Conditions: GERD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 75
Healthy volunteers: yes

Brief summary:
This is a Phase I, single-center, open label parallel-group, randomized study designed to evaluate the pharmacokinetics (PK), pharmacodynamics (PD, by continuous intragastric pH measurment), safety and tolerability of single and repeated oral doses of linaprazan glurate in 3 different dose levels given once- (QD) or twice daily (BID), for 14 days, with an additional single dose after 2, 4 or 6 days of drug holiday. The population will include healthy male and female subjects.

The subjects will be followed up to 28 days post IMP dosing.

Detailed description:

Arms:
arm 1: 25 mg (one 25 mg oral tablet) linaprazan glurate once daily (QD) for 14 days arm 2: 50 mg (two 25 mg oral tablets) linaprazan glurate once daily (QD) for 14 days arm 3: 75 mg (three 25 mg oral tablet) linaprazan glurate once daily (QD) for 14 days arm 4: 25 mg (one 25mg oral tablet) linaprazan glurate twice daily (BID) for 14 days arm 5: 50 mg (two 25 mg oral tablets) linaprazan glurate twice daily (BID) for 14 days arm 6: 75 mg (three 25 mg oral tablet) linaprazan glurate twice daily (BID) for 14 days

Interventions: intervention 1: linaprazan glurate 25 mg QD intervention 2: linaprazan glurate 50 mg QD intervention 3: linaprazan glurate 75 mg QD intervention 4: linaprazan glurate 25 mg BID intervention 5: linaprazan glurate 50 mg BID intervention 6: linaprazan glurate 75 mg BID
Intervention descriptions: intervention 1: The subjects will receive 25 mg dose in the evening, in a non-fasted condition 30 minutes after the evening meal, for 14 days. Subjects are to follow a standardized food intake schedule.

After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more in the evening (non-fasted). intervention 2: The subjects will receive 50 mg dose in the evening, in a non-fasted condition 30 minutes after the evening meal, for 14 days. Subjects are to follow a standardized food intake schedule.

After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more in the evening (non-fasted). intervention 3: The subjects will receive 75 mg dose in the evening, in a non-fasted condition 30 minutes after the evening meal, for 14 days. Subjects are to follow a standardized food intake schedule.

After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more in the evening (non-fasted). intervention 4: The subjects will receive 25 mg dose twice daily, in the morning and in the evening for 14 days. Subjects will be fasted for ≥10 hours overnight before dosing on Day 1 and day 14, until 30 minutes post-dose. During fasting, tap water, but no other drinks, are allowed as desired, except for 1 hour before and 30 minutes after dosing. The second daily dose will be administered 30 minutes after the evening meal, i.e. in a non-fasted condition. The subjects are to follow a standardized food intake schedule. After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more (in fasted condition in the morning, non-fasted in the evening). intervention 5: The subjects will receive 50 mg dose twice daily, in the morning and in the evening for 14 days. Subjects will be fasted for ≥10 hours overnight before dosing on Day 1 and day 14, until 30 minutes post-dose. During fasting, tap water, but no other drinks, are allowed as desired, except for 1 hour before and 30 minutes after dosing. The second daily dose will be administered 30 minutes after the evening meal, i.e. in a non-fasted condition. The subjects are to follow a standardized food intake schedule. After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more (in fasted condition in the morning, non-fasted in the evening). intervention 6: The subjects will receive 75 mg dose twice daily, in the morning and in the evening for 14 days. Subjects will be fasted for ≥10 hours overnight before dosing on Day 1 and day 14, until 30 minutes post-dose. During fasting, tap water, but no other drinks, are allowed as desired, except for 1 hour before and 30 minutes after dosing. The second daily dose will be administered 30 minutes after the evening meal, i.e. in a non-fasted condition. The subjects are to follow a standardized food intake schedule. After a drug holiday period of either 2, 4 or 6 days, linaprazan glurate will be given once more (in fasted condition in the morning, non-fasted in the evening).

Protocol document:
Prot_000.pdf: 













































































































































































SAP_001.pdf: 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
 
Client Study Code: 
CX842A2107 
Study Title: 
A phase 1, open label, randomized, parallel-group, single center study to 
investigate pharmacokinetics and pharmacodynamics (intragastric pH) of 
linaprazan glurate/linaprazan after single and 14 days repeated oral administration 
of linaprazan glurate to healthy subjects. 
 
 


 
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Document Control 
 
Control 
Document Name 
Statistical Analysis Plan 
Based on most recently 
amended clinical study 
protocol 
CSP CX842A2107 Final V 4.0  
EudraCT number 
2022-002725-10 
Version (Date) 
Version 2.0 (04-Oct-2023) 
Study statistician 
Jouni Junnila  
Trial coordinating 
investigator 
Prof. Matjaž Fležar , MD, PhD,  
CRS Klinične raziskave in storitve d.o.o. 
Ukmarjeva ulica 6 
1000 Ljubljana, Slovenia 
Authors 
Kristofer Katkits Nilsson 
Jouni Junnila 
Peter Unge 
Gunilla Huledal 
Status
Final
 
 
 




 
Statistical Analysis Plan  
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History  
Version
Modified By 
Date 
 Description of Changes 
0.1 
Aziz Ali, SDS Life Science 
David Dahlgren, SDS Life Science 
02-Feb-2023 First draft 
1.0 
Aziz Ali, SDS Life Science 
David Dahlgren, SDS Life Science 
01-June-2023 Changes made after review comments 
2.0 
Kristofer Katkits Nilsson,  
Jouni Junnila 
Peter Unge 
Gunilla Huledal 
27-Sep-2023 Update of sections 2.6 urine metabolites 
omitted.  
Section 4.1 clarification on determining the 
PKAS.  
Section 5.2.3 added to describe the 
calculations of the pharmacodynamic data 
(pH) 
Section 5.7 updated with more detailed 
descriptions of presenting the PD related 
(pH) data and pH in relationship to PK.  
Minor corrections throughout the 
document.  
 
