Clinical trial NCT05706623
Conditions: Hepatic Impairment
Keywords: Hepatic Impairment Liver Function Hepatic Function
Sponsor: VectivBio AG
Start date: 2023-01-30; Completion date: 2023-04-04
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to assess the pharmacokinetics (PK) of apraglutide in subjects with hepatic impairment compared with matched control subjects with normal hepatic function following single subcutaneous (SC) dose administration.

Detailed description:
A two stage design, open label, multi-center, non-randomized trial to evaluate the the safety and tolerability of a single subcutaneous dose of apraglutide in subjects with varying degrees of hepatic function. The hepatic function will estimated with the Child-Pugh classification.

Part 1: 8 subjects with moderate hepatic impairment (Cohort 1) and 8 subjects with normal hepatic function (Cohort 2).

Part 2: 8 subjects with mild hepatic impairment (Cohort 3) and 8 subjects with normal hepatic function (from Cohort 2 where possible and additional subject). Part 2 will be conducted only if the geometric mean ratio (GMR) of area under the curve extrapolated to infinity (AUCinf) or area under the curve from zero to the last measurable point (AUClast) for the moderate hepatic impairment group compared to the control group is ≥2.

Arms: arm 1: Child-Pugh B arm 2: None arm 3: Child-Pugh A
Interventions: intervention 1: Apraglutide
Intervention descriptions: intervention 1: Single dose of apraglutide

Protocol documents:
Prot_000.pdf: 











































































































































SAP_001.pdf: 


 
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2.0 Table of Contents 
1.0 Approvals ................................................................................................................................................ 1 
2.0 Table of Contents .................................................................................................................................... 2 
3.0 Introduction ............................................................................................................................................. 4 
4.0 Changes from Previous Version of Approved SAP ................................................................................ 4 
5.0 Study Objectives and Endpoints ............................................................................................................. 4 
5.1 Primary Objectives .............................................................................................................................. 4 
5.1.1 Primary Endpoint .......................................................................................................................... 4 
5.2 Secondary Objective ........................................................................................................................... 4 
5.2.1 Secondary Endpoint ..................................................................................................................... 4 
6.0 Study Design ........................................................................................................................................... 5 
6.1 Sample Size Considerations ............................................................................................................... 6 
6.2 Randomization .................................................................................................................................... 6 
7.0 Overview of Planned Analysis ................................................................................................................ 6 
7.1 Changes from Protocol ....................................................................................................................... 6 
7.2 Interim Analysis and Key Results ....................................................................................................... 6 
7.3 Final Analysis ...................................................................................................................................... 7 
8.0 Data Review ............................................................................................................................................ 7 
8.1 Data Management ............................................................................................................................... 7 
8.2 Acceptance of Data for Summarization .............................................................................................. 7 
9.0 Definitions and General Analysis Methods ............................................................................................. 7 
9.1 Analysis Data Presentation ................................................................................................................. 7 
9.1.1 Rounding ...................................................................................................................................... 7 
9.1.2 Imputation .................................................................................................................................... 7 
9.1.3 Descriptive Statistics .................................................................................................................... 8 
9.1.4 Pooling ......................................................................................................................................... 8 
9.1.5 Unscheduled Measurements ....................................................................................................... 8 
9.2 Analysis Data Definitions .................................................................................................................... 8 
9.2.1 Baseline Definition ....................................................................................................................... 8 
9.2.2 Treatment/Subject Grouping ........................................................................................................ 8 
