An Open Label, Parallel Group, Multi-centre, Phase III Study to Assess the Efficacy and Safety of D961H for the Maintenance Therapy Following Initial Treatment in Japanese Paediatric Patients With Reflux Esophagitis and for the Prevention of Recurrence of Gastric Ulcer or Duodenal Ulcer in Japanese Paediatric Patients Treated With Non-steroidal Anti-inflammatory Drugs or Low-dose Aspirin
Phase: PHASE3
Conditions: Reflux Esophagitis, Gastric Ulcer, Duodenal Ulcer
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance
D961H
Study Code
D961WC00001
Version
Date
6-Sep-2022
An Open Label, Parallel Group, Multi-centre, Phase III Study to Assess the 
Efficacy and Safety of D961H for the Maintenance Therapy Following Initial 
Treatment in Japanese Paediatric Patients with Reflux Esophagitis and for the 
Prevention of Recurrence of Gastric Ulcer or Duodenal Ulcer in Japanese 
Paediatric Patients Treated with Non-steroidal Anti-inflammatory Drugs or 
Low-dose Aspirin
Sponsor:
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan

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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
VERSION HISTORY ..........................................................................................2
TABLE OF CONTENTS .....................................................................................4
1.
PROTOCOL SUMMARY ...................................................................................8
1.1
Schedule of Activities (SoA)................................................................................8
1.2
Synopsis.............................................................................................................15
1.3
Schema ..............................................................................................................22
2.
INTRODUCTION .............................................................................................22
2.1
Study rationale ...................................................................................................22
2.2
Background........................................................................................................23
2.3
Benefit/risk assessment ......................................................................................24
3.
OBJECTIVES AND ENDPOINTS ....................................................................24
4.
STUDY DESIGN...............................................................................................27
4.1
Overall design....................................................................................................27
4.2
Scientific rationale for study design....................................................................28
4.3
Justification for dose ..........................................................................................29
4.4
End of study definition.......................................................................................30
5.
STUDY POPULATION.....................................................................................30
5.1
Inclusion criteria ................................................................................................30
5.2
Exclusion criteria ...............................................................................................31
5.3
Lifestyle restrictions...........................................................................................33
5.4
Screen failures....................................................................................................34
6.
STUDY TREATMENTS ...................................................................................34
6.1
Treatments administered ....................................................................................35
6.1.1
Investigational products .....................................................................................35
6.2
Preparation/handling/storage/accountability .......................................................36
6.3
Measures to minimise bias: randomisation and blinding .....................................36
6.4
Treatment compliance ........................................................................................37
6.5
Concomitant therapy..........................................................................................37
6.5.1
Other concomitant therapy .................................................................................38
6.6
Dose modification..............................................................................................38
6.7
Treatment after the end of the study ...................................................................39

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7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL...39
7.1
Discontinuation of study treatment.....................................................................39
7.1.1
Procedures for discontinuation of a subject from investigational product............39
7.2
Lost to follow-up................................................................................................40
7.3
Withdrawal from the study.................................................................................40
8.
STUDY ASSESSMENTS AND PROCEDURES...............................................41
8.1
Efficacy assessments..........................................................................................46
8.1.1
Evaluation of efficacy composite endpoints........................................................46
8.1.2
Gastrointestinal symptom assessments ...............................................................47
8.1.3
EGD...................................................................................................................48
8.2
Safety assessments .............................................................................................50
8.2.1
Clinical safety laboratory assessments................................................................50
8.2.2
Physical examination..........................................................................................52
8.2.3
Vital signs..........................................................................................................52
8.3
Collection of AEs...............................................................................................52
8.3.1
Method of detecting AEs and SAEs....................................................................53
8.3.2
Time period and frequency for collecting AE and SAE information ...................53
8.3.3
Follow-up of AEs and SAEs...............................................................................53
8.3.4
AE data collection..............................................................................................53
8.3.5
Causality collection............................................................................................54
8.3.6
AEs based on signs and symptoms .....................................................................54
8.3.7
AEs based on examinations and tests..................................................................55
8.3.8
Hy’s law.............................................................................................................55
8.3.9
Disease under study............................................................................................55
8.4
Safety reporting and medical management .........................................................56
8.4.1
Reporting of SAEs .............................................................................................56
8.4.2
Pregnancy ..........................................................................................................56
8.4.2.1
Maternal exposure..............................................................................................56
8.4.2.2
Paternal exposure ...............................................................................................57
8.4.3
Overdose............................................................................................................57
8.4.4
Medication Error................................................................................................58
8.5
Pharmacokinetics ...............................................................................................58
8.6
Pharmacodynamics ............................................................................................58
8.7
Genetics .............................................................................................................59
8.7.1
Collection of mandatory genetic samples............................................................59
8.7.2
Optional exploratory genetic sample ..................................................................60
8.7.3
Storage and destruction of genetic samples.........................................................60
8.8
Biomarkers.........................................................................................................61
8.9
Health economics...............................................................................................61
9.
STATISTICAL CONSIDERATIONS................................................................61

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9.1
Statistical hypotheses .........................................................................................61
9.2
Sample size determination..................................................................................61
9.3
Populations for analyses.....................................................................................62
9.4
Statistical analyses .............................................................................................63
9.4.1
Efficacy analyses................................................................................................64
9.4.2
Safety analyses...................................................................................................65
9.4.3
Pharmacodynamic analyses................................................................................66
9.5
Interim analyses .................................................................................................66
10.
REFERENCES ..................................................................................................67
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .........................................................................................68
LIST OF TABLES
Table 1
Schedule of Activities (SoA) in maintenance therapy for healed 
reflux esophagitis (RE) (Groups 1 and 2).................................................9
Table 2
Schedule of Activities (SoA) for prevention of gastric ulcer (GU) or 
duodenal ulcer (DU) recurrence associated with long term non-
steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin 
(LDA) Therapy (Groups 3 and 4) ..........................................................12
Table 3
Study objectives ....................................................................................25
Table 4
Study treatments....................................................................................36
Table 5
Prohibited medications..........................................................................38
Table 6
LA classification ...................................................................................49
Table 7
Modified LANZA score ........................................................................50
Table 8
The items of laboratory safety ...............................................................51
Table 9
Volume of blood to be drawn from each subject....................................52
LIST OF FIGURES
Figure 1
Study design..........................................................................................22
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations ..........................68

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Appendix B
AE definitions and additional safety information...................................72
Appendix C
Handling of Human Biological Samples................................................76
Appendix D
Genetics ................................................................................................78
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law .........................................................................79
Appendix F
Abbreviations........................................................................................85

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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)

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Table 1
Schedule of Activities (SoA) in maintenance therapy for healed reflux esophagitis (RE) (Groups 1 and 2)
Informed consent ~ 
Registration
Initial healing therapy 
period
Maintenance therapy period
Maintenance therapy extended 
period
Activity
Enrolment
Start of 
initial 
healing 
therapy
Site visits
Start of 
maintenance 
therapy
Site visits
Study 
closure 11)
Site visit 
extended2)
Study
closure 23)
Visit number
1
2
3
4
5, 6, 7, 8, and 
9
10
11, 12, 13 
and 14
15
Week
-4 ~ -1
0
4
8
12, 16, 20, 
24, and 28
32
36, 40, 44, 
and 48
52
Day (allowance)
-28 ~ -1
1
29
(±7)
57
(±7)
85, 113, 141, 
169, and 197
(±7)
225
(±7)
253, 281, 
309, and 337
(±7)
365
(±7)
Informed consent/assent4)
X
Registration to initial healing therapy
X5)
Registration to maintenance therapy
X6)
Review inclusion/exclusion criteria
X
X
X7)
Demographic data
X
Medical/surgical history
X
Physical examination
X
X
X
X
X
X
X
Vital signs8)
X
X
X
X
X
X
X
Clinical laboratory tests9)
X
X
X
X
Urine pregnancy test10)
X
H. pylori test (IgG antibody)
X
Genetic test for CYP2C1911)
X
EGD12)
X13)
(X)
(X)
(X)
Gastroesophageal 12-hour pH 
monitoring (optional)
(X) 14)

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Informed consent ~ 
Registration
Initial healing therapy 
period
Maintenance therapy period
Maintenance therapy extended 
period
Activity
Enrolment
Start of 
initial 
healing 
therapy
Site visits
Start of 
maintenance 
therapy
Site visits
Study 
closure 11)
Site visit 
extended2)
Study
closure 23)
Visit number
1
2
3
4
5, 6, 7, 8, and 
9
10
11, 12, 13 
and 14
15
Week
-4 ~ -1
0
4
8
12, 16, 20, 
24, and 28
32
36, 40, 44, 
and 48
52
Day (allowance)
-28 ~ -1
1
29
(±7)
57
(±7)
85, 113, 141, 
169, and 197
(±7)
225
(±7)
253, 281, 
309, and 337
(±7)
365
(±7)
RE-related symptoms assessed by 
investigator15) 
X
X
X
X
X
X
X
Dispense investigational product16)
X
X
X
X
X
X
Administration of the investigational 
product17)
Check concomitant medication
Efficacy primary endpoint
AEs and SAEs18)
1)
Study closure visit for first period (to Week 32). Subjects who early discontinued the investigational product and/or withdrawn consent during first period (to Week 32) will
be performed the activities described in Visit 10, if possible.
2)
Site visits for subjects that extend treatment (after Week 32)
3)
Study closure visit for extended period (after Week 32). Subjects who early discontinued the investigational product and/or withdrawn consent during extended therapy (after 
Week 32) will be performed the activities described in Visit 15, if possible.
4)
The signed and dated informed consent form (ICF) should be obtained from the patient’s guardian (including informed consent to a genetic test) prior to conducting of any 
study related procedure. Assent form will be signed by the patient as much as possible.
5)
Perform registration whether the initial treatment is started or not; if an enrolled subject is not started initial treatment, this will be noted in the electronic case report form 
(eCRF). 
6)
Perform registration whether the maintenance therapy is started or not; if an enrolled subject is not started maintenance therapy, this will be noted in the eCRF.
7)
Subjects who completed the healing therapy for 8 weeks at Visit 4 do not have any reflux esophagitis (RE)-related symptoms (none or not more than mild symptoms) on the 
RE-related symptom questionnaire, and if esophagogastroduodenoscopy (EGD) is done, no visible esophageal mucosal breaks, will continue into the maintenance phase.
8)
Blood pressure, pulse rate and body temperature will be measured.
9)
See Section 8.2.1.

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10)
A urine pregnancy test will be required for all post-menarcheal female patients, and the result must be negative at registration to the initial healing therapy. This test will be 
performed at each study site. 
11)
If the genotyping of CYP2C19 data are already available at each study site, it may be used with the consent of subject’s guardian. According to the subject's body weight, it 
is possible to do it at Visit 3 or after for the purpose of reducing blood collection volume of Visit 2.
12)
EGD should be conducted once at Visit 1. Post assessments are optional and allowed to perform anytime, and encouraged when RE relapse is suspected.
13)
The EGD data within 4 weeks before the start of initial treatment could be used if available and given the consent of subject’s guardian.
14)
Optional evaluation. The pH monitoring is preferably done at Week 32, but is also suggested if signs of RE relapse either before (Week 8 to 32) or after (Week 32 to 52) this 
time point.
15)
The RE-related symptom questionnaire will be provided at Visit 2 and following every visit to the subject. The subject and/or guardian will recall 1 week to date 
gastrointestinal symptoms and record them in the card. The card will be reviewed and collected by the investigator. The investigator will evaluate RE relapse every visit 
during the maintenance therapy.
16)
Administration of the investigational product should be started on Day 1. Following administrations should be after breakfast. The subjects assigned to Group 1 will be 
treated with D961H 10 mg in the RE initial healing therapy and maintenance therapy, respectively. The subjects assigned to Group 2 will be treated with D961H 20 mg in the 
RE initial healing therapy, and treated with D961H 10 mg for the RE maintenance therapy. The dose may be increased to 20 mg at any visit during the RE maintenance 
therapy based on investigator’s discretion. Dosing down back to 10 mg will not be allowed. The treatment period in both groups will be at least 32 weeks, and may be 
extended up to 52 weeks by investigator’s discretion. The reason for the extension/no extension will be recorded in the eCRF.
17)
When the subjects who assigned to Group 1 reach 20 kg after the start of investigational product administration in the maintenance therapy period, their treatment dose may
be reconsidered as that of the treatment regimen for Group 2. 
18)
Adverse events (AEs) will be recorded from Visit 2. Serious adverse events (SAEs) will be recorded from the time of informed consent (Visit 1). 

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Table 2
Schedule of Activities (SoA) for prevention of gastric ulcer (GU) or duodenal ulcer (DU) recurrence 
associated with long term non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA)
Therapy (Groups 3 and 4)
Informed consent ~ 
Registration
Prevention therapy period
Prevention therapy extended period
Activity
Enrolment
Start of 
treatment17)
Site visits
Study closure
11)
Site visit 
extended2)
Study closure
23)
Visit number
1
2
3, 4, 5, 6, 7, 8,
and 9
10
11, 12, 13 and 14
15
Week
- 4 ~ -1
0
4, 8, 12, 16, 
20, 24, and 28
32
36, 40, 44, and 
48
52
Day (allowance)
-28 ~ 0
1
29, 57, 85, 113, 
141, 169, and 
197
(±7)
225
(±7)
253, 281, 309,
and 337
(±7)
365
(±7)
Informed consent/assent4)
X
Registration to prevention therapy
X5)
Review inclusion/exclusion criteria
X
X
Demographic data
X
Medical/surgical history
X6)
Physical examination
X
X
X
X
X
Vital signs7)
X
X
X
X
X
Clinical laboratory tests8)
X
X
X
Urine pregnancy test9)
X
H. pylori test (IgG antibody)
X
Genetic test for CYP2C1910)
X
EGD11)
(X)
(X)
Gastroesophageal 12-hour pH monitoring 
(optional)
(X) 12)

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Informed consent ~ 
Registration
Prevention therapy period
Prevention therapy extended period
Activity
Enrolment
Start of 
treatment17)
Site visits
Study closure
11)
Site visit 
extended2)
Study closure
23)
Visit number
1
2
3, 4, 5, 6, 7, 8,
and 9
10
11, 12, 13 and 14
15
Week
- 4 ~ -1
0
4, 8, 12, 16, 
20, 24, and 28
32
36, 40, 44, and 
48
52
Day (allowance)
-28 ~ 0
1
29, 57, 85, 113, 
141, 169, and 
197
(±7)
225
(±7)
253, 281, 309,
and 337
(±7)
365
(±7)
GU/DU-related symptoms assessed by the 
investigator13)
X
X
X
X
X
Dispense investigational product14)
X
X
X
X
Administration of the investigational product15)
Check concomitant medication
Efficacy primary endpoint
AEs and SAEs16)
1)
Study closure visit for first period (to Week 32). Subjects who early discontinued the investigational product and/or withdrawn consent during first period (to Week 32) will
be performed the activities described in Visit 10, if possible.
2)
Site visits for subjects that extend treatment (after Week 32)
3)
Study closure visit for extended period (after Week 32). Subjects who early discontinued the investigational product and/or withdrawn consent during extended therapy (after 
Week 32) will be performed the activities described in Visit 15, if possible.
4)
The signed and dated ICF should be obtained from the patient’s guardian (including informed consent to a genetic test) prior to conducting of any study related procedure. 
Assent form will be signed by the patient as much as possible.
5)
Perform registration whether the prevention therapy is started or not; if an enrolled subject is not started prevention therapy, this will be noted in the eCRF.
6)
At Visit 2, the investigator will document the symptoms and/or signs which are considered past gastric ulcer (GU) or duodenal ulcer (DU) in the medical record.  
7)
Blood pressure, pulse rate and body temperature will be measured.
8)
See Section 8.2.1.
9)
A urine pregnancy test will be required for all post-menarcheal female patients, and the result must be negative at registration to the prevention therapy. This test will be 
performed at each study site.
10)
If the genotyping of CYP2C19 data are already available at each study site, it may be used with the consent of subject’s guardian. According to the subject's body weight, it 
is possible to do it at Visit 3 or after for the purpose of reducing blood collection volume of Visit 2.
11)
EGD (optional) should be conducted once at Visit 10 or Visit 15. Also, allowed to perform any time when GU/DU recurrence is suspected, for instance.
12)
Optional evaluation. The pH measurement is preferably done at Week 32, but is also suggested if signs of GU/DU recurrence either before (Week 0 to 32) or after (Week 32 
to 52) this time point.

