Clinical trial NCT03473561
Conditions: Diarrhea, Infantile
Sponsor: Abbott
Start date: 2018-08-25; Completion date: 2020-01-08
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, open-label, multicenter, single-arm study evaluating the efficacy and safety of Racecadotril the treatment of children aged 3 to 60 months suffering from acute diarrhea

Detailed description:
Subjects presenting with acute diarrhea will be evaluated for eligibility. If eligible, demographics, number of stools during the last 12 hours will be assessed as baseline values. On Day 1, the subject will start with study treatment.

Subjects will be treated with Racecadotril three times daily according to the body weight dose requirement on an out-patient basis for maximum 5 days in addition to ORS. ORS will be prescribed by the investigator. The parent(s)/caregiver(s)/legal representative(s) will be instructed to stop treatment when the patient recovered. Recovery is defined by the evacuation of the first of two consecutive normal stools or no stool within 12 hours. In the evening of each day, the parent(s)/caregiver(s)/legal representative(s) will fill in their 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.

The last dose of study drug intake will be the morning dose of day 6, if not recovered earlier. The parent(s)/caregiver(s)/legal representative(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)/legal representative(s) will return the diaries and unused medication.

A phone call contact will be performed 5-7 days after the end of the treatment period or recovery for the safety follow-up.

Arms: arm 1: Racecadotril Infants Granules for Oral Suspension 10 mg (in addition to standard treatment i.e. oral rehydration solution) Racecadotril Children Granules for Oral Suspension 30 mg (in addition to standard treatment i.e. oral rehydration solution)
Interventions: intervention 1: Racecadotril plus ORS
Intervention descriptions: intervention 1: 1.5 mg/kg of Racecadotril will be administered, 3 times daily, via the oral route (in addition to standard treatment i.e. oral rehydration solution).

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.

Protocol documents:
Prot_000.pdf: 
 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 1 of 48 
CLINICAL STUDY PROTOCOL 
Cover Page 
Protocol No.: 
RACE3002 
Protocol Date: 
Amendment 1 
Amendment 2 
09 OCT 2017 
07 NOV 2018 
22 NOV 2019 
Study Title: 
Efficacy and Safety of Racecadotril in the treatment of 
Taiwanese children aged 3 to 60 months suffering from acute 
diarrhea: A prospective, open-label, multicenter, single-arm 
study 
 
IND No.: 
 
EudractCT No: 
N/A 
 
N/A 
 
 
Phase of Development: 
III 
 
Sponsor: 
 
Global Clinical Director 
 
 
 
Protocol Author (s) 
Abbott Laboratories Services Corp Taiwan Branch 
 
 
 
 
 
 
 
 
 
 
 
 
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. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 2 of 48 
SYNOPSIS 
 
Name of Sponsor: 
Abbott Taiwan  
Name of Finished Product: 
Hidrasec Infants Granules for 
Oral Suspension 10 mg 
Hidrasec Children Granules for 
Oral Suspension 30 mg  
Name of Active Ingredient(s): 
Racecadotril 
Title of Study: 
Efficacy and Safety of Racecadotril in the treatment of Taiwanese children aged 3 to 60 months 
suffering from acute diarrhea: A prospective, open-label, multicenter, single arm study  
 
 
 
  
 
Study Duration: 
approximately 2 years  
(from First Subject First Visit until Last Subject Last Visit) 
End of Study is defined as Last Subject Last Visit. 
Phase of Development: 
III (post approval 
commitment) 
Objectives: 
 
Primary objective: 
The primary objective is to evaluate the efficacy of Racecadotril in addition to standard treatment 
oral rehydration solution (ORS) in infants and children (3 months until 60 months) with acute 
diarrhea measured as duration of diarrhea (hours) between the start of treatment until final 
diarrheal/watery stool or end of study treatment (treatment duration maximal 5 days).  
Duration of diarrhea is defined as date and time of the evacuation of the final watery/diarrheal 
stool derived from the daily diary. 
Secondary objective(s): 
 
• Time until recovery, defined as date and time of the evacuation of the first of two 
consecutive normal stools or no stool within 12 hours after the first normal stool. 
 
• Number of recovered subjects in total and until each individual treatment day. Mean and 
median time until recovery. 
 
• Global Physician Assessment (GPA) at the end of treatment (at the discretion of the 
investigator): 
o 1 = Complete relief of acute diarrhea, 
o 2 = marked improvement of acute diarrhea, 
o 3 = moderate improvement of acute diarrhea,  


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 3 of 48 
Name of Sponsor: 
Abbott Taiwan  
Name of Finished Product: 
Hidrasec Infants Granules for 
Oral Suspension 10 mg 
Hidrasec Children Granules for 
Oral Suspension 30 mg  
Name of Active Ingredient(s): 
Racecadotril 
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 only: 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 and tolerability: To evaluate the safety and tolerability of Racecadotril in addition to 
ORS in infants and children with acute diarrhea by adverse events, physical examination and 
vital signs. 
Methodology: 
This is a prospective, open-label, multicenter, single-arm study evaluating the efficacy and safety 
of Racecadotril in infants and children 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 including 
vaccination history and concomitant medication. If the subjects are eligible, demographics, 
number of stools during the last 12 hours will be assessed as baseline values. On Day 1, the 
subject will start with study treatment. The starting dose will either be the noon or 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 basis for maximum 5 days in addition to ORS. ORS will be 
prescribed by the investigator. The parent(s)/caregiver(s)/legal representative(s) will be 
instructed to stop treatment when the patient recovered. Recovery is defined by the evacuation of 
the first of two consecutive normal stools or no stool within 12 hours. In the evening of each day, 
the parent(s)/caregiver(s)/legal representative(s) will fill in their 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 (last dose 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 4 of 48 
Name of Sponsor: 
Abbott Taiwan  
Name of Finished Product: 
Hidrasec Infants Granules for 
Oral Suspension 10 mg 
Hidrasec Children Granules for 
Oral Suspension 30 mg  
Name of Active Ingredient(s): 
Racecadotril 
will be taken in the morning after recovery, ORS can be continued until Visit 2) 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)/legal representative(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)/legal representative(s) will return the diaries and unused 
medication.  
 
Safety follow-up call (Day 11-13)  
A phone call contact will be performed 5-7 days after the end of the treatment period or recovery 
for the safety follow-up. 
 
Table 1. Flow Chart of Study Assessments 
Period 
Screening 
End of Treatment 
period 
Safety follow-up 
(phone call, 7 days 
after Visit 2) 
Visit 
1 
2 
3 
Day 
1 
62 
11-13 
Informed consent 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demographic data 
X 
 
 
Medical history including 
vaccination history 
X 
 
 
Physical examination 
X 
X 
 
Vitals signs 
X 
X 
 
Dispense study drug 
X 
 
 
Concomitant medication 
X 
X 
X 
Compliance check 
 
X 
 
Global physician 
assessment 
 
X 
 
Adverse events 
X 
X 
X 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 5 of 48 
Name of Sponsor: 
Abbott Taiwan  
Name of Finished Product: 
Hidrasec Infants Granules for 
Oral Suspension 10 mg 
Hidrasec Children Granules for 
Oral Suspension 30 mg  
Name of Active Ingredient(s): 
Racecadotril 
Collect study drug 
 
X 
 
Dispense diary  
X1 
 
 
Collect diary 
 
X 
 
1 Subjects’ parent(s)/caregiver(s)/legal representative(s) have to fill in their daily diaries continuously. 
2 or within 24 hours (in exceptional justified cases within 48 hours) after recovery if this occurs before day 6 
Number of Subjects (Planned): 
A maximum number of 48 subjects will be enrolled. with a minimum number of 20 subjects in 
each age group (< 24 months of age and ≥ 24 months of age). Recruitment will be stopped 
once 40 subjects completed the study. 
Approximately 50 subjects should be screened. 
Diagnosis and Main Criteria for Inclusion:  
(1) Signed informed consent from one of the parent(s)/legal representative(s). 
(2) Subjects, both genders, aged 3 to 60 months. 
(3) Subjects with acute diarrhea (defined as the passage of three or more unformed or liquid 
stools within the last 24 hours and lasting for less than 3 days). 
Exclusion Criteria: 
(1) Known allergy to Racecadotril or any of its ingredients. 
(2) Subjects suffering from renal or hepatic impairment.  
(3) Subjects with fever > 39 degrees Celsius 
(4) Subjects with bloody and/or purulent stools.  
(5) Subjects suffering from antibiotic (e.g. amoxicillin)-associated diarrhea, chronic 
diarrhea or iatrogenic diarrhea. 
(6) Subjects with alternating bouts of diarrhea and constipation. 
(7) Diarrhea due to exacerbation of chronic gastrointestinal diseases such as irritable bowel 
syndrome, irritable bowel disease or pancreatic exocrine insufficiency. 
(8) Cystic fibrosis or coeliac disease. 
(9) Subjects suffering from prolonged or uncontrolled vomiting. 
(10) Subjects with rare hereditary problems of fructose intolerance, glucose-galactose 
malabsorption syndrome or sucrase isomaltase insufficiency. 
(11) Subjects having received antibiotic treatment within 2 weeks prior to the current 
diarrhea event. 
(12) Subjects having received antidiarrheal drugs (except pre-or probiotics see section 7.7) 
48 hours prior to Day 1. 
(13) Subjects with severe dehydration requiring intravenous fluid, electrolyte replacement or 
hospitalization treatment 
(14) Subject with a history of angioedema or who had reported angioedema with angiotensin 
converting enzyme inhibitors (such as captopril, enalapril, lisinopril, perindopril, 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 6 of 48 
Name of Sponsor: 
Abbott Taiwan  
Name of Finished Product: 
Hidrasec Infants Granules for 
Oral Suspension 10 mg 
Hidrasec Children Granules for 
Oral Suspension 30 mg  
Name of Active Ingredient(s): 
Racecadotril 
ramipril)  
(15) Subjects with combined diseases or medical situations that would prevent to be enrolled 
into the study, depending on the judgment of the investigator 
(16) Intake of experimental drug within 30 days prior to study start. 
(17) Subjects with contraindications to ORS or susceptible to the warnings of ORS. 
 
