Clinical trial NCT02710591
Conditions: Muscular Dystrophy, Duchenne
Keywords: Rimeporide
Sponsor: EspeRare Foundation
Start date: 2016-03-01; Completion date: 2018-02-01
Enrollment: 20 participants; Allocation: ; Intervention model: SEQUENTIAL

Brief summary:
In Duchenne Muscular Dystrophy (DMD) there is an imbalance between the levels of calcium and sodium in the muscles cells which is thought to be important in the damage which occurs overtime. Sodium/proton type 1 exchanger (NHE-1) inhibition is an innovative pathway that has proved to efficiently prevent the accumulation of muscle damage (inflammation and fibrosis) in animal models of muscular dystrophies and heart failure. Based on prior safety and efficacy results in animal and humans, NHE-1 inhibition with Rimeporide represents a new therapeutic approach with no restriction on age and on genetic subtypes which could be combined to other treatments that restore or augment dystrophin.This study examines the safety and tolerability and effects on the muscles of rimeporide, in patients aged 6 to 14 years with Duchenne Muscular Dystrophy (DMD).

Detailed description:
This study is designed as a phase Ib, multicenter, european, open label study to evaluate the safety and tolerability and biomarkers of a new drug, rimeporide, in boys aged 6 to 14 years with Duchenne Muscular Dystrophy (DMD).

Rimeporide will be taken orally for 4 weeks, three times a day. Dose will be adapted to body weight. The study will enrol 20 patients with DMD, aged 6 to 14 years. 4 dose levels will be tested, in 4 different cohorts with 5 patients taking the drug at each dose level.

During the study, there will be 6 visits in the Hospital over a maximum of 10 weeks. At each visit, patients will undergo safety examinations including vital signs, physical and neurological examinations, ECG, safety and hematology, biochemistry and urinalysis, concomitant treatments review, and any symptoms and side effects review. In addition, blood samples will be withdrawn for the evaluation of Rimeporide in plasma. Finally, additional blood \& urine samples will be collected to explore efficacy markers. Patients will also undergo 2 NMR (at screening and End of study) to develop non invasive biomarkers for further investigations in DMD patients.

The decision to progress to the next higher dose will be made after safety and tolerability data are reviewed for the preceding dose for 5 patients by SMC and determined that it is safe to proceed to the next dose level.

Arms: arm 1: Multiple oral doses of rimeporide ranging from 50 to 300 mg will be administered three times a day (TID) for a total of 4 weeks. 4 ascending dose levels will be studied sequentially in ascending order. Rimeporide is provided as hard gel 25 mg or 50 mg capsules.

Each patient will participate in only 1 dose cohort. 5 patients are expected to be recruited in each cohort through all participating sites.
Interventions: intervention 1: Rimeporide
Intervention descriptions: intervention 1: Cohort 1:

50 mg TID in patients with a body weight ≤ 30kg at Baseline and 75 mg TID in patients with a body weight \> 30kg at Baseline

Cohort 2:

100mg TID in patients with a body weight ≤ 30kg at baseline and 150 mg TID in patients with a body weight \> 30kg at Baseline

Cohort 3:

150 mg TID in patients with a body weight ≤ 30kg at baseline and 200 mg TID in patients with a body weight \> 30kg at Baseline

Cohort 4:

200 mg TID in patients with a body weight ≤ 30kg at Baseline and 300 mg TID mg TID in patients with a body weight \> 30kg at Baseline

Protocol documents:
Prot_000.pdf: 
EspeRare_RIM_001 
Rimeporide in DMD patients 
Page 1 of 85 
 
EudraCT Number 2015-002530-50  
 
CONFIDENTIAL 
[Rim4DMD] – Final Version 2.1_ February 19th, 2016   
 
 
Clinical Study Protocol 
 
 
 
 
Study title: 
A phase Ib, open label study to evaluate the safety, 
tolerability, pharmacokinetics and 
pharmacodynamics of multiple ascending oral 
doses of Rimeporide in patients with Duchenne 
Muscular Dystrophy 
Acronym: 
Rim4DMD 
Sponsor: 
EspeRare Foundation  
14 Chemin des Aulx  
1228 Plan-les-Ouates   
Switzerland 
Study Sponsor’s number:  
ESPERARE_RIM_001 
EudraCT number: 
2015-002530-50 
Version: 
2.1 
 
Date: 
February 19th, 2016 
Amendment number: 
2 
 
 
 
This document is a confidential communication of EspeRare. 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 as required to permit review by 
responsible Ethics Committees and Health Authorities or to obtain informed consent from potential patients. 


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EudraCT Number 2015-002530-50  
 
CONFIDENTIAL 
[Rim4DMD] – Final Version 2.1_ February 19th, 2016   
 
Investigator Agreement 
 
Protocol Number: EspeRare_RIM_001 
EudraCT Number: 2015-002530-50 
Protocol version and date: 2.1._ February 19th 2016 
Sponsor: EspeRare Foundation 
 
Study drug:  Rimeporide.  
Study title: A phase Ib, open label study to evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple ascending oral doses of rimeporide in patients with Duchenne Muscular 
Dystrophy. 
Acronym: Rim4DMD. 
 
 
Investigator endorsement: 
 
I, the undersigned, am responsible for the conduct of this study at this site and agree to conduct the 
study according to the protocol and any approved protocol amendments, study specific procedures, all 
applicable laws and regulatory authority requirements including but not limited to European directives, 
ICH Good Clinical Practice (GCP), the Ethical principles that have their origins in the Declaration of 
Helsinki and applicable privacy laws. 
Nothing in this document is intended to limit the authority of a physician to provide emergency medical 
care under applicable regulations. 
I have read and understand fully the Investigator Brochure for rimeporide and I am familiar with the 
investigational product and its use according to this protocol. 
 
 
 
 
 
 
 
_______________________________________  
 
 
____________________ 
Site Investigator’ Signature 
 
 
 
 
 
Date of signature  
(DD MM YYYY) 
 
 
___________________________ 
Site Investigator’s Name and title (print)  
 
CONTACT LIST 


EspeRare_RIM_001 
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EudraCT Number 2015-002530-50  
 
CONFIDENTIAL 
[Rim4DMD] – Final Version 2.1_ February 19th, 2016   
 
 
Sponsor: 
EspeRare 
14 Chemin des Aulx 
1228 Plan les Ouates 
Switzerland 
Phone: +41 22 794 4004  
Fax: +41 22 794 4005 
Study Location: 
 
Multicentre study 
Study Investigator coordinator: 
 
Professor Francesco Muntoni, FRCPCH, FMedSci 
UK 
Principal Investigator 
 
Professor Francesco Muntoni, FRCPCH, FMedSci  
UCL Institute of Child Health and Great Ormond Street 
Hospital  
30 Guilford Street, London WC1N 1EH, United Kingdom. 
Phone :    +44207 905 2111            
Fax:         + 44207 905 2832 
e-Mail: f.muntoni@ucl.ac.uk 
 
Italy  
Investigator  
Dr. Stefano C. Previtali 
San Raffaele hospital 
Via Olgettina 60,  
20132 Milano, Italia. 
Phone: + 02 26433036. 
Fax :     +39 02 26434813 
e-Mail: previtali.stefano@hsr.it 
 
France 
Investigator 
Dr. Teresa GIDARO 
Armand Trousseau Hospital 
I-Motion – Paediatrics Clinical Trial units 
26 Avenue du Dr Arnold Netter 
75012 Paris - France 
Tél : + 33 (0)1 71 73 80 42 
Fax : + 33 (0)1 44 73 65 83 
e-Mail: t.gidaro@institut-myologie.org 
 
 
Spain 
Dr. Jordi Diaz Manera 


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CONFIDENTIAL 
[Rim4DMD] – Final Version 2.1_ February 19th, 2016   
 
Principal Investigator 
Santa Creu i St Pau Hospital 
Neuromuscular diseases unit,  
Department of Neurology  
c/Mas Casanovas 90, Bloc A, Planta -2, AGDAC 
08041 Barcelona, Spain 
Tel +34.93.553.71.15 
Fax +34.93.553.71.27 
e-Mail: JDiazM@santpau.cat 
 
Research and Development 
Director EspeRare: 
 
Florence PORTE 
          Phone : +41 22 794 4004 
e-Mail : porte.florence@esperare.org 
 
Clinical Operations Leader 
EspeRare: 
Hanane GHEIT 
          Phone : +41 22 794 4004 
e-Mail : gheit.hanane@esperare.org 
 
Medical Advisor EspeRare 
 
Dr Julian Arnold GRAY 
Phone : + 00358 44 967 4957  
e-Mail : gray.julian@esperare.org 
 
Pharmacovigilance, 
Safety Officer: 
Jennie Moore  
Head of Pharmacovigilance and Safety 
The Learning House | Snowdon Drive | Winterhill 
Milton Keynes |MK6 1BP|UNITED KINGDOM 
Main: +44 1908 251 480  
Fax: +44 1908 251 499 
DDI: +44 (0) 1963 350 862 


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EudraCT Number 2015-002530-50  
 
CONFIDENTIAL 
[Rim4DMD] – Final Version 2.1_ February 19th, 2016   
 
SIGNATURE PAGE 
 
Protocol Number: EspeRare_RIM_001 
EudraCT Number: 2015-002530-50 
Protocol version and date: 2.1 February 19th 2016 
Sponsor: EspeRare Foundation 
 
Study drug:  Rimeporide   
 
Study title: A phase Ib, open label study to evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple ascending oral doses of rimeporide in patients with Duchenne Muscular 
Dystrophy. 
 
Acronym: Rim4DMD. 
 
This protocol has been approved by:  
 
 
Name: Professor Francesco Muntoni  
 
 
Trial Role:  Study Investigator coordinator. 
 
 
Signature:  
 
 
 
 
 
Date 
 
 
 
 
 
 
 
This protocol describes the Rim4DMD clinical trial and provides information about procedures for 
patients taking part in the Rim4DMD trial. The protocol should not be used as a guide for treatment of 
patients not taking part in the Rim4DMD trial.


EspeRare_RIM_001 
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EudraCT Number 2015-002530-50  
 
CONFIDENTIAL 
[Rim4DMD] – Final Version 2.1_ February 19th   2016 
 
 
 
SIGNATURE PAGE 
 
Protocol Number: EspeRare_RIM_001 
EudraCT Number: 2015-002530-50 
Protocol version and date: 2.1_ February 19th 2016   
Sponsor: EspeRare Foundation 
 
Study drug:  Rimeporide   
 
Study title: A phase Ib, open label study to evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple ascending oral doses of rimeporide in patients with Duchenne Muscular 
Dystrophy. 
 
Acronym: Rim4DMD. 
 
This protocol has been approved by:  
 
Name: Florence Porte Thomé 
 
 
Trial Role:  Research and Development Director at EspeRare Foundation 
 
 
 
 
 
Signature:  
 
 
 
 
 
 
Date 
 
 
 
 
 
 
This protocol describes the Rim4DMD clinical trial and provides information about procedures for 
patients taking part in the Rim4DMD trial. The protocol should not be used as a guide for treatment of 
patients not taking part in the Rim4DMD trial. 


EspeRare_RIM_001 
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EudraCT Number 2015-002530-50  
 
CONFIDENTIAL 
[Rim4DMD] – Final Version 21_ February 19th 2016  
SIGNATURE PAGE 
 
Protocol Number: EspeRare_RIM_001 
EudraCT Number: 2015-002530-50 
Protocol version and date: 2.1 February 19th 2016 
Sponsor: EspeRare Foundation 
 
Study drug:  Rimeporide   
 
Study title: A phase Ib, open label study to evaluate the safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple ascending oral doses of rimeporide in patients with Duchenne Muscular 
Dystrophy. 
 
Acronym: Rim4DMD. 
 
This protocol has been approved by:  
 
 
 
Name: Dr Julian Gray 
 
 
Trial Role:  Medical advisor 
 
 
 
 
 
Signature:  
 
 
 
 
 
 
Date 
 
 
 
 
 
This protocol describes the Rim4DMD clinical trial and provides information about procedures for 
patients taking part in the Rim4DMD trial. The protocol should not be used as a guide for treatment of 
patients not taking part in the Rim4DMD trial.  


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CONFIDENTIAL 
[Rim4DMD] – Final Version 21_ February 19th 2016  
AMENDMENT(S) 
The following amendments and/or administrative changes have been made to this protocol since the 
implementation of the first approved version: 
 
Protocol version number  
Date of amendment  
Type of amendment  
2.0 
December 15th  2015 
Substantial 
Summary of main amendments: 
Page 34_section 4.1.1 inclusion criteria: I.5: Ability to swallow capsules has been added 
Page 35_section 4.1.2 Exclusion criteria E.10.has been added. E17 has been extended to all patients 
Page 30_ 2.1.2_ Secondary objectives and 2.1.3_Exploratory objectives 
The biomarkers endpoints in the study are reclassified as exploratory. 
Page 31_sections 2.2.1 Primary endpoints and 2.2.2 Secondary endpoints and 2.2.3 Exploratory  
x For safety parameters: to correct the inconsistencies with the content of the protocol. Serum gastrin 
level will be measured only at the beginning and end of the study and will not be used for routine safety 
assessment during the study.   
x To correct the classification of secondary endpoints according to the changes performed in the study 
secondary and exploratory objectives 
Page 33 (new section called recruitment plan) 
x For safety reasons, the SMC has advised that a time interval of at least one week should be maintained 
between administrations of the first dose in the first three patients in each cohort.  
x It has been clarified also that recruitment is competitive. 
x The duration of the recruitment period has been corrected: 12 months instead of 15 months which is 
the duration of the overall study as initially indicated in the Study Duration section. 
Pages 33 to 34_ sections 3.1 to 3.5 screening period, Treatment period and Follow-up. 
x It is clarified in the text that 5 patients per cohort will be enrolled.  
x It is proposed that the patient will be followed for 1-2 weeks rather than 2 weeks after either the planned 
end of treatment at week 4 or after premature discontinuation of treatment. This is because any 
withdrawal phenomena are expected to be apparent within one week in view of the short half-life of the 
compound.   
x An additional safety visit after one week of treatment is added to further enhance safety monitoring. 
x The visits followed by the patients during the study have been written in more detail to increase clarity.  
x The process of reviewing data concerning eligibility of subjects at screening by the medical advisor is 
detailed in the protocol.  
Page 36_section 5.1.4.2 Administration  
x The relationship between timing of intake of study medication and food is clarified.  
x The procedure to follow if patients have difficulty swallowing the capsules at the first administration 
is detailed in the protocol.  
x The timing between intake of the study medication and other medications is detailed in the protocol. 
x The table 2: Number of rimeporide capsules of 25mg or 50mg to be administered per dose and per day 
has been updated given the flexibility window for each study visits at hospital (+/-2 day) and dispensing 
frequency. 
Page 38_section 5.1.4.2  drug dispensing  
The local pharmacy may, if required for logistical reasons, deliver to the investigator to provide to the 
patient the study treatment medication needed to cover 1 week (+/-2 days) of treatment period the day 
before the Study Day 1 (SD1) if the patient eligibility is confirmed. For this purpose, before any 
prescription, the eligibility criteria including any AE, physical abnormalities, and changes in concomitant 
medications must be re-verified on day 1 by the investigator before prescribing the study drug. 


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CONFIDENTIAL 
[Rim4DMD] – Final Version 21_ February 19th 2016  
Page 38_section 5.3.1_Possible concomitant therapies 
Page 39_section 5.3.2 Prohibited therapies 
x To avoid potential drug-drug interactions at the renal level, prohibited concomitant medications have 
been amended to exclude concomitant use of antibiotics with predominant renal secretion (e.g., 
cephalosporins), immunosuppressive agents with the exception of corticosteroids, continuous 
treatment with non-steroidal, anti-inflammatory drugs (NSAIDs), or lithium to reflect the guidance 
regarding exclusion of renally eliminated agents as listed in the IB. 
x It is clarified that the use of prescription or over the counter medications should be approved by the 
investigator except in an emergency. 
 Page 40_section 5.5 Photosensitivity guidance 
The UV spectrum of Rimeporide shows the longest wavelength absorption band at 282.5 nm. No 
absorbance is observed at higher wavelength. Consequently, and in accordance with the ICH guideline 
S10, since Rimeporide does not absorb light within the range of natural sunlight (290nm-700nm), treatment 
with Rimeporide is considered not to pose a risk of photosensitivity and therefore no special guidance for 
patients on this issue is required. 
Page 42_ section 6.3_Supine and standing blood pressure  
In order to have a full picture of any potential effects of the study medication on blood pressure, blood 
pressure will be measured in both supine and standing positions at all visits.   
Page 42_secion 6.5_Monitoring of ECG evolution parameters (including QTc) 
ECG must be read by a local cardiologist as ongoing basis. The following parameters must be recorded: 
Heart Rate, PR Interval, QRS Duration, QT Interval, QTcB Interval, QTcF, and QRS Axis.  
ECGs will be read centrally at the end of the study. 
Pages 43 to 49 sections_6.9 to 6.11 Safety blood and urine analysis and Pharmacodynamics and 
pharmacokinetics endpoints  
x In order to be in accordance with the WHO guidance concerning the maximum blood volume to be 
collected in children within 24 hours, we will collect the blood samples for all the exploratory PD 
biomarkers at screening (once patients and parents have sign the consent) instead of at the study day 1. 
x Local and central blood tests have been updated: troponin I has been removed. Others biomarkers to 
monitor muscle damage will be measured within central laboratories. 
x Gastrin levels will be measured only at day 1 and day 28 as this is not required for routine safety 
monitoring. 
x CRP levels will be measured only at Screening and day 28 as this is not required for routine safety 
monitoring. 
x The method use for population PK analysis has been changed and will be described in a separate PK 
analysis plan. 
x The volume of blood drawn over the whole study per subject has been increased to 60 ml from 48 ml. 
The fact that this volume refers to the total amount over the study (8 to 10 weeks) rather than the volume 
at each visit has been corrected. 
Page 50_section 7.1 screening 
The procedure for review of eligibility data by the sponsor’s medical advisor is re-stated in this 
section. The necessity to obtain informed consent/assent prior to conducting any study procedures 
is added. 
Page 51_ section 7.3.1.1 Confirmation of patient eligibility at study day 1 (SD1) 
The need to confirm patient eligibility on the day of dosing is stated. Procedures regarding 
handling of screening failures is detailed.   
Page 51 and 55_ NMRI  (NMRS if applicable) before first dose at day 1 and day 27  
Due to technical difficulties in measurement of 31 phosphor NMRS and 23 sodium MRI, this 
measurement will be limited to patient enrolled in France who will undergo this procedure at the study 
site in Paris. Such patients will also undergo standard NMRI imaging in Paris. Patients in other countries 
will undergo only standard NMRI which will be performed locally. 


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CONFIDENTIAL 
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Page 53 section 7.3.5 After the Second dose of rimeporide  
Patients will be kept under observation for at least 6 hours after the second dose of study 
medication.  Temperature (tympanic), heart and respiratory rate, blood pressure (supine and 
standing) will be repeated at 1 hour, 2 hours and 4 and 6 hours after the second administration of 
study medication. 
Page 54_section 7.5 week 1 (day 7+/- 2days)  
An additional safety visit after one week of treatment is added to further enhance safety monitoring. 
Page 56_section 7.11 Withdrawal Visit (1-2 weeks +/- 2 days after decision) 
As requested by the SMC, patients will be requested to continue to be followed up according to the study 
protocol even if they have discontinued the study medication. Corresponding text has been added to the 
study protocol. Patients discontinuing the study will be asked to confirm that their data and biological 
samples can continue to be used.  
 
 Pages 62_ section 8.2.1 Suspected Unexpected Serious Adverse Reactions Reporting 
The text regarding definition of serious adverse reactions and SUSARs has been corrected as per the 
request of the UK regulatory authority (MHRA).   
Page 65_ section 9.1 to 9.2 stopping rules  
 
x The corresponding grading of adverse events in terms of severity has been specified according to the 
request of the MHRA i.e. Grade I= mild, Grade II = Moderate, Grade IIII = severe).  
x Handling of cases of suspension of dosing at the individual level will be conducted primarily by the 
medical advisor with the investigator, with consultation of the SMC as needed, rather than primarily by 
the SMC to ensure a sufficiently rapid response 
x The stopping rule regarding elevation of serum creatinine is altered to use Cystatin C instead of creatinine 
since the latter is usually abnormally low in patients with DMD.  
2.1 
February 19th 2016 
Non substantial  
Synopsis and section 2.2.3 Exploratory endpoints on pages 14 and 31; section 6.10 PD endpoints on 
page 46; blood samples volumes on page 48, section 7.1 screening page 48, section 7.5 week 2 on 
page 53, section 7.8 week 4 on page 54: The exploratory biomarkers: Plasma/ Serum levels of 
myomesin-3, miRNAs panel and the fibrosis biomarkers MMP-9 and the urine samples to follow the 
concentration of titin fragments have been removed. The nature of the other exploratory biomarkers that 
have been added in the version 2.0 has been clarified: these Blood samples will be collected for further 
investigation and namely to evaluate other cytokines involved in the inflammatory processes and to target 
several RNA coding for key proteins in DMD. The overall blood volume to be withdrawn in each patient 
during the whole study is decreased to 56.5 mL instead of 60 mL 
Page 16 and 52 schedule of assessment and section 7.3.1.1 Confirmation of patient eligibility at Study 
day 1: The term randomisation has been added by error. The PK sampling profile will be allocated as 
described initially in the section 6.10.2 “The sampling time points will be allocated to patients according 
to their inclusion order into the study” and as initially approved in the initial protocol version.   
Pages 42 sections 6.3 supine and standing blood pressure; page 43 section 6.4 heart rate and 
respiration rate; section 7 outline of study procedures. In the substantial amendment of the protocol 
version 2.0, it has been approved that In order to have a full picture of any potential effects of the study 
medication on blood pressure, blood pressure will be measured in both supine and standing positions at all 
visits. Several inconsistencies throughout the protocol concerning the positions in which the blood pressure 
is measured have been identified and corrected in the herein version 2.1. It has been also clarified the 
corresponding positions for the heart rate measurement.   
Page 37_section 5.1.4.2 Administration  
The format of the table 2: Number of rimeporide capsules of 25mg or 50mg to be administered per dose 
and per day has been modified for clarification 
Page 50_ Confirmation of patient eligibility at study day 1 (SD1) 
The process to be followed for the screening data review by the medical advisor has been updated. 


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CONFIDENTIAL 
[Rim4DMD] – Final Version 21_ February 19th 2016  
 
STUDY SYNOPSIS 
Title: 
A phase Ib, open label study to evaluate the safety, tolerability, 
pharmacokinetics and pharmacodynamics of multiple ascending oral 
doses of rimeporide in patients with Duchenne Muscular Dystrophy 
(DMD) 
Study Acronym 
RIM4DMD 
Sponsor: 
EspeRare Fondation, Switzerland 
Version and Date 
2.1_  February 19th, 2016 
Sponsor protocol Number 
EspeRare_RIM _001 
EudraCT Number 
2015-002530-50 
Coordinating Investigator 
Professor Francesco Muntoni, FRCPCH, FMedSci 
UCL Institute of Child Health and Great Ormond Street Hospital, UK.       
Number of Sites 
4 specialized sites in EU will participate in this study. 
 
UCL Institute of Child Health and Great Ormond Street Hospital, 
London, United Kingdom. 
 
Armand Trousseau Hospital, I-Motion unit , Paris, France  
 
San Raffaele Hospital, Milan,, Italy. 
 
Santa Creu i Sant Pau Hospital, Barcelona, Spain. 
Indication 
Duchenne Muscular Dystrophy (DMD). 
Study Type, Phase and 
Design: 
x 
Interventional Phase Ib study. 
x 
Open-label, multiple ascending oral doses, international multicentre pilot 
study. 
Study Population: 
x 
Ambulant DMD paediatric patients. 
Inclusion Criteria: 
x 
Duchenne muscular dystrophy genetically confirmed; 
x 
Males between 6 and 14 years old; 
x 
Able to walk independently at least 75 meters; 
x 
Patients on a stable dose of corticosteroids at least 6 months prior to 
baseline; 
x 
Patients able to swallow capsules size 4 according to the parents and 
investigator opinion; 
x 
Willing and able to comply with all protocol requirements and procedures; 
x 
Signed informed consents by the parent(s)/legal guardian(s); 
x 
France only: Affiliated to or a beneficiary of a social security system  


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[Rim4DMD] – Final Version 21_ February 19th 2016  
Exclusion Criteria: 
 
x 
Patients with significant renal disease or impairment, with Glomerular 
Filtration Rate estimated using plasma cystatin C level using the Filler 
formula less than 90ml/min/1.73m2  
x 
Current or history of liver disease or impairment, 
x 
History of any significant medical disorder which may confound the 
interpretation of either efficacy or safety data e.g. inflammatory, 
coagulation disease, unstable cardiac or respiratory disease 
x 
Acute illness within 4 weeks of the first administration of study medication 
which may interfere with study assessments; 
x 
Significant change of dosage and/or dosing regimens for corticosteroids 
planned for the duration of study medication; 
x 
Use of beta blockers / and ACEI or ARB unless at stable dose for at least 
3 months prior to baseline; 
x 
Use of Proton Pump Inhibitors unless at a stable dose for at least 3 months 
prior to baseline 
x 
Use of aldosterone antagonists (i.e. spironolactone, eplerenone) within 3 
months prior to first administration of study medication; 
x 
Use of anticoagulants, antithrombotics or antiplatelet agents, 
x 
Use of antibiotics with predominant renal secretion (e.g., cephalosporins), 
immunosuppressive 
agents 
exception 
corticosteroids, 
continuous 
treatment with non-steroidal, anti-inflammatory drugs (NSAIDs), or 
lithium; 
x 
Previous treatment with idebenone or other forms of Coenzyme Q10 
within 1 month of the first administration of study medication; 
x 
Previous treatment with investigational drugs within 4 weeks (or 7 half-
life if longer than 4 weeks) of the first administration of study medication 
including placebo; 
x 
A baseline QTc>450msec,or history of risk factors for torsades de pointes 
(eg, heart failure, hypokalaemia, family history of long QT syndrome); 
x 
LVEF≤ 45%  at screening or within the past 6 months and/or history of 
acute heart failure; 
x 
Ventilator dependent; 
x 
Known individual hypersensitivity to any of the ingredients/excipients of 
the study medication; 
x 
Patients with specific contraindication to MRI (e.g.: metallic foreign body, 
claustrophobia, etc.). 


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CONFIDENTIAL 
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Study Drug: 
x 
Rimeporide (EMD 87580): 25-mg and 50-mg hard gel capsules. 
Dosing Regimen 
Frequency of Administration: 
 
x 
Multiple oral doses of rimeporide ranging from 50 to 300 mg administered 
three times a day will be evaluated in patients with Duchenne Muscular 
Dystrophy.  
x 
The following doses will be studied sequentially in ascending order: 50 
mg, 100 mg, 150 and 200 mg TID in patients with a body weight less than 
or equal to 30kg at baseline; and 75 mg, 150, 200 and 300 mg TID in 
patients with a body weight more than 30kg at baseline. Safety will be 
reviewed by the Safety Monitoring Committee before each dose escalation 
is undertaken.  
Treatment Duration: 
x Rimeporide administration is foreseen for 4 weeks, with a two week 
follow-up period. 
Background Therapy  
Concomitant Medication: 
x Rimeporide will be administered on a background of corticosteroids with 
or without the addition of stable ACEI/ARB medication.  
Study objectives 
Primary objective: 
x 
To determine the preliminary safety and tolerability profile of multiple oral 
administrations of rimeporide. 
 
