Clinical trial NCT05633147
Conditions: Safety Issues Pharmacokinetics Drug Interaction Tolerability
Sponsor: Cinclus Pharma Holding AB
Start date: 2022-11-27; Completion date: 2023-05-30
Enrollment: 35 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a phase I, open-label, fixed sequence design, drug-drug-interaction (DDI) study divided in 2 parts. Part I is designed to evaluate whether concomitant treatment with linaprazan glurate and clarithromycin, a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein P (PgP), leads to an effect on the systemic exposure to linaprazan glurate and linaprazan and whether there is an effect on the pharmacokinetics of clarithromycin after a single dose of linaprazan glurate. Part II is designed to evaluate the effect of repeated doses of linaprazan glurate on the pharmacokinetics (PK) of a sensitive substrate of CYP3A (midazolam).

Detailed description:

Arms: arm 1: Part I: Linaprazan glurate in base form, 100 mg once daily will be administered under fasting conditions at day 1 and day 10.

Part II: Linaprazan glurate hydrochloride (HCl), 75 mg twice a day for 13 days. The morning dose will be administered under fasting conditions on Day 2 and Day 14.
Interventions: intervention 1: Linaprazan glurate intervention 2: Drug drug interaction (DDI) - Clarithromycin (Part I) intervention 3: Drug drug interaction (DDI) - Midazolam (Part 2)
Intervention descriptions: intervention 1: Investigational Medicinal Product: Linaprazan glurate (tablets).

Part I:

Linaprazan glurate in base form, 100 mg once daily Day 1 and Day 10.

Part II:

Linaprazan glurate hydrochloride (HCl), 75 mg twice daily for 13 days. intervention 2: Index inhibitor (perpetrator drug) Clarithromycin 500 mg twice daily for 9 days (tablets). intervention 3: Substrate for CYP3A. Midazolam 2.5 mg once daily (2.5 mL oral solution).

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
Title: A phase I, open-label, fixed-sequence, single-center study to determine 
the effect of repeated dosing with clarithromycin on the pharmacokinetics of 
linaprazan glurate/linaprazan and the effect of a single dose of linaprazan glurate 
on the pharmacokinetics of clarithromycin, and single and repeated dosing with 
linaprazan glurate on the pharmacokinetics of midazolam administrated to 
healthy subjects 
 
NCT number: NCT05633147 
Document date: Final v4.0; 20JAN2023 


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Clinical Study Protocol 
EudraCT no. 
2022-001403-41 
Investigational medicinal product Linaprazan glurate 
Study code 
CX842A2105 
Protocol version and date 
Final v4.0; 20JAN2023 
 
 
A phase I, open-label, fixed-sequence, single-center study to determine the effect 
of repeated dosing with clarithromycin on the pharmacokinetics of linaprazan 
glurate/linaprazan and the effect of a single dose of linaprazan glurate on the 
pharmacokinetics of clarithromycin, and single and repeated dosing with 
linaprazan glurate on the pharmacokinetics of midazolam administrated to 
healthy subjects 
 
 
Phase 
I 
Indication 
Gastroesophageal reflux disease (GERD) and 
eradication of Helicobacter pylori infection 
Test product and dose 
Linaprazan glurate (formerly X842) 
(Part I: 100 mg victim drug and Part II: 75 mg) 
Index inhibitor and dose 
Clarithromycin, 500 mg oral tablets 
(Part I: perpetrator drug) 
Substrate for CYP3A 
Midazolam, 2.5 mg (Part II) 
Sponsor signatory 
 MD, PhD, CMO 
Cinclus Pharma Holding AB 
World Trade Center, Kungsbron 1 
SE-111 22 Stockholm, Sweden 
Principal Investigator 
 MD 
CTC Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Clinical study conduct and management 
CTC Clinical Trial Consultants AB 
Uppsala University Hospital, 
Entrance 85, 2nd level 
SE-751 85 Uppsala, Sweden 
CTC Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
CTC Clinical Trial Consultants AB 
Karolinska vägen 22 
SE-171 64 Solna, Sweden 


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The following amendments have been made to the first regulatory approved version of this 
Clinical Study Protocol (version 2.0). 
 
Type of change 
Date 
Summary of changes 
Revised 
protocol 
version 
Substantial 
amendment 
 
Non-substantial 
amendment 
 
 
 
Substantial 
amendment 
20SEP2022 
In Part I of the study clarithromycin 500 mg BID will 
be used as perpetrator drug instead of itraconazole. 
The study design has been adjusted accordingly. 
02NOV2022 
Administrative changes: 
-correction of tables and figures (Section 7) 
-correction of table (Section 10) 
-corrected SUSAR definition in Section 11.4.1.5 
27JAN2023  In Part II of the study linaprazan glurate 75 mg BID 
will be administered instead of 100 mg BID. 
After finishing Part I and Part II respectively, the data 
will be analysed. After finishing Part II, the CSR will 
be prepared following the final DBL. 
Administrative changes: 
-the address to the Pharmacy has been updated 
(Section 5). 
-the risk assessment with regard to the Covid-19 
pandemic has been removed according to the updated 
guidelines. 
Version 2.0 
 
 
Version 3.0 
 
 
 
 
Version 3.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This clinical study protocol is the property of Cinclus Pharma Holding AB and is a 
confidential document. It is not to be copied or distributed to other parties without 
written approval from Cinclus Pharma Holding AB. 


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1 
STUDY SYNOPSIS 
 
Study title 
A phase I, open-label, fixed-sequence, single-center study to determine the effect of repeated dosing 
with clarithromycin on the pharmacokinetics of linaprazan glurate/linaprazan and the effect of a 
single dose of linaprazan glurate on the pharmacokinetics of clarithromycin, and single and repeated 
dosing with linaprazan glurate on the pharmacokinetics of midazolam administrated to healthy 
subjects. 
Study code 
CX842A2105 
EudraCT no. 
2022-001403-41 
Planned study period 
Q4 2022 -Q2 2023 
Phase of development 
I 
Principal Investigator 
 MD 
CTC Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Study design 
This is a phase I, open-label, fixed design, drug-drug-interaction (DDI) study divided in 2 parts. 
Part I is designed to evaluate whether concomitant treatment with linaprazan glurate and 
clarithromycin, a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein P (PgP), 
leads to an effect on the systemic exposure to linaprazan glurate and linaprazan and whether there is 
an effect on the pharmacokinetics of clarithromycin after a single dose of linaprazan glurate. Part II 
is designed to evaluate the effect of repeated doses of linaprazan glurate on the pharmacokinetics 
(PK) of a sensitive substrate of CYP3A (midazolam). 
Objectives 
Part I: 
Primary objective: 
• 
To investigate the effect of repeated administration of clarithromycin on linaprazan glurate 
and linaprazan PK after single dose of linaprazan glurate. 
Secondary objectives: 
• 
To assess the safety and tolerability after single dose of linaprazan glurate with and without 
co-administration of clarithromycin. 
• 
To evaluate additional PK characteristics of linaprazan glurate and linaprazan. 
• 
To investigate the effect of linaprazan glurate on clarithromycin PK. 
Exploratory objective: 
• 
To explore the metabolites of linaprazan glurate in plasma with and without co- 
administration of clarithromycin. 
Part II: 
Primary objective: 
• 
To investigate the effects after single and repeated administration of linaprazan glurate on 
the PK properties of midazolam. 


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Secondary objective: 
• 
To assess the safety and tolerability after repeated doses of linaprazan glurate with and 
without co-administration of midazolam. 
• 
To evaluate PK data of linaprazan glurate and linaprazan after single and repeated oral doses 
of linaprazan glurate. 
• 
To evaluate additional PK characteristics of midazolam in the presence and absence of 
linaprazan glurate administration 
Exploratory objective (Part II): 
• 
To explore the metabolites of linaprazan glurate in plasma and urine after single and repeated 
doses of linaprazan glurate. 
Endpoints 
Part I: 
Primary endpoint: 
• 
Linaprazan glurate and linaprazan PK parameters with and without co-administration of 
clarithromycin: 
o Area under the plasma concentration curve from 0 to infinity (AUCinf) 
o AUC from time 0 to time t (AUC0-t) 
o Maximum plasma concentration (Cmax) 
Secondary endpoints: 
• 
Frequency, seriousness, and intensity of adverse events (AEs). 
• 
Clinically significant changes in physical examinations, vital signs (blood pressure and 
pulse), electrocardiograms (ECG), and laboratory variables (hematology, clinical chemistry, 
and urinalysis). 
• 
Additional PK parameters for linaprazan glurate and linaprazan, not limited to: 
o Time of occurrence of Cmax (Tmax) 
o Terminal elimination half-life (T1/2) 
o Apparent clearance (CL/F) 
o Apparent volume of distribution (V/F) 
o Percent extrapolated AUC (AUCextr%) 
• 
Clarithromycin PK parameters with and without co-administration of linaprazan glurate: 
o AUC to the end of the dosing period (AUCtau) 
o Cmax 
• 
Additional PK parameters for clarithromycin, not limited to: 
o Tmax 
o 
T1/2 
Exploratory endpoint: 
• 
Plasma collected for future exploratory analyses of linaprazan glurate metabolites. 
Part II: 
Primary endpoints: 
• 
Midazolam PK parameters in the presence and absence of linaprazan glurate administration: 
o AUCinf 
o AUC0-t 
o Cmax 


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Secondary endpoints: 
• 
Frequency, seriousness and intensity of AEs. 
• 
Clinically significant changes in physical examinations, vital signs (blood pressure and 
pulse), ECG, and laboratory variables (hematology, clinical chemistry, and urinalysis). 
• 
Linaprazan glurate and linaprazan PK parameters after repeated administration of linaprazan 
glurate twice daily (BID) for 13 days (if feasible): 
o AUCinf 
o AUC0-t 
o Cmax 
o Tmax 
o T1/2 
o AUCextr% 
o CL/F 
o V/F 
o Accumulation ratio (Racc). 
• 
Midazolam PK parameters in the presence and absence of linaprazan glurate administration 
(if feasible): 
o Tmax 
o T1/2 
o AUCextr% 
o CL/F 
o V/F 
Exploratory endpoint: 
• 
Plasma and urine collected for future exploratory analyses of linaprazan glurate metabolites. 
Number of subjects planned 
In Part I, 18 healthy subjects are planned to be included in the study to ensure 12 evaluable subjects. 
In Part II, 18 healthy subjects are planned to be included in the study to ensure 12 evaluable subjects. 
In total, approximately 54 subjects will be screened in the study (27 subjects for each part). 
Diagnosis and eligibility criteria 
Healthy male subjects and healthy female subjects of non-childbearing potential, 18-60 years of age 
(inclusive), with a body mass index (BMI) of 18-30 kg/m2, who are willing to comply with study 
procedures and who have given written informed consent are eligible for the study. 
Subjects with a history or presence of any clinically significant disorders, as judged by the 
Investigator, will not be included in the study. Use of CYP3A4 inhibitors, antacids, proton pump 
inhibitors (PPIs) or any medication that changes gastric pH or use of any prescribed or non- 
prescribed CYP3A4-inducing medication (e.g., efavirenz, nevirapine, rifampicin, rifabutin, 
modafinil, phenytoin, carbamazepine, glitazones, oral glucocorticoids) or other metabolic enzyme 
inducers, including herbal remedies such as St John’s wort, within 14 days prior to administration of 
first dose of linaprazan glurate is prohibited. 


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Methodology 
Part I: 
The subjects will come for 10 visits to the clinical research unit (CRU). 
Screening (Visit 1) will take place at any time point between Day -28 and Day -1 and will include an 
eligibility check and collection of demographic and medical history data as well as a review of health 
status, including a physical examination and collection of vital signs and safety laboratory blood 
samples. 
At Visit 2, eligible subjects will be admitted to the CRU on Day -1 and stay until the morning on Day 
2. The subjects will be dosed in the morning of Day 1, with a single dose of linaprazan glurate 
(100 mg: 4x25 mg oral tablets). The subjects must fast for at least 8 hours before the anticipated 
dosing time on Day 1. During fasting, water, but no other drinks, is allowed as desired. No drinks are 
allowed for 1 hour before and 30 minutes after dosing. Blood will be sampled for PK analysis up to 
24 hours after dose (24-hour sample on Day 2) and safety will be assessed. The subjects will leave 
the CRU in the morning of Day 2 (after the 24-hour sample) and return in the evening of Day 2 
(Visit 3) for the 36-hour PK-blood sample. The subjects will thereafter return to the CRU for blood 
sampling at 48 hours on Day 3 (Visit 4) and at 72 hours on Day 4 (Visit 5). At Visit 5, the subjects 
will start clarithromycin dosing, (500 mg BID) and continue dosing until Day 12. 
On Day 9 (Visit 6), the subjects will be admitted to the CRU and stay until Day 11. In the morning 
on Day 9 clarithromycin (500 mg BID) will be administered. The subjects must fast for at least 8 
hours before the anticipated dosing time on Day 9 and Day 10. During fasting, water, but no other 
drinks, is allowed as desired. No drinks are allowed for 1 hour before and 30 minutes after dosing. 
Thereafter, blood samples for PK analysis of clarithromycin will be collected up to 12 h after dose. 
In the morning on Day 10, linaprazan glurate (100 mg: 4x25 mg tablets) and clarithromycin (500 mg, 
BID) will be co-administered and blood samples for PK analysis of linaprazan glurate and linaprazan 
will be collected up to 24 hours after dose (24-hour sample on Day 11) and the subjects will leave the 
CRU in the morning on Day 11 (after the 24-hour PK sample). 
In the evening on Day 11 (Visit 7), the subjects will return to the CRU for the 36-hour PK sample. 
The subjects will thereafter return to the CRU for blood sampling on 48 hours on Day 12 (Visit 8) 
and at 72 hours on Day 13 (Visit 9). 
A final end-of-study visit (Visit 10) will take place on Day 14 (±2) or after early withdrawal. 
Blood samples for analysis of PK parameters for linaprazan glurate and linaprazan will be collected 
prior to linaprazan glurate administration (pre-dose) and 15, 30, 45 min, 1.15, 1.5, 2, 3, 4, 6, 8, 10, 
12, 18, 24, 36, 48 and 72 hours after dosing (on dosing Days 1 and 10). 
Blood samples for analysis of PK parameters for clarithromycin will be collected prior to 
clarithromycin administration (pre-dose) and 30 min, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours 
after dosing (on dosing Day 9 when dosed alone and on Day 10 when dosed with linaprazan glurate). 
The subjects will be carefully monitored by clinical staff during and after dosing. The subjects will 
be served standardized meals while they are in the CRU. AEs will be recorded from the first dose of 
linaprazan glurate and throughout the study. 
Part II: 
The subjects will come for 5 visits to the CRU. Screening (Visit 1) will take place at any time point 
between Day -28 and Day -1 and will include an eligibility check and review of health status. 
Screening (Visit 1) will take place at any time point between Day -28 and Day -1, and will include an 
eligibility check, collection of demographic and medical history data as well as a review of health 
status, including a physical examination and collection of vital signs and safety laboratory blood 
samples. 
At Visit 2, eligible subjects will be admitted to the CRU on Day -1. In the morning of Day 1, the 
subjects will be administered a single dose of midazolam (2.5 mg), followed by PK blood sampling 


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up to and including 24 hours after dosing. Starting on Day 2, after the 24-hour PK blood sample, the 
subjects will be co-administered linaprazan glurate (75 mg:3x25 mg oral tablets, BID) and 
midazolam (2.5 mg QD) in the morning. The subjects must fast for at least 8 hours before the 
anticipated dosing time on Day 1 and Day 2 until 2 hours post-dose. During fasting, water, but no 
other drinks, is allowed as desired except for 1 hour before and 30 minutes after dosing. 
From Day 2 to Day 4, blood sampling for linaprazan glurate and linaprazan PK will take place at pre- 
determined time points until 24 hours after the morning doses. The subjects will be discharged from 
the CRU on Day 4 and will be home-based until Day 13 when they will be re-admitted for Visit 3. 
The subjects will self-administer linaprazan glurate (75 mg:3x25 mg oral tablets, BID) at home. An 
electronic diary will be handed out for the subjects to record the intake of linaprazan glurate at home 
between Visit 2 and Visit 3. 
On Day 13, the subjects will be admitted to the CRU (Visit 3). In the morning of Day 14, the subjects 
will be co-administering a second dose of midazolam (2.5 mg) together with the morning dose of 
linaprazan glurate (75 mg:3x25 mg oral tablets), followed by blood sampling for midazolam PK in 
the presence of linaprazan glurate at pre-determined time points up to and including 24 hours after 
co-administration as well as blood sampling for linaprazan glurate PK until 36 hours. The subjects 
must fast for at least 8 hours before the anticipated dosing time on Day 14. During fasting, water, but 
no other drinks, is allowed as desired except for 1 hour before and 30 minutes after dosing. The 
subjects will be discharged from the CRU on Day 15 (after the 36-hour sample) and return in the 
morning of Day 16 (Visit 4) for the 48-hour PK sample. 
A final end-of-study visit will take place as a telephone call on Day 22 (±2 days) (Visit 5) or after 
early withdrawal. 
The subjects will be carefully monitored by clinical staff during and after dosing. The subjects will 
be served standardized meals while they are in the CRU. 
AEs will be recorded continually from the first dose of midazolam during visits to the CRU. Upon 
re-admission to the CRU on Day 13 subjects will be asked to report any AEs that arose between 
discharge on Day 4 and re-admission on Day 13. 
Investigational Medicinal Product (IMP) dosage and mode of administration 
Linaprazan glurate will be provided as tablets for oral administration. 
Part I: 
• 
Linaprazan glurate in base form, 100 mg once daily (4x25 mg oral tablets) will be 
administered under fasting conditions (8 hours after meal until 2 hours post-dose). 
Part II: 
• 
Linaprazan glurate hydrochloride (HCl), 75 mg twice a day (3x25 mg oral tablet, BID) for 
13 days. The morning dose will be administered under fasting conditions on Day 2 and 
Day 14 (8 hours after meal until 2 hours post-dose). During home-administration there are no 
fasting requirements. 
Index inhibitor (perpetrator drug) (Part I) 
Clarithromycin 500 mg will be provided as tablets for oral administration. 
Clarithromycin 500 mg twice daily (500 mg in the morning and 500 mg in the evening, 
approximately 12 hours apart). Clarithromycin may be administered with food except when co- 
administered with linaprazan glurate i.e., on the linaprazan glurate co-administration and 
clarithromycin PK sampling days. The fasting requirements for linaprazan glurate apply for the 
morning dose. 


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Substrate for CYP3A (Part II) 
Midazolam (substrate for CYP3A): midazolam APL will be provided as an oral solution, 1 mg/mL. 
Midazolam 2.5 mg once daily (2.5 mL oral solution). Midazolam will be administered under fasting 
conditions (8 hours after meal until 2 hours post-dose). 
Duration of treatment 
Part I: Subjects will be administered 2 oral doses of linaprazan glurate (100 mg) and 18 doses of 
clarithromycin 500 mg. 
Part II: Subjects will be administered oral 75 mg doses of linaprazan glurate BID for 13 consecutive 
days. In total, 26 doses will be given. Subjects will also be administered 3 doses of midazolam 
(2.5 mg). 
Duration of each subject’s involvement in the study 
Part I: Each subject is expected to participate in the study for approximately 42 (±2) days, including 
an up to 28-day screening period. 
Part II: Each subject is expected to participate in the study for approximately 49 (±2) days, including 
an up to 28-day screening period. 
The Screening visits will be performed within 28 days prior to dosing (Day 28 to Day -1) for Part I 
and Part II. 
Safety assessments 
Safety assessments will include AEs, physical examination, vital signs, ECG, and clinical laboratory 
assessments. 
AEs will be recorded from the first dose of linaprazan glurate in Part I and midazolam in Part II and 
throughout the study. Prior medications will be recorded from 14 days before screening (Visit 1) and 
concomitant medications will be recorded from Day 1, until the last visit in the study. 
Pharmacokinetic (PK) assessments 
Blood sampling for bioanalysis and subsequent calculation of PK parameters. 
Statistical methods 
Continuous data will be presented in terms of evaluable and missing observations, arithmetic mean, 
standard deviation (SD), median, minimum, and maximum value. In addition, for the parameters 
AUC and Cmax the geometric mean and geometric coefficient of variation (CV%) will be presented. 
Categorical data will be presented as counts and percentages. When applicable, summary data will be 
presented by treatment, and by assessment time. Individual subject data will be listed by subject 
number, treatment, and, where applicable, by assessment time. 
All descriptive summaries and statistical analyses will be performed using SAS Version 9.4 or later 
(SAS Institute, Inc., Cary, NC). The PK parameters will be calculated by non-compartmental 
analysis (NCA) using the software Phoenix WinNonlin® version 8.3 or later (Certara, U.S.A.). 
Baseline will be defined as the visit with last data collection point prior to the first administration of 
linaprazan glurate (Part I) and midazolam (Part II). 
In Part I, the PK parameters AUC, AUC(0-t) and Cmax will be analyzed using a mixed model 
following a natural logarithmic transformation, with fixed effect for treatment and random effect for 
subject. Ratios of geometric means together with 2-sided 90% CI of test treatment (linaprazan glurate 
+ clarithromycin) and reference treatment (linaprazan glurate alone) will be estimated and presented. 
The corresponding statistical analysis will be performed and presented for clarithromycin. 


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In Part II, for AUCinf, the AUC will be calculated to the time point of the last quantifiable plasma 
concentration and then extrapolated to infinity using the concentration in the last quantifiable sample 
and the estimated terminal elimination rate constant (Lambdaz). Midazolam PK parameters will be 
presented and statistically analyzed using the same mixed-effects model as in Part I. The ratios of 
geometric least squares mean (midazolam in the presence and absence of linaprazan glurate) with the 
corresponding 90% confidence interval (CI) will be presented. If the CI for AUCinf is between 0.8 
and 1.25, and the CI for Cmax is between 0.7 and 1.43, it can be concluded that linaprazan glurate has 
no effect on CYP3A. 
No imputation of missing data will be performed. 
Study reporting 
For Part I and Part II respectively, when all data have been entered, and discrepancies solved, clean 
file will be declared, the database will be locked, and the data will be analyzed. The International 
Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E3 
guideline-(ICH-E3) compliant clinical study report (CSR) will be prepared following the final DBL. 


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2 
TABLE OF CONTENTS 
1 
STUDY SYNOPSIS .......................................................................................................... 3 
2 
TABLE OF CONTENTS ............................................................................................... 10 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................... 16 
4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ................................................................................................................... 20 
4.1 
Medical emergencies contact ................................................................................. 20 
5 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE .................... 21 
6 
INTRODUCTION .......................................................................................................... 23 
6.1 
Background ............................................................................................................. 23 
6.1.1 
Clinical experience ............................................................................................. 23 
6.1.2 
Pharmacokinetic summary ................................................................................. 24 
6.1.3 
Indication ............................................................................................................ 25 
6.1.4 
Dosage ................................................................................................................ 25 
6.1.5 
Mechanism of action .......................................................................................... 25 
6.1.6 
Drug description ................................................................................................. 25 
6.1.7 
Non-clinical toxicology ...................................................................................... 26 
6.2 
Study rationale ........................................................................................................ 26 
6.3 
Risk/benefit assessment .......................................................................................... 27 
6.3.1 
General risk/benefit assessment .......................................................................... 27 
6.3.2 
Risk/benefit conclusion ...................................................................................... 28 
7 
STUDY OBJECTIVES AND ENDPOINTS ................................................................ 29 
7.1 
Study objectives and endpoints Part I .................................................................. 29 
7.1.1 
Primary objective ................................................................................................ 29 
7.1.2 
Primary endpoint ................................................................................................ 29 
7.1.3 
Secondary objectives .......................................................................................... 29 
7.1.4 
Secondary endpoints ........................................................................................... 29 
7.1.5 
Exploratory objective.......................................................................................... 29 
7.1.6 
Exploratory endpoint .......................................................................................... 30 
7.2 
Study objectives and endpoints Part II ................................................................. 31 
7.2.1 
Primary objective ................................................................................................ 31 
7.2.2 
Primary endpoint ................................................................................................ 31 
7.2.3 
Secondary objectives .......................................................................................... 31 
7.2.4 
Secondary endpoints ........................................................................................... 31 
7.2.5 
Exploratory objectives ........................................................................................ 32 
7.2.6 
Exploratory endpoints ......................................................................................... 32 
8 
STUDY DESIGN ............................................................................................................ 33 


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8.1 
Overall study design and schedule of events, Part I ............................................ 33 
8.2 
Overall study design and schedule of events, Part II .......................................... 41 
8.3 
Rationale for study design ..................................................................................... 50 
8.3.1 
Selection of doses ............................................................................................... 51 
9 
STUDY POPULATION ................................................................................................. 52 
9.1 
Recruitment ............................................................................................................. 52 
9.2 
Screening and enrolment log ................................................................................. 52 
9.3 
Number of subjects ................................................................................................. 52 
9.4 
Inclusion criteria ..................................................................................................... 52 
9.5 
Exclusion criteria .................................................................................................... 53 
9.6 
Restrictions during the study ................................................................................. 54 
9.6.1 
General restrictions ............................................................................................. 54 
9.6.2 
Prior and concomitant therapy ............................................................................ 56 
9.6.2.1 
Prohibited prior medications ....................................................................... 56 
9.6.2.2 
Prohibited concomitant medication. ............................................................ 56 
9.6.2.3 
Allowed medications ................................................................................... 56 
9.7 
Screen failures ......................................................................................................... 56 
9.8 
Subject withdrawal ................................................................................................. 57 
9.8.1 
General withdrawal criteria ................................................................................ 57 
9.8.2 
Procedures for discontinuation of a subject from the study ............................... 57 
9.8.3 
Subject replacement ............................................................................................ 57 
9.9 
Randomization ........................................................................................................ 58 
9.10 
Blinding.................................................................................................................... 58 
10 STUDY TREATMENTS ................................................................................................ 59 
10.1 
Identity of investigational medicinal products ..................................................... 59 
10.1.1 Investigational medicinal product ...................................................................... 59 
10.1.2 Index inhibitor (perpetrator drug), Part I ............................................................ 59 
10.1.3 Substrate of CYP3A, Part II ............................................................................... 59 
10.2 
Manufacturing, packaging, labelling and release ................................................ 59 
10.3 
Conditions for storage ............................................................................................ 59 
10.4 
Preparation and accountability ............................................................................. 60 
10.5 
Treatment administration ...................................................................................... 60 
10.5.1 Treatment with linaprazan glurate and clarithromycin, Part I ............................ 60 
10.5.2 Treatment with linaprazan glurate and midazolam, Part II ................................ 62 
10.6 
Continuation of treatment with investigational medicinal product ................... 63 
10.7 
Treatment compliance ............................................................................................ 63 
10.8 
Return and destruction of investigational medical product ............................... 64 


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11 STUDY ASSESSMENTS ............................................................................................... 65 
11.1 
Recording of data .................................................................................................... 65 
11.2 
Demographics and other baseline characteristics ................................................ 65 
11.2.1 Informed consent ................................................................................................ 65 
11.2.2 Eligibility criteria ................................................................................................ 65 
11.2.3 Demographic information ................................................................................... 65 
11.2.4 Height, weight and body mass index .................................................................. 65 
11.2.5 Medical/surgical history ..................................................................................... 65 
11.2.6 Prior and concomitant medication ...................................................................... 65 
11.2.7 HIV and hepatitis B/C ........................................................................................ 66 
11.2.8 Urine drug screen ................................................................................................ 66 
11.2.9 Alcohol test ......................................................................................................... 66 
11.2.10 
Baseline symptoms ......................................................................................... 66 
11.3 
Assessments related to pharmacokinetic endpoints ............................................ 66 
11.3.1 Pharmacokinetic sampling and analysis ............................................................. 66 
11.4 
Safety assessments .................................................................................................. 67 
11.4.1 Adverse events .................................................................................................... 67 
11.4.1.1 
Definition of adverse event ......................................................................... 67 
11.4.1.2 
Definition of serious adverse event ............................................................. 67 
11.4.1.3 
Definition of adverse reaction (AR) ............................................................ 68 
11.4.1.4 
Definition of serious adverse reaction (SAR) ............................................. 68 
11.4.1.5 
Definition of suspected unexpected serious adverse reaction (SUSAR) .... 68 
11.4.1.6 
Time period and frequency for collecting adverse events ........................... 68 
11.4.1.7 
Assessment of intensity ............................................................................... 68 
11.4.1.8 
Assessment of causal relationship ............................................................... 69 
11.4.1.9 
Assessment of outcome ............................................................................... 69 
11.4.1.10 Reporting of action taken with study treatment ......................................... 70 
11.4.1.11 Collecting adverse events .......................................................................... 70 
11.4.1.12 Recording adverse events .......................................................................... 70 
11.4.1.13 Reporting of serious adverse events .......................................................... 70 
11.4.1.14 Reporting of suspected unexpected serious adverse reactions to 
EudraVigilance, local competent authority and independent ethics committee ........... 71 
11.4.1.15 Treatment and follow-up of adverse events ............................................... 72 
11.4.1.16 Procedures in case of pregnancy ................................................................ 72 
11.4.1.17 Treatment of overdose ............................................................................... 72 
11.4.2 Physical examinations......................................................................................... 73 
11.4.3 Vital signs ........................................................................................................... 73 