Test Product, Dose and Mode of Administration: 
Racecadotril Infants Granules for Oral Suspension10 mg 
Racecadotril Children Granules for Oral Suspension 30 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. 
 
Racecadotril will be given three times daily in addition to standard treatment ORS. For 
concomitant medication (please see section 7.7). 
 
Standard treatment is oral rehydration solution (ORS) according to the registered local label and 
the instruction of the investigator. At the start of the trial, alignment will be reached on the 
understanding of treatment of standard ORS with the principal investigator with the aim to use 
the same brand of ORS and the same age-appropriate standardized treatment pattern for the 
subjects throughout the trial. 
Duration of Treatment: 
The first dose of Racecadotril will be taken on day 1, either noon, or evening dose. The treatment 
duration lasts until recovery (last dose in the morning after recovery), maximally 5 days, until the 
morning dose of day 6. 
 
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 as date and time of the evacuation of the final watery/diarrheal stool before recovery 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 7 of 48 
Name of Sponsor: 
Abbott Taiwan  
Name of Finished Product: 
Hidrasec Infants Granules for 
Oral Suspension 10 mg 
Hidrasec Children Granules for 
Oral Suspension 30 mg  
Name of Active Ingredient(s): 
Racecadotril 
derived from the daily diary. 
Secondary Efficacy Variables: 
• Time until recovery, defined as date and time of the evacuation of the first of two 
consecutive normal stools or no stool within 12 hours after the first normal stool. 
 
• Number of recovered subjects in total and until each individual treatment day. Mean and 
median time until recovery. 
 
• Global Physician Assessment (GPA) at the end of treatment (at the discretion of the 
investigator): 
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 only: 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. 
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 primary efficacy parameter, duration of 
diarrhea, will be analyzed using descriptive statistics. In addition, a Kaplan-Meier plot will be 
generated for which summary statistics will be presented as well. 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. Severity and drug-event relationship of treatment 
emergent AEs are summarized separately. Vitals signs, including changes from baseline will be 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 8 of 48 
Name of Sponsor: 
Abbott Taiwan  
Name of Finished Product: 
Hidrasec Infants Granules for 
Oral Suspension 10 mg 
Hidrasec Children Granules for 
Oral Suspension 30 mg  
Name of Active Ingredient(s): 
Racecadotril 
summarized. A frequency table will be presented for markedly abnormal values. 
Sample size 
In total, 40 subjects will be allocated to receive Racecadotril treatment, 20 subjects in each age 
group (< 24 months of age and ≥ 24 months of age). Results of a recently finalized study in 
Russian children showed that all children under Racecadotril treatment recovered within 3 days 
of drug treatment. A sample size of 40 subjects is sufficient to estimate a two-sided 95% 
confidence interval with the precision of 3.1 percentage points for a recovery of at least 99% of 
the subjects after 3 days of Racecadotril treatment. In order to account for drop-outs, maximum 
48 subjects will be recruited. Recruitment will be stopped once 40 subjects have completed 
the study. 
 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 9 of 48 
TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
SYNOPSIS ......................................................................................................................................2 
TABLE OF CONTENTS ..............................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................12 
1 
ETHICS......................................................................................................................14 
1.1 
Independent Ethics Committee or Institutional Review Board ..................................14 
1.2 
Ethical Conduct of the Study ......................................................................................14 
1.3 
Subject Information and Consent ................................................................................14 
2 
INTRODUCTION .....................................................................................................16 
3 
STUDY OBJECTIVES .............................................................................................17 
3.1 
Primary Objective(s) ...................................................................................................17 
3.2 
Secondary Objective(s) ...............................................................................................17 
3.3 
Safety Objective(s) ......................................................................................................17 
4 
STUDY DESIGN .......................................................................................................18 
4.1 
Overall Study Design and Plan-Description ...............................................................18 
4.2 
Discussion of Study Design, Including the Choice of Control Groups ......................19 
5 
SELECTION OF STUDY POPULATION.............................................................20 
5.1 
Inclusion Criteria.........................................................................................................20 
5.2 
Exclusion Criteria .......................................................................................................20 
6 
REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT ................21 
7 
TREATMENTS .........................................................................................................23 
7.1 
Treatments to Be Administered ..................................................................................23 
7.2 
Packaging and Labeling ..............................................................................................23 
7.3 
Storage and Dispensing of Study Drug .......................................................................24 
7.4 
Method of Assigning Subjects to Treatment Groups ..................................................24 
7.5 
Selection of Doses and Timing in the Study ...............................................................24 
7.6 
Blinding and Treatment Code Information .................................................................24 
7.7 
Prior and Concomitant Therapy ..................................................................................25 
7.8 
Treatment Compliance ................................................................................................26 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 10 of 48 
8 
STUDY ASSESSMENTS AND FLOW CHART ...................................................27 
8.1 
Efficacy Measurements ...............................................................................................27 
8.2 
Safety Measurements ..................................................................................................27 
8.3 
Other Assessments ......................................................................................................28 
8.4 
Appropriateness of Measurements ..............................................................................29 
8.5 
Primary Efficacy/ Variable(s) .....................................................................................29 
8.6 
Flow Chart of Study Assessments ..............................................................................29 
9 
ADVERSE EVENTS.................................................................................................31 
9.1 
Adverse Events ...........................................................................................................31 
9.1.1 
Recording of Adverse Events .....................................................................................31 
9.1.2 
Follow-up of Adverse Events .....................................................................................33 
9.2 
Serious Adverse Events (SAEs) ..................................................................................33 
9.2.1 
Reporting Serious Adverse Events .............................................................................34 
9.3 
Pregnancy ....................................................................................................................34 
10 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ....35 
10.1 
General Definitions and Conventions .........................................................................35 
10.2 
Subject Samples ..........................................................................................................36 
10.3 
Efficacy .......................................................................................................................37 
10.4 
Safety ..........................................................................................................................38 
10.5 
Other Assessments ......................................................................................................38 
10.6 
Subgroup Analysis ......................................................................................................39 
10.7 
Interim Analysis ..........................................................................................................39 
10.8 
Determination of Sample Size ....................................................................................39 
11 
INVESTIGATOR OBLIGATIONS ........................................................................40 
11.1 
Essential Study Documents .........................................................................................40 
11.2 
Case Report Form (CRF) Completion ........................................................................40 
11.3 
Essential Records Retention........................................................................................41 
11.4 
Investigator Agreement ...............................................................................................42 
12 
SPONSOR OBLIGATIONS ....................................................................................43 
12.1 
Protocol Amendments .................................................................................................43 
12.2 
Study Monitoring ........................................................................................................43 
12.3 
Quality Assurance Audits ...........................................................................................44 
13 
PUBLICATION POLICY ........................................................................................45 
14 
INSURANCE .............................................................................................................46 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 11 of 48 
15 
REFERENCES ..........................................................................................................47 
16 
APPENDICES ...........................................................................................................48 
16.1 
Appendix – Participating Countries’ National Insurance Requirements ....................48 
16.2 
Appendix – Coordinating Investigator Signature of Clinical Study Report ...............48 
16.3 
Appendix – Medical expert for the trial. .....................................................................48 
16.4 
Appendix –Clinical laboratory(ies) involved in the trial ............................................48 
 
LIST OF IN-TEXT TABLES 
Es konnten keine Einträge für ein Abbildungsverzeichnis gefunden werden. 
 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 12 of 48 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ACE 
Angiotensin converting enzyme 
ADR 
adverse drug reaction 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
CFR 
Code of Federal Regulations 
CRF 
case report form (paper or other media) 
CRO 
Contract Research Organization 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
EU 
European Union 
FA 
full analysis 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GPA  
Global physician assessment 
HLGT 
high level group term 
HLT 
high level term 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LLT 
lowest level term 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
ORS 
oral rehydration solution 
N/A 
not applicable 
PP 
per-protocol 
PT 
preferred term 
SADR 
serious adverse drug reaction 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 13 of 48 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
standard deviation 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse drug reaction 
TEAE 
treatment emergent adverse event 
TFDA 
Taiwan Food and Drug Administration 
WHO 
World Health Organization 
 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 14 of 48 
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/legal representative of each 
subject prior to performing any study-related procedures. Each parent/legal representative will be 
given both verbal and written information describing the nature and duration of the clinical 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 15 of 48 
study. The informed consent process will take place under conditions where the parent/legal 
representative 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/legal 
representative has signed an approved informed consent written in a language that is 
understandable to the subject’s parent/legal representative. 
The IEC/IRB approved informed consent form will be signed and personally dated by the 
parent/legal representative and the person who conducted the informed consent discussion. Each 
parent/legal representative 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/legal representative 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 parent(s)/legal representative(s) 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. 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 16 of 48 
2 
INTRODUCTION 
Racecadotril (acetorphan), an enkephalinase inhibitor, represents a promising approach to the 
treatment of diarrhea. 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 anti-secretory 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 anti-secretory 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. 
 