9.2.3 Common Variable Derivations ..................................................................................................... 9 
9.2.4 QC ................................................................................................................................................ 9 
9.2.5 ADaM Datasets and Metadata ................................................................................................... 10 
9.3 Software ............................................................................................................................................ 10 
9.4 Statistical Methods ............................................................................................................................ 10 
9.4.1 Statistical Outlier Determination ................................................................................................. 10 
9.4.2 Predetermined Covariates and Prognostic Factors ................................................................... 10 
9.4.3 Hypothesis Testing ..................................................................................................................... 10 
9.5 TFL Layout ........................................................................................................................................ 10 
10.0 Analysis Sets ....................................................................................................................................... 11 
10.1 Enrolled Set ..................................................................................................................................... 11 
10.2 Safety Set ........................................................................................................................................ 11 
10.3 Pharmacokinetic Concentrations Set .............................................................................................. 11 
10.4 Pharmacokinetic Parameter Set ..................................................................................................... 11 
11.0 Subject Disposition .............................................................................................................................. 12 
12.0 Protocol Deviations ............................................................................................................................. 12 
13.0 Demographic and Baseline Characteristics ........................................................................................ 12 
13.1 Demographics ................................................................................................................................. 12 
13.2 Medical History ................................................................................................................................ 12 
13.3 Other Baseline Characteristics ....................................................................................................... 12 
14.0 Concomitant Medications .................................................................................................................... 12 
15.0 Treatment Compliance and Exposure ................................................................................................ 12 
16.0 Pharmacokinetic Analyses .................................................................................................................. 13 
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16.1 Pharmacokinetic Variables ............................................................................................................. 13 
16.1.1 Plasma Variables ..................................................................................................................... 13 
16.2 Pharmacokinetic Summaries .......................................................................................................... 16 
16.2.1 Pharmacokinetic Concentrations ............................................................................................. 16 
16.2.2 Pharmacokinetic Parameters ................................................................................................... 16 
17.0 Safety Analyses .................................................................................................................................. 17 
17.1 Safety Variables .............................................................................................................................. 17 
17.1.1 Adverse Events ........................................................................................................................ 18 
17.1.2 Deaths and Serious Adverse Events ....................................................................................... 19 
17.1.3 Laboratory Data ....................................................................................................................... 19 
17.1.4 Vital Signs ................................................................................................................................ 20 
17.1.5 Electrocardiograms .................................................................................................................. 20 
17.1.6 Other Observations Related to Safety ..................................................................................... 20 
18.0 References .......................................................................................................................................... 20 
Appendix 1: Glossary of Abbreviations ....................................................................................................... 21 
Appendix 2: Schedule of Assessments ....................................................................................................... 22 
Appendix 3: List of End of Text Outputs ..................................................................................................... 24 
Document History ........................................................................................................................................ 27 
 