 
 
 
 
 


 
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Table of Contents 
Abbreviations ................................................................................................................................................... 7 
1. 
Introduction ........................................................................................................................................ 10 
2. 
Study Objectives and Endpoints .......................................................................................................... 10 
2.1 
Primary Objectives..................................................................................................................................................10 
2.2 
Secondary Objectives .............................................................................................................................................10 
2.3 
Exploratory Objectives............................................................................................................................................10 
2.4 
Primary endpoints ..................................................................................................................................................10 
2.5 
Secondary endpoints ..............................................................................................................................................11 
2.6 
Exploratory endpoints ............................................................................................................................................11 
3. 
Study Details ....................................................................................................................................... 11 
3.1 
Study Design ...........................................................................................................................................................11 
3.2 
Study population ....................................................................................................................................................12 
3.3 
Randomisation and Blinding ...................................................................................................................................12 
3.4 
Number of Subjects ................................................................................................................................................13 
3.4.1 
Sample Size ......................................................................................................................................................................... 13 
3.5 
Subject Replacement ..............................................................................................................................................13 
4. 
Assessments ........................................................................................................................................ 13 
4.1 
Protocol Deviations ................................................................................................................................................13 
4.2 
Demographic and Baseline Characteristics .............................................................................................................13 
4.3 
Medical/Surgical History .........................................................................................................................................14 
4.4 
Prior and Concomitant Medications .......................................................................................................................14 
4.5 
Safety Variables ......................................................................................................................................................14 
4.5.1 
Adverse Events.................................................................................................................................................................... 14 
4.5.2 
Laboratory Evaluations ....................................................................................................................................................... 14 
4.5.3 
Physical Examination .......................................................................................................................................................... 16 
4.5.4 
Vital Signs ............................................................................................................................................................................ 16 
4.5.5 
ECGs .................................................................................................................................................................................... 16 
4.6 
Pharmacokinetic Assessments................................................................................................................................16 
4.6.1 
Primary and secondary analyses ......................................................................................................................................... 16 
4.6.1 Exploratory analyses .................................................................................................................................................................. 17 
5. 
Analysis Methods ................................................................................................................................ 18 
5.1 
Analysis Sets ...........................................................................................................................................................18 
5.1.1 
Full Analysis Set (FAS) ......................................................................................................................................................... 18 
5.1.2 
PK Analysis Set (PKAS) ......................................................................................................................................................... 18 
5.1.3 
PK/PD Analysis Set (PK/PDAS) ............................................................................................................................................. 18 
5.2 
General Principles for Presenting Study Data .........................................................................................................18 
5.2.1 
Presentation of Data ........................................................................................................................................................... 18 
5.2.2 
Calculation of PK Data ......................................................................................................................................................... 19 
5.2.3 
Calculation of PD data (intragastric pH) .............................................................................................................................. 19 


 
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5.3 
Statistical/Analytical issues .....................................................................................................................................20 
5.3.1 
Missing Data and Handling of Dropouts .............................................................................................................................. 20 
5.3.1.1 
PK drug concentration data ........................................................................................................................................ 20 
5.3.2 
Outliers ............................................................................................................................................................................... 20 
5.3.3 
Multicentre Studies............................................................................................................................................................. 20 
5.4 
Disposition and Background Information data .......................................................................................................20 
5.4.1 
Subject Disposition ............................................................................................................................................................. 20 
5.4.2 
Protocol Deviations ............................................................................................................................................................. 20 
5.4.3 
Demographic and Baseline Characteristics ......................................................................................................................... 20 
5.4.4 
Medical History ................................................................................................................................................................... 20 
5.4.5 
Prior and Concomitant Medications ................................................................................................................................... 20 
5.4.6 
Treatment Compliance ....................................................................................................................................................... 21 
5.4.7 
Subject Discontinuation ...................................................................................................................................................... 21 
5.5 
Safety Analyses .......................................................................................................................................................21 
5.5.1 
Adverse Events.................................................................................................................................................................... 21 
5.5.2 
Laboratory Evaluations ....................................................................................................................................................... 21 
5.5.3 
Concomitant Medications ................................................................................................................................................... 22 
5.5.4 
Physical Examination .......................................................................................................................................................... 22 
5.5.5 
Vital Signs ............................................................................................................................................................................ 22 
5.5.6 
Electrocardiogram............................................................................................................................................................... 22 
5.6 
Pharmacokinetic Analyses ......................................................................................................................................22 
5.7 
Summaries of Intragastric pH-metry ......................................................................................................................23 
5.7.1 
Relationship between plasma concentration of Linaprazan and intra gastric acid secretion (pH) ...................................... 24 
5.8 
Changes to Planned Analysis ..................................................................................................................................24 
6. 
References .......................................................................................................................................... 25 
7. 
Appendix ............................................................................................................................................. 26 
8. 
Addendum to SAP on handling of pH-metry data ................................................................................ 29 
 
 
 


 
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Abbreviations 
Abbreviation 
Term 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT
Alanine aminotransferase
APTT 
Activated partial thromboplastin clotting time 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration vs. time curve 
AUC0-t 
AUC from time 0 to time t  
AUC0-24, 0-12, 12-24, 24-48 
AUC from time 0-24, 0-12, 12-24, 24-48 hours, respectively 
AUCextrap% 
AUC percent extrapolation 
AUCinf 
AUC from 0 to infinity 
AUC 
AUC from 0 to time of last measurable plasma concentration 
BID 
Bis in die (twice daily)  
BMI 
Body mass index 
BP
Blood pressure
Caver 
 
Average concentration 
CL/F 
Apparent total body clearance following extravascular administration 
Cmax 
Maximum observed concentration 
Cmin 
Minimum observed concentration 
Ctrough
The plasma concentration observed at the start of a dosing interval.
CS 
Clinically significant 
CRS 
Klinične raziskave in storitve d.o.o. 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
CV 
Coefficient of variation 
DSUR
Development safety update report


 
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Abbreviation 
Term 
ECG 
Electrocardiogram 
eCRF 
Electronic Case report form 
EDC
Electronic data capture
eGERD 
Erosive GERD 
FIH
First-in-human
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GERD
Gastroesophageal reflux disease
Hb 
Hemoglobin 
HIV
Human immunodeficiency virus
HR 
Heart rate 
HTR 
Holding Time Ratio (%) 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IME 
Important medical event 
IMP
Investigational medicinal product
IR 
Immediate release 
ISF 
Investigator site file 
IUS 
Intra-uterine system 
LLOQ 
Lower limit of quantification 
MAD
Multiple-ascending dose
MCH 
Mean corpuscular hemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
NCA 
Non-compartmental analysis 
NCS
Not clinically significant
PD 
Pharmacodynamics 


 
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Abbreviation 
Term 
PK 
Pharmacokinetics 
PK(INR) 
Prothrombin complex international normalized ratio 
PKAS
PK analysis set
PT 
Preferred term 
QC
Quality control
QD 
Quaque die (once daily) 
QRS interval 
(ECG) The time required for stimulus to spread through the heart’s 
ventricles 
QT interval 
(ECG) The time from the beginning of the QRS complex to the end of 
the T wave 
QTcF 
(ECG) Corrected QT interval by Fredericia 
Racc 
Accumulation ratio 
RSI 
Reference safety information 
SAE
Serious adverse event
SAP 
Statistical analysis plan 
SAR
Serious adverse reaction
SD 
Standard deviation 
SOC 
System organ class 
SOP 
Standard operating procedures 
SUSAR 
Suspected unexpected serious adverse reaction 
TMF
Trial Master File
Tmax 
Time of occurrence of Cmax 
T1/2 
Terminal elimination half-life 
Vz/F 
Volume of distribution following extravascular administration 
WHO 
World Health Organization 
 


