Clinical trial NCT05055128
Conditions: Erosive Esophagitis
Keywords: Lansoprazole Los Angeles Grade Double-blind Active comparator-controlled Proton-pump inhibitor Dose selection
Sponsor: Cinclus Pharma AG
Start date: 2021-08-11; Completion date: 2022-09-01
Enrollment: 248 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will be conducted in patients with erosive esophagitis due to gastro-esophageal reflux disease (GERD) Los Angeles (LA) grades C or D, and in patients with at least partial symptom response but still endoscopically unhealed (LA grades A or B) after 8 weeks history of standard treatment healing course with PPI, designed to support dose selection for Phase 3 and to investigate safety, tolerability, and healing rates after 4 weeks treatment of X842 or Lansoprazole, and symptom pattern during subsequent 4 weeks treatment with Lansoprazole.

Detailed description:
This is a randomized, double-blind, active comparator-controlled study with a parallel-group design including four arms with X842 and one arm with Lansoprazole.

Randomization to one of the treatments with X842 twice daily (BID) 25 mg, 50 mg, 75 mg, 100 mg, or Lansoprazole 30 mg once daily (QD) will be based on a 1:1:1:1:1 scheme.

The duration of each patient's participation in the study, including screening, blind treatment period, and open-label treatment period will be approximately 60 days. The patients will be randomized for 4 weeks of double-blind treatment and will be provided with investigational medicinal product for 35 days.

All patients will have an endoscopic evaluation after 4 weeks of treatment. Following the endoscopic evaluation, all patients will receive subsequent 4 weeks of open-label treatment with Lansoprazole. Repeated symptom evaluation to detect symptom patterns will be assessed during this period.

Arms: arm 1: Patients will receive 2 tablets (X842 25mg + X842 dummy) and 1 capsule (Lansoprazole dummy) in the morning, and 2 tablets (X842 25 mg + X842 dummy) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks. arm 2: Patients will receive 2 tablets (X842 50 mg + X842 dummy) and 1 capsule (Lansoprazole dummy) in the morning, and 2 tablets (X842 50 mg + X842 dummy) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks. arm 3: Patients will receive 2 tablets (X842 50 mg + X842 25 mg) and 1 capsule (Lansoprazole dummy) in the morning, and 2 tablets (X842 50 mg + X842 25 mg) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks. arm 4: Patients will receive 2 tablets (X842 50 mg×2) and 1 capsule (Lansoprazole dummy) in the morning, and 2 tablets (X842 50 mg×2) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks. arm 5: Patients will receive 2 tablets (X842 dummy×2) and 1 capsule (Lansoprazole 30 mg) in the morning, and 2 tablets (X842 dummy×2) in the evening during 4-week double-blind treatment. Thereafter, patients will receive 1 capsule of Lansoprazole 30 mg QD for 4 weeks.
Interventions: intervention 1: X842 intervention 2: X842 Dummy intervention 3: Lansoprazole intervention 4: Lansoprazole Dummy
Intervention descriptions: intervention 1: Patients will receive X842 tablets. intervention 2: Patients will receive matching placebo tablets for X842. intervention 3: Patients will receive Lansoprazole capsule. intervention 4: Patients will receive matching placebo capsules for Lansoprazole.

Protocol documents:
Prot_000.pdf: 
Cinclus Pharma AG 
Clinical Study Protocol 
CX842A2201 
CONFIDENTIAL 
 
Final, version 3.0 
1 of 99 
25 Feb 2022 
 
Title Page 
Protocol Title: A randomized double-blind, double dummy, active comparator-controlled 
dose-finding study in patients with erosive esophagitis due to gastro-esophageal reflux disease 
(GERD) Los Angeles grade C or D, and patients with at least partial symptom response but 
endoscopically still unhealed after 8 weeks history of standard treatment healing course with 
proton-pump inhibitor (PPI), to investigate safety, tolerability, and healing rates after 4 weeks 
treatment of X842 or lansoprazole, and symptom pattern during subsequent 4 weeks treatment 
with lansoprazole 
Protocol Number: CX842A2201 
Amendment Number: 2.0 
Version Number: 3.0 
Compound Number: X842 
Sponsor Name and Legal Registered Address:  Cinclus Pharma AG  
Gartenstrasse 101, 
CH-4002 Basel, Switzerland  
Regulatory Agency Identifying Number(s):  
European Clinical Trials Database (EudraCT No.): 2020-003319-91 
Approval Date: 25 February 2022 
Date and Version of Previous Protocol: 19 July 2021; Version 2.0  
 
 
 


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CX842A2201 
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Final, version 3.0 
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Sponsor Signatory: 
PPD
PPD
PPD


Cinclus Pharma AG 
Clinical Study Protocol 
CX842A2201 
CONFIDENTIAL 
 
Final, version 3.0 
3 of 99 
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Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Version 
Date 
Amendment 2.0 
Version 3.0 
25 Feb 2022 
Amendment 1.0 
Version 2.0 
19 Jul 2021 
Original Protocol 
Version 1.0 
03 Sep 2020 
 
 
Amendment 2.0 (25 Feb 2022) 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the 
document 
Formatting, grammar, and logical errors were 
corrected throughout the document. 
To maintain 
consistency 
throughout the 
document. 
Section 1.1 Synopsis, 
Section 3 Objectives 
and Endpoints, and 
Section 9.4.7 
Efficacy Analyses 
“Percentage of 24-hour days with at most mild 
heartburn symptoms during the Weeks 1-8 
(Visits 2-9) based on eDiary (RESQ-eDiary), 
including splits into day- and nighttime 
evaluations” added to list of endpoints. Splits 
into day- and nighttime evaluations also added 
for “Percentage of heartburn-free 24-hour days 
during the Weeks 1-8 (Visits 2-9) based on 
eDiary (RESQ-eDiary)””. 
Clarification added 
that several degrees 
of symptom relief 
are of interest, as 
well as day- and 
nighttime 
evaluations, to 
describe efficacy. 
Section 1.3 Overall 
Schedule of 
Assessment 
(Table 1), 
 
Symptom diary provision/training/ review is 
removed from the Screening visit.0  
Footnote 10 updated to include the following 
bold text: 
Patients will be trained on how to complete the 
symptoms diary during Visit 2 and the actual 
diary will be provided at Visit 2. 
Footnote updated 
for clarity 
Section 1.3 Overall 
Schedule of 
Assessment 
(Table 1), 
Section 5 
Footnote 14 added to include the following: 
For the screening only, 7 days are counted as 7 
working days and not calendar days. Non-
working days are weekend (Saturday, Sunday) 
and any country specific public holiday. 
 
Footnote 15 updated to include the following: 
Endoscopy video/digital image taken prior to 
ICF signature can be used as index endoscopy 
for the enrollment, if taken within 7 working
Footnotes updated 
for clarity 


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Section # and Name 
Description of Change 
Brief Rationale 
days of the planned treatment day. For 
patients invited for screening upper 
endoscopy based on their past medical 
history (see Section 5), the ICF will be 
signed prior to the endoscopy. The 
screening procedures must start with 
endoscopy and in case the patient doesn’t 
show LA grade C or D erosions, the rest of 
the screening procedures must not be 
conducted. This screening endoscopy must 
be obtained within 7 calendar days of 
planned randomization. 
Section 4.1 Study 
Design 
Following text deleted:  
The endoscopy assessments before the 
screening visit is a pre-study investigation, 
while the endoscopy assessment after 4 weeks 
of treatment is part of the study assessments.   
As per FDA 
feedback 
Section 5 Study 
Population 
Section is updated by adding the following: 
The patients possibly eligible will be identified 
as the following: 
1. Patients identified during their routine 
endoscopy.  
 Patients must have erosive 
esophagitis identified during the 
routine endoscopy, before being 
considered for study screening (prior 
to signing the ICF). 
 This routine endoscopy will also 
serve as the index endoscopy in the 
study and the report should contain 
the endoscopy findings using the Los 
Angeles (LA) classification.  
 This routine endoscopy must be 
obtained within 7 working days of 
planned randomization, please refer 
to Inclusion criterion #4. 
2. Patients invited for screening upper 
endoscopy based on their past medical 
history (both criteria must be met): 
a) LA grade C or D disease 
within the past 5 years before 
screening, demonstrated with 
endoscopy (endoscopy report 
issued by a 
Text updated to 
clarify criteria for 
patients identified 
during their routine 
endoscopy and for 
patients invited for 
screening 
endoscopy based on 
their past medical 
history. 


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Section # and Name 
Description of Change 
Brief Rationale 
gastroenterologist/endoscopist 
is accepted) 
b) In Investigator’s judgement the 
patient presents clear symptom 
relapse: patient may be treated 
with PPI, discontinued PPI 
treatment (patient’s decision) 
or treatment naïve. 
 
For patients invited for screening upper 
endoscopy, the ICF will be signed prior 
to the endoscopy. The screening 
procedures must start with endoscopy 
and in case the patient doesn’t show LA 
grade C or D erosions, the rest of the 
screening procedures must not be 
conducted. This screening endoscopy 
must be obtained within 7 working days 
of planned randomization  
The index/screening endoscopy video/digital 
image will be anonymized and saved for 
central storage. Imaging data must meet 
quality standards for adequate LA grading and 
must be accompanied by a report and 
videos/digital images to allow retrospective 
analysis of the endoscopy findings. 
Section 5.1 Inclusion 
Criteria 
Inclusion Criteria #4 updated to include 
Gastro-esophageal reflux disease with 
endoscopically confirmed erosive esophagitis. 
 
 LA grade C or D ≤ 7 working days 
before randomization (with or 
without historical PPI treatment) 
or 
 LA grade A or B ≤ 7 working days 
before randomization  
o history of treatment with standard 
healing course of PPI* for 
minimum of 8 weeks prior to 
screening and ≤ 7 working days of 
non-treatment during this period**. 
Additionally, it is clarified that “Non-treatment 
Inclusion criteria 
updated for clarity 


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Section # and Name 
Description of Change 
Brief Rationale 
days are counted from the last day of standard 
healing course of PPI therapy until endoscopy 
used for eligibility assessment demonstrating 
erosive esophagitis due to GERD”
Section 5.2 Exclusion 
Criteria 
Following note added to Exclusion Criteria 
#12: 
Patients with positive anti-HBcAg along with 
negative HBsAg at screening will not be 
excluded IF they have a positive local anti-
HBs test results not older than 6 months and 
active HBV infection has been ruled out by the 
Investigator.
Exclusion criteria 
updated for clarity 
Section 8.2 Efficacy 
Assessments 
Following text is modified: 
All videos and digital images will be 
centrally reviewed retrospectively. This 
review will include reassessment of the LA 
grading and other findings which may 
constitute exclusion criterion. Central 
reading of the videos/digital images is not 
planned. However, if Sponsor deems necessary 
to implement central reading, based on 
unexpectedly high healing rates, t The central 
reading evaluation will override the 
investigators evaluations. Data obtained from 
patients deemed to have been ineligible for 
study enrollment following the retrospective 
analysis will be excluded from the per 
protocol analysis.
Per FDA feedback 
Section 8.5 
Treatment of 
Overdose 
Text updated to display that “In the case of 
suspected overdose, the patient should be 
monitored. Lansoprazole is not significantly 
eliminated removed from the circulation by 
hemodialysis. In the event of over-exposure, 
treatment should be symptomatic and 
supportive.
Text updated to 
reflect changes as 
per lansoprazole 
SmPC 
Appendix 9 
Medications that may 
Interact with X842 or 
Linaprazan 
Footnote added for hormone based 
contraceptives to include the following: 
Except for patients using hormonal 
contraception defined in Exclusion criterion #1 
Footnote added for 
clarity. 
Appendix 10 
COVID-19 Specifics 
Publication date updated for the EMA 
Guidance on the Management of Clinical 
Trials during the COVID-19 (Coronavirus) 
pandemic. 
Publication date updated for the FDA 
Reference list 
updated for the 
updated versions of 
EMA and FDA 
guidance. 


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Section # and Name 
Description of Change 
Brief Rationale 
Guidance on Conduct of Clinical Trials of 
Medical Products during COVID-19 Public 
Health Emergency. 
Section 11 
References 
Lansoprazole SmPC updated link added 
Reference list 
updated for the 
updated versions of 
lansoprazole SmPC. 
 
 
 
Amendment 1.0 (19 Jul 2021) 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout the 
document 
Several different medical terms are used to 
describe the underlying disease, such as 
“reflux esophagitis”, “erosive GERD”, 
“erosive esophagitis”. As per FDA advice, 
used the term “erosive esophagitis due to 
GERD” throughout the document. 
As per Competent 
Authority 
suggestion. 
Throughout the 
document 
The word “participant”, “patient” and 
“subject” are used in the document. For clarity 
and consistency these terms are replaced with 
“patient”. 
The study will be 
conducted in 
patients with 
GERD; hence, for 
clarity and 
consistency, 
“participant” and 
“subject” are 
changed to 
“patient”. 
Throughout the 
document 
Study Intervention replaced with Study Drug 
Study Intervention 
replaced with Study 
Drug for 
consistency. 
Throughout the 
document 
Screening assessment days were changed from 
“5 days” to “7 days”. 
Screening day 
changed as per the 
Sponsor request. 
Throughout the 
document 
Study monitor replaced with CRA 
For clarity. 
Throughout the 
document 
Formatting, grammar, and logical errors were 
corrected throughout the document. 
To maintain 
consistency 
throughout the 
document. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
(Treatment Groups 
and Duration) 
The study drugs should be taken with 100 mL 
of noncarbonated water irrespective of at least 
30 minutes prior to meals. 
Updated for clarity. 
Section 1.3 Overall 
Schedule of 
Assessment Table 1 
Screening period “Day -0” changed to 
“Day 0”. 
 
Daily symptom diary (RESQ-eDiary) 
completion by patient is removed for screening 
period. 
 
Footnote is revised to indicate the following:  
5. Hematology, blood chemistry, coagulation 
(central laboratory), urinalysis (local 
laboratory at site). Serum gastrin at screening 
and at Visit 5 (central laboratory). 
6. H. pylori will be analyzed in central 
laboratory from serum and the result will not 
be needed for randomization. 
Updated for clarity. 
 
 
Deleted per 
RESQ-eDiary 
schedule change in 
Table 1. 
Footnote updated 
for clarity. 
Section 1.3 Overall 
Schedule of 
Assessments Table 1 
(footnote #14), 
Section 5, Section 8.2 
and Section 10.1.3 
Amendment made to indicate that endoscopy 
results in both video and Image format is 
acceptable by adding the term digital images 
along with video i.e., videos/digital images. 
Text updated for 
clarity. 
Section 2.1 
Background 
The expansion of AUC was revised from 
“area under the curve” to “area under the 
concentration-time curve” 
Updated for clarity. 
Section 2.3.1 
Summary of Risk 
Management, 
Section 10.1.4 Patient 
Identification Card, 
Section 10.1.5 Patient 
Data Protection and 
Section 10.1.8 
Archiving 
“Patient information card” is replaced with 
“Patient Identification” card. 
 
Patient 
Identification card 
was submitted in all 
countries to the 
Authorities. 
Section 5.1 Inclusion 
Criteria  
Criterion #4: Gastro-esophageal reflux 
disease with endoscopically confirmed 
esophagitis:  
LA grade C or D ≤ 57 days before 
randomization (with or without historical PPI 
treatment)
Criterion #4: As 
per Competent 
Authority 
suggestion, to 
exclude 
lansoprazole from 


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Section # and Name 
Description of Change 
Brief Rationale 
or 
LA grade A or B ≤ 57 days before 
randomization  
and  
history of treatment with standard healing 
course of PPI* for minimum of 8 weeks prior 
to screening and ≤ 57 days of non-treatment 
during this period**. 
and 
at least partial symptom response during the 
minimum of 8 weeks of PPI treatment.  
Note: pPartial symptom response is defined as 
a clear symptom improvement (heartburn or 
regurgitation) after start of the PPI treatment 
course. To qualify, the patient’s response must 
be YES to the Investigator´s standardized 
question to the patient: Did you feel a clear 
symptom improvement in (heartburn or 
regurgitation) after you started the PPI 
treatment course? Patient´s response must be 
YES or NO) 
*  All PPIs EXCEPT lansoprazole 
** Non-treatment days are counted from end 
day of PPI therapy until endoscopy 
demonstrating erosive esophagitis due to 
GERD.” 
 
Criterion #5: Willing and able to comply with 
all aspects of the protocol (including PK 
sampling, capsule swallowing, diary 
completion, etc.) 
the primary 
treatment.  
Change in 5 days to 
7 days was done 
based on extension 
of screening period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Criterion #5: PK 
sampling is added 
for completeness of 
procedures. 
Section 5.2 Exclusion 
Criteria  
Criterion #1: Female patients of childbearing 
potential, defined as all women 
physiologically capable of becoming pregnant, 
unless they are using one of the following 
adequate methods of contraception during 
dosing and for at least seven (7) days after the 
last dose of study medication: 
Total abstinence (when this is in line with the 
preferred and usual lifestyle of the patient). 
Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and 
Criterion #1: A 
note regarding 
female patients who 
are using hormonal 
contraceptive 
included for 
adequate control of 
contraception  
 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
withdrawal are not acceptable methods of 
contraception 
Female sterilization (have had surgical 
bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 
6 weeks before taking the first dose of study 
treatment. In case of oophorectomy alone, only 
when the reproductive status of the patient has 
been confirmed by follow-up hormone level 
assessment. 
Male sterilization (at least 6 months prior to 
screening). For female patients on the study, 
the vasectomized male partner should be the 
sole partner for that patient. 
Placement of a non-hormonal IUD 
Double barrier methods of contraception: 
condom in combination with occlusive cap 
(diaphragm or cervical/vault cap) with 
spermicidal foam/gel/film/cream/vaginal 
suppository 
Note: Patients who are already on hormonal 
contraceptives prior to study enrollment must 
agree to: 
 replace hormonal contraception with double 
barrier method or  
use double barrier contraception method in 
addition to the hormonal contraceptives  
 
Criterion #2: Female patients of 
non-childbearing potential not requiring a 
contraceptive method, are defined as:  
•Pre-menopausal females with a documented 
tubal ligation or hysterectomy; or  
•Post-menopausal females defined as at least 
12 months of amenorrhea (without an 
alternative medical cause) and confirmed with 
simultaneous serum follicle stimulation 
hormone (FSH), consistent with post-
menopausal status according to central 
laboratory ranges do not need to use a 
contraceptive method.  
Patients who do not meet one of these two 
criteria above will be considered being of 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Criterion #2: text 
added for 
clarification 
 
 
 
 
 
 
 
 
 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
childbearing potential, and are excluded unless 
using one of the adequate contraceptive 
methods defined in Exclusion Criterion #1. 
 
Criterion #8: Presence of esophageal ulcer, 
stricture, Barrett´s esophagus or suspected 
esophagitis secondary to infection, 
inflammatory disease, ingestion of erosive 
chemicals or history of any surgical or medical 
condition which might significantly alter the 
GERD status or the absorption, distribution, 
metabolism or excretion of drugs. The 
Investigator is to be guided by evidence of any 
of the following: history of major 
gastrointestinal surgery such as gastrectomy, 
gastroenterostomy, bowel resection or 
transjugular intrahepatic portosystemic shunt 
(TIPS) 
 
Criterion #11: Any clinically significant 
laboratory parameter outside reference value 
that, in the opinion of the Investigator, may 
suggest a new or insufficiently understood 
disease, may present an unreasonable risk to 
the patient as a result of his/her participation in 
the study, or may interfere with study 
assessments. 
Any of these screening laboratory tests results 
are exclusionary: 
Serum ALT or AST > 1.5 times the upper limit 
of normal (ULN) for the central laboratory 
conducting the test 
Serum Total Bilirubin > 1.5 x ULN for the 
central laboratory conducting the test 
Serum Creatinine > 1.5 x ULN for the central 
laboratory conducting the test 
Estimated glomerular filtration rate ≤ 59 
mL/min (calculated using the Modification of 
Diet in Renal Disease equation) 
 
Criterion #13: After 10 min supine rest at the 
time of screening, any vital signs values 
outside the following ranges: 
 
 
 
Criterion #8: 
Amended to add 
medical conditions 
which might 
significantly alter 
the GERD or the 
absorption, 
distribution, 
metabolism or 
excretion of study 
drug. 
 
 
 
Criterion #11: As 
per Competent 
Authority 
suggestion to 
include laboratory 
test results 
exclusion criteria. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Criterion #13: 
Lower limit added 
to cover both 


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• Systolic blood pressure (BP) > 160 mmHg or 
< 90 mmHg 
• Diastolic BP > 100 mmHg or < 60 mmHg 
• Heart rate < 40 or > 95 beats per min  
extreme of the BP, 
necessary aspect for 
selecting patient. 
 
Section 6.3.1 
Randomization 
Randomization cap should will be set as 
approximately 40% 50% of patients with LA 
grade A and B allowing at least 60% of 
patients being randomized from and 
approximately 60% 50% of patients being with 
LA grade C or D. 
Updates are done as 
per Competent 
Authority 
suggestion. 
Section 6.8 
Intervention After the 
End of the Study 
There will be no treatment with X842 or 
lansoprazole available, provided by Sponsor, 
after the End of Study participation. Following 
discontinuation of study treatment some 
patients may need additional therapy for their 
erosive esophagitis due to GERD. The 
Investigator should ensure patients re-establish 
care with a physician during the open-label 
treatment period in order to avoid a lapse. 
As per Competent 
Authority 
suggestion, updates 
done to avoid 
relapse. 
8.2 Efficacy 
Assessments 
Upper endoscopy for the examination of 
esophagus will be used to confirm patient 
eligibility as well as the confirmation of the 
primary endpoint. Imaging data must meet 
quality standards for adequate LA grading and 
must be accompanied by a report and 
videos/digital images to allow retrospective 
analysis of the endoscopy findings. 
Statement included 
to ensure quality 
imaging for better 
assessments 
Section 8.3.2 Weight 
and BMI 
Weight will be measured wearing light clothes 
and without shoes as designated on the SoA. 
The method of weight assessment will be the 
same across all visits. Body mass index (BMI) 
unit is kg/m2 and calculated as weight in kg 
and height in meter. 
Updates are done as 
per the Competent 
Authority 
suggestion. 
Section 8.3.5 Clinical 
Safety Laboratory 
Assessments 
(Laboratory 
parameter table and 
footnotes) 
“Urine drug abuse screen” is moved from 
“Urinalysis (dip stick)” section to “Others” 
section in the table 
Footnote is amended accordingly. 
 
As urine drug abuse 
screen is not a dip 
stick, footnote was 
amended for clarity. 
8.3.7 Reflux Related 
Symptoms Assessed 
Based on PRO 
Reflux related symptoms will be also assessed 
based on a modified RESQ-eDiary; an 
electronic symptom diary developed for use in 
Modified RESQ-
eDiary added for 
clarity and “every 


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Section # and Name 
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Brief Rationale 
partial responders to PPI. RESQ-eD has three 
Domains (i.e. Heartburn, Other GERD 
signs/symptoms and Regurgitations/Reflux) 
and eight Items. Patients will be asked to 
report twice daily every 12-hours, once before 
the morning dose and once before the evening 
dose of the IMP. 
12-hours” was 
added to be more 
specific in reporting 
time. 
8.3.8 Reflux Related 
Symptoms Assessed 
by Investigator 
Section is updated by adding following: 
The potential frequency is defined as 7-graded 
Likert scale:  
• All of the time;  
• Most of the time;  
• Quite a lot of the time;  
• Some of the time;  
• A little of the time;  
• Hardly any of the time;  
• None of the time. 
Text updated to 
define frequency of 
symptoms on 7-
graded Likert scale.  
Section 8.3.9 
Pharmacokinetic 
Samples and Analysis
PK samples will be collected 12 hours after the 
previous study drug dose administration or as 
close to this timepoint as possible, but always 
pre-dose (close before the first and the second 
dose administration at Days 7, 14 and 28). 
 
Updated to clarify 
pre-dose. 
Section 8.4.1.3 - 
Table 2 (Liver Event 
and Laboratory 
Trigger Definitions) 
A. LIVER LABORATORY TRIGGERS is 
changed from “3×ULN < ALT or AST ≤ 5× 
ULN 
1.5 ×ULN < TBL ≤ 2×ULN” to  
“ALT or AST > 3 × ULN, but ALT and AST ≤ 
5 × ULN 
 TBL > 1.5 × ULN, but TBL≤ 2 × ULN”. 
Liver laboratory 
range revised to 
clarify ULN. 
8.4.6 Reporting of 
Serious Adverse 
Events 
Following text changed from 
“Serious adverse events reporting should be 
performed by the Investigator within 24 hours 
of awareness via the eCRF or by e-mailing a 
copy of an SAE Form. All available 
information regarding the SAE should be 
entered in the AE Log for the specific patient.  
The SAE report is reviewed by a designated 
person at Parexel to ensure that the report is 
valid and correct. For fatal or life-threatening 
SAEs where important or relevant information 
Reporting of serious 
adverse events 
updated as per 
current practice at 
Parexel. 


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is missing, immediate follow-up is undertaken 
and queries to the site are raised. Investigators 
or other site personnel should inform 
designated person of any follow-up 
information on a previously reported SAE 
immediately but no later than the end of the 
next business day of when he/she becomes 
aware of it.  
If an SAE report is updated, the designated 
study personnel will be informed. 
The appointed Medical Monitor will provide 
his/her causality assessment and make an 
expectedness assessment once the report is 
judged to be complete. The reference 
document for definition of expectedness is the 
Reference Safety Information in the current 
version of IB.  
If any additional documentation is required 
(e.g. hospital discharge letter, autopsy report, 
etc.), designated person will request this 
information from the study site.  
In case the eCRF cannot be accessed, the SAE 
should be reported by manually completing the 
paper SAE Form, provided in the investigator 
site file (ISF). completed, signed and dated 
paper SAE Form should, within 24 hours, be 
scanned and e-mailed to:  
Telephone:
 
E-mail:
A copy 
be e-
mailed to Parexel at: 
CinclusADR@parexel.com”. 
 
To 
On discovery, all SAE/AESIs should be 
immediately reported (latest within 24 hours of 
knowledge of the event) to Parexel Safety 
Services by: 
Entering the AE in the appropriate section (AE 
page and/or SAE page) of the eCRF, indicating 
that the event is considered serious, and 
PPD
PPD
PPD


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Section # and Name 
Description of Change 
Brief Rationale 
providing all the details per the eCRF 
completion guidelines 
and 
Completing the SAE report form and 
e-mailing/faxing the documents to Parexel 
Safety Services as per details below: 
France (Paris) Mailbox: 
249403_Safety@parexel.com 
France (Paris) Fax numbers: +33 1 44 90 32 
75 or +33 1 44 90 35 34 
In the event that the site is unable to complete 
the SAE form or eCRF entry to report the 
event within 24 hours of their knowledge of 
the event, the investigators may report the 
SAE over the telephone via the SAE 
answering service, and then provide the 
completed SAE form via (fax or email), or 
complete the eCRF entry of the event (within 
the next 24 hours). If questions arise regarding 
the reporting procedures or the specifics of the 
reporting of an event, sites may call (English) 
utilizing the following numbers: 
Paris: +33 1 44 90 32 90 
In case the eCRF cannot be accessed, the SAE 
should be reported by manually completing the 
paper SAE Form, provided in the investigator 
site file (ISF).  
 
The SAE report is reviewed by a designated 
person at Parexel to ensure that the report is 
valid and correct. For fatal or life-threatening 
SAEs where important or relevant information 
is missing, immediate follow-up is undertaken 
and queries to the site are raised by Parexel. 
Investigators or other site personnel should 
inform designated person of any follow-up 
information on a previously reported SAE 
immediately but no later than the end of the 
next business day of when he/she becomes 
aware of it.  
If an SAE report is updated, the designated 
study personnel will be informed. 
If any additional documentation is required 


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Section # and Name 
Description of Change 
Brief Rationale 
(e.g., hospital discharge letter, autopsy report, 
etc.), designated person will request this 
information from the study site.  
 