Secondary objectives: 
x 
Pharmacokinetics: To evaluate the pharmacokinetic profile of rimeporide 
in pediatric patients with DMD.  
 
Exploratory objectives: 
x 
Pharmacodynamics/ pharmacokinetics: 
- 
To measure inflammatory  and muscular injury biomarkers; 
- 
To explore the PK/PD relationship of a 4-week rimeporide treatment 
on those surrogate biomarkers. 
- 
To explore the relationship between safety endpoints  and 
pharmacokinetic parameters 
x 
For all patients: To explore using Nuclear Magnetic Resonance (NMR) 
imaging the effect of a 4-week treatment with rimeporide on biomarkers 
including degree of inflammation, oedema, fat fraction, muscle 
composition.  


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CONFIDENTIAL 
[Rim4DMD] – Final Version 21_ February 19th 2016  
x 
For patients recruited in Paris: To explore using Nuclear Magnetic 
Resonance (NMR) Spectroscopy the effect of a 4-week treatment with 
rimeporide on biomarkers including intracellular pH and intracellular Na. 
 
Study endpoints  
 
Primary endpoints: 
x Safety parameters  
- Incidence, severity, causality and outcomes of AEs and SAEs  
- Vital signs, Supine and standing blood pressure, heart rate and 
respiratory rate 
- Substantial changes in laboratory parameters from blood and urine 
samples. 
- Number of patients withdrawn for safety issues 
 
 
Secondary endpoints: 
x 
Pharmacokinetic profile of rimeporide in plasma derived from 
modelling using sparse sampling: blood samples will be collected at 
different time points to determine the pharmacokinetic profile of orally 
administered rimeporide in plasma. 
 
Exploratory endpoints: 
Pharmacodynamics 
x 
Changes of plasma/ serum biomarkers:  
- 
Plasma/ Serum levels of the inflammation markers: C - reactive protein 
(CRP), Tumor Necrosis Factor alfa (TNFα), Transforming Growth 
Factor beta (TGFβ-1) and other exploratory biomarkers to monitor 
muscle damages (cytokine panels and specific RNA targeting); 
 
x 
For all patients: Changes in NMRI indices in skeletal muscle will be 
explored through NMRI indices (water T2, fat fraction). 
x 
For patients recruited in France: Changes in NMRS indices in skeletal 
muscle will be explored through: 
- 
31P NMRS indices; 
- 
23Na NMRS indices may also be included. 
 


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Study Safety Monitoring:  
x 
A Safety Monitoring Committee (SMC) will oversee the study conduct, 
reviewing safety data generated at the end of each cohort. 
Safety assessment will be done on data collected in each cohort and during 
the 4 weeks treatment and 1-2 weeks of follow-up. The decision to progress 
to the next higher dose will be made after safety and tolerability data are 
reviewed for the preceding dose for 5 patients by a data Safety Monitoring 
Committee and determined that it is safe to proceed to the next dose level. 
Statistical Analysis: 
x 
Descriptive statistics will be used to analyse the data. In view of the small 
sample size no formal hypothesis testing will be undertaken.  
Sample Size: 
x 
20 completed patients with 4 cohorts of 5 patients each will participate in 
this pilot study.   
Recruitment Duration: 
x 
The recruitment period will vary depending on the recruitment speed; the 
objective being to recruit the foreseen 20 evaluable patients within 12 
months. 
x 
Recruitment will be competitive among the 4 participating sites. 
x 
For each cohort, the first 3 patients must receive rimeporide with an interval 
of at least 1 week.  If no safety issue is raised for the first 3 patients, then 
patients 4 and 5 can receive their first study treatment administration 
without a minimum time interval. 
Study Duration:  
Study End Definition:   
x Expected study duration: 15 months  
x End of the study is defined as last patient last visit.  
 
 


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CONFIDENTIAL 
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Table 1: Schedule of Assessments 
Visit Number 
VS 
V1 
V2 
V3 
V4 
V5 
V6 
UNSCHEDULED 
VISIT 
Time points 
SCR 
D1 
W1 
W2  
W3 
W4 
EOS 
Site Visit 
X 
X 
X 
X 
 
X 
X 
X 
Phone Call 
 
 
 
 
X 
 
 
 
Inclusion 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Review and confirmation 
of eligibility criteria 
X 
X 
 
 
 
 
 
 
Medical history 
Demographic data 
X 
 
 
 
 
 
 
 
6-Minute Walk Test 
X 
 
 
 
 
 
 
 
Pulmonary Function Tests 
by spirometry  
X 
 
 
 
 
 
 
 
Echocardiography 
X 
 
 
 
 
 
 
 
Local Safety Evaluations  
 
 
 
 
 
 
 
 
Physical and neurological 
examination, weight, vital 
signs, Heart Rate, 
Respiratory rate, Blood 
Pressure  
X 
X 
X 
X 
 
X 
X 
X 
12 lead ECG, including QTc 
X 
X 
X 
X 
 
X 
X 
X 
Local Biochemistry, 
hematology, urinalysis. 
X 
X 
X 
X 
 
X 
 
X 
Gastrin levels 
 
X 
 
 
 
X 
 
 
AEs/SAEs review 
X 
X 
X 
X 
X 
X 
X 
X 
PK  sampling profile 
allocation 
 
X 
 
 
 
 
 
 
PK blood 
 
X 
 
 
 
X 
 
 
Local NMRI (NMRS if 
applicable) 
 
Xa 
 
 
 
Xb 
 
 
Blood Samples (for central 
analysis: CK total, CK-
isoenzymes,  TNFa and 
TGFβ-1, and other 
biomarkers) 
X 
 
 
 
 
X 
 
 
Treatment delivery  
 
Xc  
X c 
Xc 
 
 
 
 
Treatment compliance  
 
 
X 
X 
 
X 
 
X 
Concomitant treatments 
X 
X  
X 
X 
X 
X 
X 
X 
 
(a) The day before the SD1  
(b) Day 27+/- 2 days, just before the end of treatment period. 
(c) See section 5.1.4.2 drug dispensing of this protocol. 
 


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CONFIDENTIAL 
[Rim4DMD] – Final Version 21_ February 19th 2016  
CONTENTS 
PART I ............................................................................................................................................................. 23 
1 
BACKGROUND INFORMATION ................................................................................................................. 23 
1.1 
DUCHENNE MUSCULAR DISTROPHY (DMD) ................................................................................................... 23 
1.1.1 
Description of the Disease ................................................................................................................ 23 
1.1.2 
Currently available therapies ........................................................................................................... 24 
1.2 
RIMEPORIDE ............................................................................................................................................. 25 
1.2.1 
Description and mode of action ....................................................................................................... 25 
1.2.2 
Preclinical Data ................................................................................................................................ 25 
1.2.3 
Clinical Data ..................................................................................................................................... 27 
1.3 
RATIONALE FOR USE OF RIMEPORIDE IN DMD ................................................................................................ 28 
1.4 
RATIONALE FOR DOSE SELECTION .................................................................................................................. 29 
2 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................................................... 30 
2.1 
STUDY OBJECTIVES ..................................................................................................................................... 30 
2.1.1 
Primary objective: ............................................................................................................................ 30 
2.1.2 
Secondary objective: ........................................................................................................................ 30 
2.1.3 
Exploratory objectives: ..................................................................................................................... 30 
2.2 
STUDY ENDPOINTS ..................................................................................................................................... 31 
2.2.1 
Primary endpoints: ........................................................................................................................... 31 
2.2.2 
Secondary endpoints: ....................................................................................................................... 31 
2.2.3 
Exploratory endpoints: ..................................................................................................................... 31 
3 
STUDY DESIGN ......................................................................................................................................... 31 
3.1 
OVERALL DESIGN ....................................................................................................................................... 32 
3.2 
RECRUITMENT PLAN .................................................................................................................................... 33 
3.3 
SCREENING PERIOD ..................................................................................................................................... 33 
3.4 
TREATMENT PERIOD ................................................................................................................................... 33 
3.5 
FOLLOW-UP PERIOD AND END OF STUDY VISIT ................................................................................................. 34 
4 
TARGET POPULATION .............................................................................................................................. 34 
4.1 
ELIGIBILITY CRITERIA ................................................................................................................................... 34 
4.1.1 
Inclusion Criteria .............................................................................................................................. 34 
4.1.2 
Exclusion Criteria .............................................................................................................................. 34 
5 
DESCRIPTION OF IMP ............................................................................................................................... 35 
5.1 
IMP HANDLING ........................................................................................................................................ 36 
5.1.1 
Packaging and Labelling .................................................................................................................. 36 
5.1.2 
IMP Supply ....................................................................................................................................... 36 
5.1.3 
IMP Receipt and Storage .................................................................................................................. 36 
5.1.4 
IMP Preparation, Administration, Accountability and Destruction .................................................. 36 
5.2 
PATIENT BACKGROUND TREATMENT AND CARE ............................................................................................... 39 
5.2.1 
Background Therapy with corticosteroids ........................................................................................ 39 
5.2.2 
Prophylactic treatment .................................................................................................................... 39 
5.3 
CONCOMITANT THERAPY ............................................................................................................................. 39 
5.3.1 
Possible concomitant therapies ....................................................................................................... 39 
5.3.2 
Prohibited therapies ......................................................................................................................... 40 
5.4 
CONTRACEPTION GUIDANCE ......................................................................................................................... 40 


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5.5 
PHOTOSENSITIVITY GUIDANCE ...................................................................................................................... 40 
5.6 
PATIENT STUDY CARD .................................................................................................................................. 41 
5.7 
PATIENT DIARY .......................................................................................................................................... 41 
5.8 
RESCUE THERAPY ....................................................................................................................................... 41 
6 
STUDY ASSESSMENTS .............................................................................................................................. 41 
6.1 
ADVERSE EVENTS ....................................................................................................................................... 42 
6.2 
PHYSICAL AND NEUROLOGICAL EXAMINATION ................................................................................................. 42 
6.3 
SUPINE AND STANDING BLOOD PRESSURE ....................................................................................................... 42 
6.4 
HEART RATE AND RESPIRATORY RATE ............................................................................................................. 43 
6.5 
MONITORING OF ECG EVOLUTION PARAMETERS (INCLUDING QTC) ..................................................................... 43 
6.6 
SPIROMETRY: PULMONARY FUNCTION TESTS ................................................................................................... 43 
6.7 
6-MINUTE WALK TEST ................................................................................................................................ 43 
6.8 
ECHOCARDIOGRAPHY .................................................................................................................................. 43 
6.9 
SAFETY HEMATOLOGY, BIOCHEMISTRY AND URINALYSIS ..................................................................................... 44 
6.10 
PHARMACOKINETIC ENDPOINTS .................................................................................................................... 45 
6.10.1 
Optimal number of samples ........................................................................................................ 45 
6.10.2 
Sampling times ............................................................................................................................ 45 
6.10.3 
Blood samples collection, handling and storage ......................................................................... 45 
6.10.4 
Pharmacokinetic analysis ............................................................................................................ 46 
6.11 
PHARMACODYNAMIC ENDPOINTS ................................................................................................................. 46 
6.11.1 
Blood samples collection, handling and storage ......................................................................... 47 
6.12 
BLOOD SAMPLE VOLUMES............................................................................................................................ 48 
7 
OUTLINE OF STUDY PROCEDURES ............................................................................................................ 48 
7.1 
SCREENING ............................................................................................................................................... 48 
7.2 
NMRI (NMRS IF APPLICABLE)  BEFORE FIRST DOSE AT STUDY DAY 1 ............................................................... 50 
7.3 
STUDY DAY 1 (FIRST DOSE OF RIMEPORIDE) ................................................................................................... 50 
7.3.1 
Before rimeporide administration at Study Day 1 visit .................................................................... 50 
7.3.2 
First Rimeporide administration....................................................................................................... 51 
7.3.3 
After first dose of rimeporide ........................................................................................................... 51 
7.3.4 
Second rimeporide administration ................................................................................................... 52 
7.3.5 
After the Second dose of rimeporide ................................................................................................ 52 
7.4 
WEEK 1 (DAY 7 +/- 2 DAYS) ........................................................................................................................ 52 
7.5 
WEEK 2 (DAY 14 +/- 2 DAYS) ...................................................................................................................... 53 
7.6 
WEEK 3 (DAY  21 +/- 2 DAYS) ..................................................................................................................... 53 
7.7 
NMRI (NMRS IF APPLICABLE) AT DAY 27 (+/-2 DAYS) OF THE STUDY ................................................................. 54 
7.8 
WEEK 4 (DAY 28 +/- 2 DAYS) ...................................................................................................................... 54 
7.9 
END OF THE STUDY VISIT (1-2 WEEKS +/- 2 DAYS POST LAST RIMEPORIDE DOSE) .................................................. 55 
7.10 
WITHDRAWAL VISIT (1-2 WEEKS +/- 2 DAYS AFTER DECISION) ........................................................................... 55 
7.11 
ASSESSMENTS IN CASE OF UNPLANNED (UNSCHEDULED) VISITS .......................................................................... 56 
8 
SAFETY PROCEDURES ............................................................................................................................... 57 
8.1 
DEFINITION ...................................................................................................................................... 57 
8.1.1 
Adverse events ................................................................................................................................. 57 
8.1.2 
Serious Adverse Events ..................................................................................................................... 59 
8.1.3 
Abnormal Laboratory Test Values .................................................................................................... 59 
8.2 
REPORTING PROCEDURES .......................................................................................................... 60 
8.2.1 
Suspected Unexpected Serious Adverse Reactions Reporting .......................................................... 60 
8.2.2 
Provision of follow-up information .................................................................................................. 62 


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8.2.3 
Reporting period .............................................................................................................................. 62 
8.2.4 
Post study SAEs and SUSARs: ........................................................................................................... 62 
8.2.5 
Development Safety Update Report (DSUR) .................................................................................... 62 
8.3 
FOLLOW-UP OF SAFETY PARAMETERS ............................................................................................................ 62 
8.3.1 
Treatment and Follow-up of Adverse Events ................................................................................... 62 
8.3.2 
Follow-up of Abnormal Laboratory Test Values ............................................................................... 63 
8.3.3 
Pregnancy ........................................................................................................................................ 63 
8.4 
SAFETY MONITORING COMMITTEE ..................................................................... ERROR! BOOKMARK NOT DEFINED. 
9 
STOPPING RULES ..................................................................................................................................... 63 
9.1 
STOPPING OR SUSPENSION OF DOSING AT THE INDIVIDUAL PATIENT LEVEL ............................................................. 63 
9.2 
STOPPING OR SUSPENSION OF DOSING AT THE STUDY LEVEL ................................................................................ 64 
9.2.1 
Non Serious Adverse Events: ............................................................................................................ 64 
9.2.2 
Serious Adverse Events (SAE): .......................................................................................................... 64 
9.3 
SUSPENSION OF DOSE ESCLATION .................................................................................................................. 64 
10 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .......................................................................... 65 
10.1 
SAMPLE SIZE ............................................................................................................................................. 65 
10.2 
ANALYSIS SETS .......................................................................................................................................... 65 
10.2.1 
Safety Analysis Set ....................................................................................................................... 65 
10.2.2 
Intent-to-Treat Analysis Set ......................................................................................................... 65 
10.3 
STATISTICAL AND ANALYTICAL METHODS ........................................................................................................ 65 
10.3.1 
Safety Data .................................................................................................................................. 65 
10.3.2 
Pharmacodynamics Data ............................................................................................................ 66 
10.3.3 
Missing Data ............................................................................................................................... 66 
10.4 
REPLACEMENT POLICY ................................................................................................................................ 66 
10.4.1 
For Patients ................................................................................................................................. 66 
10.4.2 
For Centres .................................................................................................................................. 66 
11 
DEFINITION OF THE END OF THE STUDY ................................................................................................... 66 
PART II ........................................................................................................................................................... 67 
12 
ETHICAL AND LEGAL ASPECTS .................................................................................................................. 67 
12.1 
GOOD CLINICAL PRACTICE ........................................................................................................................... 67 
12.2 
RESPONSIBILITIES ....................................................................................................................................... 67 
12.3 
CONSENT ................................................................................................................................................. 70 
12.4 
SUBJECT COMPENSATION ............................................................................................................................ 72 
12.5 
ARCHIVING ............................................................................................................................................... 73 
12.6 
CONFIDENTIALITY AND DATA PRIVACY............................................................................................................ 73 
12.7 
PROTOCOL AMENDMENTS ........................................................................................................................... 74 
12.8 
APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS ..................................................................... 74 
12.9 
ONGOING INFORMATION FOR INDEPENDENT ETHICS COMMITTEE ....................................................................... 74 
12.10 
CLOSURE OF THE STUDY .............................................................................................................................. 75 
12.11 
LIABILITY AND INSURANCE ........................................................................................................................... 75 
12.12 
FINANCIAL DISCLOSURE ............................................................................................................................... 75 
12.13 
DISCLOSURE OF PROTOCOL AND PUBLICATION POLICY ...................................................................................... 75 
13 
MONITORING AND AUDITING.................................................................................................................. 76 
13.1 
STUDY MONITORING AND SOURCE DATA VERIFICATION .................................................................................... 76 
13.2 
ON-SITE AUDITS ........................................................................................................................................ 78 


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13.3 
SERIOUS GCP BREACHES ............................................................................................................................. 78 
14 
DOCUMENTATION AND USE OF STUDY FINDINGS ................................................................................... 79 
14.1 
DOCUMENTATION OF STUDY RESULTS............................................................................................................ 79 
14.2 
USE OF COMPUTERISED SYSTEMS AT THE CLINICAL TRIAL CENTRE ....................................................................... 79 
14 
REFERENCES ............................................................................................................................................. 81 
APPENDIX 1: WMA DECLARATION OF HELSINKI ................................................................................................ 83 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
aPTT 
Activated Prothrombin Time 
ARB 
Angiotensin receptor blockers 
AST 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
AUC 
Area Under the Curve 
BSA 
Body Surface Area 
CBC 
Complete blood cell count 
CHF 
Congestive heart failure 
CL 
Systemic drug clearance 
Cmax 
Peak drug plasma concentration  
CMH 
cardiomyopathic hamster 
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
CRF 
Case report form 
CRP 
C-reactive protein 
Ctrough 
Plasma drug concentration immediately prior next dosing 
eCRF 
Electronic case report form 
EMA 
European Medicines Agency 
EOS 
End of Study 
GRMD 
Golden retriever muscular dystrophy 
ICMJE 
International Committee of Medical Journal Editors  
IMP 
Investigational medicinal product 
IFNγ 
Interferon gamma 
ITT 
Intention-to-treat 
KD 
Dissociation constant 
KO 
Knock Out  


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LVEF 
Left Ventricular Ejection Fraction 
MMP-9 
Matrix metalloproteinase 
NCX 
Sodium-calcium exchanger 
NMRI 
Nuclear Magnetic Resonance Imaging 
NMRS 
Nuclear Magnetic Resonance Spectroscopy 
NaCl 
Sodium Chloride 
ODD 
Orphan Drug designation 
OPN 
Osteopontin 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PPD 
Purified protein derivative 
PPI 
Proton-pump inhibitor 
PK 
Pharmacokinetic 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAD 
Single ascending dose 
SMC 
Safety Monitoring Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2  
Elimination half-life 
TGFβ 
Transforming growth factor beta 
Tmax 
Time when plasma concentration is at peak 
TMDD 
Target mediated drug disposition 
TMF 
Trial Master File 
TNFα 
Tumor necrosis factor alfa 
WD 
Withdrawal 
 


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CONFIDENTIAL 
[Rim4DMD] – Final Version 2.1_ February 19th, 2016 
PART I 
 
1 BACKGROUND INFORMATION 
 
1.1 
DUCHENNE MUSCULAR DISTROPHY (DMD) 
 
1.1.1 
Description of the Disease 
Duchenne muscular dystrophy is a genetic disorder characterized by the progressive loss and 
degeneration of skeletal muscle, primarily in boys. DMD affects approximately 1 in 3,802 to 6,291 live 
male births worldwide (Mendell, 2012) (Moat SJ, 2013). The condition is inherited in an X-linked 
manner. Mutations in the DMD gene lead to the disease by preventing the expression of a key protein 
called dystrophin, an important structural component in muscle tissue.  
The lack of the protein dystrophin leads to membrane instability and uncontrolled calcium influx which 
contributes to the degenerative process (Iwata Y and Wakabyashi 2012). 
 
Muscle weakness generally becomes apparent in the first few years of life with a delay in motor 
milestones, and a mean age of walking around 18 months. Children with DMD typically display skeletal 
muscle weakness by the age of 2–6 years and are diagnosed around the age of 5 years when typical 
motor function delays are apparent. Progressive muscle weakness leads to a loss of independent 
ambulation before the age of thirteen without disease modifying treatment. In non-ambulatory boys and 
young men, there is gradual loss of upper limb and neck functions, so that grooming, toileting, bathing, 
dressing, and eating become impaired or impossible to do independently, affecting the quality of life of 
patient, their caregivers and families. 
Weakness in the limbs is accompanied by involvement of the respiratory muscles. By the age of 15 to 
18 years, most patients with DMD start to develop serious respiratory complications, leading to the 
need for ventilatory assistance at night. Involvement of the heart muscles (cardiomyopathy) is also a 
universal phenomenon. Structural and functional changes associated with cardiomyopathy precede 
clinical manifestations. Cardiomyopathy is characterised by normal or thinned left ventricular (LV) 
wall thickness and progressive decline in ejection fraction or fractional shortening and clinical 
symptoms of congestive heart failure including (pulmonary) oedema, fatigue, dizziness and arrhythmia. 
Immobility of patients can temporarily disguise clinical manifestation of cardiomyopathy. However, in 
the late stage of the disease cardiomyopathy is severe and symptomatic and a major cause of death. 
While advances in respiratory care have improved respiratory outcomes, dilated cardiomyopathy and 
heart failure remain the leading causes of death in patients with DMD. Patients rarely survive beyond 
early adulthood and the current average life expectancy is 27 years (DMD Patient Leaflet, 2013).   


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Natural history studies have shown that the use of corticosteroids and the management of spine 
deformity, pulmonary and cardiac dysfunctions have altered the timing of some of the clinical 
milestones of the disease. But with limited medical management have come new complications, and, 
quality of life often suffers. Once ambulation or some other functional capacity is lost in an individual 
with Duchenne Muscular Dystrophy, it is gone forever and sudden death may occur at any time, even 
in younger boys. 
 
1.1.2 
 
Currently available therapies 
There is currently no known cure for patients with Duchenne muscular dystrophy. Recently, in the EU, 
the orphan drug, Ataluren (Translarna), has received conditional approval for treatment of DMD 
resulting from stop codon mutations in ambulatory patients aged 5 years and older. Approximately 13% 
of patients with DMD have stop codon mutations and are, thus, eligible for treatment with Ataluren, 
thus this treatment has potential benefit in a small proportion of DMD patients. Ataluren has not been 
shown to prevent cardiomyopathy. 
Corticosteroids, such as prednisolone and deflazacort, are the only drugs currently available which can 
help improve muscle function in DMD (MedlinePlus, 2014). However, although they may slow the 
progression of the disease, they have only been shown to be effective for six months to two years (NHS 
choices, 2013) and are not licensed for use in this condition. Their side-effects, especially with long-
term treatment, can lead to complications. These include weight gain, which can further compromise 
mobility and a reduction in bone mineral density with increased risk of fractures, diabetes, cataracts and 
raised intraocular pressure can also occur (Angelini C., 2012). Steroid therapy (dose, frequency and 
duration of administration) is handled with notable differences across centres. However, it is rarely 
continued beyond the mid teen age years because of the side effects. 
There are other unlicensed treatments and supplements which are also used to help alleviate signs and 
symptoms, such as albuterol and coenzyme Q10, although their efficacy is unknown. Additional 
treatments aimed at relieving particular aspects of the disease, which often worsen as it progresses, are 
also often required. These include orthopaedic appliances, treatment for heart failure, such as ACE-
inhibitors, ARB, beta blockers and assisted ventilation to improve respiratory function. Non-
pharmacological treatments can be very invasive, including corrective surgery for scoliosis and tendon 
contractures, insertion of a feeding tube when dysphagia prevents adequate nutrition and night-time 
ventilation when signs of respiratory failure become apparent.  
In all patients, a mainstay of therapy is managing signs and symptoms of the condition and, therefore, 
needs to be tailored to the needs of an individual as their symptoms emerge and progress. The disease 
progresses despite treatment with steroids and/or ataluren in all patients, hence a significant unmet 
medical need exists that can only be addressed by additional treatments for DMD. 
 
 


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1.2 
RIMEPORIDE 
 
1.2.1 Description and mode of action 
Rimeporide is a potent and selective inhibitor of the sodium-hydrogen exchanger (NHE-1). NHE-1 is a 
key membrane transporter regulating the intracellular pH, Na+ concentration, cell volume and 
catalyzing the electroneutral counter transport of Na+ and H+ through the plasma membrane (Orlowski 
et al., 2004). The NHE-1 isoform present on muscle fibers, is activated rapidly in response to various 
stimuli, causing a cascade of events leading to significant increase in intracellular [Na+] and driving the 
Na+/Ca2+ exchanger (NCX) into reverse mode hence, triggering an intracellular [Ca2+] overload (Shi et 
al., 2013). NHE-1 inhibitors can block the activation of NHE-1, therefore decrease intracellular Na+ 
overload and, by normalizing the activity of the NCX, decrease intracellular Ca2+.  
 
Figure 1 
Rimeporide mechanism of action (Modified from Stanbouly et al, 2008) 
 
 
 
 
 
 
 
 
 
1.2.2  Preclinical Data  
1.2.2.1 Non-clinical Pharmacology 
The pharmacology of rimeporide has been investigated in a series of in vitro models and cellular assay 
systems.  Rimeporide has subsequently been characterised as a highly selective and potent NHE-1 
inhibitor.  It has been demonstrated to have negligible activity on other cellular membrane transport 
systems, hormone receptors and ion channels and does not inhibit the binding of other ligands to these 
receptor systems.  
Rimeporide has been investigated in models of heart failure. In the post MI heart failure studies in rats 
(Pfeffer model) at London Ontario, the compound has been administrated for 3 months either 
immediately after MI, or 2 or 4 weeks after coronary ligation. In these studies, rimeporide markedly 
diminished the elevation of left ventricular end diastolic pressure and the loss of systolic function seen 
in non-treated controls with all treatment protocols. Left ventricular dilatation and hypertrophy as 
assessed by heart weight and by cell size as well as ANP expression were reversed to sham or near 
sham levels (Chen L, 2004). 
Rimeporide 


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Effects of rimeporide were also investigated in hereditary cardiomypathic hamsters (CMHs). This 
sarcoglycan deficient model of cardiomyopathy and muscular dystrophy is indirectly related to 
Duchenne muscular dystrophy because sarcoglycans and dystrophin are part of a common dystrophin-
glycoprotein complex (Blain et al 2011). Cardiomyopathy in CMHs is characterized by excessive 
intracellular Ca2+ and Na+ overload and increased NHE-1 expression. Treatment with rimeporide for 50 
days prevented the increase of NHE-1 protein levels as well as Na+ and Ca2+ overload and necrosis. 
Treatment for 198 days prevented cardiac hypertrophy and necrosis (Chahine, et al., 2005). Treatment 
for 310 days prevented Na+ and Ca2+ overload, hypertrophy, and necrosis and reduced mortality of the 
hamsters from 73% in controls to 22% in treated animals (G. Bkaily, unpublished results. See IB 
rimeporide).  
 
