Clinical trial NCT04699032
Conditions: Chronic Kidney Disease
Keywords: Renal Function Renal Impairment Kidney Function
Sponsor: VectivBio AG
Start date: 2020-12-08; Completion date: 2021-07-05
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study of pharmacokinetics and safety of apraglutide in participants with normal and impaired kidney function.

Detailed description:
A two stage design, open label, multi-center, non-randomized trial to evaluate the PK and safety of a single subcutaneous dose of 5 mg apraglutide in subjects with varying degrees of renal function. The renal function was calculated by the estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology (CKD-EPI) Creatinine Equation.

Part 1: 8 subjects with severe renal impairment (Cohort 1) and 8 subjects with normal renal function (Cohort 2).

Part 2: 8 subjects with moderate (Cohort 3) and 8 subjects with mild (Cohort 4). Enrollment into Part 2 was conditional on the results of Part 1.

Arms: arm 1: eGFR (mL/min/1.73 m2): \<30 not on hemodialysis arm 2: eGFR (mL/min/1.73 m2): ≥90 arm 3: eGFR (mL/min/1.73 m2): ≥30 to 60 arm 4: eGFR (mL/min/1.73 m2): ≥60 to 90
Interventions: intervention 1: Apraglutide
Intervention descriptions: intervention 1: Single dose of apraglutide 5 mg.

Protocol documents:
Prot_000.pdf: 
Protocol Number: TA799-014 
 
Official Title: A Phase 1, Open-Label Evaluation of the Pharmacokinetics and Safety of a Single 
Dose of Apraglutide in Subjects with Normal and Impaired Renal Function 
 
NCT Number: NCT04699032 
 
Document Date: 11 January 2021 


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Clinical Trial Protocol 
A Phase 1, Open-Label Evaluation of the Pharmacokinetics and Safety 
of a Single Dose of Apraglutide in Subjects with Normal and Impaired 
Renal Function 
 
 
The information contained in this document is confidential and the property of VectivBio AG. The 
information may not - in full or in part - be transmitted, reproduced, published, or disclosed to 
others than the applicable Institutional Review Board(s) and Regulatory Authority(ies) without 
prior written authorization from VectivBio AG except to the extent necessary to obtain informed 
consent from those who will participate in the trial. 
The trial will be conducted according to this protocol and in compliance with Good Clinical 
Practice (GCP) [1], with the Declaration of Helsinki [2], the FDA regulations [3] and with other 
applicable regulatory requirements. 
 
Trial Type: 
Phase 1 
IND: 
To be inserted
Trial Identifier: 
TA799-014 
Sponsor: 
VectivBio AG 
Aeschenvorstadt 36 
4051 Basel 
Switzerland 
Investigational medicinal product Apraglutide (TA799) 
Protocol Version and Date 
Version 4.0, 11-JAN-2021 
Contract Research Organization 
Pharmaceutical Research Associates Inc. 
4130 Parklake Avenue, Suite 400 
Raleigh, NC 27612 
USA 
 
 


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Declaration of Sponsor  Responsible Medical Officer 
This trial protocol was subject to critical review. The information it contains is consistent with 
current knowledge pursuant to the risks and benefits of the investigational medicinal product, as 
well as with the moral, ethical principles governing clinical research as set out in the Declaration of 
Helsinki [2]. FDA regulations [3] and all guidelines on GCP [1].  
 
I approve this protocol on behalf of the Sponsor. 
 
SVP Head of Clinical Development and 
Medical Affairs 
 
 
 
 
 


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Table of Contents 
 
 
Clinical Trial Protocol ............................................................................................. 1 
 ........................................ 2 
Table of Contents ..................................................................................................... 3 
List of Tables ............................................................................................................ 7 
List of Figures ........................................................................................................... 7 
List of Abbreviations and Definition of Terms ..................................................... 8 
Protocol synopsis .................................................................................................... 10 
1 
Introduction .................................................................................................... 19 
1.1 
Background ................................................................................................................... 19 
1.2 
Rationale ....................................................................................................................... 20 
1.3 
Risk-benefit Assessment ............................................................................................... 20 
1.3.1 
Nonclinical Experience ................................................................................... 21 
1.3.2 
Clinical Experience.......................................................................................... 22 
2 
Trial Objectives and Endpoints..................................................................... 25 
2.1 
Objectives ..................................................................................................................... 25 
2.1.1 
Primary Objective ............................................................................................ 25 
2.1.2 
Secondary Objective ........................................................................................ 25 
2.2 
Endpoints ...................................................................................................................... 25 
2.2.1 
Primary Endpoints ........................................................................................... 25 
2.2.2 
Secondary Endpoints ....................................................................................... 25 
3 
Overall Design and Plan of the Trial ............................................................ 26 
3.1 
Overview ....................................................................................................................... 26 
3.1.1 
Part 1 of Clinical Trial ..................................................................................... 27 
3.1.2 
Part 2 of Clinical Trial ..................................................................................... 27 
3.1.3 
For Both Parts 1 and 2 of Clinical Trial .......................................................... 27 


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3.1.4 
Re-screening .................................................................................................... 29 
3.2 
Drug, Route, Dosage and Treatment Plan .................................................................... 29 
3.3 
End of Trial Definition ................................................................................................. 30 
4 
Trial Population .............................................................................................. 31 
4.1 
Inclusion Criteria .......................................................................................................... 31 
4.2 
Exclusion Criteria ......................................................................................................... 32 
4.3 
Lifestyle Considerations ............................................................................................... 35 
4.3.1 
Meals and Dietary Restrictions ....................................................................... 35 
4.3.2 
Caffeine, Alcohol, and Tobacco ...................................................................... 35 
4.3.3 
Activity ............................................................................................................ 35 
4.3.4 
Contraception and Definition of Woman of Child-bearing Potential.............. 36 
5 
Premature Discontinuation of Subjects or Trial .......................................... 38 
5.1 
Subject Discontinuation ................................................................................................ 38 
5.2 
Subject Withdrawal of Consent and Subjects Considered Lost to Follow-up .............. 39 
5.3 
Trial Termination .......................................................................................................... 40 
6 
Investigational Medicinal Product and Concomitant Medications ........... 41 
6.1 
Investigational Medicinal Product ................................................................................ 41 
6.1.1 
Investigational Medicinal Product Description ............................................... 41 
6.1.2 
Dosing and Administration.............................................................................. 41 
6.1.3 
Drug Accountability ........................................................................................ 41 
6.1.4 
Reconstitution of Investigational Medicinal Product ...................................... 41 
6.1.5 
Packaging, Labelling, and Storage .................................................................. 42 
6.2 
Concomitant Medications ............................................................................................. 42 
6.2.1 
Previous and Concomitant Medication ........................................................... 42 
6.2.2 
Prohibited Previous and Concomitant Medication .......................................... 42 
7 
Trial Schedule and Assessments .................................................................... 44 
7.1 
Screening Visit .............................................................................................................. 44 
7.2 
Safety Assessments ....................................................................................................... 45 


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7.2.1 
Laboratory Tests .............................................................................................. 45 
7.2.2 
Physical Examinations..................................................................................... 47 
7.2.3 
Vital Signs ....................................................................................................... 47 
7.2.4 
Twelve-lead Electrocardiogram ...................................................................... 48 
7.2.5 
Clinical Safety Laboratory Assessments ......................................................... 48 
7.2.6 
Pregnancy and Confirmation of Postmenopausal Status ................................. 49 
7.2.7 
Injection Site Reaction Assessments ............................................................... 49 
7.3 
Trial Procedures at Each Visit ...................................................................................... 49 
7.3.1 
Day -1 .............................................................................................................. 49 
7.3.2 
Day 1 ............................................................................................................... 50 
7.3.3 
Day 2 ............................................................................................................... 51 
7.3.4 
Day 3 ............................................................................................................... 51 
7.3.5 
Day 4 ............................................................................................................... 51 
7.3.6 
Day 5 ............................................................................................................... 51 
7.3.7 
Day 6 ............................................................................................................... 52 
7.3.8 
Day 7 ............................................................................................................... 52 
7.3.9 
Day 8 ............................................................................................................... 52 
7.3.10 Day 11 (Outpatient Visit) ................................................................................ 53 
7.3.11 Follow-up Visit Day 14±2 days (also Early Termination Visit Procedures) .. 53 
7.4 
Pharmacokinetics .......................................................................................................... 54 
8 
Statistical Methods ......................................................................................... 55 
8.1 
Determination of Sample Size ...................................................................................... 55 
8.2 
Population for Analysis ................................................................................................ 55 
8.3 
Statistical Analysis ........................................................................................................ 55 
8.4 
Safety Assessments ....................................................................................................... 56 
8.5 
Pharmacokinetic Analysis ............................................................................................ 57 
8.5.1 
Derivation of Pharmacokinetic Parameters Prior to Analysis ......................... 57 
9 
Documentation and Operational Considerations ........................................ 58 


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9.1 
Early Termination ......................................................................................................... 58 
9.2 
Protocol Amendments .................................................................................................. 58 
9.3 
End of Trial Report ....................................................................................................... 58 
9.4 
Regulatory and Ethical Considerations ........................................................................ 58 
9.4.1 
Subject Information and Consent .................................................................... 59 
9.4.2 
Institutional Review Board .............................................................................. 59 
9.4.3 
Subject Confidentiality .................................................................................... 60 
9.4.4 
Liability and Insurance .................................................................................... 60 
9.5 
Reporting of Safety Concerns and Serious Breaches of the Protocol or ICH GCP...... 60 
9.6 
Financial Disclosure ..................................................................................................... 60 
9.7 
Informed Consent Process ............................................................................................ 60 
9.8 
Data Protection ............................................................................................................. 61 
9.9 
Data Handling and Record Keeping ............................................................................. 62 
9.9.1 
Data Collection ................................................................................................ 62 
9.9.2 
Database Management and Quality Control .................................................... 63 
9.9.3 
Record Retention ............................................................................................. 64 
9.10 Source Documents ........................................................................................................ 64 
9.11 Trial and Site Closure ................................................................................................... 64 
9.12 Publication Policy and Public Disclosure ..................................................................... 65 
9.13 Protocol Compliance and Deviations ........................................................................... 65 
10 Safety................................................................................................................ 67 
10.1 Safety Data Reporting and Collection Period ............................................................... 67 
10.2 Definition and Assessment of (Serious) Adverse Events and Other Safety Related 
Events 67 
10.3 Safety Reporting ........................................................................................................... 69 
10.3.1 Reporting of Adverse Events........................................................................... 69 
10.3.2 Reporting of Adverse Events of Special Interest ............................................ 69 
10.3.3 Reporting of Serious Adverse Events.............................................................. 69 
10.3.4 Reporting of Suspected Unexpected Serious Adverse Events ........................ 70 


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10.4 Pregnancy Reporting .................................................................................................... 70 
10.5 Medication Errors ......................................................................................................... 71 
10.6 Severity Assessment ..................................................................................................... 71 
10.7 Causality Assessment ................................................................................................... 71 
10.8 Adverse Event Outcome ............................................................................................... 72 
10.9 Treatment Given ........................................................................................................... 72 
10.10 Liver Safety: Suggested actions and Follow-up Assessments for Potential Cases of 
Drug-Induced Liver Injury............................................................................................ 72 
11 References........................................................................................................ 75 
 
List of Tables 
Table 1: Schedule of Assessments ..................................................................................................... 17 
Table 2: CKD-EPI Equation .............................................................................................................. 26 
Table 3: Criteria to establish Stable Renal Function.......................................................................... 29 
Table 4: Reconstitution of Investigational Medicinal Product .......................................................... 41 
Table 5: Sampled Blood Volume ....................................................................................................... 46 
Table 6: Safety Laboratory Tests ....................................................................................................... 46 
Table 7: Pharmacokinetic Time Points .............................................................................................. 54 
Table 8: Populations Description ....................................................................................................... 55 
Table 9: Plasma PK Parameters ......................................................................................................... 57 
Table 10: Assessment of Causality of Adverse Events...................................................................... 72 
List of Figures 
Figure 1: Trial Schematic ................................................................................................................... 26 
 
 


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List of Abbreviations and Definition of Terms 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine transaminase 
ANOVA 
Analysis of variance 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
BMI 
Body mass index 
BP 
Blood pressure 
CI 
Confidence interval 
CIC 
Colon In Continuity 
CKD 
Chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
CQ 
Customer Queries 
CRU 
Clinical research unit 
CTR 
Clinical Trial Report 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DILI 
Drug-induced liver injury 
DPP4 
Dipeptidyl peptidase-4 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicine Agency 
EOT 
End of trial 
ET 
Early termination 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMR 
Geometric mean ratio 
GLP 
Glucagon-like peptide 
HbA1c 
Glycated hemoglobin 
HBsAg  
Surface antigen of the hepatitis B virus (HBV) 
HBcAb 
Hepatitis B core antibody 
HCVAb 
Hepatitis C antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRT 
Hormone replacement therapy 
ICF 
Informed consent form 


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ICH 
International Council for Harmonisation (formerly known as 
International Conference on Harmonisation) 
ID 
Identifier 
IF 
Intestinal failure  
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IV 
Intravenous(ly) 
KDOQ 
Kidney disease outcomes quality initiative 
LFT 
Liver function test  
MedDRA 
Medical dictionary for regulatory activities 
NCI-CTCAE 
National Cancer Institute  Common Terminology Criteria for Adverse 
Events 
PD 
Pharmacodynamic(s) 
PE 
Physical examination 
PK 
Pharmacokinetic(s) 
PS 
Parenteral support 
QT 
Interval between Q-wave and T-wave 
QTcF 
 
 
Changes from baseline in QTcF 
 
Placebo-corrected changes from baseline in QTcF 
QW 
Once per week 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBS 
Short bowel syndrome 
SBS-IF 
SBS with intestinal failure  
SBS-II 
SBS with intestinal insufficiency 
SC 
Subcutaneous 
SMQ 
Standardized MedDRA query 
SUSAR 
Suspected unexpected serious adverse event 
t1/2 
Terminal half-life 
TBili 
Total bilirubin 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
WFI 
Water For Injection 
WOCBP 
Women of child-bearing potential 
WHO 
World Health Organization 






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Inclusion/Exclusion Criteria 
 
Inclusion Criteria 
 All Subjects 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
Age and Sex 
1. Male or female subjects who are between the ages of 18 75 years, inclusive, at Screening 
Type of Subject and Disease Characteristics 
2. Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory 
tests, and other trial procedures 
3. 
2; and a total body weight of >50 kg (110 lb) 
4. Capable of giving signed informed consent which includes compliance with the requirements 
and restrictions listed in the informed consent form (ICF) and in this protocol  
5. Women of childbearing potential must agree to practice effective contraception and to use a 
highly effective method of contraception during the trial and for 1 month 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, vasectomized partner. To be considered sterilized or infertile, females must have 
undergone surgical sterilization (bilateral tubectomy, hysterectomy, or bilateral ovariectomy) or 
be postmenopausal (defined as at least 12 months amenorrhea; it may be confirmed with follicle-
stimulating hormone test if there is doubt and/or the woman is under 60 years of age and not 
using hormonal contraception or hormone replacement therapy)  
6. Male subjects with a female partner of childbearing potential must commit to practice highly 
effective methods of contraception (e.g., condom) and abstain from sperm donation during the 
trial and for 1 month after the EOT visit  
 Additional Inclusion criteria for Healthy Subjects with Normal Renal Function (Cohort 2 only)
7. No clinically relevant abnormalities identified by detailed medical history, full physical 
examination, including body temperature, blood pressure (BP), and heart rate measurement, 
12-lead electrocardiogram (ECG), and clinical laboratory tests  
8. Normal renal function (average eGFR measured by CKD-
0 mL/min/1.73 m2) at two 
screening visits where Screening 2 can be performed at admission on Day -1 
9. Demographically comparable to the group of subjects with impaired renal function: 
a. That each subject s age within ±10 years of the mean age and ±15 kg of the severe renal 
impairment cohort (Cohort 1)  
b. Attempts will be made to ensure that the male-to-female composition of Cohort 2 is 
comparable to that in the severe renal impairment cohort (Cohort 1) 
c. Other demographic characteristics such as race and ethnicity matched as closely as possible 
to the renal impairment cohort  
 Additional Inclusion criteria for Subjects with Impaired Renal function (Cohort 1 and Cohorts 
3 and 4 [if applicable] only) 
10. Good general health commensurate with the population with chronic kidney disease (renal 
medical history, full physical examination, measurement of heart rate and 12-lead ECG, as well 