 
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1. 
Introduction 
This Statistical Analysis Plan (SAP) provides a detailed and technical description of the planned 
pharmacokinetic (PK) and pharmacodynamic (PD) analyses and statistical evaluations of Cinclus 
Pharma AB’s study CX842A2107: “A phase 1, open label, randomized, parallel-group, single center 
study to investigate pharmacokinetics and pharmacodynamics (intragastric pH) of linaprazan 
glurate/linaprazan after single and 14 days repeated oral administration of linaprazan glurate to 
healthy subjects.”.  
The SAP is prepared in compliance with the guidelines for Statistical Principles for Clinical Trials (ICH 
E9). 
A full description of the investigational plan, eligibility criteria, assessments, etc. is given in the 
Clinical Study Protocol (CSP) CX842A2107 v4.0 dated 10MAR2023. 
In case this SAP deviates from the statistical analysis described in the CSP, the reason for the 
deviation and/or alternative or additional statistical analyses will be documented in amendments to 
the CSP or in this SAP. 
2. 
Study Objectives and Endpoints 
This is a Phase I, single-center, open parallel-group, randomized study designed to evaluate the 
pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of single and repeated oral 
doses of linaprazan glurate at 3 dose levels in healthy male and female subjects. 
2.1 
Primary Objectives 
 
To characterize the PK and PD of linaprazan glurate and linaprazan after once daily (QD evening 
dose) and twice (BID) daily dosing after single and repeated administration of linaprazan 
glurate. 
2.2 
Secondary Objectives 
 
To assess the safety and tolerability after single and repeated doses of linaprazan glurate.   
2.3 
Exploratory Objectives 
 
 To establish the relationship between plasma concentration of linaprazan and control of 
intragastric acid secretion, defined as pH >4 and pH >6, as assessed by intragastric pH-metry. 
 
 To explore the PK characteristics after 2 to 6 days drug holiday after end of 14 days repeated 
dosing. 
 
To explore additional PD characteristics (intragastric pH). 
 
To explore the metabolites of linaprazan glurate in plasma and urine. 
2.4 
Primary endpoints 
 
Linaprazan glurate and linaprazan PK parameters after single and repeated administration of 
linaprazan glurate (when applicable): 
o Area under the plasma concentration vs. time curve (AUC) at different timepoints: 
AUC0-24, AUC0-12, AUC12-24, AUC24-48, and AUC0-t.   
o The minimum, end-of dosing interval, maximum and average plasma concentrations 
Ctrough, Cmax, Caver. 


 
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o Terminal elimination half-life (t½,) and time of occurrence of Cmax (tmax). 
 
Percentage of time gastric pH >4 at Day 1 and Day 14, over a 24-hour monitoring period 
following linaprazan glurate administration.  
2.5 
Secondary endpoints 
 
Additional PK parameters for linaprazan glurate and linaprazan PK parameters (e.g., but not 
limited to apparent clearance [CL/F], apparent volume of distribution [V/F], accumulation ratio 
[RAcc], Cmin, AUC from 0 to infinity [AUCinf] and AUC percent extrapolation [AUCextrap%]).  
 
 Frequency, intensity and seriousness of adverse events (AEs). 
 
 Clinically significant changes in: 
o Electrocardiogram (ECG) 
o Vital signs 
o Physical examinations  
o Safety laboratory parameters 
2.6 
Exploratory endpoints 
 
To explore exposure response relationship after single and repeated dosing of linaprazan 
glurate. 
 
Linaprazan glurate and linaprazan PK parameters (when applicable AUC0-24, AUC0- 12, AUC12-24, 
AUC24-48, AUC0-t, Cmax, t½, tmax) after single administration of linaprazan glurate after different 
length of drug holiday (2 to 6 days). 
 
PD parameters; Percentage of time gastric pH >5 and pH >6 at Day 1 and Day 14, over a 24-
hour monitoring period following linaprazan glurate administration. Mean gastric pH 0-12 
hours after dose (evening dose for BID) at Day 1 and 14. 
 
Plasma and urine samples collected for future exploratory analyses of potential linaprazan 
glurate metabolites. No reliable urine samples were collected in the trial, therefore urine 
metabolite analysis was omitted.  
The exploratory endpoints may be reported separately from the clinical study report (CSR).  
3. 
Study Details 
3.1 
Study Design 
This is a Phase I, single-center, open parallel-group, randomized study designed to evaluate the PK, 
PD, safety, and tolerability of single and repeated oral doses of linaprazan glurate at three dose levels 
in healthy male and female subjects.  
An overview of the study design is shown in   
Figure 1. The overall schedule of events is presented in Appendix Table 1. The detailed schedule of 
events for individual visits are tabulated in the CSP (see Tables 8.1-2 to 8.1-7 of the CSP for details).  
Subjects will be randomized into 1 of 6 dose groups. There will be 6 dose groups as follows:  
 
No 1: 25 mg linaprazan glurate (1x25 mg oral tablet) QD for 14 days  
 
No 2:  50 mg linaprazan glurate (2x25 mg oral tablet) QD for 14 days 
 
No 3:  75 mg linaprazan glurate (3x25 mg oral tablets) QD for 14 days 


 
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 
No 4: 25 mg linaprazan glurate (1x25 mg oral tablet) BID for 14 days 
 
No 5:  50 mg linaprazan glurate (2x25 mg oral tablet) BID for 14 days 
 
No 6:  75 mg linaprazan glurate (3x25 mg oral tablets) BID for 14 days 
Subjects participating in the study will attend 7 visits to the clinical research unit (CRU): a 
screening visit (Visit 1) followed by 6 visits (Visit 2-7). Visit 2, Visit 5 and Visit 7 are residential 
stays at the CRU and Visit 3, Visit 4, and Visit 6 are outpatient visits. The participants will also 
be followed by a remote follow-up/end-of-study visit via telephone (Visit 8), 7 days (±2 days) 
after the final dose.  
Figure 1. Overview of study design 
 
3.2 
Study population 
The subjects participating in this study will be healthy male and female subjects 18–65 (both 
inclusive) years of age, have with a body mass index (BMI) of 18.5 - 30.0 kg/m2 (inclusive), and are 
eligible for the study. More details regarding the study population, including inclusion and exclusion 
criteria, can be found in the CSP section 9. 
3.3 
Randomization and Blinding 
Block randomization (block size=6) stratified by gender will be used to generate the randomization 
list, which will show the assignment of subjects to 1 of the 6 dose groups given in Section 3.1.  
In addition, the subjects in each dose group will be randomized to a drug holiday period of 2 (n=4), 4 
(n=4) or 6 days (n=4) after the end of the 14 days treatment period. On Day 16, 18 or 20, a new single 
dose (QD or BID depending on previous randomization) will be administered for further PK 
evaluation. 
The randomization list of the study was be prepared by a statistician at CRS Tomaz Vovk, and 
transferred to the Trial Master File (TMF) for archiving. 
As this is an open label study, the dose group to which each subject is allocated will be recorded in 
the eCRF. A computer-generated randomization list will be created using SAS Proc Plan, SAS Version 
9.4 or later (SAS Institute, Inc., Cary, NC) or equivalent program. The randomization list will contain 
subject number, block, gender, drug holiday period, and dose group.  
The randomization list will be generated and kept by CRS.    
No blinding procedures will be followed. 