 
Figure 2 : Survival curve of CMHs after a 310-day treatment period. CM (n=26): untreated CMHs, 
Rimeporide (n=27): 310-days Rimeporide treated CMH. ***p<0.001 (See IB rimeporide). 
 
Curative treatment for 85 days with rimeporide which started in 275 days old CMHs was also effective 
to normalize NHE-1 expression, intracellular Na+ and Ca2+ levels as well as to reduce hypertrophy and 
prevent necrosis. Mortality during treatment was significantly reduced (Figure 2). The ACE inhibitor 
Cilazapril was not effective in this setting (Bkaily G 2015) 
 
1.2.2.2 Toxicology 
Repeated oral toxicity studies up to 26-week in rats and up to 39-week in beagle dogs were run. The 
main target organs were fundic parietal cells in rats and dogs; this finding is monitorable in the clinic 
by assessing gastrin levels as a surrogate marker for signs of adverse effects on the parietal cells.  


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No mutagenic activity and no teratogenic potential were shown. Rimeporide did not impair male and 
female fertility. The compound has no skin sensitizing properties and local tolerance studies revealed 
only minor effects after intra-arterial injection. 
 
1.2.2.3 Safety pharmacology 
No significant adverse effects were seen in specific studies of cardiovascular and renal function. The 
electrophysiological characterisation of rimeporide demonstrated that it has no pro-arrhythmic 
potential, even at very high concentrations. 
 
1.2.3 Clinical Data 
Seven Phase 1 clinical studies have been conducted with rimeporide. In these studies single oral, 
multiple oral and single iv doses of rimeporide have been investigated. To date, a total of 166 adult 
humans have received rimeporide comprising 145 healthy volunteers and 21 subjects with congestive 
heart failure (CHF), as the product was initially developed for this indication. 
 
1.2.3.1 Clinical pharmacokinetics 
Following oral administration of rimeporide, Cmax values are reached in the range of 0.75 to 2.5 hours 
post dose in non-fasted and fasted adult healthy volunteers. Thereafter, concentrations decline rapidly, 
with a half-life of approximately 4 hours in healthy human volunteers. Pharmacokinetics of rimeporide 
is dose proportional in the range of 50 to 600 mg. No food effect was observed. Rimeporide is highly 
bioavailable by the oral route. Rimeporide is negligibly metabolized, with the major route for 
elimination of being clearance of unchanged drug via the renal route.  
No pharmacokinetic drug-drug interaction (DDI) was found between digoxin and rimeporide and since 
rimeporide is not metabolized and neither induces nor inhibit CYP450 enzymes, no DDIs are expected 
with co-administered drugs which are metabolized by or affect the activity of these enzymes.  
 
1.2.3.2 Clinical experience to date  
Rimeporide was well tolerated in healthy male subjects as single oral dose up to 600 mg, as multiple 
oral three times daily doses up to 3 x 200 mg for seven days, and as a single intravenous dose over 15 
minutes up to 350 mg. . A maximum tolerated dose could not be defined. Retrospective QT analysis of 
ECG data of the double-blind, placebo controlled oral single and multiple rising dose studies did not 
indicate an effect of rimeporide on prolongation of the QT interval.  In studies with oral rimeporide, 
adverse events included chest discomfort, abdominal discomfort, postural dizziness, vaso-vagal 
episodes, dizziness, headache, lightheadedness, paresthesia, skin reactions (toxic erythema and 
urticaria), respiratory tract disorders, and diarrhea. After intravenous administration of rimeporide, 
elevated liver enzymes and a single case of an angioneurotic edema were reported. The relationship of 
the angioneurotic edema to study drug is considered remote. A total of five subjects were withdrawn 


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from phase I studies. Three subjects (one placebo, two on oral rimeporide) were withdrawn for a mild 
generalized skin reaction; two subjects were withdrawn for ECG abnormalities in the digoxin 
interaction study. 
In a study with CHF patients, rimeporide given as a 50 mg or 100 mg dose up to three times daily for a 
total of eight days was well tolerated. The study drug had no adverse effects on blood pressure, heart 
rate, or on ECG parameters. Laboratory parameters including gastrin values appeared to be unaffected 
by the study drug. However, due to the small size of this clinical trial and the uncontrolled study design 
a definitive conclusion on the laboratory safety of rimeporide cannot be drawn from these trial data. 
One serious adverse event was reported (worsening heart failure), but considered unrelated to the study 
drug. 
In conclusion, rimeporide was well tolerated in human healthy volunteers and in patients with CHF 
investigated so far.  
 
1.3 
 RATIONALE FOR USE OF RIMEPORIDE IN DMD 
 
A pathological increase in intracellular free calcium has long been considered to be an important 
contributor to the pathophysiology of DMD (Cullighan et Ohlendieck 2002). Different factors are 
involved in causing this increase in calcium level.  
First, lack of dystrophin leads to mechanical disruption of the sarcolemma, leading to leakage of 
calcium into the cells.  
Secondly, enhanced calcium entry into the cells may occure secondary to a pathological increase in 
sodium (Na+) levels, which have been observed in skeletal and cardiac muscles of DMD patients 
(Weber et al 2012; Fanchaouy et al, 2009 ). 
The increase in sodium level in the muscle cells in turn leads to enhancement of calcium entry through 
the so-called Na+/Ca2+ exchanger (NCX1) system (Burr, et al, 2014). 
In 2007 Iwata et al (2007) published data showing that Cariporide,  an NHE-1 inhibitor previously 
under development for treatment of cardiac failure, reduced intracellular sodium and calcium overloads 
in dystrophic muscle cells (mdx mice and BIO 14.6 hamster) and had significant beneficial effects on 
muscle functionalities and cellular mechanism in mdx mice (Iwata Y et al., 2007). NHE-1 inhibitors 
have also been shown to regulate a number of inflammatory processes (Yang et al., 2013) that are also 
involved in DMD pathophysiology (Evans et al., 2009).  
Animal studies also provide support for the rationale of using rimepride, another NHE-1 inhibitor, in 
the treatment of DMD. In summary: 
x 
Lifelong treatment with the rimeporide in the Syrian cardiomyopathic hamster, a widely used 
model of cardiomyopathy, led to a marked decrease of intracellular sodium and calcium and a 
clear significant improvement in overall survival (Chahine et al., 2005).  


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x 
In vitro studies  have confirmed a potent effect of Rimeporide on NHE-1 expression and 
associated changes in intracellular pH in cultured wild type and dystrophic myotubes   
(Dorchies et al 2015) 
x 
In vivo studies in mdx mice showed reduced inflammation and fibrosis in skeletal muscle as 
well as in the diaphragm and heart muscles (Nagaraju et al 2014 and 2015).  
 
On the basis of these preclinical findings, the European Medicines Agency recently granted Orphan 
Drug Designation to rimeporide for the treatment of Duchenne Muscular Dystrophy.   
 
1.4 
RATIONALE FOR DOSE SELECTION 
 
Based on mdx mice and hamster efficacy studies, expected Rimeporide concentration required to 
achieve efficacy in patients with DMD is anticipated to be within the range of 500 –2500ng/mL. Given 
the extensive pharmacokinetic data available from completed clinical studies in adult subjects, 
(including both healthy adult volunteers and patients with CHD) it has been possible to develop a 
pharmacokinetic model to determine the optimal dose regimen in paediatric patients with DMD.  The 
proposed regimens of multiple ascending doses of 50mg, 100mg, 150mg and 200mg TID in patients 
with a body weight less than or equal to 30kg and of 75mg, 150mg, 200mg and 300mg TID in those 
patients with a body weight of greater than 30kg should enable a constant rimeporide plasma 
concentration within the estimated therapeutic range.  
 
Doses of up to 200mg TID given daily for 10 days  have been administered to adults in phase I studies 
and been found to be safe and well tolerated and doses up to 10 times the proposed maximum clinical 
dose have been evaluated in non-clinical studies thereby characterizing the anticipated safety profile. 
 
Each dose level will be studied only after thorough evaluation of safety data in all subjects completing 
dosing at the previous dose level. Although the top dose of 200mg tid in patients with under 30kg  body 
weight or 300 mg tid in patients with over 30kg body weight is higher than that studied in adult 
volunteers, this will only be administered if safety and tolerability are deemed acceptable by the safety 
monitoring committee at the previous dose level.  
 
 


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2 STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 
STUDY OBJECTIVES 
 
2.1.1 Primary objective: 
x 
To determine the preliminary safety and tolerability profile of multiple oral administrations of 
rimeporide  
 
 
2.1.2 Secondary objective: 
x 
Pharmacokinetics:  
- 
To obtain the pharmacokinetic profile of rimeporide in pediatric patients with DMD.  
 
2.1.3 Exploratory objectives: 
x 
Pharmacodynamics: 
- 
To measure inflammatory  and muscular injury biomarkers; 
- 
To explore the PK/PD relationship of a 4-week rimeporide treatment on those surrogate 
biomarkers. 
- 
To explore the relationship between safety endpoints and pharmacokinetic parameters  
x 
For all patients: To measure noninvasively spectroscopy biomarkers after a 4 -week treatment of 
rimeporide in patients with DMD NMR-I (inflammation, oedema, fat fraction, muscle 
composition). In particular: 
- 
To evaluate by NMR imaging;  
o Muscle water T2, proportion of muscle with elevated T2 which selectively 
measures muscle inflammation. 
o Heterogeneity of T2 within the muscle which reflects tissue disorganisation, fat 
fraction in the muscle 
x 
For patients recruited in Paris: To measure noninvasively spectroscopy biomarkers after a 4 -week 
treatment of rimeporide in patients with DMD NMR-S (intracellular pH and intracellular Na). In 
particular: 
o To explore the PK/PD relationship of Rimeporide on intracellular pH, as measured 
by 31P Spectroscopy and on intracellular sodium, as measured by 23Na NMR 
spectroscopy; 
 


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2.2 
STUDY ENDPOINTS 
 
2.2.1 Primary endpoints: 
x Safety parameters to be collected and assessed: 
- 
Incidence, severity, causality and outcomes of AE and SAE; 
- 
Vital signs, Supine and standing blood pressure, heart rate and respiratory rate; 
- 
Substantial changes in laboratory parameters from blood and urine samples; 
- 
Number of patients withdrawn for safety issues. 
 
 
2.2.2 Secondary endpoints: 
 
x 
Pharmacokinetics parameters: Pharmacokinetic profile of rimeporide in plasma derived from 
modelling using sparse sampling. Blood samples will be collected to determine the pharmacokinetic 
profile of orally administered rimeporide. 
 
2.2.3 Exploratory endpoints: 
x 
Pharmacodynamics: Exploratory evaluation of the early biological response of a 4 week treatment 
by rimeporide through changes of plasma / serum biomarkers:  
o Plasma / Serum levels of the inflammation markers: C - reactive protein (CRP), Tumor 
Necrosis Factor alfa (TNFα), Transforming Growth Factor beta (TGFβ-1) and other 
exploratory biomarkers to monitor muscle damages (cytokine panels and specific RNA 
targeting); 
 
x 
For all patients: changes in NMRI indices in skeletal muscle will be explored through NMRI 
indices (water T2, fat fraction); 
 
x 
For patients recruited in Paris: changes in NMRS indices in skeletal muscle will be explored 
through 31P NMRS indices and 23Na NMRS indices may also be included. 
 
 
 
3 STUDY DESIGN 
 


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3.1 
OVERALL DESIGN  
This is a pilot phase Ib,  open label, sequential-group study of ascending oral doses of rimeporide 
administered three-times daily (TID) for 28 days to patients with DMD. 
  
The study foresees a screening, a treatment and a follow-up period.  
 
There will be 4 dose levels. Patients with a body weight less than or equal to 30kg at baseline will be 
administered 50 or, 100, or 150 or 200-mg TID. Patients with a body weight more than 30kg at baseline 
will be administered 75 or 150 or 200 or 300-mg TID.  
 
Each subject will participate in only 1 dose cohort and will receive rimeporide for a total of 4 weeks. 5 
patients are expected to be recruited in each cohort through all participating sites. 
Safety assessments will be made in the clinic at baseline, and after one, two and four weeks of treatment 
as well as 1-2 weeks following the end of treatment period or withdrawal of the study medication. 
After the screening visit and if eligibility criteria are confirmed, patients will return to hospital for 4 
study visits during the 4 week treatment period. The first 2 doses of study treatment will be taken in the 
clinic as well as the last dose 28 days later. In between, 2 safety visits at hospital are scheduled at weekly 
intervals during the 2 first weeks of study treatment. A phone call is also planned 3 weeks after the first 
dose to discuss the clinical condition of the patient, and note any possible adverse events reported by 
the patient or his parents.  
Safety assessments will also be made in the clinic 1- 2 weeks following the end of treatment period or 
after any premature withdrawal of the study medication. The details of examinations and tests that must 
be performed at study visits are provided in table 1 “Schedule of Assessments” and also in the 
subsequent sections of this protocol. 
The decision to progress to the next higher dose will be made after safety and tolerability data are 
reviewed for the preceding dose for 5 patients by a data Safety Monitoring Committee and determined 
that it is safe to proceed to the next dose level. 


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3.2 
RECRUITMENT PLAN 
The recruitment of patients will be competitive over the 4 participating sites. 
For safety reason, Patients must be recruited in order to avoid first study treatment administration on 
the same day. For each cohort, the first 3 patients must receive rimeporide at with an interval of at 
least 1 week.   If no safety issue is raised for the first 3 patients, then patients 4 and 5 can receive their 
first study treatment administration without a minimum time interval.   
 
3.3 
SCREENING PERIOD 
Screening will be carried out within 4 week prior to first administration of rimeporide (SD1) to enable 
confirmation of patient eligibility and following the signature of the Informed Consent Form. 
For each patient screened, an anonymized eligibility form must be sent by email to the Sponsor 
representative and medical advisor following the screening visit. This eligibility form summarizes the 
eligibility criteria, the concomitant medications, and the medical history. This form will be reviewed by 
the medical advisor to approve inclusion of each patient based on the screening data and to prevent 
protocol violations. 
 
3.4 
TREATMENT PERIOD 
Rimeporide will be taken for 4 weeks, three times a day, after meals starting on Study Day 1 (SD1) and 
finishing on week 4 (28 days totally). After screening visit and if eligibility criteria are confirmed 
patients will return to hospital for 4 study visits during the 4 week treatment period. The first 2 doses 
of study treatment will be taken at hospital as well as the last dose 28 days later. In between, 2 safety 


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visits at hospital are scheduled each week during the 2 first weeks of study treatment. A phone call is 
also planned 3 week after the first dose to discuss the clinical conditions of the patient, and note any 
possible adverse event reported by the patient or his parents. The details of examinations and tests that 
must be performed at study visits are provided in table 1 “Schedule of Assessments” and also in the 
subsequent sections of this protocol.  
 
3.5 
FOLLOW-UP PERIOD AND END OF STUDY VISIT 
All patients who have received at least one dose of rimeporide will be monitored for 1-2 weeks after 
the last administration of rimeporide, independently of the duration of treatment with rimeporide. A 1-
2 weeks follow-up period is justified by rimeporide half-life (approximately 4h to 7h, with greater than 
99% elimination of rimeporide being expected to occur within  seven half-lives , i.e.: 28h to 49h). The 
details of examinations and tests that must be performed at the end of study visit are provided in table 
1 “Schedule of Assessments” and also in the subsequent sections of this protocol. 
 
 
4 TARGET POPULATION 
 
4.1 
ELIGIBILITY CRITERIA 
Patients included in the study must be compliant with the following inclusion/exclusion criteria: 
 
 
4.1.1  Inclusion Criteria 
I.1. Duchenne muscular dystrophy genetically confirmed; 
I.2. Males between 6 and 14 years old; 
I.3. Able to walk independently at least 75 meters; 
I.4. Patients on a stable dose of corticosteroids at least 6 months prior to baseline; 
I.5. Patients able to swallow capsules size 4 according to the parents and investigator opinion; 
I.6. Willing and able to comply with all protocol requirements and procedures; 
I.7. Signed informed consents by the parent(s)/legal guardian(s); 
I.8. France only: Affiliated to or a beneficiary of a social security system 
 
4.1.2 Exclusion Criteria 
 
E.1. Patients with significant renal disease or impairment, with Glomerular Filtration Rate 
estimated using plasma cystatin C level using the Filler formula less than 90ml/min/1.73m2  
E.2. Current or history of liver disease or impairment, 


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E.3. History of any significant medical disorder which may confound the interpretation of either 
efficacy or safety data e.g. inflammatory, coagulation disease, unstable cardiac or respiratory 
disease; 
E.4. Acute illness within 4 weeks of the first administration of study medication which may 
interfere with study assessments; 
E.5. Significant change of dosage and/or dosing regimens for corticosteroids planned for the 
duration of study medication; 
E.6. Use of beta blockers / and ACEI or ARB unless at stable dose for at least 3 months prior to 
baseline; 
E.7. Use of Proton Pump Inhibitors unless at a stable dose for at least 3 months prior to baseline 
E.8. Use of aldosterone antagonists (i.e. spironolactone, eplerenone) within 3 months prior to first 
administration of study medication; 
E.9. Use of anticoagulants, antithrombotics or antiplatelet agents, 
E.10. Use of antibiotics with predominant renal secretion (e.g., cephalosporins), 
immunosuppressive agents exception corticosteroids, continuous treatment with non-steroidal, anti-
inflammatory drugs (NSAIDs), or lithium; 
E.11. Previous treatment with idebenone or other forms of Coenzyme Q10 within 1 month of the 
first administration of study medication; 
E.12. Previous treatment with investigational drugs within 4 weeks (or 7 half-life if longer than 4 
weeks) of the first administration of study medication including placebo; 
E.13. A baseline QTc>450msec, or history of risk factors for torsades de pointes (eg, heart failure, 
hypokalaemia, family history of long QT syndrome); 
E.14. LVEF≤ 45% at screening or within the past 6 months and/or history of acute heart failure; 
E.15. Ventilator dependent; 
E.16. Known individual hypersensitivity to any of the ingredients/excipients of the study 
medication; 
E.17. Patients with specific contraindication to MRI (e.g.: metallic foreign body, claustrophobia, 
etc.). 
 
5 DESCRIPTION OF IMP 
Rimeporide (EMD 87 580), a benzoyl-guanidine derivative is a Na+/H+ exchange inhibitor for oral 
use. The full chemical name of EMD 87 580 is: N-(4,5-Bis methanesulfonyl-2-methyl-
benzoyl)guanidine hydrochloride monohydrate 
Rimeporide hard gelatine capsules at manufactured by GLATT and is supplied to study sites by PHAST. 
The nominal composition of the rimeporide is hard gelatin capsules. The capsules are immediate release 
formulations. The capsules contain mannitol, hydroxypropyl methylcellulose, low-substituted 


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hydroxypropyl cellulose, and magnesium stearate as excipients. These excipients are regarded as safe 
and conform to current pharmacopoeias. 
 
5.1 
IMP HANDLING 
 
5.1.1  Packaging and Labelling 
Rimeporide will be supplied to the sites in hard gel capsules in bottles of 50 capsules each. Doses will 
be supplied as 25mg or 50mg per capsules. The drug will be appropriately labeled in the local language 
and adapted to the national requirements. 
 
5.1.2  IMP Supply 
As the study is not blinded, rimeporide study medications will be supplied to the study sites as open-
label supplies. 
 
5.1.3  IMP Receipt and Storage 
Rimeporide bottles will be transported with temperature deviation alarms, in order to ensure consistent 
temperatures during shipment. When the study drug is received at the site, the Pharmacist or designee 
will check for accurate delivery and absence of temperature deviation alarms. Storage is recommended 
at a room temperature not exceeding 25° C.  All bottles must be stored in a secure locked location in a 
temperature-controlled room. Any deviations from the recommended storage conditions should be 
immediately reported to the Sponsor. Affected bottles should not be used and should be quarantined 
until the Sponsor has authorised their use. Pharmacist or its designee must check the conformity of the 
shipment with the QP release documentation sent with rimeporide bottles. Any discrepancies raised 
must be notified immediately to the sponsor. Bottles must be quarantined until Sponsor authorization. 
 
 
5.1.4  IMP Preparation, Administration, Accountability and Destruction 
 
5.1.4.1 Preparation  
Investigation drug is provided as hard gel 25 mg or 50 mg capsules ready to be swallowed. No 
preparation is required. 
 
5.1.4.2 Administration 
Multiple oral doses of rimeporide ranging from 50 to 300 mg administered three times a day will be 
evaluated in patients with Duchenne as shown in the table below:.   
 


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Cohorts 
Cohort 1 
Cohort 2  
Cohort 3 
Cohort 4 
Weight at 
baseline 
≤ 30 kg  > 30 kg  
≤ 30 kg  
> 30 kg  
≤ 30 kg  
> 30 kg  
≤ 30 kg  
> 30 kg  
Total dose 
(per Day) 
150mg  
225 mg  
300mg 
450 mg 
450 mg 
600 mg 
600 mg 
900 mg 
# 25 mg 
capsules  
2 caps. 
TID 
(6 
per 
days) 
3 caps. 
TID 
(9 
per 
days) 
 
 
 
 
 
 
# 50 mg 
capsules 
 
 
2 caps. 
TID 
(6 
per 
day) 
3 caps. 
TID 
(9 
per 
day) 
3 caps. 
TID 
(9 
per 
day) 
4 
caps. 
TID 
(12 
per 
day) 
4 caps. 
TID 
(12 per 
day) 
6 
caps. 
TID 
(18 
per 
day) 
# 
bottles 
per patient 
(+ overage) 
5 bottles 
of 
50 
capsules 
(25 mg) 
7 bottles 
of 
50 
capsules 
(25 mg) 
5 bottles 
of 
50 
capsules 
(50 mg) 
7 bottles 
of 
50 
capsules 
(50 mg) 
7 bottles 
of 
50 
capsules 
(50 mg) 
9 bottles 
of 
50 
capsules 
(50 mg) 
9 bottles 
of 
50 
capsules 
(50 mg) 
13bottles 
of 
50 
capsules 
(50 mg) 
Table 2: Number of rimeporide capsules of 25mg or 50mg to be administered per dose and per day  
 
Each patient enrolled in the study will receive test drug under fed conditions three times a day.  
At each study visit, patient will take his study treatment at hospital (the morning dose and lunch dose 
at SD1 but only the morning dose SD28). A standard meal will be taken within 30 minutes before drug 
administration for the purpose of evaluation PK profile during study visit 1 and 28 since food intake 
could impact the time at which the maximum serum concentration is achieved after that the drug has 
been administered (tmax/Cmax) but has no influence on total drug exposure over time (AUC). The 
examinations and test timpoints proposed in this study are based on an expected tmax of about 1.5 hours 
following a standard meal. 
There is no specific recommendation for food and fluid during the treatment period. Outside study visits 
at hospital patients can take their study treatment at their convenience after a meal. The drug product 
can be administered with any kind of fluid. Ideal time points are:  
- 
Morning administration between 7:00 and 8:00 am (after breakfast); 
- 
Afternoon administration between 12:00 and 1:00 pm (after lunch); 
- 
Evening administration between 7:00 to 8:00 pm (after dinner). 
However these time points could be adapted according to the local/ patient habits. 
 


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Capsules must be swallowed as a whole and not in combination with other medications. Capsules are 
sealed and could not be opened. At the first administration of the study treatment, if the patient does not 
succeed to swallow the capsules (e.g. vomiting, etc.), the dose must not be given again and patient must 
wait until the second dose administration. If the patient still cannot swallow the capsules, the patients 
will be withdrawn from the study.  
 
5.1.4.3 Drug Dispensing  
 
 
At study day 1, each patient will receive all capsules needed for the first 7 days + 2 days overage 
of treatment. 
The local pharmacy may, if required for logistical reasons, deliver to the investigator to provide to the 
patient the study treatment medication needed to cover 1 week (+/-2 days) of treatment period the day 
before the Study Day 1 (SD1) if the patient eligibility is confirmed. 
For this purpose, before any prescription, a physical examination including vital signs and a 12 lead 
ECG must be performed by the investigator the day before the study Day 1 (SD1). A careful review of 
the AEs experienced by the patient and the potential concomitant medication changes occurred during 
the screening period must be reviewed by the investigator.  
If the eligibility is confirmed, the Pharmacist is authorised to deliver the study medication to the 
investigator. Bottles will be kept then within the clinical unit in a secured place which meet the IMP 
storage conditions, the protocol and the ICH/GCP requirements until the morning of the day after (SD1).  
 
At each subsequent study visit a new prescription will be made by the investigator and the local 
pharmacy will deliver the IMP needed to the investigator to provide to the patient as following: 
x At Study day 7, each patient will receive all capsules needed for the next 7 days + 2 days overage 
of treatment; 
x At study day 14, patients will receive all capsules needed for a further 16 days of treatment (14 
days plus 2 days overage). 
 
5.1.4.4 Accountability 
When the study drug is received at the site, the Investigator or Pharmacist (or appropriate designee) 
should acknowledge its receipt by signing (or initialling) and dating the documentation. Documentation 
should be returned to Sponsor (or its designee) and a copy retained in the Investigator’s file. The 
dispensing of the study drug shall be carefully recorded on Drug Accountability Forms and an accurate 
accounting must be available for verification by the Monitor at each pharmacy monitoring visit. 


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Drug Accountability forms must be completed by pharmacist (or its designee) for each patient. 
Dispensing and return of unused drug (number of capsules) should be detailed on these forms. 
Drug accountability records shall include: 
x 
Confirmation of the study drug’s delivery to the study site; 
x 
The inventory at the study site; 
x 
The use of study drug by each patient;  
x 
The return to the Sponsor or alternative disposition of unused products. 
 
The records should include dates, quantities, expiration dates, if applicable, and batch number and 
patient number. Unused study drug must not be discarded or used for any purpose other than the present 
study. Study drug that has been dispensed to a patient and returned unused must not be re-dispensed to 
a different patient.  
 
 
5.1.4.5 
Destruction, Return and Disposal  
Pharmacy monitoring visit must be performed before any drug return request from site.  Drug 
Accountability Forms will be verified before any arrangements for study drug return and authorisation 
of destruction.  No destruction on site is planned.  Any unused IMP should be returned to PHAST for 
destruction. A certificate of destruction will be send to site once performed.  
 