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11.4.4 Safety 12-lead electrocardiograms ...................................................................... 73 
11.4.5 Safety laboratory assessments ............................................................................ 73 
11.5 
Assessments related to exploratory endpoints (Part I and Part II) ................... 74 
11.5.1 Collection of plasma (Part I and Part II) and urine (Part II) for future exploratory 
analyses of linaprazan glurate metabolites ....................................................................... 74 
11.6 
Appropriateness of measurements ........................................................................ 74 
12 PROCEDURES FOR BIOLOGICAL SAMPLES ...................................................... 75 
12.1 
Sample collection .................................................................................................... 75 
12.2 
Volume of blood ...................................................................................................... 75 
12.3 
Handling, storage and destruction of laboratory samples .................................. 75 
12.4 
Chain of custody of biological samples ................................................................. 76 
12.5 
Withdrawal of informed consent for donated biological samples ...................... 76 
13 QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL .............................................................................................................................. 77 
13.1 
Quality management: critical process, system and data identification ............. 77 
13.2 
Quality assurance and quality control .................................................................. 77 
14 ETHICAL AND REGULATORY REQUIREMENTS ............................................... 78 
14.1 
Ethical conduct of the study .................................................................................. 78 
14.2 
Ethics and regulatory review ................................................................................. 78 
14.3 
Subject information and consent ........................................................................... 78 
14.4 
Subject information card ....................................................................................... 79 
14.5 
Subject data protection .......................................................................................... 79 
14.6 
Changes to the approved clinical study protocol ................................................. 79 
14.7 
Audits and inspections ............................................................................................ 80 
14.8 
Insurance ................................................................................................................. 80 
15 STUDY MANAGEMENT ............................................................................................. 81 
15.1 
Training of study site personnel ............................................................................ 81 
15.2 
Clinical monitoring ................................................................................................. 81 
15.3 
Source data documents .......................................................................................... 82 
15.4 
Study agreements .................................................................................................... 82 
15.5 
Study timetable and end of study .......................................................................... 82 
15.6 
Termination of the study ........................................................................................ 82 
15.7 
Reporting and publication ..................................................................................... 83 
15.7.1 Clinical study report ........................................................................................... 83 
15.7.2 Annual safety report ........................................................................................... 83 
15.7.3 Confidentiality and ownership of study data ...................................................... 83 
15.7.4 Publication .......................................................................................................... 83 
15.8 
Archiving ................................................................................................................. 83 


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16 DATA MANAGEMENT ................................................................................................ 84 
16.1 
The web-based eCRF .............................................................................................. 84 
16.2 
The entering of data into the eCRF....................................................................... 84 
16.3 
Electronic patient reported outcome .................................................................... 84 
16.4 
The query process ................................................................................................... 85 
16.5 
Audit trail ................................................................................................................ 85 
16.6 
External data ........................................................................................................... 85 
16.7 
Medical coding ........................................................................................................ 85 
16.8 
Database lock .......................................................................................................... 85 
17 STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .......... 86 
17.1 
General .................................................................................................................... 86 
17.2 
Determination of sample size ................................................................................. 86 
17.3 
Analysis data sets .................................................................................................... 86 
17.3.1 Full analysis set .................................................................................................. 86 
17.3.2 Pharmacokinetic analysis set .............................................................................. 86 
17.4 
Description of study population ............................................................................ 87 
17.4.1 Demographics and baseline characteristics ........................................................ 87 
17.4.2 Medical/surgical history and prior/concomitant medication .............................. 87 
17.4.3 Exposure ............................................................................................................. 87 
17.5 
Analysis of pharmacokinetic endpoints ................................................................ 87 
17.5.1 Analysis of pharmacokinetics ............................................................................. 87 
17.6 
Analysis of safety endpoints ................................................................................... 89 
17.6.1 Adverse events .................................................................................................... 89 
17.6.2 Physical examinations......................................................................................... 89 
17.6.3 Vital signs ........................................................................................................... 89 
17.6.4 12-lead safety ECG ............................................................................................. 89 
17.6.5 Safety laboratory analyses .................................................................................. 89 
17.7 
Analysis of exploratory endpoints ......................................................................... 89 
18 REFERENCES ............................................................................................................... 90 
19 SIGNATURES ................................................................................................................ 92 
19.1 
Principal Investigator statement ........................................................................... 92 
19.2 
Approval of the clinical study protocol ................................................................. 93 
List of tables 
Table 4.1-1 Medical emergencies contact 
20 
Table 8.1-1 Overall schedule of events, Part I 
35 
Table 8.1-2 Detailed schedule of events for Visit 2, Part I 
38 


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Table 8.1-3 Detailed schedule of events for Visit 6 (Day 9, PK blood sampling for 
clarithromycin), Part I 
39 
Table 8.1-4 Detailed schedule of events for Visit 6 (Day 10 to Day 11), Part I 
40 
Table 8.2-1 Overall schedule of events, Part II 
43 
Table 8.2-2 Detailed schedule of events, Part II – Visit 2, Day -1 to Day 2 
45 
Table 8.2-3 Detailed schedule of events, Part II – Visit 2, Day 2 to Day 4 
46 
Table 8.2-4 Detailed schedule of events, Part II – Visit 3 
48 
Table 10.5-1 Administration of linaprazan glurate and clarithromycin, Part I 
61 
Table 10.5-2 Administration of linaprazan glurate and midazolam, Part II 
62 
Table 11.4-1 Safety laboratory parameters 
74 
Table 12.2-1 Estimated blood volumes, Part I 
75 
Table 12.2-2 Estimated blood volumes, Part II 
75 
 
List of figures 
Figure 8.1-1 Overview of the study design, Part I 
33 
Figure 8.2-1 Overview of the study design, Part II 
41 


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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Explanation 
 
AE 
Adverse event 
ADL 
Activities of daily living 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AR 
Adverse reaction 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the plasma concentration vs. time curve 
AUC0-t 
AUC from time 0 to time t 
AUCextr 
Extrapolated AUC 
AUCextr% 
AUC percent extrapolation 
AUCinf 
AUC from 0 to infinity 
BMI 
Body mass index 
BID 
Bis in die, twice daily 
CA 
Competent authority 
Cavg 
Average concentration 
CHL 
Chinese hamster lung 
CIOMS 
Council for International Organizations of Medical Sciences 
CL/F 
Apparent total body clearance following extravascular 
administration 
Cmax 
Maximum observed concentration 
CK 
Creatinine kinase 
CL/F 
Apparent total body clearance following extravascular 
administration 
CNS 
Central nervous system 
CRU 
Clinical research unit 
CS 
Clinically significant 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTC 
Clinical Trial Consultants AB 
CTCAE 
Common terminology criteria for adverse events 
CV% 
Coefficient of variation 
CYP 
Cytochrome P450 


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Abbreviation 
Explanation 
 
DDI 
Drug-drug interaction 
DMP 
Data management plan 
DMSO 
Dimethyl sulfoxide 
DSUR 
Development safety update report 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EEA 
European Economic Area 
eGERD 
Erosive GERD 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
ePRO 
Electronic patient reported outcomes 
EU 
European Union 
FAS 
Full analysis set 
FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GDPR 
General data protection regulation 
GERD 
Gastroesophageal reflux disease 
GMP 
Good manufacturing practice 
Hb 
Hemoglobin 
HBsAg 
Hepatitis B surface antigen 
HCL 
Hydrochloride 
HCVAb 
Hepatitis C antibodies 
HIV 
Human immunodeficiency virus 
H. pylori 
Helicobacter pylori 
HR 
Heart rate 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
IMPD 
Investigational medicinal product dossier 


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Abbreviation 
Explanation 
 
IR 
Immediate release 
ISF 
Investigator site file 
IUD 
Intra-uterine device 
IUS 
Intra-uterine system 
Lambdaz 
Terminal elimination rate constant, 
LLOQ 
Lower limit of quantification 
MAD 
Multiple-ascending dose 
MDMA 
Methylenedioxy-methamphetamine 
MedDRA 
Medical dictionary for regulatory activities 
MPA 
Medical products agency 
MTD 
Maximum tolerated dose 
NCA 
Non-compartmental analysis 
NCS 
Not clinically significant 
NOAEL 
No observed adverse effect level 
P-CABs 
Potassium-competitive acid blockers 
PD 
Pharmacodynamic 
PgP 
P-glycoprotein 
PII 
Personally identifiable information 
PK 
Pharmacokinetics 
PKAS 
PK analysis set 
PPI 
Proton pump inhibitors 
PT 
Preferred term 
QA 
Quality assurance 
QC 
Quality control 
QP 
Qualified person 
Racc 
Accumulation ratio 
RBM 
Risk based monitoring 
SAD 
Single-ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SD 
Standard deviation 
SDV 
Source data verification 
SMP 
Safety management plan 


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Abbreviation 
Explanation 
 
SmPC 
Summary of product characteristics 
SOC 
System organ class 
SOP 
Standard operating procedures 
SUSAR 
Suspected unexpected serious adverse reaction 
THC 
Tetrahydro-cannabinoids 
TMF 
Trial master file 
T1/2 
Terminal elimination half-life 
Tmax 
Time of occurrence of Cmax 
V/F 
Volume of distribution following extravascular 
administration 
WHO 
World Health Organization 


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4 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR 
 
4.1 
Medical emergencies contact 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes a serious adverse event (SAE) and is to be reported as such. Detailed SAE 
reporting procedures are described in Section 11.4.1.13. 
In the case of a medical emergency, the Investigator may contact the Sponsor’s medical 
representative (Table 4.1-1). 
Table 4.1-1 Medical emergencies contact 
 
Name 
Function in the study 
Telephone number 
E-mail 
 
Sponsor’s medical 
representative 
 
 
 


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5 
INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE 
 
Sponsor 
Cinclus Pharma Holding AB 
World Trade Center, Kungsbron 1 
SE-111 22 Stockholm, Sweden 
 
 
 
 
 
 
 
 
Clinical conduct 
Clinical Trial Consultants (CTC) AB 
Uppsala University Hospital 
Entrance 85, 2nd level 
SE-751 85 Uppsala, Sweden 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Karolinska vägen 22 
SE-171 64 Solna, Sweden 
Study management 
Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
Sponsor’s medical representative 
 MD, PhD, CMO 
Phone: 
 
E-mail:
Sponsor’s project manager 
(until December 2022) 
Phone: 
 
E-mail: 
 MSc (from 22DEC2022) 
Phone: 
 
E-mail:
Principal Investigator 
 MD 
CTC Clinical Trial Consultants AB 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
 
 
 
 
 
Clinical research manager 
 BSc 
Phone: 
 
E-mail: 
 
Biostatistician 
 MSc 
Phone: 
 
E-mail: 
 
Pharmacokineticist 
 PhD 
Phone: 
 
E-mail: 
 
Medical writer 
 PhD 
Phone: 
 
E-mail: 
 
Medical monitor 
 MD 
Phone: 
 
E-mail: 
 


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Laboratories (safety) 
Clinical Microbiology 
Uppsala University Hospital 
Dag Hammarskjölds väg 38 
SE-752 37 Uppsala, Sweden 
Clinical Chemistry and Pharmacology 
Uppsala University Hospital 
Entrance 61, 2nd level 
SE-751 85 Uppsala, Sweden 
Laboratory (bioanalysis) 
Lablytica Life Science AB 
Virdings Allé 16 
SE-754 50 Uppsala, Sweden 
Phone: +46 76 614 87 39 
Investigational Medicinal Product (IMP) 
manufacturing (Part I) 
 
IMP packaging, labelling and qualified person 
(QP) release (Part I) 
 
IMP manufacturing, packaging, and labelling 
(Part II) 
Recipharm Pharmaceutical Development AB 
Gårdsvägen 10A 
SE-169 70 Solna, Sweden 
Clinigen Clinical Supplies Management SA 
Watson & Crick Hill, Rue Granbonpré 11 
1435 Mont-Saint-Guibert, Belgium 
Xcelience, a Lonza company 
4910 Savarese Circle 
Tampa FL 33636, United States 
IMP import and QP release (Part II) 
Nextpharma Ploërmel 
ZI de Camagnon 
Ploërmel 56804, France 
Pharmacy 
Apoteket AB Nationella Enheten Uppsala 
Clinical Trial Unit 
Södra Depågatan 2 
SE-754 54 Uppsala, Sweden 
Electronic data capture (EDC) system provider 
Viedoc Technologies AB 
Stationsgatan 23 
SE-753 40 Uppsala, Sweden 
 
Signatures are provided in Section 19. 


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6 
INTRODUCTION 
 
6.1 
Background 
Gastroesophageal reflux disease (GERD) is a common chronic disorder with high prevalence 
in North America and Europe, where at least weekly reflux symptoms range from 10% to 
30%. Epidemiologic data are limited but suggest a lower prevalence in Asia [1], although 
prevalence is increasing in this region and other developed countries [2]. A universally 
accepted definition of treatment success in GERD is not available [1]. 
The Taipei Global Consensus emphasized the role of Helicobacter pylori (H. pylori) 
eradication in accomplishing the goal of reducing or eliminating deaths from gastric cancer. A 
number of different therapies have been introduced, including triple therapies consisting of a 
proton pump inhibitor (PPI), amoxicillin and clarithromycin and also PPI and amoxicillin dual 
therapy. The recent introduction of potassium-competing acid blockers has rekindled interest 
in these therapies based on the observation that the marked acid suppression obtained resulted 
in an increase in efficacy with amoxicillin-containing regimens [3]. 
A new class of molecules, potassium-competitive acid blockers (P-CABs), present a new 
mode of action, that, in principle, allows full intragastric acid control both day and night. Such 
acid inhibitory properties in humans are likely to allow for the successful treatment of 
subjects with erosive GERD (eGERD), the most acid-sensitive GERD sub-population. 
Linaprazan, the main metabolite of the study drug of the present study, linaprazan glurate 
(previously designated X842), has been shown to provide a modest duration of effective acid 
control in humans [4,5]. After oral administration, linaprazan glurate shows a slower uptake 
compared to linaprazan. This results in a lower maximum observed concentration (Cmax) and 
longer plasma residence time of linaprazan after the administration of linaprazan glurate. This 
should translate into a lower load of linaprazan to the liver and a prolonged control of 
intragastric acidity. Previous studies have shown a lower Cmax and area under the plasma 
concentration vs. time curve (AUC) for linaprazan after repeated dosing with linaprazan 
glurate [6]. 
The investigational medicinal product (IMP) in the first-in-human (FIH) study of linaprazan 
glurate (single ascending dose [SAD], and multiple ascending dose [MAD]), study 
CX842A2101 (EudraCT no. 2016 002506-39) [7], was a liquid formulation to allow dosing 
per kg. 
An immediate release (IR) tablet formulation was developed for use in a Phase II study. The 
pharmacokinetic (PK) and pharmacodynamic (PD) properties of this tablet formulation have 
been evaluated in 2 Phase I studies: a 2-period crossover relative bioavailability study, 
CX842A2102 [8] and an exploratory PK/PD parallel-group study CX842A2103 [9]. Both 
studies were designed to support the dose selection for future Phase II studies of linaprazan 
glurate. 
6.1.1 
Clinical experience 
In the FIH SAD/MAD study CX842A2101, the safety, tolerability, and PK properties of 
linaprazan glurate and linaprazan were evaluated [7]. The study concluded that linaprazan 
glurate was well tolerated in single doses up to 4.0 mg/kg and multiple doses up to 2.0 mg/kg, 
and that the intragastric pH correlated with the plasma concentration of linaprazan during the 
time interval 0-24 hours after dose. 


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In the relative bioavailability study CX842A2102 (EudraCT no. 2019-001231-31) [8], the 
anticipated target plasma concentration of linaprazan for optimal intragastric acid control 
could not be achieved with once daily dosing and the primary endpoint could not be 
calculated from the collected study data. It was therefore needed to explore the PK and PD 
properties of linaprazan glurate oral tablets given twice daily (BID) for 3 consecutive days to 
support the dose selection for Phase II studies. In the exploratory PK/PD study CX842A2103 
(EudraCT no. 2019-003963-24) [9], an increase in exposure to linaprazan after the 
administration of linaprazan glurate produced an increase in PD effect with respect to elevated 
control of intragastric pH (evaluated as the time and percentage of time with an intragastric 
pH >4). 
In the previous studies (CX842A2101, CX842A2102 and CX842A2103), linaprazan glurate 
was found to be safe and well-tolerated as assessed by the evaluation of adverse events (AEs), 
vital signs, physical examinations, electrocardiograms (ECGs) and safety laboratory 
parameters. 
There have been no SAEs nor any AEs that led to subject withdrawal after the administration 
of linaprazan glurate in any of the 3 previous clinical studies. The number of subjects 
experiencing AEs assessed as related to the IMP did not increase with larger doses of 
linaprazan glurate, and there have been no clinically relevant findings or dose-dependent 
mean changes over time in physical examinations, vital signs, ECGs, or laboratory 
parameters. 
6.1.2 
Pharmacokinetic summary 
Plasma concentrations of linaprazan glurate were mostly low and close to the lower limit of 
quantification (LLOQ) in the SAD/MAD study with the oral suspension [7]. Thus, PK 
parameters and dose linearity could not be calculated for linaprazan glurate in this study. For 
the active metabolite linaprazan, the exposure after a single administration of linaprazan 
glurate showed a less than dose proportional increase in exposure, with regard to both Cmax 
and AUC, in the dose range 0.08 mg/kg to 4.0 mg/kg. Dose linearity was shown for 
linaprazan for SAD Cohort 1-5, but not for SAD Cohort 6-7. The exposure after a single 
administration of the highest dose (4.0 mg/kg) was lower than expected, and the variability 
among subjects was high. No indication of food interaction was seen, however there was a 
high variability for both Cmax and AUC under fed conditions. 
The exposure in the MAD part of the study was lower than expected after the first dose as 
compared to the corresponding SAD doses. In MAD Cohorts 2 and 3, given multiple 
2.0 mg/kg doses of linaprazan glurate, the exposure was lower than expected after the first 
dose as compared to SAD Cohort 5 (2.0 mg/kg) and MAD Cohort 1 (1.0 mg/kg). High 
variability was also seen among subjects. The exposure was also lower on Day 5 as compared 
to Day 1 at both dose levels (1.0 and 2.0 mg/kg). High variability was again seen among 
subjects. 
In the relative bioavailability study with a tablet formulation [8], linaprazan glurate was 
detectable but plasma concentrations were low and variable. There was an approximate linear 
increase in linaprazan glurate plasma exposure between 50 mg and 150 mg on Day 1. The 
50 mg dose resulted in comparable mean Cmax and AUC on Day 1 and Day 2. For the 150 mg 
dose, mean exposure (Cmax and AUC) was lower on Day 2 compared to Day 1. There was a 
less than dose proportional increase in both Cmax and AUC when the dose was increased from 
50 mg to 150 mg on Day 1. On Day 2 there was no further increase in exposure with the 
150 mg dose compared to the 50 mg dose. 


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In the explorative PK/PD study, with 50 mg, 100 mg and 150 mg doses [9], a non-dose 
proportional increase of linaprazan plasma concentrations was observed with increasing doses 
of linaprazan glurate for each dosing interval. The highest average concentration (Cavg) for 
any of the dose intervals was seen after administration of the first linaprazan glurate dose for 
all 3 treatment arms. The mean Cavg indicated a non-dose proportional increase of exposure 
with increasing dose of linaprazan glurate. 
The terminal elimination half-life (T1/2) of linaprazan is 12-21 hours, according to the results 
from the FIH SAD/MAD study and the bioavailability study. 
6.1.3 
Indication 
Linaprazan glurate is under development for the treatment of GERD and for eradication of 
H. pylori infection. 
6.1.4 
Dosage 
The dose levels of linaprazan glurate to be tested in this study are 100 mg (Part I, 2 single 
doses) and 75 mg (Part II, BID for 13 days). For rationale for selection of doses, refer to 
Section 8.3.1. 
6.1.5 
Mechanism of action 
The active substance linaprazan is a member of the class of compounds that inhibit gastric 
H+, K+-ATPase by K+-competitive binding [10]. Based on the results of clinical studies with 
linaprazan, a series of new compounds with improved properties has been developed [4,5]. 
The intention with the prodrug linaprazan glurate was to attain a lower acute Cmax than 
linaprazan compared to after the administration of linaprazan, and to increase the plasma 
residence time of the compound, hence increasing the number of hours of full intragastric acid 
control. Linaprazan glurate was found to inhibit the H+, K+-ATPase activity in isolated 
membrane vesicles in a concentration-dependent manner. Furthermore, linaprazan glurate was 
found to inhibit acid formation in rabbit gastric glands in vitro, a more complex model than 
isolated membrane vesicles. Linaprazan glurate was also tested in 2 in vivo models, in chronic 
gastric fistula rats and in Heidenhain pouch dogs. In both models, linaprazan glurate was 
shown to be a potent inhibitor of gastric acid secretion. 
6.1.6 
Drug description 
The drug substance is linaprazan glurate. It is a prodrug for the active substance linaprazan, 
(8-[(2,6-dimethylbenzyl) amino]-N-[2-hydroxyethyl]-2,3-dimethylimidazo[1,2-a] pyridine-6- 
carboxamide). 
In its base form, (5-(2-(8-((2,6-dimethylbenzyl) amino)-2,3-dimethylimidazo[1,2-a] pyridine- 
6-carboxamido) ethoxy)-5-oxopentanoic acid), it has been used in previous studies and will be 
used in Part I of the study. As a hydrochloride (HCl) salt, 5-{2-[({8-[(2,6-Dimethylbenzyl) 
amino]-2,3-dimethylimidazo[1,2-a] pyridin-6-yl} carbonyl) amino] ethoxy}-5-oxopentanoic 
acid HCl (1:1), it will be used in Part II of the study. Linaprazan glurate lacks a chiral center. 
Linaprazan glurate as base is soluble in dimethyl sulfoxide (DMSO), slightly soluble in 
methanol and nearly insoluble in dichloromethane and water. For linaprazan glurate HCl the 
solubility in water is 0.03 mg/mL. It is unstable in 0.1 M HCl and degrades to the active 
structure linaprazan. The solubility of both linaprazan and linaprazan glurate is pH-dependent 
and increases exponentially at pH values below the pKa (6.1 for linaprazan and 5.5 for 
linaprazan glurate). 


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6.1.7 
Non-clinical toxicology 
Male and female Sprague-Dawley rats were administered linaprazan glurate in single oral 
doses of up to 250 mg/kg and repeated oral doses of up to 150 mg/kg for 28 consecutive days 
followed by a 4-week recovery period. Male and female beagle dogs were administered 
linaprazan glurate in single oral doses of up to 120 mg/kg and repeated oral doses up to 
48 mg/kg for 28 consecutive days followed by a 28-day recovery phase. 
No signs of treatment-related toxicity have been noted following single oral administration of 
linaprazan glurate at dose levels of up to 250 mg/kg in rats. Some emesis has been seen at all 
dose levels investigated in dogs. However, this is a common clinical sign in toxicity studies in 
dogs and is not regarded as having any toxicological relevance unless it is very pronounced 
and/or frequent. The maximum tolerated dose (MTD) following a single dose of linaprazan 
glurate was above the maximum given doses of 250 mg/kg in rats and 120 mg/kg in dogs. 
In the 28-day repeat-dose study in rats, and a study of fertility and early embryonic 
development also in rats, the no observed adverse effect level (NOAEL) was considered to be 
150 mg/kg in both males and females. In the 28-day repeat-dose study in dogs, the NOAEL 
was considered to be 48 mg/kg in both males and females. In all instances, these were the 
highest doses given in each study. 
In vitro (Ames test and chromosome aberrations in Chinese hamster lung [CHL] cells) and in 
vivo (micronucleus test in rats) genotoxicity studies showed that linaprazan glurate did not 
show mutagenic activity either with or without metabolic activation. 
For detailed information, refer to the Investigator’s brochure (IB) for linaprazan glurate. 
 
6.2 
Study rationale 
This is a Phase I, single-center, drug-drug interaction (DDI) study divided in 2 parts designed 
to evaluate whether concomitant treatment with linaprazan glurate and a strong inhibitor of 
cytochrome P450 3A4 (CYP3A4) and P-glycoprotein P (PgP) leads to an effect on the 
systemic exposure to linaprazan glurate and linaprazan and if single and/or repeated doses of 
linaprazan glurate have effect on the PK of a sensitive CYP3A substrate. 
Based on in vitro data the elimination of both linaprazan glurate and its active metabolite 
linaprazan is metabolized by CYP3A4. Furthermore, linaprazan glurate and linaprazan have 
both showed a potential of CYP3A induction in vitro and linaprazan glurate has shown a 
potential to inhibit CYP3A4 at the intestinal level in vitro. 
Part I of the study will investigate whether concomitant treatment with linaprazan glurate and 
a strong inhibitor of CYP3A4/PgP (clarithromycin) leads to an increase of systemic exposure 
to linaprazan glurate and linaprazan. Clarithromycin is also part of the standard of care 
regimen in the treatment of H. pylori, an indication of clinical interest for combination 
therapy with linaprazan glurate. 
Part II of the study will investigate the potential for clinically relevant inhibition and/or 
induction caused by linaprazan glurate of a sensitive CYP3A substrate (midazolam). 


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6.3 
Risk/benefit assessment 
6.3.1 
General risk/benefit assessment 
As the healthy subjects in this study are unlikely to experience any medical benefit from their 
participation, their safety and wellbeing is of the utmost importance. Toxicology studies and 
previous clinical studies on linaprazan and linaprazan glurate have indicated a low toxicity 
with no major concerns at the studied dose levels. No treatment related changes were 
observed in studies on embryo-fetal development in rats and rabbits or in fertility mating 
behavior and early embryonic development in rats. Nevertheless, there is a clear need for 
attention to risk mitigation. 
Only limited data is available at this stage on reproductive toxicology. Contraception 
requirements will be applied to prevent pregnancy and only females of non-childbearing 
potential will be included in the study. 
Based on the results from previous studies with linaprazan glurate (refer to Section 6.1.1), 
together with published data on administration of linaprazan going back nearly 2 decades, 
linaprazan has been considered safe and well tolerated at exposures higher than the exposures 
estimated for the present study. Linaprazan glurate is a glutaric acid prodrug of linaprazan, a 
P-CAB that has been extensively studied by AstraZeneca in more than 2000 patients and 
400 healthy subjects. Based on published data, linaprazan was safe and well tolerated [4]. 
In Part I of the study, 2 single doses of 100 mg linaprazan glurate in its base form will be 
administered to healthy males and females of non-childbearing potential. The second dose 
will be co-administered with clarithromycin. The predicted systemic exposure to linaprazan 
glurate is not expected to exceed what was achieved in the FIH single ascending dose study 
with a maximum dose level of 4 mg/kg linaprazan glurate. The highest SAD dose level is 
approximately 3-fold compared to the dose level in Part I. The major metabolic pathway for 
linaprazan glurate in liver microsomes was via ester hydrolysis to the active metabolite 
linaprazan. Furthermore, linaprazan was formed by several CYPs, among them CYP3A4, 
when investigated in vitro with recombinant cytochrome P450s, therefor a large increase in 
linaprazan glurate exposure is not expected when co-administered with a CYP3A4 inhibitor. 
Severe adverse reactions (ARs) associated with linaprazan glurate are hence not expected. 
Overdosing of linaprazan glurate is not likely to occur in Part I since all linaprazan glurate 
will be administered by clinic personnel under medical supervision. In Part II, the subjects 
will take some of the doses of linaprazan glurate at home. In cases of accidental overdose of 
linaprazan glurate, subjects will be urged to contact the clinical research unit (CRU) and 
standard supportive measures should be adopted as required. For further information 
regarding overdosing, refer to Section 11.4.1.17. 
Aside from the risks related to the administration of linaprazan glurate as detailed above, there 
may also be risks related to the administration of clarithromycin in Part I and midazolam in 
Part II of the study. The most common adverse effects associated with clarithromycin include 
central nervous system (CNS) events such as dizziness, headache and dysgeusia, 
psychological disturbances such as insomnia and anxiety, gastrointestinal evens such as 
abdominal pain, diarrhea, vomiting, nausea and dyspepsia, skin and subcutaneous tissue 
disorders such as rash, administration site conditions as well as general disorders such as 
pyrexia. Clarithromycin has been associated with prolongation of the QT interval and 
infrequent cases of arrhythmia; however, clarithromycin is a commonly used index inhibitor 
of CYP3A4 and is part of standard of care regimen for the treatment of H. pylori, making it 
important to study together with acid controlling agents. 