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 
antidiarrheal has a positive safety profile and have limited or no effects on motility and basal 
intestinal secretion. 
 
 
 
 
 
 
 
  
 
  
 


 
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Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 17 of 48 
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) in infants and children (3 months until 60 months) with acute 
diarrhea measured as duration of diarrhea (hours) between the start of treatment until final 
watery/diarrheal stool before recovery or end of study treatment (treatment duration maximal 5 
days).  
 
Duration of diarrhea is defined as date and time of the evacuation of the final watery/diarrheal 
stool before recovery derived from the daily diary. 
 
3.2 
Secondary Objective(s) 
• Time until recovery, defined as date and time of the evacuation of the first of two 
consecutive normal stools or no stool within 12 hours after the first normal stool. 
 
• Number of recovered subjects in total and until each individual treatment day.  
 
• Global Physician Assessment (GPA) at the end of treatment (at the discretion of the 
investigator): 
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 only: 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) in infants and children (3 months until 60 months) with acute diarrhea by adverse events, 
physical examination and vital signs. 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 18 of 48 
4 
STUDY DESIGN 
4.1 
Overall Study Design and Plan-Description 
This is a prospective, open-label, multicenter, single-arm study evaluating the efficacy and safety 
of Racecadotril in infants and children with acute diarrhea in out-patients. The number of 
subjects to be screened is 50 in order to achieve 40 subjects treated with standard treatment (oral 
rehydration solution, 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 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. 
 
Standard treatment is oral rehydration solution (ORS) according to the registered local label and 
the instruction of the investigator. At the start of the trial, alignment will be reached on the 
understanding of treatment of standard ORS with the principal investigator with the aim to use 
the same brand of ORS for the subjects throughout the trial. ORS treatment 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 vital signs, a review of their medical history including 
vaccination history and concomitant medication. If the subjects are eligible, demographics, 
number of stools during the last 12 hours will be assessed as baseline values. On Day 1, the 
subject will start with study treatment. The starting dose will either be the noon, or evening dose 
depending on the timing of Visit 1. 
 
Treatment period (until recovery, maximally 5 days) 
Subjects will be treated with Racecadotril three times daily according to the body weight dose 
requirement on an out-patient basis for maximum 5 days. The subjects 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)/legal 
representative(s) will be instructed to stop study drug treatment when the patient recovered. On 
each day, the parent(s)/caregiver(s)/legal representative(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 or no stool within 12 hours, the parent(s)/caregiver(s)/legal representative(s) can 
stop recording of the diary and 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 or the day 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 19 of 48 
when no stool within 12 hours after the first normal stool was observed. 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 (last dose 
will be the morning dose after recovery, ORS can be continued until Visit 2). On the same day, 
or within 24 hours after recovery (in exceptional cases within 48 hours), the 
parent(s)/caregiver(s)/legal representative(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 5-7 days after the end of the treatment period for the safety 
follow-up. 
 
 
 
4.2 
Discussion of Study Design, Including the Choice of Control Groups 
 
 
 
 
 
 
 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 20 of 48 
5 
SELECTION OF STUDY POPULATION 
5.1 
Inclusion Criteria 
(1) 
Signed informed consent from one of the parent(s)/legal representative(s). 
(2) 
Subjects, both genders, aged 3 to 60 months. 
(3) 
Subjects with acute diarrhea (defined as the passage of three or more unformed or 
liquid stools within the last 24 hours and lasting for less than 3 days). 
5.2 
Exclusion Criteria  
(1) 
Known allergy to Racecadotril or any of its ingredients. 
(2) 
Subjects suffering from renal or hepatic impairment.  
(3) 
Subjects with fever > 39 degrees Celsius 
(4) 
Subjects with bloody and/or purulent stools.  
(5) 
Subjects suffering from antibiotic (e.g. amoxicillin)-associated diarrhea, chronic 
diarrhea or iatrogenic diarrhea. 
(6) 
Subjects with alternating bouts of diarrhea and constipation. 
(7) 
Diarrhea due to exacerbation of chronic gastrointestinal diseases such as irritable 
bowel syndrome, irritable bowel disease or pancreatic exocrine insufficiency. 
(8) 
Cystic fibrosis or coeliac disease. 
(9) 
Subjects suffering from prolonged or uncontrolled vomiting. 
(10) Subjects with rare hereditary problems of fructose intolerance, glucose-galactose 
malabsorption syndrome or sucrase isomaltase insufficiency. 
(11) Subjects having received antibiotic treatment within 2 weeks prior to start of the 
current diarrhea episode. 
(12) Subjects having received antidiarrheal drugs (except pre- or probiotics see section 7.7.) 
48 hours prior to Day 1. 
(13) Subjects with severe dehydration requiring intravenous fluid or electrolyte 
replacement or hospitalization treatment. 
(14) Subject with a history of angioedema or who had reported angioedema with 
angiotensin converting enzyme inhibitors (such as captopril, enalapril, lisinopril, 
perindopril, ramipril)  
(15) Subjects with combined diseases or medical situations that would prevent to be 
enrolled into the study, depending on the judgment of the investigator 
(16) Intake of experimental drug within 30 days prior to study start. 
(17) Subjects with contraindications to ORS or susceptible to the warnings of ORS. 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 21 of 48 
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 and an end of treatment visit 
should be performed. 
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’s parent(s)/caregiver(s)/legal representative(s) fails to 
return to the study site for scheduled visits and does not respond to telephone or written 
attempts to contact. 
- 
Withdrew consent: subject’s parent(s)/legal representative(s) decides to stop subject’s 
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 will terminate the study at the discretion of the investigator and will undergo further 
diagnosis and alternative treatment under the following conditions. 
1. If the subject needs alternative treatments or rescue medication which are prohibited 
concomitant therapies in this study 
Any comedication which may interfere with the evaluation of the efficacy parameters of this 
study should be avoided (see section 7.7). 
Subjects who cannot complete the study duration of five days without continuous intake of 
concomitant medication or who need rescue medication should be withdrawn. The 
investigator should consult with the CRO/sponsor prior to withdrawal of the subject. 
2. If the subject develops fever > 39 degrees Celsius (> 39 degrees Celsius in two repeated 
measurements within one hour)  
3. If the subject develops bloody and purulent stools 
4. If the subject has watery stool more than 10 times per day showing signs of apathy 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 22 of 48 
5. If the subject’s disease state worsens, e.g. dehydration or increased vomiting 
6. If the subject needs hospitalization 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 23 of 48 
7 
TREATMENTS 
Study drug (Racecadotril) 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 Suspension 10 mg 
Racecadotril Children Granules for Oral Suspension 30 mg 
 
1.5 mg/kg of Racecadotril will be administered, 3 times daily (morning, noon, 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. 
 
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. At the start of the trial, alignment will be reached on the understanding of treatment 
of standard ORS with the principal investigator with the aim to use the same brand of ORS and 
the same age-appropriate standardized treatment pattern for the subjects throughout the trial. 
ORS treatment will be documented in the CRF. Reporting obligations for ORS by the 
investigator will follow local regulations for marketed products. Racecadotril will be given in 
addition to ORS. 
7.2 
Packaging and Labeling 
 
 
 
  
 
 
 
 
 
 
 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 24 of 48 
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 assigned a 5-digit enrollment number . The medication will be identified using 
6-digit kit numbers. 
 
The subject numbers will be provided by Clinical Supply Management (Product Development) 
of Abbott Healthcare Products BV. 
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. 
 
This dosing regimen is registered by TFDA and described in the SmPC.  
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 of ORS. 
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. 
 