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13)
The GU/DU-related symptom questionnaire will be provided at Visit 2 and following every visit to the subject. The subject and/or guardian will recall 1 week to date 
gastrointestinal symptoms and record them in the card. The card will be reviewed and collected by the investigator. The investigator will evaluate GU/DU recurrence every 
visit during treatment.
14)
Administration of the investigational product should be started on Day 1. Following administration should be after breakfast. The subjects assigned to Group 3 will be treated 
with D961H 10 mg throughout the treatment period. The subjects assigned to Group 4 will be treated with D961H 10 mg as a starter, and the dose may be increased to 20 mg 
at any visit based on investigator’s discretion. Dosing down back to 10 mg will not be allowed. The treatment period in both groups will be at least 32 weeks, and may be 
extended up to 52 weeks by investigator’s discretion. The reason for the extension/no extension will be recorded in the eCRF.
15)
When the subjects who assigned to Group 3 reach 20 kg after the start of investigational product administration in the prevention therapy period, their treatment dose may be 
reconsidered as that of the treatment regimen for Group 4. 
16)
AEs will be recorded from Visit 2. SAEs will be recorded from the time of informed consent (Visit 1).
17)
Start of treatment (Visit 2) can be performed on the same day as informed consent (Visit 1).

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1.2
Synopsis
Co-ordinating investigator or principal investigators
The details of co-ordinating investigator or principal investigators refer to the Addendum A.
Protocol Title: 
An Open Label, Parallel Group, Multi-centre, Phase III Study to Assess the Efficacy and Safety 
of D961H for the Maintenance Therapy Following Initial Treatment in Japanese Paediatric 
Patients with Reflux Esophagitis and for the Prevention of Recurrence of Gastric Ulcer or 
Duodenal Ulcer in Japanese Paediatric Patients Treated with Non-steroidal Anti-inflammatory 
Drugs or Low-dose Aspirin
Rationale: 
D961H is considered a medical need, not only in adults but also, in children for:
!
Maintenance therapy after the initial reflux esophagitis (RE) healing therapy 
!
Prevention of gastric ulcer (GU) or duodenal ulcer (DU) recurrence in children treated 
with non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA)
It is considered appropriate to evaluate the safety, tolerability and efficacy of treatment for 32 or 
52 weeks with once-daily oral administration of D961H for both the maintenance of RE healing 
and for the prevention of GU/DU recurrence when treated with NSAIDs or LDA in Japanese 
paediatric patients.

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Study Objectives:
Primary Objectives:
Outcome Measures:
Maintenance therapy for healed RE study part:
!
To assess the efficacy and safety of once-
daily oral administration of D961H for the 
maintenance of RE healing in Japanese 
paediatric patients aged 1 to 14 years that 
have symptomatically healed RE (defined as 
no more than mild RE-related symptoms) and 
if esophagogastroduodenoscopy (EGD) is 
done, no visible mucosal breaks observed.
Maintenance therapy for healed RE study part:
!
Presence/absence of RE relapse from 8 to 
32 weeks for all subjects by assessment of 
the composite endpoint (RE-related 
symptoms or optional EGD findings) during 
the maintenance therapy. 
!
Safety from 8 to 32 weeks for all subjects by 
the assessment of;
a) Adverse events (AEs)
b) Laboratory variables
c) Vital signs
Prevention of GU/DU recurrence associated with 
long term NSAIDs/LDA therapy study part:
!
To assess the efficacy and safety of once-
daily oral administration of D961H for the 
prevention of GU/DU recurrence in Japanese 
paediatric patients aged 1 to 14 years treated 
with long term NSAIDs/LDA therapy.
Prevention of GU/DU recurrence associated with 
long term NSAIDs/LDA therapy study part:
!
Presence/absence of GU/DU recurrence from 
0 to 32 weeks for all subjects by assessment 
of the composite endpoint (GU/DU-related 
symptoms or optional EGD findings) during 
the prevention therapy.
!
Safety from 0 to 32 weeks for all subjects by 
the assessment of;
a) AEs
b) Laboratory variables
c) Vital signs

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Secondary Objectives:
Outcome Measures:
Maintenance therapy for healed RE study part:
!
To assess the efficacy of once-daily oral 
administration of D961H for the maintenance 
of symptomatically healed RE (defined as no 
more than mild RE-related symptoms) and if 
EGD is done, no visible mucosal breaks 
observed, for 8 to 52 weeks for subjects who 
continued the study treatment after Week 32.
!
To assess the safety of once-daily oral 
administration of D961H in the initial healing 
therapy period (0 to 8 weeks) for all subjects.
!
To assess the safety of once-daily oral 
administration of D961H for the maintenance 
of symptomatically healed RE (defined as no 
more than mild RE-related symptoms) and if 
EGD is done, no visible mucosal breaks 
observed for 8 to 52 weeks for subjects who 
continued the study treatment after Week 32.
!
To assess the RE-related symptoms during 
the initial healing therapy period (0 to 
8 weeks) for all subjects.
!
To assess the RE-related symptoms during 
the maintenance therapy from 8 to 32 weeks
for all subjects, and 8 to 52 weeks for 
subjects who continued the study after Week 
32.
!
To assess upper endoscopic findings during 
the maintenance therapy for subjects who had 
at least 1 EGD during the maintenance 
therapy .
!
To assess the pharmacodynam ics with 
gastroesophageal pH monitoring during the 
maintenance therapy for subjects who had at 
least 1 pH monitoring during the 
maintenance therapy .  
!
Maintenance therapy for h ealed RE study 
part:
!
Presence/absence of RE relapse from 8 to 
52 weeks (8 to 32 weeks and 32 to 52 weeks) 
for subjects who continued the study 
treatment after Week 32 by assessment of the 
composite endpoint (RE-related symptoms or 
optional EGD findings) during the 
maintenance therapy.
!
Safety from 0 to 8 weeks for all subjects by 
the assessment of;
a) AEs
b) Laboratory variables
c) Vital signs
!
Safety from 8 to 52 weeks (8 to 32 weeks and 
32 to 52 weeks) for subjects who continued 
the study treatment after Week 32, by the 
assessment of;
a) AEs
b) Laboratory variables
c) Vital signs
!
RE-related symptoms during the initial 
healing therapy period (0 to 8 weeks)
!
RE-related symptoms during the maintenance 
therapy
!
Endoscopic findings
!
Gastroesophageal pH measurement

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Secondary Objectives:
Outcome Measures:
Prevention of GU/DU recurrence associated with 
long term NSAIDs/LDA therapy study part:
!
To assess the efficacy of once-daily oral 
administration of D961H for the prevention 
of GU/DU recurrence for 0 to 52 weeks for 
subjects who continued the study treatment 
after Week 32.
!
To assess the safety of once-daily oral 
administration of D961H for the prevention 
of GU/DU recurrence for 0 to 52 weeks for 
subjects who continued the study treatment 
after Week 32.
!
To assess GU/DU-related symptoms from 0 
to 32 weeks for all subjects, and 0 to 52 
weeks (0 to 32 weeks and 32 to 52 weeks) for 
subjects who continued the study treatment 
after Week 32.
!
To assess the endoscopic findings for 
subjects who had at least 1 EGD at post-dose.
!
To assess the pharmacodynamics with 
gastroesophageal pH monitoring for subjects
who had at least 1 pH monitoring at post-
dose.
Prevention of GU/DU recurrence associated with 
long term NSAIDs/LDA therapy study part:
!
Presence/absence of GU/DU recurrence from 
0 to 52 weeks (0 to 32 weeks and 32 to 
52 weeks) for subjects who continued the 
study treatment after Week 32 by assessment 
of the composite endpoint (GU/DU-related 
symptoms or optional EGD findings) during 
the prevention therapy.
!
Safety from 0 to 52 weeks (0 to 32 weeks and 
32 to 52 weeks) for subjects who continued 
the study treatment after Week 32, by the 
assessment of;
a) AEs
b) Laboratory variables
c) Vital signs
!
GU/DU-related symptoms
!
Endoscopic findings
!
Gastroesophageal pH measurement 
Overall design:
This is an open label, parallel group, multi-centre, phase III study to assess the safety and 
efficacy of D961H in maintenance therapy following initial healing therapy in Japanese 
paediatric patients with RE, and to assess the safety and efficacy of D961H in Japanese 
paediatric patients treated with long term NSAIDs or LDA therapy who have a documented 
medical history of GU or DU diagnosis.
Study Period:
Estimated date of first subject enrolled: April 2018
Estimated date of last subject completed: December 2022
Number of Subjects:
Maintenance therapy for healed RE study part:
!
Group 1: aged 1 to 14 years (weight ≥10 kg, <20 kg), Maintenance phase, n=5 to 10

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!
Group 2: aged 1 to 14 years (weight ≥20 kg), Maintenance phase, n=10 to 20
Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
!
Group 3: aged 1 to 14 years (weight ≥10 kg, <20 kg), n=5 to 10 at Week 0
!
Group 4: aged 1 to 14 years (weight ≥20 kg), n=10 to 20 at Week 0
Physically disabled patients are allowed to participate in the study up to 3 subjects/group in 
Groups 1 and 3, and up to 6 subjects/group in Groups 2 and 4, respectively.
Treatments and treatment duration:
Maintenance therapy for healed RE study part:
!
Group 1: Initial healing phase (8 weeks), D961H 10 mg once-daily; Maintenance 
phase (24 or 44 weeks), D961H 10 mg once-daily
!
Group 2: Initial healing phase (8 weeks), D961H 20 mg once-daily; Maintenance 
phase (24 or 44 weeks) starts with D961H 10 mg once-daily, and may be increased to 
20 mg once-daily based on investigator’s discretion
Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
!
Group 3: D961H 10 mg once-daily (32 or 52 weeks)
!
Group 4: D961H starts with 10 mg once-daily, and may be increased to 20 mg once-
daily based on investigator’s discretion (32 or 52 weeks)
When the subjects who assigned to Group 1 or 3 reach 20 kg after the start of investigational 
product administration in the maintenance/prevention therapy period, their treatment dose may 
be reconsidered as that of the treatment regimen for Group 2 or 4. However, during initial RE 
healing period of Group 1, the dose of D961H should not be changed.
Statistical methods:
Efficacy Analysis:
All efficacy analyses will be performed on Efficacy Analysis Set, which consists of all subjects 
who take at least 1 dose of investigational product and have at least 1 efficacy datum assessment
during the maintenance/prevention therapy period, and who have no important protocol 
deviation.
Maintenance therapy for healed RE study part:
For all subjects in Efficacy Analysis Set who have at least 1 efficacy assessment during the 
maintenance therapy period, the percentage of subjects with RE relapse and the time to RE 

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relapse will be analysed by the Kaplan-Meier method for each treatment group by assessing any 
composite endpoint (RE-related symptoms or optional EGD findings) from Week 8 to 32 as a 
primary analysis. The time to RE relapse is defined as the number of days from the start date of 
maintenance phase to the earliest date of satisfying the RE relapse criteria in any composite 
endpoints. The censored subject is defined at the last evaluable date with symptom or EGD.
For subjects in Efficacy Analysis Set who continued the study treatment after Week 32, the 
percentage of subjects with RE relapse and the time to RE relapse will be analysed by the 
Kaplan-Meier method for each treatment group by assessing the similar composite endpoint of
the primary analysis from Week 8 to 52 (8 to 32 weeks and 32 to 52 weeks, respectively).
RE-related symptoms (heartburn, acid regurgitation, dysphagia and epigastric pain) will be 
summarised by frequency and intensity from Week 0 to 8, and from Week 8 to 32 or 52, 
separately. For all subjects in Efficacy Analysis Set, the number of subjects and their percentage 
of disappearance, exacerbation and recurrence for each symptom will be summarised by group 
from Week 0 to 8 and from Week 8 to 32 separately. For subjects in Efficacy Analysis Set who 
continued the study treatment after Week 32, the similar number and percentage for each 
symptom will be summarised by group from Week 8 to 52 (8 to 32 weeks and 32 to 52 weeks,
respectively). 
Regarding endoscopic assessment of healed RE, the number of subjects who had RE relapse 
endoscopically will be summarised for all subjects in Efficacy Analysis Set who had an EGD 
result at post-dose by group. The number of subjects with each grade of the Los Angeles (LA) 
classification (graded A to D) for these subjects will be summarised by group.
Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
For all subjects in Efficacy Analysis Set, the percentage of subjects with GU/DU recurrence and 
the time to the recurrence will be analysed by the Kaplan-Meier method for each treatment group 
by assessing any composite endpoint (GU/DU-related symptoms or optional EGD findings) from 
Week 0 to 32 as a primary analysis. The time to GU/DU recurrence is defined as a number of 
days from the start date of investigational product to the earliest date of satisfying the recurrence 
criteria of GU or DU in any composite endpoints.  The censored subject is defined at the last 
evaluable date with symptom or EGD.
For subjects in Efficacy Analysis Set who continued the study treatment after Week 32, the 
percentage of subjects with GU/DU recurrence and the time to the recurrence will be analysed by 
the Kaplan-Meier method for each treatment group by assessing the similar composite endpoint 
of the primary analysis from Week 0 to 52 (0 to 32 weeks and 32 to 52 weeks, respectively).
GU/DU-related symptoms (epigastric pain, discomfort in the stomach, abdomen enlarged 
feeling, nausea/vomiting, heartburn and anorexia) will be summarised by frequency and 
intensity. For all subjects in Efficacy Analysis Set, the number of subjects and its percentage of 
disappearance, exacerbation and recurrence of each symptom will be summarised by group from 