9.2 Sample Size 
Determination 
Text updated for 
clarity. 
CCI


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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.4 
The following duplicated text was removed: 
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 the SAP, 
which will be approved and singed prior to 
database lock. 
The primary study objective is to estimate the 
X842 dose for Phase 3 study with good 
precision, and hence comparison of different 
doses of X842 to the active comparator arm 
(lansoprazole 30 mg) will not involve any 
formal statistical testing. 
The primary analysis evaluating the dose-
response relationship based on different doses 
of X842, as well as secondary analyses will 
additionally assess the two subgroups, eGERD 
LA grade C or D and eGERD LA grade A or B 
(partial responders to PPI treatment).  
All data measured on a continuous scale will 
be presented using summary statistics. 
Summary statistics is defined as number (N), 
arithmetic mean, standard deviation (SD), 
median, minimum Q1, Q3 and maximum 
value. Where appropriate 95% confidence 
intervals 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 patient data will 
be listed by patient number, treatment, and, 
where applicable, by assessment time. 
Duplicated text 
removed. 
10.1.9 Study and Site 
Closure 
The following was added in this section as 
amendment: 
Study stopping rules 
are added according 


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Brief Rationale 
The Investigator may initiate study site closure 
at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the 
intended termination. 
The study may be placed on hold for 
evaluation of possible risk to patients, prior to 
decision as to whether to terminate the study if 
any of the following criteria are met: 
At least 3 patients experience a similar 
unexpected AE, which is assessed as severe 
and is probable/possible related to the IMP. 
The occurrence of an SAE, if considered 
probable/possible related to the IMP. 
A study termination will be initiated pending 
the outcome of any SAE investigation; 
termination will be based on the circumstances 
surrounding the event and findings with 
unblinding of the Sponsor medical monitor, if 
necessary.  
The study will be discontinued for any of the 
following reasons: 
If overall 5 (five) X842-treated patients 
develop the same type of AESI and the 
frequency is at least 2 × higher than in the 
comparator group. 
If 3 (three) X842-treated patients meet Hy’s 
Law criteria (≥ 3 × ULN for ALT or AST with 
total bilirubin ≥ 2 × ULN and no other 
explanation for these elevations). 
If one or more clinically significant, life-
threatening, or significantly 
disabling/incapacitating events that are likely 
related to X842 and that, in the opinion of the 
Investigator in consultation with the Sponsor, 
may constitute sufficient reason to stop the 
study. 
If the Sponsor judges it necessary for medical, 
safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP. 
to FDA suggestion 
 
 
 
 
 


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Table of Contents 
 
Title Page ........................................................................................................................................ 1 
Protocol Amendment Summary of Changes Table ......................................................................... 3 
Table of Contents .......................................................................................................................... 19 
List of Tables ................................................................................................................................. 23 
List of Figures ............................................................................................................................... 23 
1 
Protocol Summary .................................................................................................................. 24 
1.1 
Synopsis .............................................................................................................................. 24 
1.2 
Schema ............................................................................................................................... 27 
1.3 
Schedule of Assessments (SoA) ......................................................................................... 27 
2 
Introduction............................................................................................................................. 32 
2.1 
Background......................................................................................................................... 32 
2.1.1 
Investigational Medicinal Product .................................................................................. 32 
2.2 
Study Rationale .................................................................................................................. 35 
2.3 
Benefit/Risk Assessment .................................................................................................... 36 
2.3.1 
Summary of Risk Management ...................................................................................... 37 
3 
Objectives and Endpoints ....................................................................................................... 39 
4 
Study Design ........................................................................................................................... 40 
4.1 
Overall Design .................................................................................................................... 40 
4.2 
Scientific Rationale for Study Design ................................................................................ 41 
4.3 
Justification for Dose .......................................................................................................... 42 
4.4 
End of Study Definition...................................................................................................... 42 
5 
Study Population ..................................................................................................................... 43 
5.1 
Inclusion Criteria ................................................................................................................ 44 
5.2 
Exclusion Criteria ............................................................................................................... 45 
5.3 
Lifestyle Considerations ..................................................................................................... 47 
5.3.1 
General Restrictions ....................................................................................................... 47 
5.3.2 
Prior and Concomitant Medication and Therapy/Procedures ......................................... 48 
5.4 
Screen Failures ................................................................................................................... 49 
6 
Study Drug .............................................................................................................................. 50 


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6.1 
Study Drugs Administered ................................................................................................. 50 
6.2 
Preparation/Handling/Storage/Accountability ................................................................... 50 
6.3 
Measures to Minimize Bias: Randomization and Blinding ................................................ 51 
6.3.1 
Randomization ................................................................................................................ 51 
6.3.2 
Blinding .......................................................................................................................... 51 
6.3.3 
Emergency Unblinding During the Study ...................................................................... 52 
6.4 
Study Drug Compliance ..................................................................................................... 52 
6.5 
Return and Destruction of Investigational Medicinal Products ......................................... 52 
6.6 
Prior and Concomitant Therapy ......................................................................................... 52 
6.6.1 
Rescue Medication ......................................................................................................... 53 
6.7 
Dose Modification .............................................................................................................. 53 
6.8 
Intervention After the End of the Study ............................................................................. 53 
7 
Discontinuation of Study Drug and Patient Discontinuation ................................................. 53 
7.1 
General Withdrawal Criteria ............................................................................................... 53 
7.2 
Procedures for Discontinuation of a Patient from the Study .............................................. 54 
7.3 
Patient Replacement ........................................................................................................... 54 
7.4 
Loss of Patients to Follow-Up ............................................................................................ 54 
8 
Study Assessments and Procedures ........................................................................................ 55 
8.1 
Demographics and Other Baseline Characteristics ............................................................ 56 
8.1.1 
Informed Consent ........................................................................................................... 56 
8.1.2 
Eligibility Criteria ........................................................................................................... 56 
8.1.3 
Demographic Information .............................................................................................. 56 
8.1.4 
Weight and Height .......................................................................................................... 56 
8.1.5 
Medical/Surgical History ................................................................................................ 56 
8.1.6 
Prior and Concomitant Medication ................................................................................ 56 
8.1.7 
Serology (HIV and Hepatitis B/C Virus) Testing ........................................................... 57 
8.1.8 
Pregnancy Test ................................................................................................................ 57 
8.1.9 
Urine Drug Screen .......................................................................................................... 57 
8.2 
Efficacy Assessments ......................................................................................................... 57 
8.3 
Safety Assessments ............................................................................................................. 58 
8.3.1 
Physical Examinations .................................................................................................... 58 
8.3.2 
Weight and BMI ............................................................................................................. 58 
8.3.3 
Vital Signs ...................................................................................................................... 58 
8.3.4 
Resting 12-lead Electrocardiograms ............................................................................... 58 
8.3.5 
Clinical Safety Laboratory Assessments ........................................................................ 59 


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8.3.6 
Concomitant Medication ................................................................................................ 60 
8.3.7 
Reflux Related Symptoms Assessed Based on PRO ...................................................... 60 
8.3.8 
Reflux Related Symptoms Assessed by Investigator ..................................................... 60 
8.3.9 
Pharmacokinetic Samples and Analysis ......................................................................... 61 
8.4 
Adverse Events and Serious Adverse Events ..................................................................... 62 
8.4.1 
Definitions ...................................................................................................................... 62 
8.4.2 
Time Period and Frequency for Collecting AE and SAE Information ........................... 66 
8.4.3 
Assessment of Severity/Intensity ................................................................................... 66 
8.4.4 
Collecting Adverse Events ............................................................................................. 67 
8.4.5 
Recording Adverse Events ............................................................................................. 68 
8.4.6 
Reporting of Serious Adverse Events ............................................................................. 68 
8.4.7 
Treatment and Follow-up of Adverse Events ................................................................. 70 
8.4.8 
Pregnancy ....................................................................................................................... 70 
8.5 
Treatment of Overdose ....................................................................................................... 71 
8.6 
Handling, Storage and Destruction of Laboratory Samples ............................................... 71 
8.7 
Chain of Custody of Biological Samples ........................................................................... 72 
8.8 
Withdrawal of Informed Consent for Donated Biological Samples ................................... 72 
8.9 
Pharmacodynamics ............................................................................................................. 72 
8.10 Appropriateness of Measurements ..................................................................................... 72 
9 
Statistical Considerations........................................................................................................ 73 
9.1 
General Consideration ........................................................................................................ 73 
9.2 
Sample Size Determination ................................................................................................ 73 
9.3 
Populations for Analyses .................................................................................................... 74 
9.4 
Statistical Analyses ............................................................................................................. 75 
9.4.1 
Patient Disposition .......................................................................................................... 75 
9.4.2 
Protocol Deviations ........................................................................................................ 75 
9.4.3 
Demographics and Baseline Characteristics .................................................................. 75 
9.4.4 
Medical/surgical History and Prior/Concomitant Medication ........................................ 75 
9.4.5 
Treatment Compliance ................................................................................................... 75 
9.4.6 
Physical Examination ..................................................................................................... 75 
9.4.7 
Efficacy Analyses ........................................................................................................... 75 
9.4.8 
Safety Analyses .............................................................................................................. 77 
9.4.9 
Other Analyses ................................................................................................................ 78 
9.5 
Interim Analyses ................................................................................................................. 78 
9.6 
Data Monitoring Committee (DMC) .................................................................................. 78 


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10 Supporting Documentation and Operational Considerations ................................................. 78 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ............................ 78 
10.1.1 
Ethical Conduct of the Study .......................................................................................... 78 
10.1.2 
Ethics and Regulatory Review ....................................................................................... 78 
10.1.3 
Patient Information and Consent .................................................................................... 79 
10.1.4 
Patient Identification Card .............................................................................................. 79 
10.1.5 
Patient Data Protection ................................................................................................... 80 
10.1.6 
Audits and Inspections ................................................................................................... 80 
10.1.7 
Data Quality Assurance .................................................................................................. 81 
10.1.8 
Archiving ........................................................................................................................ 81 
10.1.9 
Study and Site Closure ................................................................................................... 82 
10.1.10 Publication Policy ........................................................................................................... 83 
10.1.11 Protocol Approval and Amendment ............................................................................... 83 
10.1.12 Insurance ......................................................................................................................... 83 
10.2 Appendix 2: Study Management ........................................................................................ 84 
10.2.1 
Training of Study Site Personnel .................................................................................... 84 
10.2.2 
Clinical Monitoring ........................................................................................................ 84 
10.2.3 
Medical Monitoring ........................................................................................................ 85 
10.2.4 
Source Data Documents ................................................................................................. 85 
10.2.5 
Study Agreements ........................................................................................................... 86 
10.2.6 
Study Timetable and End of Study ................................................................................. 86 
10.2.7 
Reporting and Publication .............................................................................................. 86 
10.2.8 
Confidentiality and Ownership of Study Data ............................................................... 87 
10.3 Appendix 3: Data Management .......................................................................................... 87 
10.3.1 
The Web Based eCRF ..................................................................................................... 87 
10.3.2 
The Entering of Data into the eCRF ............................................................................... 88 
10.3.3 
Electronic Patient Reported Outcome ............................................................................ 88 
10.3.4 
The Data Cleaning Process ............................................................................................. 88 
10.3.5 
Audit Trail ...................................................................................................................... 89 
10.3.6 
External Data .................................................................................................................. 89 
10.3.7 
Medical Coding .............................................................................................................. 89 
10.3.8 
Database Lock ................................................................................................................ 89 
10.4 Appendix 4: Abbreviations and Trademarks ...................................................................... 89 
10.5 Appendix 5: Important Medical Procedures to be Followed by The Investigator ............. 92 
10.5.1 
Medical Emergencies Contacts ...................................................................................... 92 
10.6 Appendix 6: Study Administrative Structure ..................................................................... 93 


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10.7 Appendix 7: Declaration of Helsinki .................................................................................. 94 
10.8 Appendix 8: Los Angeles Classification of Reflux Esophagitis ........................................ 94 
10.9 Appendix 9: Medications that may Interact with X842 or Linaprazan .............................. 94 
10.10 Appendix 10: COVID-19 Specifics.................................................................................... 95 
11 References............................................................................................................................... 97 
Investigator Agreement Page ........................................................................................................ 98 
 
 
List of Tables 
Table 1 
Overall Schedule of Assessments ......................................................................... 28 
Table 2 
Liver Event and Laboratory Trigger Definitions .................................................. 65 
List of Figures 
Figure 1 
Study Design ......................................................................................................... 27 
Figure 2 
Study Design ......................................................................................................... 41 
 


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1 Protocol Summary 
1.1 Synopsis 
Protocol Title: A randomized double-blind, double dummy, active comparator-controlled 
dose-finding study in patients with erosive esophagitis due to gastro-esophageal reflux disease 
(GERD) Los Angeles grade C or D, and patients with at least partial symptom response but 
endoscopically still unhealed after 8 weeks history of standard treatment healing course with 
proton-pump inhibitor (PPI), to investigate safety, tolerability, and healing rates after 4 weeks 
treatment of X842 or lansoprazole, and symptom pattern during subsequent 4 weeks treatment 
with lansoprazole  
Sponsor Study No.: CX842A2201 
Phase: Phase 2 
Sponsor: Cinclus Pharma AG  
Gartenstrasse 101 
CH-4002 Basel, Switzerland 
Study Rationale: 
This is a Phase 2, double-blind study in patients with erosive esophagitis due to GERD Los 
Angeles (LA) grades C or D, and in patients with at least partial symptom response but still 
endoscopically unhealed (LA grades A or B) after 8 weeks history of standard treatment healing 
course with PPI, designed to support dose selection for Phase 3. The pronounced acid control of 
X842 is assumed to provide high endoscopic healing rates already after 4 weeks treatment 
course. The four dose levels of X842 are selected based on data from the Phase 1 studies where 
the 50 mg twice daily (BID) dose displayed an acid control slightly stronger than observed for 
standard PPI. The dose selection for Phase 3 will be based on the proportion of endoscopic 
healing following each dose of X842, the respective safety data and the pharmacokinetic (PK) 
profile. Lansoprazole will serve as an active comparator. 


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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
The primary objective of the study is 
to support dose selection for X842, 
through assessment of healing of 
erosive esophagitis due to GERD after 
4 weeks of treatment. 
Healing of erosive esophagitis due to GERD based 
on endoscopic assessment after 4 weeks of double-
blind treatment. 
Secondary 
Evaluate the safety and tolerability of 
the four dose levels of X842 and 
lansoprazole, where lansoprazole will 
serve as the active comparator. 
Physical examination, weight, body mass index 
(BMI), vital signs, electrocardiogram (ECG) 
recordings, safety laboratory measurements 
(hematology/clinical chemistry/urinalysis), adverse 
event (AE), treatment emergent adverse event 
(TEAE), adverse event of special interest (AESI), 
serious adverse event (SAE) reporting, concomitant 
medication(s).  
Evaluate the reflux related symptom 
pattern during the initial 4 weeks 
treatment with four dose levels of 
X842 and with lansoprazole, and the 
symptom pattern during the 
subsequent additional 4 weeks 
(Weeks 5-8) open-label treatment with 
lansoprazole 30 mg QD 
 Percentage of heartburn-free 24-hour days 
during the Weeks 1-8 (Visits 2-9) based on 
eDiary (RESQ-eDiary), including splits into 
day- and nighttime evaluations.  
 Percentage of 24-hour days with at most mild 
heartburn symptoms during the Weeks 1-8 
(Visits 2-9) based on eDiary (RESQ-eDiary), 
including splits into day- and nighttime 
evaluations. 
 Investigator assessment of symptom at 
Weeks 1-8 (Visits 2-9)  
 Reflux related symptoms as measured by 
change from baseline in QOLRAD score 
assessed after 1, 2, 4 and 8 weeks of treatment 
Exploratory  
 
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Overall Design: 
The study will be conducted in multiple centers in Europe and the US. This will be a 
randomized, double-blind, active comparator-controlled study with a parallel group design 
including four arms with X842 and one arm with lansoprazole. Pharmacokinetic (PK) blood 
sampling pre-dose, before the first and the second dose administration will be performed at 
Day 7, Day 14 and Day 28 visits in all patients. Approximately 240 patients with erosive 
esophagitis due to GERD LA grade C or D and patients with erosive esophagitis due to GERD 
LA grade A or B with at least partial symptom response but still endoscopically unhealed after 
8 weeks history of standard treatment healing course with PPI, will be randomized in order to 
have 200 evaluable patients.  
Randomization to one of the treatments with X842 twice daily (BID) 25 mg, 50 mg, 75 mg, 
100 mg, or lansoprazole 30 mg once daily (QD) will be based on a 1:1:1:1:1 scheme. One site 
cannot enroll more than 20% of the overall number of patients (48 patients). 
The duration of each patient’s participation in the study, including screening, blind treatment 
period and open-label treatment period will be approximately 60 days. The patients will be 
randomized for 4 weeks (28 days, -2/+5 days) double-blind treatment and will be provided with 
investigational medicinal product (IMP) for 35 days (including one additional blister pack 
dispensed at Visit 2/Day 0) to allow for treatment up to the visit window. All patients will have 
an endoscopic evaluation after 4 weeks treatment. Following the endoscopic evaluation, all 
patients will receive subsequent 4 weeks open-label treatment with lansoprazole 30 mg QD. 
Repeated symptom evaluation to detect symptom pattern will be assessed during this period.  
Randomization
ratio 
TREATMENT GROUP 
Morning 
capsule 
Morning 
tablet 1 
Morning 
tablet 2 
Evening 
tablet 1 
Evening 
tablet 2 
1 
X842 (BID) 25 mg  
placebo 
25 mg 
placebo 
25 mg 
placebo 
1 
X842 (BID) 50 mg  
placebo 
50 mg 
placebo 
50 mg 
placebo 
1 
X842 (BID) 75 mg  
placebo 
50 mg 
25 mg 
50 mg 
25 mg 
1 
X842 (BID) 100 mg  
placebo 
50 mg 
50 mg 
50 mg 
50 mg 
1 
Lansoprazole (QD) 30 mg 
30 mg 
placebo 
placebo 
placebo 
placebo 
 
 
Number of Patients: 


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The number of patients in the study will be approximately 240; 48 patients in each treatment 
arm. 
Treatment Groups and Duration: 
Four doses of X842 (25 mg, 50 mg, 75 mg, 100 mg, and dummies) will be administered as 
tablets twice daily. The active comparator lansoprazole 30 mg and its dummy will be 
administered as capsules once daily in the morning. The study drugs should be taken with 
100 mL of noncarbonated water at least 30 minutes prior to meals. The duration of double-blind 
treatment will be 28 days -2/+5 days. To blind treatment, each patient will receive 2 tablets 
(containing doses of X842 or its dummy) and one capsule (containing lansoprazole or its 
dummy) in the morning and 2 tablets (containing doses of X842 or its dummy) in the evening. 
1.2 Schema 
Figure 1 
Study Design 
 
 
1.3 Schedule of Assessments (SoA) 
Details on procedures and timing of assessments are presented in Table 1. 
 
lansoprazole 30 mg QD.
X842 dose 25 mg BID.
Screening
Double -Blind Treatment 4 weeks
N=48 
N=48 
X842 dose 50 mg BID. 
X842 dose 100 mg BID.
N=48 
N=48
Day -7 
Day 0 Day 7±2
Day 14±3  
Day 28 -2/+5 
Symptom  
assessment 
R
X842 dose 75 mg BID. 
N=48
Endoscopy
Endoscopy 
Open-label lansoprazole 
30 mg QD for all patients, 
weekly telephone visits to 
assess symptoms and 
potential AEs 
      lansoprazole 30 mg QD. 4 weeks
Day 56±3 
End of 
Study/Early 
termination 
Day 35±3 Day 42±3 Day 49±3
Weekly Telephone visits 
BID = Twice Daily; QD = Once Daily; R = Randomization 


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Table 1 
Overall Schedule of Assessments 
Visit 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Tel 
Visit 
6  
Tel  
Visit 
7 
Tel  
Visit 
8 
Visit 9 
End of Study 
/ Early 
Termination 
Assessment/Study day 
Day -714 to Day 0 
Day 0 
Day 7 
±2 days 
Day 14 
±3 days 
Day 28 
-2/+5 days 
Day 
35 
±3 
days 
Day 
42 
±3 
days 
Day 
49 
±3 
days 
Day 56 
±3 days 
Assessment/Study week 
 
Randomization 
Week 1 
Week 2 
Week 4 
Week 
5 
Week 
6 
Week 
7 
Week 8 
 
Screening Period 
Blinded Treatment Phase 
Open-Label Phase 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
Medical/surgical history 1  
X 
 
 
 
 
 
 
 
 
Weight, height 2 
X 
 
 
 
X 
 
 
 
X 
Complete physical 
examination 
X 
 
 
 
X 
 
 
 
X 
Drugs of abuse 
X 
 
 
 
 
 
 
 
X 
Viral serology testing 3 
X 
 
 
 
 
 
 
 
 
Vital signs 4 
X 
 
X 
 
X 
 
 
 
X 
12-lead ECG evaluation 
X 
 
X 
 
X 
 
 
 
X 
Safety laboratory 5 
X 
 
X 
 
X 
 
 
 
X 
H. pylori testing 6 
X 
 
 
 
 
 
 
 
 


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Visit 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Tel 
Visit 
6  
Tel  
Visit 
7 
Tel  
Visit 
8 
Visit 9 
End of Study 
/ Early 
Termination 
Assessment/Study day 
Day -714 to Day 0 
Day 0 
Day 7 
±2 days 
Day 14 
±3 days 
Day 28 
-2/+5 days 
Day 
35 
±3 
days 
Day 
42 
±3 
days 
Day 
49 
±3 
days 
Day 56 
±3 days 
Assessment/Study week 
 
Randomization 
Week 1 
Week 2 
Week 4 
Week 
5 
Week 
6 
Week 
7 
Week 8 
 
Screening Period 
Blinded Treatment Phase 
Open-Label Phase 
Pregnancy test 7 
X 
 
 
 
X 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Patients provided with 
study drugs for blinded 
phase 
 
X 
X 
X 
 
 
 
 
 
Patients provided with 
Lansoprazole 30 mg for 
open-label phase 
 
 
 
 
X 
 
 
 
 
PK blood sampling 8 
 
 
X 
X 
X 
 
 
 
 
Upper endoscopy 
X15 
 
 
 
X 
 
 
 
 
Symptom evaluation 
using QOLRAD 
Heartburn 9 
 
X 
X 
X 
X 
 
 
 
X 
Daily symptom diary 
(RESQ-eDiary) 
completion by patient 
 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom diary 
provision/training/ 
review10  
 
X 
X 
X 
X 
X 
X 
X 
X 


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Visit 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Tel 
Visit 
6  
Tel  
Visit 
7 
Tel  
Visit 
8 
Visit 9 
End of Study 
/ Early 
Termination 
Assessment/Study day 
Day -714 to Day 0 
Day 0 
Day 7 
±2 days 
Day 14 
±3 days 
Day 28 
-2/+5 days 
Day 
35 
±3 
days 
Day 
42 
±3 
days 
Day 
49 
±3 
days 
Day 56 
±3 days 
Assessment/Study week 
 
Randomization 
Week 1 
Week 2 
Week 4 
Week 
5 
Week 
6 
Week 
7 
Week 8 
 
Screening Period 
Blinded Treatment Phase 
Open-Label Phase 
Symptom assessment by 
Investigator 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE reporting 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medications 13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE, adverse event; ECG, electrocardiogram; ICF, informed consent form; LA, Los Angeles; PK, pharmacokinetic.  
1. Including smoking (current status), alcohol consumption, and intake of drug of abuse. 
2. Height only at screening 
3. Human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis B core antigen (anti-HBcAg), antibody to hepatitis C virus 
(anti-HCV) testing at central and/or local laboratory. Patient should discontinue the study if result from central laboratory is positive. 
4. Systolic and diastolic blood pressure (BP) [mmHg], heart rate [beats per minute], body temperature and respiratory rate [per minute].  
5. Hematology, blood chemistry, coagulation (central laboratory), urinalysis (at site). Serum gastrin at screening and at Visit 5 (central laboratory). 
6. H. pylori will be analyzed in central laboratory from serum and the result will not be needed for randomization. 
7. Women of childbearing potential only. Serum pregnancy test at central laboratory at screening and urine pregnancy test at clinic/investigational site prior 
to the dose administration at Visit 5, and at End of Study / Early Termination.  
8. PK measured in all patients just before the first and the second dose on the day of the visit. At all PK sampling occasions, the time since latest study 
drug administration must be noted in the case report form (CRF). Pharmacokinetic samples will be collected 12 hours after the previous study drug dose 
administration or as close to this timepoint as possible, however, still pre-dose. 
9. QOLRAD assessment must be done pre-dose. QOLRAD will be completed by patients during site visits at Visit 2, 3, 4, 5 and 9. 
10. Patients will be trained on how to complete the symptoms diary during Visit 2 and the actual diary will be provided at Visit 2. 
. 


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11. At each visit, Investigator should assess the severity of patients’ heartburn, regurgitation and dysphagia in the 7 days prior to the visit. The assessment 
will include both the severity grade and the frequency of symptoms. Symptoms are scored as follows: none (no complaints), mild (aware of symptom, 
but easily tolerated), moderate (discomforting symptom, sufficient to cause interference with normal daily activities and/or sleep), severe (incapacitating 
symptom, with inability to perform normal daily activities and/or sleep) 
12. Collection of AEs will start directly after the informed consent form (ICF) has been signed. During the screening period, only AEs related to study 
procedure will be reported. 
13. For definitions of prior and concomitant medication, see Section 8.1.6. 
14. For the screening only, 7 days are counted as 7 working days and not calendar days. Non-working days are weekend (Saturday, Sunday) and any country 
specific public holiday. 
15. Endoscopy video/digital image taken prior to ICF signature can be used as index endoscopy for the enrollment, if taken within 7 working days of the 
planned treatment day. For patients invited for screening upper endoscopy based on their past medical history (see Section 5), the ICF will be signed 
prior to the endoscopy. The screening procedures must start with endoscopy and in case the patient doesn’t show LA grade C or D erosions, the rest of 
the screening procedures must not be conducted. This screening endoscopy must be obtained within 7 working days of planned randomization. 
 
 


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2 Introduction 
2.1 Background  
Gastro-esophageal reflux disease (GERD) is a common chronic disorder with the prevalence 
highest 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 [1]. A universally accepted 
definition of treatment success in GERD is not available [1].  
A new class of molecules, potassium-competitive acid blockers (P-CABs), presents a new mode 
of action, that, in principle, allows full acid control both day and night. Such acid inhibitory 
properties in humans are likely to allow for successful treatment of patients with erosive 
esophagitis due to GERD Grade C and D, the most acid-sensitive GERD sub-population. 
Linaprazan, the main metabolite of X842, has shown to provide effective acid control in humans 
[3, 4].  
The study drug, X842, shows a slower uptake after oral administration, compared to after oral 
administration of linaprazan. This results in a lower maximum concentration (Cmax) of linaprazan 
after administration of X842. This should translate into a lower load of linaprazan to the liver and 
to a prolonged control of intragastric acidity.  
The solubility of both linaprazan and X842 is pH dependent and increases exponentially at pH 
values below the pKa (6.1 for linaprazan and 5.5 for X842). Previous studies have shown a 
decrease in Cmax and area under the concentration-time curve (AUC) for linaprazan with repeated 
dosing [5].  
The first-in-human (FIH) study of X842 (CX842A2101) [6] was performed with a suspension 
formulation to allow dosing per kg. A tablet formulation is developed and the data from studies 
on pharmacokinetic and pharmacodynamic properties of this formulation are used for dose 
selection for this Phase 2 study and to further develop the biomarker for intragastric pH control 
(CX842A2102, CX842A2103). 
2.1.1 
Investigational Medicinal Product 
2.1.1.1 
Drug description 
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More details about IMP and lansoprazole are available in the IMPDs / Material Safety Data 
Sheet.  
2.1.1.2 
Indication 
X842 is developed for the treatment of all patients with erosive esophagitis due to GERD LA 
grade C or D and of patients with at least partial symptom response but still endoscopically 
unhealed (LA grades A or B) after at least 8 weeks history of standard treatment healing course 
with proton-pump inhibitor (PPI).  
2.1.1.3 
Dosage 
The dose levels of X842 to be tested in this study are 25, 50, 75 and 100 mg (25 and 50 mg 
tablets) given orally twice daily (BID) for 4 weeks. 
2.1.1.4 
Mechanism of action 
oved properties has been developed [3, 4].  
2.1.1.5 
 
Non-clinical toxicology 
Male and female Sprague-Dawley (SD) rats were administered X842 single oral doses up to 
250 mg/kg and repeated oral doses up to 150 mg/kg for 28 consecutive days followed by 4-week 
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recovery period. Male and female Beagle dogs were administered single oral doses of X842 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 
X842 at dose levels of up to 250 mg/kg in SD rats. Some emesis has been seen at all dose levels 
investigated in dogs. However, this is a very 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 X842 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 in rats, the no observed 
adverse effect level (NOAEL) is considered to be 150 mg/kg in both genders. In the 28-day 
repeat-dose study in dogs the NOAEL is considered to be 48 mg/kg in both genders. In all 
instances, these were the highest doses given in each study.  
In vitro (the Ames test and chromosome aberrations in Chinese hamster lung [CHL] cells) and in 
vivo (micronucleus test in rats) genotoxicity studies showed that X842 did not show mutagenic 
activity either with or without metabolic activation. 
For detailed information, refer to the Investigator´s Brochure (IB) for X842. 
2.1.1.6 
Clinical experience  
In the FIH study (single ascending dose [SAD] and multiple ascending dose [MAD]) the safety, 
tolerability and pharmacokinetic (PK) properties of X842 were evaluated [6]. The study 
concluded that X842 was well tolerated in single doses up to 4.0 mg/kg and multiple doses up to 
2.0 mg/kg (the maximum dose administered in the MAD patients) and that the intragastric pH 
correlated with the plasma concentration of linaprazan during the time interval 0-24 hours after 
dose. 
No serious adverse events (SAEs) nor adverse events (AEs) that led to withdrawal occurred after 
IMP administration and the number of patients experiencing AEs assessed as related to the IMP 
did not increase with an increasing dose. There were no clinically relevant findings or dose 
dependent mean changes over time in physical examinations, vital signs, electrocardiograms 
(ECGs) or laboratory parameters. 
With regards to PK; PK parameters and dose linearity could not be calculated for X842 due to 
low plasma concentrations. For linaprazan, the relative bioavailability after fed and fasting 
conditions was determined from the AUC 0-24 hours (AUC0-24) and Cmax. No indication of food 


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interaction was seen, however there was a high variability in both AUC0-24 and in Cmax. The 
exposure after a single administration of the highest dose (4.0 mg/kg) was lower than expected 
and the variability among patients was high. Dose linearity was shown for linaprazan for SAD 
Cohort 1-5, but not for SAD Cohort 6-7. The exposure in MAD Cohorts 2 and 3, given multiple 
doses of 2.0 mg/kg X842, 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 
patients. The reason for the non-dose linearity in SAD 6-7 and the low exposure MAD study was 
must likely the crystallization observed in the liquid formulation in the later cohorts. 
In a subsequent Phase 1, open-label, two-period cross-over, no control, PK study of X842 in 
healthy volunteers, X842 was administered as i) two doses of 50 mg X842, separated by 
24 hours and ii) two doses of 150 mg X842, separated by 24 hours. Each period is separated by 
at least 1 week. Data on this new tablet formulation showed that X842 was safe and well 
tolerated. The linaprazan plasma concentrations after dose Day 1 was increased in proportion to 
dose, while the concentrations following the dose administration Day 2 was lower than Day 1.  
A Phase 1 PK/pharmacodynamics (PD) (intragastric pH over 48 hours) study on repeated BID 
dosing of 50 mg, 100 mg and 150 mg X842 during day 1 and 2 and once daily on day 3, has 
recently concluded recruiting. X842 was safe and well tolerated and no SAE occurred. A clear 
dose response was observed. The 50 mg dose provided acid control (intragastric pH > 4) during 
68% of time while the corresponding figure for the 150 mg dose was above 90% of time. The PK 
value to predict the level of pH control was further explored. The pre-dose evening values 
showed low variability and were closely correlated to the level of pH control over time.  
2.2 Study Rationale 
This is a Phase 2, double-blind study in patients with erosive esophagitis due to GERD LA 
grades C or D, and in patients with at least partial symptom response but still endoscopically 
unhealed (LA grades A or B) after 8 weeks history of standard treatment healing course with PPI, 
designed to support dose selection for Phase 3. The pronounced acid control of X842 is assumed 
to provide high endoscopic healing rates already after 4 weeks treatment course. The four dose 
levels of X842 are selected based on data from the Phase 1 studies where the 50 mg BID dose 
displayed an acid control slightly stronger than observed for standard PPI. The dose selection for 
Phase 3 will be based on the proportion of endoscopic healing following each dose of X842, the 
respective safety data and the PK profile. Lansoprazole will serve as an active comparator. 