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as clinical laboratory tests (except serum creatinine and eGFR). Hypertension, diabetes mellitus, 
hyperparathyroidism, ischemic heart disease and other common co-morbidities in this population 
are possible exemptions, as long as, in the opinion of the Investigator, the subject is medically 
stable, is on a stable drug regimen, and can abide by the meals and dietary restrictions outlined in 
protocol in Section 4.3 
11. Meet the following eGFR criteria (based on average) during the screening period based on the 
CKD-EPI equation: 
a. Severe renal impairment: eGFR <30 mL/min/1.73 m2, but not requiring hemodialysis 
b. Moderate renal 
/1.73 m2 and 
<60 mL/min/1.73 m2 
c. Mild renal impairment (Part 2 only): eGFR 
 mL/min/1.73 m2 
The eGFR values obtained during screening visits should not be more than 25% different for 
Cohort 1 (severe), Cohort 3 (moderate), and Cohort 4 (mild)  
12. Any form of renal impairment except acute nephritic syndrome or nephrotic syndrome defined 
as proteinuria >3 g (subjects with history of previous nephritic syndrome but in remission can be 
included) 
13. Stable concomitant drug regimen (as defined in Section 6.2) for the management of individual 
cal conditions 
 
Exclusion Criteria 
 All Subjects  
Subjects excluded from the trial if any of the following criteria apply: 
Medical Conditions 
1. Renal transplant recipients 
2. History of systemic infection requiring hospitalization, parenteral antimicrobial therapy, or as 
otherwise judged clinically significant by the Investigator within 3 months prior to Screening and 
Day 1 
3. Any active malignancies or history of malignancies within the past 2 years prior to screening 
with the exception of adequately treated or excised non-metastatic basal cell or squamous cell 
cancer of the skin or cervical carcinoma in situ 
4. Other acute or chronic medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation, or behavior that may increase the risk associated with trial participation 
or investigational medicinal product (IMP) administration or may interfere with the interpretation 
of trial results and, in the judgment of the Investigator, would make the subject inappropriate for 
entry into this trial 
5. Treatment with an IMP within 30 days or five half-lives, if known, (whichever is longer) 
preceding the dose of IMP 
6. Male subjects who are unable to comply with the following requirements during the intervention 
period and up to 1 month after the dose of apraglutide, which corresponds to the time needed to 
eliminate trial interventions: 
a. Refrain from donating sperm 
b. PLUS, either be abstinent from heterosexual intercourse with a female of childbearing 
potential as their preferred and usual lifestyle abstinent on a long-term persistent basis and 
agree to remain abstinent 
c. OR must agree to use a male condom with spermicide when engaging in any activity that 
allows for passage of ejaculate to another person  
d. Vasectomy


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7. A history of clinically significant intestinal adhesions and/or chronic abdominal pain 
8. History of known colon polyps or family history of familial adenomatous polyposis  
Diagnostic Assessments 
9. Positive blood screen for hepatitis C antibody, hepatitis B surface antigen or human 
immunodeficiency virus (HIV)-1 and -2 antibodies 
10. ANY of the following abnormalities in clinical laboratory tests at Screening, and confirmed by a 
single repeat, if deemed necessary: 
a. Serum albumin concentration <25 g/L (2.5 g/dL)  
b. Hemoglobin concentration <90 g/L (9.0 g/dL)  
c. Enzymes aspartate amino transaminase (AST) or alanine amino transaminase (ALT) values 
>2 × upper limit of normal (ULN) 
d. Proteinuria of >3 g t
eligible for this trial provided the direct bil
ULN 
11. In the opinion of the Investigator (or designee), subjects have any clinically significant 
laboratory abnormality that could affect interpretation of t
in the trial. Screening laboratory tests with abnormal results may be repeated once to confirm 
abnormal results (with the same screening number); the last value will be used to determine 
eligibility 
12. Positive urine test for alcohol or illicit drugs at either Screening or admission. Renal impairment 
subjects may be eligible to participate after approval from Sponsor if their drug screen is positive 
for a prescribed substance that is not expected to interfere with the PK of apraglutide 
13. Screening 12-lead ECG in triplicate that demonstrates: 
a. Clinically significant abnormalities requiring treatment (e.g., acute myocardial infarction, 
serious tachy- or brady-arrhythmias) or indicating serious underlying heart disease (e.g., 
cardiomyopathy, Wolff-Parkinson White syndrome) 
b. 
 (QTcF) >450 msec for 
subjects with normal renal function and >480 msec for subjects with impaired renal function 
c. Long QT Syndrome, a family history of Long QT Syndrome, or a history of Torsades de 
Pointes 
Prior/Concomitant Therapy 
14. Use of prescription or non-prescription drugs and dietary supplements within 7 days or five half-
lives (whichever is longer) prior to Day 1 
Limited use of nonprescription medications that are not believed to affect subject safety or the 
overall results of the trial may be permitted on a case by case basis following approval by the 
Investigator in consultation with the Sponsor 
Herbal supplements must be discontinued at least 28 days prior to the dose of IMP 
For subjects with renal impairment, stable concomitant medications (including herbal 
supplements) may be given if they are considered necessary for the welfare of the subjects (e.g., 
standard therapy for underlying diseases), and are not contraindicated with the IMP or likely to 
interfere with the PK of the IMP. Stable is defined as no changes in current medications or 
starting new medications for 14 days prior to apraglutide administration 
Other Exclusion Criteria 
15. Investigator site staff members directly involved in the conduct of the trial and their family 
members, or any site staff members otherwise supervised by the Investigator 
16. History of regular alcohol consumption exceeding seven drinks/week for females or 
14 drinks/week for males (1 drink = 5 ounces [150 mL] of wine, or 12 ounces [360 mL] of beer, 
or 1.5 ounces [45 mL] of hard liquor) within 3 months of Screening 
17. Female subjects of childbearing potential who are unwilling or unable to use highly effective 




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clinical chemistry, hematology, and urinalysis 
Statistical methods 
Sample Size 
No formal power calculation was performed. The number of subjects per group is based on the review of 
the literature and of the European Medicine Agency (EMA) and FDA guidelines. While the EMA 
suggests 6 8 subjects per group, the FDA draft guidance does not provide an exact number of renal 
impaired patients needed for such a clinical trial [19, 22].  
The sample size of eight subjects per group is also based on the feasibility to recruit subjects with severe 
renal impairment. 
ICH/GCP  
The trial will be conducted in accordance with FDA guidelines [3] as well as the Declaration of Helsinki 
[2] and Good Clinical Practice [1]. 




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and Screening visit 2 (S2) is 
-EPI can be used to demonstrate stability if value is within 3 months prior to S1. If 
no historical value within that timeframe is available, the subject will be assessed at S1 and S2 per protocol. Note that the second eGFR calculation may occur at admission visit (Day -1) as 
long as this visit falls within the 3- to 14-day range following S1 collection. Other screening procedures completed during the first visit (S1) do not need to be repeated. Maximum delay 
accepted between screening and IMP administration is a total of 42 days. 
c. 
Demographics include race, age and sex, ethnicity and date of birth. 
d. 
Complete physical examination (PE) at S1 and abbreviated PE at Day -1. If a complete PE was not completed at S1 visit, then complete PE must be done at Day -1. Symptom-driven PE only 
at Day 3. Abbreviated PE on discharge (Day 8) and Follow-up (Day 14 or Early Termination visit.)  
e. 
Height to be obtained only at S1. BMI will be calculated at S1 only. Weight to be obtained at S1, S2, Day -1 and Day 14.  
f. 
Safety laboratory assessments include chemistry, hematology, and urinalysis (and microscopy, if needed) and will be performed at S1, on Day -1, Day 2, Day 8, Day 11, and Day 14 or Early 
Termination visit. All assessments must be performed after at least an 8-hour fast. At Day -1, the results must have no clinically significant findings as per the Investigator  judgment to 
allow investigational medicinal product administration on Day 1. An optional HbA1c and TSH will be allowed at Screening, if applicable, per the discretion of the Investigator to confirm 
stability of concurrent medical conditions (for Cohorts 1 [severe], 3 [moderate] and 4 [mild] only). 
g. 
To confirm eligibility, participants must have stable renal function defined as 25% difference for eGFR values at S2 compared to the value at S1. The average of the two screening eGFR 
values will be used for participant stratification and group assignment (provided stable renal function is still demonstrated). A historical eGFR using CKD-EPI can be used to demonstrate 
stability if the value is within past 3 months. If none available, the subject will be assessed at S1 and S2 per protocol. If the renal function stability criterion is met but the renal function 
classification category changes between S1 eGFR and the average of the S1 and S2 eGFRs, the eGFR measurement at Day -1 will also be used to determine the appropriate group 
classification category using an average of all three eGFR values, to determine whether the participant will be eligible for enrollment. The Day -1 eGFR value will be used for 
pharmacokinetic analysis. The eGFR determination will utilize the CKD-EPI equation. 
h. 
Confirmation of appropriate use only. 
i. 
This test may be performed at any other time at the discretion of the Investigator. 
j. 
Triplicate 12-lead ECG will be performed after supine rest of 10 minutes at Screening, Day -1, Day 1 pre-dose, Day 1 (4 hours), and Day 2 (24 hours) and again on Day 8, Day 11, and Day 
14. Electrocardiogram should be obtained within 45 minutes of dosing on Day 1. 
k. 
Obtain blood pressure and heart rate measurements after at least 5 minutes of rest in a supine position (Section 7.2.3). One repeat measurement may be allowed at the discretion of the 
Investigator. 
l. 
Injection site reaction assessments will be performed pre-dose and 4, 24, 48, 72, 96, 120, 144, and 168 hours post dose, as well as at Early Termination or Day 14. 
m. 
Pharmacokinetic time points will be as follows: 0 (5 minutes pre-dose), 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, and 240 hours.
n. 
Subjects will be instructed to begin fasting 8 hours prior to Day 1 dose of apraglutide. 
o. 
Changes since Screening. 
p. 
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1 Introduction 
1.1 Background 
Short bowel syndrome (SBS) is a malabsorption disorder that manifests as a collection of signs and 
symptoms such as diarrhea, steatorrhea, fluid and electrolyte disturbances, dehydration, malnutrition, 
and weight loss. Short bowel syndrome typically develops after loss of more than two-thirds of the 
vascular complications, trauma or necrotizing enterocolitis. Short bowel syndrome intestinal failure 
(IF) is defined by the inability to maintain protein, energy, fluid, electrolyte, or micronutrient balance, 
and patients with SBS-IF are dependent on intravenous fluids, electrolytes and/or nutrients, together 
termed parenteral support (PS) [4]. Other patients present a less severe form of SBS defined as 
intestinal insufficiency (II), characterized by a remnant small intestine of 200 cm or less, a fecal energy 
excretion of more than 2.0 MJ/day, or consecutive small intestinal resections exceeding 150 cm [5]. 
Generally, SBS-II patients can maintain their protein and energy balance through hyperphagia, but 
some of them are considered as borderline IF patients with a high risk to require intermittent PS. 
Following surgical resection, the remaining small intestine may undergo a process of structural and 
functional adaptation, which may lead to restoration of intestinal secretion and motility and to 
hypertrophy and hyperplasia of the mucosal surface. In patients with a preserved terminal ileum or 
colon in continuity, an increase in the endogenous hormonal secretion of the peptide hormones 
glucagon-like peptide-1 (GLP-1), GLP-2, and peptide YY (PYY) following nutrient ingestion may play 
a role in this adaptation. However, for patients with resection of the ileum and colon, these 
neuroendocrine feedback mechanisms are disrupted which may be associated with the 
pathophysiological traits in SBS patients such as accelerated gastrointestinal (GI) motility, 
hypersecretion, diminished GI blood flow, and disturbed barrier function. Together these observations 
have led to the development and pharmacological use of GLP-2 in the intestinal rehabilitation and 
treatment of SBS patients [6]. 
Glucagon-like peptide-2 is a 33-amino acid peptide derived from posttranslational processing of 
proglucagon in intestinal L-cells located primarily in the terminal ileum and colon [7, 8]. GLP-2 and 
GLP-2 receptor agonists act in a highly localized manner in the GI tract to enhance nutrient and fluid 
absorption, stimulate blood flow, increase intestinal barrier function, and inhibit gastric acid secretion 
and gastric emptying. One of the main biological actions of GLP-2 is organ-specific stimulation of 
intestinal growth through increased crypt cell proliferation and decreased apoptosis of the mucosal 
epithelial cells [6, 7]. Data from previous clinical trials with native GLP-2 and GLP-2 analogues have 
demonstrated that GLP-2 supplementation has the ability to increase crypt depth and villus height [9, 
10, 11] and enhance the intestinal absorptive capacity in patients with SBS [9, 10, 11, 12]. 
Apraglutide is a peptide analogue of GLP-2, which is under development for the treatment of SBS. 
Apraglutide acts as a full agonist at the GLP-2 receptor in vitro with potency and selectivity 
comparable to native GLP-2 [8]. The structure of this peptide is designed to have a longer elimination 
half-life by being resistant to cleavage by dipeptidyl peptidase-4 (DPP4), the major GLP-2 peptidase. 
The systemic half-life in various animal species as well as in human healthy subjects is significantly 
prolonged compared with the native human GLP-2 (approximately 30 hours when administered 
subcutaneously [SC] vs 7 minutes for native GLP-2). Apraglutide has, in various animal models, shown 


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a trophic effect on the small intestine and maintained the barrier function, thus preserving the physical 
integrity of the intestinal mucosa. 
In previous nonclinical pharmacokinetics and metabolism trials, no intact parent compound 
(apraglutide) was found in urine, suggesting renal elimination does not play a significant role in 
apraglutide removal.  
Previously, apraglutide has been administered in a first-in-human trial with healthy subjects to assess 
safety and determine pharmacokinetic (PK) characteristics, and proved safe and well tolerated at single 
and repeated SC doses ranging from 2.5 mg up to 25 mg. In humans, again, no intact parent compound 
(apraglutide) was found in urine suggesting renal elimination does not play a significant role in 
apraglutide removal in humans. 
1.2 Rationale 
This trial is a Phase 1, non-randomized, open-label, single dose, parallel-group trial of apraglutide in 
subjects with severe renal impairment and subjects with normal renal function (Part 1) and in subjects 
with mild and moderate renal impairment (Part 2) matched for age and body weight. Details on the age 
and body weight matching criteria are specified in Section 4 of the protocol.  
Since the metabolic pathway of apraglutide is expected to be degradation into small peptides and amino 
acids via catabolic pathways, similar to the catabolism for endogenous GLP-2, and in keeping with 
previous nonclinical and clinical pharmacokinetic trials that demonstrated no intact parent compound 
being recovered from the urine, it is not expected that renal impairment will have an impact on the PK 
of apraglutide. Therefore, a reduced, adaptive trial design will be pursued. In this trial design, only 
subjects with severe renal impairment and normal renal function will be studied first. In this manner, 
the effect of renal impairment on apraglutide PK will be initially evaluated in the renal impaired 
population most likely to be of impact. The impact of renal impairment expression of cytochrome P450 
(CYP) enzymes, if any, is expected to be minimal and hence can also be evaluated in the severely 
renally impaired population to estimate degree of impact. If the trial results confirm that severe renal 
impairment does not alter PK to an extent that warrants dose adjustment, no further trial is warranted. If 
the results do not support such a conclusion, Part 2 will be conducted in subjects with moderate and 
mild renal impairment, based on the decision criteria outlined in Section 3. 
Single-dose of SC apraglutide PK appears to be linear in the dose ranges between 2.8 mg to 56.9 mg 
relative to Cmax and AUCinf. No direct enzyme inhibition/induction or time-dependent enzyme 
inhibition is expected. The absolute bioavailability was 24.6% and the terminal half-life (t1/2) was 
approximately 30 hours. Considering a linear PK at the therapeutic dose range being tested in Phase 2 
trials (5 10 mg) in which single-dose PK behavior can predict multiple dose PK, a single-dose trial will 
be conducted to evaluate apraglutide PK under conditions of renal impairment.  
The trial will use a single dose of 5 mg apraglutide administered via SC injection. 
1.3 Risk-benefit Assessment 
The overall conclusion from the nonclinical and Phase 1 and 2 trials conducted with apraglutide is that 
there are no apparent safety concerns with the administration of apraglutide in the 5 mg dose selected 
for this trial. A single dose of 56.9 mg was safe and well tolerated in the single ascending dose (SAD) 