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3.0 Introduction 
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the analysis 
and reporting of data collected under VectivBio Protocol TA799-015. 
This SAP should be read in conjunction with the study protocol and electronic case report form (eCRF). 
This version of the plan has been developed using the protocol dated 06-Oct-2022 and the final eCRF(s) 
dated. 
An approved and signed SAP is a requirement for database lock. 
This SAP only covers the results that will be processed by the ICON Early Clinical & Bioanalytical Services 
(IEB) Biostatistics Department and Quantitative Pharmacology & Pharmacometrics (department calculating 
the pharmacokinetic (PK) parameters). 
ICON IEB will perform the pharmacokinetic (PK), and safety and tolerability evaluation. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified. Any post-hoc or unplanned analyses, or significant changes 
from the planned analysis in this SAP performed to provide results for inclusion in the clinical study report 
(CSR) but not included in this SAP, will be clearly identified in the CSR. Changes to planned analyses do 
not require an updated SAP but should be included in the CSR if significant. 
4.0 Changes from Previous Version of Approved SAP 
This is the first version of the SAP. 
5.0 Study Objectives and Endpoints 
5.1 Primary Objectives 
• 
Part 1: To assess the Pharmacokinetic (PK) of apraglutide in subjects with moderate hepatic 
impairment compared with matched control subjects with normal hepatic function following single 
Subcutaneous (SC) dose administration. 
• 
Part 2 (if applicable; see criteria to move to Part 2): To assess the PK of apraglutide in subjects 
with mild hepatic impairment compared with matched control subjects following single SC dose 
administration. 
5.1.1 Primary Endpoint 
• 
Area under the curve to infinity (AUCinf) or area under the curve from time zero to the last 
quantifiable concentration (AUClast) if AUCinf cannot be reliably estimated. 
• 
Area under the curve from time zero to 168 hours after apraglutide administration (AUC0-168hr) 
• 
Maximum observed plasma concentration (Cmax) 
5.2 Secondary Objective 
• 
To assess the safety and tolerability of apraglutide administered to subjects with impaired and 
normal hepatic function 
5.2.1 Secondary Endpoint 
• 
Time of maximum plasma concentration (tmax) 
• 
Apparent clearance after extravascular administration (CL/F) 
• 
Apparent volume of distribution after extravascular administration (Vz/F) 
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• 
Terminal elimination rate constant (λz) 
• 
Terminal half-life (t½) 
• 
Physical examination 
• 
The incidence, nature, and severity of adverse events (AE) with apraglutide 
• 
Changes in clinical laboratory results (chemistry, hematology, coagulation, and urinalysis) during 
and following trial treatment administration 
• 
Changes in vital signs and 12-lead electrocardiogram (ECG) during and following trial treatment 
administration 
6.0 Study Design 
This is a Phase 1, non-randomized, open-label, single-dose trial to evaluate the effect of impaired hepatic 
function on the PK, safety, and tolerability of apraglutide administered to trial subjects via SC injection. 
Subjects with mild hepatic impairment (Child-Pugh A) and moderate hepatic impairment (Child-Pugh B) will 
be enrolled. Patients with decompensation, late-stage cirrhosis, and cirrhosis-related complications (Child-
Pugh C) will not be included in this trial, as such patients are not envisioned to be treated chronically with 
apraglutide. A staged approach will be followed in the trial. Part 2 of the trial will only be conducted after 
evaluation of Part 1 if the geometric mean ratio (GMR) point estimate of apraglutide AUCinf or AUClast for 
the moderate hepatic impairment group compared to the control group is ≥2. If this criterion is not met, the 
trial will stop after Part 1. Subjects will be selected and categorized into normal hepatic function, or hepatic 
impairment groups based on their Child-Pugh score (will be described in section 9.2.2 of the SAP). 
Subjects withdrawn or discontinued from treatment in the normal, mild, or moderate hepatic impairment 
groups and are considered to be non-evaluable, with respect to the primary PK objective, can be replaced 
at the discretion of the Sponsor. 
Following consent, subjects will undergo a Screening procedure to determine their suitability for trial 
enrollment. Screening will occur within a 28-day window prior to dosing. Subjects will be admitted on  
Day -1. On Day 1 a single SC injection of 5 mg apraglutide will be administered. The subjects will remain 
at the Clinical Research Unit (CRU) post-dose, and either will be discharged on Day 11 or will be allowed 
to leave the center on Day 8 and will be asked to come back on Day 11 for an outpatient visit. 
Pharmacokinetics will be assessed on Days 1 to 8, Day 11 and Day 14. The EOT visit will take place on 
14±2 days. Pharmacokinetics of blood samples will be assessed for 312 hours (until Day 14 inclusive). 
Subjects who received apraglutide (except subjects who exit from the trial early) will return to the CRU 
approximately 14±2 days after dosing for the EOT visit where follow-up assessments will be performed 
according to the Schedule of Assessments (Appendix 2) and to determine if any AEs have occurred since 
the last trial visit. 
Please find the trial scheme below: 
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Figure 1: Trial scheme 
 