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2.3 Benefit/Risk Assessment 
The majority of patients in this study are likely to experience medical benefit from their 
participation based on the properties of X842 and the active comparator. However, the lowest 
dose of X842 is selected to be slightly less efficacious than the active comparator, but still 
efficacious. Patients’ safety and wellbeing is of utmost importance. Even though the toxicology 
studies and previous clinical studies have indicated a low toxicity with no major concerns at the 
dose levels studied, there is a clear need for attention to risk mitigation. 
The study involves administration of a tablet formulation of X842 for humans, with the aim of 
generating data supporting dose selection for Phase 3. The BID dosing of 25, 50, 75 and 100 mg 
corresponding to a daily dose of 0.7 - 2.9 mg/kg [based on 70 kg body weight] in this study was 
selected based on data from the Phase 1 studies (CX842A2101, CX842A2102, CX842A2103). 
The NOAEL in the repeat-dose toxicity studies (rat and dog) was set equal to the highest doses 
given. Normally this highest dose would be increased in a repeat study of the same duration. In 
this instance however, results from the earlier studies strongly indicated that a saturation of 
exposure to both X842 and linaprazan occurred at all higher dose levels in both species, thus 
limiting the relevance of further increasing the dose and also justifying the use of the same dose 
levels in the repeat studies. The mean AUC0-24 -values (males and females combined) noted at the 
stated highest dose levels (regarded as being the NOAELs) day 28 in the pivotal repeat-dose 
toxicity studies were 170 h*ng/mL and 2700 h*ng/mL for X842 and linaprazan, respectively, in 
rats and 270 h*ng/mL and 3200 h*ng/mL for X842 and linaprazan, respectively, in dogs. For 
linaprazan, it is therefore necessary to justify the safety of the chosen clinical doses of X842 by 
comparing the estimated exposure levels to linaprazan and X842 with those that have been 
shown to be safe and without any SAEs in previous clinical studies, rather than via a comparison 
with exposure values in the repeat-dose toxicity studies, in which even the highest dose levels of 
X842 given did not provoke any true toxic effects. 
In all three Phase 1 studies, X842 was well tolerated in doses up to 4.0 mg/kg single dose, up to 
2.0 mg/kg when administered as a once daily dose for five consecutive days, and in doses up to 
150 mg BID for two days plus one additional dose on day 3. No SAEs occurred, and no adverse 
drug reactions (ADRs) led to withdrawal from the study. In the FIH study CX842A2101, X842 
was given as a suspension at dose levels of 5.6 to 280 mg (0.08 to 4 mg/kg in a 70 kg individual). 
No PK parameters could be calculated for X842, as the plasma concentrations of this compound 
were very low or below the lower limit of quantification (LLOQ). It is anticipated that this will 
be the same in the current clinical study. 


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In the development program of X842’s active metabolite, linaprazan, the SAD study with 
linaprazan included single doses up to 4.0 mg/kg which resulted in an AUC of 39200 h*ng/mL, 
which also was MTD [10]. Linaprazan itself was also administered to humans at safe and 
tolerable doses of up to 75 mg QD (1.1 mg/kg in a 70 kg human) for 56 days [3, 4].  
Pharmacokinetic results from the all three Phase 1 studies on X842 and published data for 
linaprazan, strongly suggest that the PD-effect of linaprazan significantly lowers the 
bioavailability of linaprazan, thereby limiting the exposure of linaprazan seen 24 hours after the 
first dose administration.  
The overall evaluation is that X842 doses 25 mg, 50 mg, 75 mg and 100 mg BID will be safe and 
well tolerated based on the three Phase 1 studies on X842 and supportive published linaprazan 
data on healthy volunteers and in patients. 
2.3.1 
Summary of Risk Management 
Visits at the clinic/investigational site may be prolonged in case the Investigator finds it 
medically warranted for safety reasons. In cases of accidental overdose, standard supportive 
measures should be adopted as required. For further information regarding overdosing, refer to 
Section 8.5. 
Each patient will be provided with a Patient Identification Card with information about the 
patient participation in a study, see Section 10.1.4.  
The Principal Investigator at the research clinic/investigational site will ascertain that adequate 
facilities and procedures are available to handle emergency situations.  
Besides the risks related to the IMP as described above, there may also be risks related to the 
repeated endoscopy after 4 weeks. Other medical devices, e.g., indwelling venous catheters, 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, like blood-pressure 
measurements using a blood pressure cuff and blood sampling, may cause transient discomfort 
but the risk is deemed to be low and ethically justifiable.  
Linaprazan is the acid inhibitory metabolite of the X842 molecule. Linaprazan has been 
extensively studied and in a small number of patients increased LFTs were observed [3, 4] and 
careful evaluation concluded that the high Cmax of linaprazan was the main reason for the LFT 
increase. The Cmax of the metabolite linaprazan following administration of its prodrug X842 is 
reduced with about 75% and thereby minimizing the risk for hepatotoxicity. Overall, the 
combined safety data from the pre-clinical and clinical studies have not revealed any safety 


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issues that would outweigh the expected benefits of the study. While keeping the above-
mentioned risk factors at a minimum level in order to not expose the patients participating in the 
study for risks that would not be ethically justifiable it is concluded that the planned study 
assessments are considered sufficient to meet the scientific and medical objectives of the study. It 
is therefore concluded that the potential benefits from the study will outweigh the potential risks 
for the treated patients. 
More detailed information about the known and expected benefits and risks and reasonably 
expected ADRs of X842 is found in the IB. 


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3 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
The primary objective of the study is 
to support dose selection for X842, 
through assessment of healing of 
erosive esophagitis due to GERD after 
4 weeks of treatment. 
Healing of erosive esophagitis due to GERD based 
on endoscopic assessment after 4 weeks of double-
blind treatment. 
Secondary 
Evaluate the safety and tolerability of 
the four dose levels of X842 and 
lansoprazole, where lansoprazole will 
serve as the active comparator. 
Physical examination, weight, BMI, vital signs, 
electrocardiogram (ECG) recordings, safety 
laboratory measurements (hematology/clinical 
chemistry/urinalysis), adverse event (AE), 
treatment emergent adverse event (TEAE), adverse 
event of special interest (AESI), serious adverse 
event (SAE) reporting, concomitant medication(s). 
Evaluate the reflux related symptom 
pattern during the initial 4 weeks 
treatment with four dose levels of 
X842 and with lansoprazole, and the 
symptom pattern during the 
subsequent additional 4 weeks 
(Weeks 5-8) open-label treatment with 
lansoprazole 30 mg QD. 
 Percentage of heartburn-free 24-hour days 
during the Weeks 1-8 (Visits 2-9) based on 
eDiary (RESQ-eDiary) including splits into 
day- and nighttime evaluations.  
 Percentage of 24-hour days with at most mild 
heartburn symptoms during the Weeks 1-8 
(Visits 2-9) based on eDiary (RESQ-eDiary), 
including splits into day- and nighttime 
evaluations. 
 Investigator assessment of symptom at 
Weeks 1-8 (Visits 2-9)  
 Reflux related symptoms as measured by 
change from baseline in QOLRAD score 
assessed after 1, 2, 4 and 8 weeks of treatment.  
Exploratory  
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4 Study Design 
4.1 Overall Design 
The study will be conducted in multiple centers in Europe and the US. This will be a 
randomized, double-blind, active comparator-controlled study with a parallel group design 
including four arms with X842 and one arm with lansoprazole. Pharmacokinetic (PK) blood 
sampling pre-dose, close before the first and the second dose administration will be performed at 
Day 7, Day 14 and Day 28 visits days in all patients. Approximately 240 patients with erosive 
esophagitis due to GERD LA grade C or D and patients with erosive esophagitis due to GERD 
LA grade A or B with at least partial symptom response but still endoscopically unhealed after 
8 weeks history of standard treatment healing course with PPI, will be randomized in order to 
have 200 evaluable patients.  
Randomization to one of the treatments with X842 BID 25 mg, 50 mg, 75 mg, 100 mg, or 
lansoprazole 30 mg once daily (QD) will be based on a 1:1:1:1:1 scheme. One site cannot enroll 
more than 20% of the overall number of patients (48 patients per site). 
The duration of each patient’s participation in the study, including screening, blind treatment 
period and open-label treatment period, will be approximately 60 days. The patients will be 
randomized for 4 weeks (28 days, -2/+5 days) of double-blind treatment and will be provided 
with IMP for 35 days (including one additional blister pack dispensed at Visit 2/Day 0) to allow 
for treatment up to the visit window. All patients will have an endoscopic evaluation after 
4 weeks treatment. Following the endoscopic evaluation, all patients will receive subsequent 
4 weeks of open-label treatment with lansoprazole 30 mg QD. Repeated symptom evaluation to 
detect symptom pattern will be assessed during this period. The study design is shown below 
(Figure 2). 


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Figure 2 
Study Design 
 
The study will comprise 6 visits at the site and 3 telephone visits. Based on the endoscopy 
findings and/or signed informed consent form (ICF), the screening visit (Visit 1) will take place 
not more than 7 working days prior to randomization and the first dose administration (Visit 2). 
All patients will then visit the study clinic/investigational site after 7 (Visit 3), 14 (Visit 4) and 28 
days (Visit 5) and at the End of Study/Early Termination visit (Visit 9). There are 3 weekly 
telephone visits after Visit 5. See Table 1. 
4.2 Scientific Rationale for Study Design 
This Phase 2 study is designed to provide data to support dose selection for Phase 3 based on a 
dose-response profile. The endoscopic healing rates for the different doses of X842 will be 
assessed after 4 weeks double-blind treatment. Endoscopy evaluation only at 4 weeks is based on 
the level and duration of acid control that can be achieved with X842. Symptom evaluation 
during the first 4 weeks will be assessed using the validated patient reported outcome (PRO) 
QOLRAD (Heartburn version) and patient diaries (RESQ-eDiary). Erosive esophagitis due to 
GERD is known as a chronic disease and the need for maintenance therapy is likely. To further 
understand the symptom pattern after 4 weeks of powerful gastric acid inhibition all patients 
undergoing endoscopy at 4 weeks, the end of blinded phase, will be administered 4 weeks 
treatment with lansoprazole 30 mg QD. Weekly and daily symptom evaluations will be done 
during this open-label treatment period to detect symptom pattern and symptom evaluation will 
be based on telephone interviews and patient diaries. Patients who will terminate the study 
prematurely will be scheduled for End of Study/Early Termination visit, 4 weeks after cessation 
of study treatment. 
lansoprazole 30 mg QD.
X842 dose 25 mg BID.
Screening
Double -Blind Treatment 4 weeks
N=48 
N=48 
X842 dose 50 mg BID. 
X842 dose 100 mg BID.
N=48 
N=48
Day -7 
Day 0 Day 7±2
Day 14±3  
Day 28 -2/+5 
Symptom  
assessment 
R
X842 dose 75 mg BID. 
N=48
Endoscopy
Endoscopy 
Open-label lansoprazole 
30 mg QD for all patients, 
weekly telephone visits to 
assess symptoms and 
potential AEs 
      lansoprazole 30 mg QD. 4 weeks
Day 56±3 
End of 
Study/Early 
termination 
Day 35±3 Day 42±3 Day 49±3
Weekly Telephone visits 
AE = adverse events; BID = Twice Daily; QD = Once Daily; R = Randomization 


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Evaluation of reflux related symptoms will be assessed by RESQ-eDiary, investigator’s 
assessment and QOLRAD. 
4.3 Justification for Dose 
Four dose levels of X842 have been selected based on the results of three Phase 1 studies on 
X842 and previous development experience from its main metabolite linaprazan. PK/PD data has 
shown a close correlation between plasma concentrations of linaprazan and intragastric pH. The 
critical level of the plasma concentration of linaprazan after its Cmax needed to ensure an 
intragastric pH > 4 has been identified to be approximately 240 nmol/L. In the first Phase 1 study 
the administration of 1 mg/kg X842 as a liquid formulation (mean absolute dose of 74 mg) 
resulted in a mean plasma linaprazan concentration of 225 nmol/L 12 hours after dose and this 
translated to a fall in intragastric pH to < 4 after this time point. This is similar to what was seen 
after healing dose of linaprazan at steady-state (K Andersson pers. com). A PK study 
(CX842A2102), on X842 50 mg QD dosing showed that the plasma concentration of linaprazan 
during 8 hours indicated good pH control, while the pH control was not maintained at 12, 22 and 
24 hours. The plasma concentrations of linaprazan following 150 mg QD X842 indicated good 
pH control up to 12 hours, while concentration levels of linaprazan did not indicate maintained 
pH control at 22 and 24 hours after administration 
The dose levels in this study (CX842A2201) are selected to accommodate for severe eGERD 
patients representing a “harder to treat” population. The Phase 1 PK/PD (intragastric pH over 
48 hours) study (CX842A2103) on repeated BID dosing of 50 mg, 100 mg and 150 mg X842 
during day 1 and 2 and once daily on day 3 showed a clear dose response. The 50 mg dose 
provided acid control (intragastric pH > 4) during 68% of time while the corresponding figure 
for the 150 mg dose was above 90% of time. In this study (CX842A2201), the lowest dose, 
25 mg X842 BID is selected to provide a lower or similar pH control as seen during lansoprazole 
30 mg QD at steady-state. The 25 mg dose of X842 should therefore provide healing rates that 
are lower or similar to what is seen after lansoprazole 30 mg QD. The highest dose 100 mg X842 
BID is selected to provide intragastric pH control during 85% of the time. The intermediate 
X842 doses of 50 mg BID and 75 mg BID are selected to provide acid control of approximately 
70-80% of the time. The predicted efficacy of the 75 mg and 100 mg doses of X842 are assumed 
to be superior to lansoprazole 30 mg QD, i.e., the recommended daily healing dose for patients 
with esophagitis. 
4.4 End of Study Definition 
All patients who participate in this study and complete Visit 9 (End of Study/Early Termination) 
visit are considered to have completed the study (Table 1). 


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The end of the study is defined as the date of the last visit of the last patient in the study. 
5 Study Population 
Prospective approval of protocol deviations to eligibility criteria, also known as protocol waivers 
or exemptions, are not permitted.  
The patients possibly eligible will be identified as the follows: 
1. Patients identified during their routine endoscopy:  
 Patients must have erosive esophagitis identified during the routine endoscopy, before 
being considered for study screening (prior to signing the ICF). 
 This routine endoscopy will also serve as the index endoscopy in the study and the 
report should contain the endoscopy findings using the Los Angeles (LA) 
classification.  
 This routine endoscopy must be obtained within 7 working days of planned 
randomization, please refer to Inclusion criterion #4. 
2. Patients invited for screening upper endoscopy based on their past medical history (both 
criteria must be met): 
a) LA grade C or D disease within the past 5 years before screening, demonstrated 
with endoscopy (endoscopy report issued by a gastroenterologist/endoscopist is 
accepted) 
b) In the Investigator’s judgement the patient presents clear symptom relapse: 
patient may be treated with PPI, discontinued PPI treatment (patient’s decision) 
or is being treatment naïve. 
 
For patients invited for screening upper endoscopy, the ICF will be signed prior to the 
endoscopy. The screening procedures must start with endoscopy and in case the patient 
doesn’t show LA grade C or D erosions, the rest of the screening procedures must not be 
conducted. This screening endoscopy must be obtained within 7 working days of planned 
randomization. 
 
The index/screening endoscopy video/digital image will be anonymized and saved for central 
storage. Imaging data must meet quality standards for adequate LA grading and must be 
accompanied by a report and videos/digital images to allow retrospective analysis of the endoscopy 
findings. 
Investigators must keep a record of all screened patients even if they were not subsequently 
randomized in the study. This information is necessary to verify that patients were selected 


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without bias. The reason for screening failure should be stated for all patients screened but not 
randomized. The reason for withdrawal should be stated for all patients included but not 
completed study.  
A screening number will be allocated to each patient in connection to the informed consent 
process at the screening visit. The screening number will allow identification of patients 
irrespective of their possible eligibility for the study.  
For eligible patients, a randomization/treatment number will be assigned. 
5.1 Inclusion Criteria 
For inclusion in the study, patients must fulfill the following criteria: 
1. Written informed consent must be obtained before any study related assessment is 
performed. 
2. Male or female patient aged 18-75 years inclusive at the time of obtaining the informed 
consent. 
3. Body mass index (BMI) ≥ 18 and ≤ 40 kg/m2 at screening 
4. Gastroesophageal reflux disease with endoscopically confirmed erosive esophagitis:  
 LA grade C or D ≤ 7 working days before randomization (with or without historical 
PPI treatment) 
or 
 LA grade A or B ≤ 7 working days before randomization  
and  
o history of treatment with standard healing course of PPI* for minimum of 8 weeks 
prior to screening and ≤ 7 working days of non-treatment during this period**. 
and 
o at least partial symptom response during the minimum of 8 weeks of PPI treatment.  
Note: Partial symptom response is defined as a clear symptom improvement (heartburn 
or regurgitation) after start of the PPI treatment course. To qualify, the patient’s 
response must be YES to the Investigator´s standardized question to the patient: Did 
you feel a clear symptom improvement in heartburn or regurgitation after you started 
the PPI treatment course?  
*  All PPIs EXCEPT lansoprazole 
** Non-treatment days are counted from the last day of standard healing course of PPI 
therapy until endoscopy used for eligibility assessment demonstrating erosive 
esophagitis due to GERD.” 


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5. Willing and able to comply with all aspects of the protocol (including PK sampling, 
capsule swallowing, diary completion, etc.) 
5.2 Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
1. Female patients of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using one of the following adequate methods of 
contraception during dosing and for at least seven (7) days after the last dose of study 
medication: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least 6 weeks before taking the first dose of study 
treatment. In case of oophorectomy alone, only when the reproductive status of the patient 
has been confirmed by follow-up hormone level assessment. 
 Male sterilization (at least 6 months prior to screening). For female patients on the study, 
the vasectomized male partner should be the sole partner for that patient. 
 Placement of a non-hormonal IUD 
 Double barrier methods of contraception: condom in combination with occlusive cap 
(diaphragm or cervical/vault cap) with spermicidal foam/gel/film/cream/vaginal 
suppository 
Note: Patients who are already on hormonal contraceptives prior to study enrollment must 
agree to: 
o  replace hormonal contraception with double barrier method or  
o use double barrier contraception method in addition to the hormonal contraceptives  
2. Female patients of non-childbearing potential not requiring a contraceptive method, are 
defined as  
 Pre-menopausal females with a documented tubal ligation or hysterectomy; or 
 Post-menopausal females defined as at least 12 months of amenorrhea (without an 
alternative medical cause) and confirmed with simultaneous serum follicle stimulation 
hormone (FSH), consistent with post-menopausal status according to central laboratory 
ranges.  
Patients who do not meet one of these two criteria above will be considered being of 
childbearing potential and are excluded unless using one of the adequate contraceptive 
methods defined in Exclusion Criterion #1. 


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3. Male patients with a partner of childbearing potential, unless they are willing to use condoms 
in combination with a second method of adequate contraception (e.g., double barrier 
method), and they agree not to father a child during dosing and for at least seven (7) days 
after the last dose of study medication. Each male patient will be considered as potent unless 
surgically sterilized (at least 6 months prior to screening).  
4. History or presence of any clinically significant cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disease or disorder which, in the 
opinion of the Investigator, may either put the patient at risk because of participation in the 
study, or influence the study results or the patient’s ability to participate in the study 
5. Patients with so-called “alarm features” in symptomatology, like odynophagia, severe 
dysphagia, bleeding, weight loss, anemia, and blood in stool pointing to a possible malignant 
disease of the gastrointestinal (GI) tract. Exclusion can be based on symptoms only. 
6. Present clinically significant psychiatric diagnosis, at discretion of the Investigator 
7. History of malignancy of any organ system (other than completely treated localized basal cell 
carcinoma or non-metastatic squamous cell carcinoma of the skin or in situ cervical 
carcinoma), within the past 5 years. 
8. Presence of esophageal ulcer, stricture, Barrett´s esophagus or suspected esophagitis 
secondary to infection, inflammatory disease, ingestion of erosive chemicals or history of any 
surgical or medical condition which might significantly alter the GERD status or the 
absorption, distribution, metabolism or excretion of drugs. The Investigator is to be guided 
by evidence of any of the following: history of major gastrointestinal surgery such as 
gastrectomy, gastroenterostomy, bowel resection or transjugular intrahepatic portosystemic 
shunt (TIPS) 
9. Known severe atrophic gastritis 
10. Any planned major surgery within the duration of the study 
11. Any clinically significant laboratory parameter outside reference value that, in the opinion of 
the Investigator, may suggest a new or insufficiently understood disease, may present an 
unreasonable risk to the patient as a result of his/her participation in the study, or may 
interfere with study assessments. 
Any of these screening laboratory tests results are exclusionary: 
 Serum ALT or AST > 1.5 × the upper limit of normal (ULN) for the central laboratory 
conducting the test 
 Serum Total Bilirubin > 1.5 × ULN for the central laboratory conducting the test 
 Serum Creatinine > 1.5 × ULN for the central laboratory conducting the test 
 Estimated glomerular filtration rate ≤ 59 mL/min (calculated using the Modification of 
Diet in Renal Disease equation) 
12. History of a positive result for human immunodeficiency virus (HIV), Hepatitis B surface 
antigen (HBsAg), antibody to Hepatitis B core antigen (anti-HBcAg), or antibody to 
Hepatitis C virus (anti-HCV) or presence of these findings on screening 


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Note: Patients with positive anti-HBcAg along with negative HBsAg at screening will not be 
excluded IF they have a positive local anti-HBs test results not older than 6 months and 
active HBV infection has been ruled out by the Investigator. 
13. After 10 min supine rest at the time of screening, any vital signs values outside the following 
ranges: 
 Systolic blood pressure (BP) > 160 mmHg or < 90 mmHg 
 Diastolic BP > 100 mmHg or < 60 mmHg 
 Heart rate < 40 or > 95 beats per min 
14. History of long QTc syndrome (e.g., QTc ≥ 450 ms for males and ≥ 470 ms for females) 
15. Cardiac arrhythmias or any clinically significant abnormalities in the resting 12-lead ECG at 
the time of screening, as judged by the Investigator 
16. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by 
the Investigator, or history of hypersensitivity to drugs with a similar chemical structure or 
class to X842 or lansoprazole 
17. Administration of another new chemical entity (defined as a compound which has not been 
approved for marketing) or has participated in any other clinical study that included drug 
treatment with less than one month between administration of last dose and first dose of IMP 
in this study.  
18. Positive screen for drugs of abuse at screening (for the list of drugs for testing please refer to 
the laboratory manual).  
19. Current or history of alcohol, drug abuse and/or use of anabolic steroids within 2 years prior 
to screening 
20. Women who are pregnant or breast feeding. 
21. Patient is an employee of the Investigator or study site, with direct involvement in the 
proposed study or other studies under the direction of that Investigator or study site, as well 
as family members of the employees or the Investigator. 
22. Patients who have previously participated (completed or withdrawn) in this study 
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5.3 Lifestyle Considerations 
The patients must be willing to comply to the following restrictions during the entire study 
duration, i.e., from screening to the End of Study/Early Termination visit. 
5.3.1 
General Restrictions 
 Contraception requirements: Women of childbearing potential and male patients with a 
partner of childbearing potential are expected to use adequate methods of contraception 
during dosing of study medication and for at least seven (7) days after the last dose of study 
medication (see Exclusion Criteria 1 and 3, Section 5.2).  


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 Activity: Study patients must refrain from strenuous exercise (defined as greater than 70% of 
the maximal pulse rate for 1 hour or more) for 72 hours before each blood collection for 
clinical laboratory tests (except screening).  
 Blood donation: The patients must not donate blood or plasma during the study participation 
 Participation in other clinical studies: Study patients are not allowed to participate in any 
other clinical study during the study period. 
5.3.2 
Prior and Concomitant Medication and Therapy/Procedures 
The patients are not allowed to concomitantly use any medication or therapy during the study 
likely to influence the outcome of this clinical trial. This includes:  
 Agents affecting digestive organs  
o PPIs (e.g., omeprazole, pantoprazole, lansoprazole (except study medication), 
rabeprazole, esomeprazole, dexlansoprazole, dexrabeprazole, vonoprazan, etc.),  
o H2 receptor antagonists (e.g., cimetidine, ranitidine, famotidine, nizatidine, 
niperotidine, roxatidine, lafutidine, ebrotidine, etc.), 
o muscarinic receptor 3 antagonists (e.g., atropine, scopolamine, hyoscyamin, 
ipratropium, tiotropium, pirenzepine, darifenacin, oxybutinin, revefenacin, etc.),  
o gastrointestinal prokinetic agents (e.g., metoclopramide, cisapride, domperidone, 
bromopride, alizapride, clebopride, itopride, cinitapride, mosapride, etc.),  
o anti-cholinergic agents (e.g., pirenzepine, telenzepine),  
o prostaglandins (e.g., misoprostol, enprostil, etc.),  
o antacids, 
o anti-gastrin agents (e.g., proglumide, oxethazaine, etc.). 
 Medications that may affect the metabolism of X842 or linaprazan (cytochrome P450 [CYP] 
inhibitors and inducers) and medications that may be affected by X842 or linaprazan 
(substrates of CYP enzymes and drug transporters). For a comprehensive list, see 
Section 10.9 (Appendix 9), 
 Medications contraindicated for use in combination with lansoprazole,  
 Medications with reported drug–drug interactions with lansoprazole (warfarin, clopidogrel, 
ketoconazole, itraconazole, digoxin, tacrolimus, theophylline, methotrexate) and  
 H. pylori eradication therapy (antibiotics along with PPI). 
Patients are not permitted to undergo surgical intervention (e.g., fundoplication) for reflux 
disease or other antireflux procedures during study participation. Any planned major surgery 
within the duration of the study is exclusionary. 


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5.4 Screen Failures 
Screening failures are defined as patients who consent to participate in the clinical study but are 
not subsequently randomized/entered into the study. A minimal set of screening failure 
information is required to ensure transparent reporting of screening failure patients to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screening 
failure details, eligibility criteria and any SAE.  
Patients who do not meet the criteria for participation in this study may be rescreened once. If the 
re-screening occurs less than 3 months after the first screening visit, serology tests do not need to 
be repeated.  


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6 Study Drug 
Study drug is defined as any investigational intervention(s), marketed product(s), or placebo 
intended to be administered to a study patient according to the study protocol. 
6.1 Study Drugs Administered 
Study Drug Name: 
X842 
X842 Dummy 
Lansoprazole 
Lansoprazole 
Dummy 
Dosage Formulation: 
Immediate release 
tablet 
Tablet 
Capsule 
Capsule 
Unit Dose 
Strength(s)/Dosage 
Level(s): 
X842 25 or 50 mg 
Placebo for X842 
Lansoprazole 
30 mg  
Placebo for 
lansoprazole  
Route of Administration: 
Oral 
Oral 
Oral 
Oral 
Dosing Instructions: 
4-week double-blind treatment  
X842 25 mg BID 
2 tablets (X842 25mg + X842 dummy) and 1 capsule (lansoprazole dummy) in 
the morning, and 2 tablets (X842 25 mg + X842 dummy) in the evening. 
X842 50 mg BID 
2 tablets (X842 50 mg + X842 dummy) and 1 capsule (lansoprazole dummy) in 
the morning, and 2 tablets (X842 50 mg + X842 dummy) in the evening. 
X842 75 mg BID 
2 tablets (X842 50 mg + X842 25 mg) and 1 capsule (lansoprazole dummy) in the 
morning, and 2 tablets (X842 50 mg + X842 25 mg) in the evening. 
X842 100 mg BID 
2 tablets (X842 50 mg×2) and 1 capsule (lansoprazole dummy) in the morning, 
and 2 tablets (X842 50 mg×2) in the evening. 
Lansoprazole 30 mg QD 
2 tablets (X842 dummy×2) and 1 capsule (lansoprazole 30 mg) in the morning, 
and 2 tablets (X842 dummy×2) in the evening. 
4-week lansoprazole 30 mg QD 
For all patients continuing on open-label phase: lansoprazole 30 mg 1 capsule in 
the morning. 
Packaging and Labeling: 
 
Study drug will 
be provided in 
blister pack. Each 
blister pack will 
be labeled as 
required per 
country 
requirement.  
Study drug will be 
provided in blister 
pack. Each blister 
pack will be 
labeled as 
required per 
country 
requirement. 
Study drug will 
be provided in 
blister pack. Each 
blister pack will 
be labeled as 
required per 
country 
requirement. 
Study drug will 
be provided in 
blister pack. Each 
blister pack will 
be labeled as 
required per 
country 
requirement. 
6.2 Preparation/Handling/Storage/Accountability 
The blister packs containing the study medication will be dispensed as per randomization 
schedule by a site pharmacist or a registered nurse under supervision of other site personnel.  


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The Investigator will maintain a Drug Dispensing Log detailing the dates and quantities of study 
medication received, dispensed to and used by each patient and study medication returned or 
destroyed at the end of the study. Any discrepancies between dispensed and returned study drug 
must be explained and documented. Products deliberately and/or accidentally destroyed by the 
Investigator/pharmacy or the patient, must be accounted for. Patients will receive one additional 
blister pack at Visit 2/Day 0 to keep overage in case they return within the allowed visit window. 
Patients should return this additional blister pack for accountability at every visit and returned on 
Visit 5. 
6.3 Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Randomization 
Patients will be randomized to receive either one of the four doses of the test product (48 patients 
per dose group) or the reference product lansoprazole (48 patients). 
The randomization list will be generated, and the original randomization list will be kept.  
All patients will be centrally randomized using an Interactive Voice Response System (IVRS). 
Each patient will be assigned a unique number (randomization number) that encodes the patient’s 
assignment to one of the five arms of the study, according to the randomization schedule 
generated by Parexel using a validated computer program. Details of the procedure are described 
in the IVRS Manual provided to all clinic/investigational sites. 
Randomization will be set as approximately 50% of patients with LA grade A or B and 
approximately 50% of patients with LA grade C or D. 
6.3.2 
Blinding 
This is a double-blind study and the allocation of treatments will not be disclosed until the file 
has been declared clean and the database has been locked.  
The IMP tablets will be identical in appearance (dummy, 25 mg and 50 mg tablets) and 
lansoprazole, the reference treatment (capsule), will be identical in appearance as its dummy. All 
efforts will be made at the clinic/investigational site to maintain the blind. All study medication 
will be provided in blister packs according to the randomization list through IVRS.  