5.2 
PATIENT BACKGROUND TREATMENT AND CARE 
 
5.2.1 Background Therapy with corticosteroids 
Rimeporide will be administered on a background of stable doses (for the last six months) of 
corticosteroids. Since medical management of DMD with corticosteroids tends to be individualized, 
there is not a recommended dose as background therapy in this study.  
 
5.2.2 Prophylactic treatment  
No specific prophylaxis is required in DMD patients. 
 
5.3 
CONCOMITANT THERAPY 
 
5.3.1  Possible concomitant therapies 
x 
Analgesic treatment, antibiotics, ACE inhibitors, ARB, beta-blockers and general supportive care 
(e.g. gastro-protective agents excluding Proton-Pump Inhibitors [PPIs] unless at stable dose for at 
least 3 months prior to baseline) are permitted within the study.  


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x 
Use of any additional prescription drugs or over-the-counter medication (including herbal and 
homeopathic preparations), with the exception of multi-vitamins, requires approval from the 
Investigator except in an emergency. 
 
5.3.2  Prohibited therapies  
x 
Use of aldosterone antagonists (i.e. spironolactone, eplerenone) within 3 months prior to first study 
medication administration and during treatment period. 
x 
Use of anticoagulants, antithrombotics or antiplatelet agents,  treatment with idebenone or other 
forms of Coenzyme Q10 within 1 month before the first administration of study medication and 
during treatment period.  
x 
Previous treatment with other investigational drugs including placebo within 4 weeks (or seven 
half-lives) of the first administration of study medication and during treatment period. During 
treatment with rimeporide, no concomitant use of any other investigational drug is allowed. 
x 
Proton Pump Inhibitors within 7 days of the first administration of study medication and during the 
treatment period unless at stable dose for at least 3 months prior to baseline to avoid confounding 
effects which might occur due to these agents on serum gastrin levels. 
x 
Use of antibiotics with predominant renal secretion (e.g., cephalosporins), immunosuppressive 
agents exception corticosteroids, continuous treatment with non-steroidal, anti-inflammatory drugs 
(NSAIDs), or lithium. 
 
5.4 
CONTRACEPTION GUIDANCE 
Contraception guidance: due to the age range of this patient population, their clinical conditions, the 
short study treatment period and the short half-life of the drug (4 hours), no specific guidance to avoid 
pregnancy of a partner is provided. Moreover in animal male fertility studies no evidence of impairment 
has been shown. However is important to remind to investigators that pregnancy must be avoided during 
any clinical study. This should be reminded also to patients and their parents if applicable. 
 
5.5 
PHOTOSENSITIVITY GUIDANCE 
The UV spectrum of Rimeporide shows the longest wavelength absorption band at 282.5 nm. No 
absorbance is observed at higher wavelength. Consequently, and in accordance with the ICH guideline 
S10, since Rimeporide does not absorb light within the range of natural sunlight (290nm-700nm), 
treatment with Rimeporide is considered not to represent any photo safety risk or concern and therefore 
no special guidance for patients on this issue is required. 
 


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5.6 
PATIENT STUDY CARD 
In case of health problem, adverse events or symptoms, patients and parents will be asked to consult 
immediately the investigator to find out the most appropriate care that could be given to the patient. At 
Screening and before leaving the clinic, each patient (and/or patient’s legal representative) will be given 
a card to carry at all times in case of any visits to doctors or emergencies. The card gives details of the 
name of the drug, name of the responsible physician, and the address and telephone number of the study 
site. This card will be collected by the Investigator from the patient after the end of the study. 
Unless in case of emergency or the investigator has approved them beforehand, patients should not take 
new medicines during his study participation. This includes prescription drugs and over the counter 
medicine. 
5.7 
PATIENT DIARY 
At screening, each patient will receive a diary to record: 
 
The time of each dose taken; 
 
The number of pills swallowed at each dose; 
 
The time of the end of the last meal or collation taken before each dose; 
 
Any missing dose; 
 
Any new symptom or illness, unusual complaint: the event must be described concisely. All 
medication taken to treat symptom must be recorded as well as the onset date, the end date and 
the duration of the events; 
 
Any changes performed on the medications (dosing, frequency, stop date, interruption, etc.)  
 
Any and all new medicine (including the over the counter medication or is a natural or herbal 
remedies and homeopathic preparation, etc.); 
 
Any unplanned hospital admission. 
Precise instructions for diary completion should be given to patients and their parents or legal guardian 
at screening. Patients and parents will be asked to keep and bring any new prescription of concomitant 
medication to the investigator for review. The completed diary must be returned to the investigator and 
reviewed at each study visit at hospital. 
 
5.8 
RESCUE THERAPY 
No specific rescue therapy is foreseen for DMD. Patients who are withdrawn from the study due to a 
safety issue will be treated according to the standard of care at the site.  
 
6 STUDY ASSESSMENTS 
Safety and tolerability of multiple doses of rimeporide will be assessed as follows: 
 


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6.1 
ADVERSE EVENTS  
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. 
A patient diary will be given to each patient at Screening. Any health problems, side effect, unusual 
complaint or symptoms including any unplanned hospital admissions must be described in this diary 
that should be returned to investigator at each study visit on site. Weekly after the first rimeporide 
administration a phone call will be made to discuss the clinical conditions of the patient, and note any 
possible adverse event reported by the patient or his parents. 
On week 3, after the first rimeporide administration a phone call will be made to discuss the clinical 
conditions of the patient, and note any possible adverse event reported by the patient or his parents. 
Any adverse event experienced by patients should be recorded in the eCRF. At each study visit on site, 
investigator will also review any experienced adverse event. Clinical significance, causality and severity 
of any experienced adverse event should be evaluated by the investigator according to patient health 
status. 
Any enrolled subjects withdrawn for safety issue from the trial must be reported and explained on the 
eCRF. 
 
6.2 
PHYSICAL AND NEUROLOGICAL EXAMINATION 
Weight will be recorded in kg and height in cm. 
Physical examination will include assessment of the head, eyes, ears, nose, throat, heart, chest, lungs, 
abdomen, extremities, peripheral pulses, skin and any other physical conditions of note.  
The neurological examination will include examination of the cranial nerves, upper and lower 
extremities for muscle strength, reflexes, sensation and cerebellar function. 
  
6.3 
SUPINE AND STANDING BLOOD PRESSURE 
Blood pressure will be measured in the supine and standing positions at each study visit.  
The supine blood pressure should be measured first and should be measured after the subject has been 
lying down for 5 minutes. The subject should then be asked to stand and the standing blood pressure 
should be measured after the subject has been standing for 2 minutes.  
For each position, systolic and diastolic blood pressures will be measured with a standardized 
manometer; alternative validated methods of measurement may also be used. The point of 
disappearance of Korotkoff sounds (phase V) will be recorded as the diastolic blood pressure where a 
sphygmomanometer is used. 
The same arm should not be used for blood collection and blood pressure assessments if possible. If 
there is a clinically important change in blood pressure from the previous reading, measurements will 
be repeated immediately to confirm the change. 
 


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6.4 
HEART RATE AND RESPIRATORY RATE  
Heart rate will be determined over 60 seconds following the recording of blood pressure in the 
corresponding position (supine and standing). Respiratory rate will be measured at rest by observation. 
 
6.5 
MONITORING OF ECG EVOLUTION PARAMETERS (INCLUDING QTC) 
Heart function will be monitored by using a 12- lead ECG.  ECG equipment should be recently serviced 
and calibrated. Machine calibration records and performance data should be maintained on file. ECG 
parameters will be obtained from replicate ECG measurements (the average of the parameters from 3 
consecutive ECGs readings 5 minutes apart) to increase the precision of the potential changes in QTc. 
Care will be taken to perform ECG recording within one hour before first rimeporide dose intake and 
1.5 hours after the first and the second dose. ECG must be read by a local cardiologist as ongoing basis. 
The following parameters must be recorded: Heart Rate, PR Interval, QRS Duration, QT Interval, QTcB 
Interval, QTcF, and QRS Axis.  
ECGs will be read centrally at the end of the study. 
 
6.6 
SPIROMETRY: PULMONARY FUNCTION TESTS 
The forced vital capacity (FVC), which is the volume delivered during an expiration made as forcefully 
and completely as possible starting from full inspiration, and the forced expiratory volume (FEV-1) in 
one second, which is the volume delivered in the first second of an FVC manoeuvre will be measured 
by a recently serviced and calibrated spirometer. 
 
6.7 
6-MINUTE WALK TEST 
The 6-minute walk test (6MWT) has been the most commonly used primary outcome measure in 
clinical development programs at the time this guidance is being written.  Current thinking is that in 
DMD, the 6-minute walk distance (6MWD) is a global / integrated measure of multiple systems 
involved in walking. In this study the 6MWT will be used only as screening test to evaluate the ability 
of the patient to walk (study is only exploratory at this stage and no efficacy is tested). Indeed ability to 
walk at least 75 m is an inclusion criteria.  The test will be done according to a procedure detailed in a 
study specific manual. 
 
6.8 
ECHOCARDIOGRAPHY 
Left ventricular ejection fraction will be evaluated by a cardiologist using standard echocardiographic 
techniques at the local centre at screening. 
 


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6.9 
SAFETY HEMATOLOGY, BIOCHEMISTRY AND URINALYSIS 
All safety laboratory tests should be recorded in the eCRF from the local laboratory. Normal values of 
local laboratory should be provided to the Sponsor before any patient’s inclusion on site and recorded 
into the eCRF. Clinical significance of any observed abnormality should be assessed by the investigator. 
Rules for AE reporting are described in adverse event section. 
Blood and urinary samples for safety hematology, biochemistry and urinalysis will be analysed on site 
at each study visit as following: 
Haematology will include:  
x 
red blood cell count 
x 
hemoglobin 
x 
hematocrit 
x 
red cell indices 
x 
white blood cell count, including differential 
x 
platelet count 
x 
PT – visits 1 and 5 only 
x 
aPTT  - visits 1 and 5 only 
 
Biochemistry will include: 
x 
sodium, potassium, chloride, bicarbonate, calcium, inorganic phosphate 
x 
urea 
x 
creatinine 
x 
cystatin C 
x 
glucose 
x 
total bilirubin 
x 
total protein 
x 
albumin 
x 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase 
x 
gamma GT 
x 
creatine kinase (CK)  
x 
cholesterol, triglycerides 
x 
Uric acid.  
x 
Only at Screening and SD28: C- reactive protein 
x 
Only at SD1 and SD28: Gastrin (after 10 hours of fasting: no food or drink except for 
water)  
 


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  Urine Analysis will include: 
Dipstick 
x 
pH 
x 
protein 
x 
glucose 
x 
ketones 
x 
blood   
Microscopy 
x 
red cells 
x 
white cells  
x 
casts 
x 
crystals 
 
6.10 PHARMACOKINETIC ENDPOINTS 
 
6.10.1 Optimal number of samples 
The sampling schedule should be optimized for maximizing the chance to detect a difference between 
the population PK model predictions and the observations in the 20 patients to be enrolled. This 
optimality criterion is different from the usual D-optimality criterion, which maximizes the precision 
of parameter estimates. Hence, D-optimality is not relevant in this context. To the best of our 
knowledge, no optimality criterion has been proposed in our context. Therefore, we derive the sampling 
times by using a geometric sequence. This is reasonable, because the concentration versus time profile 
is described by a sum of exponential terms. 
To evaluate the population PK model, we wish at day 1: one point in the absorption phase, one point 
near the Cmax, and two points in the biphasic decay, i.e. four points at day 1. At week 4, we need only 
to verify the lack of time dependency of rimeporide PK. Two points are needed. Given that 20 patients 
will be enrolled, the amount of data for validation of the population PK model will be 20 x 6 = 120 
points. 
6.10.2 Sampling times 
At day 1, for half of the patients, samples will be taken before first dose of rimeporide, and in the 
following time frames: (0.5 – 1h), (1 – 2h), (2.5 – 3.5h), 6h after the first dose.  
For the other half of the patients, samples will be taken before first dose of rimeporide and in the 
following time frames: (0.5 – 1h), (1 – 2h), (2.5 – 3.5h), 6h after the second dose. In this way, samples 
will be taken up to 12h after the first dose, corresponding to approximately 3 half-lives.  
The sampling time points will be allocated to patients according to their inclusion order into the study.   
At week 4, samples will be taken in the following time frames: (0.5 – 1h), 6h after the last dose. 
6.10.3 Blood samples collection, handling and storage 
For the analysis of rimeporide, 1 to 1.5 ml blood samples should be taken by an indwelling catheter to 
avoid multiple needle punctures. Pain should be minimized by using indwelling catheters introduced 
under topical anaesthesia since repeated blood sampling is necessary. An anaesthetising patch should 
be proposed before the blood sample is taken to limit the pain associated with the introduction of the 
needle.  


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Each sample will be collected into a heparin- containing tube. Samples will be immediately be cooled 
at 0°C and centrifuged within 30 minutes at 4°C at 1500g for 10 minutes. Plasma will be separated into 
2 equal aliquots of 200µl, rapidly transferred to a polypropylene tube, stoppered and stored at -20°C in 
a secured place until shipment to the central laboratory which carry out of the rimeporide plasma level 
determination. Each tube will be labelled with the following information: study acronym, protocol 
number, patient number, site number, study day, time point, date and time of the collection. 
All plasma samples will be shipped by an authorized carrier after completion of each study cohort to 
the central laboratory in charge of the rimeporide plasma level determination according to the standard 
procedures provided by the sponsor in the laboratory manual. The samples will be transferred in a 
container filled with enough dry ice to ensure that the samples are kept frozen. Temperature will be 
controlled over the shipment. Plasma level of rimeporide will be valuated using a validated HPLC-
MS/MS technique. 
6.10.4 Pharmacokinetic analysis 
Given that 20 patients will be enrolled, the amount of data for PK analysis will be 20 x 6= 120 points. 
These data will be analysed using a population approach also called non-linear mixed effects modelling. 
Due to the sparse sampling strategy, data originating from other clinical studies (e.g. Phase I studies in 
adult healthy volunteers), could be used in order to build a population pharmacokinetic model. All 
details regarding the PK analysis will be described in a separate document. 
 
 
6.11 PHARMACODYNAMIC ENDPOINTS 
 
6.10.1 Rationale 
In DMD patients a persistent inflammatory response in their skeletal muscles leads to an altered 
extracellular environment, including an increased presence of inflammatory cells (e.g., macrophages) 
and elevated levels of various inflammatory cytokines and growth factors. Unfortunately, the signals 
that lead to successful muscle repair in healthy muscle may promote muscle wasting and fibrosis in 
dystrophic muscle30 (Gosselin 2004). Finally to evaluate the level of inflammation measurements of 
CRP, TNF-α and TGFβ will be made. 
CRP is a positive acute phase protein produced by the liver in response to stimulation by interleukin 
(IL)-6, it represents a non-specific inflammatory biomarker of inflammation, widely measured in many 
different acute and chronic inflammation conditions. This protein will be monitored as exploratory 
marker even if with the available data the use of corticosteroids may already have normalized the value. 
TNF-α has been identified as another potentially useful marker as it is an early and potent pro-
inflammatory cytokine that stimulates the inflammatory response; TNF-α increases rapidly within 
damaged myofibers and is expressed by myoblasts and myotubes. It was reported that the mean serum 


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TNF-α concentration in Duchenne muscular dystrophy patients was approximately 1,000 times higher 
than that in healthy subjects.31 (Abdel-Salam et al., 2011). 
For assessment of a potential pharmacological effect in DMD, exploratory biomarkers, creatine kinase 
(CK) total, creatine kinase-MM fraction, mostly located in the skeletal muscle, and titin fragments have 
been selected to be monitored in the proposed clinical study. Those markers have been already used as 
markers for DMD of cardiac injury. 
CK total and CK isoenzymes (that includes the MB fraction, mostly located in the myocardium, and 
the MM fraction, mostly located in the skeletal muscle) will be tested. CK-isoenzymes (namely CK-
MM) is commonly used as a blood-based biomarker for muscular dystrophy to evaluate the level of 
muscle damage and necrosis. Measurement of CK concentration is performed routinely in hospital 
laboratories (Raman 2015). 
Given that the intent of the proposed phase Ib study is exploratory for all the above listed biomarkers 
intra patients analysis will be performed when evaluating these potential markers. Blood samples will 
be also collected for further investigation and namely to evaluate other cytokines involved in the 
inflammatory processes and to target other RNA coding for key proteins in DMD. 
 
6.11.1 Blood samples collection, handling and storage 
 
For Creatine Kinase total and isoenzymes, Tumor necrosis factor alfa (TNFα), transforming 
growth factor beta (TGFβ-1) and other exploratory biomarkers to monitor muscle damages: 
Creatine Kinase total and isoenzymes, Tumor necrosis factor alfa (TNFα), Transforming growth factor 
beta (TGFβ-1) measured from blood in the central laboratory Eurofins in the Netherlands. Blood 
samples for other exploratory biomarkers will be shipped to Eurofins for storage until anlysis.  
Blood samples collection should be performed at screening and at SD28 after the last dose of 
rimeporide. Blood collection, on site preparation, handling and storage condition are described in the 
laboratory manual. 
Plasma / Serum aliquots should must be stored on site in secured and controlled freezer until shipment 
for analysis. An alarm system and a samples rescue procedures must be available on site in case of 
excursion temperature. 
All samples will must be shipped by an authorized carrier after completion of each study cohort to 
Eurofins central laboratory in the Netherland (Eurofins Central Laboratory, Bergschot 71 Bergschot 71, 
4817 PA Breda, The Netherlands). The samples will be transferred in a container filled with enough 
dry ice to ensure that the samples are kept frozen. Temperature will be controlled over the shipment. 
Collection kits, shipment material and documentation (including dry ice) and a laboratory manual will 
be provided by the Sponsor before any patient inclusion in the study. 


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6.12 BLOOD SAMPLE VOLUMES 
Biological samples collection have been defined in accordance with E6 & E11 ICH guidelines 
respectively related to Good Clinical Practice and clinical investigation of medicine products in the 
paediatrics population, EU directives 2001/83/EC, 2001/20/EC and GCP 2005/28/EC and CT 
2001/20/EC. All activities will be fully in line with the respective national guidelines as well with the 
EU directives and guidelines listed above.  
In particular blood will be withdrawn primarily to guide the safety review. Standard parameters 
(hematology, biochemistry) will be measured in each patient and urine will be tested routinely. The 
amount of blood that will be withdrawn during the study has been kept to a minimum and does not 
exceed 3% of the total blood volume within 4 week period and does not exceed 1% of total blood volume 
within 24 hours. These volume limits are set according to WHO recommendation for sample volumes 
in child health research.  
Analysis done on blood samples will favour as much as possible the use of micro-sampling techniques. 
The volumes of blood to be drawn at each visit are about 56.5  ml over 8-10 weeks from screening to 
end of study visit (depending on your weight and medical condition). 
x 
11 ml of blood should be collected at screening visit (Vscr) 
x 
5 ml of blood should be collected at each of the following study visits, V2 (SD7), V3 (SD14), 
and V5 (EOS). 
x 
Respectively 14.5 ml and 16 ml of blood should be collected at each of the following study 
visits.V1 (SD1) and V4 (SD28). 
Additional samples may be required for safety reasons, if patient’s weight and health status allow the 
drawing of additional blood. 
All blood samples will be drawn by the investigators or clinical research nurse. Painful procedures will 
be minimised by using indwelling catheters introduced under topical anaesthesia since repeated blood 
sampling is necessary during each visit.   
All samples will be labelled with the subject’s unique study number only, ensuring anonymity. 
 
7 OUTLINE OF STUDY PROCEDURES 
Patients will be recruited from specialised study sites which are reference centres for DMD. 
Analysis done on blood samples will favour as much as possible the use of micro-sampling techniques.  
 
7.1 
SCREENING 
Patients and parents who agree to participate must sign the informed consent/assent form at the 
screening visit before any study procedures are performed. 


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Screening evaluations should be completed within 4 weeks prior to the first administration of study 
drug (SD1) as detailed below.  
 
The following information must be collected and the following procedures must be performed: 
For each patient screened, an anonymized eligibility form must be sent by email to the Sponsor 
representative and medical advisor following the screening visit. This eligibility form summarizes the 
eligibility criteria, the concomitant medications, and the medical history. This form will be reviewed by 
the medical advisor to approve inclusion of each patient based on the screening data and to prevent 
protocol violations. 
Consent 
Patient information: 
 
 Signature of  Informed Consent Form 
 Demographic and medical history 
 Medications at screening 
 Date of DMD diagnosis and  method used for diagnosis and results 
must be recorded  
 Treatment for DMD already received 
Clinical Assessment: 
 
 Vital signs: temperature (tympanic), respiratory rate,  blood 
pressure and  heart rate (supine and standing). 
 Physical and neurological examination, height (in cm) and weight 
(in kg)  
 12- Lead Electrocardiogram: QT, QTcF, QTcB, PR, QRS 
duration and axis, Heart Rate. 
 Pulmonary Function Tests by spirometry (FEV1, FVC) 
 Echocardiography (LVEF) 
 6-Minutes Walking Test  
 
Local Laboratory tests 
 
 
Exploratory parameters: 
 
Other procedures  
 
  
 Blood and urinary samples collection for safety hematology, 
biochemistry and urinalysis as described in section Safety 
hematology, biochemistry and urinalysis.  
 Blood samples for centralised analysis as described in the 
Pharmacodynamics Endpoints section.  
 Instruction for patient diary completion 
 Instruction for patient diary completion. 
 Instruction for patient study card use  
 Instruction in case of new symptoms and changes of concomitant 
medication  
 Schedule the next study visits and NMRI (NMRS if applicable) 
 


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If the eCRF is available at this time, the eligibility confirmation will be performed based on the data 
recorded into the eCRF instead of the eligibility form. All the screening data must be immediately 
entered into the eCRF after screening visit to allow the review by the Medical advisor and to confirm 
the patient’s eligibility before his study day 1 (at least 48 hours are required for the medical advisor 
review). 
 
7.2 
NMRI (NMRS IF APPLICABLE) BEFORE FIRST DOSE AT STUDY DAY 1  
Once Patient eligibility is confirmed, patients will undergo to Nuclear Magnetic Resonance Imaging 
(NMRI) (and Nuclear Magnetic Resonance Spectroscopy (NMRS) if applicable) to evaluate the 
skeletal/muscle structure at baseline. 
NMRI procedures are detailed in the investigator manual. Only NMRI acquisition will be performed on 
site (Both NMRI and NMRS acquisitions will be performed for patients recruited in Paris). Anonymized 
(only study ID, subject ID and visit) imaging data will be uploaded into a secured platform according 
to ICH/GCP requirements for a central analysis. 
7.3 
STUDY DAY 1 (FIRST DOSE OF RIMEPORIDE)  
 
7.3.1 Before rimeporide administration at Study Day 1 visit 
7.3.1.1 Confirmation of patient eligibility at Study day 1  
At study day 1 visit, the eligibility criteria including any AE, physical abnormalities, and changes in 
concomitant medications must be re-verified on day 1 by the investigator before confirming the eligibility 
of the patient and to administer the study drug (these tests, examinations and reviews must be repeated 
at SD1 even if they have been done the day before to prepare the IMP delivery. See section drug 
dispensing) 
If the eligibility is confirmed on day 1, the study drug will be administered and the PK sampling profile 
will be automatically attributed via the eCRF as soon as investigator has confirmed the eligibility into 
the online platform. 
If any eligibility criteria are no longer met on day 1 prior to intake of study medication, the patient will 
be considered as a screening failure and cannot continue to participate in the study. An End of Study visit 
will be performed instead. 
The Investigator should keep a log of the patients pre-screened and screened for the study and reasons 
for non-eligibility, if applicable. 
 


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7.3.1.1 Baseline assessments at Study day 1  
Patient should come at hospital under fasting condition (No food or fluid except water for 10 hours). A 
catheter will be placed and blood samples will be collected for local laboratory tests.  
 
The following baseline assessments are conducted on SD1, before rimeporide is administered:  
 
Clinical assessments: 
 
 Vital signs: temperature (tympanic), respiratory rate, blood pressure 
and heart rate (supine and standing). 
 Physical and neurological examination, including weight.  
 
Heart Function 
 12-lead ECG Electrocardiogram: QT, QTcF, QTcB, PR, QRS 
duration and axis, Heart Rate. 
 
Local Laboratory tests : 
 Blood and urinary samples collection for safety hematology, 
biochemistry and urinalysis as described in the Safety hematology, 
biochemistry and urinalysis section. 
 
Pharmacokinetics: 
 A pre dose blood sample should be collected any time before the 
first administration of the study drug as described in the 
Pharmacokinetics Endpoints section. 
 
Other procedures  
 Patient diary review (Safety and compliance) 
 AE and SAE review. 
 Concomitant medication review. 
 Study drug prescription and delivery 
 
 
7.3.2 First Rimeporide administration 
A standard breakfast will be taken within 30 minutes before the first drug administration with no 
restriction on the kind of food or fluid given. 
 
7.3.3 After first dose of rimeporide  
The following assessments are conducted after the first dose of rimeporide  
Clinical assessments: 
 
Temperature (tympanic), respiratory rate, blood pressure and heart 
rate (supine and standing) will be repeated at 1 hour, 2 hours and 
4 hours after the first administration of study medication.  
Heart Function 
 
12-lead ECG Electrocardiogram will be repeated 1.5 hours after 
the dose. 
Pharmacokinetics: 
 
Blood samples will be collected as described in the 
Pharmacokinetics Endpoints section. 
Procedures  
 
Continuous AE and SAE review. 


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7.3.4 Second rimeporide administration 
A standard lunch will be taken within 30 minutes before second drug administration with no particular 
restriction on the kind of food or fluid given.  
 
7.3.5 After the Second dose of rimeporide  
The following assessments are conducted after the second dose of rimeporide:  
Clinical assessments: 
 
Temperature (tympanic), respiratory rate, blood pressure and heart 
rate (supine and standing) will be repeated at 1 hour, 2 hours and 
4 and 6 hours after the second administration of study medication. 
 
A12-lead ECG will be recorded 1.5 hours after the dose.  
Pharmacokinetics: 
 
Blood 
samples 
will 
be 
collected 
as 
described 
in 
Pharmacokinetics Endpoints section. 
Procedures  
 
Continuous AE and SAE review 
 
Patients will be kept under observation for at least 6 hours after the second dose of study medication. 
Prior to leaving the study site at the end of the visit, the patient must be reviewed by the investigator or 
other study physician along with the clinical and safety assessments and ECGs. If there are no safety 
concerns, the patient may go home accompanied by his parents or guardian after this period. In the 
event of any safety concerns the patient will be asked to stay overnight on site and additional safety 
observations made as clinically indicated. 
Before leaving the hospital, the patient/parent or guardian will receive the instruction for the 
administration of rimeporide at home and a patient diary will be provided, which will help to track any 
deviation of compliance and to collect information about adverse events. Patients will also receive a 
“patient study card” that they should carry with them at all times during the treatment period. Study 
title, details of the study drug and phone number to call in case of emergency will be recorded in the 
card. A general practitioner letter will also be provided to be given to the patient’s family doctor for 
information about participation of his/ her patient to the study.  
 