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Week 0 to 32. For subjects in Efficacy Analysis Set who continued the study treatment after 
Week 32, the same number and percentage for each symptom will be summarised by group from 
Week 0 to 52 (0 to 32 weeks and 32 to 52 weeks, respectively). 
Regarding endoscopic assessment of GU or DU and gastric erosions, the number of subjects will 
be summarised by group based on a clear definition of ulcer and modified LANZA score for all 
subjects in Efficacy Analysis Set who had EGD result at post-dose. The number of subjects with 
GU/DU and the number of subjects with each of the modified LANZA score (graded 0, 1+, 2+, 
3+ and 4+) will be summarised by group.
Safety analysis:
All safety analyses will be performed on Safety Analysis Set, which consists of all subjects who 
take at least 1 dose of investigational product and have any post-treatment assessment.
Frequency and incidence rate of AEs, serious adverse events (SAEs), discontinuation of 
investigational product due to adverse events (DAEs) and other significant adverse events 
(OAEs) will be presented by System Organ Class (SOC) and Preferred Term (PT) in 
International Council on Harmonisation (ICH) Medical Dictionary for Regulatory Activities 
(MedDRA) for each group. In addition, summaries of AEs will be further broken down by 
maximum intensity and relationship to the investigational product as assigned by investigators. 
Clinical laboratory variables and vital signs will be summarised by group with descriptive 
statistics using values and changes from Week 8 as baseline to Week 32 for the maintenance 
therapy for healed RE study part, and changes from Week 0 as baseline to Week 32 for 
prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study part. 
Qualitative data will be presented by group in terms of frequency and percentage, and changes 
from baseline will be presented using shift tables. The distribution of subject with values below 
and above the reference range will be provided.
In maintenance therapy for healed RE study part, the safety assessments (AE, laboratory 
variables and vital signs) will be evaluated for all subjects in Safety Analysis Set from Week 8 as 
baseline to Week 32 as the primary analysis, and the similar safety assessments will be evaluated 
from Week 0 as baseline to Week 8 as the secondary analysis. For subjects in Safety Analysis 
Set who continued the study treatment after Week 32, the safety measurement from Week 8 as 
baseline to Week 52 (8 to 32 weeks and 32 to 52 weeks, respectively) will be evaluated.
For prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part, the same safety assessments will be evaluated for all subjects in Safety Analysis Set from 
Week 0 as baseline to Week 32 as the primary analysis. For all subjects in Safety Analysis Set 
who continued the study treatment after Week 32, the same safety assessments will be evaluated 
from Week 0 to Week 52 (0 to 32 weeks and 32 to 52 weeks, respectively) as the secondary 
analysis.
Pharmacodynamic analysis:
Regarding gastroesophageal pH measurement, data will be presented as:

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!
Gastric pH: Percentages of time with intragastric pH >4 and pH >3, and median 
intragastric pH during 12 hours
!
Esophageal pH: Percentages of time with intraesophageal pH <4, number of acid 
reflux periods (pH <4) and number of acid reflux periods longer than 5 minutes during 
12 hours
1.3
Schema
The general study design is summarised in Figure 1.
Figure 1
Study design
AE, adverse event; DU, duodenal ulcer; GU, gastric ulcer; EGD, esophagogastroduodenoscopy; LDA, low-dose 
aspirin; NSAIDs, non-steroidal anti-inflammatory drugs; RE, reflux esophagitis; y, year
2.
INTRODUCTION
2.1
Study rationale
D961H is considered a medical need, not only in adults but also, in children for:
!
Maintenance therapy after the initial RE healing therapy 
!
Prevention of GU/DU recurrence in children treated with NSAIDs or LDA
It is considered appropriate to evaluate the safety, tolerability and efficacy of treatment for 32 or 
52 weeks with once-daily oral administration of D961H for both the maintenance of RE healing 
and for the prevention of GU/DU recurrence when treated with NSAIDs or LDA in Japanese 
paediatric patients.

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2.2
Background
Proton pump inhibitors (PPIs), including D961H (the trade name in Japan, Nexium capsule
10 mg and Nexium capsule 20 mg; the trade name in overseas, Nexium®; Active ingredient,
esomeprazole), are widely used for the treatment of gastrointestinal acid related diseases.
D961H has been developed as a drug containing only a single enantiomer (S-body) of
omeprazole. After approval in Sweden in 2000, it has been approved in more than 125 countries 
including EU, the US and Asia.
In Japan, repeated dose studies (5 days of repeated D961H doses at 10 mg, 20 mg and 40 mg)
have demonstrated that D961H has strong gastric antisecretory activity in Japanese healthy 
volunteers (SHQBE-0098 study, Nagashima H and Ikushima I 2011). In a phase III study using
D961H for the initial treatment of RE in Japanese adult patients (D961HC00002 study), once-
daily administration of 20 mg D961H showed high healing rates of 87.3%. In another phase III 
study using D961H for maintenance of healed RE in Japanese adult patients (D961HC00006 
study), once-daily administration of 20 mg or 10 mg D961H showed maintenance rates of 92.0% 
and 87.5%, respectively. Lastly, another study demonstrated that NSAIDs related peptic ulcer 
recurrence was prevented in Japanese adult patients receiving 20 mg D961H once-daily, with a
96.0% ulcer-free rate (D961HC00001 study).
Based on the results of these studies, etc., D961H was approved in Japan on July 1st, 2011 for 
the indication for GU, DU, Anastomotic Ulcer, RE, Non-Erosive Reflux Disease (Nexium 
capsule 10 mg only), Zollinger-Ellison syndrome, prevention of GU and DU recurrence in 
patients treated with NSAIDs/LDA and adjunct for eradication of Helicobacter pylori (H. pylori) 
in GU, DU, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, idiopathic 
thrombocytopenic purpura and metachronous development of gastric cancer after endoscopic 
resection of early gastric cancer and H. pylori gastritis (approved in February, 2013), and are 
widely used for the treatment of gastrointestinal acid related diseases.
However, so far PPIs including D961H are approved with gastrointestinal acid related diseases 
for adult only and not approved for children. Therefore, the phase I/III study for gastrointestinal 
acid related diseases (D961TC00002 study) was conducted to develop an initial paediatric 
development program for D961H in Japan. In this study, the safety, tolerability and efficacy of 
D961H for gastrointestinal acid related diseases in children was confirmed.
Among gastrointestinal acid related diseases, RE is a chronic, relapsing disease that is associated 
with a range of potentially serious complications. Some paediatric patients experience repeated 
relapses of RE. The current treatment available for these patients is a continuous use of acid 
inhibitors such as PPIs or H2-receptor antagonists, similar to the initial treatment. Especially, RE 
in children having physical disabilities has characteristics such that it is frequently refractory, 
and that natural healing is less anticipated.
NSAIDs or LDA are available agents for treatment of paediatric chronic inflammatory diseases 
(eg, paediatric idiopathic arthritis, systemic lupus erythematosus, paediatric dermatomyositis, 
and Kawasaki disease). However, NSAIDs and LDA are known to cause mucosal erosions on 
the upper gastrointestinal tract, which could progress to ulcerations and bleeding, as well as 

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upper gastrointestinal symptoms. To counteract the negative effect of NSAIDs/LDA on the 
gastrointestinal tract, these drugs are often given together with antacids, cytoprotective agents or 
gastric acid reducing medications. Treatment of paediatric patients with chronic inflammatory 
diseases is often continued over an extended period, and upper gastrointestinal symptoms caused 
by NSAIDs/LDA may cause discontinuation of treatment of the underlying disease, resulting in 
poor control and disease exacerbation.
A detailed description of the chemistry, pharmacology, efficacy, and safety of D961H is 
provided in the Investigator’s Brochure or Development Safety Update Report.
2.3
Benefit/risk assessment
D961H was approved in Japan on July 1st, 2011 for the indication for the treatment of adults
with gastrointestinal acid related disease. It has been widely used in clinical practice and the 
efficacy and safety of the drug have been well established. In overseas, pharmacokinetics, 
efficacy and safety of paediatric patients with gastroesophageal reflux disease (GERD) had been 
already confirmed, dosage for paediatric patients aged 1 to 11 years with GERD and erosive 
esophagitis had been approved in the US. D961H is commercially available in the EU and other 
worldwide markets. The phase I/III study (D961TC00002) demonstrated safety, tolerability and 
efficacy of 10- and 20-mg D961H treatment for 8 weeks in Japanese children.
Based on the available safety data and benefit of Japanese children getting access to D961H for 
RE maintenance therapy and prevention of NSAIDs/LDA related peptic ulcers recurrence, it is 
AstraZeneca´s judgement that the benefit risk assessment is positive.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of D961H may be found in the Investigator’s Brochure, or Development Safety 
Update Report.
3.
OBJECTIVES AND ENDPOINTS
Table 3 shows the primary and secondary objectives in this study.

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Table 3
Study objectives
Primary Objectives:
Outcome Measures:
Maintenance therapy for healed RE study part:
!
To assess the efficacy and safety of once-
daily oral administration of D961H for the 
maintenance of RE healing in Japanese 
paediatric patients aged 1 to 14 years that 
have symptomatically healed RE (defined as 
no more than mild RE-related symptoms) and 
if EGD is done, no visible mucosal breaks 
observed.
Maintenance therapy for healed RE study part:
!
Presence/absence of RE relapse from 8 to 
32 weeks for all subjects by assessment of 
the composite endpoint (RE-related 
symptoms or optional EGD findings) during 
the maintenance therapy. 
!
Safety from 8 to 32 weeks for all subjects by 
the assessment of;
a) AEs
b) Laboratory variables
c) Vital signs
Prevention of GU/DU recurrence associated with 
long term NSAIDs/LDA therapy study part:
!
To assess the efficacy and safety of once-
daily oral administration of D961H for the 
prevention of GU/DU recurrence in Japanese 
paediatric patients aged 1 to 14 years treated 
with long term NSAIDs/LDA therapy.
Prevention of GU/DU recurrence associated with
long term NSAIDs/LDA therapy study part:
!
Presence/absence of GU/DU recurrence from 
0 to 32 weeks for all subjects by assessment 
of the composite endpoint (GU/DU-related 
symptoms or optional EGD findings) during 
the prevention therapy.
!
Safety from 0 to 32 weeks for all subjects by 
the assessment of:
a) AEs
b) Laboratory variables
c) Vital signs

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Table 3
Study objectives
Secondary Objectives:
Outcome Measures:
Maintenance therapy for healed RE study part:
!
To assess the efficacy of once-daily oral 
administration of D961H for the maintenance 
of symptomatically healed RE (defined as no 
more than mild RE-related symptoms) and if 
EGD is done, no visible mucosal breaks 
observed, from 8 to 52 weeks for subjects 
who continued the study treatment after 
Week 32.
!
To assess the safety of once-daily oral
administration of D961H in the initial healing 
therapy period (0 to 8 weeks) for all subjects.
!
To assess the safety of once-daily oral 
administration of D961H for the maintenance 
of symptomatically healed RE (defined as no 
more than mild RE-related symptoms) and if 
EGD is done, no visible mucosal breaks 
observed from 8 to 52 weeks for subjects 
who continued the study treatment after 
Week 32.
!
To assess the RE-related symptoms during 
the initial healing therapy period (0 to 8 
weeks) for all subjects.
!
To assess RE-related symptoms during the 
maintenance therapy from 8 to 32 weeks for 
all subjects, and 8 to 52 weeks for subjects 
who continued the study after Week 32.
!
To assess upper endoscopic findings during 
the maintenance therapy for subjects who had 
at least 1 EGD during the maintenance 
therapy .
!
To assess the pharmacodynam ics with 
gastroesophageal pH monitoring during the 
maintenance therapy for subjects who had at 
least 1 pH monitoring during the 
maintenance therapy .  
!
Maintenance therapy for h ealed RE study 
part:
!
Presence/absence of RE relapse from 8 to 
52 weeks (8 to 32 weeks and 32 to 52 weeks) 
for subjects who continued the study 
treatment after Week 32 by assessment of the 
composite endpoint (RE-related symptoms or 
optional EGD findings) during the 
maintenance therapy.
!
Safety from 0 to 8 weeks for all subjects by 
the assessment of;
a) AEs
b) Laboratory variables
c) Vital signs
!
Safety from 8 to 52 weeks (8 to 32 weeks and 
32 to 52 weeks) for subjects who continued 
the study treatment after Week 32, by the 
assessment of;
a) AEs
b) Laboratory variables
c) Vital signs
!
RE-related symptoms during the initial 
healing therapy period (0 to 8 weeks)
!
RE-related symptoms during the maintenance 
therapy
!
Endoscopic findings
!
Gastroesophageal pH measurement

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Table 3
Study objectives
Secondary Objectives:
Outcome Measures:
Prevention of GU/DU recurrence associated with 
long term NSAIDs/LDA therapy study part:
!
To assess the efficacy of once-daily oral 
administration of D961H for the prevention 
of GU/DU recurrence for 0 to 52 weeks for 
subjects who continued the study treatment 
after Week 32.
!
To assess the safety of once-daily oral 
administration of D961H for the prevention 
of GU/DU recurrence for 0 to 52 weeks for 
subjects who continued the study treatment 
after Week 32.
!
To assess GU/DU-related symptoms from 0 
to 32 weeks for all subjects, and 0 to 
52 weeks (0 to 32 weeks and 32 to 52 weeks) 
for subjects who continued the study 
treatment after Week 32.
!
To assess the endoscopic findings for 
subjects who had at least 1 EGD at post-dose.
!
To assess the pharmacodynamics with 
gastroesophageal pH monitoring for subjects
who had at least 1 pH monitoring at post-
dose.
Prevention of GU/DU recurrence associated with 
long term NSAIDs/LDA therapy study part:
!
Presence/absence of GU/DU recurrence from 
0 to 52 weeks (0 to 32 weeks and 32 to 
52 weeks) for subjects who continued the 
study treatment after Week 32 by assessment 
of the composite endpoint (GU/DU-related 
symptoms or optional EGD findings) during 
the prevention therapy.
!
Safety from 0 to 52 weeks (0 to 32 weeks and 
32 to 52 weeks) for subjects who continued 
the study treatment after Week 32, by the 
assessment of:
a) AEs
b) Laboratory variables
c) Vital signs
!
GU/DU-related symptoms
!
Endoscopic findings
!
Gastroesophageal pH measurement 
4.
STUDY DESIGN
4.1
Overall design
This is an open label, parallel group, multi-centre, phase III study to assess the safety and 
efficacy of D961H in maintenance therapy following initial healing therapy in Japanese 
paediatric patients with RE, and to assess the safety and efficacy of D961H in Japanese 
paediatric patients treated with long term NSAIDs or LDA therapy who have a documented 
medical history of GU or DU diagnosis.
Doses of D961H in this study is set for the 2 groups (weight ≥10 kg, <20 kg and weight ≥20 kg) 
in the maintenance therapy for healed RE group and the prevention of GU/DU recurrence by 
NSAIDs/LDA group, because the individual difference in weight will be significant in paediatric 
subjects aged 1 to 14 years. The group of weight ≥10 kg, <20 kg (Groups 1 and 3) and the group 
of weight ≥20 kg (Groups 2 and 4) should follow different regimen.