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part of the entry into human trial. The selected dose of 5 mg is expected to produce exposures well 
below the levels previously found to be safe and well tolerated, even accounting for some increase in 
renally impaired subjects. Current data indicate that apraglutide has intestinotrophic effects on the 
intestinal epithelium, which may result in transient abdominal side effects. 
In the following sections, the current nonclinical and clinical experience with apraglutide is 
summarized. A detailed review of pre-
Brochure. 
1.3.1 Nonclinical Experience 
1.3.1.1 Pharmacokinetics 
Nonclinical trials of apraglutide have been conducted in mice, rats, monkeys and minipigs. 
The PK properties of apraglutide, administered at various dose levels either intravenously (IV) as a 
single bolus or by SC injection, were found to be consistent across species with no apparent sex 
differences. The PK profile was characterized by a low systemic clearance, small volumes of 
distribution, and a long half-life when compared to human GLP-2 and other known GLP-2 agonists. 
Following SC administration, apraglutide displayed absorption-controlled kinetics resulting in a 
protracted half-life being 5 6 times longer compared to the half-life after IV administration. It is 
believed that the low clearance and the long half-life depend, at least in part, on the high protein 
binding and slow metabolism of the drug.  
1.3.1.2 Safety 
Single-, 2-week and 5-week repeated dosing trials in rats and minipigs showed dose-related mucosal 
effects (hyperplasia and hypertrophy of intestinal villi and crypts) of apraglutide in the intestine of both 
species, demonstrating the expected mode of action of the compound and the responsiveness of both 
animal species to the treatment. 
When 
the 
intestinal 
mucosa 
was 
examined 
by 
standard 
histology, 
morphometry 
or 
immunohistochemistry for proliferation and apoptosis, no adverse forms of cell growth, e.g., aberrant 
cell division, pre-neoplastic or neoplastic changes, excessive apoptosis or cell necrosis were revealed. 
Moreover, additional investigation conducted in vitro using 50 tumor cell lines, including several colon 
cancer cell lines, showed that the expression of the GLP-2 receptor mRNA in the large majority of 
these cell lines is extremely low (100-fold to >1000-fold lower) when compared to the expression of 
the GLP-2 receptor mRNA of the positive controls. Therefore, the pharmacologic profile of apraglutide 
was found to be consistent with a minimal risk of direct action to stimulate proliferation of tumor cells 
or the release of growth factors from tumor cells. 
Data from the pivotal toxicology in vivo trials (5-week repeated treatment) also indicated that 
apraglutide was not immunogenic in the selected animal species, had no dose-limiting or adverse 
systemic changes, and no effect on the respiratory, cardiovascular or nervous systems. Apraglutide did 
not induce genotoxicity when tested using in vitro or in vivo assays and did not have effects on 
reproductive organs with regard to clinical behavior, weight of the organs or macroscopic/microscopic 
examination. 


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Regarding local tolerance, investigation in the minipig found a presumably concentration-dependent 
local irritating potential of the dose formulations that were considered to be of human relevance. The 
degree of local irritation observed, however, was minimal to slight and similar to the vehicle control. 
1.3.2 Clinical Experience 
To date, 104 subjects participated in four clinical trials with apraglutide among whom 82 subjects 
(66 healthy subjects and 16 SBS patients) received at least one dose of apraglutide. These four 
completed clinical trials are described below: 
 Two Phase 1 clinical trials in healthy subjects: 
o Clinical trial GYM-P3-698, a single-ascending dose (SAD) and multiple-ascending dose 
(MAD), placebo-controlled clinical trial of apraglutide in healthy adult subjects
evaluating safety, tolerability, PK, and PD
o Clinical trial TA799-002, a multiple-dose parallel arm clinical trial in healthy adult 
subjects to evaluate the effect of multiple SC doses of either apraglutide (1, 5, or 10 mg) 
or placebo once weekly for 6 weeks on the PD marker citrulline 
 Two Phase 2 clinical trials designed to assess the safety and tolerability and to demonstrate 
proof-of-concept for apraglutide in SBS subjects:
o Clinical trial GLY-321-2017, an open label metabolic balance clinical trial in SBS 
subjects testing a weekly dose of 5 mg apraglutide in SBS patients 
o Clinical trial GLY-311-2017, a dose-exploration clinical trial in SBS-IF subjects testing 
weekly 5 mg apraglutide against placebo and 10 mg apraglutide in an open-label 
extension 
1.3.2.1 Pharmacokinetics 
Dose-proportional PK parameters obtained by non-compartmental analysis were seen after multiple 
doses for apraglutide within the range of 5.7 mg to 56.9 mg in clinical trial GYM-P3-698 and within 
the range of 1 mg to 10 mg in clinical trial TA799-002. 
A population PK/PD model of apraglutide in healthy subjects and SBS patients [13] has been 
developed with data provided by the 82 subjects exposed to apraglutide to date. This model describes 
well apraglutide concentrations across the whole-body weight range of the subjects and for the doses of 
1 to 50 mg SC with one central compartment with zero-order absorption from the subcutaneous 
administration site and first order elimination from the central compartment. The typical PK parameters 
for a 70 kg-weight human receiving 5 mg are: 
 Absorption duration: 1.46 days 
 Apparent volume of distribution: 31.5 L 
 Clearance: 16.8 L/day 
 Half-life: 1.32 days  
The inter-individual variability (% coefficient of variation [CV]) was 35% on clearance and 41% on the 
volume of distribution. Body weight influenced clearance and the volume of distribution. No 


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statistically significant difference was found between the PK parameters of healthy subjects and SBS 
patients. 
Body weight was found to be a covariate on clearance and apparent volume of distribution. 
1.3.2.2 Pharmacodynamics 
Apraglutide increased plasma citrulline levels (a surrogate marker of small intestine enterocyte mass 
and function) and increased intestinal absorption as demonstrated by the following: 
In clinical trials GYM-P3-698 and TA799-002, plasma citrulline levels increased in a dose dependent 
manner reaching a plateau at approximately 10 mg.  
In the metabolic balance clinical trial GLY-321-2017, apraglutide at a weekly dose of 5 mg increased 
intestinal absorption after 4 weeks of treatment, as evidenced by increased wet weight absorption, 
energy absorption, and urinary output in SBS patients. 
The results seen with apraglutide in the dose-exploration clinical trial GLY-311-2017 are consistent 
with those seen in the metabolic balance clinical trial GLY-321-2017. Apraglutide increased urinary 
output, a surrogate marker of intestinal absorption. No statistically significant difference between 5 mg 
and 10 mg doses was observed.
1.3.2.3 Safety 
Apraglutide has been generally safe and well tolerated in the clinical studies conducted to date as 
demonstrated by the following: 
 Doses up to 56.9 mg were safe and well tolerated in the SAD and MAD parts of the Phase 1 
clinical trial GYM-P3-698  
 Apraglutide was well tolerated up to six weekly doses of 10 mg in clinical trial TA799-002 in 
healthy subjects 
 A dose relationship has not been seen for any adverse event (AE) in any of the studies 
 The most frequent AEs in clinical trial GLY-321-2017 included nausea, GI stoma output 
decreased, and stoma complications 
 Frequent AEs in clinical trial GLY-311-2017 were primarily related to the expected PD effects 
of apraglutide, including decreased stoma output or stoma output abnormal, polyuria, and 
decreased thirst 
 Serious AEs (SAEs) have primarily been disease complications that are common in SBS 
subjects, including device-related sepsis and device malfunction. Two subjects had three 
treatment-emergent SAEs. All of the SAEs resolved; 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 QTcF prolongation >500 milliseconds was seen in any of the clinical trials. In clinical trials 
GLY-311-2017 and GLY-321-2017, the changes from baseline in the QTcF values were 


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 msec for all subjects at all time points, except for one subject at the EOT visit and in 
another subject at pre-dose of Period 3 
 Low-titer anti-drug antibodies (ADA) have been seen in five subjects (none in clinical trial 
GYM-P3-698, one in clinical trial TA799-002, three in clinical trial GLY-311-2017, and one in 
clinical trial GLY-321-2017). ADA had no apparent effect on either the PD or PK of 
apraglutide  
 
 


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2 Trial Objectives and Endpoints 
2.1 Objectives 
2.1.1 Primary Objective 
 Part 1 of clinical trial: To assess the pharmacokinetics (PK) of apraglutide in subjects with 
severe renal impairment compared to matched control subjects with normal renal function 
following single SC dose administration 
 Part 2 of clinical trial (if applicable; see criteria to move to Part 2 in Section 3.1.1): To assess 
the PK of apraglutide in subjects with moderate and mild renal impairment compared to 
matched control subjects following single SC dose administration  
2.1.2 Secondary Objective 
 To assess the safety and tolerability of apraglutide administered to subjects with varying 
degrees of impaired renal function 
2.2 Endpoints 
2.2.1 Primary Endpoints 
 Plasma apraglutide PK parameters: Cmax and AUCinf, AUClast, AUC0-7days, Tmax, 
z, t½, CL/F, 
Vz/F  
Cmax and AUCinf or AUClast are primary PK parameters. All others as secondary PK parameters 
2.2.2 Secondary Endpoints 
 Adverse events (type, frequency and intensity), adverse events of special interest (AESIs), vital 
signs (systolic and diastolic blood pressure [BP], heart rate), recorded triplicate ECG (intervals, 
rhythm, and morphology), clinical chemistry, hematology and urinalysis 
 
 




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3.1.1 Part 1 of Clinical Trial
A total of approximately 16 subjects will be enrolled in Part1; approximately eight subjects with severe 
renal impairment (Cohort 1) and approximately eight with normal renal function (Cohort 2) to ensure at 
least six evaluable subjects in each group. Subjects from the severe renal impairment group will be 
recruited first. The demographics will be pooled across enrolled subjects to determine an average value 
for age and weight in the severe impairment group. Subsequently, the healthy subjects will be recruited 
later such that each subject
severe renal impairment group. Care will be taken when recruiting the healthy subjects such that the 
entire group is not of substantially different age or of substantially different body weight than the 
severely renally impaired subjects. 
Criteria to proceed to Part 2: After evaluation from Part 1, Part 2 will be conducted if the point estimate 
of apraglutide area under the concentration-time curve from time 0 to infinity (AUCinf or AUClast [if 
AUCinf cannot be calculated]) geometric mean ratio (GMR) for the severe renal impairment group 
2. This metric is supported by recommendations from 
Huang et al [14]. Furthermore, apraglutide was well tolerated up to 56.9 mg SC QW and very well 
tolerated at 28.4 mg SC QW, further demonstrating the large therapeutic margin of apraglutide. If this 
criterion is not met, the trial will stop after Part 1.  
If there are subjects who withdraw or discontinue treatment from the normal or severe renal 
impairment groups and who are considered to be non-evaluable with respect to the primary PK 
objective, additional subjects can be enrolled at the discretion of the sponsor.  
3.1.2 Part 2 of Clinical Trial
Based on whether the decision criterion to proceed to Part 2 is met, approximately eight subjects each 
with moderate (Cohort 3) and mild (Cohort 4) renal impairment will be enrolled to ensure at least six 
evaluable subjects in each group. As in Part 1, renal impairment classification will be based on eGFR 
[15]. Healthy subjects will not be enrolled in Part 2. Healthy subjects from Part 1 will be used as the 
control group of the moderate and mild renal impairment subjects. 
When recruiting the Part 2 subjects, attempts to match the entire group to the subjects in Part 1 with 
respect to age and body weight will be made. Other demographics such as race and ethnicity may be 
considered for matching the Part 1 and Part 2 populations when possible.  
As in Part 1, if there are subjects who withdraw or discontinue treatment from the moderate or mild 
impairment group and who are considered to be non-evaluable with respect to the primary PK 
objective, additional subjects can be enrolled at the discretion of the Sponsor.  
3.1.3 For Both Parts 1 and 2 of Clinical Trial 
All subjects in both normal and renal impairment groups will provide informed consent and undergo 
screening evaluations to determine their eligibility. Subject screening for participation in this trial will 
consist of up to two CRU outpatient visits not more than 14 days apart (but at least 3 days apart) to 
confirm renal stability. The first screening visit will occur within 28 days prior to administration of 
apraglutide. For those subjects with renal impairment, if a historical eGFR within 3 months (90 days) 
of Screening is not available to confirm stability, a second eGFR value will be obtained (3 to 14 days 


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apart). The second eGFR value may be obtained at admission, assuming the admission falls at least 
3 days, but not more than 14 days following collection of eGFR value at initial screening. 
The average of the two values will be utilized for subject classification. If the renal function stability 
criterion is met, but the renal function classification category changes between the eGFR value 
measured at Screening 1 visit (S1) and the calculated average of the eGFR value measured at S1 and 
Screening 2 visit (S2, which may be obtained at admission), then a third eGFR value may be measured 
at the Investigator  discretion within the screening window. The calculated average of all three eGFR 
values will then be utilized to determine renal function classification and subject stratification. 
Each subject will be admitted to the CRU on Day -1 (at least 12 hours prior to the dose of apraglutide 
on Day 1) and will be confined to the CRU until Day 8. 
On the morning of Day 1, the subjects will receive apraglutide as a single 5 mg SC dose after a fast of 
at least 8 hours. No food will be allowed for at least 2 hours post dose. Serial blood samples at 
specified time intervals (see Section 7) will be collected on site for up to 168 hours post dose (Day 8), 
prior to discharge from the CRU. A final PK sample will be collected at 240 hours (Day 11) during an 
outpatient visit. The average of the S1 and S2 eGFR values will be used in PK analysis. Historical 
eGFR within the past 3 months may be used with the S1 value for the average calculation for PK 
analysis, if available. 
Safety assessments will be performed during S1, and on Day -1, Day 2, Discharge Day 8, and at 
follow-up on Day 11 and Day 14±2 days. If necessary, one serum creatinine will be additionally 
assessed on S2 for eGFR estimation. Physical examination, vital signs measurements, and clinical 
laboratory tests will be conducted and AEs will be monitored from the point of informed consent to 
assess safety. The total participation time (i.e., CRU confinement time for trial procedures for each 
subject in this trial is approximately 8 nights/9 days (excluding Screening and Follow-up visits).  
 
The following CKD-EPI Creatinine Equation [16] will be used to calculate eGFR:  
1)  × max (
-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] 
Notes: eGFR is expressed as mL/min/1.73 m2 of body surface area, SCr (serum creatinine) is expressed 
in mg/dL 
 = -0.329 (females) or -0.411 (males) 
1 max
years 
To be enrolled in the trial, subjects 
either one of the following: 
- 
Use of historical eGFR provided in source (calculated by the CKD-EPI equation) to determine 
25% change based on comparison between historical value (within 3 months or 90 days) and 
Screening visit  


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- 
Based on S1 eGFR and S2 eGFR (calculated by the CKD-EPI equation). The S2 eGFR 
assessment should be performed between 3 and 14 days after the S1 eGFR assessment. S2 
assessment can be performed at check-in on Day -1 
- 
If the renal function stability criterion is met and the renal function classification category 
remains the same between history eGFR and S1 eGFR and/or the average of S1 and S2 eGFRs, 
subject is eligible for enrollment 
- 
If the renal function stability criteria are not met, an additional eGFR can be performed at the 
Investigator  discretion. The average of all three eGFR values will be utilized for subject 
stratification. If a value is deemed erroneous by the Investigator, the value will be discussed 
with the Sponsor and a determination will be made if the value can be excluded from the 
average calculation 
- 
If the renal function stability criterion is met but the renal function classification category 
changes between S1 eGFR and the average of S1 and S2 eGFRs (or average between historical 
and S1), a third eGFR value may be obtained at 
 discretion within screening 
window, and the average of all three eGFR values will be utilized for subject stratification 
3.1.4 Re-screening 
In case of screen failure related to eGFR stability and/or change in the renal function classification 
category, subjects may be re-screened once after a 30-day period, provided that the initial screen failure 
is not due to an inclusion/exclusion criterion that results in permanent disqualification from enrollment 
(e.g., medical history). This can be done only with S
 A new ICF must be signed prior 
to any clinical trial-specific procedures for all subjects approved to re-screen. 
Please see Table 3 below regarding the demonstration of stable renal function: 
Table 3: Criteria to establish Stable Renal Function 
S1= Screening Visit 1; S2= Screening Visit 2.
a. 
Parenthesis of | | represents absolute values. 
 