 
Abbott 
Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 25 of 48 
7.7 
Prior and Concomitant Therapy 
During the study, subjects are not allowed to be treated with the following treatments:   
• Anti-peristaltic drugs, e.g. loperamide 
• Antibiotics  
• Antipyretics (suppositories)  
Oral antipyretics (acetaminophen or ibuprofen) are allowed to be used concomitantly as 
needed when ear temperature is above 38.3 degrees Celsius, but not longer than two 
consecutive days during the study. If the fever increases above 39 degrees Celsius with two 
repeated measurements within one hours, the subject will be withdrawn.  
• Intestinal antiseptics, e.g. 8-hydroxyquinoline 
• Respiratory decongestants, e.g. phenylephrine  
• Antitussive medication, e.g. noscapine  
Any antitussive drugs, if indicated for pediatric patients, may be given for temporary relief of 
symptoms as PRN (administration on as needed basis) except those containing opium 
alkaloids and derivatives (e.g noscapine). 
• Pre- or Probiotics, e.g. fructooligosaccharides, lactobacilli  
Subjects on continuous probiotic treatment at study start (e.g. Lactobacillus, Bifidobacterium, 
yeast) or probiotic-containing supplements/formula of the same product/brand prior to study 
start can be included. The initiation of pre- or probiotic treatment during the study is 
forbidden as well as the adaptation of the brand/product or dose. 
• Absorbents, e. g. diosmectite, charcoal, pectin, psyllium 
• Zinc-containing medication (other than diaper rash ointments). Diaper rash ointments of 
any kind are allowed. 
• Homemade ORS 
ORS will be provided during the study as judged appropriate by the Investigator. Additional 
intake of self-purchase or self-made ORS is not allowed during the study duration 
• ACE Inhibitors 
• Antispasmodics 
Antispasmodics, indicated for pediatric patients, may be given for temporary relief of 
symptoms as PRN (administration on an as needed basis) in exceptional cases. If 
antispasmodics are needed as daily treatment during the study treatment, the subjects should 
be discontinued. 
• Drugs for symptomatic treatment of diarrhea, e.g. pancreatic enzymes, anticholinergic drugs, 
opiates, diphenoxylate 
• Intravenous fluid or electrolyte replacement. 
 
The presence of bloody or purulent stool and fever above 39 degrees Celsius may indicate either 
the presence of invasive bacteria as a reason for diarrhea or the presence of another severe 
disease. In addition, Racecadotril has not been investigated in patients with antibiotic-associated 
diarrhea. Therefore, Racecadotril should not be administered under these conditions. 


 
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Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 26 of 48 
Subjects who need treatment with the above listed medication should be withdrawn from the 
study (see section 6). 
Dietary modifications for thickening of the stools or yogurt are allowed. If needed, dietary 
consultation with dietitian or qualified healthcare worker is recommended in order to adapt the 
diet for thickening of stools or intake of yogurt. 
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. 
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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Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 27 of 48 
8 
STUDY ASSESSMENTS AND FLOW CHART 
8.1 
Efficacy Measurements  
Primary Efficacy Variable: 
Duration of diarrhea (hours) between the start of treatment until the last watery/diarrheal stool 
before recovery or the 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 as date and time of the evacuation of the final watery/diarrheal 
stool before recovery derived from the daily diary. 
Secondary Efficacy Variables: 
 
• Time until recovery, defined as date and time of the evacuation of the first of two 
consecutive normal stools or no stool within 12 hours after the first normal stool. 
 
• Number of recovered subjects in total and until each individual treatment day.  
• Global Physician Assessment (GPA) at the end of treatment, at the discretion of the 
investigator: 
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 only: 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.  


 
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Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 28 of 48 
Body temperature will be measured in the morning and in the evening with at least 12 hours 
interval. If the value is >39 degrees Celsius, the measurement has to be repeated within one hour 
to confirm the value. 
Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate are to be measured 
in pediatric appropriate setting. 
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.  
 
8.3 
Other Assessments 
Informed Consent 
Voluntary written informed consent must be obtained from one parent/legal representative prior 
to performing any study-related procedures (see Section 1.3). 
Demographic Data 
Demographic data (gender, age, year and month 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 
The parent(s)/caregiver(s)/legal representative(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). 


 
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Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 29 of 48 
Recording can be stopped after the excretion of two consecutive normal stools or no stool within 
12 hours.  
The date, time and dose of study drug intake as well as the amount ORS consumed has to be 
recorded. 
Fever will be measured twice daily, once in the morning and once in the evening with at least 12-
hour interval using the same device and method (preferably ear temperature), by the 
parent(s)/caregiver(s)/legal representative(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 as 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 2, which displays the frequency 
and timing of all measurements. 


 
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Protocol No. RACE3002  
 
Protocol Date 09 OCT 2017   
 
Amendment 1 Date 07 NOV 2018 
 
Amendment 2 Date 22 Nov 2019 
Confidential 
Page 30 of 48 
 
Table 2: Flow Chart of Study Assessments 
Period 
Screening 
End of Treatment 
period 
Safety follow-up (phone call  
7 days after Visit 2) 
Visit 
1 
2 
3 
Day 
1 
62 
11-13 
Informed consent 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Demographic data 
X 
 
 
Medical history including 
vaccination history 
X 
 
 
Physical examination 
X 
X 
 
Vitals signs  
X 
X 
 
Dispense study drug 
X 
 
 
Concomitant medication 
X 
X 
X 
Compliance check 
 
X 
 
Global physician 
assessment 
 
X 
 
Adverse events 
X 
X 
X 
Collect study drug 
 
X 
 
Dispense diary  
X1 
 
 
Collect diary 
 
X 
 
1 Subjects’ parent(s)/caregiver(s)/legal representative(s) have to fill in their daily diaries continuously. 
2 or within 24 hours (in exceptional justified cases within 48 hours) after recovery if this occurs before day 6


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 31 of 48 
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.  


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 32 of 48 
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 
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, 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 safety follow-up 
call (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. 
- 
Certain – suggests that an AE, including laboratory test abnormality, occurs in a plausible 
time relationship to drug administration, which cannot be explained by concurrent disease 
or other drugs or chemicals. The response to withdrawal of the drug (de-challenge) 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 33 of 48 
should be clinically plausible. The AE must be definitive pharmacologically or 
phenomenologically, using a satisfactory re-challenge procedure if necessary. 
 
 
Outcome 
The outcome of the adverse event should be classified according to the following definitions: 
- 
Recovered / resolved: the event has resolved (no further symptoms are present and no 
treatment is being received by the subject). 
- 
Recovered / resolved with sequelae: the event has resolved but there may be lingering 
effects present (e.g., a scar following a cut or abrasion). 
- 
Fatal: the subject died as a result of the event. This code should only be used for the event 
that caused the death, not any event that was present at the time of the subject’s death. 
Fatal events require immediately reporting to the Sponsor (or an authorized 
representative). 
- 
Unknown: may only be used in the event that the subject is lost to follow-up and no 
reliable data can be obtained. 
 
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, 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 34 of 48 
- 
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 dyscrasia, or convulsions 
that do not result in inpatient hospitalization or the development of drug dependency or 
drug abuse as well as spontaneous or elective abortions, stillbirths and ectopic 
pregnancies). 
 
9.2.1 
Reporting Serious Adverse Events 
 
 
  
 
 
9.3 
Pregnancy 
Not applicable due to the age of the subjects. 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 35 of 48 
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 the 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 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. 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 36 of 48 
In addition, the Anatomical Therapeutic Chemical (ATC) classes will be assigned to the drug ID. 
ATC codes are defined to the 4th level. For each medication, the primary ATC class will be 
assigned manually based on the generic name and the reason for use. 
Default Summary Statistics 
The default summary statistics for quantitative and ordinal variables will be the number of 
observations (n), mean, standard deviation (SD), median, minimum (Min) and maximum (Max) 
for subjects with data. Any other summary statistics will be described on an individual basis. 
Default Frequency Tabulations 
For qualitative variables, per category the numbers and frequencies of subjects with non-missing 
data (n, %) will be the default summary presentation, and if appropriate and present, the number 
of missing values. 
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. 
 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 37 of 48 
The full analysis (FA) sample will consist of all subjects who: 
- 
Were included in the safety sample; and 
- 
Had data for at least one post-baseline assessment of any efficacy measurement.  
 
The per-protocol (PP) sample will be defined through blind data review and will consist of all 
subjects who: 
- 
Were included in the FA sample; and  
- 
Did not present any major protocol violation. 
 
 
10.3 
Efficacy  
The primary efficacy variable is the duration (hours) of diarrhea (treatment duration max 5 days). 
Duration of diarrhea is defined as date of the evacuation of the last watery/diarrheal stool before 
recovery or end of treatment. 
 
The primary parameter, duration of diarrhea, will be analyzed using descriptive statistics. In 
addition, a Kaplan-Meier plot will be generated for which summary statistics will be presented as 
well.  
The secondary efficacy variables are 
• Time until recovery, defined as date and time of the evacuation of the first of two 
consecutive normal stools or no stool within 12 hours after the first normal stool. 
• Number of subjects recovered, in total and until each individual treatment day 
• Mean and median time until recovery  
• Assessment of treatment success by the physician: 
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. 
 