6.1 Sample Size Considerations 
No formal power calculation was performed. The number of subjects per group is based on a review of the 
literature, and a review of the European Medicines Agency (EMA) and Food and Drug Administration (FDA) 
guidelines.  
The sample size of approximately eight subjects per group is also based on the feasibility to recruit subjects 
with various degrees of hepatic impairment. 
6.2 Randomization 
The study is not randomized. 
7.0 Overview of Planned Analysis 
7.1 Changes from Protocol 
There are no changes from the protocol. 
7.2 Interim Analysis and Key Results 
An interim PK report will be created by the pharmacokineticist. 
After Part 1 the PK results will be sent by the PK lab to the pharmacokineticist. This will be sent per Data 
Transfer Agreements created by ICON Data management and will contain Quality controlled (QC’d) results. 
Based on these results the pharmacokineticist will calculate the required PK Parameters for the interim 
analysis based on nominal sampling time points. The PK parameters required for the interim reporting will 
be AUCinf (or AUClast) and Cmax.  
The interim report will contain the raw concentration data, a table with at least the primary PK parameters 
and a table showing the GMR point estimate of apraglutide AUCinf (or AUClast) and Cmax for the moderate 
hepatic impairment group compared to the control group. 
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If the AUCinf is extrapolated by more than 20% for 1 subject, the AUClast should be used for all subjects for 
the determination of the Geometric Mean Ratio (GMR). If the GMR for the moderate hepatic impairment 
group versus the normal group is ≥2.0, Part 2 may be conducted. 
7.3 Final Analysis 
Draft TFLs will be provided after database lock. After Sponsor comments have been incorporated, the TFLs 
will be finalized and incorporated in the first draft CSR. 
8.0 Data Review 
8.1 Data Management 
Data handling and transfer will take place under the ICON Data Management Plan for the study. 
8.2 Acceptance of Data for Summarization 
Programming of analysis datasets and tables, figures and listings (TFLs) may be ongoing during the data 
management of the study. However, programming of analysis datasets and TFLs will be completed and 
quality controlled (QC’d) after database lock. Only quality assured (QA’d) results released by the Safety 
Laboratory, Bioanalytical Laboratory, or other external data source will be used for the programming of 
analysis datasets and TFLs for the final report. Any data values requiring investigation or corrections that 
are identified while programming the analysis datasets and TFLs will be sent to the project Data Manager. 
If the issue affects the TFLs the Programmer or Statistician who identified the issue will follow it to resolution. 
9.0 Definitions and General Analysis Methods 
9.1 Analysis Data Presentation 
9.1.1 Rounding 
In listings, data will be presented with the same precision as the original data. Derived data will be rounded 
for presentation purposes.  
For all summaries, the mean and median will be presented to one decimal place greater than the data, 
standard deviation to two greater than the data, and the minimum and maximum will be presented to the 
same number of decimal places as the data. Frequency percentages will be presented with one decimal. 
Except for 100, which will be presented as an integer 
The above rule can be applied directly to collected data. For derived data (e.g. the mean values of triplicates 
ECG’s) rounding will occur for presentation purposes 
PK concentration and parameters will be presented to three significant figures except %CV (which will be 
presented with 1 decimal) and tmax (which will be presented with 2 decimals). PK Parameter values >1000 
will be presented as an integer. 
P-values will be reported to four decimal places; p-value less than 0.0001 will be reported as p <0.0001. 
9.1.2 Imputation 
Unless otherwise noted, data will not be imputed. 
Except for the substitution of any PK concentrations below the lower limit of quantification (LLOQ) (see 
Section 16.2.1), and missing severity and relationship classification, start or end date/times of Adverse 
Events (AEs) for the calculation of onset and duration (see Section 17.1.1), and the imputation for laboratory 
results as stated below, any missing data will not be imputed. 
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11.0 Subject Disposition 
The number and percentage of subjects enrolled, dosed, and members of each analysis set will be 
presented. The number and percentage of subjects who withdrew from the study prematurely and a 
breakdown of the corresponding reasons for withdrawal will also be presented for both the dosed subjects 
and screen failures. 
12.0 Protocol Deviations 
Protocol deviations will be listed by subject. 
13.0 Demographic and Baseline Characteristics 
13.1 Demographics 
All demographic data collected during the screenings visit will be listed by subject. 
Subject demographics will be summarized descriptively for all subjects by hepatic function group and 
overall. The summary will include the subjects’ age (in years), sex, race, ethnicity, weight (in kg), height (in 
cm), and BMI (in kg/m2). For female subjects the childbearing potential will be listed as well. 
Demographics will be summarized for the safety, PK concentrations and PK Parameter analysis sets, if 
they are different from one another. 
13.2 Medical History 
Medical history, categorized by preferred term according to the latest version of Medical Dictionary for 
Regulatory Activities (MedDRA), will be listed by subject. 
13.3 Other Baseline Characteristics 
Substance use (tobacco and alcohol) will be listed. 
The results of drug and alcohol screen will be listed. 
Non-compliance to in- or exclusion criteria (if any) will be listed. 
The Child-Pugh Assessment Results will be listed. 
Serology results will be listed. 
SARS-CoV-2 Results will be listed. 
Results for pregnancy, FSH and estradiol will be listed (females only, if required) 
14.0 Concomitant Medications 
Concomitant medication will be listed. Medications with an end date prior to the first dose of study drug 
will be considered prior medications and will be noted in the listing. If a partial date allows a medication to 
be considered concomitant it will be categorized as such. Concomitant medications will be coded by 
using World Health Organization Drug Dictionary. 
15.0 Treatment Compliance and Exposure 
Exposure data will be listed by subject. 
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16.0 Pharmacokinetic Analyses  
16.1 Pharmacokinetic Variables 
PK concentrations will be collected in plasma and will be analyzed by Altasciences Bioanalysis and 
Research Services. 
16.1.1 Plasma Variables 
16.1.1.1 Concentrations 
• 
Plasma concentration of apraglutide 
 