3.2 Drug, Route, Dosage and Treatment Plan 
The therapeutic relevance of SC injections with a GLP-2 analogue for the treatment of subjects with 
SBS intestinal failure has recently been established [7]. 
In the previous first-in-human, placebo-controlled, randomized Phase 1a trial, the results of the single 
ascending doses and multiple doses (once a week for three consecutive weeks) found apraglutide to be 
generally safe and well tolerated up to the 25 mg dose since the reported AEs were only mild in 
severity.
Renal function Measurement 
eGFR 
Criterion for stability 
Historical (Within 90 days) or S1 
G1 
 
S2 (Within 3 to 14 days after S1) 
G2 
=|G2-G1|×100/G1a
If  25%; stable 
If  >25%; not stable 


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Due to the long half-life of apraglutide (approximately 30 hours after SC dosing), the 25 mg dose was 
able to maintain a plasma concentration of apraglutide of not less than 60 ng/mL over a week. Based on 
literature for another GLP-
[12], adjusting for the high protein 
binding of apraglutide and a similar potency compared to teduglutide, a plasma concentration of 
60 ng/mL apraglutide is expected to be efficacious.
Recent analyses of pharmacology data collected in preclinical trials applying a large range of doses 
suggest that a lower dose of apraglutide, such as 5 mg, could also show pharmacological activity 
(increase in intestinal weight) even if it covers the 60 ng/mL threshold for less than 7 days. In fact, data 
from animal trials suggest that the intestinotrophic effect of apraglutide could be maintained for several 
days following a single dose or for several weeks after a 5-week multiple dosing both in rats and 
minipigs. Therefore, the 5 mg QW dose, when administered SC in humans, could be sufficient for 
maintaining the pharmacological effect until the next dosing on Day 7.  
Since single SC dose of apraglutide PK appear to be linear in the dose ranges of 2.8mg 56.9 mg 
relative to Cmax and AUCinf, no direct enzyme inhibition/induction or time-dependent enzyme inhibition 
has been identified to date in in vitro trials. The absolute bioavailability was 24.6% and the t1/2 was 
approximately 30 hours. Considering a linear PK at the therapeutic dose range being tested in Phase 2 
trials (5 10 mg), in which single dose PK behavior can predict multiple dose PK, a single dose trial 
will be conducted to evaluate the apraglutide PK of a single 5 mg SC injection, under conditions of 
renal impairment.  
3.3 End of Trial Definition 
A subject is considered to have completed the trial when he or she has received one investigational 
medicinal product (IMP) injection and has completed the confinement period and Follow up visit.  
The trial will be closed when all subjects have completed Day 14±2 (end of trial visit). 
 
 


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4 Trial Population 
A total of approximately 16 subjects will be enrolled in Part 1: approximately eight subjects with 
severe renal impairment (Cohort 1) and approximately eight subjects with normal renal function 
(Cohort 2) to ensure at least six evaluable subjects in each group. 
4.1 Inclusion Criteria 
 All Subjects 
Subjects are eligible to be included in the trial only if all of the following criteria apply: 
Age and Sex 
1. Male or female subjects who are between the ages of 18 75 years, inclusive, at Screening 
Type of Subject and Disease Characteristics 
2. Subjects who are willing and able to comply with all scheduled visits, treatment plan, laboratory 
tests, and other trial procedures 
3. 
2; and a total body weight of >50 kg (110 lb) 
4. Capable of giving signed informed consent which includes compliance with the requirements 
and restrictions listed in the informed consent form (ICF) and in this protocol  
5. Women of childbearing potential must agree to practice effective contraception and to use a 
highly effective method of contraception during the trial and for 1 month 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, vasectomized partner. To be considered sterilized or infertile, females must 
have undergone surgical sterilization (bilateral tubectomy, hysterectomy, or bilateral 
ovariectomy) or be postmenopausal (defined as at least 12 months amenorrhea; it may be 
confirmed with follicle-stimulating hormone test if there is doubt and/or the woman is under 
60 years of age and not using hormonal contraception or hormone replacement therapy (HRT)  
6. Male subjects with a female partner of childbearing potential must commit to practice highly 
effective methods of contraception (e.g., condom) and abstain from sperm donation during the 
trial and for 1 month after the EOT visit 
 Additional Inclusion criteria for Healthy Subjects with Normal Renal Function (Cohort 2 
only) 
7. No clinically relevant abnormalities identified by detailed medical history, full physical 
examination, including body temperature, blood pressure (BP), and heart rate measurement, 
12-lead electrocardiogram (ECG), and clinical laboratory tests  
8. Normal renal function (average eGFR measured by CKD-
2) at two 
screening visits where Screening 2 can be performed at admission on Day -1 
9. Demographically comparable to the group of subjects with impaired renal function: 
a. 
impairment cohort (Cohort 1)  


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b. Attempts will be made to ensure that the male-to-female composition of Cohort 2 is 
comparable to that in the severe renal impairment cohort (Cohort 1) 
c. Other demographic characteristics such as race and ethnicity matched as closely as possible 
to the renal impairment cohort  
 Additional Inclusion criteria for Subjects with Impaired Renal function (Cohort 1 and 
Cohorts 3 and 4 [if applicable] only) 
10. Good general health commensurate with the population with chronic kidney disease (renal 
medical history, full physical examination, measurement of heart rate and 12-lead ECG, as well 
as clinical laboratory tests (except serum creatinine and eGFR). Hypertension, diabetes mellitus, 
hyperparathyroidism, ischemic heart disease and other common co-morbidities in this 
population are possible exemptions, as long as, in the opinion of the Investigator, the subject is 
medically stable, is on a stable drug regimen, and can abide by the meals and dietary restrictions 
outlined in Section 4.3 
11. Meet the following eGFR criteria (based on average) during the screening period based on the 
CKD-EPI equation. 
a. Severe renal impairment: eGFR <30 mL/min/1.73 m2, but not requiring hemodialysis 
b. Moderate renal 
/1.73 m2 and 
<60 mL/min/1.73 m2 
c. Mild renal impairment (Part 2 only): eGFR 
 <90 mL/min/1.73 m2 
The eGFR values obtained during Screening visits should not be more than 25% different for 
Cohort 1 (severe), Cohort 3 (moderate), and Cohort 4 (mild)  
12. Any form of renal impairment except acute nephritic syndrome or nephrotic syndrome defined 
as proteinuria >3 g (subjects with history of previous nephritic syndrome but in remission can 
be included) 
13. Stable concomitant drug regimen (as defined in Section 6.2) for the management of individual 
nditions 
4.2 Exclusion Criteria 
 All Subjects  
Subjects excluded from the trial if any of the following criteria apply: 
Medical Conditions 
1. Renal transplant recipients 
2. History of systemic infection requiring hospitalization, parenteral antimicrobial therapy, or as 
otherwise judged clinically significant by the Investigator within 3 months prior to Screening 
and Day 1
3. Any active malignancies or history of malignancies within the past 2 years prior to screening 
with the exception of adequately treated or excised non-metastatic basal cell or squamous cell 
cancer of the skin or cervical carcinoma in situ 
4. Other acute or chronic medical or psychiatric condition including recent (within the past year) 
or active suicidal ideation, or behavior that may increase the risk associated with trial 
participation or investigational medicinal product (IMP) administration or may interfere with 


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the interpretation of trial results and, in the judgment of the Investigator, would make the 
subject inappropriate for entry into this trial 
5. Treatment with an IMP within 30 days or five half-lives, if known, (whichever is longer) 
preceding the dose of IMP 
6. Male subjects who are unable to comply with the following requirements during the 
intervention period and up to 1 month after the dose of apraglutide, which corresponds to the 
time needed to eliminate trial interventions: 
a. Refrain from donating sperm  
b. PLUS, either be abstinent from heterosexual intercourse with a female of childbearing 
potential as their preferred and usual lifestyle abstinent on a long-term persistent basis and 
agree to remain abstinent  
c. OR must agree to use a male condom with spermicide when engaging in any activity that 
allows for passage of ejaculate to another person  
d. Vasectomy 
7. A history of clinically significant intestinal adhesions and/or chronic abdominal pain 
8. History of known colon polyps or family history of familial adenomatous polyposis  
Diagnostic Assessments 
9. Positive blood screen for hepatitis C antibody, hepatitis B surface antigen or human 
immunodeficiency virus (HIV)-1 and -2 antibodies 
10. ANY of the following abnormalities in clinical laboratory tests at Screening, and confirmed by a 
single repeat, if deemed necessary: 
a. Serum albumin concentration <25 g/L (2.5 g/dL)  
b. Hemoglobin concentration <90 g/L (9.0 g/dL)  
c. Enzymes aspartate amino transaminase (AST) or alanine amino transaminase (ALT) values 
>2 × upper limit of normal (ULN) 
d. 
 
11. In the opinion of the Investigator (or designee), subjects have any clinically significant 
labora
in the trial. Screening laboratory tests with abnormal results may be repeated once to confirm 
abnormal results (with the same screening number); the last value will be used to determine 
eligibility 
12. Positive urine test for alcohol or illicit drugs at either Screening or admission. Renal impairment 
subjects may be eligible to participate after approval from Sponsor if their drug screen is 
positive for a prescribed substance that is not expected to interfere with the PK of apraglutide 
13. Screening 12-lead ECG in triplicate that demonstrates: 
a. Clinically significant abnormalities requiring treatment (e.g., acute myocardial infarction, 
serious tachy- or brady-arrhythmias) or indicating serious underlying heart disease (e.g., 
cardiomyopathy, Wolff-Parkinson White syndrome) 
b. 
 (QTcF) >450 msec for 
subjects with normal renal function and >480 msec for subjects with impaired renal function 
c. Long QT Syndrome, a family history of Long QT Syndrome, or a history of Torsades de 
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Prior/Concomitant Therapy
14. Use of prescription or non-prescription drugs and dietary supplements within 7 days or five 
half-lives (whichever is longer) prior to Day 1.  
Limited use of nonprescription medications that are not believed to affect subject safety or the 
overall results of the trial may be permitted on a case by case basis following approval by the 
Investigator in consultation with the Sponsor. 
Herbal supplements must be discontinued at least 28 days prior to the dose of IMP. 
For subjects with renal impairment, stable concomitant medications (including herbal 
supplements) may be given if they are considered necessary for the welfare of the subjects (e.g., 
standard therapy for underlying diseases), and are not contraindicated with the IMP or likely to 
interfere with the PK of the IMP. Stable is defined as no changes in current medications or 
starting new medications for 14 days prior to apraglutide administration 
Other Exclusion Criteria
15. Investigator site staff members directly involved in the conduct of the trial and their family 
members, or any site staff members otherwise supervised by the Investigator 
16. History of regular alcohol consumption exceeding seven drinks/week for females or 
14 drinks/week for males (1 drink = 5 ounces [150 mL] of wine, or 12 ounces [360 mL] of beer, 
or 1.5 ounces [45 mL] of hard liquor) within 3 months of Screening 
17. Female subjects of childbearing potential who are unwilling or unable to use highly effective 
methods of contraception as outlined in the protocol for the duration of the trial and for at least 
1 month after the administration of the IMP; pregnant female subjects; female subjects planning 
to become pregnant during the duration of the trial and until 1 month after the administration of 
the IMP; breastfeeding female subjects 
18. Blood donation of approximately 1 pint (500 mL) or more within 60 days prior to the dose of 
IMP. Plasma donations of approximately 1 pint (500 mL) or more within 28 days prior to the 
dose of IMP 
19. History of sensitivity to heparin or heparin-induced thrombocytopenia, only if heparin is used to 
flush intravenous (IV) catheters used during serial blood collections 
20. Unwilling or unable to comply with the Lifestyle Considerations outlined in Section 4.3 
 Additional Exclusion Criteria for Healthy Subjects with Normal Renal Function (Cohort 2 
only) 
21. Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, 
gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or allergic disease (including 
drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing) 
22. Evidence or history of clinically significant dermatological condition (in the opinion of the 
Investigator) or visible rash present during physical examination 
 Additional Exclusion Criteria for Subjects with Impaired Renal Function (Cohort 1 and 
Cohorts 3 and 4 [if applicable] only) 
23. Subjects requiring hemodialysis and/or peritoneal dialysis 


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24. Subjects with other clinically significant disease that may affect the safety of the subject or that 
may affect the PK of apraglutide (including drug allergies, but excluding untreated, 
asymptomatic, seasonal allergies at time of dosing) 
25. Subjects with any significant hepatic, cardiac, or pulmonary disease or subjects who are 
clinically nephrotic. Hypertension, diabetes mellitus, hyperparathyroidism, ischemic heart 
disease, etc. are not cause for exclusion as long as, in the opinion of the Investigator, the subject 
is medically stable and any drugs that are administered for these conditions are not expected to 
interfere with the PK of apraglutide 
26. 
 least 5 minutes of 
repeated two more times and the average of the three BP values should be used to determine the 
 eligibility. An additional set of vital signs can be obtained at the discretion of the 
Investigator 
4.3 Lifestyle Considerations 
The following guidelines are provided: 
4.3.1 Meals and Dietary Restrictions 
 Water is permitted without restriction during trial participation 
 Subjects must abstain from all food and drink (except water) at least 8 hours prior to any safety 
laboratory evaluations and 8 hours prior to IMP administration on Day 1, and for 2 hours 
following dosing. There will be no restriction to breakfast on the other days provided other 
restrictions are followed 
 Breakfast, lunch, and dinner can be scheduled according to the schedule at the CRU. An 
evening snack may be permitted prior to the start of the 8-hour fast before IMP dosing on Day 1 
4.3.2 Caffeine, Alcohol, and Tobacco 
 Subjects will abstain from caffeine-containing products for 24 hours prior to dosing until 
collection of the final PK blood sample. Subjects will additionally abstain from caffeine-
containing products at least 2 hours prior to any scheduled vital signs, and ECG measurements 
Subjects will abstain from alcohol for 24 hours prior to admission to the CRU and continue 
abstaining from alcohol until collection of the final PK blood sample. Subjects may undergo a 
urine alcohol test at the discretion of the Investigator 
 
5 cigarettes per day during the trial. Smoking will be monitored 
by the CRU 
4.3.3 Activity 
 Subjects will abstain from strenuous exercise (e.g., heavy lifting, weight training, calisthenics, 
aerobics) for at least 48 hours prior to each blood collection for clinical laboratory tests and 
during confinement. Walking at a normal pace will be permitted 
 In order to standardize the conditions on PK sampling days, subjects will be required to refrain 
from lying down (except when required for BP, heart rate, and ECG measurements), eating, and 
drinking beverages other than water during the first 2 hours after dosing 


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4.3.4 Contraception and Definition of Woman of Child-bearing Potential 
4.3.4.1 Definition of Woman of Child-bearing Potential 
 The Investigator or his or her designee, in consultation with the subject, will confirm that the 
subject has selected an appropriate method of contraception for the individual subject from the 
permitted list of contraception methods noted below and will confirm that the subject has been 
instructed in its consistent and correct use. At time points indicated in the Schedule of 
Assessments, the Investigator or designee will inform the subject of the need to use highly 
effective contraception consistently and correctly 
 A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below) 
 If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of trial intervention, additional evaluation should be 
considered  
Women in the following categories are not considered women of child-bearing potential (WOCBP): 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining trial entry. 
the subject
documentation should be recorded in the subject
trial. 
3. Postmenopausal female: 
o A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause 
o A high follicle-stimulating hormone (FSH) level in the postmenopausal range will be 
used to confirm a postmenopausal state in women who are less than 60 years old and not 
using hormonal contraception or HRT 
4.3.4.2 Contraception Methods 
Highly Effective Methods That Have Low User Dependency 
 Implantable progestogen-only hormone contraception associated with inhibition of ovulation 
 Intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner. Vasectomized partner is a highly effective contraceptive method 
provided that the partner is the sole sexual partner of the WOCBP and the absence of sperm has 


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been confirmed. If not, an additional highly effective method of contraception should be used 
(e.g., male condom with spermicide). The spermatogenesis cycle is approximately 90 days 
Highly Effective Methods That Are User-Dependent: 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition 
of ovulation: 
 Oral 
 Intravaginal 
 Transdermal 
 Injectable 
Progestogen-only hormone contraception associated with inhibition of ovulation: 
 Oral 
 Injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the trial intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the trial and the 
preferred and usual lifestyle of the subject. 
 