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Each volunteer will be provided with a subject information card with information about the 
subject’s participation in a study including known and expected benefits and risks, see 
Section 14.4. 
The Principal Investigator at the CRU will ensure that adequate facilities and procedures are 
available to handle emergency situations should they occur during the study. 
Besides the risks related to linaprazan glurate, clarithromycin and midazolam, as detailed 
above, there may also be risks related to the medical devices used in the study (e.g., 
indwelling venous catheters). However, these devices are used in routine medical care and the 
risk associated with their use is considered low and ethically justifiable. 
Study-specific evaluations and sampling procedures, such as blood-pressure measurements 
using a blood pressure cuff and frequent blood-sampling, may cause transient discomfort but 
the risk is deemed to be low and ethically justifiable. 
More detailed information about the known and expected benefits and risks and reasonably 
expected ARs is found in the current version of the IB (version 3.3, dated 11JUL2022). More 
information about risks associated with clarithromycin and midazolam can be found in the 
summary of product characteristics (SmPC) for each product. 
6.3.2 
Risk/benefit conclusion 
As a final, commercial pharmaceutical product, linaprazan glurate has the potential to confer 
significant benefits over the currently available treatments for severe GERD. Specifically, 
linaprazan glurate is expected to result in a lower load of linaprazan to the liver and a 
prolonged control of intragastric acidity compared to currently available treatments. 
The combined safety data from previous pre-clinical and clinical studies have not revealed 
safety issues that would outweigh the expected benefits of the present study. While keeping 
the identified risk factors at a minimum level, in order to not expose the subjects participating 
in the study to risks that would not be ethically justifiable, it is concluded that the planned 
study assessments are considered sufficient to meet the scientific and medical goals for the 
study. It is therefore concluded that the potential benefits from the study will outweigh the 
potential risks for the treated subjects. 


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7 
STUDY OBJECTIVES AND ENDPOINTS 
 
7.1 
Study objectives and endpoints Part I 
7.1.1 
Primary objective 
• To investigate the effect of repeated administration of clarithromycin on linaprazan 
glurate and linaprazan PK after single dose of linaprazan glurate. 
7.1.2 
Primary endpoint 
• Linaprazan glurate and linaprazan PK parameters with and without co-administration 
of clarithromycin: 
o Area under the plasma concentration curve from 0 to infinity (AUCinf) 
o AUC from time 0 to time t (AUC0-t) 
o Maximum plasma concentration (Cmax) 
7.1.3 
Secondary objectives 
• To assess the safety and tolerability after single dose of linaprazan glurate with and 
without co-administration of clarithromycin. 
• To evaluate additional PK characteristics of linaprazan glurate and linaprazan. 
• To investigate the effect of linaprazan glurate on clarithromycin PK. 
 
7.1.4 
Secondary endpoints 
• Frequency, seriousness, and intensity of AEs. 
• Clinically significant changes in physical examinations, vital signs (blood pressure and 
pulse), electrocardiograms (ECG), and laboratory variables (hematology, clinical 
chemistry, and urinalysis). 
• Additional PK parameters for linaprazan glurate and linaprazan, not limited to: 
o Time of occurrence of Cmax (Tmax) 
o Terminal elimination half-life (T1/2) 
o Apparent clearance (CL/F) 
o Apparent volume of distribution (V/F) 
o Percent extrapolated AUC (AUCextr%) 
• Clarithromycin PK parameters with and without co-administration of linaprazan 
glurate: 
o AUC to the end of the dosing period (AUCtau) 
o Cmax 
• Additional PK parameters for clarithromycin, not limited to: 
o Tmax 
o T1/2 
 
7.1.5 
Exploratory objective 
• To explore the metabolites of linaprazan glurate in plasma with and without co- 
administration of clarithromycin. 


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7.1.6 
Exploratory endpoint 
• Plasma collected for future exploratory analyses of linaprazan glurate metabolites. 


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7.2 
Study objectives and endpoints Part II 
7.2.1 
Primary objective 
• To investigate the effects after single and repeated administration of linaprazan glurate 
on the PK properties of midazolam. 
7.2.2 
Primary endpoint 
• Midazolam PK parameters in the presence and absence of linaprazan glurate 
administration: 
o AUCinf 
o AUC0-t 
o Cmax 
 
7.2.3 
Secondary objectives 
• To assess the safety and tolerability after repeated doses of linaprazan glurate with and 
without co-administration of midazolam. 
• To evaluate PK data on linaprazan glurate and linaprazan after single and repeated oral 
doses of linaprazan glurate. 
• To evaluate additional PK characteristics of midazolam in the presence and absence of 
linaprazan glurate administration 
7.2.4 
Secondary endpoints 
• Frequency, seriousness, and intensity of AEs. 
• Clinically significant changes in physical examinations, vital signs (blood pressure and 
pulse), ECG, and laboratory variables (hematology, clinical chemistry, and urinalysis). 
• Linaprazan glurate and linaprazan PK parameters after repeated administration of 
linaprazan glurate twice daily (BID) for 13 days (if feasible): 
o AUCinf 
o AUC0-t 
o Cmax 
o Tmax 
o T1/2 
o AUCextr% 
o CL/F 
o V/F 
o Accumulation ratio (Racc). 
• Midazolam PK parameters in the presence and absence of linaprazan glurate 
administration (if feasible): 
o Tmax 
o T1/2 
o AUCextr% 
o CL/F 
o V/F 


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7.2.5 
Exploratory objectives 
• To explore the metabolites of linaprazan glurate in plasma and urine after single and 
repeated doses of linaprazan glurate. 
7.2.6 
Exploratory endpoints 
• Plasma and urine collected for future exploratory analyses of linaprazan glurate 
metabolites. 
Results related to exploratory analyses may not be reported in the clinical study report (CSR). 


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8 
STUDY DESIGN 
 
8.1 
Overall study design and schedule of events, Part I 
Part I of the study is an open-label, fixed sequence, DDI study designed to evaluate whether 
concomitant treatment with linaprazan glurate and clarithromycin, a strong inhibitor of 
CYP3A4/PgP, leads to an effect of systemic exposure to linaprazan glurate and linaprazan. 
First, all subjects will be administered a single dose of linaprazan glurate (100 mg: 4x25 mg 
oral tablets) alone. Next, the CYP3A4/PgP inhibitor clarithromycin will be given from Day 4 
to Day 12 and on Day 10 linaprazan glurate (100 mg: 4x25 mg oral tablets) and 
clarithromycin will be co-administrated. 
An overview of the study design is shown in Figure 8.1-1. The schedule of events for Part I is 
presented in Table 8.1-1 and is detailed for Visit 2 in Table 8.1-2 and for Visit 6 in Table 
8.1-3 and Table 8.1-4. Study assessments are described in Section 11. 
Figure 8.1-1 Overview of the study design, Part I 
 
A total of 18 healthy male and female subjects of non-childbearing potential are planned to be 
included in Part I of the study to ensure 12 evaluable subjects. 
The subjects will come for 10 visits to the clinical research unit (CRU). 
Screening (Visit 1) will take place at any time point between Day -28 and Day -1 and will 
include an eligibility check and collection of demographic and medical history data as well as 
a review of health status, including a physical examination and collection of vital signs and 
safety laboratory blood samples. 
At Visit 2, eligible subjects will be admitted to the CRU on Day -1 and stay until the morning 
on Day 2. The subjects will be dosed in the morning of Day 1, with a single dose of 
linaprazan glurate (100 mg: 4x25 mg oral tablets). The subjects must fast for at least 8 hours 
before the anticipated dosing time on Day 1. During fasting, water, but no other drinks, is 
allowed as desired. No drinks are allowed for 1 hour before and 30 minutes after dosing. 
Blood will be sampled for PK analysis up to 24 hours after dose (24-hour sample on Day 2) 
and safety will be assessed. The subjects will leave the CRU in the morning of Day 2 (after 
the 24-hour sample) and return in the evening of Day 2 (Visit 3) for the 36-hour PK-blood 
sample. The subjects will thereafter return to the CRU for blood sampling at 48 hours on 


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Day 3 (Visit 4) and at 72 hours on Day 4 (Visit 5). At Visit 5, the subjects will start 
clarithromycin dosing, (500 mg BID) and continue dosing until Day 12. 
On Day 9 (Visit 6), the subjects will be admitted to the CRU and stay until Day 11. In the 
morning of Day 9 clarithromycin (500 mg BID) will be administered. Thereafter, blood 
samples for PK analysis of clarithromycin will be collected up to 12 h after dose. The subjects 
must fast for at least 8 hours before the anticipated dosing time on Day 9 and Day 10. During 
fasting, water, but no other drinks, is allowed as desired. No drinks are allowed for 1 hour 
before and 30 minutes after dosing. In the morning on Day 10, linaprazan glurate (100 mg: 
4x25 mg tablets) and clarithromycin (500 mg, BID) will be co-administered and blood 
samples for PK analysis of linaprazan glurate and linaprazan will be collected up to 24 hours 
after dose (24-hour sample on Day 11) and the subjects will leave the CRU in the morning on 
Day 11 (after the 24-hour PK sample). 
In the evening on Day 11 (Visit 7), the subjects will return to the CRU for the 36-hour PK 
sample. The subjects will thereafter return to the CRU for blood sampling on 48 hours on Day 
12 (Visit 8) and at 72 hours on Day 13 (Visit 9). 
A final end-of-study visit (Visit 10) will take place on Day 14 (±2) or after early withdrawal. 
Blood samples for analysis of PK parameters for linaprazan glurate and linaprazan will be 
collected prior to linaprazan glurate administration (pre-dose) and 15, 30, 45 min, 1.15, 1.5, 2, 
3, 4, 6, 8, 10, 12, 18, 24, 36, 48 and 72 hours after dosing (on dosing Days 1 and 10). 
Blood samples for analysis of PK parameters for clarithromycin will be collected prior to 
clarithromycin administration (pre-dose) and 30 min, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 
12 hours after dosing (on dosing Day 9 when dosed alone and on Day 10 when dosed with 
linaprazan glurate). 
The subjects will be carefully monitored by clinical staff during and after dosing. The subjects 
will be served standardized meals while they are in the CRU, as detailed in Table 8.1-1. 
AEs will be recorded from the first dose of linaprazan glurate and throughout the study. 






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10. Day 1 and Day 10: Pre-dose and for 24 hours post-dose. Day 2 and Day 11 at 36 hours post-dose, Day 3 and Day 12 at 48 hours post-dose and Day 4 and Day 13 at 72 hours post-dose. 
Actual time for PK blood sampling must not deviate more than ±10% from the planned time. The pre-dose sample may be taken within 60 minutes prior to IMP administration. For timing 
of PK blood sampling. refer to Table 8.1-2. 
11. Day 9 and Day 10: Pre-dose and for 12 hours post-dose (morning dose). Actual time for PK blood sampling must not deviate more than ±10% from the planned time. The pre-dose sample 
may be taken within 60 minutes prior to IMP administration. For timing of PK blood sampling on Day 9 refer to Table 8.1-3 and on Day 10, refer to Table 8.1-4. 
12. Subjects must fast for 8 hours before linaprazan glurate administration until 2 hours post-dose on Day 1, Day 9 and Day 10 (Visit 2 and Visit 6). Meals Day 1, Day 9 and Day 10: breakfast 
(2 hours post-dose), lunch, snack, dinner, and optional evening snack. Lunch will be served at least 4 hours post-linaprazan glurate (Day 1 and Day 10) or clarithromycin administration 
(Day 9). Snack, dinner and evening snack will be served approximately 6-, 9- and 12-hours post-linaprazan glurate administration (Day 1 and Day 10) or clarithromycin administration 
(Day 9), respectively. Day 2 and Day 11: optional breakfast after PK sampling. 
13. Baseline symptoms will be recorded up until the first administration of linaprazan glurate on Day 1. 
14. AEs will be recorded from first administration of linaprazan glurate. 
15. For definition of prior and concomitant medications, see Section 11.2.6. For prohibited and allowed medications, see Section 9.6.2. 








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8.2 
Overall study design and schedule of events, Part II 
Part II of the study is an open-label, fixed sequence, drug-drug-interaction (DDI) study 
designed to evaluate whether concomitant treatment with linaprazan glurate and a sensitive 
substrate of CYP3A (midazolam) leads to clinically relevant increase of systemic exposure to 
linaprazan glurate and linaprazan. The study will further evaluate if single and/or repeated 
doses of linaprazan glurate have effect on the PK of midazolam. In Part II, the PK of 
midazolam (2.5 mg) will be investigated in the presence and absence of linaprazan glurate. In 
addition, Part II of the study will explore the PK of linaprazan glurate and linaprazan, as well 
as safety and tolerability, after repeated administration of 75 mg of linaprazan glurate twice a 
day (BID) for 14 consecutive days. 
An overview of the study design of Part II is shown in Figure 8.2-1 . The overall schedule of 
events for Part II is presented in Table 8.2-1. The detailed schedule of PK blood sampling is 
presented in Table 8.2-2 (Day -1 to Day1, Table 8.2-3 (Day 2 to Day 4) and Table 8.2-4 
(Day 14 to Day 16). Study assessments are described in Section 11. 
Figure 8.2-1 Overview of the study design, Part II 
 
A total of 18 healthy male and female subjects of non-childbearing potential are planned to be 
included in Part II of the study to ensure 12 evaluable subjects. 
Screening (Visit 1) will take place at any time point between Day -28 and Day -1, and will 
include an eligibility check, collection of demographic and medical history data as well as a 
review of health status, including a physical examination and collection of vital signs and 
safety laboratory blood samples. 
At Visit 2, eligible subjects will be admitted to the CRU on Day -1. In the morning of Day 1, 
the subjects will be administered a single dose of midazolam (2.5 mg), followed by PK blood 
sampling up to and including 24 hours after dosing (see Table 8.2-2). Starting on Day 2, after 
the 24-hour PK blood sample, the subjects will be co-administered linaprazan glurate (75 mg: 
3x25 mg oral tablets, BID) and midazolam (2.5 mg) in the morning. The subjects must fast for 
at least 8 hours before the anticipated dosing time on Day 1 and Day 2 until 2 hours post-dose. 
During fasting, water, but no other drinks, is allowed as desired except for 1 hour before and 
30 minutes after dosing. 


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From Day 2 to Day 4, blood sampling for linaprazan glurate and linaprazan PK will take place 
at pre-determined time points until 24 hours after the morning doses, as detailed in (Table 
8.2-3). The subjects will be discharged from the CRU on Day 4 and will be home-based until 
Day 13 when they will be re-admitted for Visit 3. The subjects will self-administer linaprazan 
glurate (75 mg:3x25 mg oral tablets, BID) at home. An electronic diary will be handed out for 
the subjects to record the intake of linaprazan glurate at home between Visit 2 and Visit 3. 
On Day 13, the subjects will be admitted to the CRU (Visit 3). In the morning of Day 14, the 
subjects will be co-administered a second dose of midazolam (2.5 mg) together with the 
morning dose of linaprazan glurate (75 mg:3x25 mg oral tablets), followed by blood sampling 
for midazolam PK in the presence of linaprazan glurate at pre-determined time points up to 
and including 24 hours after co-administration as well as blood sampling for linaprazan 
glurate PK until 36 hours (Table 8.2-4). The subjects must fast for at least 8 hours before the 
anticipated dosing time on Day 14. During fasting, water, but no other drinks, is allowed as 
desired except for 1 hour before and 30 minutes after dosing. The subjects will be discharged 
from the CRU on Day 15 (after the 36-hour sample) and return in the morning of Day 16 
(Visit 4) for the 48-hour PK sample. 
A final end-of-study visit will take place as a telephone call on Day 22 (±2 days) (Visit 5) or 
after early withdrawal. 
The subjects will be carefully monitored by clinical staff during and after dosing. The subjects 
will be served standardized meals while they are in the CRU, as detailed in Table 8.2-1. 
AEs will be recorded continually from the first dose of midazolam during visits to the CRU. 
Upon re-admission to the CRU on Day 13 subjects will be asked to report any AEs that arose 
between discharge on Day 4 and re-admission on Day 13. 




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Standardized meals10 
9.6.1 
X 
X 
X 
X 
X 
Baseline symptoms11 
11.2.10 
X 
Adverse events (AEs)12 
11.4.1 
X 
Prior and concomitant 
medications 
11.2.6 
X 
BMI= body mass index, ECG= electrocardiogram, HIV=human immunodeficiency virus, MDZ=midazolam. 
1. 
Detailed schedule for Visit 2 and Visit 3 are shown in Table 8.2-2, Table 8.2-3 and Table 8.2-4. 
2. 
Or after early withdrawal. 
3. 
Confirmation of eligibility. Can be done on Day -1 or Day 1 prior to dosing. 
4. 
Pre-dose assessments can be done on Day -1 or Day 1 prior to midazolam administration. 
5. 
In association with discharge from the CRU. 
6. 
Resting systolic and diastolic blood pressure, pulse, blood oxygen saturation and body temperature. 
7. 
Administration of linaprazan glurate BID (75 mg:3x25 mg oral tablets, BID). 
8. 
At-home administration of linaprazan glurate (75 mg:3x25 mg oral tablets, BID). On Day 13, the morning dose will be taken at home and the evening dose will be taken at the CRU. 
9. 
For exploratory analysis of linaprazan glurate metabolites. Urine to be collected: 0-6 hours and 6-12 hours. 
10. Subjects must fast for at least 8 hours before each midazolam/linaprazan glurate administration until 2 hours-post dose. Meals Day 1 to Day3 and Day 14 and 15: breakfast, lunch, snack, 
dinner and optional evening snack. Meals Day 4: optional breakfast. Breakfast will be served approximately 2 hours after midazolam/linaprazan glurate administration. Lunch, a mid-day 
snack, dinner, and optional evening snack will be served approximately 4 hours, 6 hours, 9 hours, and 12 hours after midazolam/linaprazan glurate administration. 
11. Baseline symptoms will be recorded from the signing of the ICF up until the first administration of midazolam on Day 1. 
12. AEs will be recorded from the administration of midazolam on Day 1 up until the follow-up visit (Visit 5), or until early withdrawal. 






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9. 
Subjects must fast for at least 8 hours before each midazolam/linaprazan glurate administration until 2 hours-post dose. 
10. Pre-dose urine sample (5 mL) will be collected from the first morning void. Urine will be collected 0-6 hours and 6-12 hours after co-administration of midazolam and Day 2. 




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4. 
The PK blood sample should be taken 15 minutes after the second linaprazan glurate administration. 
5. 
Aliquoted from linaprazan glurate PK blood samples. 
6. 
Pre-dose urine sample (5 mL) will be collected from the first morning void. Urine will be collected 0-6 hours and 6-12 hours. 
7. 
Subjects must fast for at least 8 hours before each midazolam/linaprazan glurate administration until 2 hours-post dose. 


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8.3 
Rationale for study design 
The European Medicines Agency (EMA) guideline EMEA/CHMP/SWP/28367/07 Rev. 1 on 
strategies to identify and mitigate risks in FIH studies and early clinical trials [12] was 
considered when designing this study. 
The terminal T1/2 of linaprazan is approximately 12-21 hours and the Cmax of linaprazan is 
estimated to be reached after 2-3 hours, based on results from previous studies (refer to 
Section 6.1.1). In Part I, a prolongation of linaprazan T1/2 can be expected when co- 
administered with a CYP3A4/PgP inhibitor, therefore blood sampling for PK purpose up to 
72 hours is considered appropriate for the study objectives. In Part II, the 48-hour PK blood 
sampling interval, in order to capture the elimination phase, is considered appropriate for the 
study objectives. 
Based on in vitro data, the elimination of both linaprazan glurate and its active metabolite 
linaprazan is metabolized by CYP3A4. Furthermore, linaprazan glurate and linaprazan have 
both showed a potential of CYP3A induction in vitro and linaprazan glurate has shown a 
potential to inhibit CYP3A4 at the intestinal level. The design of the study is therefore based 
on the aim to study whether concomitant treatment with a strong inhibitor of CYP3A4/PgP 
leads to clinically relevant increase of systemic exposure to linaprazan glurate and linaprazan 
in a limited number of healthy volunteers. Clarithromycin is chosen as a strong inhibitor of 
CYP3A4/PgP as it is commonly used index inhibitor of CYP3A4 and used as standard of care 
in the treatment of H. pylori, an indication of clinical interest for combination therapy with 
linaprazan glurate. In Part I, when the effect of a strong CYP3A4/PgP inhibitor on the 
exposure of linaprazan glurate/linaprazan will be investigated, the formulation of linaprazan 
glurate will be in its base form. This formulation and dose levels has been used previously in 
Phase I and in an ongoing Phase II study and thus the exposure and safety are established. 
Part II of the study will further evaluate if single and/or repeated doses of linaprazan glurate 
have effect on the PK of a sensitive CYP3A substrate. This will be investigated at the first 
occasion when linaprazan glurate and midazolam is co-administrated. Furthermore, since 
linaprazan glurate is a potential inducer of CYP3A metabolism, i.e., the plasma exposure of 
midazolam may be reduced rather than increased after repeated dosing of linaprazan glurate. 
This will be investigated at the second occasion when linaprazan glurate and midazolam is co- 
administered. In Part II, when the effect of linaprazan glurate/linaprazan on the exposure of a 
CYP3A4 index drug is investigated, a new HCl salt IR tablet formulation will be used. The 
salt formulation is the intended Phase III formulation. 
The fixed-sequence design of the study was chosen to yield an efficient comparison of 
treatments. There are only few subjects required since each subject will serve as his or her 
own control. To avoid carryover effects, a washout period of 4 days has been incorporated 
between the first linaprazan dose and start of clarithromycin treatment in Part I. 


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8.3.1 
Selection of doses 
The dose level of linaprazan glurate to be used in this study is 100 mg single dose in Part I 
and 75 mg BID repeated dosing in Part II. 
In the FIH (SAD and MAD) study of linaprazan glurate, multiple daily doses close to 300 mg 
were administered to some study subjects at the 4 mg/kg body weight dose level without any 
safety concerns. Previous studies (refer to Section 6.1.1) including a Phase I PK/PD study 
(EudraCT no. 2019-003963-24) where repeated doses of 50 mg, 100 mg and 150 mg, 
linaprazan glurate were administered without any safety concerns. The selected doses of 
linaprazan glurate will lie in the projected upper therapeutic dose rage and, hence, is judged to 
be clinically relevant with regard to drug interactions. 
The dose of clarithromycin, 500 mg BID, is chosen since this is the normal dosage for 
eradication of H. pylori. The selected dosing regimen of midazolam, 2.5 mg QD, in Part II is 
within the standard recommended range in the label for the product. 


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9 
STUDY POPULATION 
Prospective approval of deviations from the eligibility criteria, also known as protocol 
waivers or exemptions, will not be allowed. 
 
9.1 
Recruitment 
The subjects will be recruited from CTC’s database of healthy volunteers, as well as from 
strategic marketing campaigns. Advertisements in social media and other media (newspapers, 
internet, radio, local distribution of flyers etc.) may be used to reach the target audience. The 
advertisement texts approved by the independent ethics committee (IEC) will be used to 
create all the digital, radio and print material for recruitment. 
 
9.2 
Screening and enrolment log 
The investigators will keep a record of all screened subjects even if they were not treated in 
the study. This information is necessary to verify that subjects were selected without bias. The 
reason for screen failure must be stated for all subjects screened but not included. In addition, 
the reason for withdrawal must be stated for all subjects that were included but not completed. 
A screening number generated automatically in the electronic case report form (eCRF) will be 
allocated to each subject in connection to the informed consent process at the screening visit 
(Visit 1). The screening number will allow identification of subjects irrespective of their 
possible eligibility for the study. 
If a subject cannot receive the planned dose of IMP within 28 days after screening (i.e., the 
time interval between signing informed consent until the first dose administration) the subject 
must be rescreened before being allowed to proceed in the study. For details on re-screening, 
see Section 9.7 
 
9.3 
Number of subjects 
In total, approximately 54 subjects will be screened in the study (27 subjects for each part). 
In Part I, a total of 18 healthy subjects are planned to be included for an estimated total of 
12 evaluable subjects. 
In Part II, a total of 18 healthy subjects are planned to be included for an estimated total of 
12 evaluable subjects. 
For the replacement of subjects who discontinue the study, see Section 9.8.3. 
 
9.4 
Inclusion criteria 
For inclusion in the study, subjects must fulfil the following criteria: 
1. Willing and able to give written informed consent for participation in the study. 
2. Healthy male and female subjects of non-childbearing potential aged 18 to 60 years, 
inclusive. 
3. Body mass index ≥ 18.0 and ≤ 30.0 kg/m2. 
4. Medically healthy subjects without abnormal clinically significant medical history, 
physical findings, vital signs, ECG, or laboratory values at the time of screening, as 
judged by the Investigator. 


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5. Females of non-childbearing potential are defined as pre-menopausal females who are 
sterilized (tubal ligation or permanent bilateral occlusion of fallopian tubes) or post- 
menopausal defined as at least 12 months of amenorrhea (in questionable cases a blood 
sample with simultaneous detection of Follicle Stimulating Hormone [FSH] ≥ 25 IU/L is 
confirmatory). 
Male subjects must be willing to use condom or be vasectomized or practice sexual 
abstinence to prevent pregnancy and drug exposure of a partner and refrain from donating 
sperm from the date of dosing until 3 months after (last) dosing with linaprazan glurate. 
Their female partner of child-bearing potential must use highly effective contraceptive 
methods with a failure rate of < 1% to prevent pregnancy (combined [estrogen and 
progestogen containing] hormonal contraception associated with inhibition of ovulation 
[oral, intravaginal, transdermal], progestogen-only hormonal contraception associated 
with inhibition of ovulation [oral, injectable, implantable], intrauterine device [IUD]or 
intrauterine hormone-releasing system [IUS]) from the first dose in the study until 
3 months after the last dose of linaprazan glurate. 
 
9.5 
Exclusion criteria 
Subjects must not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Have known allergies to any components of the linaprazan glurate formulation, or to 
clarithromycin or to any drugs of a similar class (e.g., macrolides, in Part I) or to 
midazolam or to any drugs of a similar class (e.g., benzodiazepines, in Part II), including 
excipients associated with any of the drugs. 
2. 
Use of CYP3A4 inhibitors, antacids, PPIs or any medication that changes gastric pH 
within 14 days prior to the first administration of linaprazan glurate in Part I and 
midazolam in Part II. 
3. 
Use of any prescribed or non-prescribed CYP3A4-inducing medication (e.g., efavirenz, 
nevirapine, rifampicin, rifabutin, modafinil, phenytoin, carbamazepine, glitazones, oral 
glucocorticoids) or other metabolic enzyme inducers, including herbal remedies such as 
St John’s wort, within 14 days prior to administration of first dose of linaprazan glurate 
in Part I and midazolam in Part II. 
4. 
Use of any other prescribed or non-prescribed medication within 14 days prior to the 
first administration of linaprazan glurate except occasional intake of paracetamol 
(maximum 2000 mg/day; and not exceeding 3000 mg/week) and nasal decongestants 
without cortisone, antihistamine, or anticholinergics for a maximum of 10 days, at the 
discretion of the Investigator. 
5. 
History of any clinically significant disease or disorder which, in the opinion of the 
Investigator, may either put the subject at risk because of participation in the study, or 
influence the results or the subject’s ability to participate in the study. 
6. 
History of liver disease or elevated transaminases. 
7. 
Subject has consumed grapefruit or grapefruit juice within 7 days of the first 
administration of linaprazan glurate. 
8. 
Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks 
of the administration of linaprazan glurate in Part I and midazolam in Part II. 
9. 
Malignancy within the past 5 years, with the exception of in situ removal of basal cell 
carcinoma. 


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10. Any planned major surgery within the duration of the study. 
11. Any positive result on screening for serum hepatitis B surface antigen (HBsAg), 
hepatitis C antibodies (HCVAb) and/or human immunodeficiency virus (HIV). 
12. After 10 minutes supine rest at the time of screening, any vital signs outside the 
following ranges: 
- Systolic blood pressure: <90 or >140 mmHg, or 
- Diastolic blood pressure <50 or >90 mmHg, or 
- Pulse <40 or >90 bpm 
13. Prolonged QTcF (> 450 ms), cardiac arrhythmias or any clinically significant 
abnormalities in the resting ECG at the time of screening, as judged by the Investigator. 
14. Planned treatment or treatment with another investigational drug within 3 months prior 
to Day -1 of each part. Subjects consented and screened but not dosed in previous Phase 
I studies will not be excluded. 
15. Subject has swallowing difficulties, which may affect the subject’s capability to swallow 
the IMP. 
16. Current smokers or users of nicotine products. Irregular use of nicotine (e.g., smoking, 
snuffing, chewing tobacco) less than 3 times/week before the screening visit will be 
allowed. 
17. Positive screen for drugs of abuse or alcohol at screening or on admission to the study 
clinic prior to administration of linaprazan glurate. 
18. History of or current alcohol abuse or excessive intake of alcohol, as judged by the 
Investigator. 
19. History of or current drug abuse, as judged by the Investigator. 
20. History of or current use of anabolic steroids, as judged by the Investigator. 
21. Excessive caffeine consumption defined by a daily intake of > 5 cups (1 cup = 
approximately 240 mL) of caffeine-containing beverages, as judged by the Investigator. 
22. Plasma donation within 1 month of screening or blood donation (or corresponding blood 
loss) during the last 3 months prior to screening. 
23. The Investigator considers the subject unlikely to comply with study procedures, 
restrictions and requirements. 
 