• 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.  
 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 38 of 48 
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. 
 
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. 
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 for the treatment group. 
Demographics and other baseline characteristics will be summarized for the 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. 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 39 of 48 
Concomitant medication, including coding data will be summarized per assigned treatment 
period for incidence per subject, for primary therapeutic subgroup (the 3rd level ATC code) and 
for generic name by therapeutic subgroup.  
10.6 
Subgroup Analysis 
Key efficacy and safety results will be summarized across subgroups defined by age group (< 24 
months old and ≥ 24 months old).  
10.7 
Interim Analysis 
Not applicable 
 
10.8 
Determination of Sample Size 
In total, 40 subjects will be allocated to receive Racecadotril treatment, 20 subjects in each age 
group (< 24 months of age and ≥ 24 months of age). Results of a recently finalized study in 
Russian children showed that all children under Racecadotril treatment recovered within 3 days 
of drug treatment. A sample size of 40 subjects is sufficient to estimate a two-sided 95% 
confidence interval with the precision of 3.1 percentage points for a recovery of at least 99% of 
the subjects after 3 days of Racecadotril treatment. In order to account for drop-outs maximum 
48 subjects will be recruited. Recruitment will be stopped once 40 subjects have completed 
the study. 
 
 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 40 of 48 
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 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 41 of 48 
completed (e)CRF for each subject who did not fail screening. All supportive documentation 
submitted with the (e)CRF, such as laboratory or hospital records, should be clearly identified 
with 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). 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 42 of 48 
The Investigator is required to notify the Sponsor (or an authorized representative) prior to 
changing the location or status of any essential clinical study documents. The Sponsor (or an 
authorized representative) will be responsible for informing the Investigator as to when these 
documents no longer need to be retained. 
11.4 
Investigator Agreement 
The Investigator is responsible for assuring the proper implementation and conduct of the 
clinical study including those study-related duties delegated to other appropriately qualified 
individuals. The Investigator and his/her staff will cooperate with the Sponsor (or an authorized 
representative) during monitoring and auditing visits to assist with the review of the study data 
and resolve any discrepancies. 
The Investigator will demonstrate due diligence in recruitment and screening of potential study 
subjects. The enrollment rate should be sufficient to complete the study as agreed with the 
Sponsor (or an authorized representative). The Sponsor (or an authorized representative) is to be 
notified of any projected delays, which may impact the completion of the study. 
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). 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 43 of 48 
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 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 44 of 48 
(regulatory documents, CRFs, source documents, drug disposition records, subject informed 
consent forms, etc.) as well as discussion on the conduct of the study with the Investigator and 
staff. The Investigator and staff should be available during these visits to facilitate the review of 
the clinical study records and resolve/document any discrepancies found during the visit. 
12.3 
Quality Assurance 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. 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 45 of 48 
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. 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 46 of 48 
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. 


 
 
 
Abbott 
 
Protocol No. RACE3002 
 
 
Protocol Date 09 OCT 2017 
 
 
Amendment 1 Date 07 NOV2018 
 
 
Amendment 2 Date 22 NOV 2019 
Confidential 
Page 47 of 48 
15 
REFERENCES 
 

SAP_001.pdf: 
QPS-Qualitix Clinical Research 
  CONFIDENTIAL 
Statistical Analysis Plan
Protocol No.: RACE3002 
SAP Version: 3.0 
 
SOP-BDM-016-RD-01, Version 05 (30-Mar-2018) 
Page 1 of 23 
Efficacy and Safety of Racecadotril in the treatment of Taiwanese 
children aged 3 to 60 months suffering from acute diarrhea: A 
prospective, open-label, multicenter, single-arm study 
Protocol No.: RACE3002 
STATISTICAL ANALYSIS PLAN 
Version: 3.0 
Date: 25.Aug.2020 
Biostatistician: Samantha Su 
Confidentiality Statement 
This document is the property of QPS-Qualitix Clinical Research Co., Ltd., and may not-in full or part-be passed on, 
reproduced, distributed to any person, or submitted to any regulatory authorities without prior written permission from 
QPS-Qualitix Clinical Research Co., Ltd. 




QPS-Qualitix Clinical Research 
  CONFIDENTIAL 
Statistical Analysis Plan 
    Protocol No.: RACE3002 
SAP Version: 3.0 
 
 
 
SOP-BDM-016-RD-01, Version 05 (30-Mar-2018) 
Page 3 of 23 
TABLE OF CONTENTS 
1. 
INTRODUCTION .............................................................................................................. 5 
2. 
STUDY OBJECTIVE ........................................................................................................ 5 
2.1 PRIMARY OBJECTIVE ...................................................................................................... 5 
2.2 SECONDARY OBJECTIVE(S) ............................................................................................. 5 
2.3 SAFETY OBJECTIVE(S) .................................................................................................... 6 
3. 
STUDY DESIGN ................................................................................................................ 6 
3.1 OVERALL STUDY DESIGN AND PLAN-DESCRIPTION ........................................................ 6 
3.2 SELECTION OF STUDY POPULATION ................................................................................ 6 
3.3 BLINDING AND TREATMENT CODE INFORMATION ........................................................... 7 
3.4 METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................... 7 
3.5 PRIMARY EFFICACY VARIABLE ....................................................................................... 8 
3.6 SECONDARY EFFICACY VARIABLES ................................................................................. 8 
3.7 SAFETY VARIABLES ........................................................................................................ 8 
3.8 FLOW CHART OF STUDY ASSESSMENTS .......................................................................... 9 
3.9 INTERIM ANALYSIS ....................................................................................................... 10 
3.10 SUBGROUP ANALYSIS ................................................................................................. 10 
4. 
GENERAL STATISTICAL ISSUES .............................................................................. 11 
4.1 CONTINUOUS ENDPOINTS ............................................................................................. 11 
4.2 CATEGORICAL ENDPOINTS ............................................................................................ 11 
4.3 TIME-TO-EVENT ENDPOINTS ......................................................................................... 11 
4.4 SAMPLE SIZE ESTIMATION AND POWER ........................................................................ 11 
5. 
DATA HANDLING PROCEDURES .............................................................................. 11 
5.1 CODING SYSTEM ........................................................................................................... 11 
5.2 TIME-RELATED DEFINITIONS ........................................................................................ 12 
6. 
ANALYSIS OF SUBJECT SAMPLES........................................................................... 12 
7. 
DISPOSITION OF PATIENTS AND STUDY COMPLETION .................................. 13 
8. 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS .................... 15 
8.1 MEDICAL/ SURGERY/ VACCINATION HISTORY ............................................................... 15 
8.2 CONCOMITANT MEDICATION ........................................................................................ 15 
9. 
EFFICACY ANALYSIS .................................................................................................. 15 
9.1 PRIMARY EFFICACY VARIABLE ..................................................................................... 15 
9.2 SECONDARY EFFICACY VARIABLES ............................................................................... 17 
9.2.1 TIME UNTIL RECOVERY .............................................................................................. 17 
9.2.2 NUMBER OF SUBJECTS RECOVERED ........................................................................... 18 
9.2.3 ASSESSMENT OF TREATMENT SUCCESS BY THE PHYSICIAN ........................................ 18 


QPS-Qualitix Clinical Research 
  CONFIDENTIAL 
Statistical Analysis Plan 
    Protocol No.: RACE3002 
SAP Version: 3.0 
 
 
 
SOP-BDM-016-RD-01, Version 05 (30-Mar-2018) 
Page 4 of 23 
9.2.4 NUMBER OF STOOLS AND WATERY STOOLS PER DAY FOR TOILET-TRAINED SUBJECTS
 ........................................................................................................................................... 19 
9.2.5 NUMBER OF STOOLS AND WATERY STOOLS (ADDITIONAL TABLE REQUESTED BY 
ABBOTT) ............................................................................................................................ 19 
10. 
EXTENT OF EXPOSURE AND DRUG COMPLIANCE ........................................... 19 
10.1 EXTENT OF EXPOSURE ................................................................................................ 20 
10.2 DRUG COMPLIANCE .................................................................................................... 20 
11. 
SAFETY ANALYSIS ....................................................................................................... 20 
11.1 ADVERSE EVENTS ....................................................................................................... 20 
11.2 VITAL SIGNS ............................................................................................................... 21 
11.3 PHYSICAL EXAMINATION ............................................................................................ 22 
11.4 ADDITIONAL COMMENTS ............................................................................................ 23 
12. 
COMPUTER METHODS ............................................................................................... 23 


QPS-Qualitix Clinical Research 
  CONFIDENTIAL 
Statistical Analysis Plan 
    Protocol No.: RACE3002 
SAP Version: 3.0 
 
 
 
SOP-BDM-016-RD-01, Version 05 (30-Mar-2018) 
Page 5 of 23 
1. INTRODUCTION 
This statistical analysis plan (SAP) is based on protocol RACE3002 Version Date 09 OCT 2017, 
Amendment 1 Date 07 NOV 2018, Amendment 2 Date 22 NOV 2019, TFDA Official Letter (No. 
1096009485) dated 08-Jun-2020 as well as Abbott Clarification Letter for Interim Analysis dated 
20-Aug-2020. The SAP provides details of data handling procedures, statistical analysis methods 
for efficacy and safety evaluations. It also outlines statistical programming specifications for tables 
and listings, and other details on the analyses not provided in the study protocol.  
 