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6.3.3 
Emergency Unblinding During the Study 
The treatment code may only be broken by the Investigator in case of emergency when 
knowledge of the treatment received is necessary for the proper medical management of the 
patient. 
In case of emergency the Investigator may contact the Sponsor’s Medical Monitor for drug 
specific input prior to disclosure of the treatment allocation. However, the Investigator will make 
the decision to unblind the treatment assignment. 
For unblinding procedures in case of a potential suspected unexpected serious adverse reaction 
(SUSAR), refer to Section 8.4.6.1. 
6.4 Study Drug Compliance 
The first administration will take place as early as possible after randomization until 2 pm on 
Day 0, or at 8 pm on Day 0. Diary cards will be handed out together with the study drug to the 
patients and they will be instructed to document date and time of the following administrations 
on the diary card. The patients will bring the diary card at each visit to the study 
clinic/investigational site. In addition, the patients will also bring the remaining capsules and 
tablets for reconciliation. Treatment compliance will be based on the number of remaining 
capsules and tablets. 
6.5 Return and Destruction of Investigational Medicinal Products 
Any unused study medication will be returned to the Sponsor and/or CRO for destruction. 
Used/unused blisters will be destroyed at the study sites after reconciliation by the Clinical 
Research Associate (CRA). The CRA will perform final study drug accountability reconciliation 
at the study end to verify that all unused study drug is adequately destroyed/returned and 
documented. 
6.6 Prior and Concomitant Therapy 
The patients are not allowed to concomitantly use any medication or therapy likely to influence 
the outcome of this clinical trial. This includes: agents affecting digestive organs (PPIs, H2 
receptor antagonists, muscarinic receptor 3 antagonists, gastrointestinal prokinetic agents, 
anti-cholinergic agents, prostaglandins, antacids, anti-gastrin agents), medications involved in the 
metabolism of X842 and linaprazan (CYP substrates, inhibitors, inducers and transporter 
inhibitors, as specified in Appendix 9), medications contraindicated for use in combination with 


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lansoprazole, medications with reported drug–drug interactions with lansoprazole (warfarin and 
clopidogrel) and H. pylori eradication therapy. 
For list of medication or therapy that are not allowed concomitantly, see Section 5.3.2. Other 
concomitant medications that the patient receives on a regular basis may continue, if in the 
opinion of the Investigator, it does not put the patient at undue risk or does not interfere with the 
study evaluations. 
Any change in concomitant medication during the course of the study will be recorded by the 
Investigator in the relevant section of the case report form (CRF). 
6.6.1 
Rescue Medication 
All restrictions regarding the use of medications or therapies which are likely to influence study 
outcome are applicable for the entire duration of the study (please refer to Section 5.3.2 for not 
permitted medications). 
6.7 Dose Modification 
Dose modification for an individual patient is not allowed. 
6.8 Intervention After the End of the Study 
There will be no treatment with X842 or lansoprazole available, provided by Sponsor, after End 
of Study participation. Following discontinuation of study treatment some patients may need 
additional therapy for their erosive esophagitis due to GERD. The Investigator should ensure 
patients re-establish care with a physician during the open-label treatment period in order to 
avoid a lapse. 
7 Discontinuation of Study Drug and Patient Discontinuation 
7.1 General Withdrawal Criteria 
Patients 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 should be documented. 
Patients may be discontinued from the study at any time at the discretion of the Investigator for 
any of the following reasons:  
 Severe non-compliance to study protocol procedures, as judged by the Investigator and/or 
Sponsor 


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 Significant AEs posing a risk for the patient, as judged by the Investigator and/or Sponsor 
 Withdrawal of informed consent by the patient. If consent is withdrawn, the patient will not 
receive any further study treatment or further study observation. Note that the patient may 
need to undergo additional tests to withdraw safely  
 Withdrawal of informed consent by the patient to the use of biological samples as judged by 
the Investigator and/or Sponsor 
 At the discretion of the Investigator, when he/she believes continued participation is not in 
the best interest of the patient 
 Positive pregnancy test (Pregnant women should be followed until delivery as described in 
Section 8.4.8) 
 Severe laboratory abnormalities (please refer to Treatment and follow-up of AEs in 
Section 8.4.7):  
o Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 8 x upper 
limit of normal (ULN)  
o AST or ALT > 5 x ULN (for more than 2 weeks) 
o ALT or AST > 3 x ULN with total bilirubin (TBL) > 2 x ULN (unless elevated 
bilirubin is related to confirmed Gilbert’s Syndrome) or with international normalized 
ratio (INR) > 1.5  
o ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
 Diagnosis of a malignancy during study (excluding carcinoma in situ of the cervix, or 
squamous or basal cell carcinoma of the skin). 
 The Sponsor or a Regulatory Agency requests withdrawal of the patient. 
7.2 Procedures for Discontinuation of a Patient from the Study 
A patient who prematurely discontinues participation in the study will always be asked about the 
reason(s) for discontinuation and the presence of any AEs. If possible, they will be seen by the 
Investigator and assessed according to the procedures scheduled for the End of Study/Early 
Termination visit. Any ongoing AEs will be followed as described in Section 8.4.7. 
7.3 Patient Replacement 
Patient replacement is not planned. 
7.4 Loss of Patients to Follow-Up 
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the clinic/investigational site until and including Visit 
9/End of Study/Early Termination visit. 


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The following actions must be taken if a patient fails to return to the clinic for a required study 
visit or fails to be available for a telephone visit: 
 The clinic/investigational site must attempt to contact the patient and reschedule the missed 
visit as soon as possible (and within the visit window, where one is defined) and counsel the 
patient on the importance of maintaining the assigned visit schedule and ascertain whether or 
not the patient wishes to and/or should continue in the study. 
 In cases in which the patient missed one or more visits, the Investigator or Designee must 
make every effort to regain contact with the patient (where possible, three telephone calls 
and, if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods). The last attempt to contact the patient must be at the time for Visit 9. 
These contact attempts should be documented in the patient’s medical record. 
8 Study Assessments and Procedures 
The study assessments are described in the sections below and the timing of these assessments 
are detailed in the SoA table (see Table 1).  
The Principal Investigator will provide the Sponsor/Designee with all data produced during the 
study from the scheduled study assessments. He/she ensures the accuracy, completeness, 
legibility, and timeliness of the data reported to Sponsor/Designee in the electronic CRF (eCRF) 
and in all required reports. 
It is important that PK blood sampling occurs as close as possible to scheduled time and is 
always accompanied with the time for the latest study medication tablet administration. In order 
to achieve this, the preferred timing priority order at a particular time point is: 
 QOLRAD completion 
 Blood samples for PK  
 Safety laboratory samples 
 ECG, vital signs, physical examination 
 Investigator assessment 
 Study drug administration 
The actual sampling time and the time for the latest study medication tablet administration 
should always be recorded in the eCRF and will be used in the calculation of the PK parameters. 
Blood samples will be drawn by venipuncture or an indwelling venous catheter at time-points 
specified in the detailed schedule of events in SoA (Table 1). 
Detailed instructions for collection of samples will be provided in the laboratory manual.  


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The maximum volume of blood samples (safety samples and PK samples) collected during the 
study from each patient, including extra assessments that may be required, will not exceed 
450 mL (i.e., less than the volume drawn during a regular blood donation). 
8.1 Demographics and Other Baseline Characteristics 
8.1.1 
Informed Consent 
Signed informed consent must be obtained before any screening procedures are initiated. The 
informed consent procedure is further described in Section 10.1.3. 
8.1.2 
Eligibility Criteria 
Eligibility criteria should be checked during screening period and confirmed prior to 
inclusion/randomization. The criteria are specified in Sections 5.1 and 5.2. 
8.1.3 
Demographic Information 
The following demographic data will be recorded: gender, age, and ethnic origin. 
8.1.4 
Weight and Height 
Weight and height will be measured wearing light clothes and without shoes. Body mass index 
(BMI) will be calculated from the height and weight recorded and rounded off to the nearest 
whole number. 
The body weight recorded at screening will be used for determination of eligibility and the body 
weight recorded at baseline, after the 4-week double-blind period and at the End of Study is a 
safety assessment. The method of weight assessment should be the same across all visits. 
8.1.5 
Medical/Surgical History  
Medical/surgical history will be obtained by patient interview in order to verify that the 
eligibility criteria are met. 
Medical history includes recent medical history, previous medical history (only significant 
medical or surgical illness), smoking, alcohol and intake of drugs of abuse and/or anabolic 
steroids. 
8.1.6 
Prior and Concomitant Medication 
Prior medication will be obtained by patient interview in order to verify that the eligibility 
criteria are met (see also Section 5.3.2). 


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Medications are classified as prior if the stop date was before or on the day of the first dose 
administration (pre-dose) and as concomitant if ongoing on the day of the first dose 
administration, stopped after the first dose administration or started after the first dose 
administration.  
Any use of concomitant medication from screening until the End of Study/Early Termination 
visit must be documented appropriately in the patient’s eCRF. Relevant information (i.e., name 
of medication, total daily dose, unit, start and stop dates, reason for use if consistent with the 
definition of an AE) must be recorded. All changes in medication should be noted in the eCRF. 
8.1.7 
Serology (HIV and Hepatitis B/C Virus) Testing 
Patients will be tested for HIV and hepatitis B surface antigen (HBsAg), antibody to hepatitis B 
core antigen (anti-HBcAg), antibody to hepatitis C virus (anti-HCV at central lab) prior to 
inclusion/randomization into the study in order to assess eligibility and protect personnel 
handling the blood samples. 
8.1.8 
Pregnancy Test 
All women of childbearing potential will undergo a serum pregnancy test at screening and a 
urine pregnancy test (dipstick) prior to administration of study drug dose at Visit 5, and at End of 
Study/Early Termination. 
8.1.9 
Urine Drug Screen 
Urine will be screened for drugs of abuse at screening using local drug screen tests (see the 
laboratory manual). Additional random tests can be performed during the study period. 
8.2 Efficacy Assessments 
Upper endoscopy for the examination of esophagus will be used to confirm patient eligibility as 
well as the confirmation of the primary endpoint. Imaging data must meet quality standards for 
adequate LA grading and must be accompanied by a report and videos/digital images to allow 
retrospective analysis of the endoscopy findings. The endoscopy has to be performed by an 
experienced endoscopist. The patient has to be fasting prior to endoscopy, i.e., drinking, eating, 
and smoking are not allowed from midnight prior to the assessment. The index/screening 
endoscopy must be taken within seven (7) days of the planned treatment day. Endoscopies taken 
prior to informed consent signatures can be used once the patient agrees to participate in the 
study and signs the informed consent. The endoscopy examinations must be recorded on a video 


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shot/digital images. The length, views and other technical specifications of the videos/digital 
images are described in the Image Acquisition Guidelines, separate document. 
The endoscopy videos/digital images will be evaluated by Investigator or endoscopy specialist, 
as required. Grade of erosive esophagitis due to GERD will be determined by the appropriately 
trained Investigator or endoscopist according to the LA classification (see Appendix 8). The LA 
grading of the erosive esophagitis due to GERD should be documented in the endoscopy report. 
The endoscopy videos/digital images will be collected into a central database, with the 
appropriate anonymization. All videos and digital images will be centrally reviewed 
retrospectively. This review will include reassessment of the LA grading and other findings 
which may constitute exclusion criterion. The central reading evaluation will override the 
investigators evaluations. Data obtained from patients deemed to have been ineligible for study 
enrollment following the retrospective analysis will be excluded from the per protocol analysis.  
8.3 Safety Assessments 
8.3.1 
Physical Examinations 
A complete physical examination will be performed as designated on the SoA and will include 
assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, 
cardiovascular system, abdomen (including liver and spleen), lymph nodes, genitourinary system 
(optional) and extremities (musculoskeletal system). 
8.3.2 
Weight and BMI 
Weight will be measured wearing light clothes and without shoes as designated on the SoA. The 
method of weight assessment will be the same across all visits. Body mass index (BMI) unit is 
kg/m2 and calculated as weight in kg and height in meter.  
8.3.3 
Vital Signs 
Examination of vital signs will be performed as designated on the SoA. Systolic and diastolic BP 
and heart rate (pulse) will be measured in supine position after 10 min of rest. Body temperature 
and respiratory rate will be measured pre-dose. 
8.3.4 
Resting 12-lead Electrocardiograms 
Single 12-lead ECG will be recorded as designated on the SoA in supine position after 10 min of 
rest using an ECG machine. Heart rate and PQ/PR, QRS, QT and QTcF intervals will be 
recorded. Safety ECGs will be reviewed and interpreted on-site by the Investigator. 


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Abnormalities in an ECG will be assessed as “clinically significant” or “not clinically 
significant.” An ECG abnormality may meet the criteria of an AE as described in this protocol 
(see Section 8.4). 
8.3.5 
Clinical Safety Laboratory Assessments 
Blood samples for analysis of clinical chemistry, hematology and coagulation parameters will be 
collected through venipuncture or an indwelling venous catheter and sent to the certified clinical 
chemistry laboratory and analyzed by routine analytical methods. Urine laboratory analysis will 
be performed at the research clinic/investigational site using dip sticks. Additionally, local testing 
at site includes urine drug abuse test and urine pregnancy test (dipstick) will be performed. For 
details, see the laboratory manual. 
The following safety laboratory parameters will be assessed at time-points defined in SoA 
(Table 1): 
Clinical Chemistry 
Hematology 
Alanine aminotransferase (ALAT) 
Hematocrit 
Alkaline phosphatase (ALP) 
Hemoglobin (Hb) 
Albumin 
Platelet count 
Aspartate aminotransferase (ASAT) 
Red blood cell (RBC) count 
Bilirubin (total and conjugated) 
White blood cell (WBC) count with differential count 
Calcium 
 
Chloride 
Coagulation 
Creatinine 
International Normalized Ratio 
Gamma-glutamyl transferase (GGT) 
 
Magnesium 
 
Phosphorous 
Urinalysis (dip stick) 
Potassium 
Glucose 
Sodium 
Hemoglobin/erythrocytes 
Urea nitrogen 
Nitrite 
Uric acid 
Protein 
Gastrin 
Specific gravity 
 
pH 
 
Ketones 
Viral serology 
Hepatitis B (HBsAg) 
Anti-hepatitis B core antigen (Anti-HBcAg) 
Other  
Urine pregnancy test (HCG)1 
Follicle stimulating hormone (FSH)2 


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Hepatitis C antibody (anti-HCV) 
Human immunodeficiency virus (HIV-1 and -2) 
Urine drug abuse screen3 
H. pylori4 
 
1 Women of childbearing potential only (local urine test at site) 
2 At screening, post-menopausal women only, as applicable (central laboratory) 
3 At screening, local urine sample at site 
4 H. pylori result will not be needed for randomization (central laboratory) 
8.3.6 
Concomitant Medication 
Prior medication will be obtained by patient interview in order to verify that the eligibility 
criteria are met (see also Section 6.6). 
Medications are classified as prior if the stop date was before or on the day of the first dose 
administration (pre-dose), and as concomitant if ongoing on the day of the first dose 
administration, stopped after the first dose administration or started after the first dose 
administration. 
8.3.7 
Reflux Related Symptoms Assessed Based on PRO 
Reflux related symptoms will be assessed based on QOLRAD, which is a PRO developed by 
Wiklund et al in 1998 [8]. It has been translated and evaluated in multiple languages. The 
heartburn version of the QOLRAD is a disease specific instrument and contains 25 questions 
addressing concerns associated with gastrointestinal symptoms. The questions are rated on a 
seven-grade Likert scale; the lower the value, the more severe the impact on daily functions. The 
questions are categorized into five domains: emotional distress (six questions), sleep disturbance 
(five questions), vitality (three questions), food/drink problems (six questions) and 
physical/social functioning (five questions). It will be assessed at baseline, week 1, 2, and 4 (see 
Table 1). The QOLRAD will be completed pre-dose by patients at Visits 2, 3, 4, 5, and 9 (please 
refer to SoA). 
Reflux related symptoms will be also assessed based on a modified RESQ-eDiary; an electronic 
symptom diary developed for use in partial responders to PPI. RESQ-eD has three Domains (i.e. 
Heartburn, Other GERD signs/symptoms and Regurgitations/Reflux) and eight Items. Patients 
will be asked to report every 12-hours, once before the morning dose and once before the 
evening dose of the IMP. 
8.3.8 
Reflux Related Symptoms Assessed by Investigator 
Symptoms of GERD may include: heartburn (defined as a retrosternal burning pain rising from 
the epigastrium which may radiate into the pharynx), acid regurgitation (upward flow of sour 


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fluid toward the mouth), dysphagia, epigastric pain/discomfort, retrosternal tightness, 
burping/belching, nausea/vomiting, fullness, lower abdominal pain, flatulence, coughing. 
At each visit, Investigator will assess the severity of patients’ heartburn, regurgitation and 
dysphagia in the 7 days prior to the visit. The assessment will include both the severity grade and 
the frequency of symptoms. Assessments will be captured in EDC.  
The potential frequency is defined as 7-graded Likert scale:  
 All of the time;  
 Most of the time;  
 Quite a lot of the time;  
 Some of the time;  
 A little of the time;  
 Hardly any of the time;  
 None of the time. 
Symptoms are scored as follows:  
 none (no complaints),  
 mild (aware of symptom, but easily tolerated),  
 moderate (discomforting symptom, sufficient to cause interference with normal daily 
activities and/or sleep),  
 severe (incapacitating symptom, with inability to perform normal daily activities and/or 
sleep). 
8.3.9 
Pharmacokinetic Samples and Analysis 
Venous blood samples (approximately 5 mL, exact details are provided in the laboratory manual) 
for the determination of plasma concentrations of linaprazan and X842 after administration of 
the study drug, will be collected at the pre-specified time-points (see Table 1).  
The date and time of collection of each sample and the time for the latest study drug 
administration will be recorded in the eCRF. PK samples will be collected 12 hours after the 
previous study drug dose administration or as close to this timepoint as possible, but always 
pre-dose (close before the first and the second dose administration at Days 7, 14 and 28). 
Plasma samples for determination of plasma concentrations of linaprazan and X842 will be 
analyzed by means of a validated LC-MS/MS method (see the laboratory manual). The details of 


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the analytical method used will be described in a separate bioanalytical report. Detailed 
instructions for collection, handling, labeling, storage and shipment of samples will be provided 
in the laboratory manual. 
8.4 Adverse Events and Serious Adverse Events 
8.4.1 
Definitions 
8.4.1.1 
Adverse event 
An AE is any untoward medical occurrence in a clinical study patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including clinically 
significant abnormal values from relevant tests, such as clinical safety laboratory tests, ECGs, 
vital signs), symptom, or disease temporally associated with the use of an IMP, regardless of 
whether it is considered related to the IMP. 
A TEAE is any AE only present after the initiation of IMP administration or any event already 
present that worsens in either intensity or frequency following exposure to the IMP. 
Collection of AEs will start directly after the ICF has been signed. Only AEs related to study 
procedure will be collected between screening visit and the first IMP administration. 
8.4.1.2 
Serious adverse event  
An SAE is any AE that: 
 results in death 
 is life-threatening (this refers to an event in which the patient was at immediate risk of death 
at the time of the event; it does not refer to an event that hypothetically might have caused 
death if it had been more severe) 
 requires inpatient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is medically important (this refers to an event that may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the patient or may require intervention 
to prevent any of the SAEs defined above) 
Examples of medically important 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. 


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Hospitalization is defined as any inpatient admission usually involving at least an overnight stay. 
Planned hospitalizations or surgical interventions for a condition that existed before the patient 
signed the ICF and that did not change in intensity are not SAEs. 
If there is any doubt as to whether an AE meets the definition of an SAE, a conservative 
viewpoint must be taken, and the AE must be reported as an SAE. 
8.4.1.3 
Adverse events of special interest (AESI)  
An AESI (serious or non-serious) is one of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the 
Investigator to the Sponsor can be appropriate. Such an event might warrant further investigation 
in order to characterize and understand it.  
All AESI, serious and non-serious, must be reported within 24 hours of identification using the 
same reporting process as for SAE reporting. 
The following conditions should be considered AEs of special interest and require expedited 
reporting: 
a. ALT or AST ≥ 8 x ULN 
b. ALT or AST ≥ 5 x ULN for 2 or more weeks 
c. ALT or AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN (or ALT or AST ≥ 3 x ULN and 
INR > 1.5) 
d. ALT or AST ≥ 3 x ULN accompanied by clinical symptoms believed to be related to 
hepatitis or hypersensitivity, such as new or worsening of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, or rash 
e. ALT or AST ≥ 5 x ULN but < 8 x ULN and cannot be monitored at least weekly for 
≥ 2 week 
 
Hy’s Law, defined as ≥ 3 x ULN ALT or AST with coexisting ≥ 2 x ULN total bilirubin with no 
alternative explanation for the biochemical abnormality other than IMP (for example elevated 
ALP indicating cholestasis, viral hepatitis, other medication) must always be reported without 
delay as an AESI, and, if applicable, also as an SAE. 
All potential drug-induced liver injuries (PDILI) events require immediate action, testing, and 
monitoring. If tests are done locally for more rapid results, a concurrent sample should also be 
sent to the central laboratory whenever possible.  


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PDILI events require notification of the Medical Monitor within 24 hours (e.g., by laboratory 
alert), and the patient must be discussed with the Medical Monitor as soon as possible. Patients 
with PDILI must be assessed to determine if the study drug must be discontinued (please refer to 
General withdrawal criteria, Section 7.1). 
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of liver 
events has to be followed.  
Every liver laboratory trigger or liver event as defined in Table 2 should be followed up by the 
Investigator or designated personnel at the trial site as summarized below (please also refer to 
General withdrawal criteria, Section 7.1). 
A. Liver laboratory trigger: 
 Repeating the LFT within the next week to confirm elevation. The repeat assessment can be 
done as an unscheduled study visit or at a local laboratory. In this case, local laboratory 
normal ranges should be recorded, and the results should be made available to the trial 
investigator immediately, and the data recorded on the CRF. 
 If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
B. Liver event: 
 Repeating the LFT as soon as possible to confirm elevation as appropriate 
 Monitoring of liver chemistry values at least twice per week until values normalize, stabilize, 
or return to within baseline value 
 Discontinuation of the investigational drug if appropriate 
 Hospitalization of the patient if appropriate 
 A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications) 
 An investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and the 
procedures performed should be recorded on appropriate CRF pages, including the liver event 
overview CRF pages. 
 


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Table 2 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
A. LIVER LABORATORY 
TRIGGERS 
 ALT or AST > 3 × ULN, but ALT and AST ≤ 5 × ULN 
 TBL > 1.5 × ULN, but TBL≤ 2 × ULN 
B. LIVER EVENTS 
 
Laboratory events 
(any of the listed criteria) 
ALT or AST > 5 × ULN 
 
ALP > 5 × ULN  
 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable 
increase in ALP to > 2 × ULN) 
Adverse events 
(any of the listed criteria) 
Any clinical event of jaundice (or equivalent term) 
 
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
Any adverse event potentially indicative of a liver toxicity *  
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
 
It is the responsibility of the Investigator to follow up on all SAEs until the patient has recovered, 
stabilized, or recovered with sequelae, and to report to the Sponsor or Designee 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. 
Serious adverse events spontaneously reported by a patient to the Investigator within 30 days 
after the last follow-up assessment must be handled in the same manner as SAEs occurring 
during the study. These SAEs will be reported to the Sponsor or Designee. 
8.4.1.4 
Serious adverse drug reaction  
The term serious adverse drug reaction (SADR) is to be used whenever either the Investigator or 
Sponsor or designee assessed the SAE as possibly or probably related to the IMP. 
8.4.1.5 
Suspected unexpected serious adverse reaction  
A SUSAR is any SADR whose nature or intensity is not consistent with the current version of 
the IB (unexpected). 


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8.4.2 
Time Period and Frequency for Collecting AE and SAE Information 
Collection of AEs will start directly after the ICF has been signed. During the screening period, 
only AEs related to study procedure will be reported. All AEs (including SAEs) will be collected 
until the End of Study/Early Termination visit. Any AE with start date on the day or after the 
IMP administration must be recorded with start time. At the follow-up visit, information on new 
AEs or SAEs, if any, and stop dates for AEs recorded and ongoing during the dosing period must 
be recorded. Medical occurrences that begin before the start of study drug but after obtaining 
informed consent will be recorded in the Medical History Log of the eCRF, not in the AE Log. 
Investigators are not obligated to actively seek new AE or SAE after conclusion of the study 
participation (for follow-up of AEs please refer to Section 8.4.7). However, if the Investigator 
learns of any SAE, including a death, at any time after a patient has been discharged from the 
study, and he/she considers the event to be reasonably related to the study drug or study 
participation, the Investigator must promptly notify the Sponsor or Designee. 
8.4.3 Assessment of Severity/Intensity 
The grading of the severity/intensity of AEs will follow the common terminology criteria for AEs 
(CTCAE) v4.03 [9]. 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 severity/intensity of an AE using the following definitions, and 
record it on the AE Form in the CRF: 
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)* 
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 refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 


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**Self- care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Note: a semi-colon indicates ‘or’ within the description of the grade. 
8.4.3.1 Assessment of causal relationship 
The Investigator must assess the causal relationship between an AE and the IMP using the 
definitions below and record it the AE Log of the eCRF: 
 Probable – the AE has a strong temporal relationship to the IMP or recurs on re-challenge, 
and another etiology is unlikely or significantly less likely 
 Possible – the AE has a suggestive temporal relationship to the IMP, and an alternative 
etiology is equally or less likely 
 Unlikely – the AE has no temporal relationship to the IMP or is due to underlying/concurrent 
illness or effect of another drug (that is, there is no causal relationship between the IMP and 
the AE) 
An AE is considered causally related to the use of the IMP when the causality assessment is 
probable or possible. 
8.4.3.2 
Assessment of outcome 
The Investigator must assess the outcome of an AE using the definitions below and record it on 
the AE Log of the eCRF: 
 Recovered – the patient has recovered completely, and no symptoms remain 
 Recovering – the patient’s condition is improving, but symptoms still remain 
 Recovered with sequelae – the patient has recovered, but some symptoms remain (for 
example, the patient had a stroke and is functioning normally, but has some motor 
impairment) 
 Not recovered – the patient’s condition has not improved, and the symptoms are unchanged 
(for example, an atrial fibrillation has become chronic) 
 Death 
8.4.4 
Collecting Adverse Events 
In general, abnormal findings at screening should be recorded in the patient’s Medical History. 
Adverse events identified using any of the following methods will be recorded: 
 AEs spontaneously reported by the patient 
 AEs observed by the Investigator or medical personnel 


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 AEs elicited based on non-leading questions from the Investigator or medical personnel 
8.4.5 
Recording Adverse Events 
Adverse events 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.  
Adverse events, 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. 
If the severity/intensity of an AE increases a new AE Form must be completed in the eCRF. 
Adverse events must be documented in clear, unambiguous medical language, without use of 
abbreviations or acronyms. 
8.4.6 
Reporting of Serious Adverse Events 
On discovery, all SAE/AESIs should be immediately reported (latest within 24 hours of knowledge 
of the event) to Parexel Safety Services by: 
Entering the AE in the appropriate section (AE page and/or SAE page) of the eCRF, indicating that 
the event is considered serious, and providing all the details per the eCRF completion guidelines 
and 
Completing the SAE report form and e-mailing/faxing the documents to Parexel Safety Services 
as per details below: 
France (Paris) Mailbox: 249403_Safety@parexel.com 
France (Paris) Fax numbers: +33 1 44 90 32 75 or +33 1 44 90 35 34 
In the event that the site is unable to complete the SAE form or eCRF entry to report the event 
within 24 hours of their knowledge of the event, the Investigators may report the SAE over the 
telephone via the SAE answering service, and then provide the completed SAE form via (fax or 
email), or complete the eCRF entry of the event (within the next 24 hours). If questions arise 
regarding the reporting procedures or the specifics of the reporting of an event, sites may call 
(English) utilizing the following numbers: 
Paris: +33 1 44 90 32 90 


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In case the eCRF cannot be accessed, the SAE should be reported by manually completing the 
paper SAE Form, provided in the investigator site file (ISF).  
The SAE report is reviewed by a designated person at Parexel to ensure that the report is valid 
and correct. For fatal or life-threatening SAEs where important or relevant information is 
missing, immediate follow-up is undertaken and queries to the site are raised by Parexel. 
Investigators or other site personnel should inform designated person of any follow-up 
information on a previously reported SAE immediately but no later than the end of the next 
business day of when he/she becomes aware of it.  
If an SAE report is updated, the designated study personnel will be informed. 
If any additional documentation is required (e.g., hospital discharge letter, autopsy report, etc.), 
designated person will request this information from the study site.  
 
The study site should notify the CRA 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 should be reported 
electronically as well. 
The Sponsor or Designee will assume responsibility for reporting SAEs to competent authorities 
(CAs) and the independent ethics committees (IECs) in accordance with local regulations. 
8.4.6.1 
Reporting of SUSARs to EudraVigilance, local CA and IEC 
The term SADR is used whenever either the Investigator or Medical Monitor deems a blinded 
SAE as possibly or probably related to IMP. If a SADR is assessed as unexpected by the Medical 
Monitor, it is a potential SUSAR.  
Under such circumstances, the Sponsor Medical Monitor will be unblinded (see Global Safety 
Reporting Procedure) and reported to the CAs (via the EudraVigilance database, where 
applicable), and to the IEC, in accordance with local regulations and applicable standard 
operating procedures (SOPs) within the following timelines:  
 7 calendar days if fatal or life-threatening (follow-up information within an additional 
8 days) 
 15 calendar days if non-fatal and non-life-threatening (for initial and follow-up information) 
The clock for expedited initial reporting (Day 0) starts as soon as the Sponsor or Designee has 
received the information containing the minimum reporting criteria. The date should be 
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The Medical Monitor is responsible for medical review of the SAE narrative in the Council for 
International Organizations of Medical Sciences for (or equivalent) prior to expedited reporting. 
The Sponsor or Designee is responsible for informing the Investigators concerned of relevant 
information about potential SUSARs (blinded data) that could adversely affect the safety of 
patients.  
The Sponsor or Designee is responsible for once a year throughout the clinical study (or on 
request), to submit a safety report to the CA and the IEC taking into account all new available 
safety information received during the reporting period. 
8.4.7 
Treatment and Follow-up of Adverse Events 
Patients with AEs that occur during the study must be treated according to daily clinical practice 
at the discretion of the Investigator. Adverse events must be followed up until resolution or until 
End of Study/Early Termination visit, whichever comes first. At the follow-up visit, information 
on new AEs, if any, and stop dates for previously reported AEs must be recorded. Adverse events 
assessed as stable by the Investigator at the End of Study/Early Termination visit will not have to 
be followed up until resolution. 
For the treatment and follow-up of AESIs please refer to Section 8.4.1.3. 
All SAEs not resolved by the end of the study or that have not resolved upon the patient’s 
discontinuation in the study must be followed until the event resolves, the event stabilizes, or the 
event returns to baseline if a baseline value is available. 
8.4.8 
Pregnancy 
In case of pregnancy or suspicion of possible pregnancy, the study treatment must be stopped 
immediately, and the patient discontinued from participation in the study. Pregnancy itself is not 
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 patient was discontinued from the study. 
All events of congenital abnormalities/birth defects are SAEs. Pregnancy complications or 
spontaneous miscarriages should also be reported and handled as AEs or SAEs. All outcomes of 
pregnancy must be reported to the Sponsor or Designee by the Principal Investigator on the 
pregnancy outcomes report form. Follow-up must be performed until delivery or pregnancy 
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The Investigator will attempt to collect pregnancy information on any female partner of a male 
study patient who becomes pregnant while participating in this study, and report to Sponsor or 
Designee. The partner will also be followed to determine the outcome of the pregnancy. 
Any pregnancy that occurs during study participation must be reported to the Sponsor or 
Designee on the pregnancy form, immediately or within 24 hours of the Investigator learning of 
its occurrence. 
8.5 Treatment of Overdose 
An overdose is a dose in excess of the dose specified for each cohort in this clinical study 
protocol (CSP).  
There are no data on overdosing of X842. There is no known antidote and an overdose in a study 
patient should be monitored closely and treated symptomatically. The IMP X842 is a glutaric 
acid prodrug of linaprazan 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, [6, IB]. 
There is limited data available regarding the effects of overdose of lansoprazole in humans. 
However, daily doses of up to 180 mg of lansoprazole orally and up to 90 mg of lansoprazole 
intravenously have been administered in trials without significant undesirable effects. In one 
reported overdose, a patient consumed 600 mg of lansoprazole (Prevacid) with no adverse 
reaction. Oral lansoprazole doses up to 5000 mg/kg in rats [approximately 1300 times the 30 mg 
human dose based on body surface area (BSA)] and in mice (about 675.7 times the 30 mg human 
dose based on BSA) did not produce deaths or any clinical signs [11]. 
In the case of suspected overdose, the patient should be monitored. Lansoprazole is not 
significantly eliminated by hemodialysis. If necessary, gastric emptying, charcoal and 
symptomatic therapy is recommended [12]. 
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 patient’s medical records. 
8.6 Handling, Storage and Destruction of Laboratory Samples 
All biological samples will be handled according to local regulations.  


