Multicenter, Open-label, Controlled, Randomized Clinical Study to Evaluate the Efficacy and Safety of Racecadotril in Infants, Children and Adolescents With Acute Diarrhea
Phase: PHASE3
Conditions: Diarrhea
Sponsor: Abbott

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
Page 1 of 50 
CLINICAL STUDY PROTOCOL 
Cover Page 
Protocol No.: 
RACE3003 
Protocol Date: 
30 May 2017 
 
Study Title: 
Multicenter, open-label, controlled, randomized clinical study 
to evaluate the efficacy and safety of Racecadotril in infants, 
children and adolescents with acute diarrhea  
 
IND No.: 
 
EudractCT No: 
NA 
 
NA 
 
 
Phase of Development: 
III 
 
Sponsor: 
 
Global Clinical Director 
 
Protocol Author (s) 
Abbott Laboratories GmbH 
 
 
 
 
 
 
 
 
 
 
 
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no unpublished information contained within will be published or disclosed without prior written approval, except that this document may 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 

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
Page 2 of 50 
SYNOPSIS 
 
Name of Sponsor: 
Abbott Laboratories GmbH  
Name of Finished Product: 
Hidrasec Infants: Granules for 
Oral Suspension 10 mg 
Hidrasec Children: Granules for 
Oral Suspension 30 mg 
Hidrasec: 100 mg capsules  
Name of Active Ingredient(s): 
Racecadotril 
Title of Study: 
Multicenter, open-label, controlled, randomized clinical study to evaluate the efficacy and 
safety of Racecadotril in infants, children and adolescents with acute diarrhea 
Study Center(s) (Planned): 
 
Study Duration: 
 End of Study is defined as Data Base Lock.  
Phase of Development: 
III  
Objectives: 
 
Primary objective: 
 
The primary objective is to evaluate the efficacy of Racecadotril in addition to standard treatment 
oral rehydration solution (ORS) versus ORS alone in infants, children and adolescents with acute 
diarrhea (3 months until < 18 years) measured as duration of diarrhea (hours) between the start of 
treatment until final diarrheal/watery stool before recovery or end of study treatment (treatment 
duration maximal 5 days).  
Duration of diarrhea is defined by date and time of the evacuation of the final watery/diarrheal 
stool before recovery derived from the daily diary. 
Secondary objective(s): 
 
• Time until recovery: recovery is defined by date and time of the evacuation of the first of 
two consecutive normal stools or no stool within 12 hours. 
 
• Number of recovered subjects per treatment group cumulatively and until each 
individual treatment day. Mean and median time until recovery per treatment group. 
 
• Global Physician Assessment at the end of treatment: 
o 1 = Complete relief of acute diarrhea, 
o 2 = marked improvement of acute diarrhea, 
o 3 = moderate improvement of acute diarrhea,  
o 4 =slight improvement of acute diarrhea,  
o 5 = no change in acute diarrhea,  
o 6 =worsening of acute diarrhea. (Treatment success = GPA score of 1 or 2). 
 

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
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Name of Sponsor: 
Abbott Laboratories GmbH  
Name of Finished Product: 
Hidrasec Infants: Granules for 
Oral Suspension 10 mg 
Hidrasec Children: Granules for 
Oral Suspension 30 mg 
Hidrasec: 100 mg capsules  
Name of Active Ingredient(s): 
Racecadotril 
• For toilet trained children and adolescents: number of stools per day as well as number 
of watery stools per day from start of treatment and until end of study treatment. 
 
Safety objective(s): 
To evaluate the safety and tolerability of Racecadotril in addition to ORS versus ORS alone in 
infants, children and adolescents with acute diarrhea by adverse events, physical examination 
and vital signs. 
Methodology: 
This is a controlled, randomized, open-label, parallel-group study evaluating the efficacy and 
safety of Racecadotril in infants, children and adolescents with acute diarrhea.  
 
 
Screening and Enrolment (Day 1, Visit 1) 
Subjects presenting with acute diarrhea will be evaluated for eligibility. They will undergo a 
physical examination including vital signs, a review of their medical history and concomitant 
medication. If the subjects are eligible, demographics, number of stools during the last 24 hours 
will be assessed as baseline values. The subjects will be randomized to Racecadotril plus ORS or 
ORS alone. On Day 1 the subject will start with study treatment. The starting dose will either be 
the noon or the evening dose. 
 
Treatment period (until recovery, maximally five days) 
Subjects will be treated with Racecadotril three times daily according to the body weight dose 
requirement on an out-patient or in-patient basis for maximum 5 days in addition to ORS or with 

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
Page 4 of 50 
Name of Sponsor: 
Abbott Laboratories GmbH  
Name of Finished Product: 
Hidrasec Infants: Granules for 
Oral Suspension 10 mg 
Hidrasec Children: Granules for 
Oral Suspension 30 mg 
Hidrasec: 100 mg capsules  
Name of Active Ingredient(s): 
Racecadotril 
ORS alone. ORS will be prescribed by the investigator. The parent/caregivers will be instructed 
to stop treatment when the patient recovered. Recovery is defined by the evacuation of the first 
of two consecutive normal stools. In the evening of each day, the parent(s)/caregiver(s) will fill 
in the diaries, documenting date and time of each individual stool, the stool consistency of each 
stool, ORS amount and the study drug intake. AEs are to be reported on an ongoing basis. 
Treatment will stop at recovery or after the morning dose of day 6, if not recovered. 
End of treatment (at recovery or Day 6, Visit 2) 
The last dose of study drug intake will be the morning dose of day 6, if not recovered earlier. The 
parent(s)/caregiver(s) will visit the site for the end of study visit of the child. Data on vital signs, 
AEs, physical examination and concomitant medication will be collected. The 
parent(s)/caregiver(s) will return the diaries and unused medication.  
 
Safety follow-up 
A phone call will be performed at 5-7 days after end of the treatment period or recovery for the 
safety follow-up. 
 