9.6 
Restrictions during the study 
The subjects must be willing to comply with the following restrictions during the full duration 
of the study, i.e., from screening to the end-of-study visit, unless otherwise stated. 
9.6.1 
General restrictions 
1. 
Contraception requirements: The male volunteers are expected to use condom in 
combination with use of contraceptive methods with a failure rate of <1% (see Inclusion 
Criterion No 5) to prevent pregnancy and drug exposure of a female partner and refrain 
from donating sperm from the date of first dose until 3 months after the last dose of the 
linaprazan glurate. 
2. 
Fasting: Subjects must fast overnight (at least 8 hours) prior to the anticipated dosing 
times with linaprazan glurate (Day 1 and Day 10) and with clarithromycin (Day 9) in 


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Part I and prior to dosing with midazolam or co-administration with midazolam and 
linaprazan glurate (Day1, Day 2 and Day 14) in Part II, and until 2 hours post-dose. 
During fasting, water, but no other drinks, is allowed as desired except for 1 hour before 
and 30 minutes after dosing. Linaprazan glurate will be taken in the morning together 
with a glass of water (approximately 240 mL) in Part I and in the morning and in the 
evening together with a glass of water (approximately 240 mL) in Part II. 
In Part I, clarithromycin will be taken in the morning and evening. When co- 
administered with linaprazan glurate and on the clarithromycin PK sampling day 
(Day 9), clarithromycin will be administered in the fasted state as defined for linaprazan 
glurate. Otherwise, clarithromycin may be administered with a meal. 
In Part II, midazolam will be taken in the morning. Subjects must fast overnight (at least 
8 hours) prior to the anticipated dosing with midazolam until 2 hours post-dose. During 
fasting, water, but no other drinks, is allowed as desired except for 1 hour before and 30 
minutes after dosing. 
3. 
Meals and dietary restrictions: Standardized meals will be served while the subjects are 
in the CRU. The meal selection is standardized in the sense that the nutritional content 
of the meals is similar at each time point of each treatment day at the study clinic. 
Breakfast is served approximately 2 hours post-dose and lunch is served approximately 
4 hours post-dose. A mid-day snack, dinner, and an optional evening snack is served 
approximately 6 -, 9 -, and 12- hours post-dose, respectively. 
4. 
Alcohol: The consumption of alcohol will not be allowed within 48 hours prior to the 
study visits. 
5. 
Xanthine/taurine containing beverages: The intake of energy drinks (e.g., Red Bull, 
Monster Energy) or other xanthine/taurine-containing beverages are not allowed within 
48 hours prior to administration of linaprazan glurate or clarithromycin and during 
treatment periods. 
6. 
Coffee: The consumption of up to 5 cups of coffee per day will be allowed during the 
study. 
7. 
Drugs of abuse: The use of drugs of abuse will not be allowed during the study. In 
addition to the urine drug screens described in the schedule of events in Table 8.1-1 and 
Table 8.2-1, additional random testing can be performed at any visit to the CRU. 
8. 
Nicotine: Smoking or the use of nicotine-containing products, including non-tobacco 
oral nicotine products, will not be allowed during the study. 
9. 
Grapefruit and grapefruit-containing products: The consumption of grapefruit and/or 
grapefruit-containing products such as jams, jellies, preserves and fruit juices will not be 
allowed within 7 days of the first administration of linaprazan glurate and during the 
study. This also includes Seville oranges, pomelo, exotic citrus fruits, and other 
grapefruit hybrids. 
10. Exercise: The subjects must refrain from strenuous exercise (defined as greater than 
70% of the maximal pulse rate for one hour or more) during the study. 
11. Blood donation: The subjects must not donate blood or plasma during the study period 
and until 3 months after the final medical examination at the end-of-study visit. 
12. Participation in other clinical studies: Study subjects will not be allowed to participate in 
any other interventional clinical study during the study period. 


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13. Leaving the CRU: Subjects will not be allowed to leave the CRU during study visits 
unless authorized by the study personnel. 
9.6.2 
Prior and concomitant therapy 
 
9.6.2.1 
Prohibited prior medications 
Use of CYP3A4 inhibitors, antacids, PPIs or any medication that changes gastric pH within 
14 days prior to the first administration of linaprazan glurate. 
Use of prescribed or non-prescribed CYP3A4-inducing medication (e.g., efavirenz, 
nevirapine, rifampicin, rifabutin, modafinil, phenytoin, carbamazepine, glitazones, oral 
glucocorticoids) or other metabolic enzyme inducers, including herbal remedies such as 
St John’s wort, within 14 days prior to administration of first dose of linaprazan glurate. 
Any use of other prescribed or non-prescribed medication within 14 days prior to the first 
administration of linaprazan glurate except occasional intake of paracetamol (maximum 
2000 mg/day; and not exceeding 3000 mg/week) and nasal decongestants without cortisone, 
antihistamine or anticholinergics for a maximum of 10 days, at the discretion of the 
Investigator. 
 
9.6.2.2 
Prohibited concomitant medication. 
Any use of prescribed or non-prescribed medication including CYP3A4 inhibitors and 
inducers, antacids, analgesics, herbal remedies, vitamin supplements and minerals from the 
first administration of linaprazan glurate until the last visit in the study except as detailed 
below. 
 
9.6.2.3 
Allowed medications 
• Paracetamol in doses up to 2000 mg/day for a maximum of 3 consecutive days. If this 
amount of paracetamol is insufficient for the treatment of the subject discontinuation 
from the study should be considered. 
• Nasal decongestants without cortisone, antihistamine or anticholinergics for a 
maximum of 10 consecutive days. 
• Hormone replacement therapy. 
Other medications considered necessary for the subject’s safety and wellbeing may be given 
at the discretion of the Investigator during the subject’s stay at the study clinic. Following 
consultation with the Sponsor, the Investigator will determine whether or not the subject will 
be discontinued from the study or allowed to remain. 
 
9.7 
Screen failures 
Screen failures are defined as subjects who consent to participate in the clinical study but do 
not fulfil all eligibility criteria and are not included in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure subjects. 
Minimal information includes documentation of signed and dated informed consent form 
(ICF) and reason(s) for screening failure. 
Re-screening can be performed once if any of the following were reasons for screening failure 
or non-randomization, as judged by the Investigator: 
• Practical reasons. 


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• Non-significant medical conditions (e.g., influenza, nasopharyngitis). 
• Reserve subjects 
• Plasma or blood donation outside the allowed time windows. 
For subjects who are re-screened, a new screening number will be assigned and new signed 
ICF must be collected. 
 
9.8 
Subject withdrawal 
9.8.1 
General withdrawal criteria 
The subjects are free to discontinue their participation in the study at any time and for 
whatever reason without affecting their right to an appropriate follow-up investigation or their 
future care. If possible, the reason for withdrawal of consent must be documented. 
The subjects may be discontinued from the study at any time at the discretion of the 
Investigator. 
Potential reasons for discontinuation can include: 
• Subject’s own decision. 
• Withdrawal of consent. 
• Severe non-compliance to study protocol procedures, as judged by the Investigator 
and/or Sponsor. 
• The subject is lost to follow-up. 
• Significant AEs posing a risk for the subject, as judged by the Investigator and/or 
Sponsor. 
• Withdrawal of informed consent to the use of biological samples as detailed in 
Section 12.5. 
• Death. 
• Meeting of an exclusion criterion during the study, which, in the opinion of the 
Investigator, may pose a risk for the subject. 
• The use of prohibited medication. 
9.8.2 
Procedures for discontinuation of a subject from the study 
A subject who prematurely discontinues participation in the study will always be asked about 
the reason(s) for discontinuation and the presence of any AEs. If a subject withdraws consent, 
the Investigator must ask the subject if they are willing to be assessed as soon as possible 
according to the procedures scheduled for the end-of-study visit. Any ongoing AEs will be 
followed-up as described in Section 11.4.1.15. 
The primary reason for discontinuation/early withdrawal must be specified in the eCRF and 
final drug accountability must be performed. If the reason for discontinuation was one or 
several AEs, the AEs must be specified in the end-of-study form of the eCRF. 
9.8.3 
Subject replacement 
Subjects who are prematurely withdrawn from the study for any reason except the occurrence 
of AEs assessed as possibly or probably related to study treatment may be replaced during the 
course of the study. 


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9.9 
Randomization 
This is a non-randomized study. 
 
9.10 
Blinding 
This is an open-label study, i.e., the Investigator, study staff and study subjects will know the 
type of treatment received. 


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10 
STUDY TREATMENTS 
 
10.1 
Identity of investigational medicinal products 
10.1.1 
Investigational medicinal product 
The IMP (linaprazan glurate) will be provided in tablets. 
• Part I: Linaprazan glurate in base form, 25 mg oral tablets 
• Part II: Linaprazan glurate HCl, 25 mg oral tablets 
Part I: the 25 mg oral tablets will be packed in blister strips containing 4 tablets with a carton 
as secondary packaging. 
Part II: the 25 mg oral tablets will be packed in screw-capped bottles containing 30 tablets per 
bottle. 
The composition of the tablets is provided in the investigational medicinal product dossier 
(IMPD) for each formulation. 
Part I: the 25 mg tablet is an IR oral tablet containing the base form of linaprazan glurate. It 
contains excipients commonly used in pharmaceutical preparations for oral administration. 
Part II: the 25 mg tablet is an IR oral tablet containing linaprazan glurate HCl. It also contains 
common excipients used in preparations for oral administration, however different ones from 
the base formulation. 
10.1.2 
Index inhibitor (perpetrator drug), Part I 
Clarithromycin 500 mg, oral tablets. 
10.1.3 
Substrate of CYP3A, Part II 
Midazolam APL, oral solution 1mg/mL. 
 
10.2 
Manufacturing, packaging, labelling and release 
All manufacturing, packaging, labelling and release of linaprazan glurate will comply with 
applicable good manufacturing practice (GMP) requirements [16, 17]. 
Part I: Linaprazan glurate 25 mg oral tablets are manufactured by Recipharm Pharmaceutical 
Development AB (Solna, Sweden) and packed, labelled, and QP-released by Clinigen Clinical 
Supplies Management SA (Mont Saint-Guibert, Belgium). 
Part II: Linaprazan glurate 25 mg oral tablets are manufactured, packaged and labelled by 
Xcelience, A Lonza company (Tampa FL, United States) and imported and QP-released by 
Nextpharma Ploërmel (Ploërmel, France). 
For both study parts, linaprazan glurate oral tablets will be shipped to the pharmacy in 
Uppsala, Sweden (refer to Section 5), who will provide linaprazan glurate to the study clinic 
(CTC, Uppsala, Sweden). 
Clarithromycin and midazolam APL will be purchased from the local pharmacy. 
 
10.3 
Conditions for storage 
Linaprazan glurate tablets, clarithromycin and midazolam will be stored in room temperature 
(15 to 25°C) in an access-controlled area at CTC. 


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Temperature logs will be kept for the area where the drugs are stored. The temperature will be 
noted on a daily basis. 
 
10.4 
Preparation and accountability 
Part I: 
Linaprazan glurate will always be administered by site personnel. Two nurses/site staff will 
be present, one who provides the linaprazan glurate (and clarithromycin when taken at the 
clinic) to the subject and one who checks the procedure. 
Clarithromycin will be handed out to the subjects on Day 4 (Visit 5) for home-based self- 
administration by the subjects. For details on clarithromycin administration and on 
clarithromycin and linaprazan glurate co-administration, refer to Section 10.5. 
Part II: 
Linaprazan glurate will be handed out to the subjects on Day 4 (Visit 2) for home-based self- 
administration by the subjects. 
Midazolam will always be administered by site personnel. Two nurses/site staff will be 
present, one who provides the midazolam (and linaprazan glurate when taken at the clinic) to 
the subject and one who checks the procedure. 
CTC and the Investigator will maintain a storage and accountability log as well as a drug 
dispensing log detailing the dates and quantities of study medication received, prepared for 
and used by each subject, as well as study medication returned or destroyed at the end of the 
study. Any discrepancies between prepared and returned IMP must be explained and 
documented. Products deliberately and/or accidentally destroyed by the study site or the 
subject must be accounted for. 
 
10.5 
Treatment administration 
10.5.1 
Treatment with linaprazan glurate and clarithromycin, Part I 
Following an overnight fast for at least 8 hours, the subjects will be administered 100 mg 
linaprazan glurate (4 tablets containing 25 mg linaprazan glurate) together with a glass of 
water (approximately 240 mL). The tablets should be swallowed whole. Water, but no other 
drinks, is allowed as desired except for 1 hour before and 30 minutes after linaprazan glurate 
administration. No food is allowed for at least 2 hours post-administration. Water, but no 
other drinks, is allowed as desired except for one hour before and 30 minutes after linaprazan 
glurate administration. 
There are no fasting restrictions in relation to clarithromycin administration, which may be 
taken in association with or without a meal (except on the clarithromycin PK sampling day 
(Day 9) and when co-administered with linaprazan glurate on Day 10), see Table 10.5-1. On 
each dosing occasion, 500 mg clarithromycin will be administered. After swallowing the 
clarithromycin tablet, subjects should drink a glass of water (approximately 240 mL). 
Details on linaprazan glurate and clarithromycin administration per day are provided in Table 
10.5-1. 


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Table 10.5-1 Administration of linaprazan glurate and clarithromycin, Part I 
 
Study 
day 
Treatment 
At clinic 
or at 
home 
Fasting 
requirement 
Other instructions 
Day 1 
Linaprazan glurate 100 mg 
(in the morning) 
Clinic 
Yes 
Linaprazan glurate (4x25 mg tablets) 
should be taken with a glass of water 
(approximately 240 mL). 
Day 2 
- 
- 
- 
- 
Day 3 
- 
- 
- 
- 
Day 4 
Clarithromycin 500 mg 
BID (approximately 
12 hours apart) 
Clinic 
(morning 
dose) 
No 
After swallowing each tablet, subjects 
should drink a glass of water 
(approximately 240 mL). 
Home 
(evening 
dose) 
Day 5 
Clarithromycin 500 mg 
BID (approximately 
12 hours apart) 
Home 
No 
After swallowing each tablet, subjects 
should drink a glass of water 
(approximately 240 mL). 
Day 6 
Clarithromycin 500 mg 
BID (approximately 12 
hours apart) 
Home 
No 
After swallowing each tablet, subjects 
should drink a glass of water 
(approximately 240 mL). 
Day 7 
Clarithromycin 500 mg 
BID (approximately 12 
hours apart) 
Home 
No 
After swallowing each tablet, subjects 
should drink a glass of water 
(approximately 240 mL). 
Dag 8 
Clarithromycin 500 mg 
BID (approximately 12 
hours apart) 
Home 
No 
After swallowing each tablet, subjects 
should drink a glass of water 
(approximately 240 mL). 
Dag 9 
Clarithromycin 500 mg 
BID (approximately 12 
hours apart) 
Clinic 
Yes – morning 
dose only 
After swallowing each tablet, subjects 
should drink a glass of water 
(approximately 240 mL). 
Day 10 
Clarithromycin 500 mg 
BID (approximately 12 
hours apart). 
Linaprazan glurate 100 mg 
(in the morning) 
Clinic 
Yes (morning 
dose only) 
After swallowing the tablet/tablets, 
subjects should drink a glass of water 
(approximately 240 mL). 
Day 11 
Clarithromycin 500 mg 
BID (approximately 12 
hours apart) 
Clinic 
(morning 
dose) 
No 
After swallowing each tablet, subjects 
should drink a glass of water 
(approximately 240 mL). 
Home 
(evening 
dose) 


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Day 12 
Clarithromycin 500 mg 
BID (approximately 12 
hours apart) 
Home 
No 
After swallowing each tablet, subjects 
should drink a glass of water 
(approximately 240 mL). 
10.5.2 
Treatment with linaprazan glurate and midazolam, Part II 
During co-administration with midazolam, the morning dose of linaprazan glurate will be 
administered after an overnight fast for at least 8 hours. The subjects will be administered 
75 mg linaprazan glurate (3 tablets containing 25 mg linaprazan glurate) together with a glass 
of water (approximately 240 mL). The tablets should be swallowed whole. No food is allowed 
for at least 2 hours post-administration. Water, but no other drinks, is allowed as desired 
except for one hour before and 30 minutes after linaprazan glurate administration. Water, but 
no other drinks, is allowed as desired except for 1 hour before and 30 minutes after linaprazan 
glurate administration. In the evening, subjects will be administered linaprazan with 240 mL 
of water. There are no fasting requirements during home administration with linaprazan 
glurate. 
Midazolam will be administered in the fasted state. Following an overnight fast for at least 
8 hours, the subjects will be administered 2.5 mg midazolam (2.5 mL oral solution, 
1 mg/mL). After swallowing the midazolam solution, subjects should drink a glass of water 
(approximately 240 mL). 
Midazolam will be administered once daily (Day 1, Day 2 and Day 14). 
Details on midazolam administration in relation to linaprazan glurate administration are 
provided in 
Table 10.5-2. 
Table 10.5-2 Administration of linaprazan glurate and midazolam, Part II 
 
Study 
day 
Treatment 
At clinic 
or at 
home 
Fasting 
requirement 
Other instructions 
Day 1 
Midazolam 2.5 mg. 
Clinic 
Yes 
After swallowing the dose (2.5 mL), 
subjects should drink a glass of water 
(approximately 240 mL). 
Day 2 
Midazolam 2.5 mg 
Linaprazan glurate 75 mg 
BID 
Clinic 
Yes 
Midazolam (2.5 mL) will be 
swallowed and after swallowing, 
linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 3 
Linaprazan glurate 75 mg 
BID 
Clinic 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 4 
Linaprazan glurate 75 mg 
BID 
Clinic 
(morning 
dose). 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Home 
(evening 
dose) 


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Day 5 
Linaprazan glurate 75 mg 
BID 
Home 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 6 
Linaprazan glurate 75 mg 
BID 
Home 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 7 
Linaprazan glurate 75 mg 
BID 
Home 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 8 
Linaprazan glurate 75 mg 
BID 
Home 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 9 
Linaprazan glurate 75 mg 
BID 
Home 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 10 
Linaprazan glurate 75 mg 
BID 
Home 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 11 
Linaprazan glurate 75 mg 
BID 
Home 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 12 
Linaprazan glurate 75 mg 
BID 
Home 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Day 13 
Linaprazan glurate 75 mg 
BID 
Home 
(morning 
dose). 
No 
Linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
Clinic 
(evening 
dose). 
Day 14 
Midazolam 2.5 mg 
Linaprazan glurate 75 mg 
BID 
Clinic 
Yes: 
Midazolam (2.5 mL) will be 
swallowed and after swallowing 
linaprazan glurate (3x25 mg tablets, 
BID) should be taken with a glass of 
water (approximately 240 mL). 
 
10.6 
Continuation of treatment with investigational medicinal product 
This is a Phase I study in healthy volunteers who will receive no medical benefit from the 
treatment and thus there will be no treatment with linaprazan glurate, clarithromycin or 
midazolam after the end of study participation. 
 
10.7 
Treatment compliance 
During visits at the clinic, the study drugs will be administered at the clinic under medical 
supervision. Doses administered at the clinic will be entered in the eCRF by study personnel. 
On other days, subjects will self-administer clarithromycin (Part I) or linaprazan glurate 
(Part II) at home and register each intake of study drug in an electronic diary. Text reminders 
will be sent to the subjects each day. At the compliance visit to the clinic, subjects will be 
asked to return any unused study drugs and all empty containers. 
In Part I, the number of remaining tablets as well as the date of compliance visit to the clinic 
as specified in Table 8.1-1. The weight at the compliance visit will be entered in the eCRF. 


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In Part II, the number of remaining tablets as well as the date of the compliance check as 
specified in Table 8.2-1 will be entered into the eCRF. 
 
10.8 
Return and destruction of investigational medical product 
Any unused study medication will be returned to the Sponsor or the study pharmacy for 
destruction. Empty containers will be destroyed at the study site. The Monitor will perform 
final linaprazan glurate, clarithromycin and midazolam accountability reconciliation at the 
study end to verify that all unused study medication is adequately destroyed/returned and 
documented. 


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11 
STUDY ASSESSMENTS 
Study assessments are described in the sections below. The timing of assessments is detailed 
in the schedule of events, refer to Section 8.1 (Part I) and Section 8.2 (Part II). 
 
11.1 
Recording of data 
The Principal Investigator will provide the Sponsor with all data produced during the study 
from the scheduled study assessments. The Principal Investigator will ensure the accuracy, 
completeness, legibility, and timeliness of the data reported to Sponsor in the eCRF and in all 
required reports. 
Time points for PK blood sampling, safety laboratory samples, 12-lead safety ECG and vital 
signs are outlined in Table 8.1-1 to Table 8.1-4 for Part I and in Table 8.2-1 to Table 8.2-4 for 
Part II. Allowed time windows for PK sampling are outlined in Section 11.3.1. 
 
11.2 
Demographics and other baseline characteristics 
11.2.1 
Informed consent 
Signed informed consent must be obtained before any screening procedures are initiated. The 
informed consent procedure is further described in Section 14.3. 
11.2.2 
Eligibility criteria 
Eligibility criteria must be checked during screening and verified before administration of the 
first dose of linaprazan glurate on Day 1 in Part I and before administration of the first dose of 
midazolam on Day 1 in Part II. The criteria are specified in Sections 9.4 and 9.5. 
11.2.3 
Demographic information 
The following demographic data will be recorded: gender, age, ethnicity and race. 
11.2.4 
Height, weight and body mass index 
Weight and height will be measured without shoes. Body mass index (BMI) will be 
calculated, with one decimal, from the recorded height and weight. 
11.2.5 
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 should include all relevant diseases and operations within 
2 months prior to screening as judged by the Investigator. 
11.2.6 
Prior and concomitant medication 
Prior medications taken within 14 days prior to first linaprazan glurate administration (Part I) 
or midazolam (Part II) will be obtained by subject interview in order to verify that the 
eligibility criteria are met (see also Section 9.6.2). 
Medications are classified as prior if the stop date was before or on the day of the first dose 
administration (pre-dose of linaprazan glurate in Part I and midazolam in Part II) 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. To distinguish between prior and 


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concomitant medications on Day 1 (i.e., the first dosing day), the start time of any newly 
introduced medication or the stop time of any previously ongoing medication must be 
recorded in the eCRF. 
Any use of concomitant medication from screening until the last end-of-study visit must be 
documented appropriately in the subject’s eCRF. Relevant information (i.e., name of 
medication, dose, unit, frequency, start and stop dates, reason for use) must be recorded. All 
changes in medication must be noted in the eCRF. 
11.2.7 
HIV and hepatitis B/C 
Subjects will be tested for HIV and hepatitis B virus surface antigen as well as hepatitis C 
antibodies prior to inclusion into the study. Any positive results will exclude the subject from 
participating in the study. 
11.2.8 
Urine drug screen 
Urine will be screened for drugs of abuse using the Drug-Screen Multi-15 Dip Test (Nal von 
Minden [GmBH] or equivalent). Additional random tests can be performed during the study 
period. The test screens for 4 methylpentedrone, 7 aminoclonazepam, amphetamine, 
benzodiazepines, buprenorphine, fentanyl, tetrahydro-cannabinoids (THC), cocaine, 
methadone, methamphetamine, methylenedioxy-methamphetamine (MDMA, ecstasy), 
morphine, oxycodone, pregabalin and tramadol, along with pH and creatinine. 
11.2.9 
Alcohol test 
An alcohol test will be performed at pre-specified visits. Additional random tests can be 
performed during the study period. 
11.2.10 Baseline symptoms 
A baseline symptom is defined as an event that occurs between the subject’s signing of the 
ICF until the first administration of linaprazan glurate (Part I) or midazolam (Part II) (i.e., an 
event that occurs during the screening period). Such events are not AEs and will be recorded 
as baseline symptoms in the Medical History Log in the eCRF. 
 
11.3 
Assessments related to pharmacokinetic endpoints 
11.3.1 
Pharmacokinetic sampling and analysis 
Venous blood samples for the determination of plasma concentrations and PK 
characterization of linaprazan glurate and linaprazan, clarithromycin (Part I) and midazolam 
(Part II) after administration will be collected through an indwelling venous catheter or by 
venipuncture at the pre-specified visits (Table 8.1-1 to Table 8.1-4 for Part I and Table 8.2-1 
to Table 8.2-4 for Part II). In Part II, some of the PK blood samples for linaprazan glurate and 
midazolam will be taken at the same time points, hence only 1 blood sample will be taken and 
the plasma will be aliquoted as described below (refer to Table 8.2-3 and Table 8.2-4). Actual 
time for blood PK sampling must not deviate more than ±10% from the planned time, except 
as detailed below. The date and time of collection of each sample will be recorded in the 
eCRF. 
In Part I, pre-dose PK sampling before the first dose and at Visit 6 may be performed within 
60 minutes prior to dosing. In Part II, pre-dose PK sampling will be done as close to dose with 
midazolam and linaprazan glurate as possible at the occasions when co-administered. 


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The blood samples will be collected in pre-labelled tubes. All the collected blood samples will 
be centrifuged to separate plasma, which will be divided into aliquots after centrifugation for 
PK analysis. The separated plasma from each blood sample will be divided into 3 aliquots in 
pre-labelled cryotubes (1 A sample, 1 B sample and 1 C [backup] sample approximately 
500 µL in each tube) and frozen at -70°C. Further details will be described in a separate 
laboratory manual. 
Remaining plasma will be added to a pre-labelled cryotube and frozen at -70 °C for future 
exploratory analyses of potential linaprazan glurate metabolites (see Section 11.5.1) 
Plasma samples for determination of plasma concentrations of linaprazan glurate, linaprazan 
and for midazolam (Part II) 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 details of the analytical method used will be described in a separate bioanalytical 
report. 
 
11.4 
Safety assessments 
11.4.1 
Adverse events 
The Principal Investigator is responsible for ensuring that all medical staff involved in the 
study is familiar with the content of this section and the content of the CTC standard 
operating procedures (SOPs) regarding emergencies and Phase I studies. 
 
11.4.1.1 
Definition of adverse event 
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. 
 
11.4.1.2 
Definition of serious adverse event 
An SAE is any AE which: 
• results in death, 
• is life-threatening (this refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might had led to 
death if the event was more severe), 
• requires in-patient hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is an important medical event (this refers to an event that may not be immediately life- 
threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent any of the other outcomes defined above). 
Examples of such events are intensive treatment in an emergency room for allergic 
bronchospasm or blood dyscrasias, convulsions that do not result in hospitalization, 
development of drug dependency, and drug abuse. 
Planned hospitalizations or surgical interventions for a condition that existed before the 
subject signed the ICF, and that did not change in intensity, are not SAEs. 


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If there is any doubt as to whether an AE meets the definition of an SAE, a conservative 
viewpoint will be taken, and the AE will be reported as an SAE. 
 
11.4.1.3 
Definition of adverse reaction (AR) 
The term AR will be used for all untoward and unintended responses to the IMP assessed as 
related to any administered dose. 
 
11.4.1.4 
Definition of serious adverse reaction (SAR) 
The term serious adverse reaction (SAR) will be used whenever either the Investigator or 
Sponsor or designee assesses an SAE as related to the IMP. 
 
11.4.1.5 
Definition of suspected unexpected serious adverse reaction (SUSAR) 
An SAE will be classified as a SUSAR when either the Investigator or Sponsor or designee 
assesses that there is a reasonable possibility of a causal relationship between the SAE and the 
IMP, and the Sponsor or designee assesses the event as unexpected based on the applicable 
reference safety information (i.e., the IB for linaprazan glurate or the SmPC for 
clarithromycin and midazolam). 
 
11.4.1.6 
Time period and frequency for collecting adverse events 
All AEs (including SAEs) will be collected from the start of IMP administration until the end- 
of-study visit of each part. 
Any AE with start date on the day IMP administration must be recorded with start time. 
At the end-of-study visit, information on new AEs or SAEs, if any, and stop dates for ongoing 
during events must be recorded as applicable. 
Investigators will not be obliged to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and they consider the event to be 
reasonably related to the study intervention or study participation, the Investigator must 
promptly notify the Sponsor. 
 
11.4.1.7 
Assessment of intensity 
The grading of the intensity of AEs will follow the Common terminology criteria for adverse 
events (CTCAE) v5.0 [18]. Grade refers to the severity of the AE. The CTCAE displays 
Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this 
general guideline. 
The Investigator must assess the intensity of an AE using the following definitions, and record 
it in the AE Log of the eCRF: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age- 
appropriate instrumental activities of daily living (ADL)*. 