7.4 
WEEK 1 (DAY 7 +/- 2 DAYS) 
At study day 7 +/- 2 days, patient will go back to the hospital for a safety visit.  
The following assessments are conducted:  


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Clinical assessments: 
 
 Vital signs: temperature (tympanic), heart and respiratory rate, blood 
pressure (supine and standing). 
 Physical and neurological examination including weight. 
Heart Function 
 12-lead ECG Electrocardiogram. 
Local Laboratory tests: 
 Blood and urinary samples collection for safety hematology, 
biochemistry and urinalysis as described in Safety hematology, 
biochemistry and urinalysis section. 
Other Procedures 
 Patient diary review (Safety and compliance) 
 AE and SAE review. 
 New concomitant medication or new medication changes review. 
 Study drug prescription and delivery 
 
7.5 
WEEK 2 (DAY 14 +/- 2 DAYS) 
At study day 14 (or week 2) patient will go back to the hospital safety visit.  
The following assessments are conducted:  
Clinical assessments: 
 
 Vital signs: temperature (tympanic), respiratory rate, blood pressure 
and heart rate (supine and standing). 
 Physical and neurological examination, including weight. 
Heart Function 
 12-lead Electrocardiogram. 
Local Laboratory tests: 
 Blood and urinary samples collection for safety hematology, 
biochemistry and urinalysis as described in Safety hematology, 
biochemistry and urinalysis section. 
Other Procedures 
 Patient diary review 
 AE and SAE review. 
 New concomitant medication or new medication changes review. 
 Drug accountability of returned study treatment. 
 Study drug prescription and delivery 
 
 
7.6 
WEEK 3 (DAY  21 +/- 2 DAYS) 
A phone call will be made to check that the drug has been properly taken, discuss the clinical conditions 
of the patient, and note any possible adverse event or new medication reported by the patient or his 
parents.  An unplanned visit may be scheduled if the patient needs to be assessed or treated for any 
clinical condition described during these phone calls or requires more examination in the opinion of the 
investigator (see unscheduled visit section). 
 


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7.7 
NMRI (NMRS IF APPLICABLE) AT DAY 27 (+/-2 DAYS) OF THE STUDY  
Just before the end of treatment, at Day 27 +/- 2 days of the treatment, patients who have agreed to 
this optional procedure will undergo a new local NMRI (and NMRS for patients recruited in Paris).  
NMRI procedures are detailed in the investigator manual. Only NMRI acquisition will be performed 
on site (Both NMRI and NMRS acquisitions will be performed on patients recruited in Paris). 
Anonymised (only study ID, subject ID and visit) imaging data will be uploaded into a secured platform 
according to ICH/GCP requirements for a central analysis. 
 
7.8 
WEEK 4 (DAY 28 +/- 2 DAYS) 
At study day 28 (or week 4) patient will go back to the hospital for the clinical and laboratory 
assessments and to return the unused study drug and the drug diary where drug assumption has been 
recorded.  
Patient should come at hospital under fasting condition (No food or fluid except water for 10 hours) for 
local laboratory tests. Immediately after blood sample collection, a moderate fat breakfast will be taken 
within 30 minutes before the last drug administration of the study with no restriction on the kind of food 
or fluid given.  
Then the following assessments will be performed: 
 
Clinical assessments: 
 
 
Vital signs: temperature (tympanic), respiratory rate, blood 
pressure and heart rate (supine and standing). 
 
Physical and neurological examination, including weight.  
Heart Function: 
 
12-lead ECG Electrocardiogram 1.5 hours after last 
rimeporide dose. 
Local Laboratory tests: 
 
Blood and urinary samples collection for safety hematology, 
biochemistry and urinalysis as described in Safety hematology, 
biochemistry and urinalysis section.  
Pharmacokinetics: 
 
Blood 
samples 
will 
be 
collected 
as 
described 
in 
Pharmacokinetics Endpoints section. Blood samples will be 
taken in the following time frames: (0.5 – 1h), 6h after the last dose 
of rimeporide. 
Pharmacodynamics/ 
Exploratory parameters 
 
Blood samples centralised analysis as described in 
Pharmacodynamics Endpoints section any time after last dose of 
rimeporide. 
Procedures  
 
Patient diary review 
 
AE and SAE review.New concomitant medication or new 
medication changes review. 


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 
Drug accountability of returned study treatment.  
6 hours after the last rimeporide administration, patient may go home with you unless the study doctor 
advises otherwise. 
 
7.9 
END OF THE STUDY VISIT (1-2 WEEKS +/- 2 DAYS POST LAST RIMEPORIDE 
DOSE) 
This will be last visit of the study and identified as end of study follow-up visit. Patient will undergo 
clinical and laboratory assessments and to return the unused study drug and the drug diary where drug 
assumption has been recorded.  
 
The following assessments will be performed: 
Clinical assessments: 
 
 Vital signs: temperature (tympanic), respiratory rate, blood pressure 
and heart rate (supine and standing). 
 Physical and neurological examination including weight.  
Heart Function:  
 12-lead ECG Electrocardiogram. 
Local Laboratory tests: 
 Blood and urinary samples collection for safety hematology, 
biochemistry and urinalysis as described in Safety hematology, 
biochemistry and urinalysis section. 
Procedures  
 Patient diary review. 
 AE and SAE review. 
 New concomitant medication or new medication changes review. 
 Drug accountability of returned study treatment. 
 
 
7.10  WITHDRAWAL VISIT (1-2 WEEKS +/- 2 DAYS AFTER DECISION) 
The same assessment procedures should also be followed by the Investigator for any patient who is 
withdrawn prematurely from the study within 1-2 weeks after the decision to withdraw is made. For 
any withdrawal from the study as a result of investigator’s decision, patient’s decision or the decision 
of their parent/guardian, patient will go back to the hospital for a last visit on site. Clinical and laboratory 
assessments will be performed and unused study drug, drug diary where drug assumption has been 
recorded must be returned. Investigator should ask them and patient’s parent / guardian any relevant 
information regarding their clinical conditions, note any possible adverse event or new medication to 
be reported. 
 


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Patient will undergo to the following clinical and laboratory assessments:  
 
Clinical assessments: 
 
 Vital signs: temperature (tympanic), respiratory rate, blood pressure 
and  heart rate (supine and standing) ; 
 Physical and neurological examination, including weight; 
Heart Function:   
 12-lead ECG Electrocardiogram. 
Local Laboratory tests: 
 Blood and urinary samples collection for safety hematology, 
biochemistry and urinalysis as described in Safety hematology, 
biochemistry and urinalysis section. 
Procedures  
 Patient diary review 
 AE and SAE review. 
 New concomitant medication or new medication changes review. 
 Drug accountability of returned study treatment. 
 
No other specific assessments are required unless needed to follow-up an ongoing AE/SAE. 
Patients who are withdrawn due to a serious adverse event (SAE) should be followed-up until the 
resolution of the event or until the outcome of the event is known and stable. Any withdrawal of enrolled 
subjects from the trial must be reported and explained on the eCRF. 
Patients and parents should be asked if they are willing to continue the study without study treatment. 
In this case, they should come back to the hospital for all subsequent study visits to be followed by the 
investigator and to perform the study tests and the examination as initially planned.  
Patients and parents / legal guardian who do not agree to continue study visits without study treatment 
must be asked whether they agree that all data collected so far could be used for the analysis.  
Also, they must be asked whether they agree that biological samples collected so far could be kept and 
stored in the secured place for further analysis. 
 
7.11 ASSESSMENTS IN CASE OF UNPLANNED (UNSCHEDULED) VISITS 
Unplanned visits may occur should the patient need to be assessed or treated for any clinical condition 
that arises during the study. This may include the evaluation and follow-up of AEs, SAEs or laboratory 
tests. The following assessments (as detailed in the Schedule of Assessments) should always be 
performed at minimum, but additional assessments may be added according to the clinical judgment of 
the Investigator. 
In case the patient is still on treatment period during the unscheduled visit the following assessments 
will be performed: 
 


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Clinical assessments: 
 
 Vital signs: temperature (tympanic), respiratory rate, blood pressure and 
heart rate (supine and standing).  
 Physical and neurological examination, including weight. 
Heart Function 
 12-lead ECG Electrocardiogram.  
Local laboratory tests: 
 Blood and urinary samples collection for safety hematology, biochemistry 
and urinalysis as described in Safety hematology, biochemistry and 
urinalysis section. 
Procedures  
 Patient Diary  
 AE and SAE review. 
 
New concomitant medication or new medication changes review. 
 Drug accountability of returned study treatment. 
 
 
8 SAFETY PROCEDURES 
The collection and reporting of Adverse Events (AEs) will be in accordance with EU Directive for 
Clinical Trials 2001/20/EC and the Detailed Guidance on the Collection, Verification and Presentation 
of Adverse Events/Reaction Reports Arising From Clinical Trials of Medicinal Products For Human 
Use (‘CT-3’).  
 
8.1 DEFINITION  
 
8.1.1  Adverse events 
Adverse events (AEs) are defined as any undesirable experience occurring to a subject during the study, 
whether or not considered related to the investigational product. All adverse events (AEs) reported 
spontaneously by the patients or his relatives or observed by the Investigator or his staff during the 
clinical study up to and including the end-of-study visit will be reported on the AE data collection form. 
It is the Investigator(s) responsibility to assess each AE. This may be delegated to other suitably 
qualified physicians in the research team who are trained in recording and reporting AEs. Each AE must 
be assessed for seriousness, causality and severity and expectedness. The Investigator should assess the 
seriousness and causality (relatedness) of all AEs experienced by the patient (this should be documented 
in the patient’s medical records - source data) with reference to the investigator brochure. 
All AEs will be captured in the appropriate eCRF section. All AEs occurring while a patient is 
participating in the study must be documented appropriately, regardless of causal relationship. All AEs 
will be followed to adequate resolution, whenever possible. 


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Any medical condition that is present at the time that the patient is screened will be considered as 
baseline and not reported as an AE. However, if it deteriorates at any time during or following 
administration of the first IMP infusion, it will be recorded as an AE. 
For all AEs, the following will be assessed and recorded in the eCRF: the onset, the end of the AE, the 
description of the AE, intensity, and relationship to Investigational Medicinal Product (IMP), action 
taken regarding IMP, any treatment received and outcome to date.  
 
The intensity of the AE: 
Intensity of adverse events will be graded on a three-point scale using the following definitions: 
x 
Mild: Discomfort noticed but no disruption of normal activity 
x 
Moderate: Discomfort sufficient to reduce or affect normal daily activity 
x 
Severe: Inability to work or perform normal daily activity. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event, at each level of intensity, to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The outcome of the AE: 
The outcome should be documented in the eCRF according to the following definition: 
x 
Recovered: AE disappeared 
x 
Not yet recovered: AE is still existing, or patient is recovering 
x 
Alive with sequelae: AE results in permanent disability / incapacity 
x 
Death: patient died 
x 
Unknown: only if patient was lost of the follow-up 
 
Causality to the IMP: 
The Investigator should make an assessment of whether the AE is likely to be related to the IMP 
according to the following definitions. 
x 
Unrelated: a relationship to the study medication can be definitely ruled out (reasonable 
explanation must be given  eg involved in traffic accident while in back seat of car)  
x 
Unlikely: a relationship to the study medication is considered unlikely: the time relationship to 
the administration of study medication  does not suggest a causal relationship and/or  the 
underlying disease, other concomitant illnesses or medications   appear more likely 
explanations  according to present knowledge; 
x 
Possibly related: there is a reasonable possibility that the adverse event may have been caused 
by the study medication: there is a reasonable time relationship to the administration of study 


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medication but  the nature of the event,  the underlying disease, and/or concomitant medication 
or concomitant illnesses  suggest that other explanations  are a significant possibility  
x 
Probably related: the study medication is considered to be the most likely cause of the adverse 
event:  there is a reasonable time relationship to the administration of the study medication and 
the event is considered unlikely to be or cannot be attributed to concurrent disease or 
concomitant medications.   
 
All AEs assessed as having a reasonable suspected causal relationship to the IMP (i.e. possibly, 
probably) will be considered as related to the IMP for regulatory reporting purposes. 
 
Seriousness: 
The Investigator should make an assessment of seriousness as defined below: 
 
8.1.2 Serious Adverse Events 
A serious adverse event (SAE) is any untoward medical occurrence that: 
x 
results in death (note: death is an outcome, not an event); 
x 
is life-threatening; (note: the term "life-threatening" refers to an event in which the patient 
was at immediate risk of death at the time of the event; it does not refer to an event which 
could hypothetically have caused a death had it been more severe); 
x 
requires in-patient hospitalization or prolongs an existing hospitalization; 
x 
results in persistent or significant disability/incapacity; 
x 
is a congenital anomaly/birth defect; 
x 
is medically significant or requires intervention to prevent one or other of the outcomes 
listed above (note: examples are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization).  
 
8.1.3 Abnormal Laboratory Test Values  
All safety laboratory tests (haematology and blood biochemistry), for each visit time-point, should be 
captured in the database from the local laboratory. Abnormalities should be coded as clinically 
significant or not clinically significant.  Clinically significant changes in laboratory values should also 
be reported as adverse events, however, if a laboratory abnormality leads to diagnosis of a new clinical 
event (e.g.: a high white blood cell count leads to a diagnosis of leukaemia) the clinical diagnosis should 
be reported on the AE form, not the laboratory abnormality leading to the diagnosis. 
 


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8.2 REPORTING PROCEDURES 
AE defined as serious which require reporting as an SAE should be reported to Sponsor or its delegate 
immediately. The term severe is a measure of intensity/severity: thus a severe adverse event is not 
necessarily serious. For example, nausea of several hours’ duration may be rated as severe, but may not 
be clinically serious. 
For the purpose of this study, the following will not be considered as serious adverse events: 
x 
Elective hospitalizations or surgical procedures that are a result of a patient’s pre-existing 
condition(s) which have not worsened since receiving IMP. Such events should still be 
recorded as adverse events in the eCRF 
x 
Any serious clinical adverse event or clinically significant abnormal laboratory test value 
that occurs during the course of the study, must be communicated by the Investigator to the 
Sponsor or its delegate, by fax or electronic transmission, within 24 hours of awareness. 
 
On becoming aware that a patient has experienced an SAE, the investigator (or delegate) must complete, 
the study specific SAE, report form with all available case details concerning the patient, and the event, 
date and sign the  SAE report form . The SAE report form should be faxed to pharmacovigilance 
responsible person for the trial, using one of the number listed below and no later than 24 hours after 
first becoming aware of the event: 
 
 
Contact information for SAE reporting: Jennie Moore 
Phone number: + 44 (0) 1963 350862 
Fax: + 44 1908 251 499 
E-mail: jmoore@qed-clinical.com 
 
Original and copies of SAE forms, and all related safety documentation and correspondence must be 
filed in the ISF. 
For SAE report form completed by someone other than the investigator, the investigator will be 
requested to countersign the original SAE form to confirm the causality and the severity assessments. 
The SAE report form should be returned to pharmacovigilance responsible person for the trial and a 
copy filed in the ISF. 
Investigators should also report SAEs within their own institution in accordance with local practice. 
 
8.2.1  Suspected Unexpected Serious Adverse Reactions Reporting 
On receipt of an SAE Form, seriousness and causality will be determined independently by the Medical 
Monitor of the study. An SAE judged by the investigator and/or Medical Monitor to have a causal 


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relationship (possible or probable) with the trial medication will be regarded as a Serious Adverse 
Reaction (SAR). 
The Medical Monitor will assess all SARs for expectedness according to the reference document as 
defined in the current version of the investigator's brochure. If the event meets the definition of a 
Suspected Unexpected Serious Adverse Reaction (SUSAR); that is unexpected (i.e. not defined in the 
current version of the IB), related to study drug and serious, it will be classified as a SUSAR. 
Unexpected adverse reactions are all untoward and unintended responses to an investigational product 
related to any dose administered. 
These reactions are SUSARs if the following three conditions are met: 
1. the event must be serious; 
2. there must be a certain degree of probability that the event is a harmful and an undesirable 
reaction to the medicinal product under investigation, regardless of the administered dose; 
3. unexpected against the current version of the Investigator Brochure. 
 
Fatal or life-threatening SUSARs 
All competent authorities and the Ethics Committees of participating countries will be notified as soon 
as possible in writing (CEC) / electronically (CA) but no later than 7 calendar days after the sponsor or 
delegate has first knowledge of the minimum criteria for expedited reporting. In each case relevant 
follow-up information should be sought and a report completed as soon as possible. It will be 
communicated to the competent authorities and the Ethics Committees within an additional eight 
calendar days.  
 
Non fatal and non life-threatening SUSARs 
All other SUSARs and safety issues, must be reported to all the competent authorities and the Ethics 
Committees of participating countries as soon as possible but no later than 15 calendar days after the 
sponsor has first knowledge of the minimum criteria for expedited reporting. 
Sponsor or its delegate will report all SUSARs to the EMA's EudraVigilance database within 15 days, 
as well as to the relevant National Competent Authorities when required.  
In case of incomplete information at the time of initial reporting, all the appropriate information for an 
adequate analysis of causality should be actively sought from the reporter or other available sources. 
The sponsor will report further relevant information after receipt as follow- up reports. 
The sponsor shall inform all investigators concerned of relevant information about SUSARs that could 
adversely affect the safety of subjects. Details of all SUSARs and any other safety issue arises during 
the trial will be reported to Principal investigators. A copy of any such correspondence should be filed 
in the ISF. 
 


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8.2.2 Provision of follow-up information 
Patients should be followed up until resolution of the event.  
Follow up information should be provided on a new SAE form. Relevant follow-up information on 
SAEs should be forwarded to Sponsor or its delegate as soon as it becomes available. In addition, the 
Investigator must be available to answer without delay any request for follow-up information or 
questions Sponsor or its delegate may have regarding the SAE. 
Relationship to the study drug will be established by the Investigator in order to define the need for 
expedited reporting. 
 
8.2.3 Reporting period 
Details of all AEs and SAEs will be documented and reported from the date of commencement of 
protocol defined treatment until 15 days after the administration of the last treatment. 
 
8.2.4 Post study SAEs and SUSARs: 
SAEs that are judged to be at least possibly related to the IMP and unexpected must still be reported 
in an expedited manner irrespective of how long after IMP administration the reaction occurred. 
 
8.2.5 Development Safety Update Report (DSUR) 
In addition to the expedited reporting, sponsors will submit a Development Safety Update Report 
(DSUR) once a year throughout the clinical trial (from the date of the first clinical trial competent 
authority approval received for the trial to the submission to the end of the trial declaration) or on request 
a safety report to the competent authority and the Ethics Committee of the concerned participating 
countries, taking into account all new available safety information produced during  the reporting 
period. 
Sponsor or delegate will include details of all SAEs, SUSARs and adverse events reactions will be 
reported to competent authorities on request. 
 
8.3 
FOLLOW-UP OF SAFETY PARAMETERS 
 
8.3.1  Treatment and Follow-up of Adverse Events 
All Adverse events, should be followed-up until the event has returned to baseline status or has 
stabilised. If a clear explanation is established, it should be recorded on the CRF. 
All SAEs must be followed-up until the event has either resolved or reached a stable clinical outcome. 
 


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8.3.2  Follow-up of Abnormal Laboratory Test Values 
In the event of unexplained clinically relevant abnormal laboratory test values, the tests should be 
repeated immediately and followed-up until the values have returned to within normal range and/or an 
adequate explanation of the abnormality is found. If a clear explanation is established, it should be 
recorded on the eCRF. 
 
8.3.3  Pregnancy 
Considering the age of the study patients (up to 14 years) the usual concerns in clinical trials concerning 
pregnancy in partners are less prominent. However, in the unlikely event of pregnancy occurring in 
partners of male enrolled patients, it must be reported to Sponsor or its delegate within 24 hours of 
awareness. All information pertaining to the pregnancy should be reported using the Sponsor Pregnancy 
form. Pregnancies should be followed until conclusion to obtain outcome information and reported 
using a pregnancy follow up report. 
 
8.4 
SAFETY MONITORING COMMITTEE 
An independent Safety Monitoring Committee (SMC) composed of relevant Experts including 3 
physicians of which at least one is experienced in the management of patients with Duchenne Muscular 
Dystrophy, and a pharmacologist specialized in paediatrics will review safety data during the study. 
The procedures of the SMC will be documented in a separate charter. 
The safety monitoring committee will meet at least 4 monthly to review overall safety in the study as 
well as at the end of each cohort to recommend whether the dose can be escalated as planned.   
After each meeting a recommendation to continue the study without modification, continue with 
modifications or discontinue the study will be made. In addition the safety monitoring committee will 
review SAEs on an ongoing basis and will hold additional meetings as needed to discuss these and make 
corresponding recommendations. 
 
9 STOPPING RULES 
The subsequent sections are based on the following AE grading: 
x 
Grade 1: Mild intensity  
x 
Grade II: Moderate intensity: 
x 
Grade III: Severe intensity: 
 
9.1 
STOPPING OR SUSPENSION OF DOSING AT THE INDIVIDUAL PATIENT 
LEVEL  
Dosing will be suspended at the individual level until evaluation by the medical monitor:   


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x 
If a SAE considered related (possibly and probably) to study medication is observed; 
x 
In the case of adverse reactions of moderate intensity (grade II) persisting for more than 2 weeks 
or of severe intensity (grade III) until full evaluation by the SMC; 
x 
In the case of adverse reactions of shorter duration or lower intensity if the investigator 
considers this clinically indicated; 
Each such case will be evaluated by the medical monitor in communication with the investigator. The 
medical monitor will inform the SMC about the events in a timely manner. 
 
9.2 
STOPPING OR SUSPENSION OF DOSING AT THE STUDY LEVEL  
9.2.1 Non Serious Adverse Events: 
Dosing will be interrupted at the study level to allow for review of cumulative safety data by the SMC 
if any of the following conditions are met: 
x 
≥2 severe AEs or ≥3 moderate AEs considered to be possibly/probably or definitely related to 
investigational drug product; 
x 
≥2 moderate AEs (grade II) considered to be possibly/probably or definitely related to 
investigational drug product and  intensity persisting for more than 2 weeks; 
x 
When 2 or more patients develop 2 consecutive Cystatin C levels ≥ 2 folds their respective 
average pre-treatment values;  
x 
When 2 or more patients develop a confirmed unexplained proteinuria of > 2+;  
x 
Any unexplained Gamma GT > 3 fold the upper limit of normal (ULN) in combination with 
bilirubin >2 fold the ULN. 
 
9.2.2 Serious Adverse Events (SAE): 
All SAEs will be reported to and reviewed by the SMC an ongoing basis.  
Dosing will be interrupted at the study level to allow for review of cumulative safety data by the SMC 
if any SAE considered to be possibly/probably or definitely related to investigational drug product 
 
9.3 
SUSPENSION OF DOSE ESCLATION  
If at any individual dose level, one SAE, or severe AE, or moderate AE lasting more than 2 weeks 
considered possibly/probably or definitely related to investigational drug product occurs at a particular 
dose level the SMC will decide whether dosing can proceed at the next higher dose or whether a further 
5 patients should be added at the same dose level.  
 


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10 STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
Full details of all statistical issues and planned statistical analyses will be specified in a separate 
Statistical Analysis Plan (SAP), which will be finalised prior to the locking of the study database. This 
section contains an overview of the planned methods of analysis. 
 
10.1 SAMPLE SIZE  
A sample size of 20 evaluable patients has been selected for this pilot study, based on practical 
considerations, since this is an exploratory study and not a confirmatory trial.  Additional 5 patients 
might be included in case safety allow to further escalate the dosage. 
Due to the rarity of DMD patients the recruitment is competitive across all sites in order to gather data 
in a reasonable timeframe, anticipated to be about 12 months. 
 
10.2 ANALYSIS SETS   
All analysis sets will be defined prior to final database closure. In addition to the analysis sets listed 
below, further exploratory analyses may be performed using other subgroups of patients. 
 
10.2.1 Safety Analysis Set 
The safety analysis set will include all patients who receive at least one dose of study drug. 
 
10.2.2 Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all patients who receive at least one dose of study drug 
and will be used for PK/PD analyses. 
 
10.3 STATISTICAL AND ANALYTICAL METHODS 
As this is an exploratory study, statistical methods will focus on summarising the data collected using 
appropriate graphical and tabular presentations. For measurements of continuous endpoints, summary 
statistics will include n, mean, median, standard deviation, minimum and maximum values. For binary 
data the numbers and percentages will be tabulated and 95% confidence intervals will be derived.  
 All endpoints are considered to be exploratory in this study, and no hierarchy of endpoints has been 
specified, as the objective in terms of efficacy data is to inform the planning of formal efficacy studies 
of rimeporide. 
 
10.3.1 Safety Data 
All data relating to safety will be listed and summarised using descriptive statistics.  
AEs will be coded according to MedDra and tabulated by body system and by preferred term for each 
dose level. AEs will also be tabulated by severity and relationship to the study medication 


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Summaries will also be produced of SAEs, and AEs leading to withdrawal from the study. 
For each clinical laboratory test, individual patient values will be listed and summarised and change 
from pre-treatment baseline values calculated and summarised. Any values outside the standard 
reference range will be flagged. Summaries of marked abnormalities and shift tables will be tabulated 
for each laboratory test by dose level. 
In addition, other exploratory analyses of safety data, including summaries for different subsets of 
patients, may be conducted. 
 
10.3.2 Pharmacodynamics Data 
All PD data will be summarised using appropriate graphical and tabular presentations. 
Descriptive statistics (N, arithmetic means, SD, geometric means, geometric CV, medians, Min and 
Max) will be presented for all pharmacokinetic /pharmacodynamics parameters, separately for each 
dosage level. 
In addition, other exploratory analyses of pharmacodynamics endpoints, including summaries for 
different subsets of patients, may be conducted. 
 
10.3.3 Missing Data 
No imputations of missing data will be performed.  
 
10.4  REPLACEMENT POLICY 
 
10.4.1 For Patients 
Any patient withdrawn from the study for reasons other than safety or tolerability concerns will be 
replaced. 
 
10.4.2 For Centres 
A centre may be replaced for the following administrative reasons: excessively slow recruitment, poor 
protocol adherence.  
 
11 DEFINITION OF THE END OF THE STUDY 
The end of the study will takes place at the date of the last visit of the last patients enrolled in the study.  
The EUDRA CT Declaration of the End of Trial form should be sent to the CAs and relevant ECs within 
90 days of the end of the trial, or within 15 days if the project is terminated early. Where the project is 
terminated early, or halted temporarily, reasons will be given. 


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A summary of the End of Trial Study Report should be sent to the CAs and relevant Ethics Committees 
within 12 months of the end of the trial. The summary of the final report may be enclosed with the end 
of study declaration, or sent to the CAs and relevant ethics committees subsequently.  
All correspondence with the CAs and ECs will be retained in the Trial Master File. 
 