Table 1. Flow Chart of Study Assessments  
Note: Any additional medical procedures not included into this study protocol can be performed within 
routine clinical practice in each medical institution 
Period 
Screening 
End of 
Treatment 
period 
Safety follow-up 
(phone call 5-7 
days after Visit 2) 
Visit 
1 
2 
3 
Day 
1 
62 
11-13 
Informed consent/assent 
X 
 
 
Randomization 
X 
 
 
Demographic data 
X 
 
 
Medical history 
X 
 
 
Physical examination3 
X 
X 
 
In-or outpatient  
X 
 
 
Stool frequency within the last 24 
hours 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
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Name of Sponsor: 
Abbott Laboratories GmbH  
Name of Finished Product: 
Hidrasec Infants: Granules for 
Oral Suspension 10 mg 
Hidrasec Children: Granules for 
Oral Suspension 30 mg 
Hidrasec: 100 mg capsules  
Name of Active Ingredient(s): 
Racecadotril 
Vitals signs 
X 
X 
 
Dispense study drug 
X 
 
 
Concomitant medication 
X 
X 
X if applicable 
Compliance check 
 
X 
 
Adverse events 
X 
X 
X 
Collect study drug 
 
X 
 
Dispense diary  
X1 
 
 
Collect diary 
 
X 
 
1 Subjects’ parent/caregivers have to fill in their daily diaries continuously. 
2 or within 24 h after recovery if this occurs before day 6  
3 including assessment of dehydration level 
Number of Subjects (Planned): 
A maximum number of subjects to be allocated to treatment: 62 subjects per group, 124 subjects 
in total. A minimum number of 20 subjects should be available in each age group (3 – < 24 
months, 2 years to 11 years, 12 to < 18 years). 
A maximum number of subjects to be screened: Approximately 150 should be screened. 
Diagnosis and Main Criteria for Inclusion:  
• Signed informed consent from one of the parent(s)/caregiver(s) or subject informed 
assent. 
• Children and adolescents, both genders, age from 3 months to < 18 years of age.  
• Confirmed diagnosis of acute diarrhea (defined as the passage of three or more unformed 
or liquid stools within the last 24 hours and lasting for less than three days).  
• Females of child-bearing potential should agree to continue using a medically acceptable 
method of birth control throughout the study and for 30 days immediately after the last 
dose of study drug. Medically acceptable methods of birth control include bilateral tubal 
ligation or the use of either a contraceptive implant, a contraceptive injection, an 
intrauterine device, or an oral contraceptive taken within the past three months where the 
subject agrees to continue using during the study or to adopt another birth control 
method, or a double-barrier method which consists of a combination of any two of the 
following: diaphragm, cervical cap, condom, or spermicide. 
 
Exclusion Criteria: 
• Known allergy to Racecadotril or any of its ingredients. 
• Subjects suffering from renal or hepatic impairment.  

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
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Name of Sponsor: 
Abbott Laboratories GmbH  
Name of Finished Product: 
Hidrasec Infants: Granules for 
Oral Suspension 10 mg 
Hidrasec Children: Granules for 
Oral Suspension 30 mg 
Hidrasec: 100 mg capsules  
Name of Active Ingredient(s): 
Racecadotril 
• Subjects who need treatment for diarrhea other than ORS alone. 
• Subjects with fever > 39 degrees Celsius. 
• Subjects with bloody and/or purulent stools.  
• Subjects suffering from antibiotic-associated diarrhea, chronic diarrhea or iatrogenic 
diarrhea. 
• Subjects with alternating bouts of diarrhea and constipation. 
• Diarrhea due to exacerbation of chronic gastrointestinal diseases such as irritable bowel 
syndrome, inflammatory bowel disease or pancreatic exocrine insufficiency. 
• Cystic fibrosis or coeliac disease. 
• Subjects suffering from prolonged or uncontrolled vomiting. 
• Subjects with rare hereditary problems of fructose or galactose intolerance, Lapp lactase 
deficiency, 
glucose-galactose 
malabsorption 
syndrome 
or 
sucrase 
isomaltase 
insufficiency or primary or secondary lactase insufficiency. 
• Subjects having received antibiotic treatment at any time within 30 days prior to 
inclusion into the study. 
• Subjects having received antidiarrheal drugs 48 hours prior to inclusion into the study. 
• Subjects with severe dehydration required for intravenous/parenteral rehydration. 
• Subjects who have reported angioedema with angiotensin converting enzyme inhibitors 
(such as captopril, enalapril, lisinopril, perindopril, ramipril)  
• Subjects with combined diseases or medical situations that would prevent to be enrolled 
depending in the judgment of the investigator. 
• Intake of experimental drug within 30 days prior to study start. 
• Subjects with contraindications to ORS or for whom warnings/precautions of ORS apply. 
• Adolescents (≥ 60 kg) not able to swallow capsules. 
• Pregnancy and lactation. 
 
Test Product, Dose and Mode of Administration: 
Racecadotril Infants Granules for Oral Suspension10mg 
Racecadotril Children Granules for Oral Suspension 30mg 
Racecadotril Capsules 100 mg 
 
1.5 mg/kg of Racecadotril will be administered, 3 times daily, via the oral route. 
 
In infants less than 9 kg: one 10 mg sachet 3 times daily. 
In infants from 9 kg to < 13 kg: two 10 mg sachets 3 times daily. 
In children from 13 kg to 27 kg: one 30 mg sachet 3 times daily. 
In children of more than 27 kg: two 30 mg sachets 3 times daily. 

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
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Name of Sponsor: 
Abbott Laboratories GmbH  
Name of Finished Product: 
Hidrasec Infants: Granules for 
Oral Suspension 10 mg 
Hidrasec Children: Granules for 
Oral Suspension 30 mg 
Hidrasec: 100 mg capsules  
Name of Active Ingredient(s): 
Racecadotril 
In children or adolescents of 60 kg or higher: 100 mg capsule 3 times daily 
 
Racecadotril will be given three times daily in addition to standard treatment ORS. Other 
medication to treat diarrhea (see section 7.7) is forbidden. 
Duration of Treatment: 
The first dose of Racecadotril will be taken on day 1, either the noon or evening dose. The 
treatment duration lasts until recovery, maximally 5 days, until the morning dose of day 6. 
Reference Therapy, Dose and Mode of Administration: 
Standard treatment is oral rehydration solution (ORS) according to the registered local label and 
the instruction of the investigator. The same brand of ORS and the same age-appropriate 
standardized treatment pattern for the subjects will be applied throughout the trial. No additional 
reference therapy will be administered together with oral rehydration in the control arm. 
Criteria for Evaluation: 
Efficacy: 
Primary Efficacy Variable: 
Duration of diarrhea (hours) between the start of treatment until last diarrheal/watery stool before 
recovery or end of study treatment (treatment duration maximal 5 days). Duration of diarrhea is 
defined by date and time of the evacuation of the final diarrheal stool derived from the daily 
diary. 
Secondary Efficacy Variables: 
• Number of recovered subjects per treatment group in total and until each individual 
treatment day. Mean and median time until recovery per treatment group. 
 
• Time until recovery, defined by date and time of the evacuation of the first of two 
consecutive normal stools. 
 
• Global Physician Assessment at the end of treatment: 
o 1 = Complete relief of acute diarrhea, 
o 2 = marked improvement of acute diarrhea, 
o 3 = moderate improvement of acute diarrhea,  
o 4 =slight improvement of acute diarrhea,  
o 5 = no change in acute diarrhea,  
o 6 =worsening of acute diarrhea. (Treatment success = GPA score of 1 or 2). 
 