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Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self- care ADL**. 
Grade 4 
Life-threatening consequences: urgent intervention indicated. 
Grade 5 
Death related to AE. 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, et c. 
**Self- care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 
11.4.1.8 
Assessment of causal relationship 
The Investigator must assess the causal relationship between an AE and linaprazan glurate 
and clarithromycin or midazolam, respectively, and record it the AE log of the eCRF using 
the definitions below: 
Probable 
The event has a strong temporal relationship to the IMP or recurs on re- 
challenge, and another etiology is unlikely or significantly less likely. 
Possible 
The event has a suggestive temporal relationship to the IMP, and an 
alternative etiology is equally or less likely. 
Unlikely 
The event has no temporal relationship to the IMP or is due to underlying 
or concurrent illness or effect of another drug (i.e., there is no causal 
relationship between the IMP and the event). 
 
An AE is considered causally related to the use of the IMP when the causality assessment is 
probable or possible. 
 
11.4.1.9 
Assessment of outcome 
The Investigator must assess the outcome of an AE and record it on the AE log of the eCRF 
using the definitions below: 
Recovered/resolved 
The subject has recovered completely, and no symptoms remain. 
Recovering/resolving 
The subject’s condition is improving, but symptoms still remain. 
Recovered/resolved with 
sequelae 
 
Not recovered/not 
resolved 
Fatal 
Unknown 
The subject has recovered, but some symptoms remain (e.g., the 
subject had a stroke and is functioning normally, but has some 
motor impairment). 
The subject’s condition has not improved, and the symptoms are 
unchanged (e.g., an atrial fibrillation has become chronic). 


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11.4.1.10 Reporting of action taken with study treatment 
The Investigator must report the action taken with study treatment (linaprazan glurate, 
clarithromycin or midazolam) and record it on the AE Log of the eCRF using the 
definitions below: 
Dose increased 
Dose not changed 
Dose reduced 
Drug interrupted 
Drug withdrawn 
Not applicable 
Unknown 
11.4.1.11 Collecting adverse events 
AEs identified using any of the following methods will be recorded: 
• AEs spontaneously reported by the subject. 
• AEs observed by the Investigator or medical personnel. 
• AEs elicited based on non-leading questions from the Investigator or medical 
personnel. 
 
11.4.1.12 Recording adverse events 
AEs must be recorded in the AE log of the eCRF. The Investigator must provide information 
on the AE, preferably with a diagnosis or at least with signs and symptoms; start and stop 
dates, start and stop time; intensity; causal relationship to IMP; action taken, and outcome. 
If the AE is serious, this must be indicated in the eCRF. 
AEs, including out-of-range clinically significant clinical safety laboratory values, must be 
recorded individually, except when considered manifestations of the same medical condition 
or disease state; in such cases, they must be recorded under a single diagnosis. 
 
11.4.1.13 Reporting of serious adverse events 
SAE reporting must be performed by the Investigator within 24 hours of awareness via the 
eCRF. All available information regarding the SAE must be entered in the AE log for the 
specific subject, i.e., term, intensity, causality, outcome, SAE criteria, action taken, narrative 
including rationale for causality assessment. By saving the event as “serious” in the eCRF, 
and once the Investigator has signed-off of the event, an e-mail alert is automatically sent to 
predefined recipients to highlight that an SAE has been registered. The same information is 
automatically sent to CTC’s SAE inbox at sae@ctc-ab.se. 
The SAE report will be reviewed by a designated person at CTC’s pharmacovigilance 
department to ensure that the report is valid and correct. For SAEs where important or 
relevant information is missing, follow-up is undertaken and queries to the site are raised 
promptly to keep the regulatory timelines. Investigators or other site personnel must inform 
CTC’s pharmacovigilance department of any follow-up information on a previously reported 
SAE no later than the end of the next business day of when they become aware of it. This 


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includes rationale for changes, e.g., changes in causality, assessment and intensity, that should 
be described in the SAE narrative. 
If the SAE report in the eCRF is updated, a new e-mail alert will be sent to the predefined 
recipients. 
If any additional documentation is required (e.g., autopsy report), CTC’s pharmacovigilance 
department will request this information from the study site. 
In case the eCRF cannot be accessed, the SAE must be reported by manually completing the 
paper SAE form provided in the investigator site file (ISF). The completed, signed and dated 
paper SAE form must, within 24 hours, be scanned and delivered via encrypted e-mail or 
secure file transfer to CTC’s SAE inbox at sae@ctc-ab.se. 
The study site must notify the site Monitor via phone or e-mail about the submission of the 
SAE report. As soon as the site personnel have access to the eCRF, the SAE must be 
reported electronically as well. 
The Sponsor or delegate will assume responsibility for reporting SAEs to the competent 
authority (CA) and IEC in accordance with local regulations. 
 
11.4.1.14 Reporting of suspected unexpected serious adverse reactions to EudraVigilance, 
local competent authority and independent ethics committee 
The term SAR is used whenever either the Investigator or Medical Monitor deems an SAE as 
possibly or probably related to any of the IMPs. If an SAR is assessed as unexpected by the 
Medical Monitor, it is a SUSAR and will be reported to the CA and to the IEC in accordance 
with local regulations and the SOPs applicable for the Pharmacovigilance department within 
the following timelines: 
• 7 calendar days if fatal or life-threatening. 
• 15 calendar days if non-fatal and non-life-threatening. 
The clock for expedited initial reporting (Day 0) starts as soon as the Sponsor has received the 
information containing the minimum reporting criteria. The date must be documented on an 
acknowledgement receipt. Detailed information on SUSAR processing and reporting will be 
specified in the safety management plan (SMP). 
The Medical Monitor is responsible for medical review of the SAE narrative in the Council 
for International Organizations of Medical Sciences (CIOMS) form (or equivalent) prior to 
expedited reporting. 
The Sponsor or delegate is responsible for informing the Investigators concerned of relevant 
information about SUSARs that could adversely affect the safety of subjects. 
The Sponsor or delegate is responsible for once a year throughout the clinical study (or on 
request), submit a safety report to the CA and the IEC taking into account all new available 
safety information received during the reporting period. 


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11.4.1.15 Treatment and follow-up of adverse events 
The subjects with AEs that occur during the study must be treated according to daily clinical 
practice at the discretion of the Investigator. 
AEs must be followed up until resolution or to the end-of-study visit, whichever comes first. 
At the end-of-study visit, information on new AEs, if any, and stop dates for previously 
reported AEs must be recorded (if known). AEs assessed as stable by the Investigator at the 
end-of-study visit will not have to be followed up until resolution. 
It is the responsibility of the Investigator to follow up on all SAEs until the subject has 
recovered, stabilized, or recovered with sequelae, and to report to the Sponsor all relevant new 
information using the same procedures and timelines as those for the initial report. Relevant 
information includes discharge summaries, autopsy reports, and medical consultation. 
 
11.4.1.16 Procedures in case of pregnancy 
In case of pregnancy or suspicion of possible pregnancy (female partner to male participant), 
the study treatment must be stopped immediately, and the subject discontinued from 
participation in the study. Pregnancy itself will not be regarded as an AE unless there is a 
suspicion that the IMP may have interfered with the effectiveness of the contraceptive 
medication. However, the outcome of all pregnancies (spontaneous miscarriage, elective 
termination, normal birth or congenital abnormality) must be followed up and documented 
even after the subject was discontinued from the study. 
All events of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages must 
also be reported and handled as AEs. All outcomes of pregnancy must be reported to the 
Sponsor and the Principal Investigator on the pregnancy outcomes report form. 
 
11.4.1.17 Treatment of overdose 
An overdose is a dose in excess of the dose specified for each dose group/cohort in this 
clinical study protocol (CSP). 
During in-clinic study visits, all linaprazan glurate, clarithromycin (Part I) and midazolam 
(Part II) will be administered by site personnel under medical surveillance. In cases of 
accidental overdose, subjects will be monitored appropriately, and standard supportive 
measures and symptomatic treatments will be adopted as required. 
An overdose should be documented as follows: 
• An overdose with associated AE is recorded as the AE diagnosis/symptoms in the AE 
Log of the eCRF. 
• An overdose without associated symptoms is only reported in the subject’s medical 
records. 
No known antidote to linaprazan glurate is available. Any ARs should be treated 
symptomatically. 
Management of IMP overdose: 
• Symptomatic therapy should be started for relief of symptoms. 
• If justified, gastric emptying with charcoal. 
• Controlled breathing if necessary. 
• Volume substitution and possibly the addition of inotropic agents (e.g., dopamine) in 
case of fall in blood pressure. 


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Symptoms of clarithromycin overdose and midazolam overdose are generally similar to the 
common adverse effects given in Section 6.3.1 or to the less frequent adverse effects given in 
the SmPC for clarithromycin and midazolam. Any ARs should be treated symptomatically. 
No known antidote to clarithromycin is available. Flumazenil can be used as an antidote to 
midazolam. Clarithromycin cannot be removed by hemodialysis. Midazolam will only be 
administered by site personnel under medical surveillance; hence overdosing is unlikely to 
occur. 
11.4.2 
Physical examinations 
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 clinically significant (CS) or not 
clinically significant (NCS) in the eCRF. Abnormal post-dose administration findings 
assessed by the Investigator as clinically significant will be reported as AEs. 
11.4.3 
Vital signs 
Systolic and diastolic blood pressure and pulse will be measured in supine position after 
10 minutes of rest. Blood oxygen saturation will be measured by pulse oximetry. Body 
temperature will be measured orally using a digital thermometer. 
Any vital signs outside of normal ranges will be specified and documented as CS or NCS in 
the eCRF. Abnormal post-dose administration findings assessed by the Investigator as CS will 
be reported as AEs. 
11.4.4 
Safety 12-lead electrocardiograms 
Single 12-lead ECGs will be recorded in supine position after 10 minutes of rest using an 
ECG machine. The resting heart rate (HR) and PQ/PR, QRS, QT and QTcF intervals will be 
recorded. Safety ECGs will be reviewed and interpreted on-site by the Investigator. 
Any abnormalities will be specified and documented as CS or not NCS in the eCRF. 
Abnormal post-dose administration findings assessed by the Investigator as CS will be 
reported as AEs. 
11.4.5 
Safety laboratory assessments 
Blood samples for the analysis of clinical chemistry and hematology will be collected through 
venipuncture or an indwelling venous catheter and sent to the certified clinical chemistry 
laboratory at Uppsala University Hospital (refer to Section 5) and analyzed by routine 
analytical methods. 
Urine analysis will be performed at the study clinic using dip sticks. The assessments will be 
performed at visits specified in Table 8.1-1 (Part I) and Table 8.2-1 (Part II). 
Safety laboratory parameters are defined in Table 11.4-1 and will be assessed at visits and 
time-points specified in Table 8.1-1 and Table 8.1-2 for Part I and in Table 8.2-1 to Table 
8.2-4 for Part II. 
Safety laboratory values will be specified and documented as normal, abnormal NCS, or 
abnormal CS in the eCRF. Abnormal values assessed by the Investigator as CS will be 
reported as AEs. If an abnormal value is associated with corresponding clinical signs or 
symptoms, the sign/symptom must be reported as the AE. 


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Table 11.4-1 Safety laboratory parameters 
 
Category 
Parameter 
Clinical chemistry 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
Alanine aminotransferase (ALT) 
Albumin 
Alkaline phosphatase (ALP) 
Aspartate aminotransferase (AST) 
Bilirubin (total) 
Calcium 
Creatinine (estimated glomerular filtration rate [eGFR] included) 
Creatine kinase (CK) 
Glucose 
Potassium 
Sodium 
Leukocyte count with differential count 
Hemoglobin (Hb) 
Thrombocyte count 
Urinalysis (dip stick) 
Glucose 
Urobilinogen 
Protein 
FSH-test 
FSH (at screening, postmenopausal females, in questionable cases only) 
 
 
11.5 
Assessments related to exploratory endpoints (Part I and Part II) 
11.5.1 
Collection of plasma (Part I and Part II) and urine (Part II) for future exploratory 
analyses of linaprazan glurate metabolites 
One (1) aliquot of separated plasma will be taken from PK blood samples at all days in Part I 
and in Part II (refer to Section 11.3.1) collected at the time-points specified in Table 8.1-1 and 
Table 8.2-1 and stored frozen pending exploratory analyses of potential linaprazan glurate 
metabolites. 
In Part II, pre-dose urine sample (5 mL) will be collected from the first morning void. 
Thereafter, urine will be collected on Day 2 and Day 14. Urine will be collected and pooled 
for each subject at 0-6 hours and 6-12 hours and aliquoted in pre-labelled polypropylene 
cryotubes and frozen at -70°C within 1 hour after collection. The date and time of collection 
of each sample will be recorded in the eCRF. 
The sampling procedures will be described in further detail in a separate sampling instruction. 
Samples will be analyzed by a validated bioanalytical method at a certified laboratory. 
Metabolite data will not be reported in the CSR. 
 
11.6 
Appropriateness of measurements 
All methods used for safety assessments are commonly used in standard medical care and in 
Phase I clinical studies. Non-compartmental analysis (NCA) of PK parameters is standard for 
Phase I clinical studies. 


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12 
PROCEDURES FOR BIOLOGICAL SAMPLES 
 
12.1 
Sample collection 
The sample collection procedure for PK and urine analysis is described in Section 11.3.1. 
Safety laboratory samples will be collected according to standard procedures. 
12.2 
Volume of blood 
The anticipated volume of blood samples collected during the study from each subject will be 
approximately 325 mL in Part I (Table 12.2-1) and 368 mL in Part II (Table 12.2-2). For 
reference, a regular blood donation consists of between 350 mL to 450 mL (±10 %) for 
persons weighing at least 45-50 kg [17]. 
An additional 4 mL blood will be drawn from post-menopausal women (questionable cases). 
Table 12.2-1 Estimated blood volumes, Part I 
 
Assessment 
Estimated number of 
sampling occasions 
Estimated volume 
per occasion (mL) 
Total (mL) 
PK blood sampling 
54 
5 
270 
HIV, Hepatitis B/C 
1 
4 
4 
Clinical chemistry, hematology, microbiology 
3 
14 
42 
Glucose 
3 
3 
9 
Total: 
325 
Table 12.2-2 Estimated blood volumes, Part II 
 
Assessment 
Estimated number of 
sampling occasions 
Estimated volume 
per occasion (mL) 
Total (mL) 
PK blood sampling 
57 
5 
285 
HIV, Hepatitis B/C 
1 
4 
4 
Clinical chemistry, hematology, microbiology 
5 
14 
70 
Glucose 
3 
3 
9 
Total: 
368 mL 
 
12.3 
Handling, storage and destruction of laboratory samples 
All biological samples will be registered in a biobank at CTC (Swedish Health and Social 
Care Inspectorate biobank registry number 893). 
Any remains from the safety laboratory samples will be disposed of after analyses. 
The samples for analyses of PK parameters will be stored at ≤ 70 °C until analyzed. The 
samples will be disposed of after the CSR has been finalized. 
All plasma and urine samples transferred to the Sponsor’s biobank will, if not used, be 
disposed of after 10 years. 


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12.4 
Chain of custody of biological samples 
A full chain of custody will be maintained for all samples throughout their lifecycle. 
CTC will keep full traceability of collected biological samples from the study subjects while 
in storage at the study clinic and until shipment. CTC will keep documentation of receipt of 
arrival. The sample receiver (the analytical laboratory) will keep full traceability of the 
samples while in their custody until the samples are used up or disposed of. 
The Sponsor will keep oversight of the entire life cycle of the samples through internal 
procedures, monitoring of study sites and auditing of external laboratory providers. 
 
12.5 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of the donated biological samples, the samples will 
be disposed of/destroyed, if not already analyzed and documented. 
The Principal Investigator will ensure that: 
• The subject’s withdrawal of consent is notified immediately to the Sponsor. 
• Biological samples from the subject, if stored at the study clinic, are immediately 
identified, disposed of/destroyed and the action is documented. 
The Sponsor must ensure that the laboratory/laboratories holding the samples is/are informed 
about the withdrawn consent immediately and that samples are disposed of/destroyed or 
returned to the study clinic and the action is documented. 


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13 
QUALITY MANAGEMENT, QUALITY ASSURANCE AND QUALITY 
CONTROL 
 
13.1 
Quality management: critical process, system and data identification 
During CSP development, the Sponsor will identify those processes, systems (facilities, 
computerized systems) and data that are critical to ensure human subject protection and the 
reliability of trial results according to applicable SOPs and the International Council for 
Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6(R2) 
guideline [19]. 
Identified risks will be categorized separately from the CSP. See also Section 6.3.1. 
 
13.2 
Quality assurance and quality control 
The Sponsor has delegated the responsibilities outlined below to CTC whilst maintaining 
overall study oversight: 
• Implementing and maintaining quality assurance (QA) and quality control (QC) 
systems with written SOPs with regard to management of identified risks, CSP 
compliance, good clinical practice (GCP) compliance and applicable regulatory 
requirements. 
• Securing agreements with involved subcontractors and to perform regular 
subcontractor oversight to ensure CSP compliance, GCP compliance and compliance 
with applicable regulatory requirements. 
• Implementing a risk-based validated EDC system and maintain SOPs for the whole 
life- cycle of the system. 
• QC application to each stage of data handling to ensure that all data are reliable and 
have been processed correctly. 


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14 
ETHICAL AND REGULATORY REQUIREMENTS 
 
14.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki [19] and are consistent with the ICH E6 (R2) guideline for GCP [20], 
applicable sections of the EU Clinical Trials Directive 2001/20/EC [21], and applicable local 
regulatory requirements. 
 
14.2 
Ethics and regulatory review 
The Principal Investigator is responsible for submission of the CSP, the subject information 
and ICF, any other written information to be provided to the subjects and any advertisements 
used for recruitment of subjects to applicable IEC for approval. 
The Sponsor has delegated to CTC the responsibility for submission of study documents to 
the applicable CA according to local regulatory requirements. 
Approval must be obtained in writing from both IEC and CA before the first subject can be 
recruited. 
The Sponsor will provide the CA, IEC and Principal Investigator with safety updates/reports 
according to local requirements. Progress reports and notifications of SUSARs will be 
provided to the IEC according to local regulations and guidelines. 
 
14.3 
Subject information and consent 
It is the responsibility of the Investigator or an authorized associate to give each potential 
study subject adequate verbal and written information before any study specific assessments 
are performed. 
The information will include the objectives and the procedures of the study as well as any 
risks or inconvenience involved. It will be emphasized that participation in the study is 
voluntary and that the subject may withdraw from participation at any time and for any 
reason, without any prejudice. All subjects will be given the opportunity to ask questions 
about the study and will be given sufficient time to consider participation before signing the 
ICF. 
Before performing any study-related procedures the ICF must be signed and personally dated 
by the subject and by the Investigator. A copy of the subject information including the signed 
ICF will be provided to the subject. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation and in the eCRF. The subject information card and the signed ICF must 
be filed by the Investigator for possible future audits and/or inspections. 
The final approved version of the subject information and ICF must not be changed without 
approval from the Sponsor and the applicable IEC. 


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14.4 
Subject information card 
The subject will be provided with a subject information card including the following 
information: 
• That they are participating in a clinical study. 
• Subject study ID. 
• That they are treated with linaprazan glurate. 
• The name and phone number of the Investigator. 
• The name and address of the Sponsor. 
 
14.5 
Subject data protection 
The ICF includes information that data will be recorded, collected, and processed and may be 
transferred to European Economic Area (EEA) or non-EEA countries. In accordance with the 
European Union (EU) general data protection regulation (GDPR) 2016/679 [13], the data will 
not identify any persons taking part in the study. 
The potential study subject must be informed that by signing the ICF they approve that 
authorized representatives from the Sponsor and CTC, as well as the concerned IEC and CA, 
have direct access to their medical records for verification of clinical study procedures. For 
further details on the subject information and ICF process, refer to Section 14.3. 
The subject has the right to request access to his/her personal data and the right to request 
rectification of any data that is not correct and/or complete in accordance with EU regulation 
2016/679 [13] and the request will be raised to the Principal Investigator. 
The Investigator must file a subject identification list which includes sufficient information to 
link records, i.e., the eCRF and clinical records. This list must be preserved for possible future 
inspections/audits but must not be made available to the Sponsor except for monitoring or 
auditing purposes. 
Personal data that are collected in the study such as health information and ethnicity are 
considered as sensitive personal data. This data will be pseudonymized, i.e., personally 
identifiable information (PII) will be removed and replaced by a unique subject ID and will be 
processed by the Sponsor and other involved parties during the study. After the study end, 
only pseudonymized data can be used. 
For this study, the Sponsor is the data controller of all data processed during the study (e.g., 
TMF, study reports) and CTC AB is the data processor. Any subcontractors used in the study 
are also data processors. 
For data that are processed at the clinic (s) (e.g., medical records and ISF), CTC AB is the 
data controller. 
 
14.6 
Changes to the approved clinical study protocol 
Any proposed change to the approved final CSP, including appendices, will be documented in 
a written and numbered clinical protocol amendment. All substantial amendments to the 
protocol must be approved by the appropriate IEC and/or CA before implementation 
according to applicable regulations. 


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14.7 
Audits and inspections 
Authorized representatives of the Sponsor, CA, or IEC may perform audits or inspections at 
the study clinic, including source data verification (SDV). The purpose of an audit or 
inspection is to examine all study-related activities and documents systematically and 
independently, to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, ICH-GCP guidelines and any 
applicable regulatory requirements. The Investigator will contact the Sponsor immediately if 
contacted by the CA about an inspection at the study site. 
 
14.8 
Insurance 
The subjects will be covered under Cinclus Pharma’s liability insurance policy through the 
Swedish Pharmaceutical Insurance (Läkemedelsförsäkringen). The certificate of insurance 
and an information leaflet containing essential information about the insurance coverage can 
be provided upon request. The participating patients are also protected in accordance with 
national regulations, as applicable. CTC has a company insurance covering services 
performed by CTC. 


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15 
STUDY MANAGEMENT 
 
15.1 
Training of study site personnel 
Before inclusion of the first study subject, a Sponsor representative or delegate will perform a 
study initiation visit at the study clinic. The requirements of the CSP and related documents 
will be reviewed and discussed, and the investigational staff will be trained in any study 
specific procedures and system(s) that are required. 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are 
fully informed of all relevant aspects of the study and have a detailed knowledge of and 
training in the procedures that are to be executed by them. Any new information of relevance 
to the performance of this study must be forwarded to the staff involved in a timely manner. 
The Investigator will keep a list of all personnel involved in the study together with their 
function and study related duties delegated. A Curriculum Vitae will be available for all staff 
delegated study-specific duties. 
 
15.2 
Clinical monitoring 
The Sponsor is responsible for securing agreement from all involved parties to ensure direct 
access to all study related sites, source data/documents, and reports for the purpose of 
monitoring and auditing by the Sponsor, and inspection by domestic and foreign regulatory 
authorities. 
As defined in the risk-based monitoring (RBM) plan, approved by the Sponsor and provided 
separately, the responsible Monitor will periodically visit the study site at times agreed upon 
by the Investigator and the Monitor. At the time of each monitoring visit, the role of the 
Monitor will be (but will not be limited to) the following: 
• To provide information and support to the investigational team. 
• To confirm that facilities and resources remain acceptable. 
• To confirm that the investigational team is adhering to the CSP, applicable SOPs, 
guidelines, manuals and regulatory requirements. 
• To verify that data are being accurately and timely recorded in the eCRFs and that 
IMP accountability checks are being performed. 
• To verify that data in the eCRF are consistent with the clinical records (SDV) in 
accordance with the RBM plan. 
• To verify that the correct informed consent procedure has been adhered to for 
participating subjects. 
• To ensure that withdrawal of informed consent to the use of the subject’s biological 
samples will be reported and biological samples are identified and disposed 
of/destructed accordingly, and that this action is documented and reported to the 
subject. 
• To verify that AEs are recorded and reported in a timely manner and according to the 
CSP. 
• To raise and escalate any serious quality issues, serious GCP breach and any data 
privacy breach to the Sponsor. 
Centralized monitoring will also be performed continuously by study team members at CTC 
in accordance with the RBM plan. 


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When the study has been completed and all queries have been resolved and the database has 
been locked, the Monitor will perform a close-out visit. 
 
15.3 
Source data documents 
A separate origin of source data list will be generated for each site before the start of 
enrolment, specifying the location of the source of derived information appearing in the 
eCRF. This document must be signed by the Principal Investigator and the Monitor to confirm 
agreement before start of recruitment. 
Source documents are all documents used by the Investigator or hospital that relate to the 
subject’s medical history, and that verify the existence of the subject, the inclusion and 
exclusion criteria, and all records covering the subject’s participation in the study. They 
include laboratory notes, memoranda, material dispensing records, subject files, et c. The 
eCRF may constitute source data if clearly defined in the origin of source data list. 
The Investigator must guarantee access to source documents to the Monitor, CAs and the 
IECs, if required. 
 
15.4 
Study agreements 
The Principal Investigator must comply with all the terms, conditions, and obligations of the 
clinical study agreement for this study. 
Agreements between the Sponsor, and CTC must be in place before any study-related 
procedures can take place, or subjects can be enrolled. 
 
15.5 
Study timetable and end of study 
The study is expected to start in Q4 2022 and to be completed by Q2 2023. 
A subject is considered to have completed the study if they have completed all visits in the 
study, including the end-of-study visit. 
The end of the study is defined as the date of the last visit of the last subject participating in 
the study. 
 
15.6 
Termination of the study 
The Investigator or the Sponsor may terminate this study prematurely for any reasonable 
cause. The IEC and CA must be informed promptly. Conditions that may warrant study 
termination include, but are not limited to the following: 
• The discovery of an unexpected, significant, or unacceptable risk to the subjects 
included in the study or potential study subjects. 
• A decision by the Sponsor to suspend or discontinue the development of the IMP. 
If the CA obtains information that raises doubts about the safety or scientific validity of the 
study, the CA may also suspend or prohibit the study. Before the CA reaches its decision, it 
shall, except where there is imminent risk, ask the Sponsor and/or the Investigator for their 
opinion, to be delivered within one week (Directive 2001/20/EC, Article 12, Section 1) [21]. 
If the study is prematurely terminated or suspended for any reason, the Investigator/institution 
must promptly inform the study subjects and must assure appropriate follow-up for the 
subjects. 


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15.7 
Reporting and publication 
15.7.1 
Clinical study report 
A summarizing report will be submitted to a publicly available database (EudraCT) within 
12 months after completion of the study, in accordance with applicable regulations. 
After completing Part I, unblinded data will be prepared from the cleaned database for that 
part. An ICH E3 [14] guideline-compliant clinical study report (CSR) will be written based on 
data from Part I and Part II. The CSR, describing the conduct of the study, any statistical 
analyses performed, and the results obtained will be prepared by the Sponsor or their 
designee. The CSR will be reviewed and approved by, as a minimum, the Principal 
Investigator, the Statistician and the Sponsor. The study results will be reported in the 
EudraCT database per applicable regulations within 12 months after completion of the study. 
All results obtained from any exploratory analyses will be reported separately. 
15.7.2 
Annual safety report 
If the study duration exceeds one year, the Sponsor must submit development safety update 
report (DSUR) to the CA and to the IEC. The report must summarize all pertinent safety 
information collected during the reporting period and contain an update of the risk-benefit 
evaluation if there has been any change since the approval of the clinical study. 
15.7.3 
Confidentiality and ownership of study data 
Any confidential information relating to the IMP or the study, including any data and results 
from the study, will be the exclusive property of the Sponsor. The Investigator and any other 
persons involved in the study are responsible for protecting the confidentiality of this 
proprietary information belonging to the Sponsor. 
15.7.4 
Publication 
The results from this study may be submitted for publication at the discretion of the Sponsor. 
 
15.8 
Archiving 
The Principal Investigator is responsible for maintaining essential documents, (as defined in 
ICH E6(R2), Section 8 [20]) for 10 years after finalization of the CSR. This includes any 
original source documents related to the study, the subject identification list (providing the 
sole link between named subject source records and pseudonymous eCRF data), the original 
signed ICFs and detailed records of IMP disposition. 
It is the responsibility of the Sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
The Sponsor will archive the TMF in accordance with the ICH E6(2) guideline, Section 8 
[20], and applicable regulatory requirements [21]. 
The data from the eCRFs will be sent to the Sponsor and a copy will be sent to the clinic and 
filed in the Investigator Study File for archiving for 10 years after finalization of the CSR. 
The completed original eCRFs are the sole property of the Sponsor and must not be made 
available in any form to third parties, except for authorized representatives of appropriate 
health/regulatory authorities, without written permission from the Sponsor. 