 
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3.4 
Number of Subjects 
3.4.1 Sample Size 
Approximately, 116 healthy volunteers are planned to be screened to achieve 72 randomized 
subjects. An estimated total of 12 subjects will be included per dose level (in total 6 dose groups). If 
less than 9 subjects are evaluable per dose level, addition of new a subject to replace a discontinued 
subject can be allowed. 
3.5 
Subject Replacement 
Subjects who consented to study participation but discontinued prior to IMP administration (dosing) 
may be replaced. Subjects withdrawn after dosing may be replaced at the Sponsor’s discretion after 
consultation with the Investigator. 
4. 
Assessments 
The overall Schedule of Assessments is given in Appendix Table 1. Details about each visit and the 
assessments made during the visit are given in the sections in the CSP that are listed in Appendix 
Table 1.   
4.1 
Protocol Deviations 
Deviations from the CSP should not occur. If deviations from the CSP occur, the implications and 
classification (minor or major) of each deviation will be decided and documented at the clean file 
meeting prior to database lock. If a subject is classified with a major protocol deviation potentially 
altering the treatment outcome, it will lead to exclusion of data from the PK analysis set and any such 
case should be clearly justified.  
Major protocol deviations include: 
 
Significant non-compliance with study procedures. 
 
Any serious unforeseen deviation in dosing of the subjects.  
 
Vomiting or diarrhea within 6 hours after dosing which could render the plasma 
concentration-time profile unreliable. 
 
Intake of prohibited medication that may influence the PK results (i.e., known to interact with 
the PK of linaprazan glurate). 
 
All protocol deviations will be assessed whether they affect the PK analysis to such an extent that the 
subject needs to be excluded from the PKAS (see section 5.1.2 for the PKAS definition). This 
assessment will be performed by the Clinical Pharmacology Specialist and be documented in the final 
Protocol Deviations Log.  
Blood sampling outside of the allowed timeframe will not be considered as a major protocol 
deviation.   
4.2 
Demographic and Baseline Characteristics 
The demographic and baseline data collected in this trial are gender, age, ethnicity, race, height and 
weight. BMI will be calculated from height and weight and recorded with 1 decimal point. 


 
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4.3 
Medical/Surgical History 
Medical/surgical history will be obtained by subject interview in order to verify that the eligibility 
criteria are met. The medical/surgical history will include all relevant diseases and operations within 
2 months prior to screening as judged by the Investigator.  
4.4 
Prior and Concomitant Medications 
Prior medications taken within 2 weeks prior to first IMP administration are obtained by subject 
interview in order to verify that the eligibility criteria are met. 
Medications are classified as prior if the stop date was before or on the day of the first dose 
administration (pre-dose) and as concomitant if ongoing on the day of the first dose administration, 
stopped after the first dose administration or started after the first dose administration.  
Any use of concomitant medication from screening until the end-of-study visit will be documented 
appropriately. Relevant information (i.e., name of medication, dose, unit, frequency, dose form, 
route, start and stop dates, reason for use) will be recorded.  
4.5 
Safety Variables 
4.5.1 Adverse Events 
An AE is defined as any untoward medical occurrence in a subject administered a medicinal product 
and which does not necessarily have a causal relationship with this treatment. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Definitions for the different types of AE including the definition for Serious Adverse Events (SAEs), 
Adverse Reaction (AR), Serious Adverse Reaction (SAR) and Suspected Unexpected Serious Adverse 
Reaction (SUSAR) are given in section 11.4 of the CSP. 
The following variables will be collected for each AE and SAE: 
 
Start date and time  
 
Stop date and time  
 
Whether the AE is serious 
 
Intensity (Grading using CTCAE v5.0)  
 
Causal relationship to IMP (Probable, Possible, Unlikely) 
 
Assessment of outcome (Recovered/resolved, Recovering/resolving, Recovered/resolved 
with sequelae, Not recovered/not resolved, Fatal, Unknown)  
 
Action taken with study treatment (Dose increased, Dose not changed, Dose reduced, Drug 
interrupted, Drug withdrawn, Not applicable, Unknown) 
An AE is considered causally related to the use of the IMP when the causality assessment is probable 
or possible. 
AEs will be followed up until resolution or end-of-study visit, whichever comes first. 
4.5.2 Laboratory Evaluations 
Blood and urine samples for the assessment of safety and eligibility will be collected as shown in 
Table 3. Safety laboratory values will be specified and documented as Normal, Abnormal NCS (not 


 
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clinically significant), or Abnormal CS (clinically significant). Abnormal post-dose findings assessed by 
the Investigator as CS will be reported as AEs. 
 
 
 
Table 3. Safety Laboratory Parameters 
 Category  
Parameter  
Clinical chemistry  
Alanine aminotransferase (ALT)  
Albumin  
Alkaline phosphatase (ALP)  
Aspartate aminotransferase (AST)  
Bilirubin (total and conjugated)  
Calcium  
Creatinine  
Glucose  
Phosphate  
Potassium  
Sodium  
Urea   
Hematology  
Erythrocyte count  
Leukocyte count with differential count  
Hematocrit (B-EVF)  
Hemoglobin (Hb)  
Mean corpuscular volume (MCV)  
Mean corpuscular hemoglobin (MCH)  
Platelet count  
Coagulation  
Activated Partial Thromboplastin Time (APTT)  
Prothrombin Complex International Normalized Ratio (PK[INR])  
Urinalysis (dip stick)  
Erythrocytes  
Glucose  
Ketones  
Leukocytes  
Nitrite  
pH  
Protein  
Specific gravity  
Urobilinogen  


 
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 Category  
Parameter  
FSH -test (at screening, postmenopausal 
females only)  
Follicle stimulating hormone (FSH)  
Pregnancy test (female subjects of 
childbearing potential only)  
Urine pregnancy test.  
 