 


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5 Premature Discontinuation of Subjects or Trial 
5.1 Subject Discontinuation 
The subjects have the right to withdraw from the trial at any time and for any reason, without the need 
to justify their decision and without prejudice to their current or future medical care by the investigator 
or hospital. 
If the reason for withdrawal is an AE, the AE should be reported and the subject should be followed up 
as outlined in the protocol.  
Withdrawn subjects who have been dosed with the IMP must have an early termination (ET) visit 
performed as soon as possible after the dose for safety assessments. Regardless of the reason for 
withdrawal, the Investigator will make every effort to ensure an ET visit is performed for subjects who 
have been dosed with IMP.
The Investigator also has the right to discontinue subjects at any time based on the best interest of 
subjects. 
Reasons for withdrawal from the trial: 
 Withdrawal of consent
 Important protocol deviation that, in the opinion of the Investigator and after discussion with 
the Sponsor, may invalidate the trial results 
 
 
 Pregnancy occurring between ICF signature and dosing 
 Adverse events that might place the subject at unacceptable risk if participation is continued 
 Subject is lost to follow-up 
 The clinical trial is terminated by the Sponsor 
A subject may be withdrawn if he/she develops an AESI such as hypotension, fluid overload, persistent 
abdominal pain, gall bladder, biliary and pancreatic disease of Grade 3 and above, according to the 
National Cancer Institute 
 Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
version 5 [17]. 
Furthermore, during the trial liver toxicity will be closely monitored according to guidelines from the 
USA Food and Drug Administration (FDA) and subjects will be withdrawn from the trial if any of the 
following stopping criteria are met. Further enrolment and dosing will be interrupted if a single subject 
experiences documented liver function abnormalities that meet the following criteria (see also Section 
10.10): 
 ALT or AST >8 × ULN once 
 ALT or AST >5 × ULN for more than 2 weeks 
 ALT or AST >3 × ULN and total bilirubin >2 × ULN or INR >1.5 
 ALT or AST >3 × ULN and clinical signs of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 


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Study enrollment may potentially be resumed following the review of all available safety data by the 
investigator 
and 
Institutional 
Review 
Board/Independent 
Ethics 
Committee, 
with 
a 
concurrent/consensus opinion that the totality of the data suggests that this event is unlikely to be 
related to the study drug. 
For all withdrawn subjects, site will attempt to perform EOT assessments matching the Day 14 visit at 
an ET Visit. The Investigator will document the date of discontinuation and, if possible, the main 
reason for the subject
subject
  
5.2 Subject Withdrawal of Consent and Subjects Considered Lost to Follow-up  
Subjects who request to discontinue receipt of trial treatment will remain in the trial and must continue 
to be followed for protocol-specified follow-up procedures. The only exception to this is when a 
subject specifically withdraws consent for any further contact with him or her or persons previously 
authorized by the subject to provide this information. The withdrawal of consent should be explained in
detail in the medical records by the Investigator, as to whether the withdrawal is only from further 
receipt of IMP or also from trial procedures and/or posttreatment trial follow-up, and entered on the 
appropriate case report form page.  
All reasonable efforts must be made to locate withdrawn subjects to determine and report their ongoing 
status. This includes follow-up with persons authorized by the subject as noted above. All attempts 
should be documented in the 
 medical record. For subject who are lost to follow-up (e.g., have 
not completed the trial, but cannot be reached), the site will use legally permissible methods to 
determine of the subject has died and to obtain the date and cause of death (for example, through use of 
public domain information or a release signed by the family to obtain health records). If the 
Investigator uses a third-party representative to assist in the follow-up portion of the trial and that has 
Investigator may use those means to access 
follow-up. The Investigator can also use other public vital status data necessary to complete the follow-
up portion of the trial if necessary. If after all attempts, the subject remains lost to follow-up, then the 
last-known-alive date, as determined by the Investigator, should be reported and documented in the 
 
trial at any time at their own request, or they may be withdrawn at 
any time at the discretion of the Investigator or Sponsor for safety, as noted in the protocol or for 
behavioral reasons, or the inability of the subject to comply with the protocol-required schedule of trial 
visits or procedures at a given Investigator site. The ET visit applies only to subjects who are 
randomized and then are prematurely withdrawn from the trial.  
It may be appropriate for the subject to return to the clinic for final safety assessments to be scheduled 
as early as feasible following the decision to withdraw from the trial.  
Lack of completion of all or any of the withdrawal/early termination procedures will not be viewed as a 
protocol deviation so long as subject safety was preserved.  
If the subject withdraws from the trial and also withdraws consent for disclosure of future information, 
no further evaluations should be performed, and no additional data should be collected. The Sponsor 
may retain and continue to use any data collected before such withdrawal of consent.  


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Subjects who withdraw from the trial may be replaced at the discretion of the Investigator upon 
discussion with the Sponsor.  
5.3 Trial Termination 
If the Investigator, the Sponsor, or the Safety Medical Monitor (who reviews medical information and 
safety data, and consults with the site on eligibility criteria) becomes aware of conditions or events that 
suggest a possible hazard to subjects if the trial continues, the trial may be terminated after appropriate 
consultation between the relevant parties. The trial may also be terminated early at the S
discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
 The discovery of an unexpected, significant or unacceptable risk to the subjects enrolled in the 
trial 
 Failure of the site to enroll subjects at an acceptable rate 
 A decision on the part of the Sponsor to suspend or discontinue development of the drug 
 The site cannot comply with the requirements of the protocol 
 It is not possible for the site to comply with GCP standards 
 IRB or a regulatory decision 
 Enrollment and further dosing of new subjects will be interrupted if two or more subjects 
experience any of the AESIs mentioned in Section 5.1. of moderate intensity (NCI-CTCAE 
Grade 3) and/or if one or more subjects experience a Grade 4 event (unless clearly not 
attributable to the study drug) 
 




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The solution can be drawn up into the syringe immediately following reconstitution and kept at room 
temperature until administration or the syringe can be drawn up just before administration. The 
required amount of reconstituted apraglutide (0.2 mL for 5 mg) will be withdrawn from the vial into the 
syringe for SC injection. After drawing up the syringe, it will be inspected for foreign particles and 
used if judged acceptable for administration. 
6.1.5 Packaging, Labelling, and Storage 
Packaging and labelling of the IMP is performed by the Clinical Trial Supplies (CTS) vendor in 
accordance with GMP and applicable regulatory requirements. 
The freeze-dried apraglutide powder is filled in 2 mL vials, sealed with rubber stoppers and aluminium 
caps. IMP individual vials will be labelled according to EudraLex Volume 4, Annex 13 [18] and 
national regulatory requirements.  
The Investigator must ensure that the IMP is stored refrigerated between 2 8°C in a secure location 
with controlled access. At the site, the temperature will be continuously monitored and the electronic 
log must be checked once daily during working days. Temperature deviations outside the allowed 
range must be reported and evaluated prior to use of the apraglutide. Details will be provided to the site 
in the IMP Manual. 
6.2 Concomitant Medications 
6.2.1 Previous and Concomitant Medication 
Concomitant medication is any medication apart from the IMP that is used during the subject
participation in the trial. All concomitant medication used, including vitamins and mineral 
supplements, must be recorded from the time of signature of the ICF to the end of the trial. The 
Investigator or delegate must seek information on concomitant medication use at each trial visit. The 
information collected for concomitant medication must include: 
 Medication name (preferably generic name) 
 Indication 
 Dosage 
 Frequency 
 Route of administration 
 Start and stop date or continuation 
6.2.2 Prohibited Previous and Concomitant Medication 
Any use of growth hormone, glutamine or growth factors such as GLP-1, GLP-2 or analogues thereof 
is prohibited within the last 3 months prior to Screening and throughout the trial. 
Systemic corticosteroids, methotrexate, cyclosporine, tacrolimus, sirolimus, infliximab or other 
biologic therapy/immune modifiers are prohibited within 30 days of Screening and throughout the trial. 
Use of prescription or non-prescription drugs and dietary and herbal supplements are prohibited within 
28 days or five half-lives, if known, (whichever is longer) prior to the first dose of IMP unless deemed 
necessary by the Investigator for the treatment of concurrent disease consistent with subjects with renal 
impairment.  


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Acetaminophen 
 
No new medication should be started during the trial, unless medically necessary and prescribed by the 
Investigator or another qualified designee involved in the subject
subject
 
All concomitant treatments taken during the trial must be recorded with indication, daily dose, and start 
and stop dates of administration. Concomitant drug and non-drug treatment will be collected. All 
subjects will be questioned about concomitant treatment at each clinic visit. 
Treatments taken within 28 days before the first dose of IMP will be documented as a prior treatment. 
Treatments taken after the first dose of IMP will be documented as concomitant treatments.
6.2.2.1 Subjects with Healthy Renal Function (Cohort 2 only) 
In general, subjects will abstain for all concomitant treatments (prescription or over the counter) as 
described in the Section 4.2, except for the treatment of AEs.  
6.2.2.2 Subjects with Impaired Renal Function (Cohort 1 and Cohort 3 and 4 [if applicable]) 
Subjects are permitted to be on stable doses (defined as no changes in current medications or new 
medications within 14 days prior to apraglutide administration) of background medications if they are 
considered necessary for the welfare of the trial subjects (e.g., standard therapy for the underlying 
disease), are not contraindicated with the IMP, and are unlikely to interfere with the PK of the IMP. 
Whenever possible, attempts must be made to not alter the doses and regimens of the concomitant 
medications after Day 1 and until the EOT on Day 14±2 days.  
 
 


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7 Trial Schedule and Assessments 
7.1 Screening Visit  
 
Subjects will be screened within 28 days prior to administration of the IMP to confirm that they meet 
the subject selection criteria for the trial. The Investigator (or designee) will obtain informed consent 
from each subject in accordance ICH/GCP guidelines. If the time between screening and dosing 
exceeds 28 days as a result of unexpected delays (e.g., delayed drug shipment), then subjects do not 
require rescreening if the Day -1 laboratory results meet eligibility criteria. Maximum delay accepted 
between screening and IMP administration is a total of 42 days. 
Subjects who qualified for this protocol but did not enroll from an earlier cohort/group may be used in 
a subsequent cohort/group without rescreening, provided the Day -1 laboratory results meet the 
eligibility criteria for this trial within 1 month after the date of screening.  
The following procedures will be completed (Table 1): 
 Obtain written informed consent 
 Confirm and document that the subject meets the inclusion/exclusion criteria 
 The Investigator or his/her designee will discuss with the subject the need to use highly 
effective contraception consistently and correctly according to the contraception guidelines and 
will confirm highly-effective, proper contraception is being used 
 Collect demography (subject race, ethnicity, date of birth, age, sex) 
 Collect height and weight and calculate BMI 
 Obtain medical history, including history of prior illegal drug, alcohol and tobacco use 
 Obtain complete medication history for all prescription or non-prescription drugs, and dietary 
and herbal supplements taken within 28 days prior to the planned dose 
 Obtain a supine BP and heart rate after at least 5 minutes of rest in a supine position. One repeat 
measurement may be allowed at the discretion of the investigator 
 Obtain body temperature 
 Conduct a full physical examination (PE); this must be performed by trained medical personnel 
at the CRU 
 Collect 12-lead ECG in triplicate after supine rest of 10 minutes or per CRU standard operating 
procedure 
 Assess baseline symptoms/AEs 
 If applicable, obtain as source document, prior/historical eGFR from the past 3 months using 
CKD-EPI equation (for Cohorts 1 [severe], 3 [moderate] and 4 [mild] only) 
 Collect blood and urine specimens for the following: 
o Safety laboratory tests (hematology, clinical chemistry and urinalysis) 
o Urine drug or alcohol test 
o Serum follicle-stimulating hormone concentration for any female subject who has 
been amenorrhoeic for at least 12 consecutive months and is under 60 years of age; 
serum pregnancy test for any woman of child bearing potential 


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o Collect blood for HIV, HBsAg, HBcAb, and HCV core Ab testing
o Serum creatinine and eGFR calculation using CKD-EPI equation 
o An optional glycosylated hemoglobin (HbA1c) and thyroid stimulating hormone 
(TSH) will be allowed at screening if applicable per the discretion of the investigator 
to confirm stability of concurrent medical conditions (for Cohorts 1 [severe], 3 
[moderate], and 4 [mild] only) 
 To prepare for trial participation, subjects will be instructed on all pertinent lifestyle
requirements and restrictions 
 
 If no historical serum creatinine/eGFR using CKD-EPI is available within the past 3 months 
(90 days), the subject will be asked to return to the CRU at least 72 hours but no more than 
14 days following initial collection of eGFR for Screening 2 for the determination of serum 
creatinine/eGFR using CKD-EPI and confirmation of renal stability alone (for Cohorts 1 
[severe], 3 [moderate], and 4 [mild] only). This second eGFR value may be obtained at 
admission  
 Weight 
 Contraception check 
 Concomitant medication
 Adverse event/SAE monitoring 
7.2 Safety Assessments 
Every effort should be made to ensure that protocol required tests and procedures are completed as 
described. However, it is anticipated that from time to time there may be circumstances outside of the 
control of the Investigator that may make it unfeasible to perform the test. In these cases, the 
Investigator must take all steps necessary to ensure subject safety. When a protocol-required test cannot 
be performed, the Investigator will document the reason in the source documents for the missed test. 
This will be reported as a protocol deviation. Corrective and preventative actions will be discussed with 
the site by the Monitor to ensure that required processes are adhered to, as soon as possible.  
For samples being collected and shipped, detailed collection, processing, storage and shipment 
instructions and contact information will be provided to the Investigator  site prior to initiation of the 
Trial.  
7.2.1 Laboratory Tests 
The following safety laboratory tests (Table 5, Table 6) will be performed at times defined in the trial 
procedures section of this protocol (Table 1). Additional laboratory results may be reported on these 
samples as a result of the method of analysis or the type of analyzer used by the clinical laboratory; or 
as derived from a calculated value. These additional tests would not require additional collection of 
blood. Unscheduled laboratory measures may be obtained at any time during the trial to assess a 
perceived safety concern and updated rationale and outcome documented in the source documents. 


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Table 5: Sampled Blood Volume 
 
Table 6: Safety Laboratory Tests 
a  
Only if urine dipstick is positive for blood protein, nitrites or leukocyte esterase.  
b  
At Screening only, in females who are amenorrhoeic for at least 12 consecutive months who are less than 60 years old and not using 
hormonal contraception or hormone replacement therapy.  
c  
At Screening only.  
 