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
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Name of Sponsor: 
Abbott Laboratories GmbH  
Name of Finished Product: 
Hidrasec Infants: Granules for 
Oral Suspension 10 mg 
Hidrasec Children: Granules for 
Oral Suspension 30 mg 
Hidrasec: 100 mg capsules  
Name of Active Ingredient(s): 
Racecadotril 
• For toilet trained children and adolescents: number of stools per day as well as number 
of watery stools per day from start of treatment and until end of study treatment. 
 
Safety: 
Adverse events, vital signs, physical examination in both treatment arms. 
Statistical Methods: 
Efficacy: 
In order to compare the primary efficacy parameter, duration of diarrhea between the treatment 
groups a Kaplan Meier analysis will be performed. The log-rank test will be used to test whether 
the difference of the duration of diarrhea between two treatment groups is statistically 
significant, i.e. p-value <0.05. 
Secondary efficacy parameters will be analyzed similarly. All parameters will be summarized 
using descriptive statistics. 
 
Safety: 
The safety sample will be used for the analysis of the safety and tolerability data. 
Treatment emergent AEs are summarized by unique treatment. Severity and drug-event 
relationship of treatment emergent AEs are summarized separately. Vitals signs, including 
changes from baseline will be summarized. A frequency table will be presented for markedly 
abnormal values. 
Sample size 
The sample size of this study is based on the results obtained with a randomized, double blind, 
study with Racecadotril in the treatment of  hospitalized children aged 3-60 months suffering 
from acute watery diarrhea (Bio-Projet Study nr. 45, Salazar Lindo et al. 1998). A total of 135 
subjects were analyzed in this study. Data of the study showed following recovery rates over 
time: 
 
Duration of treatment 
Percentage of recovered patients 
 
 
Placebo 
Racecadotril 
Sample size per group 
required for a power of 80% 
using log-rank test (+10% 
drop out rate) 
after 1 day (24 hours) 
18.3% 
46.6% 
41 (46) 
After 2 days (50 hours) 
35.8% 
70.1% 
36 (40) 
After 3 days (72 hours) 
59.4% 
84.2% 
55 (62) 

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
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Name of Sponsor: 
Abbott Laboratories GmbH  
Name of Finished Product: 
Hidrasec Infants: Granules for 
Oral Suspension 10 mg 
Hidrasec Children: Granules for 
Oral Suspension 30 mg 
Hidrasec: 100 mg capsules  
Name of Active Ingredient(s): 
Racecadotril 
After 4 days (96 hours) 
76.3% 
90.1% 
119 (132) 
After 5 days (120 hours)  
80.6% 
94.7% 
90 (100) 
 
The mean duration of diarrhea was 64 (±4.6) hours in the placebo group (median 64 hours) and 
40 (±4.1) hours in the Racecadotril group (median 28 hours). Therefore an appropriate approach 
to investigate a difference between recovery rates of the two treatment groups would be after a 
treatment duration of at least 3 days (i.e. 72 hours).When the sample size in each group is 55 
(with a total number of recoveries of at least 26), the two-sided log-rank test for equality of 
survival curves will have 80% power to detect the difference between 84.2% rate of recovery in 
the Racecadotril group and the 59.4% rate of recovery in the placebo group after a treatment 
duration of 72 hours. Adding a 10% drop-out rate the sample size per groups would be 62 
subjects i.e. 124 subjects in total. A minimum number of 20 subjects should be available in each 
age group (3 – < 24 months, 2 years to 11 years, 12 to < 18 years). A subgroup analysis per age 
group (3 – < 24 months, 2 years to 11 years, 12 to < 18 years) will be performed. 
 
 

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
SYNOPSIS ......................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................13 
1 
ETHICS......................................................................................................................15 
1.1 
Independent Ethics Committee or Institutional Review Board ..................................15 
1.2 
Ethical Conduct of the Study ......................................................................................15 
1.3 
Subject Information and Consent ................................................................................15 
2 
INTRODUCTION .....................................................................................................17 
3 
STUDY OBJECTIVES .............................................................................................19 
3.1 
Primary Objective(s) ...................................................................................................19 
3.2 
Secondary Objective(s) ...............................................................................................19 
3.3 
Safety Objective(s) ......................................................................................................19 
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 ......................21 
5 
SELECTION OF STUDY POPULATION.............................................................22 
5.1 
Inclusion Criteria.........................................................................................................22 
5.2 
Exclusion Criteria .......................................................................................................22 
6 
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT ................24 
7 
TREATMENTS .........................................................................................................25 
7.1 
Treatments to Be Administered ..................................................................................25 
7.2 
Packaging and Labeling ..............................................................................................25 
7.3 
Storage and Dispensing of Study Drug .......................................................................26 
7.4 
Method of Assigning Subjects to Treatment Groups ..................................................26 
7.5 
Selection of Doses and Timing in the Study ...............................................................26 
7.6 
Blinding and Treatment Code Information .................................................................26 
7.7 
Prior and Concomitant Therapy ..................................................................................27 
7.8 
Treatment Compliance ................................................................................................28 

 
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Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
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8 
STUDY ASSESSMENTS AND FLOW CHART ...................................................29 
8.1 
Efficacy Measurements ...............................................................................................29 
8.2 
Safety Measurements ..................................................................................................29 
8.3 
Other Assessments ......................................................................................................30 
8.4 
Appropriateness of Measurements ..............................................................................31 
8.5 
Primary Efficacy/ Variable(s) .....................................................................................31 
8.6 
Flow Chart of Study Assessments ..............................................................................31 
9 
ADVERSE EVENTS.................................................................................................33 
9.1 
Adverse Events ...........................................................................................................33 
9.1.1 
Recording of Adverse Events .....................................................................................33 
9.1.2 
Follow-up of Adverse Events .....................................................................................35 
9.2 
Serious Adverse Events (SAEs) ..................................................................................35 
9.2.1 
Reporting Serious Adverse Events .............................................................................36 
9.3 
Pregnancy ....................................................................................................................36 
10 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ....37 
10.1 
General Definitions and Conventions .........................................................................37 
10.2 
Subject Samples ..........................................................................................................38 
10.3 
Efficacy .......................................................................................................................39 
10.4 
Safety ..........................................................................................................................39 
10.5 
Other Assessments ......................................................................................................40 
10.6 
Subgroup Analysis ......................................................................................................41 
10.7 
Interim Analysis ..........................................................................................................41 
10.8 
Determination of Sample Size ....................................................................................41 
11 
INVESTIGATOR OBLIGATIONS ........................................................................42 
11.1 
Essential Study Documents .........................................................................................42 
11.2 
Case Report Form (CRF) Completion ........................................................................42 
11.3 
Essential Records Retention........................................................................................43 
11.4 
Investigator Agreement ...............................................................................................44 
12 
SPONSOR OBLIGATIONS ....................................................................................45 
12.1 
Protocol Amendments .................................................................................................45 
12.2 
Study Monitoring ........................................................................................................45 
12.3 
Quality Assurance Audits ...........................................................................................46 
13 
PUBLICATION POLICY ........................................................................................47 
14 
INSURANCE .............................................................................................................48 