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16 
DATA MANAGEMENT 
The data management routines include procedures for handling of the eCRF, database set-up 
and management, data entry and verification, data validation, QC of the database, and 
documentation of the performed activities including information of discrepancies in the 
process. The database, data entry screens, and program will be designed in accordance with 
the CSP. 
Data validation/data cleaning procedures are designed to assure validity and accuracy of 
clinical data. These procedures consist of computerized online edit checks identifying e.g., 
data values that are outside the allowed range and SAS-programmed offline checks on data 
exports. All study-specific and standard data validation programming will be tested prior to 
being used on final data. 
Detailed information on data management will be described in a study-specific Data 
Management Plan (DMP). 
 
16.1 
The web-based eCRF 
Clinical data will be entered into a 21 CFR Part 11-compliant eCRF (Viedoc™) provided by 
Viedoc Technologies AB. The eCRF includes password protection and internal quality 
checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, 
or inaccurate. Clinical data will be entered directly from the source documents or at bedside 
(if the eCRF data constitutes source data). Source data are to be defined at the site before 
inclusion of the first subject (Section 15.3). 
Authorized site personnel designated by the Investigator will complete data collection. 
Appropriate training and security measures will be completed with the Investigator and all 
authorized trial site personnel prior to the trial being initiated and any data being entered into 
the system for any study subject. 
 
16.2 
The entering of data into the eCRF 
All entries, corrections, and alterations are to be made by the Investigator or designee. Neither 
the Monitor nor any other study team member besides site staff can enter data in the eCRF. 
All data will be entered in English. The eCRFs will be completed as soon as possible during 
or after the subject’s visit. To avoid inter-observer variability, every effort will be made to 
ensure that preferably same individual who made the initial baseline determinations completes 
all corresponding follow-up evaluations. The Investigator must verify that all data entries in 
the eCRFs are accurate and correct. If some assessments are not done, or if certain 
information is not available, not applicable or unknown, the Investigator or assigned clinical 
staff will record such information in the eCRF. The Investigator will be required to 
electronically sign off on the clinical data. This will be performed by means of the 
Investigator’s unique User ID and password; date and time stamps will be added 
automatically at time of electronic signature. 
 
16.3 
Electronic patient reported outcome 
Subject reported intake of clarithromycin (Part I) and linaprazan glurate (Part II) will be 
recorded using an electronic patient reported outcome (ePRO) system (ViedocMe™) linked to 
the eCRF during home-administration. The ePRO system includes password protection and 
internal quality checks. Text reminders will be sent to the subject through the ePRO. All data 
registered in the ePRO are stored together with the eCRF data. 


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16.4 
The query process 
The Monitor will review the eCRFs and evaluate them for completeness and consistency. 
Data in the eCRF will be compared with the respective source documents to ensure that there 
are no discrepancies for critical data as described in the risk-based monitoring plan. All 
entries, corrections, and alterations are to be made by the Investigator or designee. Neither the 
Monitor nor any other study team member besides site staff can enter data in the eCRF. 
If corrections are needed, queries will be raised within the eCRF. An appropriate member of 
the site staff will answer the queries in the eCRF either by correcting the data or by entering a 
response to the query. 
 
16.5 
Audit trail 
All entries in the eCRF will be fully recorded in a protected audit trail. Once clinical data 
have been saved, corrections to the data fields will be audit trailed, meaning that the reason 
for change, the name of the person who made the change, together with time and date will be 
logged. 
 
16.6 
External data 
External data consists of data that are not recorded in the eCRF. Data may be received in 
electronic format or as a paper printout. Key variables are defined in order to uniquely 
identify each sample record. File and data formats are agreed with the external data provider. 
 
16.7 
Medical coding 
Medical coding will be performed by trained personnel at CTC. AEs and medical/surgical 
history verbatim terms are coded using the medical dictionary of regulatory activities 
(MedDRA, latest version available at eCRF setup). Prior and concomitant medications will be 
coded according to the World Health Organization (WHO) drug dictionary classification 
system WHODrug. All coding will be approved by the Sponsor prior to database lock. 
 
16.8 
Database lock 
For Part I and Part II respectively, when all data have been entered and discrepancies solved, 
clean file will be declared, the database will be locked, and the data will be analyzed. A 
complete CSR including both parts of the study will be written following the final DBL. 


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17 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
The principal features of the statistical analysis to be performed are described in this section. 
A more technical and detailed elaboration of the principal features will be presented in a 
separate statistical analysis plan (SAP), which will be signed and approved prior to database 
lock. 
The analyses of the primary and secondary endpoints will be performed by CTC. 
 
17.1 
General 
Continuous data will be presented in terms of evaluable, arithmetic mean, standard deviation 
(SD), median, minimum, and maximum value. In addition, for the parameters AUC and Cmax 
the geometric mean and geometric coefficient of variation (CV%) will be presented. 
Categorical data will be presented as counts and percentages. When applicable, summary data 
will be presented by treatment, and by assessment time. Individual subject data will be listed 
by subject number, treatment, and, where applicable, by assessment time. 
All descriptive summaries and statistical analyses will be performed using SAS Version 9.4 or 
later (SAS Institute, Inc., Cary, NC). The PK parameters will be calculated by non- 
compartmental analysis (NCA) using the software Phoenix WinNonlin® version 8.3 or later 
(Certara, U.S.A.). 
Baseline will be defined as the last non-missing data collection point prior to administration 
of IMP (i.e., linaprazan glurate in Part I) and midazolam (Part II). 
No imputation of missing data will be performed. 
 
17.2 
Determination of sample size 
No formal sample size calculation has been performed for this study. The proposed sample 
size is considered sufficient to provide adequate information to meet the study objectives. 
 
17.3 
Analysis data sets 
17.3.1 
Full analysis set 
The full analysis set (FAS) will consist of all subjects who have received at least 1 dose of 
linaprazan glurate and who provided at least 1 post-baseline data point. There will be 1 FAS 
per part. 
The FAS will also be used for all safety analyses. 
17.3.2 
Pharmacokinetic analysis set 
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. There will be 1 PKAS per part. 
The compliance criteria for self-administration of clarithromycin in Part I and linaprazan 
glurate in Part II will be specified in the SAP. Individual PK values may be excluded from the 
analysis as specified in the SAP. 
All protocol violations will be judged as major or minor prior to database lock. 


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17.4 
Description of study population 
17.4.1 
Demographics and baseline characteristics 
Descriptive statistics for demographics, weight and height will be presented for all enrolled 
subjects. 
All data will be listed by subject. 
17.4.2 
Medical/surgical history and prior/concomitant medication 
Medical/surgical history will be presented by system-organ-class (SOC) and preferred term 
(PT). Prior/concomitant medications will be presented by anatomical therapeutic chemical 
(ATC) level as applicable. 
All data will be listed by subject. 
17.4.3 
Exposure 
The number of subjects treated in each study part and their individual doses will be listed. 
 
17.5 
Analysis of pharmacokinetic endpoints 
17.5.1 
Analysis of pharmacokinetics 
The PK analysis will be based on the PKAS. The PK parameters will be calculated by NCA 
using the software Phoenix WinNonlin® version 8.3 or later (Certara Inc, Princeton NJ, 
United States). 
Part I: 
The following primary NCA PK parameters will be assessed for linaprazan glurate and 
linaprazan: 
• AUCinf 
• AUC0-t 
• Cmax 
The following secondary NCA PK parameters will be assessed for linaprazan glurate and 
linaprazan, but are not limited to: 
• Tmax 
• T1/2 
• CL/F 
• V/F 
• AUCextr% 
The PK parameters AUC, AUC(0-t) and Cmax will be analyzed using a mixed model following 
a natural logarithmic transformation, with fixed effect for treatment and random effect for 
subject. Ratios of geometric means together with 2-sided 90% CI of test treatment (linaprazan 
glurate + clarithromycin) and reference treatment (linaprazan glurate alone) will be estimated 
and presented. 


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The following secondary NCA PK parameters will be assessed for clarithromycin with and 
without co-administration of linaprazan glurate, not limited to: 
• AUC to the end of the dosing period (AUCtau) 
• Cmax 
• Tmax 
• T1/2 
Part II: 
The following primary NCA PK parameters will be assessed for midazolam, in the presence 
and absence of linaprazan glurate administration: 
• AUCinf 
• AUC0-t 
• Cmax 
The following secondary NCA PK parameters will be assessed for midazolam, in the presence 
and absence of linaprazan glurate administration (if feasible): 
• Tmax 
• T1/2 
• AUCextr% 
• CL/F 
• V/F 
Midazolam PK parameters will be presented and statistically analyzed using the same mixed- 
effects model as in Part I. The ratios of geometric least squares mean (midazolam in the 
presence and absence of linaprazan glurate) with the corresponding 90% confidence interval 
(CI) will be presented. If the CI for AUCinf is between 0.8 and 1.25, and the CI for Cmax is 
between 0.7 and 1.43, it can be concluded that linaprazan glurate has no effect on CYP3A. 
The following secondary NCA PK parameters will be assessed for linaprazan glurate and 
linaprazan (if feasible): 
• AUCinf 
• AUC0-t 
• Cmax 
• AUCextr% 
• CL/F 
• V/F 
• Racc 
• Tmax 
• T1/2 
Additional PK parameters may be determined if deemed appropriate. 
For AUCinf, AUC will be calculated to the time point of the last quantifiable plasma 
concentration and then extrapolated to infinity using the concentration in the last quantifiable 
sample and the estimated terminal elimination rate constant (Lambdaz). PK data will be 
presented by using summary statistics with number of measurements, arithmetic mean, SD, as 


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well as median, minimum and maximum values. In addition, for the parameters AUC and 
Cmax the geometric mean and coefficient of variation (CV%) will be presented. 
All data will be listed by subject. 
 
17.6 
Analysis of safety endpoints 
17.6.1 
Adverse events 
An overview of all AEs, including SAEs, intensity, relationship to IMP, and deaths will be 
presented. The incidence of AEs and SAEs will be summarized by SOC and PT by treatment 
and overall. An overview of any treatment-related AEs will be summarized by SOC and PT if 
considered appropriate. 
All AE data will be listed by subject and include the verbatim term entered by the 
Investigator. 
17.6.2 
Physical examinations 
Clinically significant and non-clinically significant abnormal findings will be specified and 
presented by subject and summarized by treatment. 
All data will be listed by subject. 
17.6.3 
Vital signs 
Vital signs (systolic/diastolic BP, pulse rate, and body temperature) will be summarized by 
treatment and overall. Data will be presented with absolute and percent change from baseline. 
All data will be listed by subject. If warranted, a separate listing may contain all values that 
were judged to be clinically significant. 
17.6.4 
12-lead safety ECG 
All ECGs will be categorized as ”normal”, ”abnormal, not clinically significant”, or 
”abnormal, clinically significant” (as judged by the Investigator) and summarized by 
treatment using frequency tables. 
All data will be listed by subject. 
17.6.5 
Safety laboratory analyses 
Safety laboratory data will be summarized by treatment, with absolute and percent change 
from baseline at each visit. 
Abnormal, clinically significant values will be summarized separately if considered 
appropriate. 
All data will be listed by subject. 
 
17.7 
Analysis of exploratory endpoints 
Data related to exploratory analyses in Part I and Part II of the study will not be included in 
the study database, and analyses related to exploratory analyses will not be covered by the 
SAP. 


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18 
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Cinclus Pharma AG. 2019. A single-center, open, randomized, two-treatment, two- 
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Cinclus Pharma AG. 2019. A single-center, open-label, randomized, three-treatment, 
parallel group, exploratory pharmacokinetic/pharmacodynamic study of X842 given as 
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Vakil N. 2004. Review article: new pharmacological agents for the treatment of gastro- 
esophageal reflux disease. Alimentary Pharmacology & Therapeutics 19(10): 1041 
1049. https://doi.org/10.1111/j.1365-2036.2004.01957.x 
11. 
Nilsson CA, Albrektson E, Rydholm H, Rohss K, Hassan Alin M, Hasselgren G. 
Tolerability, Pharmacokinetics and Effects on Gastric Acid Secretion After Single Oral 
Doses of the Potassium-Competitive Acid Blocker (p-Cab) Azd0865 in Healthy Male 
Subjects. 2005. Gastroenterology, Vol 128, Issue 4, Supplement 2. 
12. 
European Medicines Agency. Strategies to identify and mitigate risks for first-in-human 
and early clinical trials with investigational medicinal products. Revision 1. November 
15, 2016. EMEA/CHMP/SWP/28367/07 Rev. 1. Published on ema.europa.eu. 
https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline- 
strategies-identify-mitigate-risks-first-human-early-clinical-trials-investigational_en.pdf 
(last accessed 11APR2022). 
13. 
European Commission. Regulation (EU) 2016/679 of the European Parliament and of 
the Council of 27 April 2016 on the protection of natural persons with regard to the 
processing of personal data and on the free movement of such data, and repealing 
Directive 95/46/EC (General Data Protection Regulation). 2016. Published on eur-lex- 
europa.eu. https://eur-lex.europa.eu/eli/reg/2016/679/oj (last accessed 11APR2022) 


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14. 
Swedish Medical Products Agency (Läkemedelsverket). Läkemedelsverkets föreskrifter 
(LVFS 2011:19) om kliniska läkemedelsprövningar på människor. 2011. Published on 
lakemedelsverket.se. https://www.lakemedelsverket.se/sv/lagar-och- 
regler/foreskrifter/2011-19 (last accessed on 11APR2022). 
15. 
European Medicines Agency. ICH E3 Structure and content of clinical study reports. 
July 1, 1996. CPMP/ICH/137/95. Published on ema.europa.eu. 
https://www.ema.europa.eu/en/ich-e3-structure-content-clinical-study-reports (last 
accessed 11APR2022). 
16. 
European Medicines Agency. ICH Q7 Good manufacturing practice for active 
pharmaceutical ingredients. November 1, 2000. CPMP/ICH/4106/00. Published on 
ema.europa.eu. https://www.ema.europa.eu/en/ich-q7-good-manufacturing-practice- 
active-pharmaceutical-ingredients (last accessed 11APR2022). 
17. 
European Commission. EudraLex, The rules governing medicinal products in the 
European Union. Volume 4, Good manufacturing practice, Medicinal products for 
human and veterinary use. Annex 13, Investigational medicinal products. February 3, 
2010. Published on ec.europa.eu. https://ec.europa.eu/health/system/files/2016- 
11/2009_06_annex13_0.pdf (last accessed 11APR2022). 
18. 
National Cancer Institute Cancer Therapy Evaluation Program. Common terminology 
criteria for adverse events, CTCAE v5.0 (2017). 
19. 
The World Medical Association. Declaration of Helsinki – Ethical Principles for 
Medical Research Involving Human Subjects. July 9, 2018. Published on 
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principles-for-medical-research-involving-human-subjects (last accessed 11APR2022). 
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European Medicines Agency. ICH E6(R2) Guideline for Good Clinical Practice. July 1, 
2002. Last updated December 15, 2016. EMA/CHMP/ICH/135/1995. Published on 
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accessed 11APR2022). 
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European Commission. Clinical Trials – Directive 2001/20/EC. April 4, 2001. 
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trials/directive_en (last accessed 11APR2022). 





SAP_001.pdf: 
Statistical Analysis Plan for Part I and Part II 
Title: A phase I, open-label, fixed-sequence, single-center study to determine 
the effect of repeated dosing with clarithromycin on the pharmacokinetics of 
linaprazan glurate/linaprazan and the effect of a single dose of linaprazan glurate 
on the pharmacokinetics of clarithromycin, and single and repeated dosing with 
linaprazan glurate on the pharmacokinetics of midazolam administrated to 
healthy subjects 
 
NCT number: NCT05633147 
Document date: Final v1.0; 06MAR2023 


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This Statistical Analysis Plan is the property of Cinclus Pharma Holding AB and is a 
confidential document. It is not to be copied or distributed to other parties without 
written approval from Cinclus Pharma Holding AB. 
 
 
 
Statistical Analysis Plan for Part 
I and Part II 
EudraCT no. 
2022-001403-41 
Investigational medicinal product Linaprazan glurate 
Study code 
CX842A2105 
Protocol version and date 
Final v4.0; 20JAN2023 
 
 
 
 
 
 
A phase I, open-label, fixed-sequence, single-center study to 
determine the effect of repeated dosing with clarithromycin on 
the pharmacokinetics of linaprazan glurate/linaprazan and the 
effect of a single dose of linaprazan glurate on the 
pharmacokinetics of clarithromycin, and single and repeated 
dosing with linaprazan glurate on the pharmacokinetics of 
midazolam administrated to healthy subjects 
 
 
Sponsor signatory 
, MD, PhD, CMO 
Cinclus Pharma Holding AB 
World Trade Center, Kungsbron 1 
SE-111 22 Stockholm, Sweden 
CTC biostatistician 
, MSc 
Clinical Trial Consultants AB (CTC) 
Dag Hammarskjölds väg 10B 
SE-752 37 Uppsala, Sweden 
 
 
 
 
 
 
 
 




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2 
TABLE OF CONTENTS 
1 
SIGNATURES .................................................................................................................. 2 
2 
TABLE OF CONTENTS ................................................................................................. 3 
3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................. 5 
4 
INTRODUCTION ............................................................................................................ 7 
4.1 
Study design .............................................................................................................. 7 
4.2 
Study objectives and endpoints Part I .................................................................... 7 
4.3 
Study objectives and endpoints Part II ................................................................... 8 
4.3.1.1 
Additional PK parameters Part II .................................................................. 9 
4.4 
Randomisation and number of subjects ............................................................... 10 
4.5 
Subject replacement ............................................................................................... 10 
4.6 
Blinding.................................................................................................................... 10 
5 
STATISTICAL AND ANALYTICAL PLANS ............................................................ 11 
5.1 
Statistical hypotheses .............................................................................................. 11 
5.2 
Sample size calculation ........................................................................................... 11 
5.3 
Definition of analysis sets ....................................................................................... 11 
5.4 
Compliance .............................................................................................................. 11 
5.5 
Definition of baseline .............................................................................................. 12 
5.6 
Rounding principles ............................................................................................... 12 
5.7 
Significance level ..................................................................................................... 12 
5.8 
Multiple comparisons/multiplicity ......................................................................... 12 
5.9 
Handling of dropouts, missing data and outliers ................................................. 12 
6 
CHANGES FROM THE CLINICAL STUDY PROTOCOL .................................... 14 
7 
CLINICAL DATABASE PROCESSING .................................................................... 15 
7.1 
General information ............................................................................................... 15 
7.1.1 
CDISC Compliance ............................................................................................ 15 
7.2 
Database modeling of study design ....................................................................... 16 
8 
STATISTICAL DELIVERABLES ............................................................................... 17 
9 
STATISTICAL METHODOLOGY ............................................................................. 18 
9.1 
Pharmacokinetic calculations ................................................................................ 18 
9.2 
Analysis of the primary endpoint .......................................................................... 21 
9.2.1 
Analysis of PK parameters ................................................................................. 21 
9.2.2 
Mixed model for PK parameters Part I ............................................................... 21 
9.2.3 
Mixed model for PK parameters Part II ............................................................. 22 
9.3 
Analysis of secondary endpoints ........................................................................... 22 
9.3.1 
Adverse events .................................................................................................... 22 


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9.3.2 
Physical examinations......................................................................................... 22 
9.3.3 
Vital signs ........................................................................................................... 22 
9.3.4 
12-lead safety ECG ............................................................................................. 22 
9.3.5 
Safety laboratory analyses .................................................................................. 22 
9.3.6 
Additional PK parameters Part I for linaprazan glurate and linaprazan, not 
limited to: ......................................................................................................................... 22 
9.3.7 
Clarithromycin PK parameters Part I with and without co-administration of 
linaprazan glurate: ............................................................................................................ 23 
9.3.8 
Additional Midazolam PK parameters Part II in the presence and absence of 
linaprazan glurate administration (if feasible): ................................................................ 23 
9.3.9 
Linaprazan glurate and linaprazan PK parameters Part II (if feasible): .............. 23 
9.4 
Description of study population ............................................................................ 23 
10 DATA DISPLAY PLAN ................................................................................................ 24 
10.1 
Table of contents DDP ............................................................................................ 24 
 
 
List of tables 
Table 1 
Analysis sets 
11 
List of figures 
Figure 1 
Schematic representation of the SDTM study design 
16 


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3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Explanation 
 
ADaM 
Analysis Data Model 
AE 
Adverse event 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the plasma concentration vs. time curve 
AUC0-t 
AUC from time 0 to time t 
AUCextr% 
AUC percent extrapolation 
AUCinf 
AUC from 0 to infinity 
AUCtau 
AUC to end of dosing period 
BID 
Bis in die, twice daily 
CDISC 
Clinical Data Interchange Standards Consortium 
CF 
Clean File 
CI 
Confidence interval 
CL 
Apparent total body clearance following i.v. administration 
CL/F 
Apparent total body clearance following extravascular 
administration 
Clast 
Last observed plasma concentration 
Cmax 
Maximum observed concentration 
CS 
Clinically significant 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CT 
Controlled terminology 
CTC 
Clinical Trial Consultants AB 
CV 
Coefficient of variation 
DDI 
Drug-drug interaction 
DDP 
Data display plan 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FAS 
Full analysis set 
FDA 
United States Food and Drug Administration 
Geo 
Geometric 
IG 
Implementation guideline 
IMP 
Investigational medicinal product 
lin 
Linear 


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Abbreviation 
Explanation 
 
LLOQ 
Lower limit of quantification 
LS 
Least square 
Max 
Maximum 
MedDRA 
Medical dictionary for regulatory activities 
Min 
Minimum 
NA 
Not applicable/not available 
NC 
Not calculated 
NCA 
Non-compartmental analysis 
NCS 
Not clinically significant 
PgP 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PKAS 
PK analysis set 
PT 
Preferred term 
Racc 
Accumulation ratio 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
SOC 
System organ class 
Tlast 
Time of occurrence of Clast 
Tmax 
Time of occurrence of Cmax 
T1/2 
Terminal elimination half-life 
V/F 
Volume of distribution following extravascular 
administration 


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4 
INTRODUCTION 
 
4.1 
Study design 
This is a phase I, open-label, fixed design, drug-drug-interaction (DDI) study divided in 2 parts. 
Part I is designed to evaluate whether concomitant treatment with linaprazan glurate and 
clarithromycin, a strong inhibitor of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein P 
(PgP), leads to an effect on the systemic exposure to linaprazan glurate and linaprazan and 
whether there is an effect on the pharmacokinetics of clarithromycin after a single dose of 
linaprazan glurate. Part II is designed to evaluate the effect of repeated doses of linaprazan 
glurate on the pharmacokinetics (PK) of a sensitive substrate of CYP3A (midazolam). 
For more details on the study design, please refer to the CSP. 
 
4.2 
Study objectives and endpoints Part I 
 
Objectives 
Endpoints 
Assessments 
Analyses 
Data display 
plan (DDP) 
Primary 
Primary endpoint, 
Assessments, Part I 
Analyse, Part I 
DDP, Part I 
objective, 
Part I 
Part I 
To investigate 
Linaprazan glurate 
Pharmacokinetic sampling 
Summary statistics for Table PP 1, 
the effect of 
and linaprazan PK 
and analysis 
PK parameters. See 
repeated 
parameters with and 
Section 9. 
Table PC 1 and 
administration 
without co- 
Figure PC 1 
of 
administration of 
Linear mixed-effects 
clarithromycin clarithromycin: 
analysis of variance 
on linaprazan 
glurate and 
linaprazan PK 
after single 
dose of 
linaprazan 
glurate. 
 
Area under the plasma 
concentration curve 
from 0 to infinity 
(AUCinf) 
 
 
AUC from time 0 to 
time t (AUC0-t) 
model, see Section 
9.2.2 
 
 
 
 
 
 
 
after single 
dose of 
linaprazan 
glurate with 
and without 
co- 
administration 
of 
clarithromycin. 
 
 
To evaluate 
additional PK 
characteristics 
Clinically significant 
changes in physical 
examinations, vital 
signs (blood pressure 
and pulse), 
electrocardiograms 
(ECG), and laboratory 
variables 
(haematology, clinical 
chemistry, and 
urinalysis). 
Additional PK 
parameters for 
linaprazan glurate and 
Physical examinations, 
Vital signs, 12-lead 
electrocardiograms, Safety 
laboratory assessments 
 
 
 
 
 
 
 
Pharmacokinetic sampling 
and analysis 
Descriptive statistics, 
Section 9.3.2 to 9.3.5 
 
 
 
 
 
 
 
 
 
Summary statistics for 
PK parameters. See 
Section 9.3.6 
Table PE 1, 
Table VS 1, 
Table EG 1, 
Table EG 3, 
Table LB 1, 
Table LB 3 and 
Table LB 5 
 
 
 
 
Table PP 5 
 
 
Maximum plasma 
concentration (Cmax) 
Secondary 
objective, 
Part I 
Secondary endpoint, 
Part I 
Assessments, Part I 
Analyse, Part I 
DDP, Part I 
To assess the 
safety and 
tolerability 
Frequency, 
seriousness, and 
intensity of AEs. 
Adverse events 
Descriptive statistics, 
Section 9.3.1 
Table AE 1, 
Table AE 3 


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Objectives 
Endpoints 
Assessments 
Analyses 
Data display 
plan (DDP) 
of linaprazan 
linaprazan, not limited 
glurate and 
to: 
linaprazan. 
Time of occurrence of 
Cmax (Tmax) 
Terminal elimination 
half-life (T1/2) 
Apparent clearance 
(CL/F) 
Apparent volume of 
distribution (V/F) 
Percent extrapolated 
AUC (AUCextr%) 
To investigate 
Clarithromycin PK 
Pharmacokinetic sampling 
Summary statistics for 
the effect of 
parameters with and 
and analysis 
PK parameters. See 
linaprazan 
without co- 
Section 9.3.7 
glurate on 
administration of 
clarithromycin linaprazan glurate: 
PK. 
AUC to the end of the 
dosing period 
(AUCtau) 
Cmax 
Additional PK 
Pharmacokinetic sampling 
parameters for 
and analysis 
clarithromycin, not 
limited to: 
Tmax 
T1/2 
Exploratory 
Exploratory 
Assessments, Part I 
Analyse, Part I 
DDP, Part I 
objective, 
endpoint, Part I 
Part I 
To explore the Plasma collected for 
Not covered in the SAP 
NA 
NA 
metabolites of 
future exploratory 
linaprazan 
analyses of linaprazan 
glurate in 
glurate metabolites. 
plasma with 
and without 
co- 
administration 
of 
clarithromycin. 
 
4.3 
Study objectives and endpoints Part II 
 
Objectives 
Endpoints 
Assessments 
Analyses 
Data display plan 
(DDP) 
Primary 
Primary endpoint, 
Assessments, Part II 
Analyse, Part II 
DDP, Part II 
objective, 
Part II 
Part II 
To investigate 
Midazolam PK 
Pharmacokinetic 
Summary statistics 
the effects 
parameters in the 
sampling and analysis 
for PK parameters. 
after single 
presence and 
See Section 9. 
and repeated 
absence of 
 


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0-t 
 
 
 
 
 
 
 
 
 
 
 
after repeated 
doses of 
linaprazan 
glurate with 
and without 
co- 
administration 
of midazolam. 
 
 
 
To evaluate 
PK data on 
linaprazan 
glurate and 
linaprazan 
after single 
and repeated 
oral doses of 
linaprazan 
glurate. 
 
 
 
 
 
 
 
 
 
 
 
 
To evaluate 
additional PK 
characteristics 
of midazolam 
in the presence 
and absence of 
linaprazan 
Clinically 
significant changes 
in physical 
examinations, vital 
signs (blood 
pressure and pulse), 
ECG, and laboratory 
variables 
(haematology, 
clinical chemistry, 
and urinalysis). 
Linaprazan glurate 
and linaprazan PK 
parameters after 
repeated 
administration of 
linaprazan glurate 
twice daily (BID) 
for 13 days (if 
feasible): 
AUCinf 
AUC0-t 
Cmax 
Tmax 
T1/2 
AUCextr% 
CL/F 
V/F 
Accumulation ratio 
(Racc). 
Midazolam PK 
parameters in the 
presence and 
absence of 
linaprazan glurate 
administration (if 
feasible): 
Physical examinations, 
Vital signs, 12-lead 
electrocardiograms, 
Safety laboratory 
assessments 
 
 
 
 
 
 
Pharmacokinetic 
sampling and analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
sampling and analysis 
Descriptive 
statistics, Section 
9.3.2 to 9.3.5 
 
 
 
 
 
 
 
 
Summary statistics 
for PK parameters. 
See Section 9.3.9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summary statistics 
for PK parameters. 
See Section 9.3.8 
Table PE 2, Table VS 2, 
Table EG 2, Table EG 
4, Table LB 2, Table LB 
4, Table LB 6 
 
 
 
 
 
 
 
 
4.3.1.1 
Additional 
PK 
parameters 
Part II 
Table PP 7 
 
 
Objectives 
Endpoints 
Assessments 
Analyses 
Data display plan 
(DDP) 
administration linaprazan glurate 
Linear mixed- 
Table PP 2, 
of linaprazan 
administration: 
effects analysis of 
glurate on the 
PK properties 
of midazolam. 
AUCinf 
AUC 
Cmax 
variance model, 
see Section 9.2.3 
Table PC 2 and 
Figure PC 3 
Secondary 
Secondary 
Assessments, Part II 
Analyse, Part II 
DDP, Part II 
objective, 
endpoint, Part II 
Part II 
To assess the 
Frequency, 
Adverse events 
Descriptive 
Table AE 2, Table AE 4 
safety and 
seriousness, and 
statistics, Section 
tolerability 
intensity of AEs. 
9.3.1 


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Objectives 
Endpoints 
Assessments 
Analyses 
Data display plan 
(DDP) 
glurate 
administration. 
 