Type 
Volume per sample (mL) 
Sample number 
Total (mL) 
Serology
6.5 
1 
6.5
Hematology 
3
6 
18
Chemistry 
7 
6 
42 
Thyroid-stimulating hormone (not additional if 
added to Chemistry panel)
3.5 
1 
3.5 
Glycosylated hemoglobin 
3 
1 
3 
Pharmacokinetic samples 
3 
30 
90 
Total
163 mL
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC count
MCV 
MCH 
MCHC 
Platelet count 
WBC COUNT
Total neutrophils (%, Abs) 
Eosinophils (%, Abs) 
Monocytes (%, Abs) 
Basophils (%, Abs) 
Lymphocytes (%, Abs) 
BUN 
Creatinine 
Glucose (fasting) 
Calcium 
Sodium 
Potassium 
Chloride 
Total CO2 
AST, ALT 
Total bilirubin 
ALP 
Uric acid 
Albumin 
Total protein 
Lipase 
Amylase 
Magnesium 
Phosphate 
Ferritin 
Lactate dehydrogenase 
C reactive protein 
Additional Tests 
 
AST, ALT (repeat) 
Total bilirubin (repeat) 
Albumin (repeat) 
ALP (repeat) 
Direct bilirubin 
Indirect bilirubin 
CK 
GGT 
PT/INR 
Total bile acids 
pH 
Glucose (qualitative) 
Protein (qualitative) 
Blood (qualitative) 
Ketones 
Nitrites 
Leukocyte esterase 
Urobilinogen 
Urine bilirubin 
Specific Gravity 
Microscopya 
TSH 
HbA1c 
FSHb 
Urine drug test 
Urine alcohol test 
Serum pregnancy test 
-hCG) 
eGFR 
HBsAgc 
HBcAbc 
HCV core antibodyc 
HIV -1, -2c 


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The total blood volume drawn will be approximately 163 mL per subject. Additional samples may be 
added if any laboratory result is outside of the normal range or for safety purposes. The samples will be 
destroyed after analysis.  
The minimum requirement for drug screening includes cocaine, tetrahydrocannabinol, opiates/opioids, 
benzodiazepines and amphetamines. Additional drugs of abuse screening that is part of the CRU 
protocol (on-site drug screen) will also be allowed. Subjects may undergo random urine drug testing at 
the discretion of the Investigator.  
Subjects will also be tested for alcohol in urine samples. 
7.2.2 Physical Examinations 
A complete physical examination (PE) will include, at a minimum, head, ears, eyes, nose, mouth, skin, 
heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and basic 
neurological systems. 
An abbreviated PE will include, at a minimum, assessments of general appearance, the respiratory, 
abdominal, and cardiovascular systems, and subject-reported symptoms. 
Symptom-directed PE can be performed at the discretion of the Investigator at any time if clinically 
indicated. 
practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the protocol. For measuring weight, a 
scale with appropriate range and resolution is used and must be placed on a stable, flat surface. 
Subjects must remove shoes, bulky layers of clothing, and jackets so that only light clothing remains. 
They must also remove the contents of their pockets and remain still during measurement of weight. 
7.2.3 Vital Signs 
 and recorded to 
the nearest mmHg after approximately 5 minutes of rest. The same arm (preferably the dominant arm) 
will be used throughout the trial. Every effort should be made to utilize the same method of 
measurement during the trial (automated versus manual). Subjects should be instructed not to speak 
during measurements. 
The same properly sized and calibrated BP cuff will be used to measure BP each time. Any repeat vital 
signs measurement will be taken manually. The use of an automated device for measuring BP and heart 
rate is acceptable; however, when done manually, heart rate will be measured in the brachial/radial 
artery for at least 30 seconds. When the timing of these measurements coincides with a blood 
collection, BP and heart rate should be obtained prior to the nominal time of the blood collection. 
Additional collection times, or changes to collection times, of BP and heart rate will be permitted, as 
necessary, to ensure appropriate collection of safety data. 
In some cases, it may be appropriate to repeat abnormal vital signs to rule out measurement errors due 
to e.g., improperly placed BP measurement cuff. 


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Temperature will be measured using non-contact temperature assessment devices. No eating, drinking, 
or smoking is allowed for 10 minutes prior to the measurement. 
7.2.4 Twelve-lead Electrocardiogram 
Twelve-lead ECG will be performed in triplicate in a consecutive manner after the subject has been 
resting in the supine position for at least 10 minutes. The readings should be at least 1 minute apart. 
The average value of the triplicate ECG will be collected for inclusion criteria for the QTcF. The ECGs 
in this manner should be collected at times specified in this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTc and QTcF intervals and QRS 
complex.  
To ensure safety of the subjects, a qualified individual at the Investigator site will make comparisons to 
baseline measurements (pre-dose on Day 1). Additional ECG monitoring will occur if a) a post-dose 
scheduled ECG. If either of these conditions occurs, then two additional ECGs will be collected 
approximately 2 to 4 minutes apart to confirm the original measurement. If the QTc values from these 
repeated ECGs remain above the threshold value, then a single ECG must be repeated at least hourly 
until QTc values from two successive ECGs fall below the threshold value that triggered the repeat 
measurement. 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality. It is important that leads be placed in the same positions each 
time in order to achieve precise ECG recordings. If a machine-read QTc value is prolonged, as defined 
above, repeat measur
determines that the QTc values are in the acceptable range using calipers.  
Triplicate ECG recordings should be performed before vital signs and laboratory blood collections at 
the same time point.
Sponsor upon request. Any clinically significant changes will be recorded and evaluated further, as 
clinically warranted.  
7.2.5 Clinical Safety Laboratory Assessments 
The Investigator must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the trial in the AE section of the eCRF. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying disease, unless 
judged by the I
 
All laboratory tests with values considered clinically significantly abnormal during participation in the 
trial should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or the Safety Medical Monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the sponsor notified. 
All protocol-required laboratory assessments must be conducted in accordance with the laboratory 
manual and the schedule of those assessments per protocol.  


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If laboratory values from non-protocol-
local laboratory require a change in subject management or are considered clinically significant by the 
Investigator (e.g., SAE or AE or dose modification), then the results must be recorded in the eCRF. 
Subjects may undergo random urine drug testing at the discretion of the Investigator.  
7.2.6 Pregnancy and Confirmation of Postmenopausal Status 
Pregnancy tests will be serum tests, but must have a sensitivity of at least 25 mIU/mL. Pregnancy tests 
will be performed in WOCBP at the times listed in the schedule of the assessments (Table 1). Women 
of child-bearing potential must be using a permitted contraceptive method to be eligible for trial 
participation. Following a negative pregnancy test result at Screening, appropriate contraception must 
be commenced, and a second negative pregnancy test result will be required at the baseline visit prior 
IMP. Pregnancy tests will also be done whenever a menstrual cycle is 
missed during the active treatment period (or when potential pregnancy is otherwise suspected) and at 
the end of the trial. Pregnancy tests may also be repeated if requested by IRBs or if required by local 
regulations. 
An FSH test will also be performed on any woman who is not of child-bearing potential on the basis of 
amenorrhea for a consecutive 12-month period who is less than 60 years old and not using hormonal 
contraception or HRT.  
7.2.7 Injection Site Reaction Assessments  
Subjects will be assessed for any injection site reaction related to apraglutide administration. This will 
include the following: bleeding, bruising, redness, tenderness, swelling, rash, discharge, and 
temperature. Any injection site reactions deemed by the Investigator will be documented as AEs.  
7.3 Trial Procedures at Each Visit 
For the trial period described below, when multiple procedures are scheduled at the same time point(s) 
relative to dosing; the following chronology of events should be adhered to, where possible.  
 Electrocardiogram in triplicate: obtain prior to vital signs measurements after a 10-minute 
supine rest and as close as possible to the scheduled time, but prior to blood specimen collection 
 Vital Signs: obtain BP/heart rate as close as possible to scheduled time, but prior to blood 
specimen collection and after 5 minutes of supine rest; body temperature will be taken using a 
non-contact assessment device 
 Pharmacokinetic blood specimens 
 Other procedures: obtain all other procedures as close as possible to the scheduled time, but 
may be obtained before or after blood specimen collection 
7.3.1 Day -1 
Subjects will be admitted to the CRU on Day -1 prior to Day 1 dosing. The following procedures will 
be completed following admission to the CRU: 
 Review of inclusion and exclusion criteria. 
 Obtain blood and urine samples for safety laboratory tests (hematology, clinical chemistry, 
urinalysis) after 8 hours fast. The results must have no clinically significant findings as judged 


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by the investigator, in order for a subject to be given IMP on Day 1. A serum pregnancy test for 
any WOCBP  
 Measure weight 
 Collection of urine for drug screen and alcohol test. These tests may be performed at any other 
time at the discretion of the Investigator
 The Investigator or his/her designee will discuss with subjects the need to use highly effective 
contraception consistently and correctly according to the contraception guidelines and will 
confirm highly effective contraception is being used  
 Serum creatinine, eGFR calculation using CKD-EPI 
 Collect 12- lead ECG in triplicate after supine rest of 10 minutes or per CRU standard operating 
procedure  
 Obtain supine BP and heart rate after at least 5 minutes of rest in a supine position. One repeat 
measurement may be allowed at the discretion of the Investigator 
 Obtain body temperature 
 Assess baseline symptoms/AEs 
 Review prior and concomitant medication(s) 
 Review changes in 
 medical history, including medication history since Screening  
 Conduct a complete PE only when a complete PE was not performed at S1 visit. If a complete 
PE was performed at screening visit, an abbreviated PE will be done at this point 
 Begin overnight fasting (8 hours) prior to Day 1 dose 
7.3.2 Day 1 
Prior to apraglutide dosing, the following procedures will be completed.  
 Injection Site Assessment 
 Assess baseline symptoms/AEs 
 Collect 12 lead triplicate ECG measurements within 45 minutes of dosing 
 Collect supine BP/heart rate, and body temperature within 45 minutes of dosing 
 Collect blood sample for PK analysis of apraglutide at approximately 5 minutes pre-dose  
Dosing 
 Dosing with 5 mg SC apraglutide will be given in the abdomen of the trial subject at time zero 
by the Investigator or qualified/trained designee  
After dosing, the following procedures will be completed: 
 Collect 12-lead triplicate ECG measurements at approximately 4 hours post-dose 
 Assess supine BP/heart rate and body temperature at 1 and 4 hours post-dose 
 Collect blood samples for PK analysis at 6 and 12 hours post-dose on Day 1 
 Review concomitant treatments 
 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
nonleading
 
 Injection site reaction assessment at approximately 4 hours post-dose 


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7.3.3 Day 2 
The following procedures will be completed: 
 Assess supine BP/heart rate and body temperature approximately 24 hours after dosing on 
Day 1
 Collect triplicate ECG at approximately 24 hours post-dose  
 Collect blood and urine samples for safety laboratory tests (hematology, clinical chemistry, 
urinalysis) 24 hours after dosing on Day 1 
 Collect blood samples for PK analysis of apraglutide at 24, 28, 36, and 40 hours after dosing on 
Day 1
 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
nonleading
 
 Review concomitant treatments 
 Injection site assessment at approximately 24 hours post-dose  
7.3.4 Day 3 
The following procedures will be completed: 
 Assess supine BP/heart rate and body temperature approximately 48 hours after dosing on 
Day 1
 Collect blood samples for PK analysis of apraglutide at 48 and 60 hours after dosing on Day 1 
 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
nonleading
 
 Review concomitant treatments 
 Symptom-driven PE, if indicated, to be performed by the Investigator or trained medical 
professional/designee  
 Injection site reaction assessment at approximately 48 hours post-dose
7.3.5 Day 4 
The following procedures will be completed: 
 Assess supine BP/heart rate and body temperature approximately 72 hours after dosing on 
Day 1
 Collect blood samples for PK analysis of apraglutide at 72 hours after dosing on Day 1 
 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
nonleading
 
 
 Review concomitant treatments 
 Injection site assessment at approximately 72 hours post-dose 
7.3.6 Day 5 
The following procedures will be completed: 
 Assess supine BP/heart rate and body temperature approximately 96 hours after dosing on 
Day 1
 Collect blood samples for PK analysis of apraglutide at 96 hours after dosing on Day 1 


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 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
nonleading
 
 Review concomitant treatments 
 Injection site assessment at approximately 96 hours post-dose  
7.3.7 Day 6 
The following procedures will be completed: 
 Assess supine BP/heart rate and body temperature approximately 120 hours after dosing on 
Day 1
 Collect blood samples for PK analysis of apraglutide at 120 hours after dosing on Day 1 
 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
nonleading questio
H
 
 Review concomitant treatments 
 Injection site assessment at approximately 120 hours post-dose  
7.3.8 Day 7 
The following procedures will be completed: 
 Assess supine BP/heart rate and body temperature approximately 144 hours after dosing on 
Day 1
 Collect blood samples for PK analysis of apraglutide at 144 hours after dosing on Day 1 
 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
nonleading question 
H
 
 Review concomitant treatments 
 Injection site assessment at approximately 144 hours post-dose  
7.3.9 Day 8 
Subjects may be discharged from the CRU after completion of assessments. The following procedures 
will be completed 168 hours after apraglutide dosing on Day 1: 
 Abbreviated PE will be conducted  
 Collect 12-lead ECG in triplicate after supine rest of 10 minutes or per CRU standard operating 
procedure 
 Assess supine BP/heart rate and body temperature approximately 168 hours after dosing on 
Day 1
 Assessment of eGFR using CKD-EPI
 Collect blood samples for PK analysis of apraglutide at 168 hours after dosing on Day 1 
 Collect blood and urine samples for safety laboratory tests (hematology, clinical chemistry, and 
urinalysis) 
 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
 


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 The Investigator or designee will discuss with the subject the need to use highly effective 
contraception consistently and correctly according to the contraception guidelines and will 
confirm highly effective, proper contraception is being used up to 1 month after EOT 
 Review concomitant treatments 
 Subjects will be instructed on all pertinent lifestyle requirements and restrictions 
 Injection site assessment at approximately 168 hours post-dose  
 Discharge from CRU confinement 
If a subject has any clinically significant trial-related abnormalities at the conclusion of a scheduled 
inpatient portion of the trial, the Safety Medical Monitor (or designated representative from the 
Sponsor) should be notified and the subject may be asked to remain in the CRU until such 
abnormalities are deemed not clinically significant, or it is safe for outpatient follow-up. If the subject 
is unable or unwilling to remain in the CRU and/or when outpatient follow-up is deemed appropriate, 
the Safety Medical Monitor (or designated representative) should be notified and the Investigator 
should make every effort to arrange follow-up evaluations at appropriate intervals to document the 
course of the abnormalities. 
7.3.10 Day 11 (Outpatient Visit) 
 Collect 12-lead ECG in triplicate after supine rest of 10 minutes or per CRU standard operating 
procedure 
 Assess supine BP/heart rate and body temperature  
 Collect blood samples for PK analysis of apraglutide at 240 hours after dosing on Day 1 during 
an outpatient visit  
 Collect blood and urine samples for safety laboratory tests (hematology, clinical chemistry, and 
urinalysis), including measurement of eGFR 
 Review concomitant treatments 
 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
H
 
7.3.11 Follow-up Visit Day 14±2 days (also Early Termination Visit Procedures) 
Subjects will return to the CRU for a follow-up visit where the following procedures will be done. 
Additional follow-up visits (unscheduled) may be required to follow up on outstanding clinical events 
or AE(s).  
 Conduct abbreviated PE and weight measurement 
 The Investigator or designee will discuss with the subject the need to use highly effective 
contraception consistently and correctly according to the contraception guidelines and will 
confirm highly-effective, proper contraception is being used up to a month after EOT 
 Assess supine BP/heart rate and body temperature 
 Collect 12-lead ECG in triplicate after supine rest of 10 minutes or per CRU standard operating 
procedure  
 Review concomitant treatments 
 Collect blood and urine samples for safety laboratory tests (hematology, clinical chemistry, and 
urinalysis); a serum pregnancy test for any WOCBP  


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 Assess symptoms by spontaneous reporting of AEs and by asking the subjects to respond to a 
nonleading
 
 Injection site reaction assessment 
7.4 Pharmacokinetics 
Up to two blood samples of approximately 3 mL, to provide a minimum of 1.2 mL, will be collected 
into appropriately labeled tubes containing potassium ethylenediaminetetraacetic acid (K2-EDTA) for 
measurement of plasma concentrations of apraglutide at times noted in this section (Table 7). The 
appropriate additives will be added to the sample collected for all PK samples if indicated. Instructions 
for the collection and handling of biological samples will be provided in the laboratory manual or by 
the Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded.
Table 7: Pharmacokinetic Time Points 
The actual times may change but the number of samples will remain the same. All efforts will be made 
to obtain samples at the exact nominal time relative to dosing. Collection of samples up to and 
including 10 hours after IMP administration that are obtained within 10% of the nominal time (e.g., 
within 6 minutes of a 60 minute sample) relative to dosing will not be captured as a protocol deviation, 
as long as the exact time of the collection is noted on the source document and data collection tool 
(eCRF). Collection of samples more than 10 hours after IM
away from the nominal time relative to dosing will not be captured as protocol deviation, as long as the 
exact time of the collection is noted on the source document and data collection tool (eCRF).  
Samples will be used according to objective and analysis defined in the protocol. Genetic analysis will 
not be performed on these plasma samples. Subject confidentiality will be maintained. 
Samples collected for measurement of plasma concentration (PK) of apraglutide will be analyzed using 
a validated analytical method in compliance with applicable standard operating procedures.  
The PK samples must be processed and shipped as indicated in the instructions provided to the 
Investigator/CRU to maintain sample integrity. Any deviations from the PK sample handling procedure 
(e.g., sample collection and processing steps, interim storage, or shipping conditions), including any 
actions taken, must be documented and reported to the Sponsor. On a case-by-case basis, the Sponsor 
can make a determination as to whether sample integrity has been compromised. No PD parameters 
will be evaluated in this trial.  
 