4.5.3 Physical Examination 
A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, 
thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and 
extremities.  
Any abnormalities will be specified and documented as CS or NCS. Abnormal post-IMP administration 
findings assessed by the Investigator as clinically significant will be reported as AEs. 
4.5.4 Vital Signs 
Vital signs will include systolic and diastolic blood pressure, pulse rate and body temperature. Any 
vital signs outside of normal ranges will be specified and documented as CS or NCS. Abnormal post-
dose findings assessed by the Investigator as CS will be reported as AEs. 
4.5.5 ECGs 
A 12-lead ECG will be recorded pre-IMP administration and at 24 hours post IMP-administration 
during visits 1, 2, 5 and 7.   
The following variables will be recorded: 
 
Resting Heart Rate (HR) 
 
PQ/RR 
 
QRS 
 
QT 
 
QTcF 
Any abnormalities will be specified and documented as CS or NCS. Abnormal post-IMP findings 
assessed by the Investigator as CS will be reported as AEs. 
4.6 
Pharmacokinetic Assessments 
Blood sampling time points for PK analyses and their allowed sampling time windows are detailed in 
section 11.3.1 of the CSP. The actual blood sampling time points will be recorded in the CRFs.   
Plasma samples for determination of plasma concentrations and PK characterization of linaprazan 
glurate and linaprazan will be analyzed by Lablytica Life Science AB, Uppsala, Sweden, by means of a 
validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The PK 
parameters to be determined are listed and defined below. For further details regarding the 
calculation of these parameters, see section 5.6. 
4.6.1 Primary and secondary analyses  
PK parameters: 


 
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When applicable, the following PK parameters will be obtained or calculated from the plasma 
concentration-time data of linaprazan glurate and linaprazan after QD or BID dosing with linaprazan 
glurate:   
• 
AUCinf (the area under the concentration–time curve from time zero extrapolated to infinity) 
• 
AUCextrap% (% extrapolated AUC) 
• 
AUC0-t (area under the concentration-time curve from time zero to t=last) 
• 
Partial AUC (area under the concentration-time curve from time zero to t=12h and 24h, from 12h 
to 24h, and from 24h to 48h) 
• 
Cmax (maximum observed concentration) 
• 
Cmin (minimum observed concentration) 
• 
Ctrough (Concentration before next dose) 
• 
Caver (average concentration in a 12 or 24 h dose interval) 
• 
Tmax (time to maximum observed concentration) 
• 
T1/2 (terminal half-life) 
• 
CL/F (apparent total clearance) 
• 
V/F (apparent volume of distribution) 
• 
Racc (accumulation ratio for Cmax and AUC in a 12 or 24 h dose interval) 
Additional PK parameters may be determined, such as: 
 z (elimination rate constant) 
 Tlag (Delay between the time of dosing and the time of appearance of plasma 
concentration) 
• AUCtau (the area under the concentration–time curve in a dosing interval) 
 
4.6.1 Exploratory analyses 
After different length of drug holiday (2, 4 or 6 days) after end of 14 days repeated dosing, additional 
PK parameters for linaprazan glurate and linaprazan will be explored.  
The following non-compartmental PK parameters will be assessed if sufficient data is available (when 
applicable):  
 
AUC0-24 
 
AUC0-12 
 
AUC12-24 
 
AUC0-t 
 
Cmax 
 
t1/2 
 
tmax 
Additional PK parameters may be calculated if considered valuable. Results related to exploratory 
objectives/endpoints may not be reported in the clinical study report (CSR). 


 
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5. 
Analysis Methods 
All statistical analyses will be performed using SAS® (Version 9.4 or higher, SAS Institute Inc., Cary, 
NC, USA).  
All PK analyses will be performed on individual plasma concentration-time data by non-
compartmental analysis (NCA) using the software Phoenix WinNonlin® 8.3 or higher (Certara Inc, 
Princeton NJ, United States).  
All statistical and PK analyses will be performed after this SAP is finalized and approved, the Clean 
File Report including decisions on analysis sets has been signed, and the database has been locked. 
 
5.1 
Analysis Sets  
5.1.1 Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all subjects who have been randomized and received at least 
1 dose of IMP and who provided at least 1 post-baseline assessment of data.  
The FAS will also be used for all safety analyses. 
 
5.1.2 PK Analysis Set (PKAS) 
The PK analysis set (PKAS) will consist of all subjects who received at least 1 dose of linaprazan 
glurate and provided an evaluable plasma concentration profile, and who have no AEs or protocol 
deviations judged to affect the PK analysis. Individual PK values may be excluded from the analysis as 
specified in section 5.6.   
5.1.3 PK/PD Analysis Set (PK/PDAS) 
The PK/PD Analysis set (PK/PDAS) is a subset of the PK Analysis Set, excluding subjects without an 
evaluable and appropriate pH profile. 
5.2 
General Principles for Presenting Study Data 
5.2.1 Presentation of Data  
Continuous data will be summarized using descriptive statistics where the following statistics will be 
reported: 
 
Number of observations (n), 
 
Arithmetic Mean 
 
Arithmetic Standard deviation (SD), 
 
Median, 
 
Min. and Max. 
 
Geometric Mean for log-normal PK parameters 
 
Geometric Coefficient of Variation (CV%) for log-normal PK parameters 
Categorical data will be presented as the number and percentage of subjects or observations in each 
category. 


 
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Percentages will be based on number of subjects with data at a certain time point in the analysis set 
of interest except for presentations of medical history, medications, and AEs where the percentages 
will be based on the number of subjects in the study population. 
In general, all data will be listed. All summary tables will be structured with a column for each dose 
group and will be annotated with the total population size relevant to that table/dose group, 
including any missing observations.   
A separate TLF plan will be prepared by the study statistician. 
5.2.2 Calculation of PK Data  
Individual and mean PK profiles for concentrations of linaprazan glurate and linaprazan will be 
plotted in Phoenix® WinNonlin® and reported for all subjects in the PK analysis sets. Mean 
concentration data will be plotted against scheduled (nominal) sampling times while individual 
concentration data will be plotted against actual sampling times. 
PK concentration data 
All individual PK concentrations will be presented in listings included in the appendices of the CSR. 
These data will be presented and analyzed with the same precision as the source data provided by 
the bioanalytical laboratory.  
PK parameters 
The derived parameters will be listed individually by subject and summarized by treatment using 
descriptive statistics. PK parameters and actual elapsed sample collection times will be rounded for 
reporting purposes in by-subject listings.  
PK data will be presented by treatment using summary statistics with number of measurements, 
arithmetic mean, SD, as well as median, minimum and maximum values. For the PK parameters 
AUCinf, AUC0-t, partial AUCs, Cmax, Caver, Ctrough, and Cmin the geometric mean and geometric coefficient 
of variation (CV%) will also be presented. For the PK parameters Tlag and Tmax, only the median, 
minimum, and maximum values will be presented. For the PK parameter Racc and AUCextrap%, the 
geometric mean and CV% will also be presented. All data will be listed by treatment and subject. 
Individual and mean linaprazan glurate and linaprazan plasma concentrations will be plotted against 
time for each dose group.  
In export datasets, PK parameters will be provided with full precision, and will not be rounded. 
Descriptive statistics of PK parameter data will be calculated using full precision values and rounded 
for reporting purposes only. 
5.2.3 Calculation of PD data (intragastric pH) 
The raw pH-data presents pH values for each second of the patient's pH recording period. In the 
derivations, subject specific time windows based on subject’s first dose of the day were used.  
For the calculation of Holding Time Ratio (HTR),  both raw pH-data (every second measurements) and 
the raw data compressed into 10-minute periods by calculating the median for each 10-minute 
period, were used. For all other analyses described in section 5.7 the 10-minute median values were 
used.  
Before the described derivations, the raw pH-data was processed according to the rules defined in 
the SAP addendum (“Process to manage issues associated with the pH-metry recordings and data”).   
 