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For an overview of the study design see Figure 1, Section 1.3; Table 1 and Table 2, Section 1.1.
For details on treatments given during the study, see Section 6.1 Treatments administered and 
Section 8 Study Assessments and Procedures.  
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives and 
Endpoints and Section 8.1 Efficacy assessments.  
4.2
Scientific rationale for study design
Rationale for treatment duration:
RE study part: The duration of initial healing therapy in this study was set to 8 weeks, based on 
the durations in the previous phase I/III study for Japanese paediatric subjects and the approved 
duration of treatment with D961H for adult patients with RE. The duration of maintenance 
therapy for healed RE in this study was set to 24 weeks, based on the duration in the previous 
study of Japanese adult subjects with healed RE showing the efficacy and safety of D961H for 
24 weeks. Further, this study was designed to evaluate the long term efficacy and safety of 
D961H for a maximum of 52 weeks, in consideration of the medical needs for long term PPI 
treatment.
NSAIDs/LDA study part: The treatment duration for prevention of GU recurrence in paediatric 
patients who need long term treatment of NSAIDs/LDA was set to 32 weeks, based on 2 studies 
of Japanese adult subjects with NSAIDs showing the efficacy and safety of D961H for 24 weeks
and 52 weeks, respectively. Further, this study was designed to evaluate the long term efficacy 
and safety of D961H for a maximum of 52 weeks, in consideration of the medical needs for long 
term PPI treatment.
Rationale for not selecting comparator groups:
There is no comparator in this study, because the use of placebo is judged unethical.
Rationale for a genetic test:
D961H is primarily metabolised by cytochrome P450 (CYP) subtype CYP2C19, an enzyme with 
known gene and corresponding functional polymorphism. Individuals can be classified based on
their genotype of CYP2C19 either as functionally poor metabolisers (PMs) or as functionally
extensive metabolisers (EMs). Subjects that are CYP2C19 PM will metabolize D961H more 
slowly, with the plasma concentration of D961H higher than that in subjects that are CYP2C19 
EM. Based on the estimated difference in pharmacokinetics, and potential differences in 
pharmacodynamics and safety, there is a rationale to investigate the genotypes of CYP2C19 in 
the subjects of this study. 
Rationale for EGD:
EGD is the most common method to evaluate esophageal reflux disease, as well as GU/DU and 
erosions. However, EGD is known to be linked to a physical burden especially in children. 
Therefore, it was decided that EGD is only mandatory to confirm eligibility for the maintenance 
therapy for healed RE. As indicated in Figure 1, for other study visits in the RE maintenance 

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therapy study part and NSAIDs/LDA study part, evaluation with EGD is encouraged but 
optional, and will be done only upon agreement from patient/patient’s guardian to participate in 
this examination.
Rationale for gastroesophageal pH monitoring:
The gastric pH monitoring is the standard test to investigate gastric antisecretory activity.
Esophageal pH monitoring is used to evaluate this effect in the distal esophagus. The 
intragastric/esophageal cut off at pH 4 is generally correlated to clinical effect in the treatment of 
acid related diseases. Therefore, it was decided to conduct gastroesophageal pH monitoring as a 
complement to evaluate pharmacodynamics as a measure of gastric antisecretory activity; the 
gastroesophageal pH monitoring for 12 hours is an optional test considering subjects’ burden. 
Rationale for an H. pylori test:
Although it is known that GU and DU are mostly caused by infection with H. pylori, GERD 
(including RE) is also cited as one of the ‘diseases investigated for the significance of H. pylori
eradication’ by the H. pylori infection diagnosis and treatment guideline (The Japanese Society 
for Helicobacter Research 2016). Therefore, it was decided to collect information on the 
presence or absence of H. pylori infection in this study.
Rationale for assessment of upper gastrointestinal symptoms:
GERD (including RE) is associated with upper gastrointestinal symptoms, such as heartburn,
acid regurgitation, dysphagia and epigastric pain. This is mainly due to reflux of acidic gastric 
content into the esophagus.
Intake of NSAIDs/LDA is associated with GU/DU-related upper gastrointestinal symptom such 
as epigastric pain, stomach discomfort, bloating, nausea/vomiting, heartburn and anorexia.
Therefore, it was decided to obtain these relevant data (upper gastrointestinal symptoms) and to
evaluate upper gastrointestinal symptoms in detail from the questionnaire (Addendum B).
4.3
Justification for dose
The dosage for paediatric patients aged 1 to 11 years with GERD and erosive esophagitis has 
been approved in the US (Symptomatic GERD, 10 mg once-daily up to 8 weeks; Erosive 
esophagitis, 10 mg once-daily up to 8 weeks for weights <20 kg, or 10 mg or 20 mg once-daily 
up to 8 weeks for weights ≥20 kg). 
The results of the phase I/III study (D961TC00002 study), which was conducted with the 
approved dosage in the US, showed the safety, tolerability and efficacy of 8 weeks D961H 
treatment in Japanese paediatric subjects with gastrointestinal acid related disease. When 20 mg 
D961H was administered to the paediatric subjects aged 1 to 11 years weighting ≥20 kg, higher 
exposure was observed compared to that of 20 mg D961H in adult subjects. Similar exposure 
was also observed in some paediatric subjects compared to that of 40 mg in the adult subjects.
Based on the study results above dose is considered justified:

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RE study part: Subjects assigned to Group 1 will be treated with 10 mg D961H and subjects 
assigned to Group 2 will be treated with 20 mg D961H during the RE initial healing therapy for 
8 weeks. Subjects who entered in the maintenance therapy period will be treated with 10 mg as a 
starter. The dose in the subjects weighting ≥20 kg may be increased to 20 mg at any visit during 
the treatment period based on investigator’s discretion.
NSAIDs/LDA study part: The subjects assigned to Group 3 will be treated with 10 mg D961H 
throughout the treatment period. The subjects assigned to Group 4 will be treated with 10 mg 
D961H as a starter. The dose in the subjects weighting ≥20 kg may be increased to 20 mg at any 
visit during the treatment period based on investigator’s discretion. 
4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study.
A subject is considered to have completed the study when he/she has completed his/her last visit.
See Appendix A 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to registration/assigned to start treatment with the investigational product
(D961H). Under no circumstances can there be exceptions to this rule. Subjects who do not meet 
the entry requirements are screen failures, refer to Section 5.4.
In this protocol, “enrolled” subjects/subject’s guardians are defined as those who sign informed 
consent.  
For procedures for withdrawal of incorrectly enrolled subjects see Section 7.3.
5.1
Inclusion criteria
Subjects are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply:
Maintenance therapy for healed RE study part:
For initiation of the initial healing therapy phase, the study patients should fulfil the following 
criteria (1 to 3):

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1.
Provision of signed written informed consent from the patient’s guardian (including 
informed consent to a genetic test) prior to conducting of any study-related procedure. 
Signed assent obtained from the patient as much as possible.
2.
Patients aged 1 to 14 years inclusive at the time of informed consent.
3.
Endoscopically verified RE, Grade A or higher according to the LA classification as 
judged by central evaluation committee (CEC). Endoscopic image taken within 
4 weeks prior to initiation of the treatment with D961H could also be used for 
evaluation of eligibility. The EGD data prior to informed consent are also applicable if 
the consent of patient’s guardian is obtained.
For initiation of the maintenance therapy phase after the initial healing therapy for 8 weeks, the 
study subjects should fulfil the following criteria (4):
4.
Symptomatically healed RE, defined as no more than mild RE-related symptoms. If 
EGD is done, no visible mucosal breaks observed. 
Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
For inclusion, the study patients should fulfil the following criteria:
1.
Provision of signed written informed consent from the patient’s guardian (including 
informed consent to a genetic test) prior to conducting of any study-related procedure. 
Signed assent forms will be obtained from the patient as much as possible.
2.
Patients aged 1 year to 14 years inclusive at the time of informed consent.
3.
Patients with documented medical history of GU or DU diagnosis based on upper 
gastrointestinal symptoms, fecal occult blood, EGD finding, etc.
4.
Expected to require a long term NSAIDs/LDA therapy (same dose is preferable) for at 
least 32 weeks during the study treatment.
5.
If the patient has been taken disease modifying anti-rheumatic drug (DMARD) (such 
as methotrexate), the drugs should be taken for 4 weeks or longer before start of study 
treatment at the constant dose.
5.2
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled. The 
criteria are applicable for both the maintenance therapy for healed RE study part and the 
prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study part. 
1.
Patients less than 10 kg in weight.

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2.
Use of any other investigational compounds or participations in another clinical trial 
within 4 weeks prior to the enrolment.
3.
Significant clinical illness within 4 weeks prior to the informed consent, eg,
unintentional weight loss, gastrointestinal bleeding requiring abstinence from food, 
jaundice, or any other signs indicating serious or malignant diseases.
4.
Presence of hepatic diseases or other conditions that could interfere with evaluation of 
the study as judged by investigators.
5.
Positive pregnancy urinary test result for post-menarcheal or lactating female patients. 
6.
Previous total gastrectomy.
7.
Any conditions that are predicted to require a surgery during the study period (from 
the day of informed consent to the day of the last scheduled visit or discontinuation).
8.
Prior treatment in this study.
9.
Patients with diseases/symptoms allowing no administration of investigational 
products, such as known or suspected allergy or sensitivity to PPIs.
10.
History of drug addiction or alcoholism within 12 months prior to the informed 
consent.
11.
Involvement in the planning and conduct of the study, such as sponsor staff or staff at 
the study site (this applies to family of patients).
12.
Anticipated need for H. pylori eradication therapy during the study period.
13.
Anticipated need for concomitant therapy with any of the following after enrolment in 
this study*
−
PPIs (except for the investigational products)
−
H2-receptor antagonists
−
Anticholinergic agents for gastrointestinal related diseases or symptoms
−
Antacids drugs (except for magnesium oxide for constipation) 
−
Prostaglandin analogue indicated for peptic ulcers (eg, Misoprostol) 
−
Gastrointestinal promotility drugs
−
Mucosal protectants
*All the subjects are allowed to use any gastrointestinal drug until the day before the 
first dosing of investigational product (D961H) including the subjects during transit 

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CEC judgement on endoscopic image on condition of not changing dose and 
administration.  
*Gastrointestinal drugs (Chinese medicines, etc.) other than the drugs above and drugs 
that have no indication as the gastrointestinal drugs will be allowed.
∀
Any drugs known to have drug-drug interactions with D961H (eg, atazanavir 
sulphate, rilpivirine hydrochloride, diazepam, phenytoin, cilostazol, high-dose 
methotrexate, warfarin, tacrolimus hydrate [except external use], digoxin, 
methyldigoxin, itraconazole, gefitinib, nilotinib, erlotinib, voriconazole, 
clopidogrel, nelfinavir mesilate, saquinavir mesilate, rifampicin and St. John's 
wort, etc.)  
∀
Anticancer drugs (DMARD, eg, methotrexate is a “anticancer drug” that could be 
used for non-cancer Rheumatic disease treatment are allowed) 
∀
Continuous therapy of NSAIDs (oral, intravenous, intramuscular, suppository 
more than 8 days) - for subjects enrolled in the maintenance therapy for healed RE
study part only
14.
Inability or unwillingness to take the study medication according to the dosing 
instructions, as judged by the investigators. For physically disabled patients, this 
applies if objective assessment of symptoms or EGD findings by investigators is not 
possible, or investigators judge that they are not able to report gastrointestinal
symptoms. 
15.
Patients who, for whatever reason are unlikely to comply with study requirements as 
judged by the investigators.
5.3
Lifestyle restrictions
Subjects must follow the following restrictions during the study period:
!
Refrain from eating and drinking, except for water, for at least 4 hours before the 
laboratory tests, EGD and gastroesophageal pH monitoring. 
!
Post-menarcheal patients must maintain effective contraception from informed consent 
day to the last day of scheduled visit or day of discontinuation.
!
Refrain from H. pylori eradication therapy during the study period.
!
Refrain from taking any of the concomitant therapy specified in the exclusion criterion 
No. 13 during the study period.
!
If subject has been taking DMARD (such as methotrexate), the dose is expected to be 
taken at the constant dose during the period from start of study treatment to the day of 
the last scheduled visit or withdrawal.

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5.4
Screen failures
Screen failures are defined as subjects who signed the informed consent form (ICF) to participate 
in the clinical study but are not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAEs. Subjects who discontinued before the 
initial study treatment do not need tests for the study discontinuation.
These subjects should have the reason for study withdrawal recorded in the electronic case report 
form (eCRF).
Individuals who do not meet the RE Grade criteria according to the LA classification for 
participation in this study (screen failure) may be rescreened at another episode. Rescreened 
subjects should not be assigned the same subject number (E code) as for the initial screening. 
However, rescreening should be documented so that its effects on study results, if any, can be 
assessed.
6.
STUDY TREATMENTS
Study treatment is defined as any investigational products (including marketed product 
comparator and placebo) intended to be administered to a study participant according to the 
study protocol. Study treatment in this study refers to D961H.
All study treatments will be given orally once-daily after breakfast.
Maintenance therapy for healed RE study part:
!
Group 1: Initial healing phase (8 weeks), D961H 10 mg once-daily; Maintenance 
phase (24 or 44 weeks), D961H 10 mg once-daily
!
Group 2: Initial healing phase (8 weeks), D961H 20 mg once-daily; Maintenance 
phase (24 or 44 weeks) starts with D961H 10 mg once-daily and may be increased to 
20 mg once-daily based on investigator’s discretion
The subjects assigned to Group 1 will be treated with 10 mg D961H and the subjects assigned to 
Group 2 will be treated with 20 mg D961H during the RE initial healing therapy for 8 weeks. 
The subjects who are eligible for the maintenance therapy (see Section 5.1) at the completion of 
the initial healing therapy will be moved to the maintenance phase for 24 or 44 weeks. During 
the maintenance therapy, all subjects in Groups 1 and 2 will start with 10 mg D961H. For the 
subjects assigned to Group 2, the dose may be increased to 20 mg at any visit during the 
treatment period based on investigator’s discretion. Dosing down back to 10 mg will not be 
allowed.

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Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
!
Group 3: D961H 10 mg once-daily (32 or 52 weeks)
!
Group 4: D961H starts with 10 mg once-daily, and may be increased to 20 mg once-
daily based on investigator’s discretion (32 or 52 weeks)
The subjects assigned to Group 3 will be treated with 10 mg D961H for 32 or 52 weeks. 
The subjects assigned to Group 4 will be treated with 10 mg D961H for 32 or 52 weeks, and the 
dose may be increased to 20 mg at any visit based on investigator’s discretion. Dosing down 
back to 10 mg will not be allowed.
However, the time of D961H administration and eating time around D961H administration in the 
scheduled visit will be adjusted according to test items (EGD, gastroesophageal pH monitoring,
laboratory test, etc.). The drug formulation of D961H (granule or capsule) will be selected for 
each subject based on investigator’s discretion.
The D961H sachet 10 mg will be dispersed in 15 mL of water in a cup prior to use. The contents 
will be stirred and left for a few minutes to thicken. The suspension will then be administered 
orally. An additional 15 mL of water will be used to suspend any esomeprazole granules 
remaining in the cup, and will be administered orally to the subjects. The suspension will be 
administered within 30 minutes from the stir, and stirred immediately before administration if 
there is more than a few minutes delay between re-constitution and administration.
6.1
Treatments administered
6.1.1
Investigational products
Choice of granule or a capsule is to be decided by investigator’s discretion.