16.1.1.2 Parameters 
• 
PK Parameters for apraglutide as defined in Table 3: Plasma Parameters. 
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for the number of points (minimum of 3, excluding Cmax) 
used in the estimation of Kel  
Kel_Start 
The start time used in the regression for the 
determination of Kel  
Lambda_z_lower  
from WNL  
Kel_End 
The end time used in the regression for the determination 
of Kel  
Lambda_z_upper  
from WNL  
Kel_N 
The number of points used in the regression for the 
determination of Kel  
No_points_lambda_z 
from WNL  
Note: AUCs will be calculated using linear up / log down, expressed in units of concentration x time. 
 
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16.2 Pharmacokinetic Summaries 
16.2.1 Pharmacokinetic Concentrations 
Plasma concentrations for apraglutide below the quantifiable limit (BQL) will be set to ½ lower limit of 
quantification (LLOQ) in the computation of mean concentration values. Descriptive statistics (number of 
subjects, arithmetic mean, geometric mean, standard deviation (SD), coefficient of variation (CV), 
Geometric CV, median, minimum, and maximum) will be used to summarize the plasma concentrations by 
hepatic function group at each scheduled time point. If over ½ the subjects in a given cell have values BQL 
then the descriptive statistics will not be presented and will instead display as BQL for the mean and 
minimum. With the exception of maximum all other statistics will be missing. The individual plasma 
concentrations data will be presented together with the descriptive statistics. 
Linear and semi-logarithmic plots of the geometric mean (including Error Bars) plasma concentration by 
scheduled sampling time will be provided by hepatic function group. These plots will show time in hours. 
The plots will match the summary table results and will not have an observation at a given time point if more 
than half of the subjects have values BQL. 
Linear and semi-logarithmic plots of the individual plasma concentration by actual sampling time will be 
provided by subject. These plots will show time in hours. Individual plots will use the BQL handling 
procedure described below for “Pharmacokinetic Parameters”. 
Combined individual plasma concentrations both on a linear and semi-logarithmic scale versus actual 
sampling time in hours, showing all subjects together in a single plot, will be presented by hepatic function 
group. 
16.2.2 Pharmacokinetic Parameters 
PK parameters for apraglutide will be estimated using non-compartmental methods with WinNonlin®. 
The plasma PK parameters will be estimated from the concentration-time profiles. In estimating the PK 
parameters, BQL values at the beginning of the profile will be set to zero. BQL values that occur after the 
first quantifiable point will be considered missing. Values that are embedded between BQLs, or quantifiable 
values occurring after two or more BQLs, will be set to missing at the discretion of the pharmacokineticist. 
Actual sampling times, rather than scheduled sampling times, will be used in all computations involving 
sampling times. If the actual time or dose time is missing, the scheduled time may be substituted in order 
to calculate the PK parameter. 
Descriptive statistics (number of subjects, mean, geometric mean, standard deviation, coefficient of 
variation, Geometric CV, median, minimum, and maximum) will be used to summarize the calculated PK 
parameters by hepatic function group. For tmax, only median, min and max will be presented. The individual 
PK parameters will be presented together with the descriptive statistics. 
The points to be included in the kel range will be determined by the pharmacokineticist after inspection of 
the semi-log concentration-time profiles. At least 3 points will be required to be used. The Cmax data point 
will not be included. 
Parameters based on adjusted r2 below 0.80 or %AUCextra above 20% will be flagged but not excluded from 
descriptive statistics. 
Box and whisker plots for individual subject parameters (AUCinf or AUClast and Cmax) will be constructed by 
hepatic function group and overlaid with geometric means. 
16.2.2.1 Statistical Analyses 
Part 1: 
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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 hepatic function group 
(Reference) and the moderate impaired hepatic group (Test).  
If there is a dropout in the moderate hepatic function group, the “matched” subject in the normal hepatic 
function group will be excluded from this analysis. The subject from the normal hepatic group may 
however be used in in the analysis for part 2 if there is a matched Mild hepatic function group subject. 
 