 
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5.3 
Statistical/Analytical issues 
5.3.1 Calculation of PD data (intragastric pH) 
All available data, except as described in 8. Addendum to SAP on handling of pH-metry data will be 
used in the statistical analysis. A subject who withdraws prior to the last planned visit in the study 
will be included in the analyses up to the time of discontinuation. No imputation of missing data will 
be performed. 
The addendum attached to the SAP provides guidance on how to handle pH-metry recordings and 
data for analysis and reporting. 
5.3.2 PK drug concentration data 
Concentration results that are below the lower limit of quantification (LLOQ) will be identified as 
below limit of quantification or not quantifiable (NQ) by the Bioanalysis lab.  
For the PK analysis and plots of data, values <LLOQ before the first observed concentration will be 
entered as zero and values <LLOQ at any other time point will be excluded from the analysis (i.e., 
handled as missing data). The handling of these values will be justified and documented. Not 
quantifiable samples will be treated as missing data. In plots, the method used for handling values 
<LLOQ will be described in a footnote. 
5.3.3 Outliers 
In general, no outliers will be removed from analyses. However, if an outlier is identified in the PK 
analysis sets, an outlier analysis will be performed to determine the outlier effect on study results. 
5.3.4 Multicentre Studies 
The study will be performed at a single center.  
5.4 
Disposition and Background Information data 
Descriptive summaries for continuous data and for categorical data will be provided in accordance 
with Section 5.22. 
5.4.1 Subject Disposition 
Number of subjects screened, screening failures, randomized, randomized and not taken IMP, 
randomized and taken IMP, completing the study, withdrawals (including withdrawal reason) and 
number of subjects in each analysis set will be summarized by dose group. 
5.4.2 Protocol Deviations 
Protocol deviations will be presented in listings.  
5.4.3 Demographic and Baseline Characteristics 
Demographic and baseline data will be summarized as appropriate depending on the data type 
(continuous or categorical), dose group and total. 
5.4.4 Medical History 
Medical coding will be performed by trained personnel at the Consultinc Oy. AEs and 
medical/surgical history verbatim terms are coded using the medical dictionary of regulatory 
activities (MedDRA, latest version available at eCRF setup) and will be presented in listings.  
5.4.5 Prior and Concomitant Medications 


 
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Prior and concomitant medications will be coded according to the World Health Organization (WHO) 
drug dictionary classification system (WHODrug). 
5.4.6 Treatment Compliance 
During residential visits at the clinic (visits 2, 5 and 7), IMP will be administered at the clinic under 
medical supervision and entered in the eCRF by study personnel. On other days, subjects will self-
administer IMP at home and register each intake of study drug in a paper diary. Text reminders to 
mobile phones will be sent to the subjects each day. At visit 5 (day 14) to the clinic, subjects will be 
asked to return any unused study drugs and all empty containers. Percent compliance will be 
calculated for the home administration period as: 
% Compliance = 100 × (# tablets dispensed – # of tablets returned) / Expected # of tablets taken 
The subjects in each dose level and dose group and their individual doses will be listed. 
5.4.7  Subject Discontinuation 
Subjects who discontinue the study will be summarized by reason for discontinuation and dose group 
and total. 
5.5 
Safety Analyses 
No formal analyses will be performed for safety endpoints. Descriptive summaries for continuous 
and categorical safety data will be provided in accordance with Section 5.2 if not otherwise stated. 
Complete listings of all subject safety evaluations will be provided to support each summary table. 
All presentations will be based on the full analysis set. 
5.5.1 Adverse Events 
All adverse events (Aes) occurring during this clinical trial will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), latest version available at the time of eCFR setup. 
Aes will be tabulated by System Organ Class (SOC) and Preferred Term (PT). Summary tables will 
include number of subjects reporting the AE and as percentage of number of subjects by dose group 
and total. Event counts will be tabulated together with the subject counts. 
Aes will be counted as follows: 
• 
In summaries of number of subjects experiencing Aes, subjects with more than one AE within a 
particular SOC are counted only once for that SOC. Similarly, subjects with more than one AE 
within a particular PT are counted only once for that PT. 
• 
In summaries of number of subjects experiencing Aes, subjects reporting an AE more than once 
within that SOC/PT, but with different severities or different relationships, the worst category 
of severity/relationship will be used. 
 
All Aes will be listed in by-subject data listings including verbatim term, MedDRA coded term, 
treatment, severity, relationship to IMP and action taken with respect to IMP.  
SAEs will be summarized and listed separately.  
5.5.2 Laboratory Evaluations 
Descriptive summaries for clinical chemistry, hematology, coagulation, and urinalysis including 
absolute and relative (%) change from their baselines will be presented by dose group.  


