the 
Sponsor. Electronic Case Report Forms also remain the property of the Sponsor. The 
Investigator agrees to use this information for purposes of trial execution through 
finalization and will not use it for other purposes without the written consent of the 
Sponsor.
The information developed in this trial will be used by the Sponsor in connection with 
the future development of an investigational product and thus may be disclosed as 
required to other clinical Investigators or government regulatory agencies.
The information generated by this trial is the property of the Sponsor who will disclose 
the trial results in accordance with applicable regulatory requirements and laws. Once 
the multi-center publication has been published (or if no such publication has occurred) 
within the time period established in the Clinical Trial Agreement (the “Agreement”) 
since the completion or earlier termination of the trial at all participating sites (including 
the final database lock), the Investigator may publish the results of this trial obtained by 
him/her or otherwise present them at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to the Sponsor within the time 
period established in the Agreement for the Sponsor to provide comments and approval 
before the relevant publication submission deadline. If during this initial review period 
the Sponsor so requests, the Investigator shall delay the publication or presentation for 
an additional time period which allows the Sponsor to protect proprietary information.
Authorship will be determined in line with International Committee of Medical Journal 
Editors authorship requirements.
The publication policy with respect to the Investigator and clinical trial site will be 
detailed further in a separate document (the “Agreement”). In the event of any 
inconsistency between the Agreement and the protocol, the protocol shall prevail for 

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scientific matters and subject care issues, while the Agreement shall prevail for all other 
matters, including the publication and dissemination policy.

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13 INSURANCE 
The Sponsor will cover this trial by means of adequate insurance of the participating 
subjects. This will be in place prior to the start of the trial.
Per local regulations, details about the insurance are described in the subject 
information sheet and ICF. A copy of the insurance certificate is filed in the ISF and the 
subject can request a copy.

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14 FUNDING AND SUPPORT 
A contract/agreement will be made (as appropriate) with the Investigator and/or 
institution. 
The Sponsor will pay the trial sites through the CRO as per the site-signed contract. The 
signed contract details the amount to be paid (including overhead fee, if applicable) to 
cover site staff work in relation to the trial. Furthermore, the signed contract details that 
the Sponsor will reimburse the following expenses for trial subjects: travel expenses, 
meals, subject hotel stay (where relevant). All amounts will be paid to a research bank 
account held by the trial site. Bank account details are specified in the signed contract.
Details on payment to sites and reimbursement payments for subjects are also given in 
the Subject Information Letter and ICF.

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15 REFERENCES 
21 CFR
United States Food and Drug Administration, Code of Federal 
Regulations, Title 21 – Food and Drugs. https://www.ecfr.gov/
Allard, 2021
Allard J, Genestin E, Gondolesi G, et al. A Prospective, Multicenter 
Registry for Patients With Short Bowel Syndrome (SBS Registry): Long-
term Safety Analysis in the Context of Teduglutide Treatment. JPEN J 
Parenter Enteral Nutr. 2021;45:S1. Abstract P26
Apraglutide 
Investigator 
Brochure 
Apraglutide Investigator Brochure, current version
Brooks, 1996
Brooks R. EuroQol: the current state of play. Health Policy. 
1996;37(1):53–72.
Crenn, 2003
Crenn P, Vahedi K, Lavergne-Slove A, Cynober L, Matuchansky C, 
Messing B. Plasma citrulline: A marker of enterocyte mass in villous 
atrophy-associated small bowel disease. Gastroenterology. 
2003;124(5):1210-1219
Declaration of
Helsinki
For rest of the world: Declaration of Helsinki, Version October 2013. 
https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-
principles-for-medical-research-involving-human-subjects/
For USA: Declaration of Helsinki, Version September 1989. 
https://www.wma.net/wp-content/uploads/2018/07/DoH-Sept1989.pdf
EudraLex Vol 4, 
2010
EudraLex. The Rules Governing Medicinal Products in the European 
Union. Volume 4. EU Guidelines to Good Manufacturing Practice, 
Medicinal Products for Human and Veterinary Use, Annex 13. 
Investigational Medicinal Products. 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
4/2009_06_annex13.pdf
EuroQol Group, 
1990
The EuroQol Group. EuroQol-a new facility for the measurement of 
health-related quality of life. Health Policy. 1990;16(3):199–208
FDA, 2013
US Food and Drug Administration. Center for Drug Evaluation and 
Research (CDER). Center for Biologics Evaluation and Research 
(CBER). Guidance for Industry Electronic Source Data in Clinical 
Investigations. September 2013.
https://www.fda.gov/media/85183/download
Gattex® USPI
GATTEX (teduglutide [rDNA origin]), for injection, for subcutaneous use 
Initial U.S. Approval: 2012.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203441Ori
g1s000lbl.pdf; 
GLY-311-2017
Safety, Efficacy, PD of FE203799 in Short Bowel Syndrome on 
Parenteral Support. https://clinicaltrials.gov/ct2/show/NCT03415594
GLY-321-2017
Metabolic Balance Study of FE203799 in Patients With SBS With 
Intestinal Insufficiency. https://clinicaltrials.gov/ct2/show/NCT03408132  
Hargrove, 2020
Hargove DM, Alagarsamy S, Croston G, Laporte R, Qi S, et al. 
Pharmacological Characterization of Apraglutide, a Novel Long-Acting 
Peptidic Glucagon-Like Peptide-2 Agonist for the Treatment of Short 
Bowel Syndrome. J Pharmacol Exp Ther. 2020;373(2):193–203
Harris, 2016
Harris A, Young R, Devine S, et al. International, Multicentre 
Standardization of Acute Graft-Versus-Host Disease Clinical Data 
Collection: A Report from the Mount Sinai Acute GVHD International 

