Clinical trial NCT02473445
Conditions: Mitochondrial Diseases
Keywords: Inherited mitochondrial disease Leigh Syndrome Leber's Hereditary Optic Neuropathy (LHON) Myoclonic epilepsy and ragged-red fibers (MERFF) Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS) Kearn-Sayre syndrome Polymerase gamma (POLG) -related disorders Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE)
Sponsor: Amgen
Start date: 2015-05-19; Completion date: 2017-03-06
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A long-term extension study to assess the safety, tolerability and efficacy of cysteamine bitartrate delayed-release capsules (RP103) in children with inherited mitochondrial diseases who previously enrolled into study RP103-MITO-001 (NCT02023866).

Detailed description:
Patients with inherited mitochondrial diseases associated with nuclear or mitochondrial deoxyribonucleic acid (DNA) mutations that impair the respiratory chain. These include, but are not limited to the following clinical syndromes: Leber's hereditary optic neuropathy; myoclonic epilepsy and ragged-red fibers (MERFF); mitochondrial encephalomyopathy, lactic acidosis, and stroke