If the AUCinf is extrapolated by more than 20% for 1 subject, the AUClast should be used for all subjects 
for the determination of the Geometric Mean Ratio (GMR). 
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. 
The following SAS PROC MIXED pseudo-code may be used:  
proc mixed data = adpp;  
by parameter;  
class hepatic_group;  
model log(aval) = hepatic_group;  
lsmeans hepatic_group / cl alpha = 0.1;  
estimate “Moderate hepatic impairment vs Normal hepatic function” 
hepatic_group 1 -1 /e cl alpha=0.1;  
run; 
 
Part 2 (if conducted): 
Part 2 may be conducted if apraglutide AUCinf (or AUClast when AUCinf cannot be calculated) GMR for 
the moderate hepatic impairment group versus the normal group is ≥ 2. 
Analysis of variance will be used to compare the natural log transformed AUCinf or AUClast and Cmax for 
apraglutide between normal hepatic function group from Part 1 (Reference) and the mild impaired hepatic 
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 GMR (Test/Reference) and 90% CIs for the ratios. 
The following SAS PROC MIXED pseudo-code may be used:  
proc mixed data = adpp;  
   by parameter;  
   class hepatic_group;  
   model log(aval) = hepatic _group;  
   lsmeans hepatic _group / cl alpha = 0.1;  
   estimate “Mild hepatic impairment vs Normal renal function” hepatic_group 
1 -1 /e cl alpha=0.1; 
run; 
17.0 Safety Analyses  
17.1 Safety Variables 
The following safety variables will be summarized: 
• 
Adverse Events (AEs) 
• 
Vital Signs 
o 
Supine Blood Pressure  
 
Systolic Blood Pressure (SBP) 
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 
Diastolic Blood Pressure (DBP) 
o 
Pulse rate 
o 
Temperature 
• 
Electrocardiograms (ECG) 
o 
Heart Rate 
o 
PR Interval 
o 
QRS-Duration 
o 
QT Interval 
o 
QTc (Frederica) Interval 
o 
RR Interval 
• 
Clinical Laboratory Evaluations 
o 
Clinical Chemistry  
o 
Hematology 
o 
Hemostasis 
17.1.1 Adverse Events 
All AE summaries will include only treatment-emergent adverse events. Treatment-emergent adverse 
events (TEAE) are those which occur or worsen after the dose of study drug. 
An overview of AEs with number of events, and numbers and percentages of subjects reporting TEAEs, 
TEAEs related to study drug (related or unrelated), TEAEs by common terminology criteria for AEs 
(CTCAE) grade/severity, serious AEs (SAEs), AEs of Special Interest, AEs of Particularly Interest, and 
subjects who discontinued due to an AE, will be presented by hepatic function group and overall.  
A breakdown of the number of events, and number and percentage of subjects reporting each TEAE, 
categorized by body system and preferred term coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA) (Version according to the coding conventions), will be presented by hepatic function 
group and overall. Counting will be done by subject only, not by event; subjects will only be counted once 
within each body system or preferred term. A similar table for all drug-related TEAEs will be presented per 
treatments. 
A summary of events reported, categorized by relationship to study drug, will be provided and presented 
by hepatic function group and overall. Subjects with multiple events within a particular body system or 
preferred term will be counted under the category of their most drug-related event within that body system 
or preferred term. Relationship will be mapped to related/unrelated based on the CRF categories. TEAEs 
reported as definitely, probably, and possibly will be considered related. Unlikely and unrelated will be 
mapped to unrelated. 
A summary of events reported, categorized by severity as recorded on eCRF, will be provided and 
presented by hepatic function group and overall. Subjects with multiple events within a particular body 
system or preferred term will be counted under the category of their most severe event within that body 
system or preferred term. 
Listings of adverse events of special interest (AESI) (as reported by the investigators) will be provided 
separately for each type of AESI. Similarly, listings of adverse events of particularly interest (defined in 
Table 4) will be provided separately for each medical concept.  
Table 4 Adverse Events of Particularly Interest 
 
AEPI 
Definition 
Acceleration of neoplastic growth 
including Intestinal neoplastic 
growth/hypertrophic effect 
SOC: Neoplasms benign, malignant and unspecified (incl cysts and 
polyps) 
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including polyps 
Benign neoplasia of the 
Gastrointestinal tract 
including the hepatobiliary system 
(not including 
polyps). 
SMQ: Gastrointestinal premalignant disorders 
(Level 1, narrow scope) 
 
SMQ: Biliary neoplasms benign (incl cysts and polyps) (Level 3, 
narrow scope) 
 
Gastrointestinal obstruction 
SMQ: Gastrointestinal obstruction (Level 2, Narrow scope) 
 