 
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Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
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15 
REFERENCES ..........................................................................................................49 
16 
APPENDICES ...........................................................................................................50 
16.1 
Appendix – Participating Countries’ National Insurance Requirements ....................50 
16.2 
Appendix – Coordinating Investigator Signature of Clinical Study Report ...............50 
16.3 
Appendix – Medical expert for the trial. .....................................................................50 
16.4 
Appendix –Clinical laboratory(ies) involved in the trial ............................................50 
 
Table 1. 
Flow Chart of Study Assessments ...........................................................................4 
 
 

 
Abbott 
Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
Confidential 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADR 
adverse drug reaction 
Ae 
amount of unchanged drug excreted into the urine 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
bpm 
beat per minute 
CFR 
Code of Federal Regulations 
CRF 
case report form (paper or other media) 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
EDC 
Electronic Data Capture 
EEG 
electroencephalogram 
EU 
European Union 
EudraCT 
European clinical trials database 
FA 
full analysis 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GPV 
Global Pharmacovigilance  
HLGT 
high level group term 
HLT 
high level term 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IXRS 
Interactive Voice/Computer/Remote Response System 
LLT 
lowest level term 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 

 
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Protocol Date 30 May 2017 
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Min 
Minimum 
N/A 
not applicable 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PP 
per-protocol 
PT 
preferred term 
SADR 
serious adverse drug reaction 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse drug reaction 
WHO 
World Health Organization 
 

 
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Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
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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 and the rules of the EU Clinical Trial Directive, 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 wellbeing 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 one parent/caregiver of each subject 
prior to performing any study-related procedures. Each parent/caregiver will be given both 
verbal and written information describing the nature and duration of the clinical study. The 

 
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Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
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Page 16 of 50 
informed consent process will take place under conditions where the parent/caregiver has 
adequate time to consider the risks and benefits associated with the child’s participation in the 
study. Subjects will not be screened or treated until the parent/caregiver has signed an approved 
informed consent written in a language that is understandable to the subject. The participation of 
the study should be discussed with the subject <14 years of age according to the child’s age and 
ability and verbal assent should be obtained. The informed consent will be given by the signature 
of one parent. 
Voluntary written informed assent will be obtained from adolescents ≥ 14 years in addition to 
parent’s written informed consent. Each subject will be given both verbal and written 
information describing the nature and duration of the clinical study. The informed assent process 
will take place under conditions where the subject has adequate time to consider the risks and 
benefits associated with the participation in the study. Subjects will not be screened or treated 
until the subject has signed an approved informed assent written in a language that is 
understandable to the subject.  
The IEC/IRB approved informed consent/assent form will be signed and personally dated by the 
parent/caregiver (or legally acceptable representative, when appropriate) and the person who 
conducted the informed consent discussion. Each parent/caregiver 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 parent/caregiver 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 parents/caregivers 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. 

 
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Protocol No. RACE3003  
 
Protocol Date 30 May 2017 
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2 
INTRODUCTION 
Racecadotril (acetorphan), an enkephalinase inhibitor, represents a promising approach to the 
treatment of diarrhoea. Water and electrolyte transport in the intestinal mucosa is regulated by 
local messengers (neuropeptides, amines, and eicosanoids). Most of them act via the mediation 
of cyclic adenosine monophosphate (cAMP), activating or inhibiting its production from 
adenosine triphosphate. An increase in cAMP is induced by endogenous (e.g. VIP, PGE2) or 
exogenous agents (e.g. V. cholerae, E. coli toxins) and leads to net hypersecretion of water and 
electrolytes. Opiate neuropeptides are localized in the intestine myenteric and submucosal 
plexuses, where they modulate motility (mu receptors) and secretion (delta receptors). Activation 
of mu receptors prolongs intestinal transit while activation of delta receptors reduces intestinal 
secretion of water and electrolytes. Enkephalins activate delta receptors and inhibit 
adenylcyclase, thus facilitating a decrease in cAMP levels with a consequent reduction in water 
and electrolyte secretion. This antisecretory action, however, is brief because enkephalins are 
rapidly degraded by the membrane peptidase enkephalinase (EC 3.4.24.11). Racecadotril is a 
prodrug that is rapidly hydrolysed in man into the active metabolite thiorphan, which is a 
powerful and selective enkephalinase inhibitor. Thus, the antisecretory action of enkephalins is 
prolonged in the presence of thiorphan. Furthermore, unlike opiates and loperamide, 
Racecadotril does not act on mu receptors and therefore it does not prolong intestinal transit, nor 
does it favour bacterial growth in the small intestine.  
Racecadotril is devoid of any central or peripheral nervous side effect, at the opposite of opiates, 
such as respiratory depression or inhibition of intestinal transit. 
 
The trade names are Tiorfan® in France, where it has been approved in capsules since July 1992 
and launched in March 1993, and Hidrasec® in other countries. Pediatric dosage form of 
racecadotril (Tiorfan® sachet 10 mg and 30 mg) were approved in France in October 1999. 
Hidrasec® capsules were registered in Russia for adult use in 2017. The products are currently 
approved in 85 countries. 
 
Diarrhea is defined as the passage of unusually loose or watery stools, with a frequency of at 
least three times in a 24 hour period. The objective for treatment of acute diarrhea associated 
symptoms is to prevent and treat dehydration at first, to prevent nutritional damage and to reduce 
the duration and severity of diarrhea. Antidiarrheal drugs have been developed to prevent 
dehydration and to resolve diarrhea on top of with oral rehydration solution (ORS). Ideally 
antidiarrheals have a positive safety profile and have limited or no effects on motility and basal 
intestinal secretion. 
Racecadotril has been shown to be effective and well tolerated for the complementary 
symptomatic treatment of acute diarrhea in pediatric subjects older than 3 months. 
This study is conducted to assess the efficacy and safety profile of Racecadotril in Russia 
pediatric and adolescent subjects. 
The dosing regimen of Racecadotril is 1.5 mg/kg 3 times daily, via the oral route resulting in the 
following instruction: 

 
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In infants less than 9 kg: one 10 mg sachet 3 times daily. 
In infants from 9 kg to < 13 kg: two 10 mg sachets 3 times daily. 
In children from 13 kg to 27 kg: one 30 mg sachet 3 times daily. 
In children of more than 27 kg: two 30 mg sachets 3 times daily. 
In children or adolescents of 60 kg or higher: 100 mg capsule 3 times daily 
 

 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective(s) 
The primary objective is to evaluate the efficacy of Racecadotril in addition to standard treatment 
oral rehydration solution (ORS) versus ORS alone in infants, children and adolescents (3 months 
until <18 years) with acute diarrhea measured as duration of diarrhea (hours) between the start of 
treatment until final diarrheal/watery stool before recovery or end of study treatment (treatment 
duration maximal 5 days).  
 