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Consortium. Biol Blood Marrow Transplant. 2016;22:4–10 
Herdman, 2011
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary 
testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life 
Res. 2011;20(10):1727–36.
ICH E3, 1995
International Council for Harmonisation: Structure and Content of 
Clinical Study Reports; 30 November 1995.  
https://database.ich.org/sites/default/files/E3_Guideline.pdf
ICH E6 (R2), 
2016
International Council for Harmonisation: Guideline for Good Clinical 
Practice E6(R2); 09 November 2016. 
https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
ICH E2A, 1995
International Council on Harmonization ICH Topic E2A. Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting. 
01 June 1995.
https://www.ema.europa.eu/en/ich-e2a-clinical-safety-data-
management-definitions-standards-expedited-reporting
Kochar, 2018
Kochar B and Herfarth HH. Teduglutide for the treatment of short bowel 
syndrome - a safety evaluation. Expert Opin Drug Saf. 2018;17(7):733–
739 
Lohsiriwat, 2010
Lohsiriwat V. Colonoscopic perforation: incidence, risk factors, 
management and outcome. World J Gastroenterol. 2010;16(4):425-30.
NCI-CTCAE, 
2017
National Institutes of Health and National Cancer Institute: Common 
Terminology Criteria for Adverse Events (CTCAE) Version 5.0; 
published 27 November 27, 2017. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/do
cs/CTCAE_v5_Quick_Reference_8.5x11.pdf
Norona, 2020
Norona J, Apostolova P, Schmidt D, et al. Glucagon-like peptide 2 for 
intestinal stem cell and Paneth cell repair during graft-versus-host 
disease in mice and humans. Blood. 2020;136(12):1442–1455.
Rabin, 2001
Rabin R and de Charro F. EQ-5D: a measure of health status from the 
EuroQol Group. Ann Med. 2001;33(5):337–343.
Revestive, 
SmPC
Revestive, INN-teduglutide; European Medicines Agency, E European 
public assessment report (EPAR)/Summary of Product Characteristics 
(EMEA/H/C/002345); update of 29/04/2019.
https://www.ema.europa.eu/en/documents/product-
information/revestive-epar-product-information_en.pdf  
Schwartz, 2001
Schwartz JM, Wolford JL, Thornquist MD, et al. Severe gastrointestinal 
bleeding after hematopoietic cell transplantation, 1987-1997: incidence, 
causes, and outcome. Am J Gastroenterol 2001;96(2): 385–393
Slim, 2019
Slim GM, Lansing M, Wizzard P. Novel Long-Acting GLP-2 Analog, FE 
203799 (Apraglutide), Enhances Adaptation and Linear Intestinal 
Growth in a Neonatal Piglet Model of Short Bowel Syndrome with Total 
Resection of the Ileum. JPEN J Parenter Enteral Nutr. 2019;43(7):891–
898
Vokurka, 2013
Vokurka S, Svoboda T, Rajdl D, et al. Serum citrulline levels as a 
marker of enterocyte function in patients after allogeneic hematopoietic 
stem cells transplantation - a pilot study. Med Sci Monit., 2013,19:81–
85
2016
-Diaz J, Jiang G, et al. Synthesis and 
pharmacological characterization of novel glucagon-like peptide-2 
(GLP-2) analogs with low systemic clearance. J Med Chem. 
2016;59(7):3129–39