Gastrointestinal stoma obstruction 
PT: Intestinal anastomosis complication, Stoma 
obstruction 
Increase of the liver transaminases 
SMQ Drug related hepatic disorders - comprehensive search (Broad 
and Narrow)  
 
Embryofetal toxicity 
SMQ: Pregnancy and neonatal topics  (Broad and Narrow) 
Biliary adverse events 
SMQ: Functional, inflammatory and gallstone 
related biliary disorders (Broad and Narrow)  
Pancreatic adverse events 
HLT: Acute and chronic pancreatitis  
HLT: Pancreatic disorders NEC 
Cardiovascular AEs associated with 
fluid overload 
SMQ: Haemodynamic oedema, effusions and fluid 
overload (Narrow) 
SMQ: Cardiac failure (Broad and Narrow) 
 
 
A listing of adverse events leading to study discontinuation will be provided. 
All adverse events (including non-treatment-emergent events) recorded on the eCRF will be listed. 
The following missing data will be imputed as defined (for calculations only / will not be presented): 
• 
Missing AE start and / or end times for the calculation of onset and duration will be assumed to be 
at 00:01 for a start time and 23:59 for end times 
• 
Missing AE severity or relationship will be assumed to be severe or related, respectively 
• 
Missing AE start times for the determination of treatment emergence will be assumed to occur after 
treatment unless partial date documents the AE as happening prior to treatment 
• 
Missing AE start times for the determination of treatment assignment will be assumed to occur after 
treatment on the recorded date one minute after dosing 
• 
Missing AE start date will be assumed to be after treatment for the determination of TEAE and on 
treatment for single treatment studies but will not be attributed to treatment in studies with multiple 
treatments 
17.1.2 Deaths and Serious Adverse Events 
A listing of deaths and other serious adverse events (SAE) will be provided by subject. 
17.1.3 Laboratory Data 
Clinical laboratory data will be presented using units from the study data tabulation model (SDTM) 
Controlled Terminology. 
All laboratory data will be listed, including laboratory variables not listed in the protocol. A separate listing, 
including out-of-range values will also be provided. Normal ranges will be used directly from the clinical 
laboratory. Clinically significant results will be flagged. 
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Descriptive statistics summarizing continuous laboratory results of clinical chemistry, hematology and 
hemostasis (observed and derived changes from baseline) by hepatic function group and scheduled time 
will be included in the listings.  
17.1.4 Vital Signs 
Descriptive statistics will be provided to summarize vital signs values (observed and changes from baseline) 
by hepatic function group and scheduled time/visit and individual vital signs results will be listed. 
The arithmetic mean (including Error Bars) of the vital signs parameters (observed and change from 
baseline) will be plotted over time per Hepatic Function Group. 
17.1.5 Electrocardiograms 
All ECG parameters (including changes from baseline) and the corresponding abnormalities and 
physicians’ conclusions will be listed by subject. 
The observed measurements for all ECG parameters and the corresponding abnormalities will be listed for 
all timepoints. The means of triplicate measurements for continuous parameters and the change from 
baseline of the mean triplicate measurements at each scheduled timepoint will be listed by subject. 
For ECG, baseline is defined as the mean of the triplicate measurements recorded at the last timepoint 
before dosing. If no triplicate is available before the first study drug administration, the mean of the last 
recorded duplicate closest to the first study drug administration will be considered as baseline. If no triplicate 
or duplicate is available, the last single ECG recorded before the first study drug administration will be 
considered as baseline. 
Descriptive statistics will be provided to summarize mean ECG parameters (observed and changes from 
baseline) by hepatic function group and scheduled time/visit. 
The arithmetic mean (including Error Bars)  of the ECG parameters (mean values of the triplicates, observed 
and change from baseline) will be plotted over time per Hepatic Function Group. 
17.1.6 Other Observations Related to Safety 
Abnormal findings at physical examinations will be listed. 
18.0 References 
SAS Institute, Inc., SAS® Version 9.4 software, Cary, NC. 
Phoenix WinNonlin® version 8.1 (Certara USA, Inc. Princeton, NJ, USA) 
Clinical Study Protocol: A Phase 1, Open-Label Evaluation of the Pharmacokinetics and Safety of a 
Single Dose of Apraglutide in Subjects with Normal and Impaired Hepatic Function. Version 1.0, Final, 06 
Oct 2022. 
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Appendix 2: Schedule of Assessments 
 
 
 
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