 
 
 
 
Exploratory 
objective, 
Part II 
To explore the 
metabolites of 
linaprazan 
glurate in 
plasma and 
urine after 
single and 
repeated doses 
of linaprazan 
glurate. 
Tmax 
T1/2 
AUCextr% 
CL/F 
V/F 
Exploratory 
endpoint, Part II 
 
Plasma and urine 
collected for future 
exploratory analyses 
of linaprazan glurate 
metabolites. 
 
 
 
 
 
 
 
Assessments, Part II 
Analyse, Part II 
DDP, Part II 
 
 
Not covered in the SAP 
NA 
NA 
 
 
 
Cinclus Pharma AB is responsible for analysing the exploratory objectives/endpoints. Results 
related to exploratory objectives/endpoints in Part I and II will not be reported in the clinical 
study report (CSR). Therefore, these will not be covered in this SAP. 
 
4.4 
Randomisation and number of subjects 
This is a non-randomized study. 
In total, approximately 54 subjects will be screened in the study (27 subjects for each part). 
In Part I, a total of 18 healthy subjects are planned to be included for an estimated total of 12 
evaluable subjects. 
In Part II, a total of 18 healthy subjects are planned to be included for an estimated total of 12 
evaluable subjects. 
 
4.5 
Subject replacement 
Subjects who are prematurely withdrawn from the study for any reason except the occurrence 
of AEs assessed as possibly or probably related to study treatment may be replaced during the 
course of the study. 
 
4.6 
Blinding 
This is an open-label study, i.e., the Investigator, study staff and study subjects will know the 
type of treatment received. 


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5 
STATISTICAL AND ANALYTICAL PLANS 
 
5.1 
Statistical hypotheses 
The statistical hypothesis to be tested in Part I is that coadministration of linaprazan glurate + 
clarithromycin as opposed to linaprazan glurate alone has no effect on CYP3A. 
The statistical hypothesis to be tested in Part II is that coadministration of midazolam + 
linaprazan glurate as opposed to midazolam alone has no effect on CYP3A. 
 
5.2 
Sample size calculation 
No formal sample size calculation has been performed for this study. The proposed sample size 
is considered sufficient to provide adequate information to meet the study objectives. 
 
5.3 
Definition of analysis sets 
The analysis sets defined for the study are outlined in Table 1. 
Table 1 
Analysis sets 
 
Analysis set 
Definition 
Use of analysis set 
Full analysis set (FAS) 
The full analysis set (FAS) will 
consist of all subjects who have 
received at least 1 dose of IMP 
and who provided at least 1 
post-baseline data point. There 
will be 1 FAS per part. 
All objectives/endpoints 
except PK 
objectives/endpoints. 
 
 
Pharmacokinetic analysis 
set (PKAS) 
The PK analysis set (PKAS) 
will consist of all subjects who 
received at least 1 dose of IMP 
and provided an evaluable 
plasma concentration profile, 
and who have no AEs or 
protocol deviations judged to 
affect the PK analysis. There 
will be 1 PKAS per part. 
Subjects with a calculated 
compliance of less than 82% 
during the home administration 
period will be excluded from 
the PKAS for the 
corresponding study part. 
Individual PK values may be 
excluded from the analysis as 
specified in the SAP. 
All protocol violations will be 
judged as major or minor prior 
to database lock. 
All PK 
objectives/endpoints. 
 
 
 
5.4 
Compliance 
During visits at the clinic, the study drugs will be administered at the clinic under medical 
supervision. Doses administered at the clinic will be entered in the eCRF by study personnel. 
On other days, subjects will self-administer clarithromycin (Part I) or linaprazan glurate (Part 
II) at home and register each intake of study drug in an electronic diary. Text reminders will be 


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sent to the subjects each day. At the compliance visit to the clinic, subjects will be asked to 
return any unused study drugs and all empty containers. 
Percent compliance will be calculated, per study part, for the home administration period as 
100 * (number of tablets delivered – number of tablets returned) / expected number of tablets 
taken 
If the electronic diary indicates the morning dose being taken later than 12.00 or the evening 
dose being taken before 17.00, the corresponding tablet will be judged as “returned” in the 
formula above. Calculated percent compliance will have an impact on inclusion to the PKAS, 
as described in Table 1 
Analysis sets. 
 
5.5 
Definition of baseline 
Baseline will be defined as the last non-missing data collection point prior to administration of 
IMP (i.e., linaprazan glurate in Part I) and midazolam (Part II). 
 
5.6 
Rounding principles 
Generally, no rounding of data will be done prior to calculating statistics. However, if reported 
data contains more than 8 significant digits it will be rounded to 8 significant digits in the 
database. 
In statistical output and descriptive summaries, the following principles will be followed: 
• Data will be presented as reported in input data in listings. 
• 2 significant digits will be used for percentages (for example relative change from 
baseline). 
• p-values and similar statistical output will be presented using 4 decimal points. 
• 3 significant digits will be used for PK parameters and similar when presenting min 
and max values in tables. 
• Descriptive summaries of PK parameters and similar (e.g. mean, SD, median etc.) will 
be presented with 4 significant digits. 
• Descriptive summaries of all other numerical data (e.g. mean, SD, median etc.) will be 
presented with one extra decimal compared to reported input data. 
 
5.7 
Significance level 
All statistical hypotheses in this study will be answered using two-sided 90% confidence 
intervals. This is not a confirmatory study. Hence, point estimates and CIs will be used 
exploratorily. 
 
5.8 
Multiple comparisons/multiplicity 
No adjustment for multiple comparison/multiplicity will be performed. All significant findings 
will be reviewed for medical relevance. 
 
5.9 
Handling of dropouts, missing data and outliers 
Outliers will be included in summary tables and listings and will not be handled separately in 
any analyses. Generally, no imputation of data will be performed. However, when calculating 
statistics for PK plasma concentrations, concentrations under LLOQ will be replaced with 
LLOQ/2 if more than 50% of the values for a given time point is above LLOQ. Otherwise, no 


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statistics will be calculated for that time point. For imputation of PK plasma concentration 
below LLOQ with the purpose of calculating PK parameters, see Section 9 below. 
In case of missing start and stop times of AEs that cannot be investigated further, missing data 
will be imputed according to a worst-case scenario. This means that start time will be imputed 
as the closest time point post first intake of IMP and end time as 23:59, resulting in the longest 
possible treatment emergent duration of the AE. 


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6 
CHANGES FROM THE CLINICAL STUDY PROTOCOL 
NA 


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7 
CLINICAL DATABASE PROCESSING 
 
7.1 
General information 
The clinical database is processed and generated according to The Clinical Data Interchange 
Standards Consortium (CDISC). CDISC is a Standard Developing Organization which 
develops and publishes standards to normalise the structure of clinical study data and thereby 
simplify submissions to and reviews by authorities such as the Food and Drug Administration 
(FDA). 
The CDISC standards for clinical studies are the Study Data Tabulation Model (SDTM) and 
the Analysis Data Model (ADaM). The study data will be structured into a database model 
reflecting the SDTM and be compliant to SDTM Implementation Guide (SDTM-IG) version 
3.2. The data used for statistical analysis will be structured to reflect the Analysis Data Model 
(ADaM) and be compliant to ADaM Implementation Guide (ADaM-IG) version 1.1. 
Data values are collected according to, or mapped into, Controlled Terminology (CT) codelists 
defined by CDISC, whenever possible. The codelists are updated quarterly at CTC and the latest 
version available at study start will be used. As per default, CT codelists will be used in all 
tables, listings, and figures. Custom codelists for test or parameter names will be used if 
applicable upon Sponsor’s request, to align with protocol texts, or to adhere to other standard 
naming conventions (e.g. PK parameter name “Tmax” will be used instead of the CDISC term 
“Time of CMAX”). These custom codelists will be mapped in the “Parameter Name” field in 
the ADaM structure, while the CT will be kept in the SDTM predecessor fields to provide 
traceability back to CDISC codelists. 
7.1.1 
CDISC Compliance 
The study database will be CDISC compliant which means that the clinical database will be 
processed and generated according to CDISC standard. The database will be validated against 
SDTM and ADaM Validation rules using Pinnacle 21. 
The following CDISC documentation will be generated: 
• SDTM Data Definition Specification (also referred to as a Define -XML) 
- 
Define-XML transmits metadata that describes any tabular dataset structure and 
supports the interchange of dataset metadata for clinical research applications in a 
machine-readable format. 
• ADaM Data Definition Specification (also referred to as a Define -XML) 
- 
Define-XML transmits metadata that describes any tabular dataset structure and 
supports the interchange of dataset metadata for clinical research applications in a 
machine-readable format. 
• Annotated eCRF 
- 
Links the data collection fields used to capture study data to the corresponding 
variables in the study database. It enables the user to understand how the study data 
were collected and to trace back from study analysis results to the origin where it 
was collected. 
• SDTM Reviewers’ Guide 
- 
Intended to provide additional context and act as a single point of orientation for the 
SDTM datasets. 
• ADaM Reviewers’ Guide 
- 
Provides regulatory agency reviewers an orientation to the submitted analysis data 
in a consistent way and usable format. 


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7.2 
Database modeling of study design 
The study design is mapped to a SDTM study design model containing the following structural 
components: 
EPOCH: An interval of time in the planned conduct of a study. An epoch is associated with a 
purpose (e.g., screening, randomization, treatment, follow-up), and applies across all arms of 
the study. Study epochs follow a controlled terminology to represent the different study parts 
(e.g. SCREENING, TREATMENT [X], FOLLOW-UP) 
ELEMENT: Building blocks used to build up the entire study length for all subjects. 
Information on ELEMENTs is extracted from the study design and schedule of events in the 
protocol. ELEMENTs are defined to span the entire study without gaps. One EPOCH may 
contain one or several ELEMENTs. All ELEMENTs must have transition rules in accordance 
with the protocol to determine start and end. 
ARM: Subjects are allocated to study arms depending on the study design, either by 
randomization or other allocation processes defined in the study protocol. ARMs are defined as 
the total number of planned ways a subject can go through the study (unique combination of 
study ELEMENTs). All ARMs must contain a unique sequence of ELEMENTs. 
VISIT: Study visits are defined as planned timepoints during the study where study data is 
collected. A visit can be performed in clinic, by off-site contact with study personnel (phone 
call, video conference or similar), or by subject initiated recordings of data. The visit schedule 
is extracted from protocol and eCRF design. 
A schematic representation of the SDTM study design is presented in Figure 1. 
 
 
Figure 1    Schematic representation of the SDTM study design 
 
Part I: 
 
 
 
Part II: 
 


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8 
STATISTICAL DELIVERABLES 
The following items will be delivered: 
• Statistical analyses, summary tables, listings and figures as described under Section 
10. 
• Clinical study database delivered as a SAS-export file. 
• Define -XML for SDTM 
• Define -XML for ADaM 
• Annotated eCRF 
• SDTM Reviewer´s Guide 
• ADaM Reviewer´s Guide 


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9 
STATISTICAL METHODOLOGY 
There will be two clean files (CF) in this study, corresponding to the two study parts. Therefore, 
output in this study (tables, figures and listings) will be done in two different sets, one per study 
part. However, there will only be one CSR including both study parts. 
All collected data will be listed by treatment and subject. 
Details on statistical analyses and descriptive summaries are specified below. 
All statistical analysis and descriptive summaries will be performed using SAS version 9.4 
(SAS institute, Cary, NC). 
 
9.1 
Pharmacokinetic calculations 
PK parameters will be calculated by Non-Compartmental Analysis (NCA) using the software 
Phoenix WinNonlin® version 8.3 (Certara, U.S.A). 
The following NCA PK parameters will be calculated for linaprazan glurate and linaprazan, 
for secondary endpoints the parameters will only be calculated when feasible: 
• Cmax – The maximum observed plasma concentration 
• AUC0-t – The area under the plasma concentration versus time curve (AUC) from 
timepoint 0 to t, where t represents the timepoint of the last detectable plasma 
concentration per dosing occasion. 
• Partial AUCs– AUC from time t1 to time t2. Partial AUCs will be calculated between 0- 
24 h, 24-48 h Day 2 and 0-24 h Day 14 (only in Part II) 
• AUC0-inf – AUC from timepoint 0 extrapolated to infinity (not calculated for steady 
state/repeated dose data) 
• AUCtau – AUC per dosing interval (calculated at steady state and for the first dose) 
• Tmax – Time to reach Cmax 
• CL/F – Total body clearance for extravascular administration (only for linaprazan 
glurate as there is no dose data for linaprazan) 
• Vz/F – Apparent volume of distribution associated with terminal slope (only for 
linaprazan glurate as there is no dose data for linaprazan) 
• T1/2 – The terminal plasma elimination half-life 
• AUCextr% – Percentage of AUC0-inf due to extrapolation from Tlast to infinity 
• Racc Cmax – Accumulation ratio for Cmax (only in Part II) 
• Racc AUC – Accumulation ratio for AUC (only in Part II) 
 
The following NCA PK parameters will be calculated for clarithromycin: 
• AUCtau – The AUC during dosing interval at steady state 
• Cmax 
• Tmax 
• T1/2 
 
The following NCA PK parameters will be calculated for midazolam: 
• AUC0-t 
• AUC0-inf 
• AUCextr% 


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• Cmax 
• Tmax 
• T1/2 
• CL/F 
• Vz/F 
 
Additional PK parameters that will be calculated (and only presented in listing if not specified 
above) for linaprazan glurate, linaprazan, clarithromycin and midazolam: 
• Lambdaz – The eliminate rate constant associated with the terminal phase of the curve 
• Rsq adj – Coefficient of determination adjusted for the independent variable time 
• No points lambdaz – Number of points used in computing lambdaz 
• Lambdaz lower – Lower limit on time included in the calculation of lambdaz 
• Lambdaz upper – Upper limit on time included in the calculation of lambdaz 
• Span – The ratio between the interval used for determination of lambdaz and the 
terminal T1/2 
• AUCextr% 
 
 
Non-compartmental analysis will be based on the actual sampling times recorded during the 
study. For the purpose of calculating PK parameters, concentrations below lower limit of 
quantification (LLOQ) occurring before Cmax will be treated as zero. Concentrations below 
LLOQ occurring after Cmax will be omitted from the analysis. 
Tmax and Cmax will be based on the observed plasma concentration data. 
All AUCs will be assessed by integration of the plasma concentration vs time curve using linear 
interpolation for increasing plasma levels and logarithmic interpolation for decreasing plasma 
levels (Linear Up-Log Down method using uniform weighting). 
AUC0-t will be calculated from time 0 to the time t of the last detectable plasma concentration. 
For AUC0-inf the area will be calculated to the last timepoint showing a measurable plasma 
concentration and then extrapolated to infinity using the concentration in the last quantifiable 
sample and lambdaz. 
𝐶𝑙𝑎𝑠𝑡 
𝐴𝑈𝐶0−𝑖𝑛𝑓 = 𝐴𝑈𝐶0−𝑡 + 𝑙𝑎𝑚𝑏𝑑𝑎 
Partial AUC (possible relevant for AUCtau calculations) will be derived according to specified 
time windows, if the end time of the interval does not occur at an actual timepoint either linear 
interpolation or extrapolation will be used for derivation of the partial AUC. Extrapolation, 
using lambdaz, will only be used if the end time of specified interval occur after last detectable 
plasma concentration. 
 
Formulas for calculation of AUC 
• Linear trapezoidal rule: 
𝐴𝑈𝐶|𝑡2 = 𝛿𝑡 × 𝐶1 + 𝐶2 
𝑡1 
2 
 
• Logarithmic trapezoidal rule: 
𝑧 


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𝐴𝑈𝐶|𝑡2 = 𝛿𝑡 × 𝐶2 − 𝐶1 
𝑡1 
𝐶2 
𝑙𝑛 (𝐶1) 
 
where t = time, c = concentration, δt = t2-t1. 
 
Formulas for interpolation (to find C* at time t* for t1 < t* < t2) 
• Linear interpolation rule: 
𝑡∗ − 𝑡1 
𝐶∗ = 𝐶1 + | 
𝑡2 − 𝑡1 | (𝐶2 − 𝐶1) 
 
• Logarithmic interpolation rule: 
 
𝑡∗ − 𝑡1 
𝐶∗ = 𝑒𝑥𝑝(𝑙𝑛(𝐶1) + | 
𝑡2 − 𝑡1 | ∗ (𝑙𝑛(𝐶2) − 𝑙𝑛(𝐶1))) 
where t = time, c = concentration 
 
Lambdaz, the first order rate constant associated with the terminal portion of the curve, will be 
determined by lin-logarithmic regression of the terminal elimination phase of individual plasma 
concentration vs time curves. Determination of lambdaz requires identification of a sufficiently 
linear terminal phase (as determined by visual inspection of the lin-log plasma concentration vs 
time plot with the regression line) consisting of at least 3 terminal concentration values (not 
including Cmax). If this is not achieved, lambdaz and its dependent PK parameters will not be 
reported for that profile. 
In the following cases, lambdaz dependent PK parameters will be flagged in listings as 
potentially unreliable: 
• Lambdaz estimation is based on a period of less than 1.5 times the resulting T½. 
• The adjusted R2 value of the regression line is < 0.85. 
• The estimated % extrapolated AUC is > 20% ((AUC0-inf -AUC0-last / AUC0-inf)*100). 
o In case the extrapolated AUC is > 30% lambdaz dependent parameter will 
excluded from analysis and descriptive statistics. 
 
T½ will be calculated by ln2 / lambdaz, and Span will be calculated by (lambdaz_upper – 
lambdaz-lower) / T1/2. 
CL/F for single doses will be calculated by Dose / AUC0-inf and CL/F at steady state will be 
calculated by Dose / AUCtau. 
Vz/F for single doses will be calculated by Dose / (lambdaz x AUC0-inf), and Vz/F at steady state 
will be calculated by Dose / (lambdaz x AUCtau). 
The accumulation ratio for Cmax will be calculated by Cmax at steady state / Cmax first dose, and 
the accumulation ratio for AUC will be calculated by AUCtau at steady state / AUCtau first dose. 


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If there is a confirmed dosing error during the study, the pharmacokinetic data for that period 
will only be included in the listings but excluded from descriptive and statistical analyses. In 
case of missed blood samples, potential impact on PK parameters will be assessed for each 
individual case. PK parameters with a high degree of uncertainty due to missing samples (e.g. 
multiple samples missing around Cmax) will be flagged as unreliable in the report and may in 
rare cases be excluded from summary tables, descriptive statistics, and statistical analysis. 
Relevant PK data will be presented by using summary statistics with number of measurements, 
arithmetic mean, SD, as well as median, minimum and maximum values. In addition, for the 
parameters AUC and Cmax the geometric mean and coefficient of variation (CV%) will be 
presented. 
 
9.2 
Analysis of the primary endpoint 
9.2.1 
Analysis of PK parameters 
Part I: 
The following PK parameters will be assessed for linaprazan glurate and linaprazan, in the 
presence (Day 10) and absence (Day 1) of clarithromycin administration: 
• AUC0-inf 
• AUC0-t 
• Cmax 
Part II: 
The following PK parameters will be assessed for midazolam, in the presence (Day2 and 14 
respectively) and absence (Day 1) of linaprazan glurate administration: 
• AUC0-inf 
• AUC0-t 
• Cmax 
 
9.2.2 
Mixed model for PK parameters Part I 
The PK parameters AUCinf, AUC0-t and Cmax will be analyzed using a mixed model following 
a natural logarithmic transformation, with fixed effect for treatment and random effect for 
subject. Kenward-Rogers approximation for degrees of freedom will be used. Model results 
will be back-transformed to the original scale to present, ratios of geometric means together 
with 2-sided 90% CI of test treatment (linaprazan glurate + clarithromycin) and reference 
treatment (linaprazan glurate alone) will be estimated and presented. The same analysis will 
also be done for linaprazan + clarithromycin vs. linaprazan alone. The SAS proc mixed code to 
be used will be: 
ods output lsmeans=lsmeans 
diffs=diffs 
solutionr=randeffects; 
proc mixed data=indata; 
by paramn param ppcat; 
class USUBJID Treatment; 
model ln_PK_var = Treatment / ddfm=kenwardroger outp=residuals 
outpm=randeffects2 RESIDUAL; 
lsmeans Treatment / alpha=0.1 diff cl adjust=tukey ADJDFE=ROW; 
random USUBJID / solution; 
run; 


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9.2.3 
Mixed model for PK parameters Part II 
Midazolam PK parameters AUCinf, AUC0-t and Cmax for the comparisons midazolam + 
linaprazan glurate Day 14 / midazolam Day 1, midazolam + linaprazan glurate Day 14 / 
midazolam + linaprazan glurate Day 2 and midazolam + linaprazan glurate Day 2 / midazolam 
Day 1 will be estimated using the same model as described under section 9.2.2 above. 
 
9.3 
Analysis of secondary endpoints 
9.3.1 
Adverse events 
An overview of all AEs, including SAEs, intensity, relationship to IMP, and deaths will be 
presented. The incidence of AEs and SAEs will be summarized by SOC and PT by treatment 
and overall. An overview of any treatment-related AEs will be summarized by SOC and PT if 
considered appropriate. 
9.3.2 
Physical examinations 
Clinically significant and non-clinically significant abnormal findings will be specified and 
presented by subject and summarized by treatment. 
9.3.3 
Vital signs 
Vital signs (systolic/diastolic BP, pulse rate, and body temperature) will be summarized by 
treatment and overall. Data will be presented with absolute and percent change from baseline. 
9.3.4 
12-lead safety ECG 
All ECGs will be categorized as ”normal”, ”abnormal, not clinically significant”, or ”abnormal, 
clinically significant” (as judged by the Investigator) and summarized by treatment using 
frequency tables. 
9.3.5 
Safety laboratory analyses 
Safety laboratory data will be summarized by treatment, with absolute and percent change from 
baseline at each visit. 
Abnormal, clinically significant values will be summarized separately if considered 
appropriate. 
9.3.6 
Additional PK parameters Part I for linaprazan glurate and linaprazan, not 
limited to: 
The following secondary NCA PK parameters will be assessed for linaprazan glurate and 
linaprazan, but are not limited to: 
• Tmax 
• T1/2 
• CL/F 
• V/F 
• AUCextr% 


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9.3.7 
Clarithromycin PK parameters Part I with and without co-administration of 
linaprazan glurate: 
The following secondary NCA PK parameters will be assessed for clarithromycin with and 
without co-administration of linaprazan glurate, not limited to: 
• AUC to the end of the dosing period (AUCtau) 
• Cmax 
• 
Tmax 
• T1/2 
 
9.3.8 
Additional Midazolam PK parameters Part II in the presence and absence of 
linaprazan glurate administration (if feasible): 
The following secondary NCA PK parameters will be assessed for midazolam, in the presence 
and absence of linaprazan glurate administration (if feasible): 
• Tmax 
• T1/2 
• AUCextr% 
• CL/F 
• V/F 
9.3.9 
Linaprazan glurate and linaprazan PK parameters Part II (if feasible): 
The following secondary NCA PK parameters will be assessed for linaprazan glurate and 
linaprazan (if feasible): 
• AUCtau 
• AUC0-t 
• Cmax 
• AUCextr% 
• CL/F (only for linaprazan glurate) 
• V/F (only for linaprazan glurate) 
• Racc 
• Tmax 
• T1/2 
Additional PK parameters may be determined if deemed appropriate. 
 
9.4 
Description of study population 
Other study population/demographics data will be presented in listings and summarized 
descriptively as described in section 10 below. 


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10 
DATA DISPLAY PLAN 
 
10.1 
Table of contents DDP 
10.2 
Study tables ............................................................................................................. 27 
10.2.1 Demographic data ............................................................................................... 27 
10.2.2 Primary endpoints ............................................................................................... 32 
10.2.2.1 
Analysis of pharmacokinetics ...................................................................... 32 
10.2.3 Secondary endpoints ........................................................................................... 36 
10.2.3.1 
Additional PK parameters Part I ................................................................. 36 
10.2.3.2 
Additional PK parameters Part II ................................................................ 38 
10.2.3.3 
Adverse events ............................................................................................ 41 
10.2.3.4 
Physical examinations ................................................................................. 43 
10.2.3.5 
Vital signs .................................................................................................... 44 
10.2.3.6 
12-lead safety ECG ..................................................................................... 45 
10.2.3.7 
Safety laboratory analyses ........................................................................... 45 
10.3 
Study figures ........................................................................................................... 46 
10.3.1 Primary endpoint(s) ............................................................................................ 46 
10.4 
Study listings ........................................................................................................... 48 
 
 
List of tables 
Table DM 1 
Baseline characteristics and demographics for Part I (Full analysis set) 
27 
Table DM 2 
Baseline characteristics and demographics for Part II (Full analysis set) 
28 
Table DS 1 
Subject disposition for Part I (All subjects) 
29 
Table DS 2 
Subject disposition for Part II (All subjects) 
30 
 
Table MH 1 
Medical history events by system organ class and preferred term part I (Full 
analysis set) 
30 
Table MH 2 
Medical history events by system organ class and preferred term part II (Full 
analysis set) 
30 
 
 
Table CM 1 
Prior medications by ATC levels 4 and 5 for Part I (Full analysis set) 
31 
Table CM 2 
Prior medications by ATC levels 4 and 5 for Part II (Full analysis set) 
31 
Table CM 3 
set) 
Concomitant medications by ATC levels 4 and 5 for Part I (Full analysis 
31 
Table CM 4 
set) 
Concomitant medications by ATC levels 4 and 5 for Part II (Full analysi
31 


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Table PP 1 
PK parameters for linaprazan glurate and linaprazan for Part I 
(Pharmacokinetic analysis set) 
32 
Table PP 2 
PK parameters for midazolam for Part II (Pharmacokinetic analysis set) 
33 
Table PP 3 
Mixed model results for PK parameters for Part I (Pharmacokinetic analysis 
set) 
34 
Table PP 4 
Mixed model results for PK parameters for Part II (Pharmacokinetic analysis 
set) 
34 
Table PP 5 
Additional PK parameters for linaprazan glurate and linaprazan for Part I 
(Pharmacokinetic analysis set) 
36 
Table PP 6 
PK parameters for clarithromycin for Part I (Pharmacokinetic analysis 
set) 
37 
Table PP 7 
Additional PK parameters for midazolam for Part II (Pharmacokinetic 
analysis set) 
38 
Table PP 8 
Additional PK parameters for linaprazan glurate and linaprazan for Part II 
(Pharmacokinetic analysis set) 
39 
Table PC 1 
Plasma concentrations for part I (Pharmacokinetic analysis set) 
35 
Table PC 2 
Plasma concentrations for part II (Pharmacokinetic analysis set) 
35 
Table AE 1 
Overview of adverse events for Part I (Full analysis set) 
41 
Table AE 2 
Overview of adverse events for Part II (Full analysis set) 
41 
Table AE 3 
Adverse events by system organ class and preferred term for Part I (Full 
analysis set) 
 42 
Table AE 4 
Adverse events by system organ class and preferred term for Part II (Full 
analysis set) 
 42 
Table PE 1 
Physical examinations for Part I (Full analysis set) 
43 
Table PE 2 
Physical examinations for Part II (Full analysis set) 
43 
Table VS 1 
Vital signs measurements for Part I (Full analysis set) 
44 
Table VS 2 
Vital signs measurements for Part II (Full analysis set) 
44 
Table EG 1 
ECG measurements for Part I (Full analysis set) 
45 
Table EG 2 
ECG measurements for Part II (Full analysis set) 
45 
Table EG 3 
ECG interpretations for Part I (Full analysis set) 
45 
Table EG 4 
ECG interpretations for Part II (Full analysis set) 
45 


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Table LB 1 
Safety laboratory measurements - clinical chemistry for part I (Full analysis 
set) 
45 
Table LB 2 
Safety laboratory measurements - clinical chemistry for part II (Full analysis 
set) 
45 
Table LB 3 
Safety laboratory measurements - haematology for part I (Full analysis 
set) 
45 
Table LB 4 
Safety laboratory measurements - haematology for part II (Full analysis 
set) 
45 
Table LB 5 
Safety laboratory interpretations – urinalysis for part I (Full analysis set) 45 
Table LB 6 
Safety laboratory interpretations – urinalysis for part II (Full analysis set) 45 
List of figures 
Figure PC 1 
Geometric mean plasma concentrations over time (lin-log) for Part I 
(Pharmacokinetic analysis set) 
46 
Figure PC 2 
Geometric mean plasma concentrations over time (lin-log) for Part II 
(Pharmacokinetic analysis set) 
46 
Figure PC 3 
Geometric mean plasma concentrations over time (lin-lin) for Part I 
(Pharmacokinetic analysis set) 
46 
Figure PC 4 
Geometric mean plasma concentrations over time (lin-lin) for Part II 
(Pharmacokinetic analysis set) 
46 
Figure PC 5 
Individual plasma concentrations over time (lin-log) for Part I (Full analysis 
set) 
47 
Figure PC 6 
Individual plasma concentrations over time (lin-log) for Part II (Full analysis 
set) 
47 
Figure PC 7 
Individual plasma concentrations over time (lin-lin) for Part I (Full analysis 
set) 
47 
Figure PC 8 
Individual plasma concentrations over time (lin-lin) for Part II (Full analysis 
set) 
47 


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10.2 
Study tables 
10.2.1 
Demographic data 
Table DM 1 Baseline characteristics and demographics for Part I (Full analysis set) 
 
 
 
Assessment (unit) 
Total 
(N=XX) 
 
Age (years) 
n 
Mean (SD) 
Median (Min, Max) 
x 
xx.x (xx.x) 
xx.x (xx, xx) 
Height (cm) 
n 
Mean (SD) 
Median (Min, Max) 
x 
xxx.x (xx.x) 
xxx.x (xxx, xxx) 
Weight (kg) 
n 
Mean (SD) 
Median (Min, Max) 
x 
xx.xx (xx.xx) 
xx.xx (xx.x, xx.x) 
Body Mass Index (kg/m2) 
n 
Mean (SD) 
Median (Min, Max) 
X 
xx.xx (xx.xx) 
xx.xx (xx.x, xx.x) 
Sex 
Female 
Male 
xx (xx%) 
xx (xx%) 
Ethnicity 
Hispanic or latino 
xx (xx%) 
Not hispanic or latino 
xx (xx%) 
Not reported 
xx (xx%) 
Unknown 
xx (xx%) 
Race 
American Indian or Alaska Native 
xx (xx%) 
Asian 
xx (xx%) 
Black or African American 
xx (xx%) 
Native Hawaiian or Other Pacific Islander 
xx (xx%) 


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Assessment (unit) 
Total 
(N=XX) 
 
White 
xx (xx%) 
Data based on [ANALYSIS SET]. N: number of subjects in treatment group. Mean values and percentages are based on n. n: Number of observations. 
SD: Standard deviation. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 
 
 
Table DM 2 Baseline characteristics and demographics for Part II (Full analysis set) 
Use the same format as for Table DM 1. 