 
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All laboratory parameters for individual subjects will be listed and subjects with clinically significant 
(according to the Investigator’s criteria) abnormal values (out of normal range reported by the 
laboratory) will be flagged and listed separately. The categorization of laboratory parameter 
observations into ‘Normal’, ‘Abnormal (Not Clinically Significant)’, or ‘Abnormal (Clinically 
Significant)’ will be summarized using shift-tables (baseline category versus the worst observed 
categorization over time points post-baseline) by dose group.  
5.5.3 Concomitant Medications 
Concomitant medications will be summarized using WHO Drug preferred names and show number 
and percentage of subjects per preferred name. 
All data will be presented by dose group and summarized overall, as well as presented in listings by 
dose group and subject. 
5.5.4 Physical Examination 
Physical examination will be presented as the number and percentage of subjects with Normal, 
Abnormal (not Clinically Significant) and Abnormal (Clinically Significant) result over time by Body 
System, dose group and total. 
5.5.5 Vital Signs 
Vital signs will be summarized by dose group and total. The summary will include absolute and 
percent change from baseline at each visit. 
5.5.6 Electrocardiogram 
Summaries of ECG results and change from baseline over time will be presented by dose group and 
total. 
5.6 
Pharmacokinetic Analyses 
The PK analysis will be performed based on the PK analysis set. All PK analyses will be performed 
according to the actual treatment and dose received. Actual sampling time points relative to dosing 
will be used in the calculations. Pre-dose concentration values will be excluded from the NCA and set 
to 0.  
The parameters to be determined in the study are presented in section 4.6. Parameters directly 
derived from the plasma concentration – time plot are not further described (i.e., Cmax, Cmin, tmax, 
Ctrough), but all other calculations to be performed are described in detail below. Missing sample 
around the anticipated Tmax may be flagged as “not accepted” upon decision by the 
Pharmacokineticist. 
Estimation of the terminal elimination rate constant (z) 
The terminal elimination rate constant (z) is calculated by log-linear regression of the terminal 
portion of the plasma concentration time profile. At least three observations will be used to estimate 
z and the data points used in each estimation are indicated in the individual PK profiles. Data points 
for calculation of T1/2 via λz are selected based on visual inspection of log-concentration-time plots of 
individual profiles and adjusted if needed. Any exclusion of data points in the terminal phase for this 
estimation should be clearly justified in the PK analysis log.  
The adjusted R2 should be considered in the selection of samples for calculation of λz and preferably 
exceed a value of 0.8. If λz cannot be reliably estimated, because of a low value of R2, it will be 
flagged as “not accepted” and the associated parameters may be reported as “not determined”. Use 


 
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of z values obtained from data spanning less than three half-lives is permissible on the judgement of 
the Pharmacokineticist. 
For subjects with insufficient PK data available leading to an extrapolated AUC (AUCextrap%) exceeding 
20%, the parameters depending on z will not be reported. The % of extrapolated AUC will be 
presented for all subjects. 
Area under the plasma concentration-time curves (AUCs) 
The area under the plasma concentration-time curves (AUCs) are calculated using the linear up -log 
down method (i.e., linear trapezoidal rule is used when concentration data is increasing and the 
logarithmic trapezoidal rule is used when concentration data is decreasing) using uniform weighing.  
AUCinf is calculated based on the AUC0-t (AUC from time of dosing to the time point of the last 
quantifiable plasma concentration) and then extrapolated to infinity using the concentration in the last 
quantifiable sample (Clast) and the estimated terminal elimination rate constant (λz), as follows:  
AUCinf= AUC0-t + (Clast/z) 
Accumulation ratio (Racc) 
Accumulation index will be calculated for the observed accumulation ratio: 
Racc AUC = AUCtau last dose / AUCtau first dose 
Racc Cmax = Cmax last dose / Cmax first dose 
terminal half-life (T1/2) 
The half-life is calculated by ln2/z. 
Apparent total clearance (CL/F) 
Total body clearance for extravascular administration, CL/F= Dose/AUCinf, or CL/F= Dose/AUCtau at 
steady state 
 
Apparent volume of distribution (V/F) 
Volume of distribution based on the terminal elimination phase, V/F =Dose/(z*AUCinf), or 
V/F=Dose/(z*AUCtau) at steady state 
Average concentration during a dosing interval (Caver)  
Caver will be calculated for repeated dosing, as follows: Caver = AUCtau/tau  
5.7 
 Summaries of Intragastric pH-metry  
The Full Analysis Set for pH measurements is defined in the SAP addendum. pH measurements will 
be analyzed as per SAP addendum Full Analysis Set #2 “Statistical analysis of either channel 1 or 2 
depending on which is deemed to be showing intragastric pH. Exclusion of “air measurements” is 
applied.”  
Exploratory analyses will be performed based on Full Analysis Sets #1 and #3 in the SAP addendum.  
Descriptive statistics of HTR pH >4, pH >5, and pH >6 over a 24-hour period during baseline, day 1, 
day 14 and day 15, will be presented by dose group.   
A Mixed Model for Repeated Measurements (MMRM) will be utilized to analyze the percentage of 
time with intragastric pH >4, pH >5, and pH >6 (each pH cut-off separately), from now on referred to 
as Holding Time Ratio (HTR). The model will include the dose group, day (day 1, day 14) and the 
interaction between the dose group and day as fixed effects, the corresponding baseline HTR as a 
covariate and subject as a random effect. Least Squares Means (LSMs) , together with their 
corresponding 95% confidence intervals (CI) will be used to estimate the HTR for each dose group 
and day.  


 
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The LSMs of HTR pH >4, pH >5, and pH >6 will also be graphically displayed together with their 
corresponding 95% CIs by visit (day 1 and day 14) for each dose group. As a sensitivity analysis a 
MMRM-model (separately for the three pH cutoffs) excluding the baseline covariate will also be 
fitted to support the results from the primary statistical model. 
  
The trajectories (profiles) for the average 24-hour intragastric pH (pH values averaged over subjects 
for each 10-minute median value) will be plotted for day 1 and day 14 separately. The plot for each 
day will show the mean 24-hour intragastric pH for the six dose groups and baseline.   
Bar plots for the frequencies of subjects showing the HTR (0-60, 60-80, 80-85, 85-90, 90-95, 95-100) 
with gastric pH >4, pH >5, and pH >6 over a 24-hour period during baseline, day 1, day 14 and day 15, 
will be presented by dose group. The horizontal axis of the bar plot will represent categorized HTR 
with gastric pH >4, pH >5 or pH >6 over a 24-hour period.    
Descriptive statistics will be presented for the mean intragastric pH 0-12 hours and 12-24 hours and 
0-24 hours after dose (mean within individuals over 0-12 hours, 12-24 hours and 0-24 hours after 
dose morning dose for BID, evening dose for QD) for days 1 and 14 by dose group.  
The mean intragastric pH 0-12 hours, 12-24 hours and 0-24 hours after dose (morning dose for BID, 
evening dose for QD) for day 1 and 14 will be plotted together and separately, with their 
corresponding 95% confidence intervals in a graph displaying the mean values by visit for each dose 
group. 
5.7.1 Relationship between plasma concentration of Linaprazan and intra gastric acid 
secretion (pH) 
To illustrate the association between pH and the linaprazan concentration, scatterplots with pH on 
the y-axis and a horizontal line to illustrate pH >4, and linaprazan concentration in the x-axis will be 
plotted. These scatterplots will be presented as follows: i) QD dosing groups, ii) BID dosing groups, iii) 
all dosing groups.  All dosing groups in one scatterplot will be presented for Day 1, Day 14 and 
together. All measurements from within <2h after first dose on Day 1 will be omitted from the 
scatter plots.    
Line plots with two y-axes (primary y-axis: pH, and secondary y-axis: plasma concentration of 
linaprazan) against time will be presented for the average pH and average concentration data added 
with error bars for the standard errors of the means. Three separate plots will be generated, i) QD 
dosing groups, ii) BID dosing groups, iii) all dosing groups. In the plots both the means pooled over 
the mentioned dosing groups and the mean for individual dosing groups will be presented for Day 1, 
Day 14 and together.  
Also, scatterplots relating HTR for pH >4 and pH >5 versus linaprazan exposure parameters (AUC, 
Cmax and Cmin) (ref: Scarpignato et al 2023) will be produced, to explore which PK-parameter would 
be most relevant. The HTR response within each subject will be explored as well. Three separate 
plots will be generated, i) QD dosing groups, ii) BID dosing groups, iii) all dosing groups. All plots will 
be presented for Day 1, Day 14 and together. . All measurements from within <2h after first dose on 
Day 1 will be omitted from the scatter plots.  
5.8 
Changes to Planned Analysis 
No changes for the main protocol planned analysis have been made.  The formal analysis of the pH 
data and the association between the concentration and pH data was not defined in the protocol but 
introduced only in the SAP. Also, the PK/PD analysis set is a new analysis dataset defined only in the 
SAP. 