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Zeiser, 2020a
Zeiser R, von Bubnoff N, Butler J, et al. Ruxolitinib for Glucocorticoid-
Refractory Acute Graft-versus-Host Disease. N Engl J Med. 2020 May 
7;382(19):1800-1810
Zeiser, 2020b
Zeiser R, von Bubnoff N, Niederwieser D, et al. Ruxolitinib Versus Best 
Available Therapy In Patients With Steroid-Refractory Acute Graft-
Versus-Host Disease: Overall Response Rate By Baseline 
Characteristics In The Randomized Phase 3 Reach2 Trial. EHA library. 
2020, 295075. Abstract S255

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16 APPENDICES
16.1 Appendix: Scales and Assessments
16.1.1 EuroQol-5 Dimension – 5 Level Survey (EQ-5D-5L)

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16.1.2 Functional Assessment of Cancer therapy – Bone Marrow 
Transplantation (FACT-BMT)

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16.1.3 Patient Global Assessment of Severity
Please mark an X in the box that best describes the severity of your Graft Versus Host 
Disease (GVHD) symptoms overall right now.
Right now, my GVHD symptoms overall are:
0 Absent
1 Mild
2 Moderate
3 Severe
4 Extremely severe

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16.1.4 Patient Global Assessment of Change
Patient Global Assessment of Change
Please mark an X in the box that best describes the change in your Graft Versus Host 
Disease (GVHD) symptoms overall since you started taking the trial medication.
                -2 A lot worse
               -1 A little bit worse
              
0 No change
               +1 A little bit improved
               +2 A lot improved

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16.1.5 Physician Global Assessment of Disease
Please mark an X in the box that best describes your current overall severity of the 
patient’s Graft Versus Host Disease (GVHD)
My overall assessment of my patient’s disease severity is: 
               0 No sign of disease
               1 Mild
               2 Moderate
               3 Severe
               4 Extremely severe

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16.2 Appendix: Definitions of Terms
The following definitions (derived from Supplementary Appendix in Zeiser, 2020a) will 
apply in this trial:
Term 
Definition
Graft failure
Primary graft failure:
Absolute neutrophil count <0.5 × 109/L by Day 28
Hemoglobin <80 g/L and platelets <20 × 109/L
Reduced intensity conditioning: Confirmation of donor cell origin is 
required
Cord blood transplant: Up to Day +42 
Secondary graft failure:
Absolute neutrophil count <0.5 × 109/L after initial engraftment not 
related to relapse, infection, or drug toxicity
Reduced intensity conditioning: Loss of donor hematopoiesis to 
<5%
Failure-free survival
The time from the date of randomization/Day 0 to the date of 
hematologic malignancy relapse/progression, non-relapse mortality, 
or addition of new systemic acute graft versus host disease 
(aGVHD) treatment
Non-relapse mortality
The time from date of randomization/Day 0 to date of death not 
preceded by hematologic malignancy relapse/progression
Overall survival
The time from the date of randomization/Day 0 to the date of death 
due to any cause
Malignancy relapse/progression
The time from date of randomization/Day 0 to hematologic 
malignancy relapse/progression
Complete response
A score of 0 for the aGVHD grading in all evaluable organs that 
indicates complete resolution of all signs and symptoms of aGVHD 
in all evaluable organs without administration of additional systemic 
therapies for any earlier progression, mixed response or non-
response of aGVHD
Complete lower gastrointestinal 
(GI)-aGVHD response
The resolution of all lower GI-aGVHD signs and symptoms GVHD 
without administration of additional systemic therapies for any earlier 
progression, mixed response, or non-response of lower GI-aGVHD
Partial response
An improvement of one Stage in one or more organs involved with 
aGVHD signs or symptoms without progression in other organs or 
sites without administration of additional systemic therapies for an 
earlier progression, mixed response, or non-response of aGVHD
Partial lower GI-aGVHD response
An improvement of one Stage in the signs and symptoms of lower 
GI-aGVHD without administration of additional systemic therapies
for any earlier progression, mixed response, or non-response of 
lower GI-aGVHD
Lack of response
Defined as stable disease, mixed response, or progression
Stable disease
An absence of improvement in all organs involved by aGVHD,
without worsening in all involved organs or development of signs or 
symptoms of aGVHD in a new organ