All data of these enrolled and randomized subjects using Protocol Version Date 09 OCT 2017 will 
be listed only. A note to file (NTF), Racecadotril dosage per sachet dated on 21-Mar-2019 is 
adapted for Racecadotril dosage collection. 
 
2. STUDY OBJECTIVE 
2.1 Primary Objective 
The primary objective is to evaluate the efficacy of Racecadotril in addition to standard treatment 
oral rehydration solution (ORS) in infants and children (3 months until 60 months) with acute 
diarrhea measured as duration of diarrhea (hours) between the start of treatment until final 
diarrheal/watery stool or end of study treatment (treatment duration maximal 5 days).  
 
Duration of diarrhea is defined as date and time of the evacuation of the final watery/diarrheal stool 
derived from the daily diary.  
 
2.2 Secondary Objective(s)  
 
Time until recovery, defined as date and time of the evacuation of the first of two consecutive 
normal stools or no stool within 12 hours after the first normal stool.  
 
Number of recovered subjects in total and until each individual treatment day. Mean and 
median time until recovery.  
 
Global Physician Assessment (GPA) at the end of treatment  (at the discretion of the 
investigator):  
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.  


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(Treatment success = GPA score of 1 or 2).  
 
For toilet trained children only: number of stools per day as well as number of watery stools 
per day from start of treatment and until end of study treatment.  
 
2.3 Safety Objective(s) 
To evaluate the safety and tolerability of Racecadotril together with oral rehydration solution (ORS) 
in infants and children (3 months until 60 months) with acute diarrhea by adverse events, physical 
examination and vital signs.  
 
3. STUDY DESIGN 
3.1 Overall Study Design and Plan-Description 
This is a prospective, open-label, multicenter, single-arm study evaluating the efficacy and safety of 
Racecadotril in infants and children with acute diarrhea in out-patients. The number of subjects to 
be screened is 50 in order to achieve 40 subjects treated with standard treatment (oral rehydration 
solution, ORS) plus Racecadotril. 
 
Figure 3-1 
Overall Study Design 
 
 
3.2 Selection of Study Population 
Inclusion Criteria 
(1) Signed informed consent from one of the parent(s)/legal representative(s).  
(2) Subjects, both genders, aged 3 to 60 months.  
(3) Subjects with acute diarrhea (defined as the passage of three or more unformed or liquid stools 
within the last 24 hours and lasting for less than 3 days).  
 
Exclusion Criteria 
(1) Known allergy to Racecadotril or any of its ingredients.  
(2) Subjects suffering from renal or hepatic impairment.  
(3) Subjects with fever > 39 degrees Celsius  


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(4) Subjects with bloody and/or purulent stools.  
(5) Subjects suffering from antibiotic (e.g. amoxicillin)-associated diarrhea, chronic diarrhea or 
iatrogenic diarrhea.  
(6) Subjects with alternating bouts of diarrhea and constipation.  
(7) Diarrhea due to exacerbation of chronic gastrointestinal diseases such as irritable bowel 
syndrome, irritable bowel disease or pancreatic exocrine insufficiency.  
(8) Cystic fibrosis or coeliac disease.  
(9) Subjects suffering from prolonged or uncontrolled vomiting.  
(10) Subjects with rare hereditary problems of fructose intolerance, glucose-galactose 
malabsorption syndrome or sucrase isomaltase insufficiency.  
(11) Subjects having received antibiotic treatment within 2 weeks prior to start of the current 
diarrhea episode.  
(12) Subjects having received antidiarrheal drugs (except pre- or probiotics see Protocol section 7.7.) 
48 hours prior to Day 1.  
(13) Subjects with severe dehydration requiring intravenous fluid or electrolyte replacement or 
hospitalization treatment.  
(14) Subject with a history of angioedema or who had reported angioedema with angiotensin 
converting enzyme inhibitors (such as captopril, enalapril, lisinopril, perindopril, ramipril)  
(15) Subjects with combined diseases or medical situations that would prevent to be enrolled into 
the study, depending on the judgment of the investigator  
(16) Intake of experimental drug within 30 days prior to study start.  
(17) Subjects with contraindications to ORS or susceptible to the warnings of ORS.  
 
3.3 Blinding and Treatment Code Information 
This is an open-label study; blinding will not be applied. 
 
3.4 Method of Assigning Subjects to Treatment Groups 
A maximum number of 48 subjects will be enrolled with a minimum number of 20 subjects in each 
age group (< 24 months of age and ≥ 24 months of age). 
Approximately 50 subjects should be screened. 
 
Subjects will be assigned a 5-digit enrollment number. The medication will be identified using 
6-digit kit numbers. 
 
The subject numbers will be provided by Clinical Supply Management (Product Development) of 
Abbott Healthcare Products BV. 


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3.5 Primary Efficacy Variable 
Duration of diarrhea (hours) between the start of treatment until the last watery/diarrheal stool 
before recovery or the 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 as date and time of the evacuation of the final watery/diarrheal stool 
before recovery derived from the daily diary.  
 
3.6 Secondary Efficacy Variables 
 
Time until recovery, defined as date and time of the evacuation of the first of two consecutive 
normal stools or no stool within 12 hours after the first normal stool.  
 
Number of recovered subjects in total and until each individual treatment day.  
 
Global Physician Assessment (GPA) at the end of treatment, at the discretion of the 
investigator:  
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 only: number of stools per day as well as number of watery stools 
per day from start of treatment and until end of study treatment.  
 
3.7 Safety Variables 
Adverse Events  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. 
 
Requirements for collecting, recording and reporting of AEs are described in Protocol 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: All AEs occurring during the study are 


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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. 
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 calendar day.  
 
Vital Signs  
Height and weight must be recorded. 
 
Body temperature will be measured in the morning and in the evening with at least 12 hours interval. 
If the value is >39 degrees Celsius, the measurement has to be repeated within one hour to confirm 
the value. 
 
Systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse rate are to be measured in 
pediatric appropriate setting. 
 
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. 
 
3.8 Flow Chart of Study Assessments 
Table 1: Flow Chart of Study Assessments 
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 
 
 
Inclusion/exclusion criteria 
X 
 
 
Demographic data 
X 
 
 
Medical history including 
vaccination history 
X 
 
 
Physical examination 
X 
X 
 


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Period 
Screening 
End of Treatment 
period 
Safety follow-up 
(phone call, 5-7 days 
after Visit 2) 
Vitals signs 
X 
X 
 
Dispense study drug 
X 
 
 
Concomitant medication 
X 
X 
X 
Compliance check 
 
X 
 
Global physician assessment 
 
X 
 
Adverse events 
X 
X 
X 
Collect study drug 
 
X 
 
Dispense diary  
X1 
 
 
Collect diary 
 
X 
 
1 Subjects’ parent(s)/caregiver(s)/legal representative(s) have to fill in their daily diaries continuously. 
2 or within 24 hours (in exceptional justified cases within 48 hours) after recovery if this occurs before day 6 
 
3.9 Interim Analysis 
No interim analysis will be performed for protocol Amendment 2, but there will be a dry run of 
Table, Listing and Figures (TLFs) based on Study Date Tabulation Model (SDTM) and Analysis 
Data Model (ADaM) datasets to Abbott at a time when 25 randomized subjects complete the study 
and 40 randomized subjects complete the study. While the subjects enrolled using protocol version 
date 09 OCT 2017 will be excluded from dry run analysis. Dry run tables will be prepared and 
reviewed in the blinded fashion.  
3.10 Subgroup Analysis 
Key efficacy and safety results will be summarized across subgroups defined by age group (< 24 months 
old and ≥ 24 months old). 
 
An additional subgroup analysis which is not included in the protocol will be summarized across 
subgroups defined by weight group (in infants less than 9 kg, in infants from 9 kg to < 13 kg, in 


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children from 13 kg to 27 kg, and in children of more than 27 kg). Subgroup analysis by weight 
groups will be only conducted in the demographics and efficacy. 
 
4. GENERAL STATISTICAL ISSUES 
4.1 Continuous Endpoints 
Descriptive statistics for quantitative and ordinal variables including number of observation (n), 
mean, standard deviation (SD), median, minimum (Min) and maximum (Max) will be presented for 
the raw data as well as change from baseline. The mean will be represented one more decimal than 
the raw number, and SD as two more decimals than the raw number. 
 