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Table 4
Study treatments
Study treatment 
name:
D961H granule for suspension 
10 mg
D961H capsule 10 mg
Dosage formulation:
Granule containing 10 mg of 
Esomeprazole (11.1 mg of 
Esomeprazole Magnesium Hydrate) 
as entire coated pellets and granule 
of additive agent in single use 
aluminium sachet.
Hard capsule containing 10 mg of 
Esomeprazole (11.1 mg of 
Esomeprazole Magnesium Hydrate) 
as entire coated pellets in HMPC 
capsule.
Route of 
administration:
Oral
Dosing instructions:
Refer to Section 6
Packaging and 
labelling:
The investigational products will be provided as the box for the D961 
granule (include 35 packages/box) or the bottle for the D961 capsule 
(include 35 capsules/bottle). Each package will be labelled in accordance 
with Good Manufacturing Practice (GMP) Annex 13 and per country 
regulatory requirement.
Provider:
AstraZeneca Sweden Operations Drug Product Supply
HMPC: Hydroxypropyl methyl cellulose
6.2
Preparation/handling/storage/accountability
The head of the medical institution or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received and any discrepancies are 
reported and resolved before use of the study treatment.
Only subjects enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labelled storage conditions with access limited to the investigator and authorised site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatment are provided 
in the ‘Procedures for drug accountability’ and ‘Procedures for drug dissolution and usage’.  
6.3
Measures to minimise bias: randomisation and blinding
This is an open label study.
If a subject withdraws from the study, then his/her enrolment/randomisation code (E code) 
cannot be reused. Withdrawn subjects will not be replaced.

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6.4
Treatment compliance
The administration of all drugs (including investigational products) should be recorded in the
appropriate sections of the eCRF from 7 days before Visit 2 to the last scheduled visit or 
withdrawal (except for drugs used for pre-treatment of EGD and gastroesophageal pH 
monitoring).
The investigational product is prescribed every 4 weeks in principle from Visits 2 to Visit 14. 
The subject’s guardian is instructed to return all unused investigational products and used 
bottles/boxes. The quantity of returned investigational products is confirmed to check the 
compliance status.
If the subject’s compliance rate is low due to missing doses, etc., the investigator will instruct 
subject’s guardian (or the subject, if properly) to comply with the treatment.
6.5
Concomitant therapy
Other medications considered necessary for the subject’s safety and wellbeing may be given at 
the discretion of the investigator. The use of all medications including investigational products 
and over-the-counter drugs during the study period (from 7 days before Visit 2 to the last 
scheduled visit or withdrawal) must be recorded in the appropriate sections of the eCRF. 
However, drugs used for pre-treatment of EGD and gastroesophageal pH monitoring (eg,
anticholinergic agents, anti-anxiety agents, etc.) will not be recorded in the eCRF.
After starting the investigational product treatment, the drugs and treatments shown in Table 5
are prohibited since these may affect interpretation of results of the investigational products or 
result in general complications (eg, gastrointestinal bleeding).
For the subjects enrolled in the prevention of GU/DU recurrence associated with long term 
NSAIDs/LDA therapy study part, NSAIDs or LDA is recommended to be received at the 
constant dose from 4 weeks before the initial study treatment to the last visit or study 
discontinuation. If the subject has received DMARD (methotrexate, etc.), the drugs is expected 
to be received at the constant dose from 4 weeks before the initial study treatment to the last visit 
or study discontinuation.

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Table 5
Prohibited medications
Prohibited medication/class of drug:
−PPIs (except for the investigational products) *
−H2-receptor antagonists*
−Anticholinergic agents for gastrointestinal related diseases or symptoms*
−Antacids drugs (except for magnesium oxide for constipation) *
−Prostaglandin analogue indicated for peptic ulcers (eg, Misoprostol) *
−Gastrointestinal promotility drugs*
−Mucosal protectants*
−Any drugs known to have drug-drug interactions with D961H (eg, atasanavir sulphate, rilpivirine 
hydrochloride, diazepam, phenytoin, cilostazol, high-dose methotrexate, warfarin, tacrolimus hydrate 
[except external use], digoxin, methyldigoxin, itraconazole, gefitinib, nilotinib, erlotinib, voriconazole, 
clopidogrel, nelfinavir mesilate, saquinavir mesilate, rifampicin and St.John’s wort, etc.)
−Anticancer drugs (DMARD, eg, methotrexate is a “anticancer drug” that could be used for non-cancer 
Rheumatic disease treatment are allowed)
−Continuous therapy of NSAIDs (oral, intravenous, intramuscular, suppository more than 8 days 
treatment)- for subjects enrolled to the maintenance therapy for healed RE study part only
*All the subjects are allowed to use any gastrointestinal drug until the day before the first dosing of investigational 
product (D961H  ) including The subjects during transit CEC judgement on endoscopic image on condition of 
not changing dose and administration.
*The gastrointestinal drugs (Chinese medicines, etc.) other than the drugs above and the drugs that have no 
indication as the gastrointestinal drugs will be allowed.
6.5.1
Other concomitant therapy
Other medications considered necessary for the subject’s safety and wellbeing may be given at 
the discretion of the investigator and recorded in the appropriate sections of the eCRF.
6.6
Dose modification
Maintenance therapy for healed RE study part:
The maintenance therapy dose for subjects assigned to Group 2 may be increased from 10 mg to 
20 mg upon investigator’s discretion that it is necessary due to development and/or persistence of 
RE-related symptoms or findings. If it is the case, investigators will clarify the reasons in the 
eCRF, citing the symptoms and/or findings, time course, and intensity. Dosing down back to 
10 mg will not be allowed.
Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
The prevention therapy dose for subjects assigned to Group 4 may be increased from 10 mg to 
20 mg upon investigator’s discretion that it is necessary due to development and/or persistence of 
GU/DU-related symptoms or findings. If it is the case, investigators will clarify the reasons in 
the eCRF, citing the symptoms and/or findings, time course, and intensity. Dosing down back to 
10 mg will not be allowed.  

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When the subjects who assigned to Group 1 or 3 reach 20 kg after the start of investigational 
product administration in the maintenance/prevention therapy period, their treatment dose may 
be reconsidered as that of the treatment regimen for Group 2 or 4. However, during initial RE 
healing period of Group 1, the dose of D961H should not be changed.
6.7
Treatment after the end of the study
Not Applicable.
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
Subjects may be discontinued from investigational product in the following situations. Note that 
discontinuation from study treatment is NOT the same thing as a complete withdrawal from the 
study.
!
Subject or subject’s guardians’ decision. The subject is at any time free to discontinue 
treatment, without prejudice to further treatment
!
Not fulfilling the criteria for continuation into the RE maintenance phase at Week 8
!
AE
!
Severe non-compliance with the Clinical Study Protocol as judged by investigator (s) 
and/or AstraZeneca and/or designee  
!
Incorrect registration, ie, the subject does not meet the required inclusion/exclusion
criteria for the study, except for when the study team physician and the investigator
agree with continuation through discussion
!
Subject lost to follow-up
!
Pregnancy
!
Others as judged appropriate by the investigators (reasons for discontinuation must be 
recorded in the eCRF)
See the Schedule of Activities (SoA) (Table 1 and Table 2) for data to be collected at the time of 
study discontinuation that need to be completed.
7.1.1
Procedures for discontinuation of a subject from investigational product
The investigator should instruct the subject/subject’s guardian to contact the study site before or 
at the time if study treatment is stopped. A subject/subject’s guardian that decides to discontinue 
study treatment will always be asked about the reason(s) and the presence of any AEs. The date 
of last intake of study treatment should be documented in the eCRF. All study treatment should 

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be returned by the subject/subject’s guardian at their next on-site study visit or unscheduled visit. 
Subjects permanently discontinuing study treatment should be given locally available standard of 
care therapy, at the discretion of the investigator.
7.2
Lost to follow-up
A subject will be considered potentially lost to follow-up if he or she fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:
!
The site must attempt to contact the subject/subject’s guardian and reschedule the 
missed visit as soon as possible and counsel the subject on the importance of 
maintaining the assigned visit schedule.
!
Before a subject is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the subject/subject’s guardian or next of kin by eg,
repeat telephone calls, certified letter to the subject´s last known mailing address or 
local equivalent methods. These contact attempts should be documented in the 
subject’s medical record. 
!
Efforts to reach the subjects/subject’s guardian should continue until the end of the 
study. Should the subject/subject’s guardian be unreachable at the end of the study the 
subject should be considered to be lost to follow-up with unknown vital status at end 
of study and censored at latest follow-up contact.
7.3
Withdrawal from the study
A subject/subject’s guardian may withdraw from the study (eg, withdraw consent), at any time 
(investigational product and assessments) at his/her own request, without prejudice to further 
treatment. A subject who discontinued from administration of investigational product  will 
withdraw from the study as well.
If the subject/subject’s guardian withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a withdrawal of consent.
If a subject/subject’s guardian withdraws from the study, he/she may request destruction of any 
samples taken, and the investigator must document this in the site study records.  
A subject/subject’s guardian who withdraws consent will always be asked about the reason (s) 
and the presence of any AEs. The investigator will follow-up subjects as medically indicated. 
See SoA, Table 1 and Table 2, for data to be collected at the time of study discontinuation that 
need to be completed. All study treatment should be returned by the subject/subject’s guardian.

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8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timings are summarised in the SoA (Table 1 and Table 2).  
The following will be assessed, measured or performed.
Visit 1 (Week -4 to -1; Enrolment within 28 days prior to initial treatment):
1.
The signed and dated ICF should be obtained from the patient's guardian (including 
informed consent to a genetic test) prior to conducting of any study related procedure. 
Assent form will be signed by the patient as much as possible. The procedure for 
informed consent refers to Appendix A (A 3 ‘Informed consent process’).
2.
Assign a unique enrolment code (E code), beginning with ‘E’ to the potential subject 
whose signed ICF has been submitted. The E code (EXXXXYYY) is composed of 4 
digits (XXXX) of study site number and 3 digits (YYY) of consecutive numbers in the 
order of informed consent at each study site. For study site number, see Addendum A 
‘Investigators and Study Administrative Structure’. E codes of subjects who failed 
screening or subjects who withdrew from this study after the registration to initial 
treatment should not be reused. At the time of the informed consent, the E code with 
consecutive number will be assigned.
3.
Review inclusion/exclusion criteria (see Section 5.1 and Section 5.2).
4.
EGD will be performed to check EGD eligibility as judged by the CEC (for RE study 
part only). The EGD data within 4 weeks before the start of initial treatment could be 
used if available and given the consent of subject's guardian.
5.
The following will be assessed, measured or performed.
!
Demographic data (sex, age, race, date of signature of informed consent, height 
and weight)
6.
Check concomitant medication (at the time of informed consent)
7.
Collection of SAEs (after informed consent has been obtained)
Visit 2 (Week 0; Day of registration, initial treatment):
1.
Review inclusion/exclusion criteria (see Section 5.1 and Section 5.2).
2.
The following will be assessed, measured or performed:
!
Medical/surgical history (eg, a condition which a subject has had in the past and 
which has been declared cured)
At Visit 2, the investigator will document the symptoms and/or signs which is 
considered past GU or DU in the medical record (for NSAIDs/LDA study part 
only)

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!
Physical examination (see Section 8.2.2)
!
Vital signs (blood pressure, pulse rate and body temperature, see Section 8.2.3)
!
Clinical laboratory tests (hematology, biochemistry and urinalysis, see 
Section 8.2.1)
!
Urine pregnancy test 
A urine pregnancy test will be required for all post-menarcheal female patients, 
and the result must be negative at registration to the study treatment. This test will 
be performed at each study site. 
!
H. pylori test (immunoglobulin G [IgG] antibody) (see Section 8.2.1)
!
Genetic test for CYP2C19 (see Section 8.7)
If the genotyping data of CYP2C19 is already available at the study site, it may be 
used with the consent of subject’s guardian. According to the subject's body 
weight, it is possible to do it Visit 3 or after for the purpose of reducing blood 
collection volume of Visit 2.
3.
Symptom assessment by the investigator: RE-related symptoms (for RE study part) or 
GU/DU-related symptoms (for NSAIDs/LDA study part) (see Section 8.1.2) 
4.
Registration to the initial healing therapy (for RE study part) or to the prevention 
therapy (for NSAIDs/LDA study part).
Subjects who meet all of the inclusion criteria and none of the exclusion criteria for 
this study should be registered to initial healing therapy (for RE study part) and 
prevention therapy (NSAIDs/LDA study part). Subjects who do not fulfill the criteria 
should not be registered for the initial healing/prevention phase, but will be noted in 
the eCRF as screen failures.
5.
Dispense/Administration of the investigational product
6.
Check concomitant medication
7.
Evaluation of efficacy composite endpoint (for NSAIDs/LDA study part only) (see 
Section 8.1.1)
8.
Collection of AEs (after the investigational product administration) and SAEs (after 
the informed consent)
Visits 3 and 5 to 9 (Weeks 4 and 12 to 28):
1.
The following will be assessed, measured or performed:
!
Physical examination (see Section 8.2.2)
!
Vital signs (blood pressure, pulse rate and body temperature, see Section 8.2.3)

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2.
Symptom assessment by the investigator: RE-related symptoms (for RE study part), or 
GU/DU-related symptoms (for NSAIDs/LDA study part) (see Section 8.1.2) 
3.
Dispense/Administration of the investigational product
4.
Check concomitant medication
5.
Evaluation of efficacy composite endpoint: Visits 5 to 9 (for RE study part) or Visits 3 
and 5 to 9 (for NSAIDs/LDA study part) (see Section 8.1.1)
6.
Collection of all AEs and SAEs 
Visit 4 – For RE study part only (Week 8; Day of initial treatment for RE maintenance 
therapy):
1.
Review inclusion/exclusion criteria for registration to the RE maintenance therapy.
Subjects who completed the healing therapy for 8 weeks and evaluated to have 
symptomatically healed RE (defined as no more than mild RE-related symptoms) at 
Visit 4, or if an EGD is done, no visible mucosal breaks observed.
2.
The following will be assessed, measured or performed.
!
Physical examination (see Section 8.2.2)
!
Vital signs (blood pressure, pulse rate and body temperature, see Section 8.2.3)
!
Clinical laboratory tests (hematology, biochemistry and urinalysis, see 
Section 8.2.1)
!
EGD (optional)
!
RE-related symptom assessment by the investigator (see Section 8.1.2)
3.
Registration for maintenance therapy
Subjects who meet the criteria for entering the RE maintenance phase should be 
registered for maintenance therapy. Subjects who do not meet the criteria for entering 
the RE maintenance phase should not be registered for maintenance therapy but be 
noted in the eCRF. For these subjects, this will be the last visit (Study closure visit).
4.
Dispense/Administration of the investigational product
5.
Check concomitant medication
6.
Evaluation of efficacy composite endpoint (see Section 8.1.1)
7.
Collection of all AEs and SAEs
Visit 4 (Week 8; for NSAIDs/LDA study part only):