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Stable disease (lower GI-aGVHD)
An absence of improvement or absence of worsening in lower GI-
aGVHD
Mixed response
An improvement of at least one Stage in the severity of aGVHD in 
one organ accompanied by progression in another organ or 
development of signs or symptoms of aGVHD in a new organ
Progression
Worsening in one or more organs by one or more stages without 
improvement in any other involved organ
Lower GI-aGVHD progression
Worsening in lower GI-aGVHD as per the MAGIC lower GI-score 
compared with baseline
Lower GI-aGVHD flare
Any increase in signs or symptoms of lower GI-aGVHD that is 
sustained for >24 hours after apraglutide treatment completion 
following a CR or PR in the lower GI and requires re-escalation of 
immunosuppressive therapy (e.g., corticosteroid, calcineurin 
inhibitors and/or ruxolitinib dosing). While all aGVHD flares will be 
captured during the trial no matter the treatment, only flares that fulfil 
either one the following criteria will be considered a failure of 
treatment:
1.
Addition of new systemic therapy for lower GI-aGVHD 
due to inability to taper corticosteroids below 
methylprednisolone (MP) 0.5 mg/kg/day (or equivalent 
<0.6 mg/kg/day of prednisone) for a minimum 7 days
or
2.
Addition of new systemic therapy for lower GI-aGVHD 
due to re-escalation of corticosteroids to MP 
>2 mg/kg/day (or equivalent >2.5 mg/kg/day of 
prednisone)
Best overall response
The best response recorded from the start of the treatment up to 
Day 91 or the start of additional systemic therapy for GI-aGVHD
Best overall lower GI-aGVHD 
response
The best response of lower GI-aGVHD response recorded from the 
start of the treatment up to Day 91 or the start of additional systemic 
therapy for GI-aGVHD

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16.3 Appendix: Mount Sinai Acute Graft Versus Host Disease International 
Consortium (MAGIC) Grading Scale [Harris, 2016Harris, 2016] 
Target Organ Staging
Stage
Skin (Active 
Erythema Only)
Liver 
(Bilirubin)
Upper GI
Lower GI 
(Stool Output/Day)
0
No active 
(erythematous) GVHD 
rash 
<2 mg/dL
No or intermittent 
nausea, vomiting, 
or anorexia
<500 mL/day or 
<3/episodes/day
1
Maculopapular rash 
<25% BSA
2–3 mg/dL
Persistent nausea, 
vomiting or 
anorexia
500–999 mL/day or 
3–4/episodes/day
2
Maculopapular rash 
25–50% BSA
3.1–6 mg/dL
1000–1500 mL/day or 
5–7/episodes/day
3
Maculopapular rash 
>50% BSA
6.1–15 mg/dL
>1500 mL/day or 
>7/episodes/day
4
Generalized 
erythroderma 
(>50% BSA) plus 
bullous formation and 
desquamation 
>5% BSA
>15 mg/dL
Severe abdominal pain 
with or without ileus or 
grossly bloody stool 
(regardless of stool 
volume)
BSA=body surface area; GI=gastrointestinal tract; GVHD=graft versus host disease 
Overall Clinical Grade
Based on the most severe target organ involvement
Grade
Description
0
No Stage 1–4 of any organ
I
Stage 1–2 skin without liver, upper GI or lower GI involvement
II
Stage 3 rash and/or Stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI
III
Stage 2–3 liver and/or Stage 2–3 lower GI, with Stage 0–3 skin and/or Stage 0–1 
upper GI
IV
Stage 4 skin, liver, or lower GI involvement, with Stage 0–1 upper GI
GI=gastrointestinal tract