 
PART II 
 
12 ETHICAL AND LEGAL ASPECTS 
 
12.1 GOOD CLINICAL PRACTICE 
Study implementation and conduct will be done in full compliance with existing national legislation 
and EC directives and rules on ethical issues that are relevant to the project. Sponsor and its delegates 
will comply with the international conventions and codes of conduct, and in particular with the Helsinki 
Declaration of the World Medical Association adopted by the World Medical Assembly. Respect for 
human rights and fundamental freedoms is enshrined in the Treaty on European Union as in Article 6 
of the Treaty on European Union as amended by the Treaty of Amsterdam, enforced on 1 May 1999. 
They will also take into account the declaration of the EU Clinical Trials Directive (2001/20/ec), ICH 
Topic E 6 (R1) “Guideline for Good Clinical Practice” (CPMP/ICH/135/95/Step5),  the following 
Regulation (EU) No 536/2014 of the EUROPEAN PARLIAMENT and of the COUNCIL of 16 April 
2014, that will become applicable, no earlier than 28 May 2016; the opinions of the European 
Convention on Human Rights and Biomedicine of the Council of Europe;  the directive 2001/83/EC of 
the European Parliament and of the Council of 6 November 2001the Council Directive of 24 November 
1986 on the approximation of the laws, regulations and administrative provisions of the Member States 
relating to the protection of animals used for experimental and other scientific purposes (86/609/EEC). 
It is the responsibility of the Principal Investigator to ensure that all subsequent amendments gain the 
necessary local site specific approval. This does not affect the individual clinicians’ responsibility to 
take immediate action if thought necessary to protect the health and interest of individual patients. 
 
12.2 RESPONSIBILITIES 
The Investigator shall ensure that the clinical study is performed in accordance with the protocol, the 
Declaration of Helsinki, the guidance on Good Clinical Practice and the regulatory requirement in force 
in the participating country concerned.  
The investigator shall ensure that all persons assisting with the trial are appropriately qualified and 
adequately informed about the protocol, amendments, study treatments, as well as study-related duties 
and functions. The investigator should maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant trial-related duties. 


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The investigator shall ensure to maintain in an investigator study file, all essential documents which 
reflect the conduct of the trial and is therefore a key element in trial reconstruction. The site file should 
be established at the beginning of the trial, be rigorously maintained and available at any time for 
monitoring, audit or inspection purposes. These documents serve to demonstrate the compliance of the 
investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable 
regulatory requirements.  
ISF should be established at the beginning of the trial. A final close-out of a trial can only be done when 
the monitor has reviewed ISF and confirmed that all necessary documents are in the appropriate files. 
 
The following documents should be generated and should be on file before the trial formally starts: 
 
Investigator brochure and Investigator’s brochure updates to document that investigator is 
informed in a timely manner of relevant information as it becomes available. 
 
Signed protocol and amendments, if any, and sample case report form 
 
Informed consent form (including all applicable translations) 
 
Any other written information to document that subjects will be given appropriate written 
information (content and wording) to support their ability to give fully informed consent 
 
Any revision of trial related documents that take effect during trial ( protocol/amendment(s) 
and case report form,  informed consent form any other written information provided to subject) 
 
Financial aspects of the trial to document the financial agreement between the 
investigator/institution and the sponsor for the trial. 
 
Insurance statement to document that compensation to subject(s) for trial-related injury will be 
available. 
 
Signed agreement between involved parties, 
 
Dated, documented favourable opinion of Ethics Committee for initial submission and 
subsequent amendment(s) and/or revision(s) 
 
Ethics committee composition to document that the Ethics Committee is constituted in 
agreement with Good Clinical Practice. 
 
Regulatory authority (ies) authorisation/ approval/notification of protocol to document 
appropriate authorisation/approval/notification by the regulatory authority (ies) has been 
obtained prior to initiation of the trial in compliance with the applicable regulatory 
requirement(s). 
 
Regulatory authority (ies) authorisation subsequent amendment(s) and/or revision(s) if any. 
 
Curriculum vitae and/or other relevant documents evidencing qualifications of investigator(s) 
and/or supporting trial staff to whom investigator tasks are delegated to document qualifications 
and eligibility to conduct trial and/or provide medical supervision of subjects.  


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Normal value(s)/range(s) for medical/laboratory/technical procedure(s) and/or test(s) included 
in the protocol to document normal values and/or ranges of the tests according to the state of 
the art. 
 
Updates to normal value(s)/range(s) for medical/ laboratory/ technical procedure(s)/test(s) 
included in the protocol to document normal values and ranges that are revised during the trial 
 
Medical/laboratory/technical procedures/tests to document competence of facility to perform 
required test(s), and support reliability of results (Certification or accreditation or established 
quality control and/or external quality assessment or calibration or other validation) 
 
Updates of medical/laboratory/technical procedures/tests to document that tests remain 
adequate throughout the trial period  
 
Instructions for handling of investigational medicinal product(s) and trial related materials to 
document instructions needed to ensure proper storage, packaging, dispensing and disposition 
of investigational medicinal products and trial-related materials. 
 
Distribution records for investigational medicinal product(s) and trial related materials to 
document distribution dates, batch numbers and method of distribution of investigational 
medicinal product(s) and trial-related materials. To allow tracking of product batch, review of 
distribution conditions, and accountability. 
 
Certificate(s) of analysis of investigational product(s) to document identity, purity, and strength 
of investigational medicinal product(s) to be used in the trial. 
 
Investigational medicinal product(s) accountability at site to document that the investigational 
medicinal product(s) have been used according to the protocol. To document the final 
accounting of investigational medicinal product(s) received at the site, dispensed to subjects, 
returned by the subjects, and returned to sponsor 
 
Documentation of investigational product destruction to document destruction of unused 
investigational products by sponsor 
 
Monitoring visit reports to document site visits by, and findings of, the monitor 
 
Relevant communications other than site visits to document any agreements or significant 
discussions regarding trial administration, protocol violations, trial conduct, adverse event (AE) 
reporting, letters, meeting notes, notes of telephone calls. 
 
Signed informed consent forms to document that consent is obtained in accordance with GCP 
and protocol and dated prior to participation of each subject in trial. Also to document direct 
access permission 
 
Source documents to document the existence of the subject and substantiate integrity of trial 
data collected. To include original documents related to the trial, to medical treatment, and 
history of subject. 
 
Signed, dated and completed case report forms to document that the investigator or authorised 
member of the investigator’s staff confirms the observations recorded 


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Documentation of case report form corrections to document all changes/additions or corrections 
made to case report form after initial data were recorded 
 
Notification by sponsor and/or investigator, where applicable, to regulatory authority(ies) and 
Ethics Committees of suspected unexpected serious adverse reactions and of other safety 
information 
 
Notification by sponsor to investigators of safety information in accordance with ‘The detailed 
guidance on the collection, verification and presentation of adverse reaction reports arising 
from clinical trials on medicinal products for human use 
 
Annual Safety reports to Ethics Committees and authority(ies) 
 
Subject screening log to document identification of trial subjects who entered pre-trial 
screening. The Investigator is responsible for keeping a record of all patients (or their legally 
authorised representative) who sign an informed consent document and are screened for entry 
into the study. Patients who fail screening must have the reason(s) recorded in their source 
documents and the study-screening log. 
 
Subject identification code list to document that investigator/institution keeps a confidential list 
of names of all subjects allocated to trial numbers on enrolling in the trial. To permit 
identification of all subjects enrolled in the trial in case follow-up is required. List should be 
kept in a confidential manner and for agreed upon time. 
 
Subject enrolment log to document chronological enrolment of subjects by trial number. 
 
Investigational medicinal product accountability at the site to document that investigational 
medicinal product(s) have been used according to the protocol. 
 
Record of retained body fluids to document location and identification of retained samples. 
 
Audit certificate 
 
Final trial close-out monitoring report to document that all activities required for trial close-out 
are completed, and copies of essential documents are held in the appropriate files. 
 
Final report by investigator to Ethics Committees where required, and where applicable, to the 
regulatory authority (ies) to document completion of the trial. 
 
Clinical study report to document results and interpretation of trial. 
Essential documents should be complete, legible, accurate, and unambiguous. They should be signed 
and dated as appropriate. 
 
12.3 CONSENT 
The paediatric population represents a vulnerable subgroup. Special measures have been taken to 
correctly inform them, to protect their rights and to shield them from undue risk.  
It is the responsibility of the Principal investigator or co-investigator, to obtain written informed consent 
from the patient’s parents or legal guardian and assent from each patient prior performing any trial 
related procedure.  


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As a rule, a paediatric subject is legally unable to provide informed consent. Consequently, paediatric 
study participants are dependent on their parent(s)/legal guardian to assume responsibility for their 
participation in clinical studies. Fully informed consent should be therefore obtained from the legal 
guardian in accordance with regional laws or regulations. All participants will be informed to the fullest 
extent possible about the study in language and terms they are able to understand. An informed consent 
and assent documents that includes both information about the study and the consent form will be 
prepared and given to the patient and parents/legal guardian respectively. A parents/legal representative 
information sheet (PIS) together with an informed consent form (ICF) and an assent form where 
appropriate (age of assent to be consistent with local legal requirements) will be provided to them to 
explain the study, the study’s procedures (not limited to invasive, painful procedures), Procedures to 
prevent or limit physical discomfort, the potential risk and benefit of participating in the study, and their 
rights. This document will contain all ICH, GCP, and locally required regulatory elements (whichever 
is more stringent).  
A PIS will be provided to each patient to make sure they have understood and agreed to take part in the 
study; two PIS will be available, one for the age ranges of 6 to 10 years old and one for 11 to 14 years 
old. The language used will be based on the maturity of the child and their ability to understand the 
study procedure. Age-appropriate explanation will be given to the child prior to any investigation or 
procedure, in order to decrease anxiety and anticipation of pain, in honest, but not frightening terms.  
The patients and parents / legal guardians should be given sufficient time to read 
 the Patient information sheet and to discuss their participation with others outside of the site research 
team if they wish do. Investigators must ensure that they had adequately explain the aim, trial treatment, 
trial procedures and examinations, and anticipated potential hazards of taking part in this trial to the 
patient, parents / legal guardians. Medical and study staff will take all the time necessary to correctly 
explain what it will happen during the examinations. The patient and/or parent/legal guardian must be 
given an opportunity to ask any they might have. Patient recruitment will be performed in a manner 
free from inappropriate inducements either to the parent(s)/legal representative or to the study 
participant.   
The investigator should also stress that the patient and/or parents/legal guardians are completely free to 
refuse to take part or withdraw from the trial at any time. The right of the patient and/or parent/legal 
guardian to refuse to participate in the trial without giving a reason must be respected. 
Information to patients will be split into a Patient Information Sheet that provides detailed information 
about the trial and its benefits and risks, and the Informed Assent/ Consent Form that is used to obtain 
the dated signature from the patient as evidence of the patient’s agreement to partake in the study. Since 
the patients in the study are minors, written assent must be obtained from the minor wherever it is 
possible to do so (as appropriate according to age and national legislation). If patient and parents/ legal 
guardian (as mandated by local rules: individual or judicial or other body authorised under applicable 
law to consent on behalf of a prospective patient to the patient’s participation in the procedures involved 


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in the research) agree their child to participate in the trial, they should be asked to sign and date the 
latest version of informed consent form. Both parents must signed the informed consent form unless 
one parent is not legally allowed to sign.: Permission of one parent is sufficient if the other parent is 
deceased, unknown, incompetent, not reasonably available, or does not have legal responsibility for the 
care and custody of the minor child.  The investigator must then sign and date the form on the same day 
as the parent/legal/guardian 
PIS and ICF will be prepared based on local requirements and law, cultural specifications, and approved 
by an Ethical Committee.  
The modalities for obtaining informed consent from the parents and Assent from the minor will be 
defined at the site initiation visit and documented in the clinical trial centre in the Investigator Site File 
(ISF). A copy of the signed ICF should be given to the patient and/or parent/legal guardian, another 
signed copy should be filed in the patient’s medical records, and the original placed in the Investigator 
Site File (ISF). 
Details of the informed consent discussions should be recorded in the patient’s medical records; this 
should include date of, and information regarding, the initial discussion, the date consent was given, 
with the name of the trial and the version number of the PIS and ICF. Throughout the trial, the patient 
and/or parent/legal guardian should have the opportunity to ask questions about the trial and any new 
information that may be relevant to the patient’s continued participation should be shared with them in 
a timely manner. On occasion it may be necessary to re-consent the patient, in which case the process 
above should be followed and the patient’s right to withdraw from the trial respected. If an amended 
protocol impacts the content of the informed consent document, the consent and assent documents must 
be revised and the patient and parent/legal guardian must again give written assent/informed consent 
respectively. Patients already participating in the study when the amended protocol is implemented 
must be re-consented with the revised version of the informed consent document. A copy of the revised 
informed consent and assent documents must be given to the parents or guardians. The Investigator will 
retain the original signed updated consent document in ISF. A copy of the signed ICF should be given 
to the patient and/or parent/legal guardian, another signed copy should be filed in the patient’s medical 
records. 
With the patient’s prior consent, their medical practitioner should also be informed that they are taking 
part in the trial.  
 
12.4 SUBJECT COMPENSATION 
Patients and their parents or guardians will not receive compensation for taking part in the study but 
will receive reimbursement for reasonable travel and accommodation costs associated with their 
participation.  
 


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12.5 ARCHIVING 
ISF must be retained securely prior to archive and then archived for sufficient periods to allow for audit 
and inspection by regulatory authorities and should be readily available upon request.  
To comply with international regulations, the records should be retained by the investigator for 15 years 
or longer in accordance with national regulations after the end or termination of the trial, or 2 years after 
the marketing authorization or the sponsor has discontinued its research with respect to such drug. The 
investigational sites must notify the sponsor in writing before destroying any data or records. 
Storage conditions should ensure that essential records are maintained in a legible condition and can be 
retrieved upon the request of a regulatory authority. Any change in the location of the stored 
documentation should be recorded in order to allow tracking. Adequate and suitable space should be 
provided for the secure storage of all essential records from completed studies. The facilities should be 
secure, with appropriate environmental controls and adequate protection from physical damage. 
The investigator is recommended to make the sponsor aware of the storage arrangements for their 
essential documents. The ultimate responsibility for the documents to be retained by the 
investigator/institution resides with the investigator/institution. If the investigator becomes unable to be 
responsible for their essential documents (e.g. relocation, retirement etc) the sponsor should be notified 
in writing of this change and informed as to whom the responsibility has been transferred. Details of 
these arrangements should be documented in the clinical trial centre TMF. 
 
12.6 CONFIDENTIALITY AND DATA PRIVACY 
Personal data recorded on all documents will be regarded as strictly confidential and will be handled 
and stored in accordance with the relevant data protection legislation in the member state. 
Patients will be identified using only their unique trial number. 
Sponsor affirms the patient's right to protection against invasion of privacy and to be in compliance 
with ICH and other local regulations (whichever is more stringent). Sponsor requires the Investigator 
to permit sponsor representatives (Monitor) and when necessary, representatives from regulatory 
authorities, to review and/or copy any medical records relevant to the study in accordance with local 
laws (any copies of patients’ records must be duly anonymised to protect patients’ confidentiality). 
Should direct access to medical records require a waiver or authorisation separate from the patient’s 
statement of informed consent, it is the responsibility of the Investigator to obtain such permission in 
writing from the appropriate individual. Representative of the sponsor may be required to have access 
to patients medical records for quality assurance purposes but patients should be reassured that their 
confidentiality will be respected at all times. 
Representative of sponsor must maintain the confidentiality of all patient’s data and will not disclosed 
information by which patients may be identified to any third party other than those directly involved in 
the treatment and organization for which the patient has given explicit consent for data transfer. 
 


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12.7 PROTOCOL AMENDMENTS 
Substantial amendments will be submitted to the IEC for written approval and where applicable to 
National Competent Authorities. Written approval must be obtained before implementation of the 
amended version occurs. The written signed approval from the IEC should specifically reference the 
Principal Investigator’s name, protocol number, study title and amendment number(s) that is/are 
applicable. 
 
12.8 APPROVAL OF THE CLINICAL STUDY PROTOCOL AND AMENDMENTS 
Before the start of the study, the study protocol, informed consent document, and any other appropriate 
documents will be submitted to the IEC with a cover letter or a form listing the documents submitted, 
their dates of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is 
sought. If applicable, the documents will also be submitted to the authorities in accordance with local 
legal requirements. 
Sponsor e can only supply study drug to an Investigator after sponsor or their authorised representative, 
an international CRO, has received documentation on all ethical and legal requirements for starting the 
study. This documentation must also include a list of the members of the IEC and their occupation and 
qualifications. If the IEC will not disclose the names of the committee members, it should be asked to 
issue a statement confirming that the composition of the committee is in accordance with GCP. Formal 
approval by the IEC should preferably mention the study title, study code, study site, and any other 
documents reviewed. It must mention the date on which the decision was made and must be officially 
signed by a committee member (chairman or secretary of the IEC. Before the first patient is enrolled in 
the study, all ethical and legal requirements must be met.  
The IEC and, if applicable, the authorities, must be informed of all subsequent protocol amendments in 
accordance with local legal requirements. Amendments must be evaluated to determine whether formal 
approval must be sought and whether the informed consent document should also be revised. 
The Investigator must keep a record of all communication with the IEC and, if applicable, between a 
coordinating Investigator and the IEC. This statement also applies to any communication between the 
Investigator (or coordinating Investigator, if applicable) and regulatory authorities. 
All documents handed over to patients or their legal representative prior to use must first be reviewed 
and approved by sponsor, and upon approval by sponsor submitted to and reviewed and approved by, 
the competent IEC. This includes but is not limited to the informed consent form, patient information 
sheet, assent form, advertisements, training materials, etc. 
 
12.9 ONGOING INFORMATION FOR INDEPENDENT ETHICS COMMITTEE 
If required by legislation or the IEC, the investigator must submit to the IEC: 
x 
Information on SAEs or SUSARs as per local applicable rules and timelines;  
x 
Periodic reports on the progress of the study; 


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x 
Deviations from the protocol or anything that may involve added risk to subjects. 
 
12.10 CLOSURE OF THE STUDY 
Sponsor reserves the right to terminate this study at any time for reasonable medical or administrative 
reasons. Any premature discontinuation will be appropriately documented according to local 
requirements (e.g., IRB/IEC, regulatory authorities). 
In addition, the Investigator or sponsor has the right to discontinue a single site at any time during the 
study for medical or administrative reasons such as: 
x 
Significant non-compliance with contractual enrolment timelines and targets 
x 
Serious or continued GCP non-compliance 
x 
Inaccurate, incomplete or delayed data collection 
x 
Failure to adhere to the study protocol 
x 
Failure to provide requested follow-up information for data queries 
 
12.11 LIABILITY AND INSURANCE 
Sponsor is responsible for obtaining insurance to set up and the conduct of the study in all participating 
countries and for ensuring that each sites are adequately covered. From time of entry into study (date 
of given consent), compulsory insurance coverage (so called subject’s insurance) will be provided for 
each subjects involved in the study. 
Liability and insurance provisions for this study are provided in the investigator contract. 
 
12.12 FINANCIAL DISCLOSURE 
Investigators are required to provide financial disclosure information to allow sponsor to submit 
complete and accurate certification or disclosure statements in accordance with applicable national and 
local regulations. In addition, investigators must provide sponsor with a commitment to promptly 
update this information if any relevant changes occur during the course of the investigation and for 1 
year following the completion of the study. 
 
12.13 DISCLOSURE OF PROTOCOL AND PUBLICATION POLICY 
Information about this trial will be posted following the principles of the International Committee of 
Medical Journal Editors (ICMJE), the International Federation of Pharmaceutical Manufacturers & 
Associations (IFPMA) Industry Position Paper and applicable national or regional regulations and laws.  
The results of this study may be published or presented at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to sponsor prior to submission. This allows 
sponsor to protect proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 


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Sponsor will comply with the requirements for publication of study results. In accordance with standard 
editorial and ethical practice, the sponsor will support publication of multicentre trials only in their 
entirety and not as individual centre data. In this case, a coordinating investigator will be designated by 
mutual agreement prior to the start of the trial. 
Authorship will be determined by mutual agreement and in line with ICMJE authorship requirements. 
Any formal publication of the study in which contribution of sponsor personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and the appropriate 
sponsor personnel. 
So-called ‘ghost writing’ is not permitted. All contributors who do not meet the criteria for authorship 
should be listed in an acknowledgments section. Examples of those who might be acknowledged 
include a person who provided purely technical help, writing assistance, or a department chairperson 
who provided only general support. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use of data 
from this study will become and remain the exclusive and unburdened property of sponsor, except 
where agreed otherwise. 
 
13 MONITORING AND AUDITING 
All aspects of the study will be monitored by sponsor or its representative for this study (sponsor 
authorised representative), for compliance with applicable government regulations with respect to 
current GCP (ICH Topic E6) and standard operating procedures. Direct access to the on-site study 
documentation and medical records must be ensured. 
 
13.1 STUDY MONITORING AND SOURCE DATA VERIFICATION 
Following training trial staff will be given access to the EDC system. Access to the EDC system is 
restricted to trial staff participating in the trial and the extent of access will depend on the participants’ 
user role in the trial. eCRF Completion Guidelines will be provided to the sites. 
Data recorded in the eCRFs will be accessible to trial staff through internet connection.  
The investigator or staff authorized by the investigator should enter subject data into electronic eCRFs 
in a timely manner. A separate eCRF will be used for each subject enrolled. The eCRFs must be 
maintained in an up-to-date condition at all times by the investigator or designee. The completed eCRFs 
will be signed by the investigator, or co-investigator(s) authorized by the investigator. This signature 
information (including date of signature) will be kept in the audit trail and is unalterable. Only medically 
qualified (co)investigators can sign data on clinical assessments/safety.  
Any corrections made by the investigator, or authorized site staff, to the eCRF after original entry will 
be documented in the audit trail. Changes to data already approved, requires the re-signature of 
investigator or authorized staff. The audit trail will identify the person making the change and the date, 
time and reason for the change.  


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After data entry systematic data validation will be performed and any data discrepancies will be 
presented electronically to the site staff through the EDC system.  
Queries for discrepant data may be generated automatically by the software upon entry or generated 
manually by authorized persons such as the monitor or the trial data manager(s). All queries, whether 
generated by the system or by trial staff, will be in electronic format.  
The trial monitor will check the eCRFs for accuracy and completion and perform source data 
verification (SDV). The trial monitor will document electronically SDV of all sections of eCRFs used. 
The systematic data validation will provide a clean and consistent database prior to the statistical 
analysis. Data will be processed in accordance with the general terms and conditions of any national 
legislation. Source data verification (SDV) is a key function in assuring the sponsor that clinical trial 
information is recorded and handled in a way that allows its accurate reporting, interpretation and 
verification. Monitors will perform SDV during the conduct of the trial, to confirm the accuracy and 
completeness of eCRFs, and consistency of CRF entries, source documents and other trial related 
records against each other. To enable SDV at the trial site, it is essential to establish and agree with the 
investigator what constitutes source data/documents for the trial data to be collected. The location of 
source data will be defined in a Location of Source Data Form prior to initiation of the trial. 
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the investigator 
must notify the sponsor to agree upon an acceptable storage solution. National competent authorities 
will be notified with the appropriate documentation.  Regular monitoring visits by representatives of 
the sponsor will be made during the study. 
Monitoring will begin with an initiation visit prior to study commencement to clarify all aspects of the 
protocol and documentation. The purpose of later visits during the implementation period will be to 
evaluate study progress and adherence to the protocol. The visit intervals and detailed monitoring 
activities will be defined in Monitoring Guidelines. During these monitoring visits the monitor must 
have full access to data and documents as she/he will check CRFs for completeness, clarity and 
consistency with the information in subject files (source data checking). In all cases, it is the 
responsibility of the monitor to maintain subject confidentiality. 
For archiving purposes each investigator will be supplied with a copy of the eCRFs, for all subjects 
enrolled at the site, via an electronic medium at completion of the trial. Audit trail information will be 
included. The investigational sites will maintain all trial documentation, and take measure to prevent 
accidental or premature destruction of these documents. 
The Investigator, or a designated member of the Investigators’ staff, must be available during 
monitoring visits, audits and inspections to review data, resolve queries and allow direct access to 
subjects’ records (e.g. medical/hospital records, office charts, hospital charts, and study related charts) 
for source data and other type of verification. The Investigator must ensure timely and accurate 
completion of CRFs and queries. 


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As part of the responsibilities commensurate with participating in the study, the investigator agrees to 
maintain and have available for monitoring, adequate case records (accurate source documents and 
CRFs) for the patients treated under this protocol. In addition, the investigator agrees to maintain all 
administrative documents (e.g. IEC correspondence, investigational product and supplies shipment 
manifests, monitoring logs, or correspondence with sponsor and with any of its representative for this 
study). 
 
13.2 ON-SITE AUDITS 
Investigators and institutions involved in the study will permit trial-related monitoring, audits, IEC 
review, and domestic or foreign regulatory inspection(s) by providing direct access to source 
documents, CRFs, and all other study documentation. 
The Investigator should promptly notify sponsor of any inspections scheduled by any regulatory 
authorities and promptly forward to sponsor copies of any audit reports received. 
To enable evaluations and/or audits from national CA or sponsor the investigator agrees to keep records 
of all study documentation, including between others the identity of all participating subjects, all 
original signed Informed Consent Forms, a copy of all eCRFs, and detailed records of drug disposition. 
These should be kept in an Investigator’s File that should be provided by the sponsor and kept regularly 
updated by the investigator. 
The eCRFs will be available for inspection by authorized representatives from sponsor, e.g. co- 
monitoring or audit by the sponsor, from National Competent Authority and/or EC. 
 
13.3 SERIOUS GCP BREACHES 
The sponsor or its delegates will notify in writing competent authorities and Ethics committees of any 
serious breach of - 
 
the conditions and principles of GCP in connection with that trial; or 
 
the protocol relating to that trial, as amended from time to time in accordance with regulations 
22 to 25, within 7 days of becoming aware of that breach. 
A “serious breach” is a breach which is likely to effect to a significant degree  
 
the safety or physical or mental integrity of the subjects of the trial; or 
 
the scientific value of the trial”. 
If the Sponsor or delegates obtains clear and unequivocal evidence that a serious breach has occurred, 
Sponsor will notify to CA and EC first, within 7 days, and investigate and take action simultaneously 
or after notification. In this case, the Sponsor will not wait to obtain all of the details of the breach prior 
to notification. In other cases, some degree of investigation and assessment may be required by the 
Sponsor prior to notification, in order to confirm that a serious breach has actually occurred. 