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The biological samples will be labeled with a unique code and be stored under Cinclus’s control 
for a maximum of 15 years (some samples may be stored for much less time) to analyse 
metabolites of X842, analyse associated medicines and explore or validate 
biomarkers/assays/new techniques to help develop ways to detect, monitor or treat reflux disease 
and other gastric acid related diseases e.g., peptic ulcer disease, H. pylori infection. 
8.7 Chain of Custody of Biological Samples 
A full chain of custody is maintained for all samples throughout their lifecycle.  
The study site should keep full traceability of collected biological samples from the patients 
while in storage at the study site until shipment and keeps documentation of receipt of arrival.  
The sample receiver (the analytical laboratory) keeps full traceability of the samples while in 
their storage and during use until used or disposed of.  
The Sponsor keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.  
8.8 Withdrawal of Informed Consent for Donated Biological Samples 
If a patient withdraws consent to the use of retained biological samples donated, the samples will 
be disposed of/destroyed, if not already analyzed.  
The Principal Investigator will ensure that:  
 Patient withdrawal of informed consent to the use of biological samples donated is notified 
immediately to Sponsor or Designee.  
 Biological samples from the patient, if stored at the study site, are immediately identified, 
disposed of/destroyed and the action is documented.  
The Sponsor has to ensure that the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent without delay and that the laboratory(ies) holding the samples ensures that 
samples are disposed of/destroyed or returned to the study site and the action is documented. 
8.9 Pharmacodynamics 
Not Applicable 
8.10 Appropriateness of Measurements 
All (other) methods used for safety assessments are commonly used in standard medical care. 


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9 Statistical Considerations 
9.1 General Consideration 
The principal features of the statistical analysis to be performed are described in this section. A 
more technical and detailed description of all statistical summaries, presentations and analyses 
will be outlined in the Statistical Analysis Plan (SAP), which will be finalized and approved prior 
to locking the database and unblinding.  
The primary study objective is to estimate the X842 dose for Phase 3 study with good precision, 
and hence comparison of different doses of X842 to the active comparator arm (lansoprazole 
30 mg) will not involve any formal statistical testing. 
The primary analysis evaluating the dose-response relationship based on different doses of X842, 
as well as secondary analyses, will be based on the overall study population. In addition, the two 
subgroups, erosive esophagitis due to GERD LA grade C or D and erosive esophagitis due to 
GERD LA grade A or B who are partial responders to PPI treatment, will be evaluated separately.  
All data measured on a continuous scale will be presented using summary statistics. Summary 
statistics is defined as number (N), arithmetic mean, standard deviation (SD), median, minimum 
Q1, Q3 and maximum value. Where appropriate 95% confidence intervals 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 patient data will be listed by 
patient number, treatment, and, where applicable, by assessment time. 
9.2 Sample Size Determination 
CCI


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9.3 Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 
Population 
Description 
Enrolled 
All patients who signed the ICF (including screening failures). 
Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all patients who have been 
randomized and received at least 1 dose of IMP. Patients will be analyzed 
according to randomized treatment (any randomized but not treated patient 
will be marked and reported as such). 
Per Protocol Set (PPS) 
The per protocol analysis set (PPS) will consist of all patients who have been 
randomized and completed the study without any major protocol deviations 
that are judged to compromise the analysis of the data. All protocol violations 
will be judged as major or minor, taking composite effects of protocol 
deviations into consideration, excluding patients for whom the clinical 
outcome is qualitatively affected by the protocol deviations. 
Safety Analysis Set 
The safety analysis set will consist of all patients who have been randomized 
and received at least 1 dose of IMP. Patients will be analyzed according to the 
treatment actually received (in case this differs from randomized treatment). 
CCI


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PK Analysis Set 
The PK analysis set will consist of all patients who received at least 1 dose of 
IMP and have at least 1 measurement of plasma concentration of 
X842/linaprazan. Patients will be analyzed according to the treatment actually 
received (in case this differs from randomized treatment). 
 
The FAS will be the primary analysis set for all efficacy analyses and the PPS will be used to 
demonstrate robustness of results for the primary efficacy endpoint(s). 
9.4 Statistical Analyses  
9.4.1 
Patient Disposition 
Patient disposition will be presented together with withdrawals from treatments, withdrawals 
from the study and the primary reason for withdrawal. 
9.4.2 
Protocol Deviations 
Protocol deviations will be collected and reviewed during the study. The final classification and 
effect of each protocol deviation as well as the composite effect of a set of protocol deviations on 
analysis populations will be assessed prior to the database lock. 
9.4.3 
Demographics and Baseline Characteristics 
Descriptive statistics for demographics, weight and height will be presented by treatment. 
9.4.4 
Medical/surgical History and Prior/Concomitant Medication 
Medical/surgical history and prior/concomitant medications will be presented by treatment using 
descriptive statistics and listings. 
9.4.5 
Treatment Compliance 
The number of patients treated, and their individual dose will be tabulated. 
9.4.6 
Physical Examination 
Abnormal findings will be specified and presented by patient and summarized by treatment and 
period. 
9.4.7 
Efficacy Analyses 
Analyses of the primary efficacy endpoint will be performed for both the FAS and PPS; analyses 
of the secondary and exploratory efficacy endpoints will be performed for the FAS only. 


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Endpoint 
Statistical Analysis Methods 
Primary 
Analysis of primary endpoints will focus on the rate of esophageal 
mucosa healing in the four X842 dose groups to identify the dose that 
will lead to having 85% of the patients have esophageal mucosa 
healing after 4 weeks of treatment. It will involve dose-response 
modeling, evaluating a sequence of dose-response models for the 
healing rate including the Linear, Exponential, Emax, Sigmoid Emax 
and Logistic models (on logit scale). The models will be compared in 
terms of model fit, and the target dose estimated as the dose 
providing the target effect of 85% healing rate from the best fitting 
model will be derived. The data will be summarized and analyzed 
descriptively by treatment utilizing statistical summary tables and 
plots.  
Secondary 
The data will be summarized and analyzed descriptively by treatment 
utilizing statistical summary tables and plots for the below secondary 
efficacy endpoints: 
 
1. Percentage of heartburn-free 24-hour days during the Weeks 1-8 
(Visits 2-9) based on eDiary (RESQ-eDiary), including splits 
into day- and nighttime evaluations. 
2. Percentage of 24-hour days with at most mild heartburn 
symptoms during the Weeks 1-8 (Visits 2-9) based on eDiary 
(RESQ-eDiary), including splits into day- and nighttime 
evaluations. 
3. Investigator assessment of symptom at Weeks 1-8 (Visits 2-9) 
4. Reflux related symptoms as measured by change from baseline 
in QOLRAD score assessed after 1, 2, 4 and 8 weeks of 
treatment  
Exploratory 
 Pre-dose plasma concentrations collected twice daily after 1, 2, 
and 4 weeks of treatment. 
The data will be summarized and analyzed descriptively by dose 
level utilizing statistical summary tables and plots. The evaluation 
will be based on the PK analysis set. 
 Association between esophageal mucosal healing and reflux 
related symptom pattern 
Reflux related symptom pattern as measured by change from baseline 
in daily diary completion by patients (RESQ-eDiary), investigator’s 
assessment and QOLRAD after 1, 2 and 4 weeks of treatment will be 
summarized by status of observed healing at 4 weeks by treatment 
group. The data will be summarized and analyzed descriptively by 
treatment utilizing statistical summary tables and plots. The 
evaluation will be based on the FAS. 


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9.4.8 
Safety Analyses 
All safety analyses will be performed on the Safety Set. 
Endpoint 
Statistical Analysis Methods 
Evaluate the safety and 
tolerability of the four 
dose levels of X842 and 
lansoprazole, where 
lansoprazole will serve 
as the active 
comparator. 
Physical examination, weight, BMI, vital signs, electrocardiogram 
(ECG) recordings, safety laboratory measurements 
(hematology/clinical chemistry/urinalysis), adverse event (AE), 
treatment emergent adverse event (TEAE), adverse event of special 
interest (AESI), serious adverse event (SAE) reporting, 
concomitant medication(s). 
Weight and BMI 
Weight and BMI will be presented by patient and summarized by 
treatment using descriptive statistics along with absolute and 
percent change. 
Vital signs 
For BP and heart rate, descriptive statistics of actual values and 
change from screening will be used for summaries by treatment 
group and assessment day. Categorically classified 
(Normal/Abnormal) results will also be summarized. 
12-lead ECG 
ECG variables will be summarized according to actual values and 
change from screening using summary statistics and will be 
presented by treatment group and assessment visit. Categorically 
classified (Normal/Abnormal) results will also be summarized. 
Safety laboratory 
analyses 
All hematology, clinical chemistry and coagulation laboratory tests 
will be summarized using descriptive statistics for actual values and 
change from screening and presented by treatment group and 
assessment day for each study site separately (due to assays 
performed locally).  
Additionally, the local laboratory normal ranges will be used to 
classify the results as: High, Normal or Low and categorical 
summaries will be presented overall according to treatment group 
and assessment visit. Pooling across all sites is possible due to the 
categorical classification. 
Adverse events 
All AEs will be summarized according to TEAE or baseline 
symptom following classification of the verbatim terms according 
to the MedDRA dictionary. The number and percentage of patients 
for all classified events will be presented according to System 
organ class (SOC) and Preferred term (PT) by treatment group and 
overall.  
Separate summaries will be presented for all AEs by event 
frequency of occurrence and also for all AEs according to 
seriousness, severity and relationship. 
Separate summaries will be presented for AEs of Special Interest 


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9.4.9 
Other Analyses 
Descriptive statistics for the C-trough will be presented by treatment group with number of 
measurements, arithmetic mean, SD, CV, median, minimum, maximum, geometric mean, 
geometric CV%. 
9.5 Interim Analyses 
No interim analyses are planned for this study. 
9.6 Data Monitoring Committee (DMC) 
Not applicable. 
10 Supporting Documentation and Operational Considerations 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 Ethical Conduct of the Study 
The study will be performed in accordance with the protocol and ethical principles that have 
their origin in the Declaration of Helsinki and are consistent with ICH/good clinical practice 
(GCP) E6 (R2), EU Clinical Trials Directive, and applicable local regulatory requirements. 
10.1.2 Ethics and Regulatory Review 
The Coordinating Investigator in each country is responsible for submission of the CSP, the 
patient information and ICF, any other written information to be provided to the patients and any 
advertisements used for recruitment of patients to applicable IEC for approval.  
The Sponsor or Designee is responsible for submission of study documents to the applicable CAs 
according to local regulatory requirements. 
Approval must be obtained in writing from both IEC and CA before the first patient can be 
recruited. 
The Sponsor will provide the CA, IEC and Principal Investigators 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. 


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10.1.3 Patient Information and Consent 
It is the responsibility of the Investigator or an authorized associate to give each potential study 
patient (or the patient’s legally acceptable representative and/or witness, as applicable) 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 patient may withdraw from participation at any time and for any reason, without any 
prejudice. All patients 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 patient (or their legally acceptable representative and/or witness, as applicable) and by the 
Investigator. A copy of the patient information including the signed ICF will be provided to the 
patient. 
By signing the ICF the patient should authorize the Investigator to use the endoscopy 
video/digital image taken prior to the ICF signature, to be the basis of eligibility evaluation and 
enrollment into the study. 
Documentation of the discussion and the date of informed consent must be recorded in the 
source documentation and in the CRF. The patient information sheet and the signed ICF should 
be filed by the Investigator for possible future audits and/¬or inspections.  
The final approved version of the patient information and ICF must not be changed without 
approval from the Sponsor and the applicable IEC.  
10.1.4 Patient Identification Card 
The patient will be provided with a Patient Identification Card including the following 
information:  
 That he/she is participating in a clinical study 
 Patient study ID  
 That he/she is treated with the IMP 
 The name and phone number of the Investigator  
 Name and address of the Sponsor 


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10.1.5 Patient 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 Data Protection Directive (95/46/EC) and General Data Protection Regulation 
(GDPR), the data will not identify any persons taking part in the study. 
The potential study patient (or the patient’s legally acceptable representative and/or witness, as 
applicable) should be informed that by signing the ICF he/she approves that authorized 
representatives from Sponsor and Parexel, the concerned IEC and CA have direct access to 
his/her medical records for verification of clinical study procedures. This agreement is to be 
substantiated in a separate document, according to local requirements. 
The patient 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 the European 
Union Data Protection Directive (95/46/EC) and the request will be raised to the Principal 
Investigator.  
The Investigator must file a Patient Identification List which includes sufficient information to 
link records, i.e. the CRF and clinical records. This list should 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 pseudoanonymized, i.e. personally 
identifiable information will be removed and replaced by a unique patient ID and will be 
processed by the Sponsor and other involved parties during the study. After the study end, only 
anonymized data, i.e. aggregated data sets, can be used.  
For this study, the Sponsor is the data controller of all data processed during the study (e.g., trial 
master file [TMF], study reports) and Parexel is the data processor. Any subcontractors used in 
the study, are also data processors.  
For data that are processed at the study sites (e.g., medical records and ISF), the respective study 
site is the data controller. 
10.1.6 Audits and Inspections 
Authorized representatives of Sponsor, a CA, or an IEC may perform audits or inspections at the 
study site, including source data verification (SDV). The purpose of an audit or inspection is to 


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systematically and independently examine all study related activities and documents, 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 a CA about 
an inspection at the study site. 
10.1.7 Data Quality Assurance 
10.1.7.1 Quality management 
10.1.7.1.1 Critical process, system and data identification 
During protocol development, the Sponsor will identify those processes, systems (facilities, 
computerized systems) and data that are critical to ensure human patient protection and the 
reliability of trial results according to applicable SOPs and International Conference on 
Harmonization (ICH) E6 R2. 
10.1.7.2 Quality assurance and quality control 
The Sponsor is responsible for implementing and maintaining quality assurance and quality 
control systems with written SOPs with regards to management of identified risks, CSP 
compliance, GCP compliance and applicable regulatory requirements.  
The Sponsor is responsible for securing agreements with involved subcontractors and to perform 
regular subcontractor oversight to ensure CSP compliance, GCP compliance and compliance 
with applicable regulatory requirements. 
The Sponsor is responsible for implementing a risk-based validated electronic data capture 
system and maintain SOPs for the whole life- cycle of the system.  
Quality control should be applied to each stage of data handling to ensure that all data are 
reliable and have been processed correctly. 
10.1.8 Archiving 
The Principal Investigator is responsible for maintaining essential documents, (as defined in ICH 
E6 GCP, Section 8) for 10 years after finalization of the clinical study report (CSR). This 
includes any original source documents related to the study, the Patient Identification List 
(providing the sole link between named patient source records and anonymous CRF data), the 
original signed ICFs and detailed records of disposition of IMP.  


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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 Trial Master File in 
accordance with ICH E6 GCP, Section 8 and applicable regulatory requirements. 
The data from the eCRFs will be sent to the Sponsor and a copy will be sent to the 
clinic/investigational site and filed in the ISF for archiving for 10 years after finalization of the 
CSR. The completed original eCRFs are the sole property of the Sponsor and should 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. 
10.1.9 Study and Site Closure 
The Sponsor or Designee reserves the right to discontinue the study at any time but intends only 
to exercise this right for valid scientific or administrative reasons. 
After such a decision, the Investigator must inform all participating patients and perform relevant 
assessments, preferably according to the scheme for the final assessments. All delivered and 
unused study products and other study materials must be returned and all CRFs completed as far 
as possible. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
The study may be placed on hold for evaluation of possible risk to patients, prior to decision as 
to whether to terminate the study if any of the following criteria are met: 
 At least 3 patients experience a similar unexpected AE, which is assessed as severe and is 
probable/possible related to the IMP. 
 The occurrence of an SAE, if considered probable/possible related to the IMP. 
A study termination will be initiated pending the outcome of any SAE investigation; termination 
will be based on the circumstances surrounding the event and findings with unblinding of the 
Sponsor medical monitor, if necessary.  
The study will be discontinued for any of the following reasons: 
 If overall 5 (five) X842-treated patients develop the same type of AESI and the frequency 
is at least 2 × higher than in the comparator group. 
 If 3 (three) X842-treated patients meet Hy’s Law criteria (≥ 3 × ULN for ALT or AST 
with total bilirubin ≥ 2 × ULN and no other explanation for these elevations). 
 If one or more clinically significant, life-threatening, or significantly 
disabling/incapacitating events that are likely related to X842 and that, in the opinion of 


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the Investigator in consultation with the Sponsor, may constitute sufficient reason to stop 
the study. 
 If the Sponsor judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and GCP. 
10.1.10 Publication Policy 
The results from this study may be submitted for publication at the discretion of the Sponsor. 
10.1.11 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be approved 
by the IEC/IRB/ CAs in accordance with local legal requirements. The Sponsor must ensure that 
all ethical and legal requirements have been met before the first patient is enrolled in the study. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IRB/IEC/Competent Authority 
approval prior to implementation (if appropriate). In the US: Following approval, the protocol 
amendment(s) will be submitted to the IND under which the study is being conducted. 
Administrative changes (not affecting the patient benefit/risk ratio) may be made without the 
need for a formal amendment. All amendments will be distributed to all protocol recipients, with 
appropriate instructions. 
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. 
10.1.12 Insurance 
Patients will be covered under Cinclus Pharma AG clinical trial insurance policy. The copy of 
certificate of insurance and an information leaflet containing essential information about the 
insurance coverage will be provided to the study sites and can be provided to the patients upon 
request. The participating patients are also protected in accordance with national regulations, as 
applicable.  
10.1.12.1 Access to source data 
During the study, a monitor will make site visits to review protocol compliance, compare eCRF 
entries and individual patient’s medical records, assess drug accountability, and ensure that the 
study is being conducted according to pertinent regulatory requirements. eCRF entries will be 


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verified with source documentation. The review of medical records will be performed in a 
manner to ensure that patient confidentiality is maintained. 
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, regulatory 
authorities of certain countries, IRBs, IECs, and/or the Sponsor’s Clinical Quality Assurance 
Group may wish to carry out such source data checks and/or on-site audit inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator assures 
Parexel and the Sponsor of the necessary support at all times. 
10.2 Appendix 2: Study Management 
10.2.1 Training of Study Site Personnel 
Before enrolment of the first study patient a Sponsor representative or Designee will perform a 
study initiation visit at the study site. 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) utilized. 
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. 
10.2.2 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 plan, approved by the Sponsor and provided separately, 
the responsible CRA will periodically visit the study sites at times agreed upon by the 
Investigator and the CRA. At the time of each monitoring visit, the role of the CRA is (but not 
limited to) to:  


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 provide information and support to the investigational team. 
 confirm that facilities and resources remain acceptable. 
 confirm that the investigational team is adhering to the CSP, applicable SOPs, guidelines, 
manuals and regulatory requirements.  
 verify that data are being accurately and timely recorded in the CRFs and that IMP 
accountability checks are being performed. 
 verify that data in the eCRF are consistent with the clinical records (SDV) in accordance with 
the Monitoring Plan.  
 verify that the correct informed consent procedure has been adhered to for participating 
patients.  
 ensure that withdrawal of informed consent to the use of the patient’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 patient. 
 verify that AEs are recorded and reported in a timely manner and according to the CSP. 
 raise and escalate any serious quality issues, serious GCP breach and any data privacy breach 
to the Sponsor.  
Remote monitoring will also be performed continuously by study team members at Parexel in 
accordance with the risk-based monitoring plan.  
When the study has been completed and all queries have been resolved and the database has been 
locked, the CRA will perform a close-out visit. 
10.2.3 Medical Monitoring 
The role of medical monitoring in the clinical trial is to capture safety information in a complete 
and timely fashion and to recognize trends that may be indicative of hazards associated with 
study treatments. In addition, medical monitoring involves advising the project team and the 
investigators of medical and scientific issues related to the conduct of the trial. 
The responsibilities of the Medical Monitor will be specified in the Medical Monitoring Plan and 
Safety Management Plan. 
Potential drug-induced liver injury events require notification of the Medical Monitor (see 
Section 8.4.1.3). 
10.2.4 Source Data Documents 
A separate SDV List will be generated for each site before 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 CRA to confirm agreement before start of 
recruitment. 


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Source documents are all documents used by the Investigator or hospital that relate to the 
patient’s medical history, that verifies the existence of the patient, the inclusion and exclusion 
criteria, and all records covering the patient’s participation in the trial. They include laboratory 
notes, memoranda, material dispensing records, patient files, etc. The eCRF is essentially 
considered a data entry form and should not constitute source data unless clearly specified in the 
SDV List.  
The Investigator should guarantee access to source documents to the CRA, CAs and the IECs, if 
required. 
10.2.5 Study Agreements 
The Principal Investigator must comply with all the terms, conditions, and obligations of the 
Clinical Study Agreement for this study. 
Agreements between Sponsor and the study site must be in place before any study related 
procedures can take place, or patients be enrolled. 
10.2.6 Study Timetable and End of Study 
The study is expected to start in Quarter 3, 2020 (Final Study Protocol) and to be completed in 
Quarter 1, 2022 (Clinical Study Report). 
All patients who participate in this study and complete Visit 9 (End of Study/Early Termination) 
visit are considered to have completed the study. The end of the study is defined as the date of 
the last visit of the last patient in the study. 
10.2.7 Reporting and Publication 
10.2.7.1 Clinical study report  
A summarizing report must be submitted to the applicable CA and IEC within 12 months after 
completion of the study (in accordance with LVFS 2011:19, Chapter 9). 
A CSR, in compliance with ICH E3 (Structure and content of clinical study reports) describing 
the conduct of the study, the statistical analysis performed, and the results obtained, will be 
prepared by Parexel. The report 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. 


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10.2.7.2 Annual safety report 
If the study duration exceeds 1 year, the Sponsor must submit an annual safety report to the CA 
and to the IEC. The report shall summarize all SAEs and contain an update of the risk-benefit 
evaluation if there has been any change since the approval of the clinical study. 
10.2.8 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.  
10.3 Appendix 3: Data Management 
The data management routines include procedures for handling of eCRF, database set-up and 
management, data verification, quality control (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 and the eCRF 
specification. 
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 in a separate testing 
environment prior to use on production data. 
Detailed information on data management will be described in a study-specific Data 
Management Plan (DMP). 
10.3.1 The Web Based eCRF 
All clinical data will be entered into a 21 CFR Part 11-compliant eCRF. 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 bedside (if the eCRF data constitutes source data). Source data are to be 
defined at the site before inclusion of the first patient. 
Authorized site personnel designated by the Investigator will complete data collection. 
Appropriate training and security measures will be completed with the Investigator and all 


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authorized site personnel prior to the study being initiated and any data being entered into the 
system for any study patient. 
The Investigator must submit a completed eCRF for each patient for whom Informed Consent 
has been obtained. Any supportive documentation submitted with the eCRF should be clearly 
identified with the Study ID and Patient Number. Any personal information, including name, 
should be removed or rendered illegible to preserve individual confidentiality. 
10.3.2 The Entering of Data into the eCRF 
All data should be entered in English. The eCRFs should be completed as soon as possible 
during or after the patient’s visit. To avoid inter-observer variability, every effort should 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 study personnel should record 
such information in the eCRF. The Investigator will be required to electronically sign-off 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. 
10.3.3 Electronic Patient Reported Outcome  
The patients themselves will record data using an electronic patient reported outcome (ePRO) 
system (QOLRAD) linked to the eCRF and the clinical database. The ePRO system includes 
password protection and internal quality checks. Text reminders can be sent to the patient 
through the ePRO. All data registered in the ePRO are stored together with the eCRF data.  
10.3.4 The Data Cleaning Process 
The CRA will review the eCRFs and evaluate them for completeness and consistency. Each 
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 CRA nor 
any other study team member besides site staff can enter data in the eCRFs. 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.  
If additional corrections are needed, the responsible CRA or Data Manager or Medical Monitor 
will raise a data clarification in the eCRF. An appropriate member of the site personnel will 


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answer the data clarifications in the eCRF. This will be audit trailed electronically within the 
eCRF, meaning that the name of study personnel, time, and date is logged. 
10.3.5 Audit Trail 
All changes will be fully recorded in a protected audit trail. A reason for the change will be 
required. 
10.3.6 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. 
10.3.7 Medical Coding 
Medical coding will be performed by trained personnel at Parexel. Adverse events and 
medical/surgical history verbatim terms are coded using the Medical Dictionary of Regulatory 
Activities (MedDRA; latest version available at start of coding). Prior and concomitant 
medications will be coded according to the World Health Organization (WHO) Anatomic 
Therapeutic Chemical (ATC) classification system. All coding will be approved by Sponsor prior 
to database lock. 
10.3.8 Database Lock 
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.  
10.4 Appendix 4: Abbreviations and Trademarks 
Abbreviation or term 
Explanation 
ADL 
Activities of daily living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALAT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ASAT 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical  
AUC 
Area under the plasma concentration-time curve 


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AUCinf 
Area under the plasma concentration-time curve 
from 0 to infinity 
AUClast 
Area under the plasma concentration-time curve 
from 0 to the last measured concentration 
BID 
Twice daily (bis in die) 
BP 
Blood pressure 
BMI 
Body mass index 
CA 
Competent authority 
Cmax 
Maximum (peak) concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRA 
Clinical Research Associate 
CRF/eCRF 
Case report form/electronic CRF 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
ECG 
Electrocardiogram 
EEA 
European Economic Area 
eGERD 
Erosive gastro-esophageal reflux disease 
FIH 
First-in-human 
FSH 
Follicle stimulating hormone 
GCP 
Good clinical practice 
GDPR 
General Data Protection Regulation 
GERD 
Gastro-esophageal reflux disease 
GI 
Gastrointestinal 
Hb 
Hemoglobin 
IB 
Investigator’s Brochure 
HBcAg 
Hepatitis B core antigen  
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
H 
Hour 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IEC 
Independent ethics committee 


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IND 
Investigational new drug 
INR 
International normalized ratio 
IMP 
Investigational medicinal product 
ISF 
Investigator site file 
LA grade 
The grade of esophagitis according to the Los 
Angeles classification system 
LFT 
Liver function test 
LLOQ 
Lower limit of quantification 
MAD 
Multiple ascending dose 
MedDRA 
Medical dictionary for regulatory activities 
Min 
Minute 
Ms 
Millisecond 
N 
Number 
NOAEL 
No observed adverse effect level 
o.m. 
Every morning 
OTC 
Over-the-counter 
P-CAB 
Potassium-competitive acid blocker 
PD 
Pharmacodynamic 
PDILI 
Potential drug-induced liver injury 
PK 
Pharmacokinetic 
pKa 
acid dissociation constant 
PPI 
Proton-pump inhibitor 
PPS 
Per protocol analysis set 
PRO/ePRO 
Patient reported outcome/electronic PRO 
PT 
Preferred term 
QD 
Once daily (quaque die) 
QOLRAD 
Quality of Life in Reflux and Dyspepsia 
RBC 
Red blood cell 
RESQ-eD 
Reflux Symptom Questionnaire electronic Diary 
S 
Second 
SAD 
Single ascending dose 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SD rats 
Sprague-Dawley rats 


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SDV 
Source data verification 
SOC 
System organ class 
SOP 
Standard operating procedures 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
TIPS 
Transjugular intrahepatic portosystemic shunt 
Tmax 
Time after drug administration when the maximum 
plasma concentration is reached 
T½ 
Half-life 
TMF 
Trial master file 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
10.5 Appendix 5: Important Medical Procedures to be Followed by The 
Investigator 
10.5.1 Medical Emergencies Contacts 
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 an 
SAE and is to be reported as such. Detailed SAE reporting procedures are included in 
Section 8.4.6. 
In the case of a medical emergency the Investigator may contact the Medical Responsible Person 
at Cinclus Pharma AG or a representative from Parexel. 
Name 
Function in the study 
Telephone number and e-mail 
 
PPD
PPD
PPD


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10.6 Appendix 6: Study Administrative Structure 
Sponsor 
Cinclus Pharma AG 
Gartenstrasse 101 
CH-4002 Basel, Switzerland  
Sponsor’s Medical Representative 
 
Sponsor’s Chief Scientific Officer  
E-mail
Study management 
Parexel International
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


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10.7 Appendix 7: Declaration of Helsinki 
http://www.up.ac.za/media/shared/Legacy/sitefiles/file/45/2875/declarationofhelsinki_fortaleza_brazil201
3.pdf 
10.8 Appendix 8: Los Angeles Classification of Reflux Esophagitis 
 
10.9 Appendix 9: Medications that may Interact with X842 or Linaprazan 
CYP3A inhibitors 
CYP3A4 inhibitors: grapefruit juice and other juices such as Seville 
oranges, cranberry juice 
Strong CYP3A4 inhibitors: ketoconazole, itraconazole, voriconazole, 
mibefradil, clarithromycin, posaconazole, telithromycin, conivaptan, 
nefazodone, protease inhibitors, antivirals 
Moderate CYP3A inhibitors: erythromycin, fluconazole, darunavir, 
diltiazem, dronedarone, crizotinib, aprepitant, casopitant, imatinib, 
verapamil, netupitant, nilotinib, tofisopam, cyclosporine, ciprofloxacin, 
isavuconazole, cimetidine 
CYP inducers  
St John’s Wort, rifampicin, carbamazepine, phenytoin, rifapentine, 
rifabutin, smoking 
CYP1A2 inhibitors 
ciprofloxacin, enoxacin, clinafloxacin, fluvoxamine 
CYP2B6 inhibitors 
voriconazole, ticlopidine, disulfiram, clopidogrel, rolapitant, prasugrel, 
hormone replacement therapy with estrogen or progesterone 
CYP2C8 inhibitors 
gemfibrozil, clopidogrel 