Duration of diarrhea is defined by date and time of the evacuation of the final watery/diarrheal 
stool before recovery derived from the daily diary. 
 
3.2 
Secondary Objective(s) 
• Number of recovered subjects per treatment group in total and until each individual 
treatment day. Mean and median time until recovery per treatment group. 
 
• Time until recovery, defined by date and time of the evacuation of the first of two 
consecutive normal stools or no stool within 12 hours. 
 
• Global Physician Assessment at the end of treatment: 
o 1 = Complete relief of acute diarrhea, 
o 2 = marked improvement of acute diarrhea, 
o 3 = moderate improvement of acute diarrhea,  
o 4 =slight improvement of acute diarrhea,  
o 5 = no change in acute diarrhea,  
o 6 =worsening of acute diarrhea. (Treatment success = GPA score of 1 or 2). 
 
• For toilet trained children and adolescents: number of stools per day as well as number 
of watery stools per day from start of treatment and until end of study treatment. 
 
3.3 
Safety Objective(s) 
To evaluate the safety and tolerability of Racecadotril together with oral rehydration solution 
(ORS) versus ORS alone in infants, children and adolescents with acute diarrhea by adverse 
events, physical examination and vital signs. 

 
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4 
STUDY DESIGN 
4.1 
Overall Study Design and Plan-Description 
This is a controlled, open-label, parallel-group study evaluating the efficacy and safety of 
Racecadotril in infants, children and adolescents with acute diarrhea. The number of subjects to 
be screened is 150 in order to enroll 124 subjects for either standard treatment (oral rehydration 
solution, ORS) alone or ORS plus Racecadotril. 
 
1.5 mg/kg of Racecadotril will be administered, 3 times daily, via the oral route. Study drug 
intake will start either with the noon or the evening dose on day 1. 
 
In infants less than 9 kg: one 10 mg sachet 3 times daily. 
In infants from 9 kg to <13 kg: two 10 mg sachets 3 times daily. 
In children from 13 kg to 27 kg: one 30 mg sachet 3 times daily. 
In children of more than 27 kg: two 30 mg sachets 3 times daily. 
In children or adolescents of 60 kg or higher: 100 mg capsule 3 times daily 
 
Standard treatment is oral rehydration solution (ORS) according to the registered local label and 
the instruction of the investigator. The same brand of ORS and the same age-appropriate 
standardized treatment pattern for the subjects will be applied throughout the trial. ORS 
treatment and dosing will be documented in the CRF. 
 
Screening and Enrolment (Day 1, Visit 1) 
Subjects presenting with acute diarrhea will be evaluated for eligibility. They will undergo a 
physical examination including assessment of dehydration level, vital signs, a review of their 
medical history and concomitant medication. If the subjects are eligible for the study, 
demographics, number of stools during the last 24 hours will be assessed as baseline values. The 
subjects will be randomized to Racecadotril plus ORS or ORS alone. On Day 1 the subject will 
start with study treatment. The starting dose will either be the noon or the evening dose 
depending on the timing of Visit 1. 
 
Treatment period (until recovery, maximally 5 days) 
Subjects will be treated with Racecadotril tid according to the body weight dose requirement on 
an in- or out-patient basis for maximum 5 days. One arm will be treated with ORS alone as 
standard treatment, the other treatment arm will be treated with ORS (according to the registered 
local label and the instruction of the investigator) in addition to Racecadotril. ORS will be 
prescribed by the investigator and will be taken according to the product label and the instruction 
of the investigator. The parent(s)/caregiver(s) will be instructed to stop study drug treatment 
when the patient recovered. On each day, the parent(s)/caregiver(s) will fill in their diaries, 
documenting the date and time of each individual stool, the stool consistency of each stool 
(diarrheal/watery or normal), the amount of ORS and the study drug intake. After the occurrence 
of two consecutive normal stools, the parent(s)/caregiver(s) can stop recording of the diary and 

 
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return to the study site for the end of treatment visit. The date of recovery is the day when the 
first of two consecutive normal stools were excreted. AEs are to be reported on an ongoing basis.  
 
End of treatment (Day 6 or early recovery, Visit 2) 
The last dose of study drug will be the morning dose of day 6, if not recovered earlier. The same 
day, or within 24 hours after recovery, the parent(s)/caregiver(s) will visit the site for the end of 
treatment visit of the child. Data on vital signs, AEs, physical examination and concomitant 
medication will be collected. Subjects will return their diaries and unused medication.  
 
Safety follow-up 
A phone call will be performed at 5-7 days after end of the treatment period for the safety 
follow-up. 
 
 
 
4.2 
Discussion of Study Design, Including the Choice of Control Groups 
Standard treatment for pediatric subjects with acute diarrhea is ORS and adequate rehydration is 
also the basic treatment regimen for adolescents. ESPGHN guidelines (Guarino et al. 2014) and 
World Gastroeneterology Organization (WGO) guidelines 2012 state that the gold standard of 
treatment of acute diarrhea in pediatric population is oral rehydration solution (ORS). Thus ORS 
is considered to be the appropriate control treatment for planned investigation.  
 
An open-label designs of Racecadotril on top of ORS versus ORS alone is appropriate as the 
primary endpoint can be measured objectively: duration of diarrhea (hours) between the start of 
treatment until final diarrheal/watery stool before recovery or end of study treatment. 
 

 
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5 
SELECTION OF STUDY POPULATION 
5.1 
Inclusion Criteria 
• Informed Consent: 
o For all subjects: signed informed consent from one of the parent(s)/caregiver(s) 
o For subjects ≥ 14 years of age: signed informed assent form in addition to parent’s 
written informed consent 
o For subjects <14 years of age: verbal assent if age and ability allows  
• Children and adolescents, both genders, age from 3 months to < 18 years of age.  
• Confirmed diagnosis of acute diarrhea (defined as the passage of three or more unformed 
or liquid stools within the last 24 hours and lasting for less than three days).  
• Females of child-bearing potential should agree to continue using a medically acceptable 
method of birth control throughout the study and for 30 days immediately after the last 
dose of study drug. Medically acceptable methods of birth control include bilateral tubal 
ligation or the use of either a contraceptive implant, a contraceptive injection, an 
intrauterine device, or an oral contraceptive taken within the past three months where the 
subject agrees to continue using during the study or to adopt another birth control 
method, or a double-barrier method which consists of a combination of any two of the 
following: diaphragm, cervical cap, condom, or spermicide. 
 