4.2 Categorical Endpoints 
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. Percentages will be presented with 2 decimals. Partial date(s) will be listed as 
provided in the listings. 
 
For AEs, medical history and concomitant medications, however, the denominator for the 
percentage calculation will be the number of subjects at risk. A subject will be considered at risk if 
the subject is in the safety sample and entered the respective study period. 
 
4.3 Time-to-event Endpoints 
The time-to-event endpoint will be analyzed by Kaplan-Meier method and presented as mean, 
median and 95% confidence interval for median.  
 
4.4 Sample Size Estimation and Power 
In total, 40 subjects will be allocated to receive Racecadotril treatment. Results of a recently 
finalized study in Russian children showed that all children under Racecadotril treatment recovered 
within 3 days of drug treatment. A sample size of 40 subjects is sufficient to estimate a two-sided 
95% confidence interval with the precision of 3.1 percentage points for a recovery of at least 99% 
of the subjects after 3 days of Racecadotril treatment. In order to account for drop-outs 48 subjects 
will be recruited. Recruitment will be stopped once 40 subjects have completed the study. 
 
5. DATA HANDLING PROCEDURES 
5.1 Coding System 


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AEs and medical history 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 dictionary, using the most recent version. 
 
Concomitant medications will be classified according to active drug substance using the World 
Health Organization (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. 
 
5.2 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 the first study drug administration.  
 
The endpoint value for efficacy variables is defined as the last non-missing value assigned to 
treatment for the subject. When a patient doesn’t recover beyond the study cutoff date, survival 
duration is stopped at the study cutoff date and it will be regarded as a censored data. The cut-off 
date will be the end of study (treatment duration maximal 5 days).  
 
All variables planned to be measured at one or more time points and supposed to be time-related 
will be windowed.  
 
6. ANALYSIS OF 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>  
 


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The safety sample will consist of all subjects who:  
- Were in the all subjects allocated to treatment sample; and  
- Had at least one dose of study medication administered.  
 
The full analysis (FA) sample will consist of all subjects who:  
- Were included in the safety sample; and  
- Had data for at least one post-baseline assessment of any efficacy measurement.  
The per-protocol (PP) sample will be defined through blind data review and will consist of all 
subjects who: 
- Were included in the FA sample; and  
- Did not present any major protocol violation.  
 
7. DISPOSITION OF PATIENTS AND STUDY COMPLETION 
The assignment of subjects to subject samples, the disposition of subjects with respect to premature 
termination, reason for premature termination will be summarized for the treatment group as Table 
14.1.1. The flow chart of subject disposition is shown as Figure 7-1.  
 
Data on visit date and the completion status with primary reason for premature termination will be 
listed in Listing 16.2.1.1.  
 
Individual subject inclusion/ exclusion criteria not met at screening will be listed in Listing 16.2.1.2. 
Only the exceptions are to be listed, that is, subjects with a response to the inclusion criteria of “No” 
and/or subjects with a response to the exclusion criteria of “Yes”. Subjects with a missing response 
to inclusion/exclusion criteria will also be presented. Eligibility and assignment will be listed in 
Listing 16.2.1.3. 
 
All minor and major protocol deviation(s) which judged by principal investigator will be listed in 
Listing 16.2.2. All subjects who excluded from any of the safety sample, FA sample or PP analysis 
as well as the reason (s) for exclusion will be listed in Listing 16.2.3.  




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8. DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS 
Subject demographics and other baseline characteristics will be listed in Listing 16.2.4.1 and Listing 
16.2.4.2 and will be summarized as Table 14.1.2.1 using Safety, FA and PP samples. Subgroup 
analysis of demographics and baseline characteristics by age group (< 24 months old and ≥ 24 
months old) will be also summarized as Table 14.1.2.2 using Safety, FA and PP samples. Subgroup 
analysis of demographics and baseline characteristics by weight group (in infants less than 9 kg, in 
infants from 9 kg to < 13 kg, in children from 13 kg to 27 kg, and in children of more than 27 kg) 
will be also summarized as Table 14.1.2.3 using Safety, FA and PP samples. 
 
8.1 Medical/ Surgery/ Vaccination 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. The medical history recorded will be listed by subject in 
Listing 16.2.4.3. The Medical history, including coding data will be summarized per primary SOC, 
per HLT by primary SOC and per PT by HLT and primary SOC as Table 14.1.2.4 using Safety 
sample. 
 
8.2 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 and will be 
listed by subject in Listing 16.2.4.4, except for study drug. Concomitant medication, including 
coding data will be summarized per assigned treatment period for incidence per subject, for primary 
therapeutic subgroup (the 3rd level ATC code) and for generic name by therapeutic subgroup as 
Table 14.1.2.5 using Safety Sample. 
 
9. EFFICACY ANALYSIS 
FA and PP Samples will be used to all efficacy analysis. 
 
9.1 Primary Efficacy Variable 
The primary efficacy variable is the duration (hours) of diarrhea (treatment duration max 5 days). 
Duration of diarrhea is defined as date and time of the evacuation of the last watery/diarrheal stool 
before recovery or end of treatment. The duration of diarrhea definition can be referred to Figure 
9-1. The primary efficacy parameter, duration of diarrhea, will be analyzed using descriptive 


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statistics. In addition, a Kaplan-Meier plot will be generated for which summary statistics will be 
presented as well. The KM algorithm will be applied to derive the median duration (hours) and the 
95% confidence intervals for the median, and mean duration. The censored number and event 
number will be presented as counts and percentage as well. 
 
The SAS code is listed as below: 
 
PROC LIFETEST DATA=duration METHOD=KM PLOTS=SURVIVAL (FAILURE ATRISK); 
TIME T*status (0); 
RUN; 
 
Note: 
The proc lifetest analysis will be performed with failure curve (an increasing trend). The duration 
(hours) of diarrhea or time (hours) until recovery is recorded in the variable T. The variable status is 
the censoring indicator. A status of 1 indicates an event time, and a status of 0 indicates a censored 
time. The event is recovery. The censored data are those did not recover during treatment period 
including drop-outs. When a patient doesn’t recover beyond the end of study (treatment duration 
maximal 5 days), duration is stopped at the end of study date and it will be regarded as a censored 
data as well. The censored times will be plotted as a plus sign on the Kaplan-Meier.  
 
An event time for the duration of diarrhea is defined as the duration from the date of dosing to the 
date of the evacuation of last watery/ diarrheal stool before recovery. A censored time for the 
duration of diarrhea is defined as the duration from the date of dosing to the date of not recovery 
during treatment period.  
 
An event time for time until recovery is defined as the time from the date of dosing to the date of 
the evacuation of the first of two consecutive normal stools or no stool within 12 hours after the first 
normal stool. A censored time for time until recovery is defined as the duration from the date of 
dosing to the date of not recovery during treatment period.  
 
Individual subject diary card dispensation and subject stool record will be listed in Listing 16.2.6.1 
and 16.2.6.2, respectively. The overall duration of diarrhea and additional table of duration of 
diarrhea for each day of the study will be summarized as Tables 14.2.1 using FA and PP samples. 
Figures for overall duration of diarrhea can refer to Figure 14.2.1.1 and Figure 14.2.1.2, 
respectively. 
 
 


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Figure 9-1 
Duration of Diarrhea and Time until Recovery Definition 
 
 
Subgroup analysis of duration (hours) of diarrhea by age group (< 24 months old and ≥ 24 months 
old) will be also summarized as Table 14.2.6 using FA and PP samples. Figures for overall duration 
of diarrhea by age group can refer to Figure 14.2.6.1 and Figure 14.2.6.2, respectively. 
 
Subgroup analysis of duration (hours) of diarrhea by weight group (in infants less than 9 kg, in 
infants from 9 kg to < 13 kg, in children from 13 kg to 27 kg, and in children of more than 27 kg) 
will be also summarized as Table 14.2.11 using FA and PP samples. Figures for overall duration of 
diarrhea by weight group can refer to Figure 14.2.11.1 and Figure 14.2.11.2, respectively. 
 
9.2 Secondary Efficacy Variables 
9.2.1 Time until Recovery  
Time until recovery is defined as date and time of the evacuation of the first of two consecutive 
normal stools or no stool within 12 hours after the first normal stool. The time until recovery 
definition and SAS code can be referred to Figure 9-1. The time until recovery and additional table 
of time until recovery for each day of the study will be summarized using Kaplan-Meier analysis as 
Tables 14.2.1 using FA and PP samples. Figures for time until recovery at end of treatment can refer 
to Figure 14.2.1.3 and Figure 14.2.1.4, respectively.  


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Subgroup analysis of time until recovery by age group (< 24 months old and ≥ 24 months old) will 
be also summarized using Kaplan-Meier analysis as Table 14.2.6 using FA and PP samples. Figures 
for time until recovery at the end of treatment can refer to Figure 14.2.6.3 and Figure 14.2.6.4, 
respectively. 
 