Day 
Pharmacokinetic Time Points (hours) 
1 
0, 6, 12
2 
24, 28, 36, 40 
3 
48, 60 
4 
72 
5 
96 
6 
120 
7 
144 
8 
168 
11 
240 


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8 Statistical Methods 
The statistical evaluation of the trial will include descriptive statistics reflecting the early phase of the 
trial and analyses will be provided for the key endpoints. 
Any deviations from the planned analyses will be described and justified in the final clinical trial 
report. 
8.1 Determination of Sample Size 
No formal power calculation was performed. The number of subjects per group is based on the review 
of the literature and of the European Medicine Agency (EMA) and FDA guidelines. 
While the EMA suggests 6 8 subjects per group, the FDA draft guidance does not provide an exact 
number of renal impaired patients needed for such a clinical trial [19, 20, 21, 22].  
The sample size of eight subjects is also based on the feasibility to recruit subjects with severe renal 
impairment.  
In Part 1, approximately eight subjects each will be enrolled into the normal renal function group and 
the severe renal impairment group so that to ensure approximately six evaluable completers in each 
group. If Part 2 is conducted, approximately eight subjects each will be enrolled to the mild and 
moderate groups to ensure approximately six evaluable completers per group.  
Subjects who discontinue from the trial before completing all assessments may be replaced at the 
discretion of the Investigator and Sponsor.  
8.2 Population for Analysis 
For purposes of analysis, the following populations are defined (Table 8). 
Table 8: Populations Description 
8.3 Statistical Analysis 
The Statistical Analysis Plan (SAP) will be developed and finalized prior to database lock. The SAP 
will describe the subject populations to be included in the analysis. Unless otherwise noted in SAP, 
missing values will not be imputed. An explanation will be given for any missing, unused, and spurious 
data affecting analysis in the relevant sections of the Clinical Trial Report (CTR). This section is a 
summary of the planned statistical analysis of the primary and secondary endpoints.  
POPULATION 
DESCRIPTION 
Pharmacokinetic (PK) Concentration 
The PK concentration population is defined as all subjects 
assigned to the IMP and treated who have at least one 
quantifiable concentration measured 
PK Parameter 
The PK parameter analysis population is defined as all subjects 
assigned to IMP and treated who have at least one of the PK 
parameters of primary interest measured 
Safety 
All assigned to IMP and who take at least one dose of IMP 


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Analysis of variance (ANOVA) will be used to compare the natural log transformed AUCinf or AUClast 
(if AUCinf cannot be calculated) and Cmax for apraglutide between normal renal function group 
(Reference) and the severe impaired renal group (Test). Estimates of the mean differences (Test-
Reference) and corresponding 90% CIs will be obtained from the model. The mean differences and 
90% CIs for the differences will be exponentiated to provide estimates of the ratio of the adjusted 
geometric means (Test/Reference) and 90% CIs for the ratios.  
Part 2 may be conducted if apraglutide AUCinf (or AUClast when AUCinf cannot be calculated) GMR for 
severe renal impairmen
2.0. This metric is supported by 
recommendations from Huang et al [14]. Furthermore, apraglutide was well tolerated up to 56.9 mg SC 
QW and very well tolerated at 28.4 mg SC QW further demonstrating the large therapeutic margin of 
apraglutide. 
 
Analysis of variance will be used to compare the natural log transformed AUCinf or AUClast and Cmax 
for apraglutide between normal renal function group from Part 1 (Reference) and each of the moderate 
and mild impaired renal groups (Test). Estimates of the mean differences (Test-Reference) and 
corresponding 90% CIs will be obtained from the model. The mean differences and 90% CIs for the 
differences will be exponentiated to provide estimates of the GMR (Test/Reference) and 90% CIs for 
the ratios.  
Box and whisker plots for individual subject parameters (AUCinf or AUClast and Cmax) will be 
constructed by renal function group and overlaid with geometric means. 
For summary statistics and median/mean plots by sampling time, the nominal PK sampling time will be 
used. For individual subject plots by time, the actual PK sampling time will be used. 
If Part 2 is executed and data for normal, mild, moderate and severe impairment groups are available, 
additional analysis will be performed to assess relationship between appropriate PK parameters and 
renal function. 
8.4 Safety Assessments 
All safety analyses will be performed on the safety population. 
Adverse events, ECGs, BP, heart rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the trial to evaluate the safety of subjects. Any clinical laboratory, ECG, BP, 
and heart rate abnormalities of potential clinical concern will be described. Safety data will be 
presented in tabular and/or graphical format and summarized descriptively, where appropriate. 
Medical history, PE, and neurological examination information, as applicable, collected during the 
course of the trial will be considered source data. However, any untoward findings identified on 
physical and/or neurological examinations conducted during the active collection period will be 
captured as AEs, if those findings meet the definition of an AE. Data collected at Screening that are 
used for inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs, will be considered 
source data and will be required to be reported in the eCRF. Demographic data collected at Screening 
will also be reported. 




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9 Documentation and Operational Considerations 
9.1 Early Termination 
Both Sponsor and the Investigator reserve the right to terminate the trial at any time. Should this be 
necessary, both parties will arrange discontinuation procedures and notify the subjects, appropriate 
regulatory authority, IRBs, etc. In terminating the trial, the Sponsor and the Investigator will assure that 
 
9.2
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 IRB 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 IRB and written verification that the modification 
was submitted should be obtained.
In the event that an amendment to this protocol is required, it will be classified into one of the 
following categories: 
 
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 apraglutide used in the trial, changes in the protocol assessment and the 
trial site team 
 Non-substantial Amendments are amendments which are not considered to meet the definition 
of substantial 
Investigators are responsible for promptly informing the IRB of any amendments to the protocol.  
Documentation of IRB approval must be sent to the Sponsor immediately upon receipt. 
9.3 End of Trial Report 
The Sponsor will notify the competent authority of the end of the trial within a period of 90 days. The 
end of the trial 
trial is ended prematurely, the 
Investigator will notify the IRB and the competent authority within 15 days, including the reasons for 
the premature termination. The Investigator will notify the IRB immediately of a temporary halt of the 
trial including the reason of such an action. 
Within 1 year after the end of the trial, the Sponsor will submit to the FDA a final CTR with the results 
of the trial including any publications/abstracts of the trial. The Principal Investigator and 
Responsible Medical Officer will be the signatories for the CTR. 
9.4 Regulatory and Ethical Considerations 
This trial will be conducted in accordance with the protocol and with the following: 


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 Consensus ethical principles derived from international guidelines including the Declaration of 
Helsinki [2] and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
 Applicable ICH GCP guidelines (latest version; [1]) 
 FDA guidelines along with applicable laws and regulations including the FDA GCP Code of 
Federal Regulations (CFR) Title 21 [3], applicable privacy laws in the country where the trial is 
conducted 
The protocol, protocol amendments, ICF, 
brochure, and other relevant documents (e.g., 
advertisements) must be reviewed and approved by the Sponsor and submitted to an IRB by the 
Investigator and reviewed and approved by the IRB before the trial is initiated. 
Any amendments to the protocol will require IRB approval before implementation of changes made to 
the trial design, except for changes necessary to eliminate an immediate hazard to trial subjects 
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the trial to the IRB annually or more frequently in 
accordance with the requirements, policies, and procedures established by the IRB 
 Notifying the IRB of SAEs or other significant safety findings as required by IRB procedures 
 Providing oversight of the conduct of the trial at the site and adherence to requirements of 21 
Code of Federal Regulations (CFR), ICH guidelines, the IRB and all other applicable local 
regulations 
9.4.1 Subject Information and Consent 
All parties must ensure protection of subject personal data and must not include subject names on any 
Sponsor forms, reports, publications, or in any other disclosures, except where required by laws. In 
case of data transfer, the Sponsor must maintain high standards of confidentiality and protection of 
subject personal data. 
The ICF must be in compliance with ICH GCP, local regulatory requirements, and legal requirements. 
The ICF used in this trial, and any changes made during the course of the trial, must be prospectively 
approved by the Sponsor first, thereafter the IRB before use.  
The Investigator must ensure that each trial subject is fully informed about the nature and objectives of 
the trial and possible risks associated with participation. The Investigator, or a person designated by the 
Investigator, must obtain written informed consent from each subject before any trial-specific activity 
. The subject 
will be provided ample time to read and ask questions on the provided ICF. The subject will be 
provided a copy of the signed and dated ICF. 
9.4.2 Institutional Review Board 
It is the responsibility of the Investigator to have prospective approval of the trial protocol, protocol 
amendments, ICF, and other relevant documents (e.g., recruitment advertisements, if applicable) from 
the IRB. All correspondence with the IRB must be retained in the Investigator Site File.


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The only circumstance in which an amendment may be initiated prior to IRB approval is where the 
change is necessary to eliminate apparent immediate hazards to the subjects. In that event, the 
Investigator must notify the IRB and Sponsor in writing, immediately after the implementation. 
9.4.3 Subject Confidentiality 
The S
S
s 
clinical trial database or documentation via a unique identification number. As permitted by all 
applicable laws and regulations, limited subject attributes such as sex, age, or date of birth, may be 
used to verify the subject and accuracy of the subject
 
To comply with ICH GCP and to verify compliance with this protocol, the Sponsor requires the 
Investigator to permit its M
Monitor representatives from any regulatory authority 
(e.g., FDA), S
A
source data and documents. 
Copies of any subject source documents that are provided to the sponsor must have certain identifiable 
information removed (i.e., subject name, address, and other identifier fields not collected in subject 
eCRF). 
9.4.4 Liability and Insurance 
The Sponsor will cover this trial by means of an adequate insurance of the participating subjects which 
will be in place prior to the start of the trial. 
As per local regulations, details about the insurance are described in the subject information sheet and 
ICF. A copy of the insurance statement is filed in the Investigator Site File and the subject can request a 
copy. 
9.5 Reporting of Safety Concerns and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable regulatory 
authority in any area of the world, or if the Investigator is aware of any new information that might 
influence the evaluation of the benefits and risks of the IMP, Sponsor immediately of any urgent safety 
measures taken by the Investigator to protect the trial subjects against any immediate hazard, and of 
any serious breaches of this protocol and/or of ICH GCP that the Investigator has become aware.  
9.6 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 regulatory authorities. Investigators are responsible for 
providing information on financial interests during the course of the trial and for 1 year after 
completion of the trial. 
9.7 Informed Consent Process 
The Investigator or his/her representative will explain the nature of the trial to the subject and answer 
all questions regarding the trial. 


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Subjects must be informed that their participation is voluntary. Subjects will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50 [23], local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements [24], where 
applicable, and the IRB or trial site. 
The Investigator must ensure that each trial subject is fully informed about the nature and objectives of 
the trial, the sharing of data related to the trial, and possible risks associated with participation, 
including the risks associated with the processing of the subject
 
The subject must be informed that his/her personal trial-related data will be used by the Sponsor in 
accordance with applicable data protection law. The level of disclosure must also be explained to the 
subject. 
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the sponsor, by appropriate IRB 
members, and by inspectors from regulatory authorities. 
The medical record must include a statement that written informed consent was obtained before the 
subject was enrolled in the trial and the date and time the written consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF. 
If applicable, subjects must be reconsented to the most current version of the ICF(s) during their 
participation in the trial. 
A copy of the ICF(s) must be provided to the subject. Subjects who are rescreened are required to sign 
a new ICF.
9.8 Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation of 
organizational and technical measures, and the General Data Protection Regulation (EU) 2016/679 [25] 
to ensure protection of subject data. USA-based sites and laboratories or entities providing support for 
this trial must, where applicable, comply with the Health Insurance Portability and Accountability Act 
of 1996 (HIPAA) [24]. A USA-based site that is not a Covered Entity, as defined by HIPAA, must 
provide documentation of this fact to the CRO. 
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 and any future 
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 designee reviews 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 the 
clinical trial drug; national or local regulatory authorities; the IRB(s) which gave approval for the trial 
to proceed. The Sponsor and/or its designees accessing the records and data will take all reasonable 
precautions 
in accordance with applicable laws, 
regulations, and guidelines. Subject
be stored at the trial site in encrypted 


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electronic form and will be password-protected to ensure that only authorized trial staff has access. To 
protect the rights and freedoms of natural persons with regard to the processing of personal data, 
subjects will be assigned a single, subject-specific numerical code. Any subject records or data sets that 
are transferred to the Sponsor will contain the numerical code; subject names will not be transferred. 
All other identifiable data transferred to the sponsor will be identified by this single, subject-specific 
code. The trial site will maintain a confidential list of subjects who participated in the trial, linking each 
subject
 to his or her actual identity.  
The results of trials  
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, or to answer 
questions asked by regulatory or health authorities, or for activities that otherwise connected to the 
trial. In case of data transfer, the Sponsor will protect t
consistent with the clinical trial agreement and applicable privacy laws. At the end of the trial, all trial 
data will be archived by the Sponsor or its designee and stored for a minimal period of 25 years. 
9.9 Data Handling and Record Keeping
9.9.1 Data Collection  
All subject data relating to the trial will be recorded using an eCRF (conforms to 21 CFR Part 11 
requirements [26]) unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the information 
entered in the eCRF. 
The location of source data will be defined in the relevant source data location form prior to trial start. 
The Investigator must ensure that the eCRFs are securely stored at the trial site in encrypted electronic 
form and are password-protected to prevent access by unauthorized third parties. 
The Investigator must permit trial-related monitoring, audits, IRB review, and regulatory agency 
inspections and provide direct access to source data documents. This verification may also occur after 
trial completion. It is important that the Investigator(s) and their relevant personnel are available during 
the monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process. 
The Sponsor or designee will provide the trial site(s) with secure access to and training on the 
electronic data capture application sufficient to permit site personnel to enter or correct information in 
the eCRFs on each subject.
An eCRF is required and must be completed for each enrolled subject. Screen failures and reasons for 
those will be captured in the eCRF system. The Investigator has ultimate responsibility for the 
accuracy, authenticity, and timely collection and reporting of all clinical, safety, and laboratory data 
entered on the eCRFs and any other data collection forms. Source documentation supporting the eCRF 


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data mus
trial procedures, AEs, other observations, and subject status.  
 correction. 
The eCRFs must be signed electronically by the Investigator to attest that the data contained on the 
eCRFs, including any changes made to the eCRFs, are correct and to endorse the final submitted data 
for the subjects for whom the Investigator is responsible.
The completed eCRFs are the sole property of the Sponsor and must not be made available in any form 
to third parties, except for authorized representatives of the sponsor or appropriate regulatory 
authorities, without written permission from the sponsor. 
The Sponsor will retain the eCRF data and corresponding audit trails. A copy of the final archival 
eCRF in the form of a compact disc or other electronic media will be provided to the site for placement 
 
9.9.2 Database Management and Quality Control 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, 
and requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring), are provided in the monitoring plan. 
The Sponsor or designee is responsible for the data management of this trial, including quality 
checking of the data. 
Trial monitors will perform ongoing source data verification to confirm that data entered into the eCRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; that the 
safety and rights of subjects are being protected; and that the trial is being conducted in accordance 
with the currently approved protocol and any other trial agreements, ICH GCP, and all applicable 
regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this trial must be retained 
by the Investigator for 25 years after trial completion unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the retention period without the 
written approval of the sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. The Investigator must ensure that the records continue to be stored 
securely for as long as they are maintained. 
When subject data are to be deleted, the Investigator will ensure that all copies of such data are 
promptly and irrevocably deleted from all systems. 
The Investigator(s) will notify the Sponsor or its designees immediately of any regulatory inspection 
notification in relation to the trial. Furthermore, the Investigator will cooperate with the Sponsor or its 
designees to prepare the Investigator site for the inspection and will allow the Sponsor or its designees, 
whenever feasible, to be present during the inspection. The Investigator site and Investigator will 
promptly resolve any discrepancies that are identified between the trial data and the subject
records. The Investigator will promptly provide copies of the inspection findings to the Sponsor or its 


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designee. Before response submission to the regulatory authorities, the Investigator will provide the 
Sponsor or its designees with an opportunity to review and comment on responses to any such findings. 
During trial conduct, the Sponsor or its designees will conduct periodic monitoring visits to ensure that 
the protocol and ICH GCPs are being followed. The Monitors will review source documents to confirm 
that the data recorded on eCRFs are accurate. The Investigator and institution will allow the S
Monitors or designees and appropriate regulatory authorities direct access to source documents to 
perform this verification. 
The trial site may be subject to review by the IRB, and/or to quality assurance audits performed by the 
Sponsor or companies working with or on behalf of the Sponsor, and/or to inspection by appropriate 
regulatory authorities. 
It is important that the Investigator and their relevant personnel are available during the monitoring 
visits and possible audits or inspections and that sufficient time is devoted to the process. 
9.9.3 Record Retention
To enable evaluations and/or audits from regulatory authorities or Sponsor, the Investigator agrees to 
keep records, including the identity of all participating subjects (sufficient information to link records, 
e.g., eCRFs, source documents), all original signed ICFs, eCRFs, SAE forms, source documents, 
detailed records of treatment disposition, and adequate documentation of relevant correspondence (e.g., 
letters, meeting minutes, telephone calls reports). The records must be retained by the Investigator 
according to the ICH, local regulations, or as specified in the Clinical Trial Agreement, whichever is 
longer. 
If the Investigator becomes unable, for any reason, to continue to retain trial records for the required 
period (e.g., retirement, relocation), the Sponsor must be prospectively notified. The trial records must 
be transferred to a designee acceptable to the sponsor, such as another Investigator, another institution, 
or to the sponsor. The Investigator must obtain the S
any records, even if retention requirements have been met. 
9.10 Source Documents 
Source documents provide evidence for the existence of the subject and substantiate the integrity of the 
data collected. Source documents are filed at the investigator site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with the 
source documents or the discrepancies must be explained. The Investigator may need to request 
previous medical records or transfer records, depending on the trial. Also, current medical records must 
be available. 
9.11 Trial and Site Closure 
The Sponsor designee reserves the right to close the trial site or terminate the trial at any time for any 
reason at the sole discretion of the sponsor. Trial sites will be closed upon trial completion. A trial site 
is considered closed when all required documents and trial supplies have been collected and a trial-site 
closure visit has been performed. 