5.2 
Exclusion Criteria  
• Known allergy to Racecadotril or any of its ingredients. 
• Subjects suffering from renal or hepatic impairment.  
• Subjects who need treatment for diarrhea other than ORS alone. 
• Subjects with fever > 39 degrees Celsius. 
• Subjects with bloody and/or purulent stools. 
• Subjects suffering from antibiotic-associated diarrhea, chronic diarrhea or iatrogenic 
diarrhea. 
• Subjects with alternating bouts of diarrhea and constipation. 
• Diarrhea due to exacerbation of chronic gastrointestinal diseases such as irritable bowel 
syndrome, inflammatory bowel disease or pancreatic exocrine insufficiency. 
• Cystic fibrosis or coeliac disease. 
• Subjects suffering from prolonged or uncontrolled vomiting. 
• Subjects with rare hereditary problems of fructose or galactose intolerance, Lapp lactase 
deficiency, 
glucose-galactose 
malabsorption 
syndrome 
or 
sucrase 
isomaltase 
insufficiency or primary or secondary lactase insufficiency. 
• Subjects having received antibiotic treatment at any time within 30 days prior to 
inclusion into the study. 
• Subjects having received antidiarrheal drugs 48 hours prior to inclusion into the study. 
• Subjects with severe dehydration required for intravenous/parenteral rehydration. 

 
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• Subjects who have reported angioedema with angiotensin converting enzyme inhibitors 
(such as captopril, enalapril, lisinopril, perindopril, ramipril)  
• Subjects with combined diseases or medical situations that would prevent to be enrolled 
depending in the judgment of the investigator. 
• Intake of experimental drug within 30 days prior to study start. 
• Subjects with contraindications to ORS or for whom warnings/precautions of ORS apply. 
• Adolescents (≥ 60 kg) not able to swallow capsules 
• Pregnancy or lactation 

 
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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 must be completed for all subjects who did not fail screening, those 
who completed and those who prematurely terminated the study. 
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: subject fails to respond to the study drug at an acceptable level where 
the subject or the Investigator feels it is in the best interests of the subject to seek another 
treatment. 
- 
Lost to follow-up: the subject fails to return to the study site for scheduled visits and does 
not respond to telephone or written attempts to contact. 
- 
Withdrew consent: subject decides to stop his/her participation in the study for any 
reason other than an AE, or is unable to complete the study as described in the clinical 
study protocol (e.g. subject is relocating to another location). 
- 
Administrative: the Sponsor decides to discontinue the study (either at the study site or 
the entire study), e.g. general safety problems leading the Sponsor to entirely stop the 
study. 
- 
Protocol violation – anything which is in direct violation of the clinical study protocol 
(e.g. inclusion/exclusion violation). 
 
Subjects with two consecutive temperature measurements of > 39 degrees Celsius during the 
study should be withdrawn from the study for further diagnosis and alternative treatments. Also 
subjects whose disease state worsens, e.g. dehydration or increased vomiting, should be 
withdrawn from the study. An end of treatment visit will be performed. 
 

 
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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 
Racecadotril Infants Granules for Oral Suspension10mg 
Racecadotril Children Granules for Oral Suspension 30mg 
Racecadotril Capsules 100 mg 
 
1.5 mg/kg of Racecadotril will be administered, 3 times daily (morning, noon, evening), via the 
oral route. For more accurate dosing the following formulations will be used for different patient 
age groups: 
 
In infants less than 9 kg: one 10 mg sachet 3 times daily. 
In infants from 9 kg to <13 kg: two 10 mg sachets 3 times daily. 
In children from 13 kg to 27 kg: one 30 mg sachet 3 times daily. 
In children of more than 27 kg: two 30 mg sachets 3 times daily. 
In adolescents of 60 kg or higher: 100 mg capsule 3 times daily 
 
 
Standard treatment for pediatric subjects with diarrhea is oral rehydration solution (ORS). ORS 
will be given according to the registered local label of the brand and the instruction of the 
investigator. The same brand of ORS and the same age-appropriate standardized treatment 
pattern for the subjects will be applied throughout the trial. No additional reference therapy will 
be administered together with oral rehydration in the control arm.. ORS treatment will be 
documented in the CRF. Racecadotril will be given in addition to ORS. No drug will be 
administered together with oral rehydration in the control arm. 
7.2 
Packaging and Labeling 
Packaging and labeling will be controlled by 
 
. 
 
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. 

 
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An Abbott Qualified Person will release all the clinical supplies prior to shipment to 
investigational sites. A Certificate of Compliance will be issued stating the expiry date of the 
Racecadotril 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. 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. 
7.4 
Method of Assigning Subjects to Treatment Groups 
Subjects will be randomized to a treatment group by the assignment of a 5-digit randomization 
number to each subject according to a randomization scheme. The medication will be identified 
using 6-digit kit randomization numbers. 
The randomization scheme will be provided by 
 
 
7.5 
Selection of Doses and Timing in the Study 
1.5 mg/kg of Racecadotril will be administered, 3 times daily (morning, noon and evening), via 
the oral route. 
 
In infants less than 9 kg: one 10 mg sachet 3 times daily. 
In infants from 9 kg to <13 kg: two 10 mg sachets 3 times daily. 
In children from 13 kg to 27 kg: one 30 mg sachet 3 times daily. 
In children of more than 27 kg: two 30 mg sachets 3 times daily. 
In adolescents of 60 kg or higher: 100 mg capsule 3 times daily 
 
Standard treatment for pediatric patients with diarrhea is oral rehydration solution (ORS). ORS 
will be given according to the registered local label of the brand and the instruction of the 
investigator. It is recommended that all subjects will be prescribed the same brand and age 
appropriate dosing regimen of ORS. In the treatment arm with Racecadotril will be given in 
addition to ORS. 
7.6 
Blinding and Treatment Code Information 
This is an open-label study; blinding will not be applied. 

 
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7.7 
Prior and Concomitant Therapy 
During the study, participants are not allowed to be treated with the following treatments in 
addition to the study drug:   
• Antiperistaltic drugs, e.g. loperamide,  
• Antibiotics   
• Antipyretics 
• Intestinal antiseptics, e.g. 8-hydroxyquinoline 
• Respiratory decongestants, e.g phenylephrine  
• Antitussive medication, e.g noscapin  
• Absorbents, e. g. diosmectite, charcoal, pectin, psyllium 
• Zinc-containing medication 
• Homemade ORS 
• ACE Inhibitors 
• Antispasmodics  
• Drugs for symptomatic treatment of diarrhea, e.g. pancreatic enzymes, anticholinergic drugs, 
opiates, diphenoxylate. 
 
 
 
Subjects on continuous probiotic treatment (e.g. Lactobacillus, Bifidobacterium, yeast) or 
probiotic- containing supplements/formula of the same product/brand for at least 4 weeks prior 
to study start can be included. 
 
The presence of bloody or purulent stool and fever may indicate either the presence of invasive 
bacteria as a reason for diarrhea or the presence of another severe disease, warranting causal (e.g. 
antibiotic) treatment or further investigation. In addition, Racecadotril has not been investigated 
in patients with antibiotic-associated diarrhea. Therefore, Racecadotril should not be 
administered under these conditions.  
Subjects who need treatment with the above listed medication should be withdrawn from the 
study. 
Dietary modifications for thickening of the stools are allowed. 
Any intake of other medication is allowed as judged appropriate by the Investigator except those 
on the list of prohibited medications above. 
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, except for 
study drug. 

