Randomized Multicentre Open-label Study to Investigate the Non-inferiority of Itopride Hydrochloride 150mg Once Daily Versus Itopride Hydrochloride 50 mg Thrice Daily in Subjects With Functional (Non-ulcer) Dyspepsia or Chronic Gastritis
Phase: PHASE3
Conditions: Functional Dyspepsia
Sponsor: Abbott

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CLINICAL STUDY PROTOCOL
Cover Page
Protocol No.:
ITOP-322-0216
        Protocol Date:         05-SEP-2023
Study Title:
A randomized, multicentre, parallel–group, open-label, active-
controlled study to investigate the non-inferiority of Itopride 
Hydrochloride 150mg extended release tablets once daily versus  
Itopride Hydrochloride 50 mg film coated tablets thrice daily in 
subjects with gastrointestinal symptoms caused by gastric 
dysmotility and delayed gastric emptying like bloating sensation, 
early satiety, postprandial fullness, upper abdominal pain or 
discomfort, anorexia, heartburn, nausea, and vomiting in 
functional (non-ulcer) dyspepsia or chronic gastritis.
IND No.:
Not applicable
EudraCT No.:
Not applicable
Phase of Development:
III
Sponsor:
Abbott Healthcare Products B.V., Weesp, The Netherlands
Global Clinical Director:
Suntje Sander-Struckmeier
Protocol Author(s) Name & 
Contact Details: 
Suntje Sander-Struckmeier, Elke Kahler
Abbott Laboratories GmBH, Hannover, Germany
Confidentiality Agreement
This document is a confidential communication of the Sponsor. Acceptance of this document constitutes the agreement by the recipient that 
no unpublished information contained within will be published or disclosed without prior written approval, except that this document may be 
disclosed to the appropriate Ethical Review Committees and Regulatory Authorities under the condition that they are requested to keep it 
confidential.

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CLINICAL STUDY PROTOCOL
Protocol Signature Page
Protocol No.:
ITOP-322-0216
Protocol Date:
       05-SEP-2023
Study Title:
A randomized, multicentre, parallel–group, open-label, active-
controlled study to investigate the non-inferiority of Itopride 
Hydrochloride 150mg extended release tablets once daily 
versus  Itopride Hydrochloride 50 mg film coated tabletsthrice 
daily in subjects with gastrointestinal symptoms caused by 
gastric dysmotility and delayed gastric emptying like bloating 
sensation, early satiety, postprandial fullness, upper abdominal 
pain or discomfort, anorexia, heartburn, nausea, and vomiting 
in functional (non-ulcer) dyspepsia or chronic gastritis.
Sponsor:
Abbott Healthcare Products B.V.
Global Clinical Director:
Suntje Sander-Struckmeier
Protocol Author(s) Name 
& Contact Details:
Suntje Sander-Struckmeier, Elke Kahler
Abbott Laboratories GmbH, Hannover, Germany
Sponsor Representative:
Suntje Sander-Struckmeier
Global Clinical Director
Abbott Laboratories GmbHFreundallee 9A
30173 Hannover
Germany
Date

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BY SIGNING BELOW, I, THE INVESTIGATOR, AGREE TO CONDUCT THE 
CLINICAL RESEARCH STUDY AS DESCRIBED IN THIS PROTOCOL.
Investigator:
<name>
<affiliation/institution>
<city, state/province, country>
Date
Confidentiality Agreement
This document is a confidential communication of the Sponsor. Acceptance of this document constitutes the agreement by the recipient that no 
unpublished information contained within will be published or disclosed without prior written approval, except that this document may be 
disclosed to the appropriate Ethical Review Committees and Regulatory Authorities under the condition that they are requested to keep it 
confidential.

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SYNOPSIS            
Name of Sponsor:
Abbott
Name 
of 
Finished 
Product:
Itopride Hydrochloride 
150mg extended release 
tablets
Name of Active Ingredient(s):
Itopride
Title of Study:
A randomized, multicentre, parallel–group, open-label, active-controlled study to investigate 
the non-inferiority of Itopride Hydrochloride 150 mg extended release once daily versus 
Itopride Hydrochloride 50 mg film coated tablets thrice daily in subjects with gastrointestinal 
symptoms caused by gastric dysmotility and delayed gastric emptying like bloating sensation, 
early satiety, postprandial fullness, upper abdominal pain or discomfort, anorexia, heartburn, 
nausea, and vomiting in functional (non-ulcer) dyspepsia or chronic gastritis.
Study Duration:
Approximately 21 months. The enrolment period is estimated to be
approximately 8 months from first subject screened. 
Phase of Development:
III
Objectives:
Primary objective(s):
To assess the comparable efficacy of Itopride Hydrochloride 150 mg extended release tablet
(administered once daily) and Itopride Hydrochloride 50 mg film coated tablets (administered 
TID) after 8 weeks treatment. 
Secondary objective(s):

To assess the comparable efficacy of Itopride Hydrochloride 150 mg extended release 
tablet (administered once daily) and Itopride Hydrochloride 50 mg film coated tablets
(administered TID) after 4 weeks treatment. 

To assess quality of life for the two treatment arms using Disease Specific Quality of 
Life (Short Form - Nepean Dyspepsia Index SF-NDI) at baseline and end of treatment

To assess the symptomatology (sensation of bloating, early satiety, postprandial 
fullness, upper abdominal pain or discomfort (epigastric pain, epigastric burning), 
anorexia (loss of appetite), heartburn, nausea and vomiting) of the disease in both 
treatment arms after 4 and 8 weeks of treatment. 

Study treatment Period 
Visit at baseline/randonnzation 
Week 4 and Week 8 
Control Arm 
N=282 
L 
Itopride Hydrochloride 50 mg film 
coated tablets 
Duration 4— 2 weeks —1.14 
Itopride Hydrochloride 150mg 
extended release tablets 
6. 3 weeks 
1 
H.— 1 week 
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Name of Sponsor:
Abbott
Name 
of 
Finished 
Product:
Itopride Hydrochloride 
150mg extended release 
tablets
Name of Active Ingredient(s):
Itopride

To assess the number of responders of adequate/satisfactory relief from FD symptoms.
Exploratory objective(s):

Treatment acceptance by subjects using 5-point Likert scale at the end of the treatment
Safety objective(s): 

To evaluate safety and tolerability in both treatment arms
Methodology:
Number of Subjects (Planned):
Number of subjects to be allocated to treatment: 564 (N= 282 per arm).
Number of subjects to be screened: Approx.700

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Name of Sponsor:
Abbott
Name 
of 
Finished 
Product:
Itopride Hydrochloride 
150mg extended release 
tablets
Name of Active Ingredient(s):
Itopride
Diagnosis and Main Criteria for Inclusion:
1. Adult male and/or non-pregnant non-lactating female subjects aged above 18 years.
2. Subjects provided written informed consent and are willing to participate in the study.
3. Subjects with functional (non-ulcer) dyspepsia according to Rome IV criteria 
including postprandial distress syndrome (PDS) and with or without EPS (epigastric 
pain syndrome) with one or more of the following:
-bothersome postprandial fullness, 
-bothersome early satiation
-bothersome epigastric pain, 
-bothersome epigastric burning 
for at least 12 weeks in the preceding 6 months 
4. No evidence of organic, systemic, metabolic or structural disease likely to explain 
symptoms - Subjects who have to undergone physical examination and lab tests 
(including white-cell and red-cell counts, measurement of fasting blood sugar and 
liver-function tests), abdominal ultrasonography, and upper GI endoscopy* in order to 
rule out structural cause for symptoms of FD. 
              *history of upper GI endoscopy within 6 months prior to enrolment or at screening.
5. Baseline severity of at least moderate symptoms on LDQ (total score ≥9) at screening. 
6. H. pylori negative documented test report within 3 months prior to enrolment or during 
screening.
Main Criteria for Exclusion
1. Known hypersensitivity to Itopride or any component of the formulation and to any 
other related drug.
2. Subject with history or presence of clinically relevant evidence of cardiovascular, 
neurological, gastrointestinal/hepatic, renal, psychiatric, respiratory, urogenital, 
hematologic/immunologic, HEENT (head, ears, eyes, nose, throat), dermatological/ 
connective tissue, musculoskeletal, metabolic/nutritional, drug hypersensitivity, 
allergy, endocrine, major surgery or other relevant disease as revealed by medical 
history requiring treatment which at investigator’s discretion might interfere with the 
study..
3. Subjects who cannot be treated with Itopride in line with the prescribing information

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Name of Sponsor:
Abbott
Name 
of 
Finished 
Product:
Itopride Hydrochloride 
150mg extended release 
tablets
Name of Active Ingredient(s):
Itopride
4. Subjects scheduled for surgery during the study.
5. Subjects with a history of difficulty in swallowing.
6. Subject requiring concomitant treatment with anticholinergic drugs, drugs with narrow 
therapeutic index, sustained release or enteric-coated formulations.
7. Subjects taking Acid release inhibitors (e.g. histamine-2-receptor [H2]- antagonists, 
proton pump inhibitors [PPI], or potassium-competitive acid blockers), antacids (e.g. 
aluminium- or magnesium hydroxide, sodium bicarbonate), gastric mucosa protectors 
(e.g. sucralfate, rebamipide).
8. Subject with history of unusual bleeding and family history for bleeding disorders.
9. Subjects with only reflux-related symptoms or who have predominantly reflux-related 
symptoms.
10. Subjects with esophagitis, Barrett`s esophagus, erosions or peptic ulcer disease within 
one year prior to the study or Zollinger-Ellison Syndrome.
11. Dyspepsia that is exclusively relieved by defecation or associated with a change in 
stool frequency or stool form to exclude IBS.
12. Clinically significant ECG abnormalities.
13. Subjects treated with Itopride or any other gastroprokinetic within 4 weeks prior to 
screening. 
14. Subjects who took non-steroidal anti-inflammatory drugs for more than 2 weeks prior 
to screening
15. Subjects with refractory FD1 (defined as FD presenting symptoms continuing for at 
least 6 months, unresponsive to at least two medical treatments such as PPIs, 
prokinetics, or H. pylori eradication) as per investigator’s discretion
16. History of or known inflammatory bowel disease (IBD) or coeliac disease.
17. History of or known severe hepatic, renal, pancreatic, cardiac, metabolic, 
hematological or malignant disease or trimethylaminuria.
18. Subjects with changed smoking status within the last three months.
19. History of or known GI malignancy or ulcers associated to malignancy or any alarm 
features for GI malignancy, e.g. GI bleeding.
20. Subjects who do not meet the criteria stated in concomitant medication section.
21. Subjects with history of severe depression, anxiety or other psychological disorders.
22. Females with child-bearing potential must agree to use an acceptable method of 
contraception during the study.

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Name of Sponsor:
Abbott
Name 
of 
Finished 
Product:
Itopride Hydrochloride 
150mg extended release 
tablets
Name of Active Ingredient(s):
Itopride
23. Subjects in whom an increase in gastrointestinal motility could be harmful, e.g.,
(history of) gastrointestinal hemorrhage, mechanical obstruction or perforation.
24. Specific food intolerance which is relieved by diet modifications (e.g. lactose 
intolerance, celiac disease).
25. Subjects with confirmed IBS as per Rome IV criteria.
26. Current alcohol or drug abuse.
27. History of abdominal surgery except appendectomy, cholecystectomy or 
hysterectomy, tubal ligations, bladder slings or vasectomies.
28. Hepatic cirrhosis or abnormal liver laboratory findings (defined as >3xULN of ALT 
or AST).
29. Subjects under hemodialysis therapy or having advanced chronic kidney disease 
(defined as eGFR <60 mL/min).
30. History of or known congestive heart failure NYHA class III and IV, or any other 
uncontrolled chronic diseases, such as: uncontrolled hypertension (systolic/diastolic 
blood pressure ≥160/100 mmHg); uncontrolled diabetes (HbA1c >8%).
31. Subjects currently being known to be afflicted by serious infection(s), or any known 
severe illness(es) which are judged by the investigator could interfere with subjects' 
safety and/or study evaluation.
Duration of Treatment:
8 weeks
Reference Therapy, Dose and Mode of Administration:
Test group - Itopride Hydrochloride 150 mg extended release tablets once daily before one of 
the main meals (preferably the same meal throughout the treatment)
Active Control group - Itopride Hydrochloride 50 mg film coated tablets 3 times daily before 
meals
Ganaton/Ganaton OD/Elthon/Elthon OD is the Abbott brand name for Itopride Hydrochloride 
in most countries and it may vary in some countries.
Criteria for Evaluation:
Efficacy:
Primary endpoint(s):

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Name of Sponsor:
Abbott
Name 
of 
Finished 
Product:
Itopride Hydrochloride 
150mg extended release 
tablets
Name of Active Ingredient(s):
Itopride
Change in the overall severity of functional dyspepsia between baseline and week 8, as 
measured by the Leeds Dyspepsia Questionnaire (LDQ) severity score
Secondary endpoint(s):

Change in the overall severity of functional dyspepsia between baseline and week 4, 
as measured by the Leeds Dyspepsia Questionnaire (LDQ) severity score

Disease Specific Quality of Life (Nepean Dyspepsia Index NDI) assessed at baseline 
and week 8

Change from baseline of NRS 11 score for symptoms (sensation of bloating, early 
satiety, postprandial fullness, upper abdominal pain or discomfort (epigastric pain, 
epigastric burning), anorexia (loss of appetite), heartburn, nausea and vomiting) after 
4 and 8 weeks of treatment

Responder analysis for adequate/satisfactory relief as assessed by LDQ and/or NRS 
11

Treatment acceptance and ease of use assessed by subjects using 5-point Likert scale 
Safety:

To evaluate the safety and tolerability of the two treatments by assessing the following 
safety endpoints: Treatment emergent adverse events (TEAEs) as detected by physical 
examination, laboratory assessments and vital signs.
Statistical Methods:
Efficacy
Primary efficacy:

An ANCOVA analysis will be performed with the change in the LDQ score as 
dependent variable and treatment group, site and LDQ baseline value as additional 
factors. The difference between the two treatment groups will be calculated for the 
non-inferiority comparisons, together with a two-sided 95% confidence interval. Non-
inferiority will be considered achieved if the lower bound of the 95% confidence 
interval of the difference between the two groups is greater than 1.75 (NI-margin). 
Normal approximation will be assumed for the parametric analyses. The primary 
analysis will be performed for both the per protocol set and the full analysis set. The 
analysis for the per-protocol set will be regarded as primary. 

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Name of Sponsor:
Abbott
Name 
of 
Finished 
Product:
Itopride Hydrochloride 
150mg extended release 
tablets
Name of Active Ingredient(s):
Itopride
Secondary efficacy:

Full analysis sample will be used for the analysis of the secondary endpoints.

All secondary efficacy variables will be assessed using descriptive statistics.

In addition, the change from baseline in LDQ score at week 4 and the NRS 11 score 
for each symptom will be evaluated using the same analysis as specified for the 
primary endpoint. 
Safety

The safety sample will be used for the analysis of the safety and tolerability data. 
Adverse Events, laboratory values and vital signs will be analyzed descriptively.
Interim analysis
Not applicable
Sample size
Assumptions for sample size calculation are based on the studies of Holtmann et al.2 and 
Talley et al.3from which a standard deviation of 7 can be assumed for the change of the LD 
questionnaire.
For the NI margin following assumptions were made:

In the Holtmann study2, a difference to placebo of 2 (95% CI: 0.03-3.97) in the LDQ 
was reported. 

In the Ang publication4 (2011), a difference of 10-15% to placebo is regarded as 
clinically relevant

NI-margin needs to be lower than 2. A difference of 15% results in 1.74. Therefore, a 
NI margin of 1.75 is chosen.
Assuming a NI margin of 1.75 and standard deviation of 7 for the change in the LDQ severity 
score, 253 subjects per treatment arm are required to conclude non-inferiority between the 2 
treatment groups with a power of 80% at α-level of 2.5% single sided. Adding a 10% drop-
out rate the total sample size would be 564 subjects (N= 282 per arm).

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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL ...........................................................................................1
SYNOPSIS.................................................................................................................................4
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS...........................................14
1
ETHICS..................................................................................................................17
1.1
Independent Ethics Committee or Institutional Review Board..................................17
1.2
Ethical Conduct of the Study....................................................................................17
1.3
Subject Information and Consent .............................................................................17
2
INTRODUCTION .................................................................................................18
3
STUDY OBJECTIVES..........................................................................................20
3.1
Primary Objective(s)................................................................................................20
3.2
Secondary Objective(s)............................................................................................20
3.3
Exploratory Objective(s)..........................................................................................20
3.4
Safety Objective(s) ..................................................................................................20
4
STUDY DESIGN ...................................................................................................20
4.1
Overall Study Design and Plan-Description .............................................................20
4.2
Discussion of Study Design, Including the Choice of Control Groups......................22
5
SELECTION OF STUDY POPULATION...........................................................24
5.1
Inclusion Criteria .....................................................................................................24
5.2
Exclusion Criteria ....................................................................................................24
6
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT................26
7
TREATMENTS .....................................................................................................27
7.1
Treatments to Be Administered................................................................................27
7.2
Packaging and Labeling...........................................................................................27
7.3
Storage and Dispensing of Study Drug.....................................................................27
7.4
Method of Assigning Subjects to Treatment Groups.................................................28
7.5
Selection of Doses in the Study................................................................................28
7.6
Selection and Timing of Dose for Each Subject .......................................................30
7.7
Blinding and Treatment Code Information...............................................................30
7.8
Prior and Concomitant Therapy ...............................................................................30
7.9
Treatment Compliance.............................................................................................31
8
STUDY ASSESSMENTS AND FLOW CHART..................................................32
8.1
Efficacy Measurements............................................................................................32
8.2
Safety Measurements...............................................................................................34
8.3
Other Assessments...................................................................................................35
8.4
Appropriateness of Measurements ...........................................................................36

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8.5
Primary Efficacy Variable(s)....................................................................................36
8.6
Flow Chart of Study Assessments............................................................................38
9
ADVERSE EVENTS .............................................................................................40
9.1
Adverse Events........................................................................................................40
9.1.1
Recording of Adverse Events...................................................................................40
9.1.2
Follow-up of Adverse Events...................................................................................42
9.2
Serious Adverse Events (SAEs) ...............................................................................42
9.2.1
Reporting Serious Adverse Events...........................................................................42
9.3
Pregnancy................................................................................................................43
10
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE.....43
10.1
General Definitions and Conventions.......................................................................44
10.2
Subject Samples.......................................................................................................45
10.3
Safety ......................................................................................................................46
10.4
Other Assessments...................................................................................................47
10.5
Subgroup Analysis...................................................................................................47
10.6
Interim Analysis ......................................................................................................47
10.7
Determination of Sample Size..................................................................................47
11
INVESTIGATOR OBLIGATIONS......................................................................49
11.1
Essential Study Documents......................................................................................49
11.2
Case Report Form (CRF) Completion......................................................................49
11.3
Essential Records Retention.....................................................................................51
11.4
Investigator Agreement............................................................................................51
12
SPONSOR OBLIGATIONS..................................................................................53
12.1
Protocol Amendments..............................................................................................53
12.2
Study Monitoring.....................................................................................................53
12.3
Quality Assurance and Quality Control....................................................................54
13
PUBLICATION POLICY .....................................................................................55
14
INSURANCE .........................................................................................................56
15
REFERENCES ......................................................................................................57
16
APPENDICES........................................................................................................59
16.1
Appendix – Participating Countries’ National Insurance Requirements....................59
16.2
Appendix – Medical expert for the trial....................................................................59
16.3
Appendix –Clinical laboratory(ies) involved in the trial ...........................................59

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LIST OF IN-TEXT TABLES
Table 1 – Study visits schedule
Table 2 – Study assessment schedule

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
ADR
Adverse drug reaction
AE
Adverse event
ANCOVA        Analysis of Covariance
ASEAN
Association of Southeast Asian Nations
AUC               Area under curve
ALT                Alanine amino transferase
AST                Aspartate amino transferase
ATC               Anatomical Therapeutic Chemical 
BPP
Biostatistics project Planning and Programming
CDM
Clinical Data Management
CFR
Code of Federal Regulations
CRF
Case report form (paper or other media)
CRO
Contract research organization
DBP
Diastolic blood pressure
ECG
Electrocardiogram
EDC
Electronic Data Capture
EMA
European Medicines Agency
EPS                 Epigastric pain syndrome
eCRF               electronic Case report form
FA
Full analysis
FGID               Functional Gastrointestinal Disorders 
GCP
Good Clinical Practice
GI                    Gastrointestinal
GMP               Good Manufacturing Practices 
GERD             Gastroesophageal Reflux Disease 
GPV
Global Pharmacovigilance 
HLT                 Highest level term
HLGT              High level group term
IB
Investigator’s Brochure

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IBD                 Inflammatory bowel disease 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug
IR                    Immediate release
IRB
Institutional Review Board
LDQ                Leeds Dyspepsia Questionnaire 
LDH                Lactate dehydrogenase
LLT                 Lowest level term
MedDRA
Medical Dictionary for Regulatory Activities
N/A
Not applicable
NI                   Non-inferior 
NDI                 Nepean Dyspepsia Index
NRS                Numerical Rating Scale 
NYHA            New York Heart Association
OD                  Once daily
PAGI-QoL      Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life 
PP
Per-protocol
PPI                  Proton pump inhibitor 
PT
Preferred term
PDS                Postprandial distress syndrome 
RSI                 Reference safety information 
SADR
Serious adverse drug reaction
SAE
Serious adverse event
SBP
Systolic blood pressure
SF NDI           Short Form - Nepean Dyspepsia Index 
SD
Standard Deviation
SSRI                Selective serotonin reuptake inhibitors
SNRI               Serotonin and norepinephrine reuptake inhibitors

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SOC
System organ class
SmPC
Summary of Product Characteristics
SUSAR
Suspected unexpected serious adverse reaction
TEAE              Treatment emergent adverse events
TID                  Ter in die (Three times a day)
UD                 Uninvestigated dyspepsia 

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1
ETHICS
1.1
Independent Ethics Committee or Institutional Review Board
The Sponsor (or an authorized representative) or the Investigator (according to national provisions) 
is responsible for obtaining written approval for the clinical study protocol (including all 
substantial protocol amendments), the written subject informed consent form (including written 
assent, when applicable), informed consent updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects from an Independent 
Ethics Committee (IEC) / Institutional Review Board (IRB) that complies with the local regulatory 
requirements.
Written approval of the study must be obtained from the IEC/IRB prior to the study being 
implemented (i.e., shipment of clinical supplies to the Investigator or screening of subjects). 
Copies of the approval documentation will be maintained by both the Investigator and the Sponsor 
(or an authorized representative) in the designated study documentation files.
The Sponsor (or an authorized representative) or the Investigator (according to national provisions) 
will submit written reports of the clinical study status to the IEC/IRB annually, or more frequently 
if requested by the IEC/IRB. A final study notification should be forwarded to the IEC/IRB within 
90 days after the study has completed, or in the event of premature termination of the study, within 
15 days with the rationale for study termination clearly explained. Copies of all clinical study status 
reports (including termination) will be maintained by both the Investigator and the Sponsor (or an 
authorized representative) in the study documentation files.
In accordance with national provisions or regulations, the Sponsor (or an authorized 
representative) will inform all participating IECs/IRBs and national authorities of all 
SAEs/SADRs/SUSARs or other safety-related information, which occur during the clinical study.
1.2
Ethical Conduct of the Study
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for 
designing, conducting, recording, and reporting studies that involve the participation of human 
subjects. The study will be conducted in compliance with GCP and the applicable national 
regulations to assure that the rights, safety, and well-being of the participating study subjects are 
protected consistent with the ethical principles that have their origin in the Declaration of Helsinki. 
1.3
Subject Information and Consent
Voluntary written informed consent will be obtained from each subject prior to performing any 
study-related procedures. Each subject will be given both verbal and written information 
describing the nature and duration of the clinical study. The informed consent process will take 
place under conditions where the subject has adequate time to consider the risks and benefits 
associated with his/her participation in the study. Subjects will not be screened or treated until the 

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subject has signed an approved informed consent written in a language that is understandable to 
the subject.
The IEC/IRB approved informed consent form will be signed and personally dated by the subject 
(or legally acceptable representative, when appropriate) and the person who conducted the 
informed consent discussion. Each subject is to receive a copy of the signed and dated written 
informed consent form and any other written subject information.
The signature of an impartial witness is to be obtained in the event the subject or the subject’s 
legally acceptable representative is unable to read. Additional signatures on the informed consent 
form may be required in accordance with IEC/IRB requirements or those of the Sponsor (or an 
authorized representative).
The Investigator is responsible for assuring the appropriate content of the informed consent form 
and that informed consent is obtained from each subject in accordance with the applicable
regulations and guidelines. The original signed informed consent is to be retained in the study 
documentation files.
The Investigator shall maintain a log of all subjects who sign the informed consent form and 
indicate if the subject received study drug or, if not, the reason why. The subject’s medical records 
should also document that the informed consent form was signed and dated prior to any study-
related procedures being performed.
2
INTRODUCTION
Dyspepsia is defined as the episodic and persistent symptoms of the upper gastrointestinal tract. It 
is the medical term for difficult digestion. Dyspepsia is associated with various symptoms which 
include bloating, fullness, heartburn, early satiation, nausea, vomiting and abdominal pain1. 
The global prevalence of dyspepsia is at least 20%5. In the meta analysis done by Ford AC et al5
overall pooled prevalence in all studies was 20.8% (95% CI 17.8% to 23.9%). The prevalence 
varied according to country (from 1.8% to 57.0%) and criteria used to define dyspepsia. The 
greatest prevalence values were found when a broad definition of dyspepsia (29.5%; 95% CI 
25.3% to 33.8%) or upper abdominal or epigastric pain or discomfort (20.4%; 95% CI 16.3% to 
24.8%) were used. The prevalence was higher in women (OR 1.24; 95% CI 1.13 to 1.36), smokers 
(OR 1.25; 95% CI 1.12 to 1.40), non-steroidal anti-inflammatory drug (NSAID) users (OR 1.59; 
95% CI 1.27 to 1.99) and Helicobacter pylori-positive individuals (OR 1.18; 95% CI 1.04 to 1.33).
The worldwide prevalence of uninvestigated dyspepsia (UD) varies from 7% to 34%, with a pooled 
UD prevalence from 21 Southeast Asian studies of 21.6%. The variation in UD prevalence seems 
to be related to the different definitions of UD used in individual surveys. Approximately 25% of 
dyspepsia cases have an underlying organic cause. In Thailand, the prevalence of dyspepsia is 
66%. Of those, 60–90% show no evidence of structural disease on endoscopy, i.e. functional 
dyspepsia (FD)6. A study from India reported prevalence of dyspepsia to be 30.4%7.

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The prevalence of dyspepsia varies considerably between different populations. Using the 
definition ‘upper abdominal pain’, the lowest UD prevalence of 7%-8% is seen in Singapore, South 
East Asia. Slightly higher rates are seen amongst the Scandinavians (14.5%) prevalence rates of 
23-25.8% are seen in the US, with 30.4% population in India and New Zealand (34.2%) having 
the highest rates. Using the definition ‘upper gastrointestinal symptoms’, a lower prevalence was
seen in Spain (23.9%), 32% UD prevalence rate was noted in the US whilst significantly higher 
rates of 38%-41% were noted in the UK and 45% in Nigeria8.
Based on the causes, dyspepsia is classified into two main categories, namely organic and 
Functional Dyspepsia (FD). Organic dyspepsia includes peptic ulcer and Gastroesophageal Reflux 
Disease (GERD) as most identifiable cause. On the other hand, FD which is one of the most 
prevalent Functional Gastrointestinal Disorders (FGIDs) is identified by pathophysiological 
mechanisms such as delayed gastric emptying, impaired gastric accommodation to a meal, burning 
sensation in the epigastrium, hypersensitivity to gastric distension, predominant epigastric pain, 
early satiety and feeling of fullness during or post meals4,9-10
Globally, most dyspepsia patients fall into the category of FD, also known as the non-ulcer 
dyspepsia. FD is further subdivided into two diagnostic categories of meal-induced dyspeptic 
symptoms [Postprandial Distress Syndrome (PDS), characterized by postprandial fullness and 
early satiation] and Epigastric Pain Syndrome [(EPS), characterized by epigastric pain and 
burning]11-12.
Large population-based studies revealed that the prevalence of FD ranges from 10% to 30% 
worldwide13. FD prevalence decreases with age, from 9.5% in those aged 18–35 years to 3.9% in 
those aged over 65 years. Dyspeptic symptoms are more common in women, smokers, and those 
taking non-steroidal anti-inflammatory drugs9.
Several pharmacological and non-pharmacological therapies with aim to reduce the symptoms and 
severity of functional dyspepsia and to improve the health-related quality of life in these patients 
are available, with some being more effective than others such as reassurance, diet, acid 
suppression, prokinetics, fundic relaxors, tricyclic antidepressants, rifaximin, and psychological 
therapy14. For patients younger than 60 years old, H. pylori test should be performed. For patients 
testing negative or not responding to H. pylori eradication, an initial trial of proton pump inhibitor 
(PPI) therapy is recommended; if ineffective, tricyclic antidepressants or prokinetic agents may be 
tried9.
Itopride is indicated for the treatment of gastrointestinal symptoms caused by gastric dysmotility 
and delayed gastric emptying, such as the sensation of bloating, early satiety, postprandial fullness, 
upper abdominal pain or discomfort, anorexia, heartburn, nausea, and vomiting; functional (non-
ulcer) dyspepsia or chronic gastritis. Eighteen randomized controlled trials (RCTs) (six placebo-
controlled and 12 reference controlled), including a total of 4410 patients, and two meta-analyses, 
each including approximately 2500 patients, provide evidence of the efficacy of itopride in FD 
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The purpose of this study is to investigate the non-inferiority of Itopride Hydrochloride 150mg 
extended release tablets vs 3 times  Itopride Hydrochloride 50 mg film coated tablets in subjects 
with gastrointestinal symptoms caused by gastric dysmotility and delayed gastric emptying, like 
bloating sensation, early satiety, postprandial fullness, upper abdominal pain or discomfort, 
anorexia, heartburn, nausea and vomiting in functional (non-ulcer) dyspepsia or chronic gastritis.
3
STUDY OBJECTIVES
3.1
Primary Objective(s)
To assess the comparable efficacy of Itopride Hydrochloride 150 mg extended release tablet
(administered once daily) and Itopride Hydrochloride 50 mg film coated tablets (administered
TID) after 8 weeks’ treatment. 
3.2
Secondary Objective(s)

To assess the comparable efficacy of Itopride Hydrochloride 150 mg extended release 
tablet (administered once daily) and Itopride Hydrochloride 50 mg film coated tablets
(administered TID) after 4 weeks treatment. 

To assess quality of life for the two treatment arms using Disease Specific Quality of Life 
(Nepean Dyspepsia Index NDI) at baseline and end of treatment

To assess the symptomatology (sensation of bloating, early satiety, postprandial fullness, 
upper abdominal pain or discomfort (epigastric pain, epigastric burning), anorexia (loss of 
appetite), heartburn, nausea and vomiting) of the disease in both treatment arms after 4 and 
8 weeks of treatment. 

To assess the number of responders of adequate/satisfactory relief from FD symptoms.
3.3
Exploratory Objective(s)

Treatment acceptance by subjects using 5-point Likert scale at the end of treatment
3.4
Safety Objective(s)

To evaluate safety and tolerability in both treatment arms
4
STUDY DESIGN
4.1
Overall Study Design and Plan-Description
This is a Phase 3, randomized, open-label, multicenter, parallel-group, active-controlled study to 
evaluate the non-inferiority efficacy of Itopride Hydrochloride 150mg extended release tablet ( 
administered once daily) compared to 
Itopride Hydrochloride 50 mg film coated tablets

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(administered TID) in subjects with gastrointestinal symptoms caused by gastric dysmotility and 
delayed gastric emptying, like sensation of bloating, early satiety, postprandial fullness, upper 
abdominal pain or discomfort, anorexia, heartburn, nausea and vomiting; functional (non-ulcer) 
dyspepsia or chronic gastritis. 
This study will enroll 564 subjects (282 subjects in each arm) and the duration of subject
participation will be approximately 11 weeks. 
Screening will be carried out to evaluate the eligibility criteria. Upper GI endoscopy will be 
conducted to rule out any organic, structural disease. The upper GI endoscopy report should be 
within 6 months prior to randomization. If it is >6 months old, then it will be performed during 
screening.
After screening, subjects will be randomized in a 1:1 ratio to one of the following treatment groups:

Test group - Itopride Hydrochloride 150 mg extended release tablets once daily before one 
of the main meals (preferably the same meal throughout the treatment)

Active Control group - Itopride Hydrochloride 50 mg film coated tablets 3 times daily 
before meals 
The study drugs will be administered, as mentioned above, for a period of 8 weeks.
The investigator or designee will explain the study to potentially interested subjects in detail, and 
if they voluntarily agree to participate in the study, consent will be obtained. After meeting the 
eligibility criteria, subjects will be enrolled in the study and will be assigned Unique Identification 
Numbers (UINs) to maintain confidentiality.

Duration 4-- 2 weeks —,14 
Study treatment Period 
Visit at baseline/randomization 
Week 4 and Week 8 
 0+4— 1 week 
Itopride Hydrochloride 50 mg film 
coated tablets 
Itopride Hydrochloride 150mg 
extended release tablets 
7-
Test Arm 
► 8 weeks 
Itopride Hydrochloride 150mg 
extended release tablets once 
daily before one of the main 
meals (preferably same meal 
throughout the treatment)
Control Arm 
Itopride Hydrochloride 50 mg 
film coated tablets 3 times 
daily before meals 
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The study drugs will be administered, as mentioned above, for a period of 8 weeks.
The endpoints will be evaluated at study visits as mentioned in section 8.
The investigator may repeat any test specified in the protocol, if needed, during the 14-day 
screening period.
A subject may be re-screened only after agreement with Sponsor representative and the subject 
may then have to undergo all screening procedures again as per protocol. In case of re-screening, 
the informed consent has to be collected again.
4.2
Discussion of Study Design, Including the Choice of Control Groups
This is an open label, randomized, multicenter, parallel-group, active-controlled Phase 3 study to 
evaluate the non-inferiority/ comparative efficacy of Itopride Hydrochloride 150 mg extended 
release tablets (administered once daily) compared to Itopride Hydrochloride 50 mg film coated 
tablets (administered TID) in subjects with functional dyspepsia. 

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The study will screen approximately 700 subjects and include 564 subjects (282 subjects in both 
arms Test and Active control arm) and the treatment will be given as follows. 

Test group - Itopride Hydrochloride 150 mg extended release tablets once daily 
before any of the main meals (preferably same meal throughout the treatment)

Active Control group - Itopride Hydrochloride 50 mg film coated tablets 3 times daily 
before meals
The duration of treatment will be 8 weeks and the subject follow up will be one week after the end 
of treatment. 
In the company-sponsored studies for the efficacy and effectiveness in FD, the total planned 
treatment duration was 2 to 8 weeks. 
The study design is chosen as non-inferiority study with statistical considerations for sample size 
and non-inferiority margin as described in the statistical section 10.7.
An open-label design was chosen because one tablet of Itopride Hydrochloride 150 mg extended
release tablets will be compared with three tablets of Itopride Hydrochloride 50 mg film coated 
tablets which allows to investigate the benefit of a lower tablet intake and the preference for the 
treatment. Itopride hydrochloride is used for the treatment of functional dyspepsia (FD) and is 
currently being dosed 50 mg thrice daily. Itopride Hydrochloride 150 mg extended release once 
daily tablets are a strategic life cycle management opportunity. By reducing the dose to once daily 
instead of thrice daily, the product may improve patient compliance and adherence. This may have,
in particular in subjects with FD, a beneficial effect on the outcome of the related symptomatology 
and disease progression. 
Following multiple oral doses ranging from 50 mg to 200 mg tid, itopride hydrochloride and its 
metabolites showed linear pharmacokinetics over a treatment period of 7 days, with minimal 
accumulation. The serum concentration of the unchanged compound was found to increase very 
rapidly (time to reach maximum drug concentration [tmax]=0.5 h) after single administration of 
itopride, and there were good linear correlations of the Cmax and AUC values with the dose 
administered. Following single oral doses of itopride hydrochloride ranging from 50 mg to 600 
mg, itopride showed no relevant deviation from linear pharmacokinetics, characterized by rapid 
onset of absorption at approximately 1 hour and a median predominant elimination t1/2 of 
approximately 6–8 hours.
Subjects have to stop most drugs which are active on gastric function prior to the study. Rescue 
medication, i.e. PPIs or antacids, for subjects with persistent symptoms of gastric hypersecretion 
may be started, after confirmation by the PI, earliest after 4 weeks (visit 3). Impact of rescue 
medication on efficacy will be assessed in the statistical analysis.

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5
SELECTION OF STUDY POPULATION
5.1
Inclusion Criteria
1. Adult male and/or non-pregnant non-lactating female subjects aged above 18 years.
2. Subjects provided written informed consent and are willing to participate in the study.
3. Subjects with functional (non-ulcer) dyspepsia according to Rome IV criteria including 
postprandial distress syndrome (PDS) and with or without EPS (epigastric pain syndrome) 
with one or more of the following:
-
bothersome postprandial fullness, 
-
bothersome early satiation
-
bothersome epigastric pain, 
-
bothersome epigastric burning 
-
for at least 12 weeks in the preceding 6 months 
4. No evidence of organic, systemic, metabolic or structural disease likely to explain 
symptoms - Subjects who have to undergone physical examination and lab tests (including 
white-cell and red-cell counts, measurement of fasting blood sugar and liver-function 
tests), abdominal ultrasonography, and upper GI endoscopy* in order to rule out structural 
cause for symptoms of FD. 
             *history of upper GI endoscopy within 6 months prior to enrolment or at screening.
5. Baseline severity of at least moderate symptoms on LDQ (total score ≥ 9) at screening. 
6. H. pylori negative documented test report within 3 months prior to enrolment or during 
screening.
5.2
Exclusion Criteria 
1. Known hypersensitivity to Itopride or any component of the formulation and to any other 
related drug.
2. Subject with history or presence of clinically relevant evidence of cardiovascular, 
neurological, 
gastrointestinal/hepatic, 
renal, 
psychiatric, 
respiratory, 
urogenital, 
hematologic/immunologic, HEENT (head, ears, eyes, nose, throat), dermatological/ 
connective tissue, musculoskeletal, metabolic/nutritional, drug hypersensitivity, allergy, 
endocrine, major surgery or other relevant disease as revealed by medical history requiring 
treatment which at investigator’s discretion might interfere with the study.
3. Subjects who cannot be treated with Itopride in line with the prescribing information.
4. Subjects scheduled for surgery during the study.
5. Subjects with a history of difficulty in swallowing.
6. Subject requiring concomitant treatment with anticholinergic drugs, drugs with narrow 
therapeutic index, sustained release or enteric-coated formulations.
7. Subjects taking Acid release inhibitors (e.g. histamine-2-receptor [H2]- antagonists, proton 
pump inhibitors [PPI], or potassium-competitive acid blockers), antacids (e.g. aluminium-

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or magnesium hydroxide, sodium bicarbonate), gastric mucosa protectors (e.g. sucralfate, 
rebamipide).
8. Subject with history of unusual bleeding and family history for bleeding disorders.
9. Subjects with only reflux-related symptoms or who have predominantly reflux-related 
symptoms.
10. Subjects with esophagitis, Barrett`s esophagus, erosions or peptic ulcer disease within one 
year prior to the study or Zollinger-Ellison Syndrome.
11. Dyspepsia that is exclusively relieved by defecation or associated with a change in stool 
frequency or stool form to exclude IBS.
12. Clinically significant ECG abnormalities.
13. Subjects treated with Itopride or another gastroprokinetic within 4 weeks prior to screening. 
14. Subjects who took non-steroidal anti-inflammatory drugs for more than 2 weeks prior to 
screening
15. Subjects with refractory FD1(defined as FD presenting symptoms continuing for at least 6 
months, unresponsive to at least two medical treatments such as PPIs, prokinetics, or H. 
pylori eradication) as per investigator’s discretion. 
16. History of or known inflammatory bowel disease (IBD) or coeliac disease.
17. History of or known severe hepatic, renal, pancreatic, cardiac, metabolic, hematological or 
malignant disease or trimethylaminuria.
18. Subjects with changed smoking status within the last three months.
19. History of or known GI malignancy or ulcers associated to malignancy or any alarm 
features for GI malignancy, e.g. GI bleeding.
20. Subjects who do not meet the criteria stated in concomitant medication section.
21. Subjects with history of severe depression, anxiety or other psychological disorders.
22. Females with child-bearing potential must agree to use an acceptable method of 
contraception during the study.
23. Subjects in whom an increase in gastrointestinal motility could be harmful, e.g., history of 
gastrointestinal hemorrhage, mechanical obstruction or perforation.
24. Specific food intolerance which is relieved by diet modifications (e.g. lactose intolerance, 
celiac disease).
25. Subjects with confirmed IBS as per Rome IV criteria.
26. Current alcohol or drug abuse.
27. History of abdominal surgery except appendectomy, cholecystectomy or hysterectomy, 
tubal ligations, bladder slings or vasectomies.
28. Hepatic cirrhosis or abnormal liver laboratory findings (defined as >3xULN of ALT or 
AST).
29. Subjects under hemodialysis therapy or having advanced chronic kidney disease (defined 
as eGFR <60 mL/min).

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30. History of or known congestive heart failure NYHA class III and IV, or any other 
uncontrolled chronic diseases, such as: uncontrolled hypertension (systolic/diastolic blood 
pressure ≥160/100 mmHg); uncontrolled diabetes (HbA1c >8%).
31. Subjects currently being known to be afflicted by serious infection(s), or any known severe 
illness(es) which are judged by the Investigator could interfere with subjects' safety and/or 
study evaluation.
6
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified, and without penalty or loss of benefits to which the subject is otherwise 
entitled.
The Study Termination form in the CRF must be completed for all subjects who have entered the 
study (i.e. have signed Informed Consent form), including subjects dropping out prior to any study 
drug administration.
In case of premature termination of the subject from the study, the primary reason for this 
premature termination is to be indicated according to the following definitions:
-
Adverse event: discontinuation due to any adverse event (AE) with a corresponding entry 
reflected on the Adverse Events form in the CRF.
-
Lack of efficacy: the lack of expected or desired effect related to a therapy.
-
Lost to follow-up: the loss or lack of continuation of a subject to follow-up.
-
Withdrawal of consent: an indication that the consent to participate in the study or one or 
more segments of the study has been revoked.
-
Protocol violation: a significant departure from processes or procedures that were required 
by the protocol. Note: subject only to be excluded from study in case of significant 
departure from processes or procedures that were required by the protocol and might e.g. 
lead to a safety issue.
-
Failure to meet randomization criteria: an indication that the subject has been unable to 
fulfill/satisfy the criteria required for assignment into a randomized group.
-
Sponsor request: an indication that the study subject was removed from the study at the 
sponsor's request.
-
Physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to subject.
-
Inclusion/exclusion criteria violated: eligibility criteria during screening period not met.
-
Other: different than the one(s) previously specified or mentioned.

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7
TREATMENTS
Study drug will only be shipped to Investigators who have provided the Sponsor (or an authorized 
representative) with all required study documents, including IEC/IRB approval, and have signed 
a final study agreement.
7.1
Treatments to Be Administered
Subjects will be randomized in a 1:1 ratio to one of the following treatment groups:

Test group - Itopride Hydrochloride 150 mg extended release tablets once daily before one 
of the main meals (preferably the same meal throughout the treatment)

Active Control group - Itopride Hydrochloride 50 mg film coated tablets 3 times daily 
before meals 
Ganaton/Ganaton OD/Elthon/Elthon OD is the Abbott brand name for Itopride Hydrochloride in 
most countries and it may vary in some countries.
Itopride hydrochloride is indicated for the treatment of gastrointestinal symptoms caused by gastric 
dysmotility and delayed gastric emptying, like bloating sensation, early satiety, postprandial 
fullness, upper abdominal pain or discomfort, anorexia, heartburn, nausea and vomiting in
functional (non-ulcer) dyspepsia or chronic gastritis.
7.2
Packaging and Labeling
Packaging and labeling will be controlled by Clinical Supply Management team of the Sponsor
(Clinical Supplies Manager). All packaging and labeling as well as the production of study drug 
will be in compliance with Good Manufacturing Practices (GMP) specifications, as mentioned in 
the Manufacturing of Investigation and Medicinal Products Volume 4 Annex 13 and in accordance 
with other applicable laws or local regulations. Details on the packaging and labeling will be
specified in the Packaging and Labeling Specifications and Supply Request (as applicable). 
Clinical supplies will be released by the quality department / prior to shipment to investigational 
sites. A Certificate of Analysis will be issued for the study drug. Certificate of Compliance/release, 
as applicable, will be issued stating the expiry date of the clinical supplies.
7.3
Storage and Dispensing of Study Drug
All clinical drug supplies are to be stored in a secure, monitored, limited-access area in accordance 
with labeled storage conditions, as mentioned in the IMP Instructions and Handling Manual. The 
Investigator will maintain accurate records of the disposition of all clinical drug supplies received 
during the study. These records shall include the amounts of drug supplies and the dates on which 
drug supplies were received from the Sponsor (or an authorized representative), dispensed to the 
subject, returned by the subject and returned to the Sponsor (or an authorized representative). If 
errors or damages in the clinical drug supply shipments occur, the Investigator must contact the 
Sponsor (or an authorized representative) immediately.

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7.4
Method of Assigning Subjects to Treatment Groups
Subjects will be assigned to a treatment group using a centralized electronic system (interactive 
voice/web response system; IXRS). The IXRS assigns a fixed randomization number to each 
subject according to a randomization scheme. The medication will be identified using kit 
randomization numbers.
The randomization scheme will be provided by the study CRO/ external contractor.
7.5
Selection of Doses in the Study
Itopride hydrochloride will be given to subjects from both arms Arm 1 (Test arm) and Arm 2 
(active control arm) in the following manner:

Test group - Itopride Hydrochloride 150 mg extended release tablets once daily before one 
of the main meals (preferably the same meal throughout the treatment)

Active Control group - Itopride Hydrochloride 50 mg film coated tablets 3 times daily 
before meals 
Itopride Hydrochloride 150 mg extended release tablet once daily and Itopride Hydrochloride 50 
mg film coated tablets three times a day have been reported to be well tolerated which has also 
been investigated in a pilot study by Kim YS et al15.
In a study by Rai et al16, Itopride showed effectiveness in addressing symptoms of reduced GI 
motility in diabetics, with improved QoL (PAGI‑QoL score reduction: 13.8 ± 11.48; P < 0.0001). 
Significant improvement in the glycemic indices such as HbA1c, FPG, and PPG was also evident 
post-treatment, which could be attributed to the positive effects of itopride in facilitating gastric 
emptying, thus restoring altered kinetics of food and drug absorption.
Following multiple oral doses ranging from 50 mg to 200 mg tid, itopride hydrochloride and its 
metabolites showed linear pharmacokinetics over a treatment period of 7 days, with minimal 
accumulation. The serum concentration of the unchanged compound was found to increase very 
rapidly (time to reach maximum drug concentration [tmax]=0.5 h) after single administration of 
itopride, and there were good linear correlations of the Cmax and AUC values with the dose 
administered. Following single oral doses of itopride hydrochloride ranging from 50 mg to 600 
mg, itopride showed no relevant deviation from linear pharmacokinetics, characterized by rapid 
onset of absorption at approximately 1 hour and a median predominant elimination t1/2 of 
approximately 6–8 hours.
The first approval for itopride was in Japan, international birth date 30 June 1995, and it has been 
marketed under the trade name Ganaton®. Currently, Abbott’s itopride is approved for treatment 
of GI symptoms of functional, non-ulcer dyspepsia (chronic gastritis) i.e., sensation of bloating, 
early satiety, upper abdominal pain or discomfort, anorexia, heartburn, nausea and vomiting in 23 

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countries (Argentina, Bahrain, Brunei Darussalam, Cambodia, Czech Republic, China, Egypt, 
India, Jordan, Kazakhstan, Kuwait, Lebanon, Malaysia, Myanmar, Pakistan, Philippines, Qatar, 
Russian Federation, Thailand, Ukraine, United Arab Emirates, Uzbekistan and Vietnam) under the 
major trade names Elthon®and Ganaton.
Two pharmacokinetic/biopharmaceutic studies were conducted with Itopride Hydrochloride 150
mg tablet formulation: 

ITOP-122-0212: single-dose food effect and comparative bioavailability study

ITOP-122-0213: multiple-dose comparative bioavailability study
With these studies it was demonstrated that the Itopride Hydrochloride 150 mg tablet formulation 
dosed once daily under proposed label conditions (i.e. intake at 30 min before breakfast) and 
Itopride Hydrochloride 50 mg tablets dosed tid are bioequivalent with respect to extent of exposure 
to itopride. The OD formulation dosed at 30 min before a normo-caloric meal showed rapid onset 
of absorption with sustained release of itopride over approximately 14 h, with less peak-trough 
fluctuation than the IR formulation and near identical minimum plasma concentrations at the end 
of the dosing interval. Intake of the OD formulation following a high-fat, high-caloric meal 
resulted in delayed and approximately 50% higher Cmax and 15% increased AUC without signs of 
dose-dumping or unexpected release characteristics, as compared to intake under fasting 
conditions. Intake before at 30 min before a normo-caloric meal resulted in rapid onset of 
absorption, and approximately 20% higher Cmax, without affecting the extent of exposure in terms 
of AUC to itopride as compared to intake under fasting conditions.
After a single oral dose of the newly developed once-daily formulation, dosed at 30 min before 
breakfast, onset of absorption of itopride is rapid and a sustained release plasma concentration-
time profile was observed up to approximately 14 h after dosing. Food has no clinically relevant 
effect on the extent of exposure to itopride after dosing of the once-daily formulation. Intake after 
a high-fat, high-caloric meal, delays and increases Cmax (with approximately 50%) relative to 
intake under fasting conditions, without signs of dose-dumping. Intake of the once-daily 
formulation at 30 min before breakfast resulted in approximately 20% higher Cmax as compared to 
intake under fasting conditions without affecting the onset of absorption of itopride or the sustained 
release characteristics of the formulation.
The registered dose of itopride hydrochloride for adult patients for treatment of GI symptoms 
caused by gastric dysmotility and delayed gastric emptying is 150 mg daily (1 IR tablet [50 mg] 
taken orally 3 times a day before meals). The dose may be reduced according to the patient’s age 
and symptoms. The proposed posology for the once-daily formulation will be one tablet of 150 
mg daily before one of the main meals (preferably same meal throughout the treatment; e.g. before 
breakfast).

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The efficacy and safety of 150 mg daily Itopride hydrochloride was investigated in 19 company 
sponsored interventional studies in subjects with functional dyspepsia and the dose of 150 mg daily is 
well established.
7.6
Selection and Timing of Dose for Each Subject
Itopride Hydrochloride 150 mg extended release tablets will be given once daily before any of the 
main meals (preferably same meal throughout the treatment); and Itopride Hydrochloride 50 mg 
film coated tablets will be given 3 times daily before meals.
One tablet of 150 mg taken daily before any one of the main meals (preferably same meal 
throughout the treatment).
Itopride hydrochloride is rapidly and almost completely absorbed from the GI tract. Relative 
bioavailability is calculated to be 60% due to liver first pass metabolism. There is no effect of food 
on bioavailability. 
Maximum drug concentration (Cmax 0.28 μg/mL) is reached after 0.5 to 0.75 hours after 
administration of 50 mg of Itopride hydrochloride.
Following multiple oral doses ranging from 50 mg to 200 mg tid, Itopride hydrochloride and its 
metabolites showed linear pharmacokinetics over a treatment period of 7 days, with minimal 
accumulation.
7.7
Blinding and Treatment Code Information
This is an open-label study; blinding will not be applied. Abbott study team will remain blinded 
throughout the whole study until the database is locked. 
7.8
Prior and Concomitant Therapy
All medication taken by the subject during the study (from signing the informed consent form 
through post-study follow-up) is to be recorded on the Concomitant Medication form in the CRF, 
except for study drug.
Forbidden Prior and Concomitant Therapy
Since Itopride has gastrokinetic effects, it could influence the absorption of concomitantly orally 
administered drugs. Particular caution should be taken with drugs with a narrow therapeutic index, 
sustained release or enteric-coated formulations. Anticholinergic drugs may reduce the action of 
Itopride. Prokinetics including itopride are not allowed within 4 weeks prior to screening and also 
not during the study (except study drug). Acid release inhibitors (e.g. histamine-2-receptor [H2]-
antagonists, proton pump inhibitors [PPI], or potassium-competitive acid blockers), antacids (e.g. 
aluminium- or magnesium hydroxide, sodium bicarbonate), gastric mucosa protectors (e.g. 
sucralfate, rebamipide) are also not allowed during the study and have to be stopped 2 weeks prior 
to screening. Medication that may alter gastric function, including macrolide antibiotics, is not 

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allowed during the study and 2 weeks prior to screening. Subjects are required not to take any non-
steroidal anti-inflammatory drugs during the study or 2 weeks prior to randomization. Low dose 
Aspirin for cardiometabolic prophylaxis up to 325 mg/day is allowed. 
Subjects are allowed to take acid release inhibitors or antacids (see above) as rescue medication 
at earliest after 4 weeks of treatment (visit 3) in case of persistent symptoms of gastric 
hypersecretion based on PI clinical judgement.
Prior and Concomitant Therapy

Treatment regimen like gastric-relevant herbal medicines can be taken if treatment started 
more than 1 month prior to the study and will be continued during the study in a stable 
dose. The same applies to anxiolytics and antidepressants: Buspirone, 5 HT1 R agonists, 
Mirtazapine (alpha 2 adrenergic antagonists, 5 HT 2,3 & H1 receptor antagonists), 
antidepressants like Amytriptyline, SSRI (e.g escitalopram), SNRI (e.g. venlafaxine). Low 
dose Aspirin for cardiometabolic prophylaxis up to 325 mg/day is allowed. 
Dietary counselling of the subjects in scope will take place prior to randomization, e.g. avoid high 
fat foods, less carbonated beverages, coffee, small meals.
In case of any concerns and to accommodate any future changes in treatment guidelines or 
practices, the Principal Investigator may consult the Sponsor representative for concomitant 
medication use.
7.9
Treatment Compliance
Drug Accountability
The Investigator is accountable for all clinical drug supplies shipped to his/her study site for the 
duration of the study. A final accounting of the clinical drug supplies will be required at the 
completion/termination of the study. The Investigator is required to provide written explanation 
for any discrepancies. 
All used and unused clinical drug supplies will be inventoried and returned to the Sponsor (or an
authorized representative) by a designated monitor.
The Investigator will not be permitted to return or destroy used or unused clinical drug supplies or 
packaging materials unless authorized by the Sponsor (or authorized representative).

LDQ 
(Leeds Dyspepsia Questionnaire) 
—0 Screening (visit 1) 
—► Week 4 (visit 3) 
—► Week 8 (visit 4) 
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8
STUDY ASSESSMENTS AND FLOW CHART
8.1
Efficacy Measurements

Symptoms of dyspepsia using Leeds Dyspepsia Questionnaire (LDQ) 

LDQ Questionnaire will be completed by the site staff through interview with patient by 
site staff trained on administration of LDQ to capture the overall symptomatology at 
screening (visit 1), week 4 (visit 3) and on week 8 (visit 4). The symptoms of dyspepsia 
are evaluated by measuring its frequency using the LDQ questionnaire which is a fully 
validated instrument to assess the symptoms of dyspepsia. A dyspepsia questionnaire 
or Leeds Dyspepsia Questionnaire (LDQ) can identify subjects with dyspepsia by 
measuring its frequency and therefore will assess the severity via a calculated overall 
score17-18
Quality of Life assessment using Short Form - Nepean Dyspepsia Index (SF-NDI) 

Quality of life is an important health outcome, which is frequently measured in various 
clinical and epidemiological studies. Disease can have various effects on quality of life, it 
depends on the area of the body afflicted and how significant that area is to the individual19-
20.

So, evaluating items by the individual patient according to their relative importance may 
be helpful and beneficial. This could be a more accurate method for evaluating how a 
disease affects the quality of life.

The Short Form Nepean Dyspepsia Index (SF-NDI) was designed to evaluate the 
impairment in each component of a subject's life as wander ability to participate and enjoy 
these aspects of their lives.

Short Form Nepean Dyspepsia Index (SF-NDI) Questionnaire will be used to measure the 
disease-specific Quality of Life of each participant of both arms (Test and Control Arm) at 
baseline (visit 2) and week 8 (visit 4). 

 b. Baseline (visit 2) 
NDI 
(Nepean Dyspepsia Index 
Questionnaire) 
► Week 8 (visit 4) 
SCALE 
0 
2 
4 
5 
6 
7 
8 
9 
10 
Very
Very 
No 
mild 
Discomfortiag Tolerable 
Distressing 
Distr. in  Intense 
Very 
Horrible 
Unbearable Unspeakable 
Intense 
SYMPTOMS 
Bloating sensation 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Early satiety 
Postprandial fullness 
Upper abdominal pain or discomfort 
(epigastric pain, epigastric burning) 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
Anorexia (loss of appetite) 
Heartburn 
Nausea 
Vomiting 
0 
0
0
0
0
0
0
0
0
0
0
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
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Symptoms of dyspepsia assessed by Numerical Rating Scale (NRS 11) 

The Numerical Rating Scale is widely used for self-reporting of pain intensity in clinical 
practices. In this study, the participants will be provided with the NRS 11 scale to mark 
changes for symptoms of sensation of bloating, early satiety, postprandial fullness, upper 
abdominal pain or discomfort (epigastric pain, epigastric burning), anorexia (loss of 
appetite), heartburn, nausea and vomiting at baseline and after 4 and 8 weeks of treatment21-
22.

NRS 11 will be used to assess responders’ analysis for adequate/satisfactory relief. 

NRS 11 and drug intake will be captured in patient diary. Drug intake will be recorded by 
the subject on a daily basis, symptoms will be recorded by the subject over the last two 
weeks prior to the visits. In addition, the baseline NRS 11 scores will be captured on site.

5-point Likert Scale 
• 
• 
Not at all 
Slightly 
Neutral 
Very 
Extremely 
Satisfied 
Satisfied 
Satisfied 
Satisfied 
0 
0 
0 
0 
0 
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Treatment acceptance and ease of use assessed by Likert Scale 

A 5-point Likert scale is a unidimensional scale which is used to collect responders’ 
opinions and acceptance for the provided medications23. 

The treatment acceptance and ease of use will be assessed by subjects by answering the 
question “Are you satisfied with the schedule of dosing of your treatment?” using the 5-
point Likert scale.

5-point Likert scale includes scale consisting of five points on which responders have to 
record their opinion to the question mentioned above. 

These five points include 1. Not at all satisfied, 2. Slightly satisfied, 3. Neutral, 4. Very 
satisfied, 5. Extremely satisfied. 
8.2
Safety Measurements
Adverse Events
Requirements for collecting, recording and reporting of AEs are described in Section 9. Each 
subject is to be evaluated at the termination visit. Should any AE be identified at this visit, the 
Investigator will continue to follow the subject as described in Section 9.1.2.
Safety Laboratory data will be collected for the determination of the following parameters: 
Laboratory evaluation:
The following laboratory parameters will be evaluated:
1. Hematology –
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count, 
platelet count, and differential blood count (only if indicated)
2. Biochemistry -

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Random blood sugar, liver function tests [ serum bilirubin, alkaline phosphatase, ALT 
(alanine amino transferase), AST (aspartate amino transferase), LDH (lactate 
dehydrogenase), gamma-glutamyl transferase], calcium, potassium, Serum Prolactin 
(Fasting), Serum Lipase (only baseline)
For all laboratory parameters with values outside the normal range (or abnormal results), the 
clinical significance will be judged by the Investigator.
Vital Signs
Height will be recorded at screening only and weight will be recorded at all visits. 
Body temperature, pulse rate, respiration rate, blood pressure, will be recorded at baseline and at 
every visit during the study period.
Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate are to be measured 
while the subject is in sitting position after 5 minutes rest.
12-Lead Electrocardiogram (ECG) 
A 12-lead ECG must be recorded while the subject is in supine position after 5 minutes rest at 
screening.
The ECG should be interpreted by the Investigator (normal/abnormal). For abnormal ECGs the 
clinical significance (yes/no) should be judged by the Investigator and the abnormality is to be 
specified. These subjects with clinically significant ECG abnormalities will not be included into 
the study.
Physical Examination
A physical examination should be performed and any relevant findings are to be recorded on the 
Medical History form in the CRF (for findings from the past that occurred prior to screening visit), 
or on the Adverse Event form in the CRF for findings presently occurring. This will be done at 
visit 1, 2, 3 and 4.
Pregnancy test
Urine pregnancy test (dipstick) will be done in all female subjects of child-bearing potential at 
the time of screening, to rule out pregnancy (if not postmenopausal or following tubal ligation or 
hysterectomy).
8.3
Other Assessments
Informed Consent

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Voluntary written informed consent must be obtained from each subject (or their legally acceptable 
representative) prior to performing any study-related procedures (see Section 1.3).
Demographic Data
Demographic data (gender, age, race) will be collected for all subjects.
Medical History
Any clinical event, including diagnosis, condition, or surgery, that occurred prior to the screening 
visit (before the informed consent is signed), is to be recorded on the Medical History form in the 
eCRF. In case a clinical event concerns a chronic disorder, which means it started in the past and 
it is still present at the screening visit, it should also be recorded on the Medical History Form in 
the eCRF. Examples of these events are diabetes, migraine, and hay fever (documentation of 
pregnancy, see section 9.3).
Concomitant Medication
All medication taken by the subject during the study (from signing the informed consent form 
through post-study follow-up) is to be recorded on the Concomitant Medication form in the eCRF, 
except for study drug.   
Compliance and treatment adherence 
The information about drug intake/adherence and NRS 11 self-reporting of symptoms will be 
captured in Patient diary. Drug intake will be recorded by the subject on a daily basis, symptoms 
will be recorded by the subject over the last two weeks prior to the visits. In addition, the baseline
NRS 11 scores will be captured on site.
8.4
Appropriateness of Measurements
All measurements will be performed using standard methods which are generally recognized as 
being reliable, accurate, and relevant.
8.5
Primary Efficacy Variable(s)
The change in the overall severity of functional dyspepsia between baseline and week 8, as 
measured by the Leeds Dyspepsia Questionnaire (LDQ) severity score has been selected as 
primary endpoint.
LDQ is a useful tool for assessing the presence and severity of dyspepsia. In a study by Moayyedi
et al.17, the LDQ had a high degree of sensitivity in detecting dyspepsia compared to the opinion 
of a gastroenterologist or a General Physician as the gold standard. LDQ questionnaire is validated 
in primary and secondary care populations and hence is suitable for general practice dyspepsia 
studies.

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Holtmann et al.2 investigated this parameter with Itopride in a placebo-controlled study. Other 
studies have used LDQ for FD as primary endpoint.

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8.6
Flow Chart of Study Assessments
All study assessments will be conducted as indicated in Table 2, which displays the frequency and timing of all measurements.
Table 2: Study Assessments
Periods
Screening period
Treatment period
Follow up 
Visits (V)
V1
V2
V3
V4 (ET/ED)
TC
Week
W4
W8
Day
Day -1
Day 1
Day 29
Day 57
Day 64
Visit window
-14 to -1 days
±1 day
±1 day
+1 day
Informed Consent
X
Demographic data 
X
Medical history
X
Inclusion/Exclusion criteria
X
X
Physical examination
X
X
X
X
Weight, Height (screening only), BMI5
X
X
X
X
Vital signs
X
X
X
X
Hematology 
X
X
Biochemistry (including RBS, Serum prolactin (fasting), 
Serum lipase7)
X
X
Pregnancy test1
X
Test report for H. pylori2
X
Upper GI Ultrasound
X
Endoscopy3
X
ECG 
X
Randomization
X
Leeds Dyspepsia Questionnaire (LDQ)
X
X
X
Short 
From 
Nepean 
Dyspepsia 
Index 
(SF-NDI) 
questionnaire
X
X

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NRS 11 onsite (baseline only)
X
Patient diary distribution
X
X
NRS 11 recorded in patient diary4
X
X
Dispense Study drug
X
X
Drug intake recorded in patient diary6
X
X
Diary return
X
X
Study drug return
X
X
Study drug accountability and adherence assessment
X
X
Adverse events 
X
X
X
X
X
Concomitant medications
X
X
X
X
X
Treatment acceptance and ease of use assessment using 
Likert scale
X
ET – End of treatment, ED – Early discontinuation, TC – Telephone contact, D – day, V – Visit
1. For women of child-bearing potential (including those without history of surgical sterilization and women with <2 years post-menopause) 
2. H. pylori test report in medical history within 3 months before randomization, otherwise to be performed during screening.
3. Endoscopy in medical history within 6 months before randomization, otherwise to be performed during screening.
4. Symptoms will be recorded by the subject over the last 2 weeks prior to the next visit. 
5. Will be calculated during analysis, not by investigator.
6. Will be recorded daily.
7. Serum Lipase at V1 (baseline) only.

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9
ADVERSE EVENTS
The reference safety information (RSI) used for both IMP and the comparator is the current 
Investigator brochure Itopride.
9.1
Adverse Events
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom (including an AE occurring from drug abuse, an AE 
occurring from drug withdrawal and any AE occurring from failure of expected pharmacological 
action), or disease temporally associated with the use of a pharmaceutical product, whether or not 
considered related to the pharmaceutical product.
An elective surgery/procedure scheduled to occur during a study will not be considered an adverse 
event if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre-planned prior to study entry.  However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than 
planned), then the deterioration of the condition for which the elective surgery/procedure is being 
done will be considered an adverse event.
9.1.1
Recording of Adverse Events
Any AE should be recorded on the Adverse Events form in the CRF and source documents. In 
order to avoid vague, ambiguous or colloquial expressions, the AE should be recorded in standard 
medical terminology rather than the subject’s own words. Whenever possible, the Investigator 
should group together into a single term signs and symptoms which constitute a single diagnosis.
The existence of or change in an AE may be concluded due to the necessity to administer a 
concomitant medication, from a spontaneous report of the subject, from the physical examination 
or from special tests like ECG, EEGs, laboratory assessments or other study specified tests (source 
of AE).
AE collection period is defined as any time after informed consent is obtained until 30 days after 
the last day of study participation.
Each AE is to be evaluated for duration, severity, seriousness and causal relationship to the 
investigational drug. The action taken with study drug, the concomitant medication given and the 
outcome as well as whether the event led to study termination will also be recorded.
Severity

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The severity of the AE should be characterized as “mild, moderate or severe” according to the 
following definitions:
-
Mild events are usually transient and do not interfere with the subject’s daily activities.
-
Moderate events introduce a low level of inconvenience or concern to the subject and may 
interfere with daily activities.
-
Severe events interrupt the subject’s usual daily activity.
Drug-Event Relationship
The causal relationship between the study drug and the AE should be characterized according to 
the following:
-
Unrelated – there is not a reasonable possibility that the study drug caused the AE.
-
Unlikely – suggests that only a remote connection exists between the study drug and the 
event. Other conditions, including concurrent illness, progression or expression of the 
disease state or reaction to concomitant medication, appear to explain the AE.
-
Possible – suggests that the association of the AE with the study drug is unknown, however 
the event is not reasonably supported by other conditions.
-
Probable – suggests that a reasonable temporal sequence of the AE with drug 
administration exists and, in the Investigator’s clinical judgment, it is likely that a causal 
relationship exists between the drug administration and the AE, and other conditions 
(concurrent illness, progression or expression of the disease state, or concomitant 
medication reactions) do not appear to explain the AE.
-
Certain - clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out. The clinical event, including an abnormal laboratory test result, 
occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. 
Outcome
The outcome of the adverse event should be classified according to the following definitions:
-
Recovered / resolved: the event has resolved (no further symptoms are present and no 
treatment is being received by the subject).
-
Recovered / resolved with sequelae: the event has resolved but there may be lingering 
effects present (e.g., a scar following a cut or abrasion).
-
Fatal: the subject died as a result of the event. This code should only be used for the event 
that caused the death, not any event that was present at the time of the subject’s death. Fatal 
events require immediately reporting to the Sponsor (or an authorized representative).
-
Unknown: may only be used in the event that the subject is lost to follow-up and no reliable 
data can be obtained.
-
Not resolved: the event is not yet resolved and is ongoing.

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All efforts should be made to classify the AE according to the above categories.
9.1.2
Follow-up of Adverse Events
All AEs occurring during the study are to be followed up in accordance with good medical practice 
until resolved or judged no longer clinically significant, or if a chronic condition, until fully 
characterized. All follow-up results are to be reported to the Sponsor (or an authorized 
representative).
9.2
Serious Adverse Events (SAEs)
Definitions of Serious Adverse Event (SAE)
Any untoward medical occurrence that at any dose:
-
results in death,
-
is life-threatening (an event in which the subject was at risk of death at the time of the 
event; it does not refer to an event which hypothetically might have caused death if it were 
more severe),
-
requires inpatient hospitalization or prolongation of an existing hospitalization,
-
results in persistent or significant disability/incapacity,
-
is a congenital anomaly/birth defect,
-
is any suspected transmission via a medicinal product of an infectious agent,
-
is considered an important medical event (an event that may not be immediately life-
threatening or result in death or hospitalization, but based on medical judgment may 
jeopardize the subject and may require medical or surgical intervention to prevent any of 
the outcomes listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that 
do not result in inpatient hospitalization, or the development of drug dependency or drug 
abuse as well as spontaneous or elective abortions, stillbirths and ectopic pregnancies).
9.2.1
Reporting Serious Adverse Events
Any SAE (fatal or life-threatening SAE and other SAEs), whether or not related to the study drug, 
must be reported immediately within 24 hours of the investigator’s awareness of the event by 
telephone and/or emailing 
the appropriate SAE forms to the Sponsor (or an authorized 
representative).
Email: safety.ganaton@tech-observer.com  
Contact (toll-free): +13054400254
.

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9.3
Pregnancy
If a subject should become pregnant during the study, the event will be reported on the Pregnancy 
Form within 1 day of the investigator’s knowledge of the pregnancy. The Pregnancy Form is to be 
fax or email to the Sponsor (or an authorized representative) at the contact numbers listed in 
Section 9.2.1.
If pregnancy occurs in a subject from the time of ICF signature who does not qualify for allocation 
to treatment, i.e. Screen Failure, the pregnancy should be recorded in patient’s medical file only, 
in accordance to local requirements. The pregnancy related medical status change information will 
not be reviewed by Abbott or delegated staff. The pregnancy will not qualify as a study (S)AE. 
If pregnancy occurs in a subject from the time of ICF signature who is not dis-qualified for 
allocation to treatment, the pregnancy should be recorded in patient’s medical file in accordance 
to local requirements and in Abbott’s pregnancy from. The pregnancy related medical status 
change information will be reviewed by Abbott or delegated staff. The pregnancy will not qualify 
as a study (S)AE.
The pregnancy evolution and outcome, i.e., the health status of the newborn, is to be reported on 
the Pregnancy Outcome Form and reported to the Sponsor (or an authorized representative) within 
1 day of the investigator’s knowledge of the event.
Pregnancy in a study subject is not considered an adverse event. However, the medical outcome 
of an elective or spontaneous abortion, stillbirth, ectopic pregnancy or congenital anomaly is 
considered a SAE and must be reported to the Sponsor (or an authorized representative) within 24 
hours of the investigator becoming aware of the event and followed-up as described in Section 
9.1.2.
10
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
Data handling will be the responsibility of the Clinical Data Management (CDM) team of the CRO. 
The data will be inspected for inconsistencies by performing validation checks. Any 
inconsistencies found will be resolved by the monitor after contacting the Investigator. When the 
data in the database are considered clean and the subjects allocated to subject samples in a blind 
data review, the database will be locked to prevent unauthorized access. Next, the database will be 
made available as SAS® files for statistical analysis.
All details regarding the statistical analysis and the preparation of tables, listings and figures will 
be described in the Statistical Analysis Plan prepared by Biostatistics projects Planning and 
Programming (BPP) team of the CRO and approved by Abbott before database lock.
The statistical analysis will be performed by the BPP team of the CRO.

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10.1
General Definitions and Conventions
Time-Related Definitions
All assessment dates will be related to the first day of study drug administration. This first day of 
drug administration is referred to as Day 1. Day –1 is the day that is preceding Day 1 and a Day 0 
will not be defined.
The baseline period will be defined as the period from informed consent to the first study drug 
administration. The baseline value for a variable is defined as the last non-missing value collected 
before first study drug administration.
The endpoint value for efficacy variables is defined as the last non-missing value assigned to 
treatment for the subject.
All variables planned to be measured at one or more time points and supposed to be time-related 
will be windowed. 
Coding Systems
AEs and medical history Investigator terms will be assigned to a lowest level term (LLT) and a 
preferred term (PT) and will be classified by high level term (HLT), high level group term (HLGT) 
and primary system organ class (SOC) according to the MedDRA (applicable version will be 
captured in Data Management Plan) thesaurus.
Concomitant medications will be classified according to active drug substance using the WHO 
drug dictionary. The generic name, the preferred name and the WHO name will be assigned.
In addition, the Anatomical Therapeutic Chemical (ATC) classes will be assigned to the drug ID. 
ATC codes are defined to the 4th level. For each medication, the primary ATC class will be 
assigned manually based on the generic name and the reason for use.
Default Summary Statistics
The default summary statistics for quantitative and ordinal variables will be the number of 
observations (n), mean, standard deviation (SD), median, minimum (Min) and maximum (Max) 
for subjects with data. Any other summary statistics will be described on an individual basis.
Default Frequency Tabulations
For qualitative variables, per category the numbers and frequencies of subjects with non-missing 
data (n, %) will be the default summary presentation, and if appropriate and present, the number 
of missing values.

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For AEs, medical history and concomitant medications, however, the denominator for the 
percentage calculation will be the number of subjects at risk for the particular treatment arm. A 
subject will be considered at risk if the subject is in the safety sample and entered the respective 
study period.
Subject Listings
Individual subject listings will be produced for all raw data and a selection of the derived data. 
10.2
Subject Samples
The main subject samples of interest are defined as follows.
The all subjects consented sample will consist of all subjects who:
-
Gave their informed consent.
The all subjects randomized to treatment sample will consist of all subjects who:
-
Were in the all subjects consented sample; and
-
Were randomized to treatment.
The safety sample will consist of all subjects who:
-
Were in the all subjects allocated to treatment sample; and
-
Had at least one dose of study medication administered.
The full analysis (FA) sample will consist of all subjects who: 
-
Were included in the safety sample; and
-
Had data for at least one post-baseline assessment of any efficacy measurement. 
The per-protocol (PP) sample will be defined through blind data review and will consist of all 
subjects who:
-
Were included in the FA sample; and 
Did not present any major protocol violation.
Efficacy
Primary efficacy:
•
An ANCOVA analysis will be performed with the change in the LDQ score as dependent 
variable and treatment group, site and LDQ baseline value as additional factors. The 
difference between the two treatment groups will be calculated for the non-inferiority 
comparisons, together with a two-sided 95% confidence interval. Non-inferiority will be 
considered achieved if the lower bound of the 95% confidence interval of the difference 

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between the two groups is greater than 1.75 (NI-margin). Normal approximation will be 
assumed for the parametric analyses. The primary analysis will be performed for both the 
per protocol set and the full analysis set. The analysis for the per-protocol set will be 
regarded as primary. 
Secondary efficacy:
•
Full analysis sample will be used for the analysis of the secondary endpoints.
•
All secondary efficacy variables will be assessed using descriptive statistics.
•
In addition, the change from baseline in LDQ score at week 4 and the NRS 11 score for 
each symptom will be evaluated using the same analysis as specified for the primary 
endpoint. 
•
Impact of rescue medication on efficacy and safety will be investigated by appropriate 
statistical methods like e.g. imputation methods depending on the number of subjects 
needing rescue medication. In addition subgroup analyses will be performed as well
10.3
Safety
The safety sample will be used for the analysis of the safety and tolerability data.
An AE that starts during a unique treatment or that already exists before the start of that unique 
treatment but worsens during the treatment, will be considered as treatment emergent for that 
unique treatment.
For the definition of treatment emergent, the following unique treatments are distinguished by 
applicable study period:
-
Itopride Hydrochloride 150 mg extended release tablets
-
Itopride Hydrochloride 50 mg film coated tablets 
AEs will be reported on a per-subject basis, i.e. counting subjects rather than events. This means 
that if a subject suffers the same AEs repeatedly during the applicable study period, the event will 
be counted only once for that period. Repeated events per subject will be summarized according 
to the following rule: if a subject suffered the same AE more than once, the event will be assigned 
the worst severity, the closest relationship to the study drug and the earliest starting date. Only 
treatment emergent AEs will be reported. In the listings, however, all occurrences of the AEs will 
be presented.
For each unique treatment, treatment emergent AEs will be summarized per primary SOC, per 
HLT by primary SOC and per PT by HLT and primary SOC. Severity and drug-event relationship 
of treatment emergent AEs are summarized separately.

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Vitals signs, including changes from baseline will be summarized. A frequency table will be 
presented for markedly abnormal values.
Laboratory variables, including changes from baseline will be summarized. A frequency table will 
be presented for markedly abnormal values. Shift tables will be presented according to the 
reference ranges (low, normal or high).
10.4
Other Assessments
The assignment of subjects to subject samples, the disposition of subjects with respect to premature 
termination, reason for premature termination, drug exposure and treatment compliance will be 
summarized per treatment group.
Demographics and other baseline characteristics will be summarized per treatment group.
Medical history, including coding data will be summarized per primary SOC, per HLT by primary 
SOC and per PT by HLT and primary SOC.
Major protocol deviations will be listed.
Concomitant medication, including coding data will be summarized per assigned treatment period 
for incidence per subject, for primary therapeutic subgroup (3rd level ATC code) and for generic 
name by therapeutic subgroup.  
10.5
Subgroup Analysis
Subgroup analyses by geographical regions will be performed. Key efficacy and safety results will 
be summarized across subgroups defined by geographical regions (country, gender and age). 
10.6
Interim Analysis
For this study, no interim analysis is planned.
10.7
Determination of Sample Size
Assumptions for sample size calculation are based on the studies of Holtmann et al.2 and Talley et 
al.3 from which a standard deviation of 7 can be assumed for the change of the LD questionnaire.
For the NI margin following assumptions were made:
•
In the Holtmann study2 a difference to placebo 2 (95% CI: 0.03-3.97) in the LDQ was reported. 
•
In the Ang4 publication (2011) a difference of 10-15% to placebo is regarded as clinically 
relevant
•
NI-margin needs to be lower than 2. A difference of 15% results in 1.74. Therefore, a NI 
margin of 1.75 is chosen.

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Assuming a NI margin of 1.75 and standard deviation of 7 for the change in the LDQ severity 
score, 253 subjects per treatment arm are required to conclude non-inferiority between the 2 
treatment groups with a power of 80% at α-level of 2.5% single sided. Adding a 10% drop-out rate 
the total sample size would be 564 subjects (N= 282 per arm).

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11
INVESTIGATOR OBLIGATIONS
The Investigator agrees to conduct the clinical study in compliance with this protocol which was 
approved by the IEC/IRB in compliance with local regulatory requirements. The Investigator and 
the Sponsor will sign the protocol to confirm this agreement.
11.1
Essential Study Documents
The Investigator is responsible for providing and maintaining essential study documents. Essential 
study documents are those documents that individually and collectively permit the evaluation of 
the conduct of the study and the quality of the data produced. These documents serve to 
demonstrate the compliance of the Investigator and the Sponsor (or an authorized representative) 
with the standards of GCPs and with all applicable national regulatory requirements.
Essential study documents will include regulatory documents as well as source documents which 
are original documents, data and records of clinical findings, observations and other activities in a 
clinical study necessary for the reconstruction and evaluation of the study. Source documents will 
include hospital records, clinical and office charts, laboratory notes, memoranda, subject diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files and records kept at the 
pharmacy, at the laboratories and at medical/technical departments involved in the clinical study.
The Investigator agrees to allow direct access to all essential clinical study documents for the 
purpose of monitoring and/or auditing by the Sponsor (or an authorized representative) and 
inspection by the appropriate national and foreign regulatory authorities.
11.2
Case Report Form (CRF) Completion
Data reflecting the subject’s participation with the study drug under investigation will be reported 
to the Sponsor (or an authorized representative). The data will be recorded on the designated 
(e)CRFs provided or approved by the Sponsor.
The (e)CRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used by 
the Investigator or hospital that relate to the subject’s medical history, that verify the existence of 
the subject, the inclusion and exclusion criteria and all records covering the subject’s participation 
in the study. They include laboratory notes, ECG results, memoranda, pharmacy dispensing 
records, patient files, etc.
The Investigator is responsible for maintaining source documents. These will be made available 
for inspection by the study monitor at each monitoring visit. The Investigator must submit a 
completed (e)CRF for each subject who did not fail screening. All supportive documentation 
submitted with the (e)CRF, such as laboratory or hospital records, should be clearly identified with 

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the study and subject number. Any personal information, including subject name, should be 
removed or rendered illegible to preserve individual confidentiality.
All data must be entered in English. The (e)CRFs should always reflect the latest observations on 
the subjects participating in the trial. Therefore, the (e)CRFs are to be completed as soon as 
possible after the subject’s eligibility has been confirmed and thereafter during or after the 
subject’s visit. To avoid inter observer variability, every effort should be made to ensure that the 
same individual who made the initial baseline determinations completes all efficacy and safety 
evaluations. The Investigator must verify that all data entries in the (e)CRFs are accurate and 
correct. If some assessments are not done, or if certain information is not available or not applicable 
or unknown, the Investigator should indicate this in the (e)CRF. The Investigator will be required 
to (electronically) sign off on the clinical data.
The monitor will review the (e)CRFs and evaluate them for completeness and consistency. The 
(e)CRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. All entries, corrections and alterations are to be made by the responsible 
Investigator or his/her designee. The monitor is not allowed to enter data in the (e)CRFs.
If additional corrections are needed, the responsible monitor or Data Manager will raise a query. 
The appropriate investigational staff will answer queries sent to the Investigator.
For each subject that has signed the informed consent but does not qualify for allocation to 
treatment, i.e. Screen Failure, only the following information is required to be collected
-
Date of Informed Consent
-
Demographics
-
Reason for Screen Failure
-
Inclusion / Exclusion Criteria Violated
-
SAEs
In case other data for screen failures is entered in the (e)CRF, these data should be clearly indicated 
in the raw datasets and removed from the analysis datasets.
EDC:
Electronic Data Capture (EDC) will be used for this trial, meaning that all CRF data will be entered 
in electronic forms at the investigational site. Data collection will be completed by authorized 
study site personnel designated by the Investigator. Appropriate training and security measures 
will be completed with the Investigator and all authorized study site personnel prior to the study 
being initiated and any data being entered into the system for any study subjects. Roles and rights 
of the site personnel responsible for entering the clinical data into the eCRF will be determined in 
advance.
Once clinical data of the eCRF have been submitted to the central server, corrections to the data 
fields will be audit trailed, meaning that the reason for change, the name of the person who 
performed the change, together with time and date will be logged. Also, the queries and resolutions 

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will be audit trailed by the EDC application meaning that the name of investigational staff, Data 
Manager and Monitor, time and date stamp are captured.
eCRF records will be automatically appended with the identification of the creator, by means of 
their unique User ID. Specified records will be electronically signed by the Investigator to 
document his/her review of the data and acknowledgement that the data are accurate. This will be 
facilitated by means of the Investigator’s unique User ID and password; date and time stamps will 
be added automatically at time of electronic signature. If an entry on an eCRF requires change, the 
correction should be made in accordance with the relevant software procedures. All changes will 
be fully recorded in a protected audit trail, and a reason for the change will be required.
11.3
Essential Records Retention
The Investigator should maintain the essential clinical study documents (including CRFs, source 
documents, clinical drug disposition records, signed subject informed consent forms, AE reports 
and other regulatory documents) as required by the applicable national regulatory requirements. 
The Investigator is to take adequate measures to prevent accidental or premature destruction of 
these documents. In the event of accidental destruction, the Investigator should notify the Sponsor 
(or an authorized representative) immediately.
Essential clinical study documents will be retained at least two (2) years after the last approval of 
a marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region OR at least two (2) years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents shall be 
retained for a longer period, however, if required by the applicable regulatory requirements or by 
an agreement with the Sponsor (or an authorized representative).
The Investigator is required to notify the Sponsor (or an authorized representative) prior to 
changing the location or status of any essential clinical study documents. The Sponsor (or an 
authorized representative) will be responsible for informing the Investigator as to when these 
documents no longer need to be retained.
11.4
Investigator Agreement
The Investigator is responsible for assuring the proper implementation and conduct of the clinical 
study including those study-related duties delegated to other appropriately qualified individuals. 
The Investigator and his/her staff will cooperate with the Sponsor (or an authorized representative) 
during monitoring and auditing visits to assist with the review of the study data and resolve any 
discrepancies.
The Investigator will demonstrate due diligence in recruitment and screening of potential study 
subjects. The enrollment rate should be sufficient to complete the study as agreed with the Sponsor 
(or an authorized representative). The Sponsor (or an authorized representative) is to be notified 
of any projected delays, which may impact the completion of the study.

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The Sponsor retains the right to terminate the clinical study at any time for any reason. In such an 
event, instructions on the requirements for the discontinuation of subjects will be provided by the 
Sponsor (or an authorized representative).

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12
SPONSOR OBLIGATIONS
12.1
Protocol Amendments
Only the Sponsor (or an authorized representative) will make modifications to the clinical study 
protocol, which will be documented in a written amendment that describes all changes that will be 
implemented. Protocol amendments will be categorized as either substantial or non-substantial.
Protocol amendments will be considered substantial when the changes have significant impact on:
-
The safety of physical or mental integrity of the subjects
-
The scientific value of the study
-
The conduct or management of the study
-
The quality or safety of any investigational medicinal product or control used in the study
Protocol amendments will be considered non-substantial when the changes affect only 
administrative issues with the conduct of the study, i.e., changes in telephone numbers or 
addresses.
The Sponsor (or an authorized representative) will be responsible for notifying the appropriate 
national regulatory authorities in writing of any amendments to the protocol prior to the changes 
being implemented except in those cases where the changes are necessary to eliminate an 
immediate hazard to the clinical study subjects.
Substantial amendments will require written approval by the IEC/IRB prior to being implemented 
by the Investigator at the study site except under those circumstances described previously. Non-
substantial amendments will not require approval by the IEC/IRB unless requested by the 
IEC/IRB.
12.2
Study Monitoring
The study will be monitored by authorized representatives of the Sponsor throughout its duration 
by means of personal visits to the Investigator’s facilities and through other communications (e.g., 
telephone calls, written correspondence). Monitoring visits will be scheduled at mutually agreeable 
times periodically throughout the study and at frequency deemed appropriate for the study. 
In addition to onsite monitoring the Sponsor may choose a combination of on-site and centralized 
monitoring. Centralized monitoring is a remote evaluation of accumulating data, performed in a 
timely manner, supported by appropriately qualified and trained persons (e.g., data managers, 
biostatisticians).
These visits will be conducted to evaluate the progress of the study, ensure the rights and well-
being of the subjects are protected, check that the reported clinical study data are accurate, 
complete and verifiable from source documents, and the conduct of the study is in compliance 
with the approved protocol and amendments, GCPs and applicable national regulatory 

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requirements. A monitoring visit will include a review of the essential clinical study documents 
(regulatory documents, CRFs, source documents, drug disposition records, subject informed 
consent forms, etc.) as well as discussion on the conduct of the study with the Investigator and 
staff. The Investigator and staff should be available during these visits to facilitate the review of 
the clinical study records and resolve/document any discrepancies found during the visit.
12.3
Quality Assurance and Quality Control
As part of the Sponsor’s (or an authorized representative’s) quality management approach, Quality 
Assurance department may conduct on-site audits of all aspects of the clinical study either during 
the study or after the study has been completed.
The clinical study may also be subject to inspection by regulatory authorities (national or foreign) 
as well as the IECs/IRBs to ascertain that the study is being or has been conducted in accordance 
with protocol requirements, GCPs, as well as the applicable regulatory requirements.

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13
PUBLICATION POLICY
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
publicly disclose the study and the study results of all applicable clinical trials following legal and 
regulatory requirements. The publication policy with respect to the Investigator and study center 
will be set forth in the Clinical Trial Agreement. 

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14
INSURANCE
The Sponsor has taken out a liability insurance, which covers this study as required by local law 
and/or national regulations and/or ICH guidelines whichever is applicable. Insurance will be 
covered by the sponsor in accordance to the local regulations. 

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15
REFERENCES
1. Shahbazkhani, B., Fanaeian, M.M., Farahvash, M.J. et al. Prevalence of Non-Celiac Gluten 
Sensitivity in Patients with Refractory Functional Dyspepsia: a Randomized Double-blind 
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59532-z.
2. Holtmann G, Talley N, Liebregts T, Adam B, Parow C. A Placebo-Controlled Trial of 
Itopride in Functional Dyspepsia. N Engl J Med 2006;354:832-40
3. Talley NJ, Tack J, Ptak T, Gupta R, Giguere M. Itopride in functional dyspepsia: results of 
two phase III multicentre, randomised, double-blind, placebo-controlled trials. Gut. 2008 
Jun 1;57(6):740-6.
4. Ang, D., Talley, N. J., Simren, M., Janssen, P., Boeckxstaens, G., & Tack, J. (2011). 
Review article: endpoints used in functional dyspepsia drug therapy trials. Alimentary 
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634–649. 
https://doi.org/10.1111/j.1365-
2036.2010.04566.x
5. Ford AC, Marwaha A, Sood R, Moayyedi P. Global prevalence of, and risk factors for, 
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dyspepsia: 
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meta-analysis. 
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2015;64(7):1049-1057. 
doi:10.1136/gutjnl-2014-307843
6. Pittayanon R, Leelakusolvong S, Vilaichone R, Rojborwonwitaya J, Treeprasertsuk S, 
Mairiang P, Chirnaksorn S, Chitapanarux T, Kaosombatwattana U, Sottisuporn J, Sansak 
I, Phisalprapa P, Bunchorntavakul C, Chuenrattanakul S, Chakkaphak S, Boonsirichan R, 
Wiwattanachang O, Maneerattanaporn M, Piyanirun W, Mahachai V.  Thailand Dyspepsia 
Guidelines: 
2018. 
 
J 
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7. Shah SS, Bhatia SJ, Mistry FP. Epidemiology of dyspepsia in the general population in 
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8. Kumar A, Patel J, Sawant P. Epidemiology of Functional Dyspepsia. JAPI March 2012. 
https://www.japi.org/u2d4b474/epidemiology-of-functional-dyspepsia
9. Talley NJ, Ford AC. Functional dyspepsia. New England Journal of Medicine. 2015 Nov 
5;373(19):1853-63.
10. Oustamanolakis P, Tack J. Dyspepsia: organic versus functional. Journal of clinical 
gastroenterology. 2012 Mar 1;46(3):175-90.
11. Lacy BE, Weiser K. Gastrointestinal motility disorders: an update. Dig Dis 2006;24:228–
42.
12. Parkman HP, Doma S. The importance of gastrointestinal motility disorders. Practical 
gastroenterology. 2006 Sep;30(9):23.
13. Moayyedi PM, Lacy BE, Andrews CN, Enns RA, Howden CW, Vakil N. ACG and CAG 
clinical guideline: management of dyspepsia. Official journal of the American College of 
Gastroenterology| ACG. 2017 Jul 1;112(7):988-1013.
14. Tack J, Palsson OS, Bangdiwala S, et al. Functional dyspepsia and its subgroups: 
prevalence and impact in the ROME IV global epidemiology study. Abstract #P0044. 

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Presented at the 28th United European Gastroenterology Week Virtual 2020. UEG Journal 
2020;8 (Suppl 1).
15. Kim YS, Kim TH, Choi CS, Shon YW, Kim SW, Seo GS, Nah YH, Choi MG, Choi SC. 
Effect of itopride, a new prokinetic, in patients with mild GERD: a pilot study. World 
journal of gastroenterology: WJG. 2005 Jul 7;11(27):4210.
16. Rai RR, Choubal CC, Agarwal M, Khaliq AM, Farishta FJ, Harwani YP, et al. A 
prospective multicentric postmarketing observational study to characterize the patient 
population with reduced gastrointestinal motility among indian diabetic patients receiving 
itopride: The progress study. Int J App Basic Med Res 2019;9:148-53.
17. Moayyedi P, Duffett S, Braunholtz D, Mason S, Richards ID, Dowell AC, Axon AT. The 
Leeds Dyspepsia Questionnaire: a valid tool for measuring the presence and severity of 
dyspepsia. Alimentary Pharmacology and Therapeutics. 1998 Dec 1;12(12):1257-62.
18. Fraser A, Delaney BC, Ford AC, Qume M, Moayyedi P. The short‐form leeds dyspepsia 
questionnaire validation study. Alimentary pharmacology & therapeutics. 2007 
Feb;25(4):477-86.
19. Talley NJ, Haque M, Wyeth JW, Stace NH, Tytgat GN, Stanghellini V, Holtmann G, 
Verlinden M, Jones M. Development of a new dyspepsia impact scale: the Nepean 
Dyspepsia Index. Alimentary pharmacology & therapeutics. 1999 Feb 1;13(2):225-35.
20. Talley NJ, Verlinden M, Jones M. Quality of life in functional dyspepsia: responsiveness 
of the Nepean Dyspepsia Index and development of a new 10‐item short form. Alimentary 
pharmacology & therapeutics. 2001 Feb 5;15(2):207-16.
21. Hartrick CT, Kovan JP, Shapiro S. The numeric rating scale for clinical pain measurement: 
a ratio measure?. Pain Practice. 2003 Dec;3(4):310-6
22. Farrar JT, Young Jr JP, LaMoreaux L, Werth JL, Poole RM. Clinical importance of 
changes in chronic pain intensity measured on an 11-point numerical pain rating scale. 
Pain. 2001 Nov 1;94(2):149-58.
23. Nemoto, T., & Beglar, D. (2014). Developing Likert-scale questionnaires. In N. Sonda & 
A. Krause (Eds.), JALT2013 Conference Proceedings. Tokyo: JALT.

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16
APPENDICES
16.1
Appendix – Participating Countries’ National Insurance Requirements
Insurance will be covered by the sponsor in accordance to the local regulations
16.2
Appendix – Medical expert for the trial.
Dr Suntje Sander-Struckmeier – Global Clinical Director- Abbott
Email: suntje.sander@abbott.com
Dr Amit Bobde- Medical Monitor- TechObserver
Email: amit.bobde@tech-observer.com
16.3
Appendix –Clinical laboratory(ies) involved in the trial
The respective local clinical laboratories will be used after site selection.