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Therefore, should an Investigator become aware of a possible serious GCP breach, e.g. a protocol 
violation, or non-reporting of critical safety information that has the potential of jeopardising patients’ 
safety, sponsor must be notified within 24 hours. 
Sponsor will also informs the relevant Chief Investigator and Principal Investigators of the breach 
notification. Communication in this regard facilitates the implementation of corrective and preventative 
actions.Sponsor must take appropriate corrective and preventative actions in response to the serious 
breach, and to document these actions in follow-up reports made in writing to CAs and ECs.Sponsor 
will make available a clear process to identify and notify the sponsor of serious breaches. (Formal SOP 
and form to be faxed to sponsors or delegate) 
 
14 DOCUMENTATION AND USE OF STUDY FINDINGS 
 
14.1 DOCUMENTATION OF STUDY RESULTS 
An electronic CRF is used in this study and a specific electronic CRF will correspond to each subject.  
All required information must be entered on the CRFs. If an item is not available or is not applicable, 
this fact should be indicated and no blank spaces must be left. The data collected on the CRF will be 
entered into the study database. If the investigator authorises other personnel to enter data into the CRF, 
the names, positions, signatures, and initials of these persons must be supplied to sponsor or their 
authorised representative before these individuals start completing CRF information. The CRF pages 
must be reviewed and signed by the Investigator named in the study protocol or by a designated sub-
investigator. Sponsor will ensure that the CRF copy left with the Investigator (print-outs and/or CD-
ROM) has never been under the direct or indirect control of sponsor. 
 
14.2 USE OF COMPUTERISED SYSTEMS AT THE CLINICAL TRIAL CENTRE 
The patient's right to protection against invasion of privacy will be in compliance with ICH and other 
local regulations (whichever is more stringent). Before entering the study each patient will receive a 
unique number (alphanumerical code) and all data will be linked to this code and not to any data or 
information that could reveal the identity of the patient. Original data content such as medical charts, 
will be reviewed only by dedicated staff (study monitor) and none of the information regarding patient 
identity will be recorded, tracked processed or exported from the clinical site. Sponsor requires the 
Investigator to permit trial monitors and when necessary, representatives from regulatory authorities, to 
review and/or copy any medical records relevant to the study in accordance with local laws (any copies 
of patients’ records must be duly anonymised to protect patients’ confidentiality). Should direct access 
to medical records require a waiver or authorisation separate from the patient’s statement of informed 
consent, it is the responsibility of the Investigator to obtain such permission in writing from the 
appropriate individual. 


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Data collected will be processed and analysed in aggregate manner and the alphanumeric code will be 
the only reference that will be used to allow identification of all the data reported for each subject in the 
respect of ICH 5.5.5. Individual data will be also kept in a database called an electronic case report form 
(e-CRF). The e-CRF will be developed in compliance with the protection of individuals with regard to 
personal data processing and data transfer. Data Management processes that will be followed during 
the study have been validated to ensure the compliance of the system both with the user requirements 
and the prevailing regulations. All means will be implemented to ensure the security, authenticity, 
integrity, and confidentiality of the data recorded in accordance with EU Directive 2002/58/EC and 
national requirements.  
System functionalities are consistent with the 21 CFR Part 11 and GCP Requirements. Data will be 
secured by both physical and electronic means against damage. Regular back-ups of all relevant data 
should be done. Integrity and accuracy of backup data and the ability to restore the data should be 
checked during validation and monitored periodically. A secured audit trail with highly regulated access 
will be available to users and internal auditors and authorities’ inspection. The system is designed to 
permit data changes in such a way that the data changes are documented and that there is no deletion of 
entered data and a list of the individuals who are authorized to make data changes will be defined 
according FDA Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance ICH, 1996 
(ICH 5.5.3). The System will support backup and restore processes that preserve all system records, 
audit trails, data entry and processing in accordance with ICH 5.5.3. Technology implemented ensures 
that electronic signature is used properly. Suitable archiving systems will be in place to safeguard the 
data integrity 
 


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14 REFERENCES 
Adam R. Burr, Douglas P. Millay, Sanjeewa A. Goonasekera,Ki Ho Park,Michelle A. Sargent, James 
Collins. 2014. Na+ dysregulation coupled with Ca2+entry through NCX1 promotes muscular 
dystrophy in mice. Vol. 11. 34 vols. Molecular and cellular Biology. 
Allen DG, Gervasio O, Yeung EW, Whitehead NP. 2010. Calcium and the damage pathways in 
muscular dystrophy. Vol. 88. Can. J. Physiol. Pharmacol. 
Barthélémy, I, E Barrey, JL Thibaud, A Uriarte, T Voit, S Blot, and JY Hogrel. 2009. "Gait analysis 
using accelerometry in dystrophin-deficient dogs." Neuromuscul Disord 19 (11): 788-796. 
Bkaily G, Chahine M, Al-Khoury J, Avedanian L, Beier N, Scholz W, Jacques D. 2015. "Na+/H+ 
exchanger inhibitor prevents and reverses early death in hereditary cardiomyopathy." 
Canadian Journal of Physiology and Pharmacology.  
Creutzfeldt, W, and R Lamberts. 1991. "Is hypergastrinemia dangerous to man?" Scandinavian 
Journal of Gastroenterology Suppl.  
Cullighan, and Ohlendieck. 2002. "Abnormal calcium handling in muscular dystrophy." Basic Appl 
Myology 2002, 12 (4): 147-157 12 (4): 147-157. 
De Paepe B, De Bleecker JL. 2013. "Cytokines and chemokines as regulators of skeletal muscle 
inflammation: Presenting the case of Duchenne muscular Dystrophy." 2013 (ID 540370). 
Deval E, Levitskyb DO, Marchanda E, Cantereaua A, Raymonda G, Cognard C. 2002. Na+/Ca2+ 
exchange in human myotubes: intracellular calcium rises in response to external sodium 
depletion are enhanced in DMD. . Vol. 12. Neuromuscular Disorders. 
Dongmei W, Kraut J, Abraha WM. 2013. "Sabiporide improves cardiovascular function, decreases 
the inflammatory response and reduces mortality in acute metabolic acidosis in pigs." PloS 
ONE.  
Evans NP, Misyakb SA, Robertson JL, Bassaganya-Rierab J, Grangea RW. 2009. Immune mediated 
mechanisms potentially regulate the disease time course of Duchenne muscular dystrophy 
and provide targets for therapeutic intervention. PMR. 
EW, Gertz. 1972. "Cardiomyopathic Syrian Hamster: A possible model of human disease." Prog Exp 
Tumor Res 242-260. 
Fanchaouy M, Polakovab E, Junga C, Ogrodnika J, Shirokovab N, Nigglia E . 2009. Pathways of 
abnormal stress-induced Ca2+ influx into dystrophic mdx cardiomyocytes. Vol. 46. Cell 
Calcium. 
I, Barthélémy. 2014. "Dis Model Mecha." Manuscript under revision.  
ICH. 2014. Addendum for ICH E6 Good clinical Practice.  
—. 1996. Good Clinical Practice consolidated guidance - E6 (R1).  
ICH Guideline, ICH harmonised Tripartite. 2003. "Stability testing of Drug Substance and Products - 
Q1A (R2)." 
ICH. 2003. Stability testing of new Drug substance and Products - Q1A (R2).  
iwara. n.d. 
2007. "Iwata." 


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J., Orlowski, and Grinstein S. 2004. "Diversity of the mammalian sodium/proton exchanger SLC9 
gene family." (Eur. J. Physiol.) 447: 549-565,. 
Jan Regnstrom, Franz Koenig, Bo Aronsson, Tatiana Reimer, Kristian Svendsen, Stelios 
Tsigkos,Bruno Flamion, Hans-Georg Eichler, Spiros Vamvakas. 2010. "Factors associated 
with success of market authorisation applications for pharmaceutical drugs submitted to the 
European Medicines Agency." European Journal of Clinical Pharmacology, 1 ed. 
Landfeldt E, Lindgren P, Bell CF, SChmitt C, and Straub V, Lochmuller H, Bushby K Guglieri M. 
2014. "The burden of Duchenne muscular dystrophy: An international, cross-sectional study 
." Neurology 529-536. 
Madaro L, Bouché M. 2014. "From innate to adaptive immune repsonse in muscular dystrophies and 
skeletal muscle regeneration: the role of lymphocytes." (BioMed Research International) 
2014 (ID 438675). 
Malik V, Rodino-Klapac LR, Mendell J . 2012. Emerging drugs for Duchenne muscular dystrophy. 
Vol. 2. 17 vols. Expert Opin. Emerging Drugs. 
Mentzer, R, C Bartels, R Bolli, S Boyce, GD Buckberg, B Chaitman, A Haverich, et al. 2008. 
"Sodium-Hydrogen Exchange Inhibition by Cariporide to Reduce the Risk of Ischemic 
Cardiac Events in Patients Undergoing Coronary Artery Bypass Grafting: Results of the 
EXPEDITION Study." Annals of Thoracic Surgery 85 (4): 1261-1270. 
Nigro, V, Y Okazaki, A Belsito, G Piluso, Y Matsuda, L Politano, G Nigro, et al. 1997. 
"Identification of the Syrian Hamster cardiomyopathy gene." (Hum Mol Genet) 6 (601-607). 
Orlowski, John, and Sergio Grinstein. 2003. The Sodium-Hydrogen Exchanger: From molecule to its 
role in disease. Kluwer Academic Publishers. 
Raman, SV, Hor KN, Wojciech M, Halnon NJ, Kissel JT, Smart S, Mc Carthy B, et al. 2015. 
"Epelerenone for early cardiomyopathy in Duchenne Muscular Dystrophy: a randomised, 
double blind, placebo controlled trial." Lancet.  
Simon, Pr N. 2014. "A population PK analysis of Rimeporide." Marseille. 
Weber MA, Nagel AM, Wolf MB, Jurkat-Rott K, Kauczor HU, Semmler W, Lehmann-Horn F. 2012. 
Permanent muscular sodium overload and persistent muscle edema in Duchenne muscular 
dystrophy: a possible contributor of progressive muscle degeneration. Vol. 11. 259 vols. J 
Neurol. 
 
 
 


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APPENDIX 1: WMA DECLARATION OF HELSINKI  
 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Recommendations guiding physicians in biomedical research involving human subjects 
Adopted by the 18th World Medical Assembly 
Helsinki, Finland, June 1964 
and amended by the 
29th World Medical Assembly, Tokyo, Japan, October 1975 
35th World Medical Assembly, Venice, Italy, October 1983 
41st World Medical Assembly, Hong Kong, September 1989 
and the 
48th General Assembly, Somerset West, Republic of South Africa, October 1996 
 
INTRODUCTION  
It is the mission of the physician to safeguard the health of the people. His or her knowledge and 
conscience are dedicated to the fulfillment of this mission.  
The Declaration of Geneva of the World Medical Association binds the physician with the words, "The 
Health of my patient will be my first consideration," and the International Code of Medical Ethics 
declares that, "A physician shall act only in the patient's interest when providing medical care which 
might have the effect of weakening the physical and mental condition of the patient."  
The purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the aetiology and pathogenesis of 
disease.  
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve hazards. 
This applies especially to biomedical research.  
Medical progress is based on research which ultimately must rest in part on experimentation involving 
human subjects.  
In the field of biomedical research a fundamental distinction must be recognized between medical 
research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the 
essential object of which is purely scientific and without implying direct diagnostic or therapeutic value 
to the person subjected to the research.  
Special caution must be exercised in the conduct of research which may affect the environment, and the 
welfare of animals used for research must be respected.  
Because it is essential that the results of laboratory experiments be applied to human beings to further 
scientific knowledge and to help suffering humanity, the World Medical Association has prepared the 
following recommendations as a guide to every physician in biomedical research involving human 
subjects. They should be kept under review in the future. It must be stressed that the standards as drafted 
are only a guide to physicians all over the world. Physicians are not relieved from criminal, civil and 
ethical responsibilities under the laws of their own countries.  
 
I. 
BASIC PRINCIPLES  
1. Biomedical research involving human subjects must conform to generally accept scientific principles 
and should be based on adequately performed laboratory and animal experimentation and on a thorough 
knowledge of the scientific literature.  


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2. The design and performance of each experimental procedure involving human subjects should be 
comment and guidance to a specially appointed committee independent of the investigator and the 
sponsor provided that this independent committee is in conformity with the laws and regulations of the 
country in which the research experiment is performed. 
 
3. Biomedical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility for the 
human subject must always rest with a medically qualified person and never rest on the subject of the 
research, even though the subject has given his or her consent. 
4. Biomedical research involving human subjects cannot legitimately be carried out unless the 
importance of the objective is in proportion to the inherent risk to the subject. 
5. Every biomedical research project involving human subjects should be preceded by careful 
assessment of predictable risks in comparison with foreseeable benefits to the subject or to others. 
Concern for the interests of the subject must always prevail over the interests of science and society. 
6. The right of the research subject to safeguard his or her integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject and to minimize the impact of the study 
on the subject's physical and mental integrity and on the personality of the subject. 
7. Physicians should abstain from engaging in research projects involving human subjects unless they 
are satisfied that the hazards involved are believed to be predictable. Physicians should cease any 
investigation if the hazards are found to outweigh the potential benefits. 
8. In publication of the results of his or her research, the physician is obliged to preserve the accuracy 
of the results. Reports of experimentation not in accordance with the principles laid down in this 
Declaration should not be accepted for publication. 
9. In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or 
she should be informed that he or she is at liberty to abstain from participation in the study and that he 
or she is free to withdraw his or her consent to participation at any time. The physician should then 
obtain the subject's freely-given informed consent, preferably in writing. 
10. When obtaining informed consent for the research project the physician should be particularly 
cautious if the subject is in a dependent relationship to him or her or may consent under duress. In that 
case the informed consent should be obtained by a physician who is not engaged in the investigation 
and who is completely independent of this official relationship. 
11. In case of legal incompetence, informed consent should be obtained from the legal guardian in 
accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain 
informed consent, or when the subject is a minor, permission from the responsible relative replaces that 
of the subject in accordance with national legislation. Whenever the minor child is in fact able to give 
a consent, the minor's consent must be obtained in addition to the consent of the minor's legal guardian. 
12. The research protocol should always contain a statement of the ethical considerations involved and 
should indicate that the principles enunciated in the present Declaration are complied with. 
 
 


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II. 
MEDICAL RESEARCH COMBINED WITH PROFESSIONAL CARE (Clinical 
Research) 
13. In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic 
measure, if in his or her judgement it offers hope of saving life, reestablishing health or alleviating 
suffering. 
14. The potential benefits, hazards and discomfort of a new method should be weighed against the 
advantages of the best current diagnostic and therapeutic methods. 
15. In any medical study, every patient - including those of a control group, if any - should be assured 
of the best proven diagnostic and therapeutic method. This does not exclude the use of inert placebo in 
studies where no proven diagnostic or therapeutic method exists. 
16. The refusal of the patient to participate in a study must never interfere with the physician-patient 
relationship. 
17. If the physician considers it essential not to obtain informed consent, the specific reasons for this 
proposal should be stated in the experimental protocol for transmission to the independent committee 
(I, 2). 
18. The physician can combine medical research with professional care, the objective being the 
acquisition of new medical knowledge, only to the extent that medical research is justified by its 
potential diagnostic or therapeutic value for the patient. 
 
III. 
NON-THERAPEUTIC BIOMEDICAL 
RESEARCH 
INVOLVING 
HUMAN 
SUBJECTS (Non-Clinical Biomedical Research) 
19. In the purely scientific application of medical research carried out on a human being, it is the duty 
of the physician to remain the protector of the life and health of that person on whom biomedical 
research is being carried out. 
20. The subject should be volunteers - either healthy persons or patients for whom the experimental 
design is not related to the patient's illness. 
21. The investigator or the investigating team should discontinue the research if in his/her or their 
judgement it may, if continued, be harmful to the individual. 
22. In research on man, the interest of science and society should never take precedence over 
considerations related to the wellbeing of the subject. 
 

SAP_001.pdf: 
 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
1 of 24 
 
Protocol Number: 
ESPERARE_RIM_001 
Version Final 1.0 
Document Date: 
10 Jan 2018 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL: ESPERARE_RIM_001 
 
 
A phase Ib, open label study to evaluate the safety, tolerability, 
pharmacokinetics and pharmacodynamics of multiple ascending 
oral doses of Rimeporide in patients with Duchenne Muscular 
Dystrophy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
3 of 24 
 
Protocol Number: 
ESPERARE_RIM_001 
Version Final 1.0 
Document Date: 
10 Jan 2018 
 
 
Contents 
Abbreviations ...................................................................................................................................... 5 
Revision History ................................................................................................................................. 6 
1. 
Introduction ................................................................................................................................. 7 
2. 
Study Objectives ......................................................................................................................... 7 
2.1 
Primary objective ................................................................................................................. 7 
2.2 
Secondary objectives ............................................................................................................ 7 
2.3 
Exploratory objectives .......................................................................................................... 7 
3. 
Study Design ............................................................................................................................... 7 
3.1 
General design and plan ....................................................................................................... 7 
3.2 
Visit Schedule and Visit Windows ....................................................................................... 9 
3.3 
Sample size justification ..................................................................................................... 10 
3.4 
Randomization and blinding .............................................................................................. 10 
3.5 
Efficacy endpoints .............................................................................................................. 10 
3.6 
Safety endpoints ................................................................................................................. 10 
3.7 
Other endpoints .................................................................................................................. 10 
3.7.1 
PK endpoints ............................................................................................................... 10 
3.7.2 
Exploratory endpoints ................................................................................................. 10 
4. 
Statistical Analysis .................................................................................................................... 11 
4.1 
General ............................................................................................................................... 11 
4.2 
Analysis sets ....................................................................................................................... 11 
4.2.1 
Intent-to-treat set ......................................................................................................... 11 
4.2.2 
Safety set ..................................................................................................................... 11 
4.2.3 
Incorrect treatment allocations .................................................................................... 11 
4.3 
Sub-group analyses ............................................................................................................ 12 
4.4 
Covariates ........................................................................................................................... 12 
4.5 
Pooling of sites ................................................................................................................... 12 
4.6 
Interim analyses .................................................................................................................. 12 
4.7 
Handling of missing and incomplete data .......................................................................... 12 
4.8 
Changes in the planned analysis ......................................................................................... 12 
4.9 
Data Review Meeting ......................................................................................................... 12 
4.10 
Software .......................................................................................................................... 12 
5. 
Evaluation of Demographic and Baseline Characteristics ........................................................ 12 
5.1 
Subject enrolment and disposition ..................................................................................... 12 
5.2 
Protocol violations .............................................................................................................. 13 
5.3 
Study discontinuations ....................................................................................................... 13 
5.4 
Demographics and baseline characteristics ........................................................................ 13 
5.5 
Medical and surgical history .............................................................................................. 14 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
4 of 24 
 
Protocol Number: 
ESPERARE_RIM_001 
Version Final 1.0 
Document Date: 
10 Jan 2018 
 
 
5.6 
Prior and concomitant medications .................................................................................... 14 
5.7 
Other baseline characteristics ............................................................................................. 16 
6. 
Evaluation of Treatment Compliance and Exposure ................................................................ 16 
6.1 
Compliance to study drug and treatment ............................................................................ 16 
6.2 
Exposure to study drug ....................................................................................................... 17 
6.3 
Evaluation of pharmacokinetics ......................................................................................... 17 
7. 
Evaluation of Efficacy .............................................................................................................. 17 
7.1 
Analysis of primary endpoint ............................................................................................. 17 
7.2 
Analysis of secondary efficacy endpoints .......................................................................... 17 
7.3 
Analysis of exploratory efficacy endpoints ........................................................................ 17 
7.4 
Evaluation of pharmacodynamics ...................................................................................... 17 
8. 
Evaluation of Safety .................................................................................................................. 18 
8.1 
Adverse events ................................................................................................................... 18 
8.2 
Clinical laboratory evaluation ............................................................................................ 19 
8.3 
Vital signs ........................................................................................................................... 19 
8.4 
ECGs .................................................................................................................................. 19 
8.5 
Physical examination .......................................................................................................... 19 
8.6 
Other safety evaluations ..................................................................................................... 20 
9. 
Tables, Figures and Listings ..................................................................................................... 20 
9.1 
Programs and tables quality control ................................................................................... 20 
9.2 
Programming conventions .................................................................................................. 20 
9.3 
Tables ................................................................................................................................. 21 
9.4 
Figures ................................................................................................................................ 22 
9.5 
Listings ............................................................................................................................... 23 
10. 
Literature ................................................................................................................................ 23 
11. 
Appendices ............................................................................................................................. 24 
11.1 
Table shells ..................................................................................................................... 24 
11.2 
Figure shells .................................................................................................................... 24 
11.3 
Listing shells ................................................................................................................... 24 
 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
5 of 24 
 
Protocol Number: 
ESPERARE_RIM_001 
Version Final 1.0 
Document Date: 
10 Jan 2018 
 
 
Abbreviations 
AE  
Adverse Event  
ATC  
Anatomical Therapeutic Chemical  
BMI 
Body Mass Index 
CI  
Confidence Interval  
DMD 
Duchenne Muscular Dystrophy 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FVC 
Forced Vital Capacity 
FEV1 
Forced Expiratory Volume at the end of the first 
second 
HPLC 
Liquid Chromatography 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT  
Intent to Treat  
LVEF 
Left Ventricular Ejection Fraction 
MedDRA  
Medical Dictionary for Regulatory Activities 
MP 
Medication Product  
NMRI 
Nuclear Magnetic Resonance Imaging 
NMRS 
Nuclear Magnetic Resonance Spectroscopy 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
SAE(s)  
Serious Adverse Event(s)  
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SI 
International System of Units 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class  
 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
6 of 24 
 
Protocol Number: 
ESPERARE_RIM_001 
Version Final 1.0 
Document Date: 
10 Jan 2018 
 
 
Revision History 
Document Version Changes Made 
Document Date 
Draft 0.1 
Draft specification based on the following documents: 
• Study protocol (Version 2.1, 19 February 2016); 
• CRF (Version 12, 06 June 2016). 
28 Jun 2016 
Draft 0.2 
Version updated after Sponsor’s revision. 
29 May 2017 
Draft 0.3 
Version updated after Sponsor’s revision. 
22 Dec 2017 
Final 1.0 
Version confirmed without additional comments. 
10 Jan 2018 
 
 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
7 of 24 
 
Protocol Number: 
ESPERARE_RIM_001 
Version Final 1.0 
Document Date: 
10 Jan 2018 
 
 
 
1.  Introduction 
This document outlines the statistical methods to be implemented in for the analysis of specific 
type of data of ESPERARE_RIM_001 Clinical Trial that will be managed by CROS NT. The 
purpose of this plan is to provide general guidelines from which the analysis will proceed, 
containing a more technical and detailed elaboration of the principal features of the analysis 
described in the protocol. Any changes to the protocol or electronic Case Report Form (eCRF) may 
necessitate updates to the Statistical Analysis Plan (SAP). In case of deviations from this updated 
SAP, explanations will be provided in the clinical study report. 
All final study data will be considered for the analysis regulated by this SAP. 
2.  Study Objectives 
2.1 
Primary objective 
The objective of the study is to assess safety and tolerability of multiple doses of Rimeporide in 
subjects affected by Duchenne Muscular Dystrophy (DMD).   
2.2 
Secondary objectives 
The secondary objective is to evaluate the pharmacokinetic profile of Rimeporide in pediatric 
patients with Duchenne Muscular Dystrophy (DMD). 
2.3 
Exploratory objectives 
The exploratory objectives are the following: 
• To measure inflammatory and muscular injury biomarkers; 
• To explore the PK/PD relationship of a 4-week Rimeporide treatment on those biomarkers; 
• To explore the relationship between safety endpoints and pharmacokinetic parameters; 
• To explore noninvasively spectroscopy biomarkers (for inflammation, oedema, fat fraction, 
muscle composition) using Nuclear Magnetic Resonance (NMR) imaging after a 4-week 
treatment with Rimeporide (for all patients); 
• To explore noninvasively spectroscopy biomarkers including intracellular pH and 
intracellular Na using Nuclear Magnetic Resonance (NMR) Spectroscopy after a 4-week 
treatment with Rimeporide (for patients recruited in Paris only). 
3.  Study Design 
3.1 
General design and plan  
The EspeRare RIM 001 is a phase Ib, open label, sequential-group study of ascending oral doses of 
Rimeporide administered three-times daily (TID) for 28 days to patients with DMD. 
The study foresees a screening, a treatment and a follow-up period. 
There will be 4 dose levels: 


 
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• Patients with a body weight less than or equal to 30kg at baseline will be administered 50 
or, 100, or 150 or 200-mg TID; 
• Patients with a body weight more than 30kg at baseline will be administered 75 or 150 or 
200 or 300-mg TID. 
 
Each subject will participate in only 1 dose cohort and will receive Rimeporide for a total of 4 
weeks. Five (5) patients are expected to be recruited in each cohort through all participating sites. 
Safety assessments will be made in the clinic at baseline, and after one, two and four weeks of 
treatment as well as 1-2 weeks following the end of treatment period or withdrawal of the study 
medication. 
After the screening visit and if eligibility criteria are confirmed, patients will return to hospital for 4 
study visits during the 4 week treatment period. The first 2 doses of study treatment will be taken in 
the clinic as well as the last dose 28 days later. In between, 2 safety visits at hospital are scheduled 
at weekly intervals during the 2 first weeks of study treatment. A phone call is also planned 3 
weeks after the first dose to discuss the clinical condition of the patient, and note any possible 
adverse events reported by the patient or his parents. 
Safety assessments will also be made in the clinic 1- 2 weeks following the end of treatment period 
or after any premature withdrawal of the study medication. The details of examinations and tests 
that must be performed at study visits are provided in table 1 “Schedule of Assessments” and also 
in the subsequent sections of this protocol. 
The decision to progress to the next higher dose will be made after safety and tolerability data are 
reviewed for the preceding dose for 5 patients by a data Safety Monitoring Committee (SMC) and 
determined that it is safe to proceed to the next dose level. 
 
 


 
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3.2 
Visit Schedule and Visit Windows 
Assessments and study visits will be performed as listed in the table below: 
 
Visit number 
VS 
V1 
V2 
V3 
V4 
V5 
V6 
Unscheduled 
Visit 
Time point 
SCR 
D1 W1 W2 W3 W4 EOS 
Site Visit 
x 
x 
x 
x 
 
x 
x 
x 
Phone call 
 
 
 
 
x 
 
 
 
Inclusion 
Informed consent 
x 
 
 
 
 
 
 
 
Review and confirmation of 
eligibility criteria 
x 
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
6-Minute Walk Test 
x 
 
 
 
 
 
 
 
Pulmonary Function Tests by 
Spirometry 
x 
 
 
 
 
 
 
 
Echocardiography 
x 
 
 
 
 
 
 
 
Local Safety Evaluation 
Physical and neurological 
examination, Weight, Vital 
Signs, Heart Rate, Respiratory 
Rate, Blood Pressure 
x 
x 
x 
x 
 
x 
x 
x 
12 lead ECG, including QTc 
x 
x 
x 
x 
 
x 
x 
x 
Local Biochemistry, 
Hematology, Urinalysis 
x 
x 
x 
x 
 
x 
x 
x 
Gastrin levels 
 
x 
 
 
 
x 
 
 
AEs/SAEs review 
x 
x 
x 
x 
x 
x 
x 
x 
PK sampling profile allocation  
 
PK Blood collection 
 
x 
 
 
 
x 
 
 
Local NMRI (NMRS if 
applicable) 
 
xa 
 
 
 
xb 
 
 
Blood Samples (for central 
analysis: CK total, CK 
isoenzymes, TNFa and TGFβ-1 
and other biomarkers) 
x 
 
 
 
 
x 
 
 
Treatment delivery 
 
xc 
xc 
xc 
 
 
 
 
Treatment compliance 
 
 
x 
x 
x 
x 
x 
x 
Concomitant treatments 
x 
x 
x 
x 
x 
x 
x 
x 
(a) The day before the SD1 
(b) Day 27+/- 2 days, just before the end of treatment period. 
(c) See section 5.1.4.2 drug dispensing of the study protocol. 
 