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Same as Visits 3, and 5 to 9.
Visit 10 (Week 32; Study Closure 1, Day of end of the first study period and start of the 
initial treatment for extension therapy):
Subjects who discontinue from investigational product treatment and/or withdraw during 
maintenance/prevention phase before Week 32 will be performed the activities described in 
Visit 10, if possible:
A) Data from the first study period will be collected.
1.
The following will be assessed, measured or performed.
!
Physical examination (see Section 8.2.2)
!
Vital signs (blood pressure, pulse rate and body temperature, see Section 8.2.3)
!
Clinical laboratory tests (hematology, biochemistry and urinalysis, see 
Section 8.2.1)
!
EGD (optional)
!
Gastroesophageal 12-hour pH monitoring (optional) (see Section 8.6)
2.
Symptom assessment by the investigator: RE-related symptoms (for RE study part), or 
GU/DU-related symptoms (for NSAIDs/LDA study part) (see Section 8.1.2)
3.
Check concomitant medication
4.
Evaluation of efficacy composite endpoint (see Section 8.1.1)
5.
Collection of all AEs and SAEs 
B) The treatment period in all groups may be extended up to 52 weeks upon investigator’s 
discretion. The reason for the extension will be recorded in the eCRF.
6.
Dispense/Administration of the investigational product (in case of extension of the 
treatment)
Visits 11 to 14 (Weeks 36 to 48; Extended period):
Same as Visits 3, and 5 to 9.
Visit 15 (Week 52; Study Closure 2, Day of end of extended period):
Subjects who discontinue from investigational product treatment and/or withdraw during the 
maintenance/prevention phase after Week 32 will be performed the activities described in 
Visit 15, if possible:

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1.
The following will be assessed, measured or performed:
!
Physical examination (see Section 8.2.2)
!
Vital signs (blood pressure, pulse rate and body temperature, see Section 8.2.3)
!
Clinical laboratory tests (hematology, biochemistry and urinalysis, see 
Section 8.2.1)
!
EGD (optional)
2.
Symptom assessment by the investigator: RE-related symptoms (for RE study part), or 
GU/DU-related symptoms (for NSAIDs/LDA study part) (see Section 8.1.2)
3.
Check concomitant medication
4.
Evaluation of efficacy composite endpoint (see Section 8.1.1)
5.
Collection of all AEs and SAEs
The investigator will ensure that data are recorded on the eCRF. The Web Based Data Capture 
(WBDC) system will be used for data collection and query handling.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and of 
the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived at 
the study site.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the subject should continue or discontinue study treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria.  
The investigator will maintain a screening log to record details of all subjects screened and to 
confirm eligibility or record reasons for screening failure, as applicable.  
Procedures conducted as part of the subject’s routine clinical management (eg, vital signs) and 
obtained before signing of the ICF may be utilised for screening or baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA (Table 1 and Table 2).

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8.1
Efficacy assessments 
The primary endpoints are shown in Table 3.
8.1.1
Evaluation of efficacy composite endpoints
Maintenance therapy for healed RE study part:
Based on the following observations, the investigator will assess development and/or 
exacerbation of RE-related symptoms/findings and their time course, and then judge RE relapse 
at every visit during the maintenance therapy period.
RE relapse is to be declared if any of the following events occur during the maintenance phase of 
the RE study:
1.
An EGD relapse is defined as an identification of a RE with LA classification grade A 
to D (see Table 6)
2.
A symptom relapse (defined by any of the 4 specified RE-related symptoms in the RE-
related symptom questionnaire, see Section 8.1.2) is defined as any of the following:
a)
Withdrawal from the study due to RE-related symptoms; this decision is to be 
taken by the investigator in collaboration with the subject/subject’s guardian
b)
Increasing the dose from 10 mg to 20 mg due to RE-related symptoms (only 
applicable in subjects weighting over 20 kg); this decision is to be taken by the 
investigator in collaboration with the subject/subject’s guardian
For subjects who are judged as having RE relapse, record the reason (symptoms and/or findings, 
time course, and intensity, etc.) in the eCRF.
Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
Based on the following observations, the investigators will assess development and/or 
exacerbation of GU/DU-related symptoms/findings and their time course, and then judge 
GU/DU recurrence at every visit during prevention therapy period.
A GU/DU recurrence is to be declared if any of the following events occur during the prevention 
phase of the NSAIDs/LDA study part:
1.
An EGD recurrence is defined as an identification of a GU or DU
2.
A symptom recurrence (defined by any of the 6 specified symptoms in the GU/DU-
related symptom questionnaire, see Section 8.1.2) is defined as any of the following:
a)
Withdrawal from the study due to GU/DU-related symptoms; this decision is to be 
taken by the investigator in collaboration with the subject/subject’s guardian

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b)
Increasing the dose from 10 mg to 20 mg due to GU/DU-related symptoms (only 
applicable in subjects weighting over 20 kg); this decision is to be taken by the 
investigator in collaboration with the subject/subject’s guardian
For subjects who are judged as having GU/DU recurrence, record the reason (symptoms and/or 
findings, time course, and intensity, etc.) in the eCRF.
8.1.2
Gastrointestinal symptom assessments
Maintenance therapy for healed RE study part:
The gastrointestinal RE-related symptom questionnaire will be provided at Visit 2 and following 
every visit of the subject. The subject and/or guardian will recall 1 week to date gastrointestinal 
symptoms and record them using the card. The card will be reviewed and collected by the 
investigator. The investigator will evaluate RE relapse at every visit during the maintenance 
therapy.
!
Heartburn: A burning feeling, rising from the stomach or lower part of the chest 
towards the neck
!
Acid regurgitation: Flow of sour or bitter fluid into mouth
!
Dysphagia: Difficulties in swallowing
!
Epigastric pain: Central upper abdominal pain
The assessment of each symptom is to include the intensity of the episode by frequency and 
intensity within the past 1 week.
Intensity of episode is classified as follows:
!
None - No symptoms
!
Mild - Awareness of symptom, but easily tolerated
!
Moderate - Discomforting symptom sufficient to cause interference with normal 
activities (including sleep)
!
Severe - Incapacitating symptoms, with inability to perform normal activities 
(including sleep)
Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
The gastrointestinal GU/DU-related symptom questionnaire will be provided at Visit 2 and 
following every visit to the subject. The subject and/or guardian will recall 1 week to date 
gastrointestinal symptoms and record them using the card. The card will be reviewed and 

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collected by the investigator. The investigator will evaluate GU/DU recurrence every visit during 
treatment.
!
Epigastric pain: Central upper abdominal pain
!
Discomfort in the stomach: Discomfort with heaviness in the abdominal area
!
Abdomen enlarged feeling: Feeling enlargement in the abdomen
!
Nausea/vomiting: Feeling of throwing up and nauseous/throwing up stomach contents
!
Heartburn: A burning feeling, rising from the stomach or lower part of the chest 
towards the neck
!
Anorexia: Having no appetite
The assessment of each symptom is to include the intensity of the most intense episode by 
frequency and intensity within the past 1 week.
Intensity of episode is classified as follows:
!
None - No symptoms
!
Mild - Awareness of symptom, but easily tolerated
!
Moderate - Discomforting symptom sufficient to cause interference with normal 
activities (including sleep)
!
Severe - Incapacitating symptoms, with inability to perform normal activities 
(including sleep)
8.1.3
EGD
The EGD of the esophagus, stomach and duodenum, which is required for diagnosis of target 
disease, will be performed on the subjects with obtained informed consent from subject’s 
guardians. The EGD is conducted by fasting condition at least 4 hours prior to the test.
The EGD is performed by the method usually employed at each study site. The drug used for the 
pre-treatment of EGD is not recorded in the eCRF. 
Subjects who get more symptoms during the maintenance therapy period (especially if they leave 
the study) should be encouraged to do an EGD, whenever possible.
Maintenance therapy for healed RE study part:
To evaluate RE, the EGD results are assessed based on the LA classification (Lundell et al 1999) 
(See Table 6). Any grades of mucosal breaks graded as A, B, C or D is considered as presence of 
RE.

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Photo documentation from the EGD will be judged by the CEC, which consists of 
gastrointestinal specialist(s) who will be appointed for this study to validate the diagnosis for 
inclusion by investigators based on the EGD findings. If investigators find any suspicious 
findings of RE on the EGD during the study, all suspicious finding photos should be sent to CEC 
for review. The CEC will report the review results to the investigators and the sponsor. When the 
results are inconsistent between the central and local assessments, the central assessment will be 
used for judgement of the enrolment. For the EGD on Visit 1, if the EGD data within 4 weeks
before the initial treatment are available, they may be used with the consent of subject’s 
guardians even though these are the results of the test conducted before obtaining informed 
consent.
Table 6
LA classification
Grade A
One (or more) mucosal break no longer than 5 mm, that does not extend between the tops of 
2 mucosal folds.
Grade B
One (or more) mucosal break more than 5 mm long that does not extend the tops of 2 
mucosal folds.
Grade C
One (or more) mucosal break that is continuous between the tops of 2 or more mucosal folds 
but which involve less than 75% of the circumference.
Grade D
One (or more) mucosal break which involves at least 75% of esophageal circumference.
Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
To evaluate GU/DU, the EGD results are assessed based on the modified LANZA score (Lanza 
et al 1988) (See Table 7). If investigators find any suspicious findings of GU/DU on the EGD 
during the study, all suspicious finding photos should be sent to CEC for review. The CEC will 
report the review results to the investigators and the sponsor. The presence of an ulcer is 
separately collected in the eCRF. An ulcer is defined as a mucosal lesion with either of following 
features:
!
A base - a circular or elliptical white or grey-white punched-out defect in the mucosa 
that could be smooth and regular;
!
A margin - discrete, sharply demarcated, regular, smooth, and usually raised in 
relation to the ulcer base; and
!
Lack of an associated mass lesion or other features suggesting malignancy.

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Table 7
Modified LANZA score
0
No visible lesions
1+
1 hemorrhage1) or erosion2)
2+
2 to 10 hemorrhages or erosions
3+
11 to 25 hemorrhages or erosions  
4+
>25 hemorrhages or erosions or an invasive ulcer3) of any size
1)
Mucosal hemorrhage with luminal bleeding. 
2)
Erosion is defined as a lesion producing a definite discontinuance in the mucosa but having no depth. 
3)
Invasive ulcer is defined as any lesion with unequivocal depth.*
*The detailed definition of an ulcer is stated as the 3 points above.
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1 and Table 2).
8.2.1
Clinical safety laboratory assessments
See Table 8 for the list of clinical safety laboratory tests to be performed and to the SoA for the 
timing and frequency. All protocol-required laboratory assessments, as defined in the table, must 
be conducted in accordance with the laboratory manual and the SoA. The date of collecting 
samples for the laboratory tests must be recorded in the eCRF. These tests will be performed in 
fasting condition at least 4 hours before test at each study site. The urinalysis is not required if 
the subjects have no ability to autonomously excrete urine.
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at study 
site as source data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.

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Table 8
The items of laboratory safety
Hematology test
(quantitative, whole blood)
Clinical chemistry test 
(quantitative, serum or 
plasma)
Urinalysis (qualitative)
RBC, hemoglobin, hematocrit, 
WBC, leukocyte differential 
count (neutrophil, eosinophil, 
basophil, lymphocyte, 
monocyte), platelet count
AST (GOT), ALT (GPT), ALP, 
γ-GTP, total bilirubin, 
creatinine, albumin, glucose, 
sodium, potassium, calcium, 
CK, LDH, BUN, CRP
Occult blood, protein, glucose
NB. In case a subject shows an AST or ALT ≥3 x upper limit normal (ULN) together with total bilirubin ≥2 x ULN 
please refer to Appendix E ‘Actions required in cases of increases in liver biochemistry and evaluation of Hy’s 
Law’, for further instructions.
If the investigator considers it clinically necessary (eg, in the case of abnormal or severe AE), 
additional samples may be taken.
The total volume of blood that will be drawn from each subject in this study is as follows (Table 
9). All the laboratory tests except for urine pregnancy test will be performed at the central
laboratory.
The urine pregnancy test will be performed at each study site by using dipstick provided from the 
central laboratory. 
At Visit 2 (Week 0), blood sample (1 mL) will be collected to measure IgG antibody to 
determine the presence or absence of H. pylori infection.

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Table 9
Volume of blood to be drawn from each subject
Assessment
Sample 
volume 
(mL)
No. of samples
Total volume (mL)
Characteristic of 
subject
H. pylori test
1
1
1
Safety
Hematology
2
RE study part: 3 (or 4*)
NSAIDs/LDA study part: 2 
(or 3*)
RE study part: 6 (or 8*)
NSAIDs/LDA study part: 4 (or 
6*)
Biochemistry
5
RE study part: 3 (or 4*)
NSAIDs/LDA study part: 2 
(or 3*)
RE study part: 15 (or 20*)
NSAIDs/LDA study part: 10 (or 
15*)
Pharmacogenetic
s
CYP2C19
2
1
2
Total
RE study part: 24 (or 31*)
NSAIDs/LDA study part: 17 (or 
24*)
* In case of the subjects continue the study after Visit 11.
8.2.2
Physical examination
At Visit 2 and all subsequent visits, general appearance, lymph node, thyroid gland, 
cardiovascular system, lung, abdomen, musculoskeletal/extremities, and reflex will be examined. 
Presence/absence of deterioration or new findings from Visit 2 will be checked, and if relevant
findings are found, they will be recorded as AEs in the eCRF.
8.2.3
Vital signs
At the Visit 2 and the all subsequent visits, blood pressure, pulse rate and body temperature will 
be measured.
8.3
Collection of AEs
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorised representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow-up AEs see 
Section 8.3.3.  

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8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
AEs will be collected from the start of investigational product (Visit 2) to the last scheduled visit 
or withdrawal, and will be recorded in the eCRF. SAEs will be recorded from the time of signing 
of ICF (Visit 1).
Hospitalisation for investigations defined in this protocol (eg, EGD, gastroesophageal pH 
monitoring) is not considered as SAE.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix B. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject’s last visit and 
he/she considers the event to be reasonably related to the study treatment or study participation, 
the investigator may notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All AEs will be followed until resolution, stabilization, explanation of 
the event, or the subject is lost to follow-up.
Any AEs that are unresolved at the subject’s last visit or study discontinuation in the study are 
followed up by the investigator for as long as medically indicated, but without further recording 
in the eCRF. AstraZeneca retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
AE data collection
'The following variables will be collected for each AE;
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity 
!
Whether the AE is serious or not

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!
Investigator causality rating against the investigational product(s) (yes or no)
!
Action taken with regard to investigational product(s)
!
Outcome
In addition, the following variables will be collected for SAEs;
!
Date AE met criteria for SAE
!
Date investigator became aware of SAE
!
AE is serious due to
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
8.3.5
Causality collection
The investigator will assess causal relationship between investigational product and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures.
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
8.3.6
AEs based on signs and symptoms
All AEs spontaneously reported by the subject or care provider or reported in response to the 
open question from the study site staff: ‘Have you/the child had any health problems since the 
previous visit/you were last asked?’, or revealed by observation will be collected and recorded in 
the eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 

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signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
8.3.7
AEs based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the clinical study report. Deterioration as compared to baseline (Visit 2) in 
protocol-mandated laboratory values, vital signs should therefore only be reported as AEs if they 
fulfil any of the SAE criteria or are the reason for discontinuation of treatment with the 
investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information. Wherever possible the reporting investigator uses the 
clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment (Visit 2) will be reported as an AE unless unequivocally 
related to the disease under study, see Section 8.3.9.
8.3.8
Hy’s law
Cases where a subject shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3 x upper limit normal (ULN) together with total bilirubin ≥ 
2 x ULN  need to be reported as SAEs. Please refer to Appendix E for further instruction on 
cases of increases in liver biochemistry and evaluation of Hy’s Law.
8.3.9
Disease under study
EGD findings of disease under the study:
The EGD findings due to target illness (see Section 8.1.3) are not reported as the AEs except for 
those that correspond to the SAE definition (see Appendix B), or those whose aggravation 
resulted in discontinuation of study.
Symptoms of disease under the study:
Symptoms due to target illness (see Section 8.1.2) are not reported as the AEs except for those 
that correspond to the SAE definition (see Appendix B), or those whose aggravation resulted in 
discontinuation of study.