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Table DS 1 
Subject disposition for Part I (All subjects) 
 
Total 
(N=XXX) 
Screened subjects 
xxx 
Withdrawn prior to dose 
xxx 
Reason for withdrawal prior to dose 
--- Reason 1 
xxx 
--- Reason 2 
xxx 
--- … 
xxx 
Subjects included in study 
xxx 
Withdrawn subjects 
--- Reason 1 
xxx 
--- Reason 2 
xxx 
--- … 
xxx 
Subjects completing all study visits 
xxx 
Included in Full analysis set 
xxx 
Included in Pharmacokinetic analysis set 
xxx 
Subjects at each visit 
--- Visit 1 
xxx 
--- Visit 2 
xxx 
--- Visit 3 
xxx 
--- Visit 4 
xxx 
--- Visit 5 
xxx 
--- Visit 6 
xxx 
--- Visit 7 
xxx 
--- Visit 8 
xxx 
--- Visit 9 
xxx 
--- Visit 10 
xxx 
Data based on All subjects. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 


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Table DS 2 
Subject disposition for Part II (All subjects) 
Use the same format as for Table DS 1. 
 
 
Table MH 1  Medical history events by system organ class and preferred term part I (Full analysis set) 
 
Total 
(N=XX) 
System organ class 
Preferred term 
n (%) 
m 
Total 
xx (xx%) 
xx 
[SOC 1] 
xx (xx%) 
xx 
[SOC 1 PT 1] 
xx (xx%) 
xx 
[SOC 1 PT 2] 
xx (xx%) 
xx 
[SOC 1 PT …] 
xx (xx%) 
xx 
[SOC 2] 
xx (xx%) 
xx 
[SOC 2 PT 1] 
xx (xx%) 
xx 
[SOC 2 PT 2] 
xx (xx%) 
xx 
[SOC 2 PT …] 
xx (xx%) 
xx 
[SOC …] 
xx (xx%) 
xx 
[SOC … PT 1] 
xx (xx%) 
xx 
[SOC … PT 2] 
xx (xx%) 
xx 
[SOC … PT …] 
xx (xx%) 
xx 
Data based on [ANALYSIS SET]. n, number of subjects. m, number of events. Percentages are based on the number of subjects in the treatment 
period. The following events are coded with multiple terms and are represented as separate events in tables and listings: '[MH TERM 1], [MH TERM 
2]'. See listings for detailed information. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM- 
DDTHH:MM:SS 
 
 
Table MH 2  Medical history events by system organ class and preferred term part II (Full analysis set) 
Use the same format as for Table MH 1. 


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Table CM 1 Prior medications by ATC levels 4 and 5 for Part I (Full analysis set) 
Total 
(N=XX) 
ATC classification 
Active ingredients 
n (%) 
m 
Total 
xx (xx%) 
xx 
[L4 1] 
xx (xx%) 
xx 
[L4 1 L5 1] 
xx (xx%) 
xx 
[L4 1 L5 2] 
xx (xx%) 
xx 
[L4 1 L5 …] 
xx (xx%) 
xx 
[L4 2] 
xx (xx%) 
xx 
[L4 2 L5 1] 
xx (xx%) 
xx 
[L4 2 L5 2] 
xx (xx%) 
xx 
[L4 2 L5 …] 
xx (xx%) 
xx 
[L4 …] 
xx (xx%) 
xx 
[L4 … L5 1] 
xx (xx%) 
xx 
[L4 … L5 2] 
xx (xx%) 
xx 
[L4 … L5 …] 
xx (xx%) 
xx 
Data based on [ANALYSIS SET]. n, number of subjects. m, number of events. Percentages are based on the number of subjects in the treatment 
period. The following records are coded with multiple terms and are represented as separate events in tables and listings: '[CM TERM 1], [CM TERM 
2]'. See listings for detailed information. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM- 
DDTHH:MM:SS 
 
Table CM 2 Prior medications by ATC levels 4 and 5 for Part II (Full analysis set) 
Use the same format as for Table CM 1. 
Table CM 3 Concomitant medications by ATC levels 4 and 5 for Part I (Full analysis set) 
Use the same format as for Table CM 1. 
Table CM 4 Concomitant medications by ATC levels 4 and 5 for Part II (Full analysis set) 
Use the same format as for Table CM 1. 


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10.2.2 
Primary endpoints 
 
10.2.2.1 
Analysis of pharmacokinetics 
Table PP 1 
PK parameters for linaprazan glurate and linaprazan for Part I (Pharmacokinetic analysis set) 
 
 
 
 
 
Assessment (unit) 
 
Linaprazan glurate 
alone 
(N=XX) 
Linaprazan glurate co- 
administred with 
clarithromycin 
(N=XX) 
 
 
Linaprazan alone 
(N=XX) 
Linaprazan co- 
administred with 
clarithromycin 
(N=XX) 
 
AUCinf (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
AUC0-t (unit) 
Geometric Mean (geo CV%) 
n 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Cmax (unit) 
Geometric Mean (geo CV%) 
n 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Geometric Mean (geo CV%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
Data based on [population]. n: Number of observations. SD: Standard deviation. CV%: Coefficient of variation described as percentage. Geo CV%: 
Geometric coefficient of variation described as percentage calculated using log-transformed standard deviation. NC: Not calculated - number of 
evaluable observations less than 3. NA: Not available - no evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM- 
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 


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Table PP 2 
PK parameters for midazolam for Part II (Pharmacokinetic analysis set) 
 
 
 
Midazolam alone, 
Midazolam co- 
administred with 
Midazolam co- 
administred with 
Day 1 
linaprazan glurate, Day 2 linaprazan glurate, Day 14 
Assessment (unit) 
(N=XX) 
(N=XX) 
(N=XX) 
 
AUCinf (unit) 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
AUC0-t (unit) 
Geometric Mean (geo CV%) 
n 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Cmax (unit) 
Geometric Mean (geo CV%) 
n 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
x.xxx (x.x%) 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Geometric Mean (geo CV%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
Data based on [population]. n: Number of observations. SD: Standard deviation. CV%: Coefficient of variation described as percentage. Geo CV%: 
Geometric coefficient of variation described as percentage calculated using log-transformed standard deviation. NC: Not calculated - number of 
evaluable observations less than 3. NA: Not available - no evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM- 
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 


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Table PP 3 
Mixed model results for PK parameters for Part I (Pharmacokinetic analysis set) 
 
Parameter 
Test treatment 
Reference treatment 
90% CI 
lower bound 
Ratio of geometric 
least square means 
90% CI 
upper bound 
AUCinf (unit) 
Linaprazan glurate co-administred with clarithromycin 
Linaprazan co-administred with clarithromycin 
Linaprazan glurate alone 
Linaprazan glurate alone 
x.xxx 
x.xxx 
x.xxxx 
x.xxxx 
x.xxx 
x.xxx 
AUC0-t (unit) 
Cmax (unit) 
Linaprazan glurate co-administred with clarithromycin 
Linaprazan co-administred with clarithromycin 
Linaprazan glurate co-administred with clarithromycin 
Linaprazan co-administred with clarithromycin 
Linaprazan glurate alone 
Linaprazan glurate alone 
Linaprazan glurate alone 
Linaprazan glurate alone 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
Pairwise treatment comparisons are based on a mixed effects model with treatment as a fixed effect and subject as a random effect. Kenward-Rogers 
approximation for degrees of freedom has been used. 
Data based on PK analysis set. 
[STUDYID], SAS program: [PROGRAM NAME]. Run by: [USERNAME], [USER EMAIL] [TIMESTAMP]. Data extracted at: [TIMESTAMP] 
 
 
 
 
Table PP 4 
Mixed model results for PK parameters for Part II (Pharmacokinetic analysis set) 
 
Parameter 
Test treatment 
Reference treatment 
90% CI 
lower bound 
Ratio of geometric 
least square means 
90% CI 
upper bound 
AUCinf (unit) 
Midazolam co-administred with linaprazan glurate, Day 14 
Midazolam co-administred with linaprazan glurate, Day 2 
Midazolam alone, Day 1 
Midazolam alone, Day 1 
x.xxx 
x.xxx 
x.xxxx 
x.xxxx 
x.xxx 
x.xxx 
AUC0-t (unit) 
Midazolam co-administred with linaprazan glurate, Day 14 
Midazolam co-administred with linaprazan glurate, Day 14 
Midazolam co-administred with linaprazan glurate, Day 2 
Midazolam co-administred with linaprazan glurate, Day 2 
Midazolam alone, Day 1 
Midazolam alone, Day 1 
x.xxx 
x.xxx 
x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx 
x.xxx 
x.xxx 
Cmax (unit) 
Midazolam co-administred with linaprazan glurate, Day 14 
Midazolam co-administred with linaprazan glurate, Day 14 
Midazolam co-administred with linaprazan glurate, Day 2 
Midazolam co-administred with linaprazan glurate, Day 2 
Midazolam alone, Day 1 
Midazolam alone, Day 1 
x.xxx 
x.xxx 
x.xxx 
x.xxxx 
x.xxxx 
x.xxxx 
x.xxx 
x.xxx 
x.xxx 
Midazolam co-administred with linaprazan glurate, Day 14 
Midazolam co-administred with linaprazan glurate, Day 2 
x.xxx 
x.xxxx 
x.xxx 
Pairwise treatment comparisons are based on a mixed effects model with treatment as a fixed effect and subject as a random effect. Kenward-Rogers 
approximation for degrees of freedom has been used. 
Data based on PK analysis set. 
[STUDYID], SAS program: [PROGRAM NAME]. Run by: [USERNAME], [USER EMAIL] [TIMESTAMP]. Data extracted at: [TIMESTAMP] 


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Table PC 1 
Plasma concentrations for part I (Pharmacokinetic analysis set) 
 
 
 
Assessment (unit) 
Assessment timepoint 
Total 
(N=XX) 
 
[PARAMETER 1] (unit) 
[Assessment timepoint 1] 
[Assessment timepoint 2] 
n 
Mean (SD) 
Median (Min, Max) 
n 
Mean (SD) 
Median (Min, Max) 
… 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
… 
Data based on [population]. Dynamic footnote based on table content: n: Number of observations. SD: Standard deviation. NC: Not calculated - 
number of evaluable observations less than 3. NA: Not available - no evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] 
YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 
 
 
Table PC 2 
Plasma concentrations for part II (Pharmacokinetic analysis set) 
Use the same format as for 
Table PC 1. 


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10.2.3 
Secondary endpoints 
 
10.2.3.1 
Additional PK parameters Part I 
Table PP 5 
Additional PK parameters for linaprazan glurate and linaprazan for Part I (Pharmacokinetic analysis set) 
 
Linaprazan glurate 
alone 
Linaprazan glurate co- 
administred with 
clarithromycin 
Linaprazan alone 
Linaprazan co- 
administred with 
clarithromycin 
Assessment (unit) 
(N=XX) 
(N=XX) 
(N=XX) 
(N=XX) 
[Tmax] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[T1/2] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[CL/F] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[V/F] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[AUCextr%] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Geometric Mean (geo CV%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
Data based on [population]. n: Number of observations. SD: Standard deviation. CV%: Coefficient of variation described as percentage. Geo CV%: 
Geometric coefficient of variation described as percentage calculated using log-transformed standard deviation. NC: Not calculated - number of 
evaluable observations less than 3. NA: Not available - no evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM- 
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 


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Table PP 6 
PK parameters for clarithromycin for Part I (Pharmacokinetic analysis set) 
 
 
 
 
Assessment (unit) 
 
Clarithromycin alone 
(N=XX) 
clarithromycin co-administred 
with linaprazan glurate 
(N=XX) 
[AUCtau] (unit) 
n 
Mean (SD) 
Median (Min, Max) 
Geometric Mean (geo 
CV%) 
[Cmax] (unit) 
n 
Mean (SD) 
Median (Min, Max) 
Geometric Mean (geo 
CV%) 
[Tmax] (unit) 
n 
Mean (SD) 
Median (Min, Max) 
[T1/2] (unit) 
n 
Mean (SD) 
Median (Min, Max) 
xx 
xx 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xxx (x.x%) 
x.xxx (x.x%) 
xx 
xx 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xxx (x.x%) 
x.xxx (x.x%) 
xx 
xx 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
xx 
xx 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Data based on [population]. n: Number of observations. SD: Standard deviation. CV%: Coefficient of variation described as percentage. Geo CV%: 
Geometric coefficient of variation described as percentage calculated using log-transformed standard deviation. NC: Not calculated - number of 
evaluable observations less than 3. NA: Not available - no evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM- 
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 


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10.2.3.2 
Additional PK parameters Part II 
Table PP 7 
Additional PK parameters for midazolam for Part II (Pharmacokinetic analysis set) 
Midazolam alone, 
Midazolam co- 
administred with 
Midazolam co- 
administred with 
Day 1 
linaprazan glurate, Day 2 linaprazan glurate, Day 14 
Assessment (unit) 
(N=XX) 
(N=XX) 
(N=XX) 
 
[Tmax] (unit) 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[T1/2] (unit) 
n 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
[CL/F] (unit) 
[V/F] (unit) 
n 
Mean (SD) 
Median (Min, Max) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
n 
Mean (SD) 
Median (Min, Max) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
[AUCextr%] (unit) 
n 
Mean (SD) 
Median (Min, Max) 
Geometric Mean (geo CV%) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
x.xxx (x.x%) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
x.xxx (x.x%) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
x.xxx (x.x%) 
Data based on [population]. n: Number of observations. SD: Standard deviation. CV%: Coefficient of variation described as percentage. Geo CV%: 
Geometric coefficient of variation described as percentage calculated using log-transformed standard deviation. NC: Not calculated - number of 
evaluable observations less than 3. NA: Not available - no evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM- 
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 


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Table PP 8 
Additional PK parameters for linaprazan glurate and linaprazan for Part II (Pharmacokinetic analysis set) 
 
 
 
 
Assessment (unit) 
Linaprazan glurate, 
Day 2 
(N=XX) 
linaprazan glurate, 
Day 14 
(N=XX) 
Linaprazan, 
Day 2 
(N=XX) 
linaprazan, 
Day 14 
(N=XX) 
 
[AUCinf] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Geometric Mean (geo CV%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
[AUC0-t] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Geometric Mean (geo CV%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
[Cmax] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Geometric Mean (geo CV%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
[AUCextr%] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Geometric Mean (geo CV%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
x.xxx (x.x%) 
[CL/F] (unit) 
n 
xx 
xx 
NC 
NC 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
NC 
NC 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
NC 
NC 
[V/F] (unit) 
n 
xx 
xx 
NC 
NC 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
NC 
NC 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
NC 
NC 
[Racc] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 


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Assessment (unit) 
 
Linaprazan glurate, 
Day 2 
(N=XX) 
linaprazan glurate, 
Day 14 
(N=XX) 
 
Linaprazan, 
Day 2 
(N=XX) 
linaprazan, 
Day 14 
(N=XX) 
 
[Tmax] (unit) 
n 
Mean (SD) 
Median (Min, Max) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
[T1/2] (unit) 
n 
xx 
xx 
xx 
xx 
Mean (SD) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
x.xx (x.xx) 
Median (Min, Max) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
x.xx (x.x, x.x) 
Data based on [population]. n: Number of observations. SD: Standard deviation. CV%: Coefficient of variation described as percentage. Geo CV%: 
Geometric coefficient of variation described as percentage calculated using log-transformed standard deviation. NC: Not calculated - number of 
evaluable observations less than 3. NA: Not available - no evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM- 
DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 


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10.2.3.3 
Adverse events 
Table AE 1 
Overview of adverse events for Part I (Full analysis set) 
 
 
 
Total 
(N=XX) 
linaprazan glurate (Visit 2 to 
4) 
(N=XX) 
clarithromycin (Visit 5) 
(N=XX) 
linaprazan glurate and 
clarithromycin (Visit 6 to 9) 
(N=XX) 
Follow-up 
(N=XX) 
 
n (%) 
m 
n (%) 
m 
n (%) 
m 
n (%) 
m 
n (%) 
m 
Any AE 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Any SAE 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Any AE leading to withdrawal from 
study 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Any AE leading to death 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Causality 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[Unlikely related] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[Possibly related] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[Probably related] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Severity 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Grade 1 - Mild 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Grade 2 - Moderate 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Grade 3 - Severe 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Grade 4 - Life-Threatening 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
Grade 5 - Death 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
 
AEs are allocated to respective columns, if the AE starts during the time window indicated by the column headings. Data based on [ANALYSIS SET]. 
N: number of subjects in treatment group. Percentages are based on N. n, number of subjects. m, number of events. The following AEs are coded 
with multiple MedDRA terms and are represented as separate AEs in tables and listings: '[AE TERM 1]', '[AE TERM 2]', '[AE TERM 3]. See listings 
for detailed information. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 
Table AE 2 
Overview of adverse events for Part II (Full analysis set) 
Use the same format as for Table AE 1. Change the column headings to the relevant victim and perpetrator drugs. 


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Table AE 3 
Adverse events by system organ class and preferred term for Part I (Full analysis set) 
 
 
linaprazan glurate (Visit 2 clarithromycin (Visit 5) 
linaprazan glurate and 
Follow-up 
Total 
(N=XX) 
to 4) 
(N=XX) 
(N=XX) 
clarithromycin (Visit 6 to 9) (N=XX) 
(N=XX) 
 
System organ class 
Preferred term 
n (%) 
m 
n (%) 
m 
n (%) 
m 
n (%) 
m 
n (%) 
m 
Total 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 1 PT 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 1 PT 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 1 PT …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 2 PT 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 2 PT 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC 2 PT …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC … PT 1] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC … PT 2] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
[SOC … PT …] 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
xx (xx%) 
xx 
AEs are allocated to respective columns, if the AE starts during the time window indicated by the column headings. Data based on [ANALYSIS SET]. 
N, number of subjects. M, number of events. Percentages are based on the number of subjects in the treatment period. The following events are 
coded with multiple terms and are represented as separate events in tables and listings: ‘[AE TERM 1], [AE TERM 2]’. See listings for detailed 
information. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 
Table AE 4 
Adverse events by system organ class and preferred term for Part II (Full analysis set) 
Use the same format as for Table AE 3. Change the column headings to the relevant victim and perpetrator drugs. 


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10.2.3.4 
Physical examinations 
Table PE 1 
Physical examinations for Part I (Full analysis set) 
 
 
 
Assessment 
Assessment timepoint 
Total 
(N=XX) 
 
[PARAMETER 1] 
Screening 
Visit 2 
End of study 
Normal 
Abnormal NCS 
Abnormal CS 
Not assessed 
Normal 
Abnormal NCS 
Abnormal CS 
Not assessed 
Normal 
Abnormal NCS 
Abnormal CS 
Not assessed 
x (xx%) 
x (xx%) 
x (xx%) 
x (xx%) 
x (xx%) 
x (xx%) 
x (xx%) 
x (xx%) 
x (xx%) 
x (xx%) 
x (xx%) 
x (xx%) 
Data based on [population]. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 
Table PE 2 
Physical examinations for Part II (Full analysis set) 
Use the same format as for Table PE 1. 


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10.2.3.5 
Vital signs 
Table VS 1 
Vital signs measurements for Part I (Full analysis set) 
 
 
 
Assessment (unit) 
Result category 
Assessment timepoint 
Total 
(N=XX) 
 
[PARAMETER 1] (unit) 
Measured value 
Absolute change from baseline 
Relative change from baseline (%) 
[Assessment timepoint 1] 
[Assessment timepoint 2] 
[Assessment timepoint 2] 
[Assessment timepoint 2] 
n 
Mean (SD) 
Median (Min, Max) 
n 
Mean (SD) 
Median (Min, Max) 
n 
Mean (SD) 
Median (Min, Max) 
n 
Mean (SD) 
Median (Min, Max) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
xx 
x.xx (x.xx) 
x.xx (x.x, x.x) 
Data based on [population]. Dynamic footnote based on table content: n: Number of observations. SD: Standard deviation. NC: Not calculated - 
number of evaluable observations less than 3. NA: Not available - no evaluable observations. SAS program: [PROGRAM NAME].sas. Run by: [USERNAME] 
YYYY-MM-DDTHH:MM:SS. Data extracted at: YYYY-MM-DDTHH:MM:SS 
 
 
Table VS 2 
Vital signs measurements for Part II (Full analysis set) 
Use the same format as for Table VS 1. 


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10.2.3.6 
12-lead safety ECG 
Table EG 1 
ECG measurements for Part I (Full analysis set) 
Use the same format as for Table VS 1. 
Table EG 2 
ECG measurements for Part II (Full analysis set) 
Use the same format as for Table VS 1. 
Table EG 3 
ECG interpretations for Part I (Full analysis set) 
Use the same format as for Table PE 1. 
Table EG 4 
ECG interpretations for Part II (Full analysis set) 
Use the same format as for Table PE 1. 
 
 
10.2.3.7 
Safety laboratory analyses 
Table LB 1 
Safety laboratory measurements - clinical chemistry for part I (Full 
analysis set) 
Use the same format as for Table VS 1. 
Table LB 2 
Safety laboratory measurements - clinical chemistry for part II (Full 
analysis set) 
Use the same format as for Table VS 1. 
Table LB 3 
Safety laboratory measurements - haematology for part I (Full analysis 
set) 
Use the same format as for Table VS 1. 
Table LB 4 
Safety laboratory measurements - haematology for part II (Full analysis 
set) 
Use the same format as for Table VS 1. 
Table LB 5 
Safety laboratory interpretations – urinalysis for part I (Full analysis set) 
Use the same format as for Table VS 1. 
Table LB 6 
Safety laboratory interpretations – urinalysis for part II (Full analysis set) 
Use the same format as for Table VS 1. 


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10.3 
Study figures 
10.3.1 
Primary endpoint(s) 
Figure PC 1 Geometric mean plasma concentrations over time (lin-log) for Part I 
(Pharmacokinetic analysis set) 
 
Data based on [ANALYSIS SET]. 
[STUDYID] [DOMAIN]: [PARAMETER CATEGORY], SAS program: [PROGRAM NAME]. Run by: [USERNAME], 
[TIMESTAMP] 
Plot all PK profiles in the same graph – Victim drug, perpetrator drug and victim drug + 
perpetrator drug -> 3 series in the same graph, with a legend outlining which data series 
corresponds to what (combination of) drugs. 
 
Figure PC 2 Geometric mean plasma concentrations over time (lin-log) for Part II 
(Pharmacokinetic analysis set) 
Use the same format as for Figure PC 1. 
 
 
Figure PC 3 Geometric mean plasma concentrations over time (lin-lin) for Part I 
(Pharmacokinetic analysis set) 
Use the same format as for Figure PC 1, but plot on linear Y-axis scale. 
 
 
Figure PC 4 Geometric mean plasma concentrations over time (lin-lin) for Part II 
(Pharmacokinetic analysis set) 
Use the same format as for Figure PC 1, but plot on linear Y-axis scale. 


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Figure PC 5 Individual plasma concentrations over time (lin-log) for Part I (Full 
analysis set) 
 
Data based on [ANALYSIS SET]. 
[STUDYID] [DOMAIN]: [PARAMETER CATEGORY], SAS program: [PROGRAM NAME]. Run by: [USERNAME], 
[TIMESTAMP] 
Plot all PK profiles in the same graph – Victim drug, perpetrator drug and victim drug + 
perpetrator drug -> 3 series in the same graph, with a legend outlining which data series 
corresponds to what (combination of) drugs. 
 
 
Figure PC 6 Individual plasma concentrations over time (lin-log) for Part II (Full 
analysis set) 
Use the same format as for Figure PC 5. 
Figure PC 7 Individual plasma concentrations over time (lin-lin) for Part I (Full 
analysis set) 
Use the same format as for Figure PC 5, but plot on linear Y-axis scale. 
Figure PC 8 Individual plasma concentrations over time (lin-lin) for Part II (Full 
analysis set) 
Use the same format as for Figure PC 5, but plot on linear Y-axis scale. 


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10.4 
Study listings 
Produce separate listings for Part I and Part II respectively. Update listings titles to reflect 
which Part is intended. 
 
 
16.2.1 Discontinued subjects 
• Listing 16.2.1- 1 
Discontinued subjects (All subjects) 
• Listing 16.2.1- 2 
Non-eligible subjects (All subjects) 
• Listing 16.2.1- 3 
Disposition (All subjects) 
• Listing 16.2.1- 4 
Subject visits (All subjects) 
• Listing 16.2.1- 5 
Subject elements (All subjects) 
16.2.2 Protocol deviations 
• Listing 16.2.2- 1 
Protocol deviations (All subjects) 
• 16.2.3 Subjects excluded from the efficacy analysis 
• Listing 16.2.3- 1 
Subjects excluded from Full analysis set (All subjects) 
• Listing 16.2.3- 2 
Subjects excluded from Pharmacokinetic analysis set (All 
subjects) 
• Listing 16.2.3- 3 
Population definitions (All subjects) 
16.2.4 Demographic data 
• Listing 16.2.4- 1 
Demography (Full analysis set) 
• Listing 16.2.4- 2 
Medical History (Full analysis set) 
• Listing 16.2.4- 3 
Prior and concomitant medications (Full analysis set) 
16.2.5 Compliance and/or Drug Concentration Data 
• Listing 16.2.5- 1 
Plasma concentration data (Full analysis set) 
• Listing 16.2.5- 2 
Pharmacokinetic parameters (Full analysis set) 
• Listing 16.2.5- 3 
Treatment compliance (Full analysis set) 


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16.2.6 Individual Efficacy Response Data 
• Listing 16.2.6- 1 
IMP administration (Full analysis set) 
16.2.7 Adverse event listings (each subject) 
• Listing 16.2.7- 1 
Adverse events (Full analysis set) 
• Listing 16.2.7- 2 
Serious adverse events (Full analysis set) 
16.2.8 Listings of individual laboratory measurements by subject 
• Listing 16.2.8- 1 
Safety laboratory measurements (Full analysis set) 
Abnormal values and assessment of clinical significance must be included. 
• Listing 16.2.8- 2 
Other laboratory measurements (Full analysis set) 
Urine drug screen, alcohol test, pregnancy test 
16.2.9 Listings of vital signs, ECG, physical examination data by subject 
• Listing 16.2.9- 1 
Vital signs (Full analysis set) 
• Listing 16.2.9- 2 
ECG (Full analysis set) 
• Listing 16.2.9- 3 
Physical examinations (Full analysis set)