 
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Paragraph no. 7 “Outline of study procedures” of Study Protocol contains additional details about 
procedures of each scheduled visit and visit time windows. 
3.3 
Sample size justification 
A sample size of 20 evaluable patients has been selected for this phase 1b study, based on practical 
considerations, since this was an exploratory study and not a confirmatory trial. Additional 5 
patients might be included in case safety allows furthering escalating the dosage. 
Due to the rarity of DMD patients the recruitment was competitive across all sites in order to gather 
data in a reasonable timeframe, anticipated to be about 12 months. 
3.4 
Randomization and blinding 
Since this is an open label study, this paragraph is not applicable. 
3.5 
Efficacy endpoints 
No efficacy endpoints were foreseen for this study. 
3.6 
Safety endpoints 
The safety endpoints (which are also the primary ones) are the following:  
• Adverse Events (AEs);  
• Vital Signs, diastolic and systolic blood pressure in supine and standing position, heart rate 
in same position (supine and standing) and respiratory rate;  
• Electrocardiogram (ECG); 
• Laboratory parameters (from blood and urine samples); 
• Patients withdrawn for safety issues. 
3.7 
Other endpoints 
3.7.1 PK endpoints 
The PK endpoints are the secondary endpoints. They consists in the determination of PK profile of 
Rimeporide in plasma derived from modelling using sparse sampling in paediatric patients with 
DMD.  
3.7.2 Exploratory endpoints 
The exploratory endpoints are the following:  
• Changes of plasma / serum levels of the inflammation markers after a 4 week treatment 
with Rimeporide, such as: 
o C - reactive protein (CRP),  
o Tumor Necrosis Factor alfa (TNFα),  
o Transforming Growth Factor beta (TGFβ-1),  
o Other exploratory biomarkers to monitor muscle damages (cytokine panels and 
specific RNA targeting). 
• Changes in NMRI indices for all patients: 


 
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o Muscle Water T2,  
o Muscle with elevated T2 which selectively measures muscle inflammation, 
o Heterogeneity of T2 within the muscle which reflects tissue disorganization, 
o Fat fraction in the muscle. 
• Changes in 31P NMRS indices and 23Na NMRS indices for patients recruited in Paris. 
4.  Statistical Analysis 
4.1 
General 
Descriptive statistics will be provided for all variables in the summary tables by cohort according 
to the type of variable summarized.  
Quantitative variables will be summarised by using n, arithmetic mean, SD, median and range 
(minimum and maximum).  
Categorical variables will be summarised by using frequency distributions and percentages. 
The baseline used in the analysis for each variable is reported in the table below: 
 
Endpoint 
Baseline 
Vital Signs 
Visit 1 - pre-dose    
ECG 
Visit 1 - pre-dose    
Laboratories 
Visit 1 (except for C-reactive protein for which Screening value will 
be used instead) 
Gastrin 
Visit 1  
 
All data collected in the eCRF, concerning CROS NT analysis, will be presented in the listings.  
 
Separate reports regarding PK, PD and NMRI/NMRS will be produced from external vendors. 
 
No multiplicity adjustment nor hypothesis testing will be implemented due to the nature of this 
study. 
4.2 
Analysis sets 
4.2.1 Intent-to-treat set 
All patients who received at least one dose of study drug will be included in the ITT set. 
The PK and exploratory variables will be analysed on the ITT. 
4.2.2 Safety set 
All patients who received at least one dose of study drug will be included in the Safety set. 
This set is defined as the ITT one. As for the safety data presentation, it will be referenced as Safety 
set. 
 
4.2.3 Incorrect treatment allocations 


 
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Not applicable. 
4.3 
Sub-group analyses 
No subgroup analysis will be performed. 
4.4 
Covariates 
Not foreseen. 
4.5 
Pooling of sites 
Not foreseen. 
4.6 
Interim analyses 
No formal interim analysis is planned for the study. 
4.7 
Handling of missing and incomplete data 
Missing values will be included in the denominator count when computing percentages. The 
number of patients with missing data will be presented under the “Missing” category, if present. 
Only the non-missing values will be evaluated for computing summary statistics. 
Missing or incomplete data will be treated as described in chapters 5, 6, 7 and 8.  
4.8 
Changes in the planned analysis 
The following changes were implemented in this SAP with respect to the analyses planned in the 
protocol: 
• 
Other exploratory analysis of safety data, such as summaries for different subsets of 
patients will not be performed according to the Sponsor decision. 
• 
For binary data, no 95% CI will be calculated and presented. 
4.9 
Data Review Meeting 
Not foreseen. 
4.10 Software 
All statistical analyses and data processing will be performed using Statistical Analysis Systems 
(SAS®) Software (release 9.4) on a Windows 7 operating system. 
5.  Evaluation of Demographic and Baseline Characteristics 
5.1 
Subject enrolment and disposition 
Definitions and data conventions 


 
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Date of first study drug intake 
The date of first study drug intake is assumed to be the date of Visit 1. 
 
Completer/discontinued Patient 
A patient will be considered as completer if the answer to the question “Did the subject complete 
the study?” will be equal to “Yes”. 
 
A patient will be considered as discontinued if the answer to the question “Did the subject complete 
the study?” will be equal to “No”. 
 
Statistical analysis 
Disposition of patients will be presented by cohort and overall for the Safety set. 
5.2 
Protocol violations 
Definitions and data conventions 
All the protocol deviations will be evaluated internally case by case from the Sponsor after the 
database soft lock. The Sponsor is expected to provide CROS NT with a list of major/minor 
protocol deviations. 
 
Statistical analysis 
Major protocol deviations will also be summarised for each cohort and overall in the Safety set. 
All protocol deviations will also be listed. 
5.3 
Study discontinuations 
Statistical analysis 
Patients who discontinued from the study prematurely will also be presented with a breakdown of 
the reasons for discontinuation by cohort and overall for the Safety set. 
5.4 
Demographics and baseline characteristics 
Definitions and data conventions 
Age (years) 
Age as already provided in the eCRF will be used for this analysis. 
 
Body Mass Index (BMI) (kg/m2) 
BMI as already provided in the eCRF will be used for this analysis. 
     
Time since DMD diagnosis (years) 
Time since DMD diagnosis (years) will be calculated using the following formula: 
 
Time since DMD diagnosis (years) = (Date of Visit 1 – Date of DMD molecular diagnosis + 
1)/365.25 
 
Statistical analysis 


 
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Baseline and demographic characteristics will be summarised by cohort and overall by means of 
descriptive statistics. 
 
The following characteristics will be provided for the Safety set: 
• 
Age (years) 
• 
Ethinicity (Hispanic or Latino, Not Hispanic or Latino) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander) 
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2) 
• 
Time since DMD diagnosis (years) 
5.5 
Medical and surgical history 
Definitions and data conventions 
Past disease 
A disease is considered as past disease if it is not ongoing at screening visit (“ongoing” box is not 
ticked). 
 
Concomitant disease 
A disease is considered as concomitant disease if it is ongoing at screening visit (“ongoing” box is 
ticked). 
 
Statistical analysis 
Past disease and concomitant diseases will be coded using Medical Dictionary for regulatory 
activities (MedDRA) dictionary (version 18.1) and frequency distributions and percentages will be 
summarised by cohort and overall for the Safety by System Organ Class (SOC) and Preferred Term 
(PT). 
Counts will be given for both SOC and PT by subject. Subjects experiencing more than one 
past/concomitant disease event will be counted only once within each SOC and PT. 
5.6 
Prior and concomitant medications 
Definitions and data conventions 
The following categories of medications will be identified: 
• previous medication (stop date ≤ date of first study medication intake); 
• concomitant medication (stop date > date of first study medication intake or stop date 
ongoing/missing). 
 
In case of missing or incomplete dates/times not directly allowing allocation to any of the two 
categories of medications, a worst-case allocation will be done according to the available parts of 
the start and the end dates. The medication will be allocated to the first category allowed by the 
available data, according to the following order: 
• concomitant medication; 
• previous medication. 


 
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Statistical analysis 
Previous and Concomitant medications 
Medications will be coded using WHO Drug Dictionary (WHO-DD), version March 1st2015, using 
the following Anatomical Therapeutic Chemical Classification (ATC) codes: 
• Anatomical Main Group (ATC 1st level code); 
• Chemical subgroup (ATC 4th level code); 
• Preferred name.  
Previous and concomitant medications will be summarized separately for Safety set by anatomical 
main group, chemical subgroup and preferred name by cohort and overall. 
Subjects experiencing more than one previous (or concomitant) medication within the same 
anatomical main group, chemical subgroup and preferred name will be counted only once. 
5.7 
Other baseline characteristics 
6-Minute Walk Test, spirometry (predicted FEV1 and FVC) and echocardiography (in particular, 
LVEF) at the screening visit will be summarised by cohort and overall by means of descriptive 
statistics. 
6.  Evaluation of Treatment Compliance and Exposure 
6.1 
Compliance to study drug and treatment 
Definitions and data conventions 
Date of first study drug intake 
The date of first study drug intake is assumed to be the date of Visit 1. 
 
Date of last study medication intake 
The date of last study medication intake is the date of last study drug intake recorded on the study 
termination form of the eCRF. 
 
Compliance to study medication 
Compliance to study medication will be evaluated on the basis of the information recorded on the 
eCRF.  
 
On a per patient basis, the evaluation of the compliance during the treatment period will be done 
using the following formula: 
 
100
period
 
 treatment
 the
during
 s
medication
study 
 
scheduled
 
of
number 
 
Total
period
 
 treatment
 the
during
 taken 
s
medication
study 
 
of
number 
 
Total
  
(%)
 
Compliance
´
=
 
 
Total number of 
Study medications taken 
Scheduled study medications 
Sum 
of 
actual 
study 
medications taken from the day 
of first study medication intake 
to 
the 
day 
of 
last 
visit 
Sum 
of 
expected 
study 
medications taken from the day 
of first study medication intake 
to the day of last visit performed 


 
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performed during of treatment 
period. 
during of treatment period. 
 
Statistical analysis 
Compliance to study medication will be summarised by cohort and overall using descriptive 
statistics on the Safety set. An additional summary displaying the number and percentage of 
patients in the following categories will also be presented by cohort and overall: [0%-10%], (10%-
20%], (20%-30%], (xx%-xx%], (90%-100%], >100%.  
6.2 
Exposure to study drug 
Definitions and data conventions 
The extent of exposure (days) will be calculated using the following formula: 
 
Extent of exposure (days) = Date of last study medication intake - Date of first study medication 
intake +1.  
  
Statistical analysis 
Extent of exposure will be summarised by cohort and overall using descriptive statistics on Safety 
set.  
6.3 
Evaluation of pharmacokinetics  
Statistical analysis 
A separate PK report including the details on the statistical analysis of PK data will be produced by 
Calvagone Sarl. 
7.  Evaluation of Efficacy 
7.1 
Analysis of primary endpoint 
Not foreseen. 
7.2 
Analysis of secondary efficacy endpoints 
Not foreseen. 
7.3 
Analysis of exploratory efficacy endpoints 
Not foreseen. 
7.4 
Evaluation of pharmacodynamics 
Statistical analysis 
A separate PD report including the details on the statistical analysis of PD data will be produced by 
Eurofins Scientific. 


 
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8.  Evaluation of Safety 
8.1 
Adverse events 
Definitions and data conventions 
 
Pre-treatment adverse events 
An adverse event (AE) will be classified as pre-treatment AE if it starts before the date/time of first 
study medication intake (AE onset date/time < date/time of first study medication intake). 
 
 
Treatment-emergent adverse event (TEAE) 
An AE will be classified as a TEAE if it starts on or after the date/time of first study medication 
intake (AE onset date/time ≥ date/time of first study medication intake). 
In case of missing or incomplete dates/times not allowing a direct allocation to any of the two 
categories of AEs, a worst-case allocation will be done according to the available parts of the onset 
and the end dates/times. The AE will be allocated to the first category allowed by the available 
data, according to the following order: 
• TEAE 
• Pre-treatment. 
 
Serious adverse event (SAE) 
A SAE is an AE judged as serious. 
 
Adverse drug reaction (ADR) 
An ADR is an AE judged as “Probably related” or “Possibly related”. 
 
Adverse event leading to drug discontinuation 
An AE leading to discontinuation is an AE with action taken equal to “Study drug withdrawn”. 
 
Adverse event leading to death 
An AE leading to death is an AE with outcome equal to “Death: patient died”. 
 
Count of adverse events 
Two AEs with the same Preferred Term (PT) and classified in the same category (pre-treatment AE 
or TEAE) will be considered as two different events when calculating the “number of events” in 
the tables.  
 
Statistical analysis 
Pre-treatment AEs and TEAEs will be presented separately. Pre-treatment AEs will be presented in 
the listings only. 
The number of treatment-emergent AEs, SAEs, ADRs, AEs leading to drug discontinuation and 
AEs leading to death, and the number and the percentage of patients experiencing treatment-
emergent AEs, SAEs, ADRs, AEs leading to drug discontinuation and AEs leading to death will be 
summarised by cohort and overall.  
AEs will be coded using the MedDRA dictionary (version 18.1). The SOCs and PTs will be used 
for tabulation. The number of AEs and the number and the percentage of patients with at least one 


 
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AE will be presented by SOC and PT for treatment-emergent AEs, SAEs, ADRs, serious ADRs, 
severe AEs, AEs leading to drug discontinuation and AEs leading to death by cohort and overall. 
8.2 
Clinical laboratory evaluation 
Statistical analysis 
Haematology parameters, biochemistry parameters, gastrin levels and the change from baseline will 
be summarised by cohort at each timepoint by means of descriptive statistics. 
In order to perform the above described summaries, different units need to be standardized 
according to SI units. The Sponsor agreed to support CROS NT in the conversion process before 
the DB hard lock. 
 
The following figures will be displayed graphically: 
• Haematology and biochemistry patient profiles during the study for each parameter as 
well as for Gastrin levels; 
• Haematology and biochemistry median values per cohort during the study for each 
parameter as well as for Gastrin levels. 
8.3 
Vital signs 
Statistical analysis 
Weight (kg), Systolic Blood Pressure – Supine (mmHg), Diastolic Blood Pressure - Supine 
(mmHg), Heart Rate – Supine (bpm), Systolic Blood Pressure Standing (mmHg), Diastolic Blood 
Pressure – Standing (mmHg), Heart Rate – Standing (bpm), Respiratory Rate (breaths/min),  
Temperature (Celsius) will be summarised by cohort at each timepoint by means of descriptive 
statistics. 
 
The following figures will be displayed graphically: 
• Vital signs patient profiles during the study for each parameter; 
• Vital signs median values per cohort during the study for each parameter. 
8.4 
ECGs 
Statistical analysis 
Heart Rate (bpm), PR interval (msec), QRS duration (msec), QTc interval (msec), QTcB interval 
(msec), QTcF interval (msec), QRS Axis (degree) and the change from baseline will be 
summarised by cohort at each timepoint by means of descriptive statistics. 
 
The following figures will be displayed graphically: 
• 12-lead ECG patient profiles during the study for each parameter; 
• 12-lead ECG median values per cohort during the study for each parameter. 
8.5 
Physical examination 
Statistical analysis 
Physical examinations will be listed only. 


 
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8.6 
Other safety evaluations 
NMRI/NMRS 
Statistical analysis 
A separate NMRI/NMRS report will be produced including the details on the statistical analysis of 
NMRI/NMRS data by CRIS scrl. 
 
Neurological examination 
Statistical analysis 
Neurological examinations will be listed only. 
9.  Tables, Figures and Listings 
9.1 
Programs and tables quality control 
The statistician-programmer of the tables, listings and figures will carefully review the programs 
and will verify that no error message is highlighted in the ‘LOG’ file.  
Moreover, a second statistician-programmer will verify the internal consistency of each table and 
figure by checking the results using different SAS programs.  
 
The following level of validation will be implemented:  
• Validation of statistical datasets: via validation of tables. 
• Validation of statistical output:  
- 
tables: Independent programming and comparison of main results; 
- 
listings: Peer review of the program code used to create the output; 
- 
figures: Peer review of the program code used to create the output. 
9.2 
Programming conventions 
All tables/figures/listings will be presented in landscape format.  
The standard font size is 9 points Arial for all tables. Listings will be presented with an 8 or 7 
points Arial.  
 
Titles will be center-aligned; footnotes will be left-aligned.  
Each table/figure/listing will have 2 titles: 
• 
The 1st title will be the table/figure/listing number with the description of the 
table/figure/listing;  
• 
The 2nd title will be a description of the study set presented in the table/figure/listing. 
Some tables will have a third title (before 2nd title) with a description of the statistical method used 
in those tables. 
 
Any footnote added to explain the table/listing/figure contents will be presented in the following 
format: 
Note 1: Percentages are calculated on the number of patients (N). 
Note 2: A serious adverse event is an .... 
Note 3: ………. 


 
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The last two footnotes of each table/figure will be footers indicating: 
• 
the reference listing of the data; 
• 
the program name, the date and time of generation and the SAS® version used. 
The last footnote of each listing will be a footer indicating the program name, the date and time of 
generation and the SAS® version used. 
 
In the tables, listing and figures the treatment under comparison will be labelled as “Cohort 1”, 
“Cohort 2”, “Cohort 3” and “Cohort 4”. 
 
Unless otherwise stated, listings will be presented by cohort, and sorted by the patient number.  
 
All the listings will be based on the Safety set. 
 
The derived variables will be identified in the listings with a flag (*). 
 
In general, dates will be presented on listings in the format ddmmmyyyy (date9.) and time in the 
format hh:mm (time5.). In case of partial dates or times, missing information will be replaced by 
dashes. Numeric variables will be listed generally with the same number of decimal places as in the 
actual data. 
 
The following rules on decimal places will be considered in the listings for the derived variables (in 
the analyses approximations will not be performed): 
• 
Age (years), extent of exposure (days): 0 decimal place; 
• 
BMI (kg/m2), time since disease diagnosis (years), compliance to study medication: 1 
decimal place; 
• 
change from baseline: same as the variable considered. 
 
The following rules on decimal places will be considered for the results of the analyses (if the 
analyses are performed on derived variables, the level of precision of the actual data is derived 
from the previous list): 
• 
Min, max: same as actual data; 
• 
Mean and its confidence limits (unadjusted and adjusted), adjusted difference between 
means and its confidence limits, SD, median: actual data + 1 decimal; 
• 
Percentage: 1 decimal place; 
9.3 
Tables 
The list of tables is provided here below: 
 
 
TABLE 
TITLE 
TABLE T14.1-1 
DISPOSITION OF PATIENTS / SUMMARY OF ALL PATIENTS  
TABLE T14.1-2.1 
PRIMARY REASONS FOR DISCONTINUATION FROM THE STUDY / 
SAFETY SET 
TABLE T14.1-3.1 
SUMMARY OF MAJOR PROTOCOL DEVIATIONS / SAFETY SET 
TABLE T14.1-4.1 
DEMOGRAPHIC CHARACTERISTICS 


 
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TABLE 
TITLE 
TABLE T14.1-5.1 
PAST DISEASES / SAFETY SET 
TABLE T14.1-5.2 
CONCOMITANT DISEASES / SAFETY SET 
TABLE T14.1-6.1 
PREVIOUS MEDICATIONS / SAFETY SET 
TABLE T14.1-6.2 
CONCOMITANT MEDICATIONS / SAFETY SET 
TABLE T14.1-7 
ECHOCARDIOGRAPHY, 6-MINUTE WALK TEST AND SPIROMETRY 
AT SCREENING / SAFETY SET 
TABLE T14.1-8 
COMPLIANCE TO STUDY MEDICATION / SAFETY SET 
TABLE T14.1-9 
EXTENT OF EXPOSURE / SAFETY SET 
TABLE T14.3.1-1 
SUMMARY OF TREATMENT-EMERGENT ADVERSE EVENTS / 
SAFETY SET 
TABLE T14.3.1-2 
TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM ORGAN 
CLASS AND PREFERRED TERM / SAFETY SET 
TABLE T14.3.1-3 
SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS BY SYSTEM 
ORGAN CLASS AND PREFERRED TERM / SAFETY SET 
TABLE T14.3.1-4 
TREATMENT-EMERGENT ADVERSE DRUG REACTIONS BY 
SYSTEM ORGAN CLASS AND PREFERRED TERM / SAFETY SET 
TABLE T14.3.1-5 
TREATMENT-EMERGENT ADVERSE EVENTS LEADING TO DRUG 
DISCONTINUATION BY SYSTEM ORGAN CLASS AND PREFERRED 
TERM / SAFETY SET 
TABLE T14.3.1-6 
TREATMENT-EMERGENT ADVERSE EVENTS LEADING TO DEATH 
BY SYSTEM ORGAN CLASS AND PREFERRED TERM / SAFETY SET 
TABLE T14.3.4-1.1 
VITAL SIGNS DURING THE STUDY AND CHANGE FROM BASELINE 
/ SAFETY SET 
TABLE T14.3.4-2.1 
12-LEAD ELECTROCARDIOGRAM PARAMETERS DURING THE 
STUDY AND CHANGE FROM BASELINE / SAFETY SET 
TABLE T14.3.4-3.1 
HEMATOLOGY LABORATORY PARAMETERS DURING THE STUDY 
AND CHANGE FROM BASELINE / SAFETY POPULATION 
TABLE T14.3.4-3.2 
BIOCHEMISTRY LABORATORY PARAMETERS AND GASTRIN 
LEVELS DURING THE STUDY AND CHANGE FROM BASELINE / 
SAFETY POPULATION 
9.4 
Figures 
The list of figures is provided here below: 
 
 
FIGURE 
TITLE 
FIGURE F14.3.4-1.1.1 
HEMATOLOGY PATIENT PROFILES DURING THE STUDY / 
<PARAMETER X> / SAFETY SET 
FIGURE F14.3.4-1.1.2 
HEMATOLOGY DURING THE STUDY / <PARAMETER X> / SAFETY 
SET 
FIGURE F14.3.4-1.2.1 
BIOCHEMISTRY AND GASTRIN PATIENT PROFILES DURING THE 
STUDY / <PARAMETER X> / SAFETY SET 
FIGURE F14.3.4-1.2.2 
BIOCHEMISTRY AND GASTRIN DURING THE STUDY / 
<PARAMETER X> / SAFETY SET 
FIGURE F14.3.4-2.1 
12-LEAD ECG PATIENT PROFILES DURING THE STUDY / 
<PARAMETER X> / SAFETY SET 
FIGURE F14.3.4-2.2 
12-LEAD ECG DURING THE STUDY / <PARAMETER X> / SAFETY 
SET 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
23 of 24 
 
Protocol Number: 
ESPERARE_RIM_001 
Version Final 1.0 
Document Date: 
10 Jan 2018 
 
 
FIGURE 
TITLE 
FIGURE F14.3.4-3.1 
VITAL SIGNS PATIENT PROFILES DURING THE STUDY / 
<PARAMETER X> / SAFETY SET 
FIGURE F14.3.4-3.2 
VITAL SIGNS DURING THE STUDY / <PARAMETER X> / SAFETY 
SET 
9.5 
Listings 
The list of listings is provided here below: 
 
 
LISTING 
TITLE 
LISTING 16.2.1-1 
DISPOSITION OF PATIENTS / SAFETY SET 
LISTING 16.2.1-2 
STUDY TERMINATION / SAFETY SET 
LISTING 16.2.2-1 
PROTOCOL DEVIATIONS / SAFETY SET 
LISTING 16.2.2-2 
VIOLATIONS OF INCLUSION/EXCLUSION CRITERIA / SAFETY SET 
LISTING 16.2.3-1 
POPULATIONS FOR ANALYSIS / SAFETY SET 
LISTING 16.2.4-1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS / SAFETY SET 
LISTING 16.2.4-2 
PHYSICAL EXAMINATIONS / SAFETY SET 
LISTING 16.2.4-3 
NEUROLOGICAL EXAMINATION / SAFETY SET 
LISTING 16.2.4-4 
6-MINUTE WALK TEST / SAFETY SET 
LISTING 16.2.4-5 
ECHOCARDIOGRAPHY / SAFETY SET 
LISTING 16.2.4-6 
SPIROMETRY / SAFETY SET 
LISTING 16.2.4-7 
PAST-CONCOMITANT DISEASES / SAFETY SET 
LISTING 16.2.5-1 
MEDICATIONS / SAFETY SET 
LISTING 16.2.5-2 
STUDY DRUG ADMINISTRATION / SAFETY SET 
LISTING 16.2.5-3 
DISMISSAL / SAFETY SET 
LISTING 16.2.5-4 
STUDY DRUG COMPLIANCE AND DISPENSATION / SAFETY SET 
LISTING 16.2.7-1.1 
TREATMENT-EMERGENT ADVERSE EVENTS / SAFETY SET 
LISTING 16.2.7-1.2 
SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS / SAFETY SET 
LISTING 16.2.7-1.3 
TREATMENT-EMERGENT ADVERSE DRUG REACTIONS / SAFETY SET 
LISTING 16.2.8-1 
VITAL SIGNS / SAFETY SET 
LISTING 16.2.8-2 
LABORATORY PARAMETERS AND GASTRIN LEVELS / SAFETY SET 
LISTING 16.2.8-3 
ABNORMAL LABORATORY PARAMETERS / SAFETY SET 
LISTING 16.2.8-4 
12-LEAD ECG / SAFETY SET 
 
 
 
 
 
     
 
 
 
 
 
 
10.  
Literature 
• 
CROS NT Standard Operating Procedure SOP ST03/V01 “Statistical Analysis Plans”;  
• 
European Medicines Agency (EMA), International Conference on Harmonisation (ICH) E3 
Harmonised Guideline (1996) “Structure and Content of Clinical Study Reports”; 
• 
EMA, ICH E9 Harmonised Guideline (1998) “Statistical Principles for Clinical Trials”. 


 
Forms  
Title 
Statistical Analysis Plan Template 
Code 
Version 
Effective Date 
Page 
FRM_ST03_032 
01 
23 Apr 2015 
24 of 24 
 
Protocol Number: 
ESPERARE_RIM_001 
Version Final 1.0 
Document Date: 
10 Jan 2018 
 
 
11.  
Appendices  
11.1 Table shells 
See document “AppendixI_ESPERARE_RIM_001_180110(Final1.0)docx”. 
11.2 Figure shells 
Not foreseen. 
11.3 Listing shells 
Not foreseen.