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 127 of 132
16.4 Appendix: Summary of Changes to Previous Protocol Versions 
Version 
No.
Version date
Changes to previous Protocol (amendments and 
indication of if substantial or not) 
1.0
Not applicable, first version 
1.2
14 Oct 2021
Additional secondary objectives added to estimate 
duration of response from Day 56 and Day 29
Clarification of inclusion criteria regarding how 
patients respond to corticosteroid and their stage of 
GI-aGVHD 
The patient may now continue to take Apraglutide if 
there are no polyps detected at Week 13 and the 
investigator deems that the subject is benefitting 
from it 
New Figure 1-2 added to show simulations of plasma 
Apraglutide and plasma Citrulline 
New Figure 1-3 added to show low and high doses 
by body weight bands and respective estimated 
mean exposure 
Dosing period updated from between 8 to 13 weeks 
to week 8 or week 13
Definition of GI-aGVHD Flare included along with 
information regarding what should be done if a flare 
occurs
Greater clarification of how the injection will be 
performed 
Greater clarification on dose reduction, modification 
and stopping rules of Apraglutide
Clarification of trial stopping criteria with three safety 
monitoring events identified: treatment-related 
deaths, grade 3–4 treatment-related organ toxicities 
and confirmed cases of Hy’s law
Improved predictions made of the overall response 
rate to help determine sample size 
Key secondary efficacy endpoint c will now be 
summarized using Kaplan-Meier analysis 
Definitions of complete response, complete 
GIaGVHD response and partial response updated
Definitions of lack of response, no response, mixed 
response, and progression added to the definition 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 128 of 132
section in Appendix 3 
2.0
29 Oct 2021
Minor administrative and grammatical changes 
throughout the protocol 
Updated abbreviations list with minor wording 
changes 
Addition of exclusion criteria to now exclude patients 
that have used enteral glutamine or growth factors 
such as GLP-2 within the previous 6 months to 
match existing concomitant medication restrictions
Updated planned timeline for first subject, first visit to 
March 2022
Updated to show that telephone calls will not be 
made in weeks when a dosing visit is scheduled 
Updated procedure list for the baseline visit to 
change the order procedures that take place 
Updated procedure list for Visits 3–14 to change the 
order that procedures take place and to remove 
some procedures from visits e.g., removal of 
unnecessary extra nutrition status on Visit 9 and 
urine pregnancy test added to Visit 6
Minimum data requirements to report an SAE 
changed to make reporting more simple
Updated reference list to include all papers cited in 
Version
Change to the pharmacokinetic information involving 
the removal of sampling at Day 90
Adverse events collected throughout the study
3.0
25 Mar 2022
Minor administrative and grammatical changes 
throughout the protocol 
Updated abbreviations list and definitions throughout 
Clarified the focus on lower GI-aGVHD
Updated the Background and Rationale of the Trial 
Synopsis, removing unessential information
Trial Objectives updated. Substantial changes made 
to Primary Objectives, Secondary Objectives and 
Exploratory Objectives
Trial Endpoints updated. Substantial changes made 
to overall endpoints; Safety Endpoints, Secondary 
Endpoints and Exploratory Endpoints
Trial design updated. Removal of repeat-dose 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 129 of 132
definition of trial. 
Extended RUX start to 0–5 days prior to first dose. 
Removal of the following sentence: In case of 
transitory lack of tolerance, it is at the discretion of 
the treating physician to temporarily lower the dose
Inclusion/exclusion criteria updated
Inclusion/exclusion criteria clarified to refer to not 
only randomized but enrolled subjects as well
Measurements and procedures schedule updated. 
Deleted questionnaires collection at Visits 3 and 5. 
Added ECG and physical examination at Visit 2. 
Deleted therapeutic drug monitoring for administered 
immunosuppressants during treatment with 
apraglutide (collected as part of the concomitant 
medications
Statistical considerations updated within the Trial 
Synopsis
Trial duration clarified to up to 116 weeks
In Germany: oral methods of hormonal contraception 
are to be combined with another accepted method of 
contraception; only subjects 18 years old and above 
will be enrolled; only colonoscopies (not 
colonographies) can be performed
Figure 1-1 has been updated to incorporate a 
screening period beginning at Day -84 and incudes 
in the footnotes that dosing is not permitted at and 
after Day 182
Table 1 updated style and formatting. Footnotes 