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8.4
Safety reporting and medical management
8.4.1
Reporting of SAEs
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform the 
appropriate AstraZeneca representatives within 1 day ie, immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar day 
ie, immediately but no later than 24 hours of when he or she becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the WBDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the investigator or other study site staff reports an
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.  
For further guidance on the definition of an SAE, see Appendix B of the Clinical Study Protocol.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:
!
If the pregnancy is discovered before the study subject has received any 
investigational product
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of learning 
of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.

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Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
8.4.2.2
Paternal exposure 
Pregnancy of the subject’s partners is not considered to be an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth or 
congenital abnormality) should, if possible, be followed up and documented.
If the subject’s partner gets pregnant, despite prevention, state that the partner will be asked to 
sign an Inform Consent for pregnant partners and be collected the information.
8.4.3
Overdose
No subject in this study is scheduled to receive a dose higher than 20 mg within 1 calendar day. 
Therefore, an overdose will be any dose greater than 20 mg taken in a 24-hour period. The 
symptoms described in connection with deliberate esomeprazole overdose (limited experience of 
doses in excess of 240 mg/day) are transient. Esomeprazole is extensively plasma protein bound 
and is therefore not readily dialyzable. As in any case of overdose, treatment should be 
symptomatic and general supportive measures should be utilized.
If an overdose occurs, the following actions should be taken:
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the overdose eCRF module.
!
An overdose without associated symptoms is only reported on the overdose eCRF 
module.

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If an overdose on an AstraZeneca investigational drug occurs in the course of the study, then
investigators or other site personnel inform appropriate AstraZeneca representatives
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all relevant 
information is provided to the AstraZeneca patient safety data entry site.
For overdoses associated with SAE, standard reporting timelines apply, see Section 8.3.2. For
other overdoses, reporting should be done to the AstraZeneca patient safety data entry site within 
30 days.
8.4.4
Medication Error
If an medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all relevant 
information is completed within 1 (initial fatal/life-threatening or follow-up fatal/life-
threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE associated 
with the medication error (see Section 8.3.2) and within 30 days for all other medication errors.
The definition of a medication error can be found in Appendix B 8.
8.5
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.6
Pharmacodynamics
The gastroesophageal pH will be measured during 12 hours as an indicator of gastric 
antisecretory activity (optional).
The gastroesophageal pH monitoring is preferably done at Visit 10 (Week 32), but is also 
suggested if signs of RE relapse or GU/DU recurrence either before (Week 8 to 32) or after 
(Week 32 to 52) this time point. The date of performing the pH monitoring must be recorded in 
the eCRF.
A combined catheter with 2 pH sensors will be introduced and gastroesophageal pH will be 
measured during 12 hours. The pH probe will be inserted nasally with the esophageal sensor 
positioned 3 cm above the lower esophageal sphincter, and the gastric sensor within the central 
part of the stomach. The precise location of the tip will be confirmed. The subject should be in 
fasting condition at least 4 hours before pH monitoring. The gastroesophageal pH will be 
recorded every 10 seconds. The results of pH monitoring (electronic data) will be submitted to 
AstraZeneca or designee. Data extraction, storage and sending will be performed according to the 
manual.
The gastroesophageal pH monitoring will be performed in the subjects obtained informed consent 
from subject’s guardians.

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8.7
Genetics
The purpose of the genetic research is to investigate the genotype of CYP2C19, a metabolising 
enzyme of D961H known to have 2 genotypes. These genotypes are named ‘Extensive,
Metaboliser (EM)’ (EM homozygotes- and EM heterozygotes- types) and ‘poor metaboliser 
(PM)’. Since changes in blood D961H concentrations showed different tendency between the 2 
metabolisers and as a different in pH time might be seen, they will be examined accordingly.
Subjects will be categorized using the 2 mutated alleles, CYP2C19*2 and CYP2C19*3. The 
wild-type allele (CYP2C19*1) will be defined if these mutation are not detected. EM 
homozygote types (homo-EMs) are to be homozygous for the wild-type allele (CYP2C19*1/*1); 
EM heterozygote types (hetero-EMs) are to be heterozygous for the CYP2C19*2 allele without 
CYP2C19*3 (CYP2C19*1/*2) or the CYP2C19*3 without CYP2C19*2 (CYP2C19*1/*3), PMs
are to be homozygous or heterozygous for either variant allele (CYP2C19*2/*2, *3/*3, *2/*3).
This test will be conducted in the central laboratory. If results of the CYP2C19 genotype are 
already available at the study site, they will be provided to AstraZeneca with the consent of 
subject’s guardian and an additional analysis will not be required.
8.7.1
Collection of mandatory genetic samples
The blood sample (2 mL) for genetic research of CYP subtype CYP2C19 will be obtained from 
the subjects at Visit 2. Only 1 sample should be collected per subject for genetics during the 
study. Samples will be collected, labelled, stored and shipped as detailed in the procedure 
manual.
Special attention is required for conducting a genetic test. The following items should be obeyed 
to conduct a genetic test and explained to the subjects at the time of informed consent is
provided:
!
Written informed consent to a genetic test must be provided by each subject’s
guardian.
!
From the aspect of this study design, implementation of a genetic test is a requirement 
for the subject to participate in the study.
!
From the aspect of this study design, personnel involved in the study at the study sites 
and AstraZeneca or designee will have knowledge of genetic information on the 
subjects based on the genetic test results.
!
Samples for the genetic test to be sent to the laboratory will not be labelled with
subject identifiers so that the information on the subject will not be revealed to any 
other parties.
!
Samples of the subject who is not assigned to treatment groups in the study will be 
destroyed immediately by central laboratory.

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!
If the genetic test for the sample of the subject who is not assigned to treatment groups 
in the study was completed, the results of the test and the records will be destroyed 
immediately by central laboratory.
!
In the case the subject’s guardian in concern wishes a release of the genetic test 
results, the results will be disclosed to subject’s guardian via investigator (s) after the 
database of this study is locked. However, the results will be disclosed to subject’s 
guardians immediately even before the database is locked only when the subject’s 
guardian requests to do so during the study period.
!
All samples collected for a genetic test will be used only for CYP2C19 genotyping and 
will be destroyed immediately after completion of the CYP2C19 genotyping by central 
laboratory.
8.7.2
Optional exploratory genetic sample
Paediatric subject samples will not be collected for optional genetic research.
8.7.3
Storage and destruction of genetic samples
The samples will be used up or disposed according to the following rules:
A full chain of custody is maintained for all samples throughout their lifecycle.
The principal investigator at each study site keeps full traceability of collected biological 
samples from the subjects while in storage at the study site until shipment or disposal (where 
appropriate) and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of
study sites and auditing of external laboratory providers.
If a subject’s guardian withdraws consent to the use of donated biological samples, the samples 
will be disposed of/destroyed, and the action documented. If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study, then the subject is 
withdrawn from further study participation.
The principal investigator:
!
Ensures subject’s guardian withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca.
!
Ensures that biological samples from that subject, if stored at the study site, are
immediately identified, disposed of/destroyed, and the action documented.

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!
Ensures the laboratory holding the samples are informed about the withdrawn consent 
immediately and that samples are disposed/destroyed, the action documented and the 
signed document returned to the study site.
!
Ensures that subject’s guardian and AstraZeneca are informed about the sample
disposal.
AstraZeneca ensures the central laboratory holding the samples are informed about the
withdrawn consent immediately and that samples are disposed of/destroyed and the action
documented and returned to the study site.
8.8
Biomarkers
Biomarkers are not evaluated in this study.
8.9
Health economics
Health economics parameter is not evaluated in this study.
9.
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
Not applicable because no formal statistical analysis is planned in this study.
9.2
Sample size determination 
Maintenance therapy for healed RE study part:
!
Group 1: aged 1 to 14 years (weight ≥10 kg, <20 kg), Maintenance phase, n=5 to 10
!
Group 2: aged 1 to 14 years (weight ≥20 kg), Maintenance phase, n=10 to 20
Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
!
Group 3: aged 1 to 14 years (weight ≥10 kg, <20 kg), n=5 to 10 at Week 0
!
Group 4: aged 1 to 14 years (weight ≥20 kg), n=10 to 20 at Week 0
In treatment Groups 1 and 3, physically disabled patients, for whom an objective assessment of 
symptoms or EGD findings is possible, or who are judged by the investigator to be able to report 
gastrointestinal symptoms, are allowed to participate in the study up to 3 subjects/group. In 
treatment Groups 2 and 4, physically disabled patients, for which objective assessment of 
symptoms or EGD findings is possible, or that are judged by the investigator to be able to report 
gastrointestinal symptoms, are allowed to participate in the study up to 6 subjects/group.
Rationale for the sample size:

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The sample size of this study is not based on any power calculations.
The sample size for maintenance therapy for the healed RE study part was set based on 
operational feasibility perspective. In reference to Japanese epidemiology data (Ohara et al 
2005), 24.5% of adult patients with heart burn had endoscopic LA grade A or higher erosive 
esophagitis. Even if the prevalence rate in Japanese paediatrics was smaller than that in adults for 
instance 15%, enrolment of achievable 150 subjects will enable 22 to 23 subjects to start the 
initial healing therapy. Then, at least 15 subjects will enter into the maintenance phase.
For the prevention of GU/DU recurrence associated with NSAIDs/LDA study part, it is 
estimated that almost all enrolled subjects will start treatment with investigational product. 
Therefore, it is considered that enrolment of 15 to 30 paediatric Japanese subjects will achieve 15 
to 30 registration of subjects to start with the investigational product.
9.3
Populations for analyses
For purposes of analysis, the following populations are defined: 
Population
Description
Efficacy Analysis Set
Maintenance therapy for healed RE study part:
1. Initial healing therapy period
All subjects registered to initial healing therapy who take at least 1
dose of the investigational product and have at least 1 efficacy 
datum assessment during the initial healing therapy period, and who 
have no important protocol deviation.
2. Maintenance therapy period
All subjects registered to maintenance therapy who take at least 1
dose of the investigational product and have at least 1 efficacy 
datum assessment during the maintenance therapy period, and who 
have no important protocol deviation.
3. Maintenance therapy extended period
All subjects registered to maintenance therapy who take at least 1
dose of the investigational product and have at least 1 efficacy 
datum assessment during the maintenance therapy extended period, 
and who have no important protocol deviation.
Prevention of GU/DU recurrence associated with long term 
NSAIDs/LDA therapy study part:
1. Prevention therapy period
All subjects who take at least 1 dose of the investigational product
and have at least 1 efficacy datum assessment during the prevention 
therapy period, and who have no important protocol deviation.
2. Prevention therapy extended period
All subjects who take at least 1 dose of the investigational product
and have at least 1 efficacy datum assessment during the prevention 

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Population
Description
therapy extended period, and who have no important protocol 
deviation.
Safety Analysis Set
Maintenance therapy for healed RE study part:
1.
Initial healing therapy period
All subjects registered to initial healing therapy who take at least 1
dose of the investigational product and have any post-treatment 
assessment during the initial healing therapy period.
2.
Maintenance therapy period
All subjects registered to maintenance therapy who take at least 1
dose of the investigational product and have any post-treatment 
assessment during the maintenance therapy period.
3.
Maintenance therapy extended period
All subjects registered to maintenance therapy who take at least 1
dose of the investigational product and have any post-treatment 
assessment during the maintenance therapy extended period.
Prevention of GU/DU recurrence associated with long term 
NSAIDs/LDA therapy study part:
1.
Prevention therapy period
All subjects who take at least 1 dose of the investigational product 
and have any post-treatment assessment during the prevention 
therapy period.
2.
Prevention therapy extended period
All subjects who take at least 1 dose of the investigational product 
and have any post-treatment assessment during the prevention 
therapy extended period.
Pharmacodynamic Analysis 
Set
Maintenance therapy for healed RE study part:
All subjects who have at least 1 gastroesophageal pH monitoring at 
post-dose without any serious protocol violation or deviant that 
would have an impact on the pharmacodynamic evaluation in 
maintenance therapy period.
Prevention of GU/DU recurrence associated with long term 
NSAIDs/LDA therapy study part:
All subjects who have at least 1 gastroesophageal pH monitoring at 
post-dose without any serious protocol violation or deviant that 
would have an impact on the pharmacodynamic evaluation.
9.4
Statistical analyses
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan will be developed and finalised before database lock and will describe the subject 
populations to be included in the analyses, and procedures for accounting for missing, unused, 

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and spurious data. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints. Any deviations from this plan will be reported in the clinical study 
report.
9.4.1
Efficacy analyses
Efficacy analyses are intended for Efficacy Analysis Set.
Maintenance therapy for healed RE study part:
For all subjects in Efficacy Analysis Set who have at least 1 efficacy assessment during the 
maintenance therapy period, the percentage of subjects with RE relapse and the time to RE 
relapse will be analysed by the Kaplan-Meier method for each treatment group by assessing any 
composite endpoint (RE-related symptoms or optional EGD findings) from Week 8 to 32 as a 
primary analysis. The time to RE relapse is defined as the number of days from the start date of 
maintenance phase to the earliest date of satisfying the RE relapse criteria in any composite 
endpoints. The censored subject is defined at the last evaluable date with symptom or EGD.
For subjects in Efficacy Analysis Set who continued the study treatment after Week 32, the 
percentage of subjects with RE relapse and the time to RE relapse will be analysed by the 
Kaplan-Meier method for each treatment group by assessing the similar composite endpoint of
the primary analysis from Week 8 to 52 (8 to 32 weeks and 32 to 52 weeks, respectively). 
RE-related symptoms (heartburn, acid regurgitation, dysphagia and epigastric pain) will be 
summarised by frequency and intensity from Week 0 to 8 and from Week 8 to 32 or 52 
separately. For all subjects in Efficacy Analysis Set, the number of subjects and their percentage 
of disappearance, exacerbation and recurrence for each symptom will be summarised by group 
from Week 0 to 8 and from Week 8 to 32 separately. 
Definitions of the disappearance, exacerbation and recurrence are given below:
!
Disappearance: the symptom disappeared during the period for subjects who had the 
corresponding symptom at the start of the period
!
Exacerbation: the symptom worsened during the period for subjects who had the 
corresponding symptom at the start of the period
!
Recurrence: the symptom occurred during the period for subjects who did not have the 
corresponding symptom at the start of the period
For subjects in Efficacy Analysis Set who continued the study treatment after Week 32, the 
similar number and percentage for each symptom will be summarised by group from Week 8 to 
52 (8 to 32 weeks and 32 to 52 weeks, respectively). 
Regarding endoscopic assessment of healed RE, the number of subjects who had RE relapse 
endoscopically will be summarised for all subjects in Efficacy Analysis Set who had an EGD 
result at post-dose by group. The number of subjects in Efficacy Analysis Set in each grade of 
the LA classification (graded A to D) for these subjects will be summarised by group.