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The Investigator may initiate trial-site closure at any time upon notification to the contract research 
organization if requested to do so by the responsible IRB or if such termination is required to protect 
the health of trial subjects. 
Reasons for the early closure of a trial site by the Sponsor may include but are not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB or local 
 
 Inadequate recruitment of subjects by the Investigator 
 Discontinuation of further trial intervention development 
Trial termination information is also provided in the clinical trial agreement. If there is any conflict 
between the clinical trial agreement and this protocol, the clinical trial agreement will control as to 
termination rights. 
9.12 Publication Policy and Public Disclosure 
The Institution and the Investigator agree that the Sponsor shall have the sole and exclusive right to the 
first publication of the results of the trial.  
The results of this trial may be published or presented at scientific meetings by the investigator after 
publication of the overall trial results or 1 year after end of the trial (or trial termination), whichever 
comes first.
The Investigator agrees to refer to the primary publication in any subsequent publications such as 
secondary manuscripts, and submits all manuscripts or abstracts to the Sponsor 30 days before 
submission. This allows the Sponsor to protect proprietary information and to provide comments and 
the Investigator will, on request, remove any previously undisclosed confidential information before 
disclosure, except for any trial or Sponsor intervention-related information necessary for the 
appropriate scientific presentation or understanding of the trial results. 
For all publications relating to the trial, the Investigator will comply with recognized ethical standards 
concerning publications and authorship, including those established by the International Committee of 
Medical Journal Editors.
Authorship of publications for the overall trial results will be determined by mutual agreement and in 
line with International Committee of Medical Journal Editors authorship requirements. 
If there are any discrepancies between the protocol and the clinical trial agreement regarding clinical 
trial-related publications, the provisions of the clinical trial agreement will prevail. 
9.13 Protocol Compliance and Deviations 
The Investigator must conduct the trial in compliance with the protocol provided by the Sponsor and 
given approval/favorable opinion by the IRB and the appropriate regulatory authorities. Modifications 
to the protocol must not be made without agreement between both the Investigator and the Sponsor. 
Changes to the protocol will require written IRB and the appropriate regulatory authority 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects. The IRB may provide, if applicable, regulatory authority 
permit, expedited review, and approval/favorable opinion for minor change(s) in ongoing trials that 


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have the approval/favorable opinion of the IRB. The Sponsor must ensure that all protocol 
modifications are submitted to the regulatory authority in accordance with the governing regulations. 
If other unexpected circumstances arise that require deviation from protocol-specified procedures, the 
Investigator must consult with the sponsor (and IRB, as required) to determine the appropriate course 
of action. 
rce documents. In the event of a 
deviation expected to influence the subject safety or the estimation of the PK parameters, the site must 
notify the sponsor (and IRB, as required). 
Protocol deviations will be identified based on conditions related to the categories below:
 Protocol entry criteria 
 Forbidden concomitant medications 
 Missing evaluations for relevant endpoints 
 Medications errors 
 Other protocol deviations occurring during clinical trial conduct 
All protocol deviations will be identified and listed where appropriate. 
 
 


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10 Safety  
10.1 Safety Data Reporting and Collection Period 
After signing informed consent, all AEs including SAEs and AESIs regardless of relationship to 
apraglutide will be collected, fully investigated and documented in source documents and eCRFs and 
will be reported either until the last protocol-specific procedure or safety follow-up.  
Investigators should report any SAEs, or other AEs of concern that are believed to be related to 
apraglutide for up to 2 weeks following the safety follow-up visit (EOT).  
Adverse events that occur between subject
and dosing will be captured as pre-treatment 
AEs.  
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 ET
visit, or a safety follow-up period. 
If an Investigator becomes aware of an SAE which occurred up to 2 weeks following the safety follow-
up visit (EOT) (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) (Section 10.3.3). 
The emergency contact details for the Sponsor can be found in the Investigator Site File (ISF).  
10.2 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 an IMP, whether or not 
related to the IMP [1]. Medical conditions present at the initial trial visit that do not worsen in severity 
or frequency during the trial are defined as baseline medical conditions (medical history) and are not to 
be considered AEs.  
The sources of AEs include:  
 
 
 Symptoms spontaneously reported by the subject 
 Investigations and examinations with findings that are assessed by the Investigator to be 
clinically significant 
 
 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is considered as 
the AE rather than the procedure itself. 
Specific information related to liver safety can be found in Section 10.10. 


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An SAE is classified as any untoward medical occurrence that: 
 Results in death 
 Is life-threatening 
 Requires in-patient 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 apraglutide 
(also applies if father was exposed to apraglutide) 
 
ent (e.g., may jeopardize the subject 
or may require medical/surgical intervention to prevent one of the outcomes listed above) [27] 
Events that Do Not Meet the Definition of an SAE: 
 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 
 Hospitalization or prolongation of hospitalization as part of a routine procedure  
 Hospitalization for a survey visit, annual physicals or social reasons
 Hospitalization that does not include an overnight stay 
 Elective hospitalizations for pre-existing conditions documented in the medical history that 
have not worsened 
 Hospitalization to facilitate treatment of disease/illness with other treatment options, although 
these treatments are not permitted as per the protocol and will be documented as a protocol 
deviation 
In case of doubt, an event should be reported within timelines. 
Definition of Adverse Events of Special Interest 
An AESI, serious or non-
product or program, for which ongoing monitoring, additional information, and rapid communication 
by the Investigator to the Sponsor can be 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. 
The following are considered AESIs for this trial: 
 Injection site reactions (ISR) 
 Gallbladder, biliary, and pancreatic disease 
 Fluid overload
 Hypotension
 Persistent abdominal pain 
Injection site reactions  
reaction stops. The individual symptoms of the ISR (e.g., injection site pain, injection site pruritus 


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[itching], injection site erythema [redness], injection site edema [swelling], injection site bruising) 
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. When IMP is administered at home, ISRs should be reported to the 
site for do
 
Gallbladder, Biliary and Pancreatic Disease 
These should be monitored by symptoms, liver enzymes (ALT, AST, alkaline phosphatase), bilirubin, 
lipase, 
 
Fluid Overload, Hypotension and Persistent Abdominal Pain 
Subjects will be monitored closely for signs and symptoms related to fluid overload (e.g., edema, due 
to increased absorption), hypotension and persistent abdominal pain. The Investigator will document 
any cases and manage as per clinical practice for the subject accordingly.  
10.3 Safety Reporting 
10.3.1 Reporting of Adverse Events 
All AEs must be reported to the CRO through the eCRF and within the data entry timeline defined for 
this trial and stipulated in the clinical trial agreement. 
10.3.2 Reporting of Adverse Events of Special Interest 
All AESIs must be reported to the CRO through the eCRF and within two weeks following the event. 
10.3.3 Reporting of Serious Adverse Events 
All SAEs must be reported immediately and within a maximum of 24 hours to the CRO and thereafter 
the CRO will report to the Sponsor of the trial. 
Serious adverse event primary information should be collected through the eCRF and the reporting is 
done via paper form, which can be submitted via email or fax to PRA Safety. 
The contact information is:
- 
North/South America 
- 
Fax: 
 
- 
Email: 
 


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The Sponsor/CRO will re-evaluate the SAE and return the form 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 reg
 
Serious AEs resulting in death will be reported to the IRB within 7 days. 
The minimum data required for a report is:  
 Subject identifier (ID) 
 Trial ID 
 Date of enrolment 
 Date and time of start of SAE 
 Description of SAE  
 Severity of SAE 
 Assessment of causality relationship to IMP 
 Name and contact details of person reporting the event 
10.3.4 Reporting of Suspected Unexpected Serious Adverse Events 
A suspected unexpected serious adverse event (SUSAR) for an event that is life-threatening or fatal 
needs to be reported to the IRB (local event via local Investigator) and competent authorities (CAs) 
within 7 calendar days. 
All other SUSARs need to be reported to the IRB (local event via local Investigator) and CAs within 
15 calendar days. 
As necessary, the Sponsor must inform the Investigator, the IRB, and competent authorities 
participating in the clinical trial of the occurrence of a SUSAR.  
For SAEs, the active reporting period begins from the time that the subject provides informed consent 
through the end of the trial. Serious AEs occurring to a subject after the active reporting period has 
ended should be reported to the sponsor if the Investigator becomes aware of them; at minimum, all 
SAEs that the investigator believes have at least a reasonable possibility of being related to the IMP are 
to be reports to the Sponsor. 
10.4 Pregnancy Reporting
Pregnancies occurring in this trial and within 90 days after dose are collected and reported. Unless 
described otherwise, pregnancies with or without serious outcomes are reportable within 24 hours of 
awareness to the CRO. 
Although pregnancies themselves are not considered to be (S)AEs, the Investigator must report any 
pregnancies reported during the trial to the CRO within the timelines for SAE reporting. The trial 
subject will give consent on enrolment that the investigator will report any pregnancy occurring after 
consenting to 90 days after the dosing and that the subject will be asked to provide information about 
the pregnancy, delivery and the health of the infant until the age of 1 month. The Investigator must 
report information on pregnancies and follow-up within 14 calendar days of obtaining the information. 
Pregnancy complications must be recorded as (S)AEs, as appropriate. If the infant has a congenital 
anomaly/birth defect this must be reported and followed up as a SAE. 


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10.5 Medication Errors 
Medication errors are reportable irrespective of the presence of an associated AE/SAE, including: 
 Medication errors involving subject exposure to the IMP 
 Potential medication errors or uses outside of what is foreseen in the protocol that do or do not 
involve the participating subject 
Whether or not the medication error is accompanied by an AE, as determined by the Investigator, the 
medication error is captured on the medication error version of the AE page, and if applicable, any 
associated AE(s) are capture on the AE eCRF. 
10.6 Severity Assessment 
The Investigator will use the adjectives MILD, MODERATE, or SEVERE to describe the maximum 
intensity of the AE. For purposes of consistency, these are defined as follows:
 MILD: Does not interfere with subject's usual function 
  MODERATE: Interferes to some extent with subject's usual function 
  SEVERE: Interferes significantly with subject's usual function 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily an SAE. 
The NCI-CTCAE system [17] will be used to grade the severity of the SAEs, AEs and AESIs. 
10.7 Causality Assessment
Both the Investigator and Sponsor will assess the causality of the event in relation to the IMP, based on 
the criteria listed in the ICH E2A guidelines [27]: 
The Investigator must also systematically assess the causal relationship of AEs to IMP(s)/trial 
treatment (including any other non-IMPs, radiation therapy, etc.) using the definitions described below. 
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, medical 
history, concomitant medication, course of the underlying disease, trial procedures. 
Not related: Not reasonably related to the IMP. Adverse event could not medically 
(pharmacologically/clinically) be attributed to the trial IMP in this clinical trial protocol. A reasonable 
alternative explanation must be 
 
Related: Reasonably related to the IMP. Adverse event could medically (pharmacologically/ clinically) 
be attributed to the IMP under trial in this clinical trial protocol. Table 10 can be used to differentiate 
between the AEs related to the IMP. Adverse events reported as definitely, probably and possibly 
 


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Table 10: Assessment of Causality of Adverse Events
10.8 Adverse Event Outcome 
An AE must be followed until recovery whether the trial has ended or not. The outcome must be 
classified according to the categories shown below: 
 Recovered/Resolved: Resolution of an AE with no residual signs or symptoms 
 Recovered/Resolved with Sequelae: Resolution of an AE with residual signs or symptoms 
 Recovering/Resolving: Improvement of an AE 
 Not Recovered/Not Resolved (Continuing): Either incomplete improvement or no 
improvement of an AE such that it remains ongoing 
 Fatal: 
ibly 
related to the AE 
 Unknown: The outcome of an AE is not known (e.g., a subject lost to follow-up) 
10.9 Treatment Given
The Investigator must ensure adequate medical care is provided to subjects for any AEs. In addition, 
the Investigator must describe whether any treatment was given for the AE. This information must be 
document on subject source. 
10.10 Liver Safety: Suggested actions and Follow-up Assessments for Potential Cases of 
Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
subjects, transaminase elevations are a harbinger of a more serious 
potential outcome. These subjects fail to adapt and therefore are "susceptible" to progressive and 
serious liver injury, commonly referred to as drug-induced liver injury (DILI). Subjects who experience 
 
Assessment of Causality 
Definitely 
Probably 
Possibly 
Unlikely 
Not Related 
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. 


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a transaminase elevation above 3 × ULN should be monitored within 48 hours and alternate causes of 
hepatitis should be investigated 
 
In the majority of DILI cases, elevations in AST and/or ALT precede total bilirubin (TBili) elevations 
(>2 × ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT is/are 
still elevated above 3 × ULN (i.e., AST/ALT and TBili values will be elevated within the same 
laboratory sample). In rare instances, by the time TBili elevations are detected, AST/ALT values might 
have decreased. This occurrence is still regarded as a potential DILI. Therefore, abnormal elevations in 
either AST OR ALT in addition to TBili that meet the criteria outlined below are considered potential 
; [19]) cases and should always be considered important medical 
events, even before all other possible causes of liver injury have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the subject
baseline values and underlying conditions. Subjects who present with the following laboratory 
abnormalities s
the etiology of the abnormal laboratory values: 
Discontinuation of treatment should be considered if: 
 ALT or AST >8 × ULN
 ALT or AST >5 × ULN for more than 2 weeks 
 ALT or AST >3 × ULN and (TBL >2xULN or INR >1.5) 
 ALT or AST >3 × ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed individually 
based on clinical judgment; any case where uncertainty remains as to whether it represents a potential 
The subject should return to the Investigator site and be evaluated as soon as possible, preferably 
within 48 hours from awareness of the abnormal results. This evaluation should include laboratory 
tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for 
additional laboratory tests should include albumin, creatine kinase, direct and indirect bilirubin, 
gamma-glutamyl transferase, prothrombin time/international normalized ratio, total bile acids, and 
alkaline phosphatase. Consideration should also be given to drawing a separate tube of clotted blood 
and an anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology. A detailed history, 
including relevant information, such as review of ethanol, acetaminophen (either by itself or as a co-
formulated product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact with a 
jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and potential 
occupational exposure to chemicals, should be collected. Further testing for acute hepatitis A, B, C, D, 
and E infection and liver imaging (e.g., biliary tract) and collection of serum sample for acetaminophen 
drug and/or protein adduct levels may be warranted. 


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All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and TBili 
liver function test (LFT) abnormalities has yet been found. Such 
be reported as SAEs, irrespective of availability of all the results of the investigations performed to 
determine etiology of the LFT abnormalities. 
investigations have been received and have excluded an alternative etiology. 
 
 


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SAP_001.pdf: 
Protocol Number: TA799-014 
 
Official Title: A Phase 1, Open-Label Evaluation of the Pharmacokinetics and Safety of a Single 
Dose of Apraglutide in Subjects with Normal and Impaired Renal Function 
 
NCT Number: NCT04699032 
 
Document Date: 02 November 2020