 
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7.8 
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. 
Compliance 
Each intake of study drug (Racecadotril) will be recorded in a patient diary and evaluated. 

 
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8 
STUDY ASSESSMENTS AND FLOW CHART 
8.1 
Efficacy Measurements  
Primary Efficacy Variable: 
Duration of diarrhea (hours) between the start of treatment until last diarrheal/watery stool before 
recovery or end of study treatment (treatment duration maximal 5 days). Treatment will stop at 
recovery or after the morning dose of day 6, if not recovered. 
Duration of diarrhea is defined by date and time of the evacuation of the final diarrheal stool 
derived from the daily diary. 
Secondary Efficacy Variables: 
• Time until recovery, defined by date and time of the evacuation of the first of two 
consecutive normal stools or no stool within 12 hours. 
 
• Number of recovered subjects per treatment group in total and until each individual 
treatment day. Mean and median time until recovery per treatment group. 
 
• Global Physician Assessment at the end of treatment: 
o 1 = Complete relief of acute diarrhea, 
o 2 = marked improvement of acute diarrhea, 
o 3 = moderate improvement of acute diarrhea,  
o 4 =slight improvement of acute diarrhea,  
o 5 = no change in acute diarrhea,  
o 6 =worsening of acute diarrhea. (Treatment success = GPA score of 1 or 2). 
 
• For toilet trained children and adolescents: number of stools per day as well as number 
of watery stools per day from start of treatment and until end of study treatment. 
 
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. 
Vital Signs 
Height and weight must be recorded.  
Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate are to be measured 
in pediatric appropriate setting. 

 
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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 allocation to 
treatment), or on the Adverse Event form in the CRF for findings presently occurring. The 
dehydration level of the subject will be assessed (mild, moderate, severe). 
Pregnancy Test 
A urine pregnancy test will be conducted on females of child-bearing potential (if child-bearing 
potential) at Visit 1. 
8.3 
Other Assessments 
Informed Consent 
Voluntary written informed consent must be obtained from one parent(s)/caregiver(s) (or their 
legally acceptable representative) prior to performing any study-related procedures (see Section 
1.3) for all subjects. For subjects < 14 years voluntary verbal assent will be obtained if age and 
ability allows in addition. 
Voluntary written informed assent will be obtained from subjects ≥ 14 years of age in addition to 
parent’s written informed consent prior to performing any study-related procedures (see Section 
1.3). 
Demographic Data 
Demographic data (gender, date of birth, race) will be collected for all subjects. 
Medical History 
Any clinical event, including diagnosis, condition, or surgery, that occurred prior to allocation to 
treatment, is to be recorded on the Medical History form. 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. Examples of these events are diabetes, 
migraine, and hay fever. 
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, except for 
study drug. 
Subject Diary 

 
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The parent(s)/caregiver(s) have to document date and time of each individual stool of the subject 
and the stool consistency (watery, normal) of each evacuation continuously. The subject 
individual stool consistency before start of the diarrhea is defined as normal (e.g. taking into 
account the age and diet, e.g. breast feeding, of the individual subject). Recording can be stopped 
after the excretion of two consecutive normal stools.  
The date, time and dose of study drug intake as well as the amount ORS and other liquids (e.g. 
water, milk formula) consumed has to be recorded. 
Fever will be measured once daily by the parent(s)/caregiver(s) and documented in the diary 
including method, time and value. 
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 duration of diarrhea is an appropriate primary efficacy variable. Duration of diarrhea is 
defined by date and time of the evacuation of the final watery/diarrheal stool before recovery 
derived from the daily diary. 
8.6 
Flow Chart of Study Assessments 
All study assessments will be conducted as indicated in Table 1, which displays the frequency 
and timing of all measurements. 
Table 2: Flow Chart of Study Assessments  
Note: Any additional medical procedures not included into this study protocol can be performed within 
routine clinical practice in each medical institution 
 
Period 
Screening 
End of 
Treatment 
period 
Safety follow-up 
(phone call 5-7 
days after Visit 2) 
Visit 
1 
2 
3 
Day 
1 
62 
11-13 
Informed consent 
X 
 
 
Randomization 
X 
 
 
Demographic data 
X 
 
 
Medical history 
X 
 
 
Pregnancy Test4 
X 
 
 
Physical examination3 
X 
X 
 

 
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In- or outpatient 
X 
 
 
Stool frequency within the last 24 
hours 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Vitals signs 
X 
X 
 
Dispense study drug 
X 
 
 
Concomitant medication 
X 
X 
X 
Compliance check 
 
X 
 
Adverse events 
X 
X 
X 
Collect study drug 
 
X 
 
Dispense diary  
X1 
 
 
Collect diary 
 
X 
 
1 Subjects’ parent/caregivers have to fill in their daily diaries continuously. 
2 or within 24 h after recovery if this occurs before day 6  
3 including assessment of dehydration level 
4 for females of child-bearing potential, urine test 
 
 

 
 
 
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9 
ADVERSE EVENTS 
 
 
9.1 
Adverse Events 
Definition of Adverse Event  
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 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). 
For each subject that has signed the informed consent and prior to study drug allocation at any 
dose, any change to medical status should be recorded in patient’s medical file in accordance to 
local requirements and the medical history CRF only.  
Any change to medical status, which occurs after study drug allocation at any dose in the 
specified study AE collection period will be handled as an (S)AE.  
For each subject that has signed the informed consent but does not qualify for allocation to 
treatment, i.e. Screen Failure, any change to medical status (from the time of ICF signature until 

 
 
 
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determination of non-qualification for the study) should be recorded in patient’s medical file 
according to local requirements. The related medical status change information will not be 
reviewed by Abbott or delegated staff, and will not qualify as a study (S)AE. 
Each AE, of the treatment arm as well as the no treatment arm, is to be evaluated for duration, 
severity, seriousness and causal relationship to the investigational drug. The action taken with 
study drug, the concomitant treatment/therapy introduced and the outcome as well as whether the 
event led to study termination will also be recorded.  
The post-study AE collection period is defined as 30 days after the subject’s termination of study 
drug (collection of (S)AEs should be passive in this period unless otherwise specified). 
Severity 
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. 
 
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). 

 
 
 
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- 
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. 
 
All efforts should be made to classify the AE according to the above categories. 
Note: when the AE is ongoing, the outcome will remain blank on the Adverse Events form in the 
CRF 
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). 

 
 
 
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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 faxing the appropriate SAE forms to the CRO. 
Local reporting requirements other than described, will be taken into account and adhered to. 
9.3 
Pregnancy 
If a subject should become pregnant during the study, the event will be reported on the 
Pregnancy Form within 24 hours of the investigator’s knowledge of the pregnancy. The 
Pregnancy Form is to be mailed or faxed to the CRO (or an authorized representative).  
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 CRO (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. 