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Prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part:
For all subjects in Efficacy Analysis Set, the percentage of subjects with GU/DU recurrence and 
the time to the recurrence will be analysed by the Kaplan-Meier method for each treatment group 
by assessing any composite endpoint (GU/DU-related symptoms or optional EGD findings) from 
Week 0 to 32 as a primary analysis. The time to GU/DU recurrence is defined as a number of 
days from the start date of investigational product to the earliest date of satisfying the recurrence 
criteria of GU or DU in any composite endpoints. The censored subject is defined at the last 
evaluable date with symptom or EGD.
For subjects in Efficacy Analysis Set who continued the study treatment after Week 32, the 
percentage of subjects with GU/DU recurrence and the time to the recurrence will be analysed by 
the Kaplan-Meier method for each treatment group by assessing the similar composite endpoint 
of the primary analysis from Week 0 to 52 (0 to 32 weeks and 32 to 52 weeks, respectively).
GU/DU-related symptoms (epigastric pain, discomfort in the stomach, abdomen enlarged 
feeling, nausea/vomiting, heartburn and anorexia) will be summarised by frequency and 
intensity. For all subjects in Efficacy Analysis Set, the number of subjects and its percentage of 
disappearance, exacerbation and recurrence of each symptom will be summarised by group from 
Week 0 to 32. 
Definitions of the disappearance, exacerbation and recurrence are given below:
!
Disappearance: the symptom disappeared during the period for subjects who had the 
corresponding symptom at the start of the period
!
Exacerbation: the symptom worsened during the period for subjects who had the 
corresponding symptom at the start of the period
!
Recurrence: the symptom occurred during the period for subjects who did not have the 
corresponding symptom at the start of the period
For subjects in Efficacy Analysis Set who continued the study treatment after Week 32, the same 
number and percentage for each symptom will be summarised by group from Week 0 to 52 (0 to 
32 weeks and 32 to 52 weeks, respectively).
Regarding endoscopic assessment of GU or DU and gastric erosions, the number of subjects will 
be summarised by group based on a clear definition of ulcer and modified LANZA score for all 
subjects in Efficacy Analysis Set who had EGD result at post-dose. The number of subjects with 
GU/DU and the number of subjects with each of the modified LANZA score (graded 0, 1+, 2+, 
3+ and 4+) will be summarised by group.
9.4.2
Safety analyses
All safety analyses will be performed on the Safety Analysis Set.

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Frequency and incidence rate of AEs, SAEs, DAEs and OAEs will be presented by MedDRA 
SOC and PT for each group. In addition, summaries of AEs will be further broken down by 
maximum intensity and relationship to the investigational product as assigned by investigators. 
Clinical laboratory variables and vital signs will be summarised by group with descriptive 
statistics using values and changes from Week 8 as baseline to Week 32 for the maintenance 
therapy for healed RE study part, and changes from Week 0 as baseline to Week 32 for 
prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study part. 
Qualitative data will be presented by group in terms of frequency and percentage, and changes 
from baseline will be presented using shift tables. The distribution of subject with values below 
and above the reference range will be provided.
In the maintenance therapy for healed RE study part, the safety assessments (AE, laboratory 
variables and vital signs) will be evaluated for all subjects in Safety Analysis Set from Week 8 as 
baseline to Week 32 as the primary analysis, and the similar safety assessment will be evaluated 
from Week 0 as baseline to Week 8 as the secondary analysis. For subjects in Safety Analysis 
Set who continued the study treatment after Week 32, the safety measurement from Week 8 as 
baseline to Week 52 (8 to 32 weeks and 32 to 52 weeks, respectively) will be evaluated.
For prevention of GU/DU recurrence associated with long term NSAIDs/LDA therapy study 
part, the same safety assessments will be evaluated for all subjects in Safety Analysis Set from 
Week 0 as baseline to Week 32 as the primary analysis. For all subjects in Safety Analysis Set 
who continued the study treatment after Week 32, the same safety assessments will be evaluated 
from Week 0 to 52 (0 to 32 weeks and 32 to 52 weeks, respectively) as the secondary analysis.
9.4.3
Pharmacodynamic analyses
Regarding gastroesophageal pH measurement, data will be presented as: 
!
Gastric pH: Percentages of time with intragastric pH >4 and pH >3, and median 
intragastric pH during 12 hours
!
Esophageal pH: Percentages of time with intraesophageal pH <4, number of acid 
reflux periods (pH <4) and number of acid reflux periods longer than 5 minutes during 
12 hours
9.5
Interim analyses
There is no plan to have any interim analyses.

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10.
REFERENCES
The Japanese Society for Helicobacter Research 2016
The Japanese Society for Helicobacter Research. The guideline for diagnosis and treatment of H. 
pylori infection (revised version, 2016). 
Lanza et al 1988
Lanza FL, Aspinall RL, Swabb EA, Davis RE, Rack MF, Rubin A. Double-blind, placebo-
controlled endoscopic comparison of the mucosal protective effects of misoprostol versus 
cimetidine on tolmetin-induced mucosal injury to the stomach and duodenum. Gastroenterology. 
1988;95(2):289-94.
Lundell et al 1999
Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, et al. Endoscopic 
assessment of oesophagitis: clinical and functional correlates and further validation of the Los 
Angeles classification. Gut. 1999;45(2):172-80.
Nagashima H and Ikushima I 2011
Nagashima H, Ikushima I. Evaluation of pharmacodynamics and pharmacokinetics of 
esomeprazole 10, 20 and 40 mg and omeprazole 10 and 20 mg in Japanese healthy male subjects. 
Japanese Journal of Therapeutics & Medicines. 2011;27(10):735-46.
Ohara et al 2005
Ohara S, Kouzu T, Kawano T, Kusano M. Nationwide epidemiological survey regarding 
heartburn and reflux esophagitis in Japanese. Journal of JSGE. 2005;102(8):1010-24.

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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:
!
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
!
Applicable Japan Good Clinical Practice (GCP) Guidelines
!
Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an institutional review board (IRB)/ independent
ethics committee (IEC) by the investigator and reviewed and approved by the IRB/IEC before 
the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.  
The head of the study site will be responsible for the following:
!
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
!
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
!
Providing oversight of the conduct of the study at the site and adherence to 
requirements of applicable guidelines, the IRB/IEC, and all other applicable local 
regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples.
A 2
Financial disclosure
Not applicable.
A 3
Informed consent process

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The investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorised representative will be required to sign a statement of informed consent that meets the 
requirements of local regulations, applicable guidelines and the IRB/IEC or study site.  
The medical record must include a statement that written informed consent was obtained before 
the subject was enrolled in the study and the date the written consent was obtained. The 
authorised person obtaining the informed consent must also sign the ICF.
Subjects must be re-consented to the most current version of the ICF(s) during their participation 
in the study.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorised 
representative.  
Subjects who are rescreened are required to sign a new ICF.
A 4
Data protection
Each subject will be assigned a unique identifier by the sponsor. Any subject records or data sets 
transferred to the sponsor will contain only the identifier; subject names or any information 
which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the subject.  
The subject must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorised personnel appointed by the sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and letters 
to investigators.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical trial and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
A 7
Data quality assurance

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All subject data relating to the study will be recorded on eCRF unless transmitted to the sponsor 
or designee electronically (eg, laboratory data). The investigator is responsible for verifying that 
data entries are accurate and correct by electronically signing the eCRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
Japan GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site.
Data reported on the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
Definitions of what constitutes source data are any data generated as a result of the subject’s 
inclusion in the study and includes all related medical examinations and other records and may 
also include past/current medical records.
A 9
Publication policy
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments.  
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 

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multi-centre studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.

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Appendix B
AE definitions and additional safety information
B 1
Definition of AEs
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence. An AE may occur at any time, including run-in or washout 
periods, even if no study treatment has been administered.
B 2
Definitions of SAE
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up), 
that fulfils 1 or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-subject hospitalisation or prolongation of existing hospitalisation 
!
Results in persistent or significant disability or incapacity.  
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above.
B 3
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the subject’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the subject was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.

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B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical treatment to prevent 1 or more outcomes listed in the definition of serious. These should 
usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse
B 6
Intensity rating scale:
1.
mild (awareness of sign or symptom, but easily tolerated)
2.
moderate (discomfort sufficient to cause interference with normal activities)
3.
severe (incapacitating, with inability to perform normal activities)
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality considers the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the subject actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

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!
No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca investigational product that either causes harm to the 
participant or has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error.  
!
occurred
!
was identified and intercepted before the participant received the drug
!
did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

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!
Drug name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given 
to the participant
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
!
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 
!
Drug not stored as instructed 
!
Wrong participant received the medication (excluding interactive voice response 
system [IVRS]/interactive web response system [IWRS] errors)
!
Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IVRS/IWRS - including those which lead to one of 
the above listed events that would otherwise have been a medication error 
!
Participant accidentally missed drug dose(s) eg, forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each study site keeps full traceability of collected biological samples from the 
subjects while in storage at the study site until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, monitoring 
of study sites, auditing or process checks, and contractual requirements of external laboratory 
providers
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
C 2
Withdrawal of Informed Consent for donated biological samples 
If a subject/subject’s guardian withdraws consent to the use of donated biological samples, the 
samples will be disposed of/destroyed, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the subject is
withdrawn from further study participation. 
The investigator:
!
Ensures subject’s withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca
!
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
!
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action 
documented and the signed document returned to the study site
!
Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed and the action documented and 
returned to the study site.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document

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LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories. For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations in the 46th edition (2005). 
Infectious substances are now classified either as Category A, Category B or Exempt. There is 
no direct relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are eg, Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number and 
proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.

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Appendix D
Genetics
Not applicable.

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Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately report 
Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. During the course of 
the study the investigator will remain vigilant for increases in liver biochemistry. The 
investigator is responsible for determining whether a subject meets potential Hy’s Law (PHL) 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; this 
includes samples taken at scheduled study visits and other visits including central and all local 
laboratory evaluations even if collected outside of the study visits; for example, PHL criteria 
could be met by an elevated ALT from a central laboratory and/or elevated TBL from a local 
laboratory.  
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational medicinal 
product (IMP). 
The investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
SAEs and AEs according to the outcome of the review and assessment in line with standard 
safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥ 2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase (ALP).  
Hy’s Law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  For PHL and HL the elevation in transaminases must 
precede or be coincident with (ie, on the same day) the elevation in TBL, but there is no 
specified timeframe within which the elevations in transaminases and TBL must occur.
E 3
Identification of potential Hy’s Law cases

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In order to identify cases of PHL it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination:
!
ALT ≥ 3 × ULN
!
AST ≥ 3 × ULN
!
TBL ≥ 2 × ULN
Central laboratories being used:
When a subject meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the investigator (and also to the AstraZeneca 
representative). The investigator will also remain vigilant for any local laboratory reports where 
the PHL identification criteria are met, where this is the case the investigator will:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) by the central laboratory without delay
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the investigator 
will without delay:
!
Determine whether the subject meets PHL criteria (see Appendix E 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)
Local laboratories being used:
Not applicable.
E 4
Follow-up
E 4.1
Potential Hy’s Law criteria not met
If the subject does not meet PHL criteria the investigator will:
!
Inform the AstraZeneca representative that the subject has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
E 4.2
Potential Hy’s Law criteria met

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If the subject does meet PHL criteria the investigator will:
!
Notify the AstraZeneca representative who will then inform the central study team 
!
Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE 
of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting.
!
For subjects that met PHL criteria prior to starting IMP, the investigator is not required 
to submit a PHL SAE unless there is a significant change# in the subject’s condition
!
The study physician contacts the investigator, to provide guidance, discuss and agree 
an approach for the study subjects’ follow-up (including any further laboratory testing) 
and the continuous review of data.
Subsequent to this contact the investigator will:
!
Monitor the subject until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as long 
as medically indicated. Completes follow-up SAE Form as required.
!
Investigate the aetiology of the event and perform diagnostic 
investigations as discussed with the study physician.This includes 
deciding which the tests available in the Hy’s law lab kit should be used
!
Complete the three Liver CRF Modules as information becomes available 
#
A ‘significant’ change in the subject’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or total 
bilirubin) in isolation or in combination, or a clinically relevant change in 
associated symptoms. The determination of whether there has been a significant 
change will be at the discretion of the investigator, this may be in consultation 
with the study physician if there is any uncertainty.
E 5
Review and assessment of potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.As 
soon as possible after the biochemistry abnormality was initially detected, the study physician 
contacts the investigator in order to review available data and agree on whether there is an 
alternative explanation for meeting PHL criteria other than DILI caused by the IMP, to ensure 
timely analysis and reporting to health authorities within 15 calendar days from date PHL criteria 
was met. The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will 
also be involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.

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Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF
!
If the alternative explanation is an AE/SAE, update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) follow the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.
∀
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay, of over 15 calendar days in obtaining the information necessary 
to assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
!
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE 
reporting.
!
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
E 6
Actions required when potential Hy’s Law criteria are met before and 
after starting study treatment
Not applicable.
E 7
Actions required for repeat episodes of potential Hy’s Law
Not applicable.

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E 8
Laboratory tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory . For studies using a local 
laboratory, the list may be modified based on clinical judgement. If required, additional 
assistance on which tests could be used to evaluate other potential causes of liver dysfunction 
consult with the Hepatic Safety Knowledge Group. Any test results need to be recorded in the 
CRF.
Hy’s Law recommended tests
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgG anti-HCV
HCV RNA*
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin)
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
* HCV RNA is only tested when IgG anti-HCV is positive or inconclusive.
References
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.

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FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’

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Appendix F
Abbreviations 
Abbreviation or 
special term
Explanation
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
CEC
central evaluation committee
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
CYP
cytochrome P450
DAE
discontinuation of investigational product due to adverse event
DILI
drug induced liver injury
DMARD
disease modifying anti-rheumatic drug
DU
duodenal ulcer
eCRF
case report form (electronic)
EGD
esophagogastroduodenoscopy
EM
extensive metaboliser
EU
European Union
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GU
gastric ulcer
HL
Hy’s Law
H. pylori
Helicobacter pylori
IATA
International Airline Transportation Association
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
independent ethics committee
IgG
immunoglobulin G
IRB
institutional review board
IVRS
interactive voice response system
IWRS
interactive web response system
LA classification
Los Angeles classification
LDA
low-dose aspirin

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Abbreviation or 
special term
Explanation
MALT
mucosa-associated lymphoid tissue
MedDRA
Medical Dictionary for Regulatory Activities
NSAIDs
non-steroidal anti-inflammatory drugs
OAE
other significant adverse event
PHL
potential Hy’s Law
PM
poor metaboliser
PPI
proton pump inhibitor
PT
preferred term
RE
reflux esophagitis
SAE
serious adverse event 
SoA
schedule of activities
SOC
system organ class
TBL
total bilirubin
ULN
upper limit normal
US
United States
WBDC
web based data capture