 
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6. 
References 
1. Clinical Study Protocol CX842A2107. Final version 4.0 dated 10MAR2023. 
2. Statistical Principles for Clinical Trials (ICH Topic E 9). EMEA. September 1998, CPMP/ICH/363/96. 


 
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7. 
Appendix 
Table 1. Overall schedule of events 
Visit → 
Assessment↓ 
CSP 
Section
Visit 1 
Screening 
Visit 2  
Residential 
Visit 3 and 
Visit 4  
Outpatient  
Visit 5 
Residential 
Visit 6 
Outpatient 
Visit 7 
Residential 
Visit 8 
Telephone 
follow-up 
Day→ 
 
Day -28 to 
Day -2 
Day -2 to 2 
Day 5 and 
Day 10 
Day 14 to  
Day 15 
Day 16 
 
Days 16-17, 18-
19  
or 20-21  
7 days (±2 
days) post-last 
dose1 
Informed consent 
11.2.1 
X 
 
 
 
 
 
 
Eligibility criteria 
9.4, 9.5 
X 
X2 
 
 
 
 
 
Demographics 
11.2.3 
X 
 
 
 
 
 
 
Weight/height (BMI) 
11.2.4 
X 
 
 
 
 
 
 
Medical/surgical history 
11.2.5 
X 
 
 
 
 
 
 
HIV, Hep B and C test 
11.2.7 
X 
 
 
 
 
 
 
FSH test3 
11.2.8 
11.2.9 
X 
 
 
 
 
 
 
Pregnancy test 
X 
X 
 
 
 
X 
 
Urine drug screen 
11.2.10
X 
X4 
 
 
 
 
 
Alcohol test 
11.2.11
X 
X4 
 
 
 
 
 
Screening for 
Helicobacter Pylori 
11.4.5 
X 
 
 
 
 
 
 
Safety laboratory profile 
11.4.3 
X 
X 
X 
X 
X 
X 
 
Vital signs5 
11.4.4 
X 
X 
 
X 
 
X 
 


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Visit → 
Assessment↓ 
CSP 
Section
Visit 1 
Screening 
Visit 2 
Residential 
Visit 3 and 
Visit 4 
Outpatient 
Visit 5 
Residential 
Visit 6 
Outpatient 
Visit 7 
Residential 
Visit 8 
Telephone 
follow-up 
Physical examination 
11.4.2 
X 
X 
X 
X 
12-lead safety ECG
9.9 
X 
X 
X 
X 
Randomization
10.5
X6
IMP administration7
11.3.1
X
X
X
X
PK blood sampling8
11.3.2
X
X
X
X
X
Intragastric pH 
measurement  
9.6.1
X 
X 
Standardized meals 
10.5 
X 
X 
X 
Hand-out of linaprazan 
glurate9 
10.7 
X 
Compliance check 
N/A 
X 
Overnight stay in clinic 
11.2.12
X 
X 
X 
Baseline symptoms10 
11.4 
-------- X -------- 
AEs11 
9.6.2 
--------------------------------------------------------- X ------------------------------------------------- 
Prior and concomitant 
medications 
11.2.1 
--------------------------------------------------- X ------------------------------------------------------- 
BMI: Body mass index. CSP: Clinical study protocol. FSH: follicle stimulating hormone. HIV: Human immunodeficiency virus. IMP: Investigational medicinal product. 
PK: Pharmacokinetic.  
1.
A final remote follow-up visit (Visit 8) will be conducted via telephone 7 days (±2 days) after the final dose of IMP, or after early withdrawal, to follow-up on AEs
and concomitant medications.
2.
Confirmation of eligibility prior to start of baseline pH-measurement.


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3.
Confirmation of menopause. Only in questionable cases at the discretion of the Investigator.
4.
Additional random alcohol and drug tests can be performed at subsequent visits at the discretion of the Investigator.
5.
Resting systolic and diastolic blood pressure, pulse and body temperature. Blood pressure and pulse should be measured with the subject in a supine position,
after 10 minutes of rest.
6.
Randomization will take place after confirmation of all eligibility criteria evaluated at the screening visit and prior to the start of Visit 2.
7.
Linaprazan glurate 25, 50 or 75 mg QD or BID for 14 days. First dose of IMP shall not be administered until after confirmation of day -2 evaluation of Eligibility
criteria, Pregnancy test, Urine drug screen, Alcohol test, Safety laboratory profile, Vital signs, Physical examination, and 12-lead safety ECG. After a drug holiday of
2, 4 or 6 days the linaprazan glurate will be administered once more according to the dosing schedule, see Section 10.5
8.
The blood sampling for PK analysis are specified in Table 8.1 2 and o Table 8.1 3 of the CSP for Visit 2, in Table 8.1 4 and Table 8.1 5 of the CSP for Visit 5 and in
Table 8.1 6 and Table 8.1 7 of the CSP for Visit 7 (QD and BID dosing, respectively).
9.
The subjects will administer linaprazan glurate at home from Day 3 to Day 13.
10. Baseline symptoms will be recorded from the signing of the informed consent form (ICF) up until first dose on Day 1. 
11. AEs will be recorded from (first) dosing on Day 1 up until the follow-up visit (Visit 8), or early withdrawal.