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CYP3A substrates 
alfentanil, alisporivir, almorexant, alpha-dihydroergocryptine, aplaviroc, 
aprepitant, atazanavir, atorvastatin, avanafil, blonanserin, bosutinib, 
brecanavir, brotizolam, budesonide, buspirone, capravirine, casopitant, 
cobimetinib, conivaptan, danoprevir, darifenacin, darunavir, dasatinib, 
dronedarone, ebastine, eletriptan, eliglustat (in subjects CYP2D6 PMs), 
elvitegravir, eplerenone, everolimus, felodipine, grazoprevir, ibrutinib, 
indinavir, isavuconazole, ivabradine, ivacaftor, lomitapide, lopinavir, 
lovastatin, lumefantrine, lurasidone, maraviroc, midazolam, midostaurin, 
naloxegol, neratinib, nisoldipine, paritaprevir, perospirone, quetiapine, 
ridaforolimus, saquinavir, sildenafil, simeprevir, simvastatin, sirolimus, 
tacrolimus, terfenadine, ticagrelor, tilidine, tipranavir, tolvaptan, 
triazolam, ulipristal, vardenafil, venetoclax, vicriviroc, voclosporin, 
hormone based contraceptives* 
CYP2C19 substrates 
pantoprazole, hexobarbital, mephobarbital, omeprazole, lansoprazole, 
mephenytoin, diazepam, gliclazide, proguanil (prodrug), rabeprazole 
CYP2C9 substrates 
Warfarin 
BCRP substrates 
anthracyclines, daunorubicin, doxorubicin, topotecan, irinotecan, 
methotrexate, imatinib, mitoxantrone, nucleoside analogs, prazosin, 
pantoprazole, topotecan, rosuvastatin, teriflunomide, chlorothiazide 
P-gp Substrates 
dabigatran etexilate, digoxin, fexofenadine, sofosbuvir 
OATP1B1 substrates 
repaglinide, pravastatin, rosuvastatin, fluvastatin, pitavastatin, lovastatin, 
simvastatin, bosentan, irinotecan, olmesartan, enalapril, temocaprilat, 
valsartan, docetaxel 
Abbreviations 
CYP: cytochrome P450; BCRP: breast cancer resistance protein; P-gp: P-glycoprotein; OATP1B1: organic anion 
transporting polypeptide 1B1 
* Except for patients using hormonal contraception defined in Exclusion criterion #1 
10.10 Appendix 10: COVID-19 Specifics 
There is currently an outbreak of the disease COVID-19 caused by a novel severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2). 
EMA and FDA have issued guidelines to provide recommendations for actions for conduct of 
clinical studies of medical products during COVID-19 pandemic. Since the pandemic situation is 


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evolving, guidelines, recommendations, national regulations and local restrictions may change. 
Given the circumstances of potentially relapsing pandemic or epidemic situation regarding the 
spread of COVID-19 in future, special attention will be paid to protect patients enrolling in the 
study and site staff involved in the investigations against infection. 
Risk mitigation measures: 
 Current country level regulations and local recommendations for prevention of pandemic 
will be strictly adhered to.  
 Patient enrollment in the study will commence only when the Sponsor and CRO in 
collaboration deem it is safe to start the study. 
 Patients participating in the study will be closely monitored for any signs and symptoms 
of COVID-19, including fever, dry cough, dyspnea, sore throat and fatigue throughout 
the study. Body temperature measurement and respiratory rate will be captured during 
vital signs examinations as designated on the Schedule of Assessments. 
 Patients participating in the study and site personnel will be advised to adhere to local 
requirements for reduction of the public viral exposure. 
 Confirmation of COVID-19 infection should follow current local regulations and 
guidance. 
The guidance from the Regulatory Authorities may continue to evolve throughout the pandemic 
and Investigators are encouraged to check for updates regularly. Also, as the situation evolves 
COVID-19 related clinical trial measures may be continuously adjusted in line with local 
regulations, guidance and needs. 
References 
Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic, 
EMA, Version 3 (088/02/2021). https://ec.europa.eu/health/document/download/74386d75-e5fd-
4d9c-9dfc-ec7d60758da9_en  
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency, March 2020, Updated on 30 August, 2021. https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-
products-during-covid-19-public-health-emergency  


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11 References 
1. El-Serag H, et al. Update on the epidemiology of gastro-esophageal reflux disease. a 
systematic review. Gut 2014 June 63, 871_880. 
2. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and 
functional correlates and further validation of the Los Angeles classification. Gut 1999; 
45: 172–80 
3. Kahrilas PJ, Dent J, Lauritsen K, Malfertheiner P, Denison H, Franzén S, Hasselgren G. A 
randomized, comparative study of three doses of AZD0865 and esomeprazole or 
lansoprazole for healing of reflux esophagitis. Clin Gastroenterol Hepatol. 2007 
Dec;5(12): 1385-91. Epub 2007 Oct 22 
4. Dent J, Kahrilas PJ, Hatlebakk J, Vakil N, Denison H, Franzén S, Lundborg P. A 
Randomized, Comparative Trial of a Potassium-Competitive Acid Blocker (AZD0865) 
and Esomeprazole for the Treatment of Patients With Nonerosive Reflux Disease. Am J 
Gastroenterol. 2008 Jan;103(1):20-6. 
5. Andersson K, Personal communication 
6. Unge P, Andersson K. A first in human, open label, healthy volunteer study of the new P-
CAB X842 demonstrating 24h acid control for treatment of acid related diseases. 
Gastroenterology 2018 Vol 154, Issue 6, Supplement 1: S-238. 
7. Andrae DA, Hanlon J, Cala ML, Scippa K, Graham C, Witherspoon B, et al. Evaluation 
and Validation of the Modified Reflux Symptom Questionnaire–Electronic Diary in 
Patients With Persistent Gastroesophageal Reflux Disease. Clin Transl Gastroenterol. 2020 
Jan;11(1): e00117. 
8. Wiklund IK, Junghard O, Grace E, Talley NJ, Kamm M, Veldhuyzen van Zanten S, et al. 
Quality of Life in Reflux and Dyspepsia patients. Psychometric documentation of a new 
disease-specific questionnaire (QOLRAD). Eur J Surg Suppl. 1998;(583):41-9 
9. National Cancer Institute Cancer Therapy Evaluation Program. Common terminology 
criteria for adverse events, CTCAE v4.03 (2010). 
10. 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. Gastroenterology, 2005 Vol 128, Issue 4, Supplement 2. 
11. Prescribing Information. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020406s087s088,021428s034
s035lbl.pdf  
12. SmPC. https://www.medicines.org.uk/emc/product/4761/smpc  
 
 


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Investigator Agreement Page 
 
Declaration of the Principal or Global Coordinating Investigator 
This page should be used for studies with EU sites, but is not mandatory for US studies.  
Title: A randomized double-blind, double dummy, active comparator-controlled dose-finding 
study in patients with erosive esophagitis due to gastro-esophageal reflux disease (GERD) Los 
Angeles grade C or D, and patients with at least partial symptom response but endoscopically 
still unhealed after 8 weeks history of standard treatment healing course with proton-pump 
inhibitor (PPI), to investigate safety, tolerability, and healing rates after 4 weeks treatment of 
X842 or lansoprazole, and symptom pattern during subsequent 4 weeks treatment with 
lansoprazole 
Note that Investigator sign-off is required for compliance with GCP, but it is the Sponsor’s (or 
Designee’s) responsibility to get this. It is not the responsibility of MWS but the Parexel team 
may obtain Investigator sign-off if requested by the Sponsor. Use “Principal Investigator” only 
when there is just one center. 
Principal or Global Coordinating Investigator 
 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 
 
 


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Declaration of the Investigator 
Title: A randomized double-blind, double dummy, active comparator-controlled dose-finding 
study in patients with erosive esophagitis due to gastro-esophageal reflux disease (GERD) Los 
Angeles grade C or D, and patients with at least partial symptom response but endoscopically 
still unhealed after 8 weeks history of standard treatment healing course with proton-pump 
inhibitor (PPI), to investigate safety, tolerability, and healing rates after 4 weeks treatment of 
X842 or lansoprazole, and symptom pattern during subsequent 4 weeks treatment with 
lansoprazole 
Responsible Investigator of the Local Study Center 
 
_____________________________________ 
_____________________ 
Signature 
Date 
_____________________________________ 
Name (block letters) 
_____________________________________ 
Title (block letters) 
_____________________________________ 
Institution (block letters) 
_____________________________________ 
Phone number 

SAP_001.pdf: 
Cinclus Pharma Holding AB 
Clinical Study Report Appendices 
CX842A2201 
16.1.9 
Documentation of Statistical Methods 
Documents included: 
•
Statistical Analysis Plan, Version 1.0, Dated 14 Oct 2022
•
Statistical Analysis Modification Requests, Dated 23 Nov 2022
•
Statistical Analysis Modification Request, Dated 02 Mar 2023
•
Statistical Analysis Plan Amendment 01, Version 1.0, Dated 11 Apr 2023
CONFIDENTIAL 
5 July 2023 


Parexel International 
Cinclus Pharma AG 
Protocol #CX842A2201 
Statistical Analysis Plan 
TP-GDO-WW-133-02 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: <Date of last signature> 
Related to:  SOP-GDO-WW-019 
Page 1 of 51 
Parexel International 
Cinclus Pharma AG 
Protocol #CX842A2201 
A randomized double-blind, double dummy, active comparator-controlled dose finding study in 
patients with erosive esophagitis due to gastro-esophageal reflux disease (GERD) Los Angeles grade C 
or D, and patients with at least partial symptom response but endoscopically still unhealed after 8 
weeks history of standard treatment healing course with proton-pump inhibitor (PPI), to investigate 
safety, tolerability, and healing rates after 4 weeks treatment of X842 or lansoprazole, and symptom 
pattern during subsequent 4 weeks treatment with lansoprazole 
Statistical Analysis Plan 
Version: 1.0 
Parexel Project Number: 249403 


Parexel International 
Cindus Pha.nna AG 
Protocol #CX842A2201 
SPONSOR SIGJSATURE PAGE 
Approved by: 
Approved by: 
TP-GDO-W'\V-133-0:! 
 
 
Cinclus Pha1ma AG 
 
 
SDS Life Science AB 
Effectl\"e Date: 26 ::-;o\· 19 
Related to: SOP-GDO-\Y\\'-019 
St.austical Analys1s Plan 
Date 
Date 
Project Document Yersion :Xo l 0 
Project Document Effective Date: <Date of last 
signature> Page 2 of51 
PPD
PPD
PPD
PPD
PPD


Parexel International 
Cinclus Pharma AG 
Protocol #CX842A2201 
Statistical Analysis Plan 
TP-GDO-WW-133-02 
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Effective Date:  26 Nov 19 
Project Document Effective Date: <Date of last signature> 
Related to:  SOP-GDO-WW-019 
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Parexel SIGNATURE PAGE 
Signatures below confirm that the Statistical Analysis Plan was developed in accordance with SOP-
GDO-WW-019 and that it is approved for release. 
This document has been approved and signed electronically on the final page by the following: 
 
 
 
 
 
 
Signatory 
Author 
 
Project Role: 
 
PPD
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Protocol #CX842A2201 
Statistical Analysis Plan 
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Project Document Effective Date: <Date of last signature> 
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TABLE OF CONTENTS 
1 
INTRODUCTION .................................................................................................................... 10 
2 
STUDY OBJECTIVES ............................................................................................................ 11 
3 
INVESTIGATIONAL PLAN .................................................................................................. 12 
3.1 
Overall Study Design and Plan ........................................................................................ 12 
3.2 
Endpoints and Associated Variables ............................................................................... 13 
3.2.1 
Efficacy Variables ...................................................................................................... 13 
3.2.1.1 Primary efficacy endpoint ........................................................................................... 13 
3.2.1.2 Secondary efficacy endpoints ..................................................................................... 13 
3.2.1.3 Exploratory efficacy endpoints ................................................................................... 14 
3.2.2 
Safety Variables .......................................................................................................... 14 
4 
STATISTICAL METHODS .................................................................................................... 14 
4.1 
Data Quality Assurance ................................................................................................... 14 
4.2 
General Presentation Considerations ............................................................................... 15 
4.3 
Software ........................................................................................................................... 15 
4.4 
Study Patients .................................................................................................................. 16 
4.4.1 
Disposition of Patients ................................................................................................ 16 
4.4.2 
Protocol Deviations .................................................................................................... 17 
4.5 
Analysis Sets ................................................................................................................... 17 
4.6 
Demographics and Baseline Characteristics ................................................................... 19 
4.7 
Medical/Surgical History ................................................................................................. 19 
4.8 
Prior and concomitant Medications and prior PPI Treatment ......................................... 20 
4.9 
Treatment Exposure / Compliance .................................................................................. 21 
4.9.1 
Treatment Exposure .................................................................................................... 21 
4.9.2 
Compliance ................................................................................................................. 22 
4.10 Efficacy Evaluation ......................................................................................................... 22 
4.10.1 
Analysis and Data Conventions .................................................................................. 22 
4.10.1.1 Multi-center Studies .................................................................................................... 23 
4.10.1.2 Adjustments for Covariates ........................................................................................ 23 
4.10.1.3 Handling of Dropouts or Missing Data ...................................................................... 23 
4.10.1.4 Multiple Comparisons/Multiplicity ............................................................................ 24 
4.10.1.5 Interim Analyses ......................................................................................................... 24 
4.10.1.6 Examination of Subgroups ......................................................................................... 24 
4.10.2 
Primary Efficacy Variable(s) ...................................................................................... 25 
4.10.3 
Secondary Efficacy Variables ..................................................................................... 30 
4.10.3.1 QOLRAD .................................................................................................................... 30 
4.10.3.2 mRESQ-eD ................................................................................................................. 31 
4.10.3.3 Heartburn assessed by investigator ............................................................................. 34 
4.10.4 
Exploratory efficacy endpoint .................................................................................... 34 
4.10.4.1 Pharmacokinetics ........................................................................................................ 34 


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4.10.4.2 Relationship between observed esophageal mucosal healing and reflux related symptom 
pattern ............................................................................................................ 35 
4.10.4.3 Concordance between investigator reading and central reading ................................ 36 
4.11 Safety Evaluation ............................................................................................................. 37 
4.11.1 
Adverse Events ........................................................................................................... 37 
4.11.2 
Adverse Events of Special Interest (AESI) ................................................................ 39 
4.11.3 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .................. 40 
4.11.4 
Clinical Laboratory Evaluation ................................................................................... 40 
4.11.5 
Vital Signs .................................................................................................................. 42 
4.11.6 
Resting 12-lead Electrocardiograms ........................................................................... 43 
4.11.7 
Physical examination .................................................................................................. 43 
4.11.8 
Weight and BMI ......................................................................................................... 44 
4.11.9 
Safety Monitoring (Independent Data Monitoring Committee [IDMC], Data Monitoring 
Committee [DMC], Data and Safety Monitoring Board [DSMB]) ............................ 44 
4.12 Determination of Sample Size ......................................................................................... 44 
4.13 Changes in the Conduct of the Study or Planned Analysis ............................................. 45 
5 
REFERENCES ......................................................................................................................... 46 
6 
APPENDICES .......................................................................................................................... 47 
6.1 
Schedule of Assessments ................................................................................................. 47 
 


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REVISION HISTORY 
Version No. 
Effective Date 
Summary of Change(s) 
Draft 0.1 
26-Oct-2021
New document (without efficacy sections) 
Draft 0.2 
02-Nov-2021
Updates following internal review + completion of efficacy 
section (without modelling of primary endpoint) 
Draft 0.3 
03-Nov-2021
Updates following internal review 
Draft 0.4 
03-Nov-2021
Updates following client review 
Draft 0.5 
03-Dec-2021
Updates following internal review (+completion primary 
endpoint) 
Draft 0.6 
11 Mar 2022 
Updates following client review 
Draft 0.7 
24 Mar 2022 
Updates following client review 
Draft 0.8 
30 May 2022 
Updates following client review 
Draft 0.9 
16 Jun 2022 
Final draft version for dry run 
Final 1.0 
14 Oct 2022 
[List the changes] 


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LIST OF ABBREVIATIONS 
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALAT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
ASAT 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BID 
Twice daily (bis in die) 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
BP 
Blood pressure 
Bpm 
Beats per minute 
CI 
Confidence interval 
Cmax 
Maximum (peak) concentration 
CRF/eCRF 
Case report form/electronic CRF 
CS 
Clinically significant 
CSP 
Clinical Study Protocol 
CSR 
Clinical study report 
CTCAE 
Common terminology criteria for adverse events 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
eGERD 
Erosive gastro-esophageal reflux disease 
EOS 
End-of-study 
ET 
Early termination 
GERD 
Gastro-esophageal reflux disease 


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Abbreviation / Acronym 
Definition / Expansion 
Hb 
Hemoglobin 
HBcAg 
Hepatitis B core antigen  
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
h 
hour 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
LA grade 
The grade of esophagitis according to the Los Angeles classification 
system 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities 
min 
minute 
mRESQ-eD 
modified Reflux Symptom Questionnaire electronic Diary 
N 
Number 
NA 
Not available 
NCS 
Not clinically significant 
o.m. 
Every morning 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic analysis set 
PPI 
Proton-pump inhibitor 
PPS 
Per protocol analysis set 
PRO/ePRO 
Patient reported outcome/electronic PRO 


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Abbreviation / Acronym 
Definition / Expansion 
PT 
Preferred term 
QD 
Once daily (quaque die) 
QOLRAD 
Quality of Life in Reflux and Dyspepsia 
QT 
The QT interval is measured from the beginning of the QRS complex 
to the end of the T wave 
QTc 
corrected QT interval 
QTcF 
QT corrected using Fridericia’s formula 
RBC 
Red blood cell 
s 
Second 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SDV 
Source data verification 
SE 
Standard error of the mean 
SOC 
System organ class 
SOP 
Standard operating procedures 
SUSAR 
Suspected unexpected serious adverse reaction 
TBL 
Total bilirubin 
TEAE 
Treatment emergent adverse event 
WBC 
White blood cell 
WHO-DD 
World Health Organisation - Drug Dictionary 
 
 
 
 
 


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1 
INTRODUCTION 
Gastro-esophageal reflux disease (GERD) is a common chronic disorder with the prevalence highest in 
North America and Europe, where at least weekly reflux symptoms range from 10 to 30%.  
Linaprazan, the main metabolite of X842, has shown to provide effective acid control in humans.  
X842 is developed for the treatment of all patients with erosive esophagitis due to GERD LA grade C or 
D and of patients with at least partial symptom response but still endoscopically unhealed (LA grades A 
or B) after at least 8 weeks history of standard treatment healing course with proton-pump inhibitor (PPI).  
 
This is a Phase 2, double-blind study in patients with erosive esophagitis due to GERD Los Angeles (LA) 
grades C or D, and in patients with at least partial symptom response but still endoscopically unhealed 
(LA grades A or B) after 8 weeks history of standard treatment healing course with PPI, designed to 
support dose selection for Phase 3. The pronounced acid control of X842 is assumed to provide high 
endoscopic healing rates already after 4 weeks treatment course. The four dose levels of X842 are 
selected based on data from the Phase 1 studies where the 50 mg twice daily (BID) dose displayed an 
acid control slightly stronger than observed for standard PPI. The dose selection for Phase 3 will be based 
on the proportion of endoscopic healing following each dose of X842, the respective safety data and the 
pharmacokinetic (PK) profile. Lansoprazole will serve as an active comparator. 
 
Symptom evaluation during the first 4 weeks will be assessed using the validated patient reported 
outcome (PRO) QOLRAD (Heartburn version) and patient diaries (mRESQ-eD). Erosive esophagitis 
due to GERD is known as a chronic disease and the need for maintenance therapy is likely. To further 
understand the symptom pattern after 4 weeks of powerful gastric acid inhibition all patients undergoing 
endoscopy at 4 weeks, the end of the blinded phase, will be administered 4 weeks treatment with 
lansoprazole 30 mg QD. Weekly and daily symptom evaluations will be done during this open-label 
treatment period to detect symptom pattern and symptom evaluation will be based on telephone 
interviews and patient diaries. Patients who will terminate the study prematurely will be scheduled for 
End of Study/Early Termination visit, 4 weeks after cessation of study treatment. 
Evaluation of reflux related symptoms and their impact will be assessed by mRESQ-eD, investigator’s 
assessment and QOLRAD. 
The study will be conducted in multiple centers in Europe and the US. This will be a randomized, double-
blind, active comparator-controlled study with a parallel group design including four arms with X842 
and one arm with lansoprazole. 
This Statistical Analysis Plan (SAP) describes the planned final analyses for the randomized, double-
blind, active comparator-controlled study with a parallel group design including four arms with X842 
and one arm with lansoprazole to be included in the Clinical Study Report (CSR). 
This SAP is based upon the following study documents: 
• Study Protocol, amendment 2.0 (25 February 2022) 
• electronic Case Report Form (eCRF) version 2.0 (24 Feb 2022) 
 
 


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2 
STUDY OBJECTIVES 
Objectives 
Endpoints 
Primary 
The primary objective of the study is to 
support dose selection for X842, through 
assessment of healing of erosive 
esophagitis due to GERD after 4 weeks of 
treatment. 
Healing of erosive esophagitis due to GERD based on 
endoscopic assessment after 4 weeks of double-blind 
treatment. 
Secondary 
Evaluate the safety and tolerability of the 
four dose levels of X842 and 
lansoprazole, where lansoprazole will 
serve as the active comparator. 
Physical examination, weight, BMI, vital signs, 
electrocardiogram (ECG) recordings, safety laboratory 
measurements (hematology/clinical 
chemistry/urinalysis), adverse event (AE), treatment 
emergent adverse event (TEAE), adverse event of 
special interest (AESI), serious adverse event (SAE) 
reporting, concomitant medication(s). 
Evaluate the reflux related symptom 
pattern during the initial 4 weeks 
treatment with four dose levels of X842 
and with lansoprazole, and the symptom 
pattern during the subsequent additional 
4 weeks (Weeks 5-8) open-label treatment 
with lansoprazole 30 mg QD. 
 Percentage of heartburn-free 24-hour days during 
the Weeks 1-8 (Visits 2-9) based on eDiary 
(mRESQ-eD), including splits into day- and 
nighttime evaluations 
 Percentage of 24-hour days with at most mild 
heartburn symptoms during the Weeks 1-8 (Visits 
2-9) based on eDiary (mRESQ-eD), including splits 
into day- and nighttime evaluations 
 Investigator assessment of symptom at Weeks 1-8 
(Visits 2-9)  
 Reflux related impact as measured by change from 
baseline in QOLRAD scores assessed after 1, 2, 4 
and 8 weeks of treatment.  
Exploratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
The study will be conducted in multiple centers in Europe and the US.  
This is a phase 2, randomized, double-blind, active comparator-controlled study with a parallel group 
design including four arms with X842 and one arm with lansoprazole.  
Approximately 240 patients with erosive esophagitis due to GERD LA grade C or D and patients with 
erosive esophagitis due to GERD LA grade A or B with at least partial symptom response but still 
endoscopically unhealed after 8 weeks history of standard treatment healing course with PPI, will be 
randomized in order to have 200 evaluable patients.  
Randomization to one of the treatments with X842 twice daily (BID) 25 mg, 50 mg, 75 mg, 100 mg, or 
lansoprazole 30 mg once daily (QD) will be based on a 1:1:1:1:1 scheme. One site cannot enroll more 
than 20% of the overall number of patients (48 patients per site). 
The duration of each patient’s participation in the study, including screening, blind treatment period and 
open-label treatment period, will be approximately 60 days.  
The patients will be randomized for 4 weeks (28 days, -2/+5 days) of double-blind treatment and will be 
provided with investigational medicinal product (IMP) for 35 days (including one additional blister pack 
dispensed at Visit 2/Day 0) to allow for treatment up to the visit window.  
Pharmacokinetic (PK) blood sampling pre-dose, close before the first and the second dose administration 
will be performed at Day 7, Day 14 and Day 28 visits days in all patients.  
All patients will have an endoscopic evaluation after 4 weeks treatment. Following the endoscopic 
evaluation, all patients will receive subsequent 4 weeks of open-label treatment with lansoprazole 30 mg 
QD. Repeated symptom evaluation to detect symptom pattern will be assessed during this period.  
 
Randomization 
ratio 
TREATMENT GROUP 
Morning 
Capsule 
Morning 
tablet 1 
Morning 
tablet 2 
Evening 
tablet 1 
Evening 
tablet 2 
1 
X842 (BID) 25 mg  
Placebo 
25 mg 
placebo 
25 mg 
placebo 
1 
X842 (BID) 50 mg  
Placebo 
50 mg 
placebo 
50 mg 
placebo 
1 
X842 (BID) 75 mg  
Placebo 
50 mg 
25 mg 
50 mg 
25 mg 
1 
X842 (BID) 100 mg  
Placebo 
50 mg 
50 mg 
50 mg 
50 mg 
1 
Lansoprazole (QD) 30 mg 
30 mg 
placebo 
placebo 
placebo 
placebo 
 
Four doses of X842 (25 mg, 50 mg, 75 mg, 100 mg, and dummies) will be administered as tablets twice 
daily. The active comparator lansoprazole 30 mg and its dummy will be administered as capsules once 
daily in the morning. The study drugs should be taken with 100 mL of noncarbonated water at least 30 
minutes prior to meals. The duration of double-blind treatment will be 28 days -2/+5 days. To blind 
treatment, each patient will receive 2 tablets (containing doses of X842 or its dummy) and one capsule 
(containing lansoprazole or its dummy) in the morning and 2 tablets (containing doses of X842 or its 
dummy) in the evening. 
 
 
 


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The study design is shown below (Figure 1). 
Figure 1 Study Design 
 
The study will comprise 6 visits at the site and 3 telephone visits. Based on the endoscopy findings and/or 
signed informed consent form (ICF), the screening visit (Visit 1) will take place not more than 7 days 
prior to randomization and the first dose administration (Visit 2). All patients will then visit the study 
clinic/investigational site after 7 (Visit 3), 14 (Visit 4) and 28 days (Visit 5) and at the End of Study/Early 
Termination visit (Visit 9). There are 3 weekly telephone visits after Visit 5. See Table 1 in section 6. 
All patients who participate in this study and complete Visit 9 (End of Study/Early Termination) are 
considered to have completed the study (Table 1). 
 
No interim analyses are planned for this study. No data monitoring committees will be used. 
 
 
3.2 
Endpoints and Associated Variables 
3.2.1 Efficacy Variables 
 
3.2.1.1 Primary efficacy endpoint 
 Healing of erosive esophagitis due to GERD based on endoscopic assessment after 4 weeks of 
double-blind treatment. 
 
3.2.1.2 Secondary efficacy endpoints 
 Percentage of heartburn-free 24-hour days during the Weeks 1-8 based on eDiary (mRESQ-eD). 
lansoprazole 30 mg QD.
X842 dose 25 mg BID.
Screening
Double - Blind Treatment 4 weeks 
N=48 
N=48 
X842 dose 50 mg BID.
X842 dose 100 mg BID. 
N=48 
N=48 
Day -7 
Day 0 Day 7± 2
Day 14±3  
Day 28 -2/+5 
Symptom  
assessment 
R 
X842 dose 75 mg BID. 
N=48 
Endoscopy 
Endoscopy 
Open-label 
lansoprazole 
30 mg QD for all patients, 
weekly telephone visits to 
assess symptoms and potential 
AEs 
     lansoprazole 30 mg QD. 4 weeks 
Day 56±3 
End of 
Study/Early 
termination 
Day 35±3 Day 42±3 Day 49±3 
Weekly Telephone visits  
AE = adverse events; BID = Twice Daily; QD = Once Daily; R = Randomization 


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 Percentage of 24-hour days with at most mild heartburn symptoms during the Weeks 1-8 based on 
eDiary (mRESQ-eD). 
 Investigator assessment of symptom at Weeks 1-8 (Visits 2-9). 
 Reflux related impact of symptoms as measured by change from baseline in QOLRAD score 
assessed after 1, 2, 4 and 8 weeks of treatment. 
 
3.2.1.3 Exploratory efficacy endpoints 
 
3.2.2 Safety Variables 
• 
Physical examinations: assessment of head, eyes, ears, nose, throat, skin, thyroid, neurological, 
lungs, cardiovascular system, abdomen (including liver and spleen), lymph nodes, genitourinary 
system (optional) and extremities (musculoskeletal system) after 4 and 8 weeks of treatment. 
• 
Weight and BMI after 4 and 8 weeks of treatment. 
• 
Vital signs: Systolic and diastolic BP, heart rate (pulse), body temperature and respiratory rate after 
1, 4 and 8 weeks of treatment. 
• 
12-lead electrocardiograms (ECG): PQ/PR, QRS, QT and QTcF intervals after 1, 4 and 8 weeks of 
treatment. 
• 
Clinical laboratory tests: hematology, clinical chemistry, coagulation, and urinalysis parameters 
after 1, 4 and 8 weeks of treatment. 
• 
Adverse event (AE) assessments: treatment emergent adverse event (TEAE), adverse event of 
special interest (AESI), serious adverse event (SAE) during the Weeks 1-8 (Visits 2-9). 
• 
Concomitant medication assessments during the Weeks 1-8 (Visits 2-9). 
 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Parexel procedures. 
CCI


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4.2 
General Presentation Considerations 
‘Baseline’ is defined as the last available pre-treatment assessment.  
‘End of Study’ is defined as the last available post-treatment assessment.  
 ‘Treatment Day’ will be calculated relative to the date of randomization i.e. Treatment Day = 
Assessment Date -Randomization Date + 1.  
 
All data measured on a continuous scale will be presented using summary statistics. Summary statistics 
is defined as number (N), arithmetic mean, standard deviation (SD), median, minimum, Q1, Q3 and 
maximum value. Where appropriate 95% confidence intervals will be presented.  
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database.  The mean, median, lower quartile and upper quartile will be reported to one 
more decimal place than the raw data recorded in the database.  The SD will be reported to two more 
decimal places than the raw data recorded in the database.  In general, the maximum number of decimal 
places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of patients providing data at the relevant 
time point (n), frequency counts and percentages.   
Percentages will be presented to one decimal place. Percentages will not be presented for zero counts.  
Percentages will be calculated using n (the number of observations with non-missing values) as the 
denominator.   
Changes from baseline in categorical data will be summarized using shift tables where appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-values 
less than 0.001 will be presented as “<0.001”. 
Confidence intervals will be presented to one more decimal place than the raw data. 
 
When applicable, summary data will be presented by treatment, and by assessment time. Individual 
patient data will be listed by patient number, treatment, and, where applicable, by assessment time. 
 
4.3 
Software 
All report outputs will be produced using SAS® version 9.4 or a later version in a secure and validated 
environment.  For quality control of primary endpoint, R version 4.1.1 will be used.  
All report outputs will be provided in Microsoft Word document/PDF format.  
 


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4.4 
Study Patients 
4.4.1 Disposition of Patients 
A clear accounting of the disposition of all patients who enter the study will be provided, from screening 
to study completion. 
• 
A summary of the number of patients screened for entry into the study, the number and percentage 
of patients excluded prior to randomization by major reason and overall, the total number of 
randomized patients, the total number of patients randomized and treated, the reasons for not being 
randomized or treated (Enrolled Set) 
• 
A summary of the number of patients randomized per country and site (Randomized Set) 
• 
A summary of the number of patients randomized and treated (with at least one dose of study 
medication), treated in DB phase, treated in DB and OL phase and the number and percentage of 
patients withdrawing from study treatment by study phase together with major reason and 
withdrawing from the study together with major reason by treatment group and overall (Randomized 
Set). 
• 
A summary of the number and percentage of patients completing each visit of the study by treatment 
group and overall (Randomized Set). 
• 
Duration of patient participation in the study (Randomized Set). 
• 
A summary of the Covid-19 impact (at least a visit impacted by the Covid-19 pandemic, visits 
impacted, type of impact to the visits and relationship to Covid-19 during participation to the study) 
(Randomized Set). 
 