Subgroup analysis of time until recovery by weight group (in infants less than 9 kg, in infants from 
9 kg to < 13 kg, in children from 13 kg to 27 kg, and in children of more than 27 kg) will be also 
summarized using Kaplan-Meier analysis as Table 14.2.11 using FA and PP samples. Figures for 
time until recovery at the end of treatment can refer to Figure 14.2.11.3 and Figure 14.2.11.4, 
respectively. 
 
9.2.2 Number of Subjects Recovered 
Number and proportion of subjects recovered, in total and until each individual treatment day will 
be summarized with count and percentage as well as 95% CI as Table 14.2.2 using FA and PP 
samples. 
 
Subgroup analysis of number and proportion of subjects recovered by age group (< 24 months old 
and ≥ 24 months old) will be also summarized with count and percentage as well as 95% CI as 
Table 14.2.7 using FA and PP samples. 
 
Subgroup analysis of number and proportion of subjects recovered by weight group (in infants less 
than 9 kg, in infants from 9 kg to < 13 kg, in children from 13 kg to 27 kg, and in children of more 
than 27 kg) will be also summarized with count and percentage as well as 95% CI as Table 14.2.12 
using FA and PP samples. 
 
9.2.3 Assessment of Treatment Success by the Physician 
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,  


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6 = worsening of acute diarrhea.  
 
Individual subject global physician assessment is listed in Listing 16.2.6.3. Treatment will be rated 
as success when the GPA score equals 1 or 2. The assessment of treatment success by the physician 
will be summarized with count and percentage as well as 95% CI as Table 14.2.3 using FA and PP 
samples. 
 
Subgroup analysis of assessment of treatment success by age group (< 24 months old and ≥ 24 
months old) will be also summarized with count and percentage as well as 95% CI as Table 14.2.8 
using FA and PP samples. 
 
Subgroup analysis of assessment of treatment success by weight group (in infants less than 9 kg, in 
infants from 9 kg to < 13 kg, in children from 13 kg to 27 kg, and in children of more than 27 kg) 
will be also summarized with count and percentage as well as 95% CI as Table 14.2.13 using FA 
and PP samples. 
 
9.2.4 Number of Stools and Watery Stools per Day for Toilet-Trained Subjects 
Number of stools per day as well as number of watery stools per day from start of treatment and 
until end of study treatment will be summarized as Table 14.2.4 using FA and PP samples.  
 
Subgroup analysis of number of stools per day as well as number of watery stools by age group (< 
24 months old and ≥ 24 months old) will be also summarized as Table 14.2.9 using FA and PP 
samples. 
 
9.2.5 Number of Stools and Watery Stools (Additional Table Requested by Abbott) 
Number of stools as well as number of watery stools from start of treatment and until end of study 
treatment and for each day of the study will be summarized as Table 14.2.5 using FA and PP 
samples.  
 
Subgroup analysis of number of stools as well as number of watery stools by age group (< 24 
months old and ≥ 24 months old) will be also summarized as Table 14.2.10 using FA and PP 
samples. 
 
10. EXTENT OF EXPOSURE AND DRUG COMPLIANCE 
The randomization (only for Protocol Version dated 09 OCT 2017) will be listed in Listing 16.2.5.1. 


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All study drug dispensation and retrieve to each subject will be listed in Listing 16.2.5.2. Individual 
subject study drug administration record will be listed in Listing 16.2.5.2. In listing 16.2.5.2, for 
data collection of Racecadotril dosage, a NTF (Abbott_RACE3002_NTF_Racecadotril dosage per 
sachet_20190321) from Abbott is adapted to extract the dosage with unit from column of “Relevant 
Information Related to Study Drug Dispensation”.  
 
10.1 Extent of Exposure 
The way of computing the extent of exposure is listed as below, 
The extent of exposure = The date of completion/ termination of the study treatment drug intake - 
The date of the first study treatment drug intake) + 1]  
 
Number of sachets scheduled to be taken during that treatment period is the collected data from 
diary card before the last dose (last dose was defined the first dose of the next day after recovery). 
The extent of exposure for the treatment group will be summarized as Table 14.1.3 using Safety, FA 
and PP Samples. 
 
10.2 Drug Compliance 
The way of computing the drug compliance is listed as below,  
The study drug compliance = Number of sachets a subject takes during the treatment period / 
Number of sachets scheduled to be taken during that treatment period)*100% 
 
The drug compliance for the treatment group will be summarized as Table 14.1.3 using Safety, FA 
and PP samples as well.  
 
11. SAFETY ANALYSIS 
The safety sample will be used for the analysis of the safety and tolerability data. 
 
11.1 Adverse Events 
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 


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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. 
 
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. 
 
All adverse event data will be listed in Listing 16.2.7. A general summary of all AEs, TEAEs and 
SAEs will be provided in Table 14.3.1.1.   
 
Other summary tables for adverse events will be summarized: 
 
Table 14.3.1.2: Incidence of Treatment-Emergent Adverse Events - MedDRA 
 
Table 14.3.1.3: Incidence of Treatment-Emergent Adverse Events >= 5% of the Subjects in the  
Treatment Group 
 
Table 14.3.1.4: Incidence of Treatment - Emergent Adverse Events by Reasonable Possibility 
for a Causal Relationship - MedDRA 
 
Table 14.3.1.5: Incidence of Treatment - Emergent Adverse Events by Severity – MedDRA 
 
Subgroup analysis of number of stools per day as well as number of watery stools by age group (< 
24 months old and ≥ 24 months old) will be also summarized: 
 
Table 14.3.1.6: Subgroup of Treatment-Emergent Adverse Events 
 
Table 14.3.1.7: Subgroup of Incidence of Treatment-Emergent Adverse Events - MedDRA 
 
Table 14.3.1.8: Subgroup of Incidence of Treatment-Emergent Adverse Events >= 5% of the 
Subjects in the Treatment Group  
 
Table 14.3.1.9: Subgroup of Incidence of Treatment - Emergent Adverse Events by 
Reasonable Possibility for a Causal Relationship - MedDRA 
 
Table 14.3.1.10: Subgroup of Incidence of Treatment - Emergent Adverse Events by Severity - 
MedDRA 
 
11.2 Vital Signs  
Vital signs including height and weight, body temperature, Systolic blood pressure (SBP), diastolic 
blood pressure (DBP) and pulse rate will be listed in Listing 16.4.1. Body temperature will be 
measured in the morning and in the evening with at least 12 hours interval. If the value is >39 
degrees Celsius, the measurement has to be repeated within one hour to confirm the value. 
Individual subject body temperature in diary card will be listed in Listing 16.4.2. 


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Vital sign values at each time point collected will be summarized using descriptive statistics (n, 
mean, SD, median, min and max) as well as the percentage of abnormal results with frequency 
tables (count and percentage). The change form baseline will be summarized for each measurement 
using descriptive statistics (n, mean, SD, median, min and max). The overall summary table will be 
summarized as Table 14.3.5.1. The normal ranges for temperature, heart rate (pulse rate) and blood 
pressure can be referred to Table 2 and Table 3. While normal ranges of body height and weight will 
be based on the percentile of World Health Organization (WHO) Child Growth Standards.  
 
Subgroup analysis of vital signs by age group (< 24 months old and ≥ 24 months old) will be also 
summarized as Table 14.3.5.2. 
 
Table 2 Normal Temperature Ranges 
Measurement method 
Normal temperature range 
Rectal 
36.6°C to 38°C (97.9°F to 100.4°F)  
Ear 
35.8°C to 38°C (96.4°F to 100.4°F)  
Oral 
35.5°C to 37.5°C (95.9°F to 99.5°F)  
Axillary 
34.7°C to 37.3°C (94.5°F to 99.1°F)  
Source: Temperature measurement in paediatrics, Paediatr Child Health. 2000 Jul-Aug; 5(5): 273–
276. 
 
Table 3 Normal Heart Rate (Pulse Rate), Body Pressure and Respiratory Rate Ranges 
according to Age 
Age 
Heart Rate 
(Pulse Rate) 
(bpm) 
Blood Pressure 
(mmHg) 
0-3 month 
100-150 
65-85/45-55 
3-6 month 
90-120 
70-90/50-65 
6-12 month 
80-120 
80-100/55-65 
1-3 year 
70-110 
90-105/55-70 
3-6 year 
65-110 
95-110/60-75 
Source: Kliegman, R.M., et al. Nelson Textbook of Pediatrics edition 20.  
 
11.3 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 


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treatment), or on the Adverse Event form in the CRF for findings presently occurring. The physical 
examinations will be listed in Listing 16.4.3. 
 
11.4 Additional Comments 
Individual subject additional comments will be listed in Listing 16.4.4. 
 
12. COMPUTER METHODS 
All statistical analyses will be conducted using SAS® software, Version 9.3 of the SAS System for 
Windows 7. Copyright ©  2013 SAS Institute Inc. SAS and all other SAS Institute Inc. product or 
service names are registered trademarks or trademarks of SAS Institute Inc., Cary, NC, USA