reflect changes made to the table
Section 1.4 updated to describe safety of the Phase 
II trial and expand upon safety of Phase I trial
Section 1.5 updated in keeping with the updates to 
the Trial Objectives and Endpoints seen in the Trial 
Synopsis
Section 1.9 updated to emphasize that the REACH 2 
data was used for soft-powering finding a reasonable 
sample size. It was also added that the Sponsor will 
try to establish a better matched control
Section 2.1 updated to clarify that 3 dose groups will 
be assessed (not 5) and to emphasize that the 
Sponsor will try to establish a better matched control 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 130 of 132
in regards to the study population and endpoints
Section 2.2 Overall design amended to read that 
dosing is not permitted at and after Day 182. 
Wording to this affect amended throughout the 
protocol as applicable
Trial Days updated to corresponding Weeks or Visits 
when applicable
The screening period cannot be extended beyond 
12 weeks as aGVHD may have transitioned into 
cGVHD, in which case the subject will be classified 
as a screen failure
Historical data for colonographies/colonoscopies 
may be used where the colonoscopy/colonography 
was performed within 6 months before the screening 
visit
Historical data for biopsy may be used during 
screening for GI involvement confirmation, if 
obtained within 60 days prior to screening visit and 
after confirmed or suspected clinical diagnosis of GI-
aGVHD.
For when treatment discontinuation may occur, the 
EOT visit will be performed 4 weeks after the last 
dose
Section 2.2.6 updated to outline the data that will be 
collected for subjects that are screen failures
Table 4 updated style and formatting, and several 
changes to dose administration under different 
circumstances
Clarified that individual apraglutide stopping events 
will not trigger iSRC meeting, but only as a part of 
Toxicity guidance rule calculation
Clarified that any investigational drug apart from 
apraglutide is prohibited during the trial
After reconstitution, the IMP must be injected within 
a maximum of 2 hours from completing reconstitution 
in order to ensure sterility is maintained
The FACT-BMT will only be completed by subjects 
Clarified that blood transfusions should be recorded 
as a concomitant procedure in the eCRF
Where apraglutide was not administered during the 
previous week, e.g., for safety reason, the pre-dose 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 131 of 132
PK sample at the current visit can be skipped
Clarified that dosing visits may also occur in Weeks: 
1416, 1820, 22-25
Ideal dates of Visits 9, 10, 11, 12, 13, 14 were 
clarified
Serious adverse events related to trial medication (in 
the Investigator’s opinion) to be reported after the 
EOT visit
If an AE or MH event worsens in severity or 
frequency during the trial, then a new AE is to be 
registered with the date of the worsening as the start 
date
Hypersensitivity and anaphylaxis (narrow SMQs) will 
be collected as AESIs
Clarified that subjects may only reduce their dose by 
one step during the trial
Toxicity Events identified for monitoring were 
clarified
Table 13 replaced with text describing the probability 
of higher effectiveness with apraglutide relative to 
the best available therapy
For every subject, visual inspection of the actual 
concentrations will be compared to a simulated PK 
profile based on a PK model developed on healthy 
volunteers and SBS patients’ data from Phase I and 
II clinical studies. The simulated PK profile will be 
constructed based on the dose received and the 
subject’s body weight. This will be performed online 
for every subject, and this will be used to check if the 
subject is correctly exposed to apraglutide
Section 7.7.1 updated in keeping with the updates to 
the Endpoints in the Trial Synopsis
Section 7.7.2 updated in keeping with the updates to 
the Endpoints in the Trial Synopsis
Section 7.7.3 incorporated into Section 7.7.2
Section 7.7.4 renumbered to: 7.7.3, and all 
information replaced with reference to the FAS and 
SAP
Updated reference list to remove references no 
longer applicable to the updated Version 3.0 content
Several terms and definitions added to Appendix 3: 

TMP no.:
TMP-CD-04_1
Version no.:
1.0
TMP effective date:
10-Oct-2019
Proof-of-concept trial of apraglutide in GVHD
TA799-101, Version 5.0, FINAL, 27/Mar/2023
Page 132 of 132
Stable disease (lower GI-aGVHD); Lower GI-aGVHD 
progression; Best overall lower GI-aGVHD response
Appendix 7 was added to present the flowcharts on 
adjustment of apraglutide and RUX doses
4.0
26 Sept 2022
Summary of changes are provided in the separate 
Protocol Amendment document.
5.0
27 Mar 2023
Summary of changes are provided in the separate 
Protocol Amendment document.