The duration of patient participation will be calculated in days and derived as: 
Duration (days) = Date of last visit or last contact– date of informed consent + 1 
 
By-patient listings will be provided. 
 Listing of screen failure patients (Enrolled Set) 
 Listing of randomization details (Randomized Set). 
 Listing of study treatment discontinuation details (including primary reason and study day at 
discontinuation, whether treatment was unblinded and the last dose date of study treatment) 
(Randomized Set). 
 Listing of study completion or withdrawal details (including primary reason and study day at 
discontinuation) (Randomized Set). 
 Listing of dates of visit including duration of patient participation and Covid-19 impact (Randomized 
Set). 
 


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4.4.2 Protocol Deviations 
All protocol violations will be judged as major or minor, taking composite effects of protocol deviations 
into consideration. 
Major protocol deviations are defined as those deviations from the protocol likely to have an impact on 
the perceived efficacy and/or safety of study treatments. Therefore, patients for whom the clinical 
outcome is qualitatively affected by the protocol deviations will be excluded. 
- 
Informed consent deviations 
- 
Inclusion/Exclusion criteria deviations 
- 
Disallowed medications 
- 
AEs/SAEs deviations 
- 
IP Administration/ study treatment deviations 
- 
Procedures/tests deviations 
- 
Visit schedule deviations 
- 
Withdrawal criteria deviations 
Protocol deviations and any action to be taken regarding the exclusion of patients or affected data from 
specific analyses are defined in the project-specific Protocol Deviation Specification. 
The final classification and effect of each protocol deviation as well as the composite effect of a set of 
protocol deviations on analysis populations will be assessed prior to the database lock/unblinding on a 
Blinded Data Review Meeting [BDRM]. Results and population assignments will be summarized in a 
BDRM report which will be signed off by all relevant scientific experts. 
The impact of major protocol deviations on the efficacy and/or safety results will be investigated by 
assessing the robustness of the study results and conclusions to the choice of analysis set, both including 
and excluding data potentially affected by major protocol deviations.  
 
The following summaries will be provided: 
• 
A summary of the number and percentage of patients with at least a major protocol deviation and by 
type of protocol deviation (Randomized Set). 
The following listing will be provided: 
• 
All major and minor protocol deviations (Randomized Set). 
 
4.5 
Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
Population 
Description 
Enrolled 
All patients who signed the ICF (including screening failures). 


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Population 
Description 
Randomized 
All patients who have been randomized. 
Full Analysis Set (FAS) 
The full analysis set (FAS) will consist of all patients who have been randomized 
and received at least 1 dose of IMP.  
Patients will be analyzed according to randomized treatment (any randomized but 
not treated patient will be marked and reported as such). 
Per Protocol Set (PPS) 
The per protocol analysis set (PPS) will consist of all patients who have been 
randomized and completed the study without any major protocol deviations that are 
judged to compromise the analysis of the data.  
Mis-randomized patients will be removed from the PPS. 
All protocol violations will be judged as major or minor, taking composite effects 
of protocol deviations into consideration, excluding patients for whom the clinical 
outcome is qualitatively affected by the protocol deviations. 
Safety Analysis Set (SS) 
The safety analysis set will consist of all patients who have been randomized and 
received at least 1 dose of IMP.  
Patients will be analyzed according to the treatment actually received (in case this 
differs from randomized treatment). 
PK Analysis Set (PKS) 
The PK analysis set will consist of all patients who received at least 1 dose of IMP 
and have at least 1 measurement of plasma concentration of X842/linaprazan.  
Patients will be analyzed according to the treatment actually received (in case this 
differs from randomized treatment). 
 
The efficacy summaries and analyses will be based on the Full Analysis Set, which is based upon the 
Intention-to-Treat principle.  
For the primary efficacy variable(s), a sensitivity analysis will be performed on the Per Protocol Set to 
assess the robustness of the study conclusions to the choice of analysis population.   
Secondary efficacy variable(s) will also be performed on the Per Protocol Set.   
The PK summaries and analyses will be based on the PK Analysis Set.   
The safety summaries and analyses will be based on the Safety Analysis Set.   
 
Upon database release, protocol deviation and analysis set outputs will be produced and will be sent to 
Cinclus Pharma for review.  An analysis population classification meeting will be arranged to discuss 
the outputs and to decide which patients and/or patient data will be excluded from certain analysis sets. 
Decisions made regarding the exclusion of patients and/or patient data from analysis sets will be made 
prior to unblinding and will be documented and approved by Cinclus Pharma.   
 
The following summary and listing on analysis sets will be provided: 


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• 
A summary of the number and percentage of patients in FAS, PPS, Safety Analysis Set and PK 
Analysis Set by study treatment group and overall and the reason for exclusion from an analysis set 
(if applicable) (Randomized Set). 
• 
A listing including patient identifier, inclusion/exclusion flag for each analysis set, reason for 
exclusion from an analysis set (if applicable), randomized and actual study treatment will be provided 
(Randomized Set).  
 
4.6 
Demographics and Baseline Characteristics 
The following summary and listing of demographic and baseline characteristics will be based on the 
FAS: 
• A summary of demographic variables: age (years), sex, ethnicity, race, childbearing potential (female 
only), height (cm), weight (kg), BMI (kg/m2) and LA grade by study treatment group and overall 
• A summary of demographic variables by LA grade by study treatment group and overall 
• A summary of viral serology results at baseline 
• A summary of H.Pylori results at baseline 
• Listing of demographics 
• Listing of viral serology and H.Pylori at baseline 
 
Age will be calculated as the number of complete years between a patient's birth date and the date of 
informed consent. 
BMI is calculated automatically in eCRF as [weight/height2] (kg/m2). 
 
4.7 
Medical/Surgical History 
Medical/surgical history will be coded by primary system organ class (SOC) and preferred term (PT) 
using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 or 
higher. 
In case of partial or completely missing start date and end date, if this is not possible to decide whether 
the medical condition is past or current, then it will be considered current. 
Smoking history, alcohol consumption history and history intake of drugs and/or anabolic steroids will 
be presented together with duration of smoking (if former smoker), average number of units of alcohol 
consumed per week (if current consumption) and time since last drug intake (if former user).  
 
The following summaries will be based on the FAS and provided by study treatment group and overall: 
• previous medical conditions or events by MedDRA SOC and PT 
• continuing medical conditions by MedDRA SOC and PT 
• Smoking history, alcohol consumption history and history intake of drugs and/or anabolic steroids 


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The following listing will be provided: 
• previous or continuing medical conditions or events  
• Smoking history, alcohol consumption history and history intake of drugs and/or anabolic steroids 
 
4.8 
Prior and concomitant Medications and prior PPI Treatment 
Prior and concomitant medications and prior PPI treatment will be coded using the latest available 
version of the World Health Organization Drug Dictionary (WHO-DD B3) Version March 2020 and will 
be classified by Anatomical Therapeutic Chemical (ATC) categories. 
 
Medication start and stop dates will be compared to the date of treatment initiation to allow medications 
to be classified as either Prior only, both Prior and Concomitant, or Concomitant only.  Medications 
starting after the completion/withdrawal date will be listed but will not be classified or summarized. 
Medications that start and stop prior to the date of treatment initiation will be classified as Prior only.  If 
a medication starts before the date of treatment initiation and stops on or after the date of treatment 
initiation, then the medication will be classified as both Prior and Concomitant.  Medications will be 
classified as Concomitant only if they have a start date on or after the date of treatment initiation. 
If medication start and/or stop dates are missing or partial, the dates will be compared as far as possible 
with the date of treatment initiation.  If there is clear evidence to suggest that the medication stopped 
prior to the first dose of study medication, the medication will be assumed to be Prior only. Medications 
will be assumed to be Concomitant only, unless there is clear evidence (through comparison of partial 
dates) to suggest that the medication started prior to the date of treatment initiation.  In that case, the 
medication will be assumed to be both Prior and Concomitant.   
Where possible, if complete start and end date are available, duration (days) of medications will be 
calculated and included in listings as duration= end date – start date + 1. 
 
The following summaries will be based on the FAS and provided by study treatment group and overall: 
• 
Prior only medications 
• 
Prior and concomitant medications 
• 
Concomitant only medications 
• 
Prior PPI treatment 
• 
Prior PPI treatment by LA grade 
• 
Newly prior PPI treatment (still on PPI treatment until 28 days prior to treatment initiation) 
• 
Newly prior PPI treatment by LA grade (still on PPI treatment until 28 days prior to treatment 
initiation) 
The following listing will be provided: 
• 
Prior only medications 


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• 
Prior and concomitant medications 
• 
Concomitant only medications 
• 
Prior PPI treatment 
• 
Newly prior PPI treatment (still on PPI treatment until 28 days prior to treatment initiation) 
 
 
4.9 
Treatment Exposure / Compliance 
4.9.1 Treatment Exposure  
Duration of exposure will be expressed in days and calculated for double blind phase, open label phase 
and overall: 
Duration DB (days) = Date of last intake of study treatment in DB phase – date of first intake of study 
treatment in DB phase + 1 
Duration OL (days) = Date of last intake of Lansoprazole in OL phase – date of first intake of 
Lansoprazole in OL phase + 1 
Duration overall (days) = Date of last intake of study treatment – date of first intake of study treatment 
+ 1 
 
The total dose of X842 study drug will be calculated for the DB phase in each treatment group receiving 
X842, based on the number of tablets of X842 (or dummy) dispensed and returned. 
Note that, in the DB phase, patients are supposed to take 4 tablets of X842 (or dummy) per day. 
 
Total dose X842 DB (mg) = (Sum of number of tablets dispensed at start of DB phase - Sum of number 
of tablets returned at end of DB phase) x Daily dose /Nb of tablets per day 
 
where daily dose is 50 mg, 100 mg, 150 mg or 200 mg depending on the treatment group and Nb of 
tablets per day is 4 for all treatment groups. 
 
The total dose of Lansoprazole will be calculated for the DB phase (Lansoprazole group only), the open 
label phase (all treatment groups) and overall (Lansoprazole group only), based on the number of 
capsules of Lansoprazole (or dummy) dispensed and returned. Note that patients are supposed to take 1 
capsule of Lansoprazole (or dummy) per day. 
 
Total dose Lansoprazole DB (mg) = (Sum of number of capsules dispensed at start of DB phase - Sum 
of number of capsules returned at end of DB phase) x 30. 
Total dose Lansoprazole OL (mg) = (Sum of number of capsules dispensed at start of OL phase - Sum 
of number of capsules returned at end of OL phase) x 30. 
Total dose Lansoprazole Overall (mg) = Total dose Lansoprazole DB + Total dose Lansoprazole OL. 
 


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The following extent of exposure summaries will be presented on the Safety analysis set by treatment 
group:  
• A Summary of the duration of exposure to treatment, by phase.  
• A summary of the total dose of Lansoprazole and X842 by phase.  
• Listing of exposure data. 
 
4.9.2 Compliance  
Compliance of each treatment group (the 4 X842 treatment groups and the Lansoprazole group) 
regarding the X842 study drug will be calculated for the DB phase based on the number of tablets of 
X842 (or dummy) dispensed and returned and on the duration of exposure in days in the DB phase.  
 
Treatment compliance X842 DB (%) = (Sum of number of tablets dispensed at start of DB phase - Sum 
of number of tablets returned at end of DB phase) / (4 x Duration DB) x 100 
 
Compliance of each treatment group (the four X842 treatment groups and the Lansoprazole group) 
regarding Lansoprazole study drug will be calculated for each phase based on the number of capsules of 
Lansoprazole (or dummy) dispensed and returned and on the duration of exposure in days in each phase.  
 
Treatment compliance Lansoprazole DB (%) = (Sum of number of capsules dispensed at start of DB 
phase - Sum of number of capsules returned at end of DB phase) / (1 x Duration DB) x 100 
 
Treatment compliance Lansoprazole OL (%) = (Sum of number of capsules dispensed at start of OL 
phase - Sum of number of capsules returned at end of OL phase) / (1 x Duration OL) x 100 
 
Treatment compliance Lansoprazole Overall (%) = (Sum of number of capsules dispensed - Sum of 
number of capsules returned) / (1 x Duration Overall) x 100 
 
The following compliance summaries will be presented on the FAS by treatment group:  
• 
A summary of the treatment compliance measures by study phase 
• 
A listing of treatment compliance 
 
 
4.10 Efficacy Evaluation 
4.10.1 Analysis and Data Conventions 
The primary study objective is to estimate the X842 dose for Phase 3 study with good precision, and 
hence comparison of different doses of X842 to the active comparator arm (lansoprazole 30 mg) will not 


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involve any formal statistical testing. Nevertheless, all results for comparator arm will be included in 
efficacy evaluation summaries. 
 
4.10.1.1 Multi-center Studies 
This study is conducted in many sites, and the randomization was not initially stratified by site. 
After 128 patients were randomised, a new randomisation scheme with stratification by site was put in 
place to ease the treatment supply on site. Randomisation was balanced by site to allow the clinical 
supplies team to better predict the required material types and make them available at each site before a 
patient is randomised. 
For the primary efficacy variable, the statistical models to be used for the estimation of dose-response 
relationship will adjust for differences between centers, by including ‘Center’ as a main effects term in 
the model.  Adjustment for center will also be performed, wherever possible, in the analysis of the 
secondary efficacy variables. 
Pooling will be applied to deal with small centers. Countries with less than 20 patients will be grouped. 
The term ‘Center’ will be used to define the resulting pseudo-centers, for the summaries and analyses. 
Descriptive summaries of primary efficacy variable data by treatment group and center will be provided. 
 
4.10.1.2 Adjustments for Covariates 
 
The primary efficacy analysis will be adjusted for the following baseline covariates: 
1. Center  
2. Erosive esophagitis due to GERD LA grade C or D, erosive esophagitis due to GERD LA grade A 
or B who are partial responders to PPI treatment 
 
4.10.1.3 Handling of Dropouts or Missing Data 
 
Primary endpoint: 
The number and percentage of patients with missing data for the primary endpoint will be summarized 
by treatment group, by LA grade, overall and by major reason. 
A patient data listing will be provided showing all patients with missing values for the primary endpoint.  
For these patients, the listing will provide important baseline characteristics, the recorded reason(s) for 
study discontinuation and the timing of study discontinuation. 


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In a primary analysis, missing healing results will be replaced with a non-responder approach. If there 
are more than 5% of patients with missing healing results, a sensitivity analysis will also be performed 
(tipping point method). Scenarios assuming probability of response 20%, 40%, 60%, 80% and 100% will 
be simulated. Fifty datasets for each probability will be generated, and for each one, an analysis will be 
conducted, Rubin rules will be used to combine the results. 
 
Secondary endpoint: QOLRAD 
Handling of missing values is described in section 4.10.3.1. 
 
Secondary endpoint: mRESQ-eD 
Handling of missing values is described in section 4.10.3.2. 
 
4.10.1.4 Multiple Comparisons/Multiplicity 
No formal statistical testing is planned.  Hence no adjustments for multiplicity are required. 
 
4.10.1.5 Interim Analyses 
No interim analysis. 
 
4.10.1.6 Examination of Subgroups 
The uniformity of the treatment effect for the primary efficacy variable will be examined for the 
following subgroups: 
1. Age (<60 years, ≥60 years) 
2. Sex (Male, Female) 
3. Erosive esophagitis due to GERD LA grade C or D, erosive esophagitis due to GERD LA grade A 
or B who are partial responders to PPI treatment.   
 
Summaries of the primary efficacy variable by treatment group and subgroup will be produced.  
Summaries of the secondary endpoints Percentage of heartburn-free 24-hour days during the Weeks 1-8 
based on eDiary (mRESQ-eD) and Percentage of 24-hour days with at most mild heartburn symptoms 
during the Weeks 1-8 based on eDiary (mRESQ-eD) by treatment group and subgroup will also be 
produced. 
 


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Statistical modeling of dose-response will be performed on subgroups defined by LA grade. No formal 
statistical analysis will be performed within the other subgroups. 
 
4.10.2 Primary Efficacy Variable(s)  
 
Upper endoscopy for the examination of esophagus will be performed to confirm patient eligibility as 
well as the primary endpoint. The endoscopy examinations will be recoded on a video shot/digital images 
and these endoscopy videos/digital images will be evaluated by Investigator or endoscopy specialist, as 
required. Grade of erosive esophagitis due to GERD will be determined by the appropriately trained 
Investigator or endoscopist according to the LA classification (see Appendix 8 of protocol).  
The endoscopy videos/digital images will be collected into a central database, with the appropriate 
anonymization. All videos and digital images will be centrally reviewed retrospectively. This review will 
include reassessment of the LA grading and other findings which may constitute exclusion criterion. The 
central reading evaluation will override the investigators’ evaluations and will be used for all reporting 
and modelling. In case central reading evaluation is missing for a patient at screening or at week 4, due 
to poor video quality for example, the investigators’ evaluations will replace the missing central reading. 
Hereafter, analyses based on central reading will consider central readings with imputations of local 
readings if missing. 
Data obtained from patients deemed to have been ineligible for study enrollment following the 
retrospective analysis will be excluded from the per protocol analysis.  
In the FAS analysis, the following subgroups of patients will be evaluated:  
- 
the subgroup of patients classified as erosive with grade A/B or C/D at screening according to 
central reading  
- 
the subgroup of patients classified as non-erosive (grade 0) at screening according to central 
reading. 
 
A sensitivity analysis will also be conducted to present the healing results based on investigator or 
endoscopy specialist assessments (local reading). A second sensitivity analysis will be presented by 
category of LA Grade as assessed by the investigator and reclassified by central reading. 
 
The primary objective of the study is to support dose selection for X842, through assessment of healing 
of erosive esophagitis due to GERD based on endoscopic assessment after 4 weeks of treatment. The aim 
is to identify the dose that will lead to having 85% of the patients have esophageal mucosa healing after 
4 weeks of treatment.  
Comparison of different doses of X842 to the active comparator arm (lansoprazole 30 mg) will not 
involve any formal statistical testing. 
Lansoprazole treatment group will be analyzed descriptively. 
 
The primary analysis will be performed for both the FAS and PPS as defined in Section 4.5. 
In addition, the two subgroups, erosive esophagitis due to GERD LA grade C or D and erosive 
esophagitis due to GERD LA grade A or B, will be evaluated separately.  


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In the subgroup of patients with LA grade A or B, some of them were classified as A or B by investigator 
and thus are partial responders to PPI, but some of them were initially classified as C or D by investigator, 
and thus may not be partial responders to PPI. A subgroup analysis will be performed on the subgroup 
of patients with LA grade A/B according to their history of PPI treatment. 
 
The rate of esophageal mucosa healing in the four X842 dose groups after 4 weeks of treatment 
(endoscopy performed at Visit 5) will be derived using the LA grading of GERD. If the grading is neither 
A, B, C or D, then the patient will be considered as having esophageal mucosa healing. 
The rate of esophageal mucosa healing will be accompanied by 95% Clopper Pearson CI. 
 
The primary analysis will involve dose-response modeling, evaluating a sequence of dose-response 
models for the healing rate including the Linear, Exponential, Emax, Sigmoid Emax and Logistic models 
(on logit scale).  
The models will be compared in terms of model fit, and the target dose estimated as the dose providing 
the target effect of 85% healing rate from the best fitting model will be derived.  
 
Several dose-response models will be fitted with the following factors: 
• randomized study treatment (X842 25mg, X842 50mg, X842 75mg and X842 100mg) 
• erosive esophagitis due to GERD (LA grade C or D / LA grade A or B) 
• Center 
 
 
Dose-Response Modeling  
Multiple Comparison Procedure – Modeling  
For all patients assigned to FAS, dose-response modeling will be performed using the multiple 
comparison procedure – modeling (MCP-Mod) approach [2, 3] with the following models in 
consideration: 
1. Emax: 𝑓𝑓(𝑑𝑑) = 𝐸𝐸0 + 𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚𝑑𝑑/(𝐸𝐸𝐸𝐸50 + 𝑑𝑑). 
2. Sigmoidal Emax with h = 3.5: 𝑓𝑓(𝑑𝑑) = 𝐸𝐸0 + 𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚𝑑𝑑3.5/(𝐸𝐸𝐸𝐸50
3.5 + 𝑑𝑑3.5). 
3. Logistic: 𝑓𝑓(𝑑𝑑) = 𝐸𝐸0 + 𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚/exp ((𝐸𝐸𝐸𝐸50 −𝑑𝑑)/𝛿𝛿). 
4. Exponential: 𝑓𝑓(𝑑𝑑) = 𝐸𝐸0 + 𝐸𝐸1𝑒𝑒𝑒𝑒𝑒𝑒ቀ
𝑑𝑑
𝛿𝛿ቁ. 
5. Linear: 𝑓𝑓(𝑑𝑑) = 𝐸𝐸0 +  𝛽𝛽∗𝑑𝑑. 
Where: 
- 
d is the dose level, 
- 
𝐸𝐸𝐸𝐸50 the dose that gives 50 percent of the maximum effect, 
- 
h the Hill coefficient, 
- 
δ the rate of change for the logistic and exponential models, 
- 
β is the slope for linear model, 
- 
𝐸𝐸0 the basal effect at d = 0 and  
- 
𝐸𝐸1 the scale parameter in the exponential model. 


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In the MCP-Mod approach, all statistically significant models listed above will be averaged in order to 
estimate the median dose for a given targeted response via inverse prediction along with associated 95% 
intervals using a bootstrap re-sampling method. 
For the contrast test the following guesstimates will be assumed. 
 
Model  
Guesstimate 
Emax 
ED50 = 50 
SigEmax1 
ED50 = 50 
Logistic, Exponential 
δ = 200 
 
 
This MCP-Mod analysis will be performed using the R software (“DoseFinding” and “ggplot2” 
packages) [5], as follows: 
 
1. MCP step: 
a. Logistic regression model on the response variable with dose levels as categorical to 
obtain coefficients estimate and the relative covariance matrix. 
b. “Mod” function of the “DoseFinding” package to perform the multiple contrast test 
(function “MCTtest”) part on the pre-specified candidate models 
c. Significant candidate models will be evaluated by t-Test statistic and the adjusted p-value. 
Candidates for the modeling part will be selected with the following criteria: 
i. Take the most significant candidate model (p<0.05) or models if the t-Test statistic 
is equal. 
ii. Stop if any of the model has not signal (p>0.05). 
 
2. Modeling step (Bootstrap):  
a. N = 1,000 bootstrap samples of dose responses will be generated by a multivariate normal 
distribution with vector mean equal to the logit coefficients estimated on the MCP step 
and covariance matrix as its coefficients related covariance matrix. 
b. For each Sample: 
i. Fit the model by the “fitMod” function and select the best with goodness of fit 
based on the AIC criteria. 
ii. Prediction of response probabilities based on the best model.  
iii. Save the predicted values. 
3. Compute the median of the bootstrap predicted values and 95% CIs. 
4. Extraction of the dose at the target response probability with 95% CI. 
 
 
Should there be three or more candidate model fail to fit on a bootstrap sample, the estimate for the 
bootstrap sample will be taken as unreliable. In case less than 70% of bootstrap sample estimates are 
taken as reliable an additional generalized linear mixed model (GLMM) analysis will be performed as 


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follows. A regression model with treatment (including Lansoprazole (QD) 30 mg group) and GERD 
category (with levels of A&B and C&D) as fixed and center as random effect will be fitted to binary data 
(logistic regression). Number of subjects with evaluable data and least squares mean estimates of 
response rates with accompanying 90% CIs will be provided for each dose level and for Lansoprazole 
(QD) 30 mg group using model estimates of the GLM described above. 
 
 
The following summaries will be provided by study treatment group based on central reading results 
where some descriptive summaries on FAS will be presented on both subgroups of erosive and non-
erosive patients at screening according to central reading. A subgroup analysis based on the LA grade 
A/B patients by prior PPI treatment will also be presented since some of the LA grade A/B patients were 
originally LA grade C/D patients as assessed by the investigator. 
• Percentage of patients with esophageal mucosa healing after 4 weeks (FAS erosive/non-erosive/PPS) 
• Percentage of patients with esophageal mucosa healing after 4 weeks by LA Grade (FAS subgroup of 
erosive patients/PPS) 
• Percentage of patients with esophageal mucosa healing after 4 weeks by age (FAS subgroup of erosive 
patients /PPS) 
• Percentage of patients with esophageal mucosa healing after 4 weeks by sex (FAS subgroup of erosive 
patients /PPS) 
• Percentage of patients with esophageal mucosa healing after 4 weeks by center (FAS subgroup of 
erosive patients /PPS) 
• Percentage of patients with esophageal mucosa healing after 4 weeks by H.Pylori at Baseline (FAS 
erosive/non erosive /PPS) 
• Percentage of patients with esophageal mucosa healing after 4 weeks by Prior PPI Treatment (FAS 
Patients with LA Grade A/B) 
• Bar-charts of percentage of patients with esophageal mucosa healing after 4 weeks (FAS erosive/non 
erosive /PPS) 
• Bar-charts of percentage of patients with esophageal mucosa healing after 4 weeks by LA Grade (FAS 
subgroup of erosive patients /PPS) 
• MCP-MOD: Testing a dose-response signal for Response Rate (FAS subgroup of erosive patients 
/PPS) 
• Figure for dose-response shapes based on model-averaging method over all models in the candidate 
set (FAS subgroup of erosive patients /PPS) 
• Results of the contrast test from the MCP-Mod analysis (FAS subgroup of erosive patients /PPS) 
• Model parameter estimates of the individual dose-response models (FAS subgroup of erosive patients 
/PPS) 


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• Estimation of potential target dose based on model-averaging method over all models in the candidate 
set (FAS subgroup of erosive patients /PPS) 
 
A sensitivity analysis based on local readings will be provided by study treatment group: 
• Percentage of patients with esophageal mucosa healing after 4 weeks (Investigator or Endoscopy 
specialist reading) (FAS) 
• Percentage of patients with esophageal mucosa healing after 4 weeks by LA Grade (Investigator or 
Endoscopy specialist reading) (FAS) 
 
A second sensitivity analysis based on local readings and how those local readings were reclassified by 
central reading will be provided by study treatment group.  
There will be 6 categories: 
- Grade C/D that stayed C/D 
- Grade C/D reclassified as A/B 
- Grade C/D reclassified as grade 0 (non erosive) – if any 
- Grade A/B reclassified as C/D – if any 
- Grade A/B that stayed A/B 
- Grade A/B reclassified as grade 0 (non erosive) 
 
• Percentage of patients with esophageal mucosa healing after 4 weeks by Investigator LA Grade and 
its reclassification (FAS) 
 
A listing of upper endoscopy results will be provided. 
 
 
 


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4.10.3 Secondary Efficacy Variables 
 
Analyses of the secondary efficacy endpoints will be performed for the FAS and the PP as defined in 
Section 4.5. 
 
QOLRAD scores and mRESQ-eD means or proportions will be estimated using a Generalized Linear 
Mixed Model (GLMM) approach using information of each week for each subject, on observed data, 
assuming missing at random.  
The models will be implemented using all available timepoints (as categorical), the X842 dose level or 
lansoprazole as covariate and the related interaction, center and erosive esophagitis due to GERD (LA 
grade C or D / LA grade A or B. 
Toeplitz covariance matrix will be assumed. In case of convergence failure, the following matrices will 
be tested until convergence is reached: 1. Compound Symmetry, 2. Autoregressive 1 (AR-1). 
Mean and standard error estimated from the model will be provided in the outputs. Median, Q1, Q3, Min 
and Max will be reported as observed data. 
 
 
4.10.3.1 QOLRAD 
Reflux related impact will be assessed based on the patient reported outcome (PRO) QOLRAD. The 
heartburn version of the QOLRAD is a disease specific instrument and contains 25 questions addressing 
concerns associated with gastrointestinal symptoms. Each question is scored from 1 to 7, where a higher 
score represents a higher (“better”) health-related quality of life. 
The QOLRAD will be completed pre-dose by patients at Visits 2 (Baseline), 3 (Week 1), 4 (Week 2), 5 
(Week 4), and 9 (Week 8) (see Table 1 in section 6.1). 
The questions are categorized into five domains: emotional distress (six questions), sleep disturbance 
(five questions), vitality (three questions), food/drink problems (six questions) and physical/social 
functioning (five questions).  
• Emotional distress (questions 12, 14, 15, 17, 19, 22) 
• Sleep disturbance (questions 8, 10, 11, 18, 21) 
• Food/drink problems (questions 3, 5, 9, 13, 16, 20) 
• Physical/social functioning (questions 2, 6, 23, 24, 25) 
• Vitality (questions 1, 4, 7) 
 
For the calculation of domain scores, in case of missing items, these missing items can be replaced under 
specific conditions (the half-scale method) as follows: 
• If 50% or more of the questions in one dimension are completed, the mean value of the completed 
items should replace the missing responses.  


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• If less than 50% of the questions in one dimension are completed, the missing responses will not be 
replaced. 
 
The score in each domain will be calculated as the mean of all items in that domain, only if all items are 
not missing after replacement. 
 
To evaluate the reflux related impact pattern during the initial 4 weeks treatment and the subsequent 
additional 4 weeks (Weeks 5-8) open-label treatment with lansoprazole 30 mg QD, the following 
summaries will be provided by study treatment group and assessment day: 
• A summary of QOLRAD domain scores and change from baseline (FAS/PP) 
• A plot of QOLRAD domain scores at baseline and Week 1, Week 2, Week 4 and Week 8 (FAS/PP). 
 
A listing of QOLRAD results will be provided. Original values and imputed values will be provided, 
together with domain scores. 
 
 
4.10.3.2 mRESQ-eD 
Reflux related symptoms will also be assessed based on the modified RESQ-eDiary. mRESQ-eD 
contains 8 items where 5 items assess severity (Did not have – Severe) and 3 items assess frequency 
(Never – Very often) of symptoms. 
• Heartburn domain (questions 1, 2) assess severity (0=Did not have, 1=Very mild, 2=Mild, 
3=Moderate, 4=Moderately severe, 5=Severe). 
• Regurgitation domain (questions 6, 7, 8) assess frequency of symptoms (0=Never, 1=Rarely, 
2=Sometimes, 3=Often, 4=Very often). 
• Difficulty swallowing (question 3) assess severity of symptoms (0=Did not have, 1=Very mild, 
2=Mild, 3=Moderate, 4=Moderately severe, 5=Severe). 
• Hoarseness (question 4) assess severity of symptoms (0=Did not have, 1=Very mild, 2=Mild, 
3=Moderate, 4=Moderately severe, 5=Severe). 
• Cough (question 5) assess severity of symptoms (0=Did not have, 1=Very mild, 2=Mild, 
3=Moderate, 4=Moderately severe, 5=Severe). 
Patients will be asked to report their symptoms every 12-hours, once before the morning dose and once 
before the evening dose of the IMP through week 1 to week 8. 
 
Missing values will be imputed if possible.  
 
Imputation of missing values: 
For each item, morning recordings will be regarded as one sequence of observations and evening 
recordings as another sequence of observations. Missing values in the sequence of morning or evening 
recordings respectively will be imputed according to the following rules: 


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If a single observation is missing, the missing value will be replaced by the larger of the two 
surrounding values.  
- 
If two or more consecutive observations are missing the values will remain missing. 
 
Item values of severity or frequency for a day (approximately a 24 h period) will then be constructed 
using the imputed sequences of evening and morning recordings of severities or frequencies. A day will 
consist of the morning and evening recording of each day starting on Day 1, the day after the first 
treatment intake. All recordings taken on the day of first treatment intake will be considered as Day 0 
recordings. There could be some pre-dose recordings and some post-dose recordings depending on the 
time the patient had the first dose. 
 
- 
The daily item severity or frequency will be defined as the maximum of the two recordings.  
- 
If either the morning or the evening recording is missing, the daily value will be set to the 
available value. 
- 
If both morning and evening recordings are missing, the daily value will be set to missing. 
 
Baseline morning, evening and 24-hour daily recording will be defined using the recordings prior to the 
first treatment dose, if these recordings are available. 
 
Domain scores: 
The domain severity or frequency on a given day, morning or evening will be derived as the highest 
severity or frequency of the items that form the domain. If some items are missing, the highest value 
will be chosen amongst available items. 
 
Heartburn domain: 
• Morning score: the highest severity score between item 1 and item 2 of the morning assessment 
(min-max 0-5).  
• Evening score: the highest severity score between item 1 and item 2 of the evening assessment 
(min-max 0-5) 
• Daily score: the highest severity score between daily assessments of item 1 and item 2 (min-max 
0-5) 
 
Regurgitation domain scores are constructed in the same way as Heartburn domain using the items that 
form the domains. 
 
Weekly means of the daily scores, of the morning scores and of the evening scores will then be 
calculated and presented by week for each domain or item. A minimum of 4 days during a week with 
severity or frequency of symptoms recorded is required to calculate weekly means for all the 3 
domains. 
 
Heartburn free: 


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Heartburn-free in a 24-hour day is defined as a daily score of 0 for the heartburn domain, and the number 
of heartburn-free days over a week will be calculated. The percentage of heartburn-free days for a patient 
over a week will be calculated as: 
% heartburn-free days = number of days with daily score =0 / number of days the severity of symptom 
is recorded x 100. 
A minimum of 4 days during a week with severity of symptoms recorded is required, otherwise, the 
percentage will be set as missing for that week. 
The percentage of heartburn-free in the morning and heartburn-free in the evening will also be calculated 
for morning and evening records respectively. 
 
Heartburn with at most mild symptoms: 
Heartburn with at most mild symptoms (either no symptoms, very mild symptoms or mild symptoms) in 
a 24-hour day is defined as all the items in the domain that have a daily score of maximum 2, and 
percentage of heartburn- at most mild symptoms days for a patient over a week will be calculated as: 
% heartburn-at most mild symptoms days = number of days where all items have daily score ≤ 2 / number 
of days the severity of symptom is recorded x 100. 
A minimum of 4 days during a week with frequency of symptoms recorded is required, otherwise, the 
percentage will be set as missing for that week. 
The percentage of heartburn-at most mild symptoms in the morning and heartburn-at most mild 
symptoms in the evening will also be calculated for morning and evening records respectively. 
 
 
The following summaries will be provided by study treatment group and assessment time (morning, 
evening or daily): 
• mRESQ-eD: Summary of weekly mean domain scores/items during the Weeks 1-8 (FAS/PP) 
• A plot of weekly mean domain scores/items during the Weeks 1-8 (FAS/PP) 
• mRESQ-eD: Percentage of heartburn-free 24-hour days during the Weeks 1-8 (FAS/PP) 
• mRESQ-eD: Percentage of heartburn-at most mild symptoms 24-hour days during the Weeks 1-8 
(FAS/PP) 
• A plot of heartburn-free rate from 1 to 8 weeks of treatment (FAS/PP) 
• A plot of heartburn- at most mild symptoms rate from 1 to 8 weeks of treatment (FAS/PP) 
 
Listings of mRESQ-eD results will be provided. Item scores, domain scores and weekly mean domain 
scores will be provided (morning, evening and daily scores). 
 
 


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4.10.3.3 Heartburn assessed by investigator 
At each visit, Investigator will assess the severity of patients’ heartburn, regurgitation and dysphagia in 
the 7 days prior to the visit. The assessment will include both the severity grade and the frequency of 
symptoms.   
 
The potential frequency is defined as one of these grades: All of the time, Most of the time, Quite a lot 
of the time, Some of the time, A little of the time, Hardly any of the time and None of the time. 
Symptoms are scored as either none, mild, moderate or severe. 
 
The following summaries will be provided by study treatment group and visit: 
• A summary of investigator assessment of symptoms (severity and frequency of heartburn, 
regurgitation and dysphagia) at Weeks 1-8 (Visits 2-9) (FAS/PP) 
• A bar chart of investigator assessment of heartburn (severity and frequency) at baseline and from 1 to 
8 weeks of treatment (FAS/PP) 
• A bar chart of investigator assessment of regurgitation (severity and frequency) at baseline and from 
1 to 8 weeks of treatment (FAS/PP) 
• A bar chart of investigator assessment of dysphagia (severity and frequency) at baseline and from 1 
to 8 weeks of treatment (FAS/PP) 
 
A listing of investigator assessment of symptom at Weeks 1-8 (Visits 2-9) will be provided: 
 
 
4.10.4 Exploratory efficacy endpoint 
 
 
 
 
 
 
 
Pre-dose plasma concentrations will be collected twice daily, pre-dose, before the first and the second 
dose administration at Day 7, Day 14 and Day 28 visits in all patients. 
 
The following descriptive statistics will be presented for plasma concentrations obtained at each nominal 
time point: n, arithmetic mean, SD, coefficient of variation (CV%), geometric mean, geometric CV%, 
median, minimum and maximum values. 
 
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s 
 
 
 
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Statistical Analysis Plan 
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4.11 Safety Evaluation 
All safety summaries and analyses will be based upon the Safety Set as defined in Section 4.5. 
 
4.11.1 Adverse Events 
An AE is any untoward medical occurrence in a clinical study patient administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including clinically significant abnormal values from 
relevant tests, such as clinical safety laboratory tests, ECGs, vital signs), symptom, or disease temporally 
associated with the use of an IMP, regardless of whether it is considered related to the IMP. 
Collection of AEs will start directly after the ICF has been signed. Only AEs related to study procedure 
will be collected between screening visit and the first IMP administration. 
A TEAE is any AE only present after the initiation of IMP administration or any event already present 
that worsens in either severity or frequency following exposure to the IMP and on or before 30 days after 
the date of last dose of study treatment. 
Where dates are missing or partially missing, adverse events will be assumed to be treatment-emergent, 
unless there is clear evidence (through comparison of partial dates) to suggest that the adverse event 
started prior to the first dose of study treatment or more than 30 days after the last dose of study treatment.   
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 
23.0 or higher for System Organ Class (SOC) and Preferred Term (PT). 
AEs are divided into defined severity grades (Grade 1: mild, Grade 2: moderate, Grade 3: severe, Grade 
4: life-threatening and Grade 5: death). 
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AEs are also divided into 3 different causal relationships (Probable, Possible and Unlikely). An AE is 
considered causally related to the use of the IMP when the causality assessment is probable or possible. 
 
The following summaries will be provided by treatment group and overall. 
• An overview table summarizing the number and percentage of patients with at least one of the 
following AEs together with the corresponding number of events for each of these AE 
categories listed below:  
- 
any AE, 
- 
any TEAE, 
- 
any severe TEAE,  
- 
any treatment related TEAE (ADR),  
- 
TEAE leading to discontinuation from the study,  
- 
Any Serious Adverse Event (SAE).  
- 
Any treatment emergent SAE,  
- 
Any treatment emergent adverse event of special interest (AESI) 
• 
A summary of the number and percentage of patients reporting a TEAE by SOC and PT, 
• 
A summary of the number and percentage of patients reporting a TEAE by PT by frequency 
of occurrence, 
• 
A summary of the number and percentage of patients reporting a TEAE by severity, SOC 
and PT, 
• 
A summary of the number and percentage of patients reporting a TEAE by causality to 
study treatment, SOC and PT, 
 
All adverse event summaries will provide the number of patients reporting at least one adverse event and 
the total number of events reported and will be ordered alphabetically for SOC and PT within SOC.  
In summary by frequency of occurrence, the preferred terms will be ordered according to the frequency 
of occurrence in the total column. 
 
AEs will be counted as follows: 
• 
In summaries of number of patients experiencing AEs, patients with more than one AE within a 
particular SOC are counted only once for that SOC.  Similarly, patients with more than one AE 
within a particular PT are counted only once for that PT. 
• 
In summaries of number of patients experiencing AEs, patients reporting a TEAE more than once 
within that SOC/ PT, but with different severities, the worst severity will be used in the 
corresponding severity summaries. 


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• 
In summaries of number of patients experiencing AEs, patients reporting a TEAE more than once 
within that SOC/ PT, but with different relationships, the worst relationship will be used in the 
corresponding relationship summaries. 
• 
If the severity is missing for a TEAE, it will be considered as missing in the summary tables. 
• 
If the causality is missing for a TEAE, it will be considered as missing in the summary tables. 
 
In addition, a listing with all AEs data will be listed by treatment including non-TEAEs. Treatment-
emergence status will be flagged in the listing.  
 
AE duration will be derived with the formula: 
AE duration = (AE end date - AE onset date + 1); in case of AE ongoing, the date of last contact with 
the patient will be used as AE end date for the scope of deriving the AE duration. 
 
A by-patient listing of all AEs (including non-treatment-emergent events: flagged) will be provided.  
These listings will be presented by treatment group and will include: patient identifier, age, sex, AE 
(SOC, PT, and verbatim term), date of onset, date of resolution or ongoing, duration, severity, NCI 
CTCAE toxicity grade, seriousness, causality to study treatment, causality to non-study treatment, action 
taken and outcome.  
 
4.11.2 Adverse Events of Special Interest (AESI) 
The following conditions should be considered AEs of special interest: 
a. ALT or AST ≥ 8 x ULN 
b. ALT or AST ≥ 5 x ULN for 2 or more weeks 
c. ALT or AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN (or ALT or AST ≥ 3 x ULN and INR > 
1.5) 
d. ALT or AST ≥ 3 x ULN accompanied by clinical symptoms believed to be related to hepatitis 
or hypersensitivity, such as new or worsening of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, or rash 
e. ALT or AST ≥ 5 x ULN but < 8 x ULN and cannot be monitored at least weekly for ≥ 2 week 
 
Hy’s Law, defined as ≥ 3 x ULN ALT or AST with coexisting ≥ 2 x ULN total bilirubin with no 
alternative explanation for the biochemical abnormality other than IMP (for example elevated ALP 
indicating cholestasis, viral hepatitis, other medication) must always be reported without delay as an 
AESI, and, if applicable, also as an SAE. 
 
All potential AESIs will be medically evaluated during the study, before the database lock and 
unblinding, by the sponsor to identify events which could possibly be AESIs.  
A list of PTs for AESIs will be provided for identification and AESIs will be flagged in the database. 


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The following summary and listing will be provided. 
• 
A summary of the number and percentage of patients reporting an AESIs by SOC and PT. 
• 
Listing of AESIs 
 
4.11.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
The following summaries will be provided by treatment group and overall. 
• 
A summary of the number and percentage of deaths (including SAEs with fatal outcome and deaths 
as PT), 
• 
A summary of the number and percentage of patients reporting a serious TEAE, by SOC and PT, 
• 
A summary of the number and percentage of patients with TEAEs leading to discontinuation of 
study treatment, by SOC and PT. 
 
The following listings will be provided: 
• 
A listing of all deaths that occurred during the study, 
• 
A listing of all SAEs, 
• 
A listing of all AEs leading to discontinuation of study treatment. 
 
4.11.4 Clinical Laboratory Evaluation 
The following laboratory parameters of hematology, blood chemistry, coagulation and urinalysis will be 
assessed at screening, Visit 3 (Day 7), Visit 5 (Days 28) and Visit 9 (EOS): 
Hematology: Hematocrit, Hemoglobin (Hb), Platelet count, Red blood cell (RBC) count and White blood 
cell (WBC) count with differential count. 
Blood chemistry: Alanine aminotransferase (ALAT), Alkaline phosphatase (ALP), Albumin, Aspartate 
aminotransferase (ASAT), Bilirubin (total and conjugated), Calcium, Chloride, Creatinine, Gamma-
glutamyl transferase (GGT), Magnesium, Phosphorous, Potassium, Sodium, Urea nitrogen, Uric acid 
and Gastrin. 
Coagulation: International Normalized Ratio. 
Urinalysis (dip stick): Glucose, Hemoglobin/erythrocytes, Nitrite, Protein, Specific gravity, pH and 
Ketones. 
Urine Drug Screen: Amphetamine, Barbiturate, Cannabinoid, Cocaïne, Benzodiazepine and Opiate. 
Serum Gastrin 
Laboratory test results for hematology, chemistry, and coagulation parameters will be classified as 
normal or abnormal (high or low) according to the applicable laboratory’s normal ranges.  


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For by-visit summaries, the last non-missing assessment (including repeat assessments) recorded at each 
visit will be summarized. Baseline is defined as the last assessment prior to study drug intake and will 
be the screening assessment. 
 
The following summaries will be based on the Safety Analysis Set. 
Summaries for actual values and change from baseline will be presented by treatment group and 
assessment day for each study site separately (due to assays performed locally). Summaries for 
categorical values of normality/abnormality will be presented by treatment group and assessment day. 
 
• Hematology and coagulation: laboratory test value and change from baseline by visit 
• Hematology and coagulation: laboratory test value and change from baseline by visit in patients with 
LA grade A/B 
• Hematology and coagulation: laboratory test value and change from baseline by visit in patients with 
LA grade C/D 
• Hematology and coagulation: number and percentage of patients experiencing low, normal or high 
laboratory test result 
• Hematology and coagulation: number and percentage of patients experiencing low, normal or high 
laboratory test result in patients with LA grade A/B 
• Hematology and coagulation: number and percentage of patients experiencing low, normal or high 
laboratory test result in patients with LA grade C/D 
• Chemistry: laboratory test value and change from baseline by visit 
• Chemistry: laboratory test value and change from baseline by visit in patients with LA grade A/B 
• Chemistry: laboratory test value and change from baseline by visit in patients with LA grade C/D 
• Chemistry: number and percentage of patients experiencing low, normal or high laboratory test result 
• Chemistry: number and percentage of patients experiencing low, normal or high laboratory test result 
in patients with LA grade A/B 
• Chemistry: number and percentage of patients experiencing low, normal or high laboratory test result 
in patients with LA grade C/D 
• Urinalysis: laboratory test category (normal, abnormal not clinically significant or abnormal clinically 
significant) and toxicity grade by visit 
• Urinalysis: laboratory test category (normal, abnormal not clinically significant or abnormal clinically 
significant) and toxicity grade by visit in patients with LA grade A/B 
• Urinalysis: laboratory test category (normal, abnormal not clinically significant or abnormal clinically 
significant) and toxicity grade by visit in patients with LA grade C/D 
• Serum Gastrin: laboratory test value and change from baseline by visit 


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• Serum Gastrin: laboratory test value and change from baseline by visit in patients with LA grade A/B 
• Serum Gastrin: laboratory test value and change from baseline by visit in patients with LA grade C/D 
 
Laboratory values (hematology, chemistry, coagulation and urinalysis) will be listed by patient and study 
time point including changes from baseline (with the exception of urinalysis).  
All values outside the clinical reference ranges will be flagged in the data listings. The abnormal values 
will be flagged with ‘L’ for values below the lower limit of the clinical reference range and ‘H’ for values 
above the upper limit of the clinical reference range and included in the listings.  
 
The following listings of laboratory parameters will be provided: 
• Hematology and coagulation parameters  
• Chemistry parameters  
• Urinalysis  
 
4.11.5 Vital Signs 
The following vital signs measurements will be assessed at screening, Visit 3 (Day 7), Visit 5 (Days 28) 
and Visit 9 (EOS): 
• Systolic blood pressure (SBP) [mmHg]. 
• Diastolic blood pressure (DBP) [mmHg]. 
• Heart rate (bpm). 
• Body temperature (oral) [°C]. 
• Respiratory rate (breaths/per minute) 
 
Systolic blood pressure, diastolic blood pressure and heart rate will be classified as normal or abnormal  
 
For by-visit summaries, the last non-missing assessment (including repeat assessments) recorded at each 
visit will be summarized. Baseline is defined as the last assessment prior to study drug intake and will 
be the screening assessment. 
 
The following summaries will be based on the Safety Analysis Set and provided by study treatment group 
and assessment day: 
• A summary of vital signs and change from baseline  
• Vital signs: number and percentage of patients with normal or abnormal values 


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A listing of vital signs results will be provided. 
 
4.11.6 Resting 12-lead Electrocardiograms 
 
Single 12-lead ECG will be recorded at screening, Visit 3 (Day 7), Visit 5 (Days 28) and Visit 9 (EOS) 
and the following parameters will be obtained: 
• Heart rate (bpm) 
• PR interval 
• QRS complex (msec) 
• QT interval (msec) 
• QTcF interval (msec) 
• PR segment 
• ST segment 
 
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, non-clinically significant (NCS)’ 
or ‘Abnormal, clinically significant (CS)’. 
 
Baseline is defined as the last assessment prior to study drug intake and will be the screening assessment. 
 
The following summaries will be based on the Safety Analysis Set and provided by study treatment group 
and assessment day: 
• A summary of 12-lead ECG and change from baseline  
• 12-lead ECG: number and percentage of patients with normal, abnormal NCS and abnormal CS values 
 
A listing of 12-lead ECG results will be provided. 
 
4.11.7 Physical examination 
A complete physical examination will be performed at screening, Visit 5 (Days 28) and Visit 9 (EOS) 
and will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, 
cardiovascular system, abdomen (including liver and spleen), lymph nodes, genitourinary system 
(optional) and extremities (musculoskeletal system). 


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The following summaries will be based on the Safety Analysis Set and provided by study treatment group 
and assessment day: 
• Physical examination: number and percentage of patients with abnormal findings by physical site 
 
A listing of physical examination will be provided. 
 
4.11.8 Weight and BMI 
Weight will be measured at screening, Visit 5 (Days 28) and Visit 9 (EOS). 
 
Body mass index (BMI) will be calculated from the height in meter and weight in kg recorded and 
rounded off to the nearest whole number. 
BMI = [weight/height2] (kg/m2). 
 
Baseline is defined as the last assessment prior to study drug intake and will be the screening assessment. 
Absolute and relative change from baseline will be calculated as follows: 
• Absolute change at Visit x= weight at Visit x – weight at baseline 
• Relative change at Visit x= (weight at Visit x – weight at baseline) / weight at baseline 
 
The following summaries will be based on the Safety Analysis Set and provided by study treatment group 
and assessment day: 
• A summary of Weight with absolute and relative change from baseline  
• A summary of BMI with absolute and relative change from baseline  
 
Weight and BMI will be listed together with vital signs. 
 
4.11.9 Safety Monitoring (Independent Data Monitoring Committee [IDMC], Data Monitoring 
Committee [DMC], Data and Safety Monitoring Board [DSMB])  
Not applicable 
 
4.12 Determination of Sample Size 
 
 
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4.13 Changes in the Conduct of the Study or Planned Analysis 
Protocol amendments don’t have statistical implication. 
Results of upper endoscopy from investigator or endoscopy specialist will not be simply overridden by 
central reading. The records will be kept and described (LA grade and healing response) and the 
concordance with central reading will be investigated. 
Descriptive table of the investigator or endoscopy specialist’s results will be prepared, as well as a 
concordance table of the investigator or endoscopy specialist and central reading results. 
 
 
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1 6 4 6- 1 6 6 1. 
[ 4] R C ore Tea m ( 2 0 2 1). R: A la n g ua ge a n d e n vir o n me nt f or statistical c o m p uti n g. R F o u n dati o n f or 
Statistical C o m p uti n g, Vie n na, A ustria. U R L htt ps:// w w w. R - pr oject. or g/. 
[ 5]  Pi n heir o,  J.  C.,  B or n ka m p,  B.,  a n d  Bretz,  F.  ( 2 0 0 6).  Desi g n  a n d  a nal ysis  of  d ose  fi n di n g  st u dies 
c o m bi ni n g m ulti ple c o m paris o ns a n d m o deli n g pr oce d ures, J o ur n al of Bi o p har mace utical Statistics, 1 6, 
6 3 9 – 6 5 6 
 


Parexel International 
Cinclus Pharma AG 
Protocol #CX842A2201 
Statistical Analysis Plan 
TP-GDO-WW-133-02 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: <Date of last signature> 
Related to:  SOP-GDO-WW-019 
Page 47 of 51 
6 
APPENDICES 
6.1 
Schedule of Assessments 
Table 1 
Overall Schedule of Assessments 
Visit 
 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Tel 
Visit 
6  
Tel  
Visit 
7 
Tel  
Visit 
8 
Visit 9 
End of 
Study / 
Early 
Termination 
Assessment/Study 
day 
Day -714 to Day 0 
Day 0 
Day 7 
±2 days 
Day 14 
±3 days 
Day 28 
-2/+5 days 
Day 
35 
±3 
days 
Day 
42 
±3 
days 
Day 
49 
±3 
days 
Day 56 
±3 days 
Assessment/Study 
week 
 
Randomization 
Week 1 
Week 2 
Week 4 
Week 
5 
Week 
6 
Week 
7 
Week 8 
 
Screening Period 
Blinded Treatment Phase 
Open-Label Phase 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
Medical/surgical 
history 1  
X 
 
 
 
 
 
 
 
 
Weight, height 2 
X 
 
 
 
X 
 
 
 
X 
Complete physical 
examination 
X 
 
 
 
X 
 
 
 
X 
Drugs of abuse 
X 
 
 
 
 
 
 
 
X 


Parexel International 
Cinclus Pharma AG 
Protocol #CX842A2201 
Statistical Analysis Plan 
TP-GDO-WW-133-02 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: <Date of last signature> 
Related to:  SOP-GDO-WW-019 
Page 48 of 51 
Visit 
 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Tel 
Visit 
6  
Tel  
Visit 
7 
Tel  
Visit 
8 
Visit 9 
End of 
Study / 
Early 
Termination 
Assessment/Study 
day 
Day -714 to Day 0 
Day 0 
Day 7 
±2 days 
Day 14 
±3 days 
Day 28 
-2/+5 days 
Day 
35 
±3 
days 
Day 
42 
±3 
days 
Day 
49 
±3 
days 
Day 56 
±3 days 
Assessment/Study 
week 
 
Randomization 
Week 1 
Week 2 
Week 4 
Week 
5 
Week 
6 
Week 
7 
Week 8 
 
Screening Period 
Blinded Treatment Phase 
Open-Label Phase 
Viral serology 
testing 3 
X 
 
 
 
 
 
 
 
 
Vital signs 4 
X 
 
X 
 
X 
 
 
 
X 
12-lead ECG 
evaluation 
X 
 
X 
 
X 
 
 
 
X 
Safety laboratory 5 
X 
 
X 
 
X 
 
 
 
X 
H. pylori testing 6 
X 
 
 
 
 
 
 
 
 
Pregnancy test 7 
X 
 
 
 
X 
 
 
 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
Patients provided 
with study drugs for 
blinded phase 
 
X 
X 
X 
 
 
 
 
 


Parexel International 
Cinclus Pharma AG 
Protocol #CX842A2201 
Statistical Analysis Plan 
TP-GDO-WW-133-02 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: <Date of last signature> 
Related to:  SOP-GDO-WW-019 
Page 49 of 51 
Visit 
 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Tel 
Visit 
6  
Tel  
Visit 
7 
Tel  
Visit 
8 
Visit 9 
End of 
Study / 
Early 
Termination 
Assessment/Study 
day 
Day -714 to Day 0 
Day 0 
Day 7 
±2 days 
Day 14 
±3 days 
Day 28 
-2/+5 days 
Day 
35 
±3 
days 
Day 
42 
±3 
days 
Day 
49 
±3 
days 
Day 56 
±3 days 
Assessment/Study 
week 
 
Randomization 
Week 1 
Week 2 
Week 4 
Week 
5 
Week 
6 
Week 
7 
Week 8 
 
Screening Period 
Blinded Treatment Phase 
Open-Label Phase 
Patients provided 
with Lansoprazole 
30 mg for open-label 
phase 
 
 
 
 
X 
 
 
 
 
PK blood sampling 8 
 
 
X 
X 
X 
 
 
 
 
Upper endoscopy 
X15 
 
 
 
X 
 
 
 
 
Symptom evaluation 
using QOLRAD 
Heartburn 9 
 
X 
X 
X 
X 
 
 
 
X 
Daily symptom diary 
(mRESQ-eD) 
completion by 
patient 
 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom diary 
provision/training/ 
review10  
 
X 
X 
X 
X 
X 
X 
X 
X 


Parexel International 
Cinclus Pharma AG 
Protocol #CX842A2201 
Statistical Analysis Plan 
TP-GDO-WW-133-02 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: <Date of last signature> 
Related to:  SOP-GDO-WW-019 
Page 50 of 51 
Visit 
 
Visit 1 
Screening 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Tel 
Visit 
6  
Tel  
Visit 
7 
Tel  
Visit 
8 
Visit 9 
End of 
Study / 
Early 
Termination 
Assessment/Study 
day 
Day -714 to Day 0 
Day 0 
Day 7 
±2 days 
Day 14 
±3 days 
Day 28 
-2/+5 days 
Day 
35 
±3 
days 
Day 
42 
±3 
days 
Day 
49 
±3 
days 
Day 56 
±3 days 
Assessment/Study 
week 
 
Randomization 
Week 1 
Week 2 
Week 4 
Week 
5 
Week 
6 
Week 
7 
Week 8 
 
Screening Period 
Blinded Treatment Phase 
Open-Label Phase 
Symptom assessment 
by Investigator 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE reporting 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medications 13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE, adverse event; ECG, electrocardiogram; ICF, informed consent form; LA, Los Angeles; PK, pharmacokinetic. 
1. Including smoking (current status), alcohol consumption, and intake of drug of abuse. 
2. Height only at screening 
3. Human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis B core antigen (anti-HBcAg), antibody to hepatitis C 
virus (anti-HCV) testing at central and/or local laboratory. Patient should discontinue the study if result from central laboratory is positive. 
4. Systolic and diastolic blood pressure (BP) [mmHg], heart rate [beats per minute], body temperature and respiratory rate [per minute].  
5. Hematology, blood chemistry, coagulation (central laboratory), urinalysis (at site). Serum gastrin at screening and at Visit 5 (central laboratory). 
6. H. pylori will be analyzed in central laboratory from serum and the result will not be needed for randomization. 
7. Women of childbearing potential only. Serum pregnancy test at central laboratory at screening and urine pregnancy test at clinic/investigational 
site prior to the dose administration at Visit 5, and at End of Study / Early Termination.  


Parexel International 
Cinclus Pharma AG 
Protocol #CX842A2201 
Statistical Analysis Plan 
TP-GDO-WW-133-02 
CONFIDENTIAL 
Project Document Version No. 1.0 
Effective Date:  26 Nov 19 
Project Document Effective Date: <Date of last signature> 
Related to:  SOP-GDO-WW-019 
Page 51 of 51 
8. PK measured in all patients just before the first and the second dose on the day of the visit. At all PK sampling occasions, the time since latest 
study drug administration must be noted in the case report form (CRF). Pharmacokinetic samples will be collected 12 hours after the previous 
study drug dose administration or as close to this timepoint as possible, however, still pre-dose. 
9. QOLRAD assessment must be done pre-dose. QOLRAD will be completed by patients during site visits at Visit 2, 3, 4, 5 and 9. 
10. Patients will be trained on how to complete the symptoms diary during Visit 2 and the actual diary will be provided at Visit 2. 
11. At each visit, Investigator should assess the severity of patients’ heartburn, regurgitation and dysphagia in the 7 days prior to the visit. The 
assessment will include both the severity grade and the frequency of symptoms. Symptoms are scored as follows: none (no complaints), mild 
(aware of symptom, but easily tolerated), moderate (discomforting symptom, sufficient to cause interference with normal daily activities and/or 
sleep), severe (incapacitating symptom, with inability to perform normal daily activities and/or sleep) 
12. Collection of AEs will start directly after the informed consent form (ICF) has been signed. During the screening period, only AEs related to 
study procedure will be reported. 
13. For definitions of prior and concomitant medication, see Section 8.1.6 of protocol. 
14. For the screening only, 7 days are counted as 7 working days and not calendar days. Non-working days are weekend (Saturday, Sunday) and 
any country specific public holiday. 
15. Endoscopy video/digital image taken prior to ICF signature can be used as index endoscopy for the enrollment, if taken within 7 days of the 
planned treatment day. For patients invited for screening upper endoscopy based on their past medical history (see Section 5 of protocol), the 
ICF will be signed prior to the endoscopy. The screening procedures must start with endoscopy and in case the patient doesn’t show LA grade 
C or D erosions, the rest of the screening procedures must not be conducted. This screening endoscopy must be obtained within 7 working days 
of planned randomization. 
 
 
 
 


Approval Signatures
Document Name:
Statistical Analysis Plan 14 Oct 2022 CX842A2201
Document Number:
Parexel Version Number:
System Version Number:
1
. 0
Document Approvals
Reason for signing: Approved
Name: 
Role: 
Date of signature: 13-Oct-2022 17:52:04 GMT+0000
Reason for signing: Approved
Name: 
Role: Sponsor
Date of signature: 14-Oct-2022 11:30:12 GMT+0000
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Parexel International
Statistical Analysis Modification Requests
Parexel Project 
Number: 249403
This document has been signed electronically on the final pages by the following:
Project Role: 
Sponsor Project 
Number: #CX842A2201
Sponsor Name: Cinclus
Date of Unblinding: 19 
October 2022
Signatory
Author:
TP-GDO-WW-170-01
Effective date: 22 Dec 21
Related to:  SOP-GDO-WW-019
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PPD
PPD


Parexel International
Statistical Analysis Modification Requests
Parexel Project 
Number: 249403
This document has been signed electronically on the final pages by the following:
Project Role: 
Sponsor Project 
Number: #CX842A2201
Sponsor Name: Cinclus
Date of Unblinding: 19 
October 2022
Signatory
Author:
TP-GDO-WW-170-01
Effective date: 22 Dec 21
Related to:  SOP-GDO-WW-019
Page 1 of 1
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