 
 
 
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10 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
Data handling will be the responsibility 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 the CRO and approved by Abbott 
before database lock. 
The statistical analysis will be performed by the CRO 
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 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. 

 
 
 
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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. 
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 <allocated to treatment> sample will consist of all subjects who: 
- 
Were in the all subjects consented sample; and 
- 
Were <allocated 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: 

 
 
 
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- 
Were included in the FA sample; and  
- 
Did not present any major protocol violation. 
 
 
10.3 
Efficacy  
The primary efficacy variable is the duration (hours) of diarrhea (treatment duration max 5 days). 
Duration of diarrhea is defined by date of the evacuation of the last diarrheal/watery stool. 
 
In order to compare the primary efficacy parameter, duration of diarrhea, between the treatment 
groups, a Kaplan Meier analysis will be performed. The log-rank test will be used to test whether 
the difference between the duration of diarrhea between two treatment groups is statistically 
significant, i.e. p-value <0.05. 
 
The secondary efficacy variables are 
• Number of stools at baseline and per treatment day for toilet-trained subjects, only 
• Number of watery stools per day for toilet-trained subjects, only.  
• Assessment of treatment success by the physician 
• Time until recovery, defined by date and time of the evacuation of the first of two 
consecutive normal stools. 
• Number of subjects recovered per treatment group, in total and until each individual 
treatment day 
• Mean and median time until recovery per treatment group 
 
The assessment of treatment success by the physician will be done using the Global Physician 
Assessment GPA score:  
 
1 = Complete relief of acute diarrhea,  
2 = marked improvement of acute diarrhea,  
3 = moderate improvement of acute diarrhea,  
4 =slight improvement of acute diarrhea,  
5 = no change in acute diarrhea,  
6 =worsening of acute diarrhea.  
 
Treatment will be rated as success when the GPA score equals 1 or 2. 
 
Secondary efficacy parameters will be analyzed similarly to the primary analysis. All parameters 
will also be summarized using descriptive statistics. 
 
10.4 
Safety 
The safety sample will be used for the analysis of the safety and tolerability data. 

 
 
 
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AEs are considered treatment emergent (TE) if they start or worsen at or after the first 
administration of study drug and before or on the day of last administration of study drug plus a 
gap period of 1 day. 
 
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. Non-TEAEs will be listed. 
Vitals signs, including changes from baseline will be summarized. A frequency table will be 
presented for markedly abnormal values. 
10.5 
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.  

 
 
 
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10.6 
Subgroup Analysis 
Key efficacy and safety results will be summarized across subgroups defined by age group (3 – < 
24 months, 2 years to 11 years, 12 to < 18 years). 
10.7 
Interim Analysis 
not applicable 
 
10.8 
Determination of Sample Size 
The sample size of this study is based on the results obtained with a randomized, double blind, 
study with Racecadotril in the treatment of hospitalized children aged 3-60 months suffering 
from acute watery diarrhea  (Bio-Projet Study nr. 45, Salazar Lindo et al. 1998). A total of 135 
subjects were analyzed in this study. Data of the study showed following recovery rates over 
time: 
 
Duration of treatment 
Percentage of recovered patients 
 
 
Placebo 
Racecadotril 
Sample size per group 
required for a power of 80% 
using log-rank test (+10% 
drop out rate) 
after 1 day (24 hours) 
18.3% 
46.6% 
41 (46) 
After 2 days (50 hours) 
35.8% 
70.1% 
36 (40) 
After 3 days (72 hours) 
59.4% 
84.2% 
55 (62) 
After 4 days (96 hours) 
76.3% 
90.1% 
119 (132) 
After 5 days (120 hours)  
80.6% 
94.7% 
90 (100) 
 
The mean duration of diarrhea was 64 (±4.6)  hours in the placebo group (median 64 hours) and 
40 (±4.1)  hours in the Racecadotril group (median 28 hours), Therefore an appropriate approach 
to investigate a difference between recovery rates of the two treatment groups would be after a 
treatment duration of at least 3 days (i.e 72 hours).When the sample size in each group is 55 
(with a total number of recoveries of at least 26), the two-sided log-rank test for equality of 
survival curves will have 80% power to detect the difference between 84.2% rate of recovery in 
the Racecadotril group and the 59.4% rate of recovery in the placebo group after a treatment 
duration of 72 hours. Adding a 10% drop-out rate the sample size per groups would be 62 
subjects i.e. 124 subjects in total.  
A minimum number of 20 subjects should be available in each age group (3 – < 24 months, 2 
years to 11 years, 12 to < 18 years). A subgroup analysis per age group (3 – < 24 months, 2 years 
to 11 years, 12 to < 18 years) will be performed. 
 

 
 
 
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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 

 
 
 
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submitted with the (e)CRF, such as laboratory or hospital records, should be clearly identified 
with 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. 
In case screen failure data is entered in the (e)CRF, these data should be clearly indicated in the 
raw datasets and removed from the analysis datasets. 
 
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 

 
 
 
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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. 
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.  
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 
requirements. A monitoring visit will include a review of the essential clinical study documents 
(regulatory documents, CRFs, source documents, drug disposition records, subject informed 

 
 
 
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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 Audits 
The Sponsor’s (or an authorized representative’s) 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 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. 

 
 
 
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15 
REFERENCES 
 
 
Dr. J.M. Vetel. 
Double-Blind Comparative Study to Evaluate the Efficacy and Tolerance of Three Doses of 
Acetorphan versus Placebo in the Treatment of Acute Diarrhoea. 
Published as Baumer Ph, Dorval ED, Bertrand J, Vetel JM, Schwartz JC, Lecomte JM. Effects of acetorphan, an enkephalinase 
inhibitor, on experimental and acute diarrhea. Gut. 1992;33:753-758. 
 
Guarino et al. 2014, Euopean Society for Pediatric Gastroenterology, hepatology and 
Nutrition/European Society for Pediatric Infectious Diseases Evidence-Based Guidelines for the 
Management of Acute Gastroenteritis in Children in Europe: Update 2014, JPGN, 59: 132-152 
 
World Gastroenterology Organisation Global Guidelines: Acute diarrhea in adults and 
children: a global perspective, Feb 2012 

 
 
 
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16 
APPENDICES 
16.1 
Appendix – Participating Countries’ National Insurance Requirements 
Not applicable 
 
16.2 
Appendix – Coordinating Investigator Signature of Clinical Study Report 
The following Investigator is regarded to be the coordinating Investigator who should sign the 
Investigator signature page of the clinical study report: 
to be determined 
16.3 
Appendix – Medical expert for the trial. 
 
 
 
16.4 
Appendix –Clinical laboratory(ies) involved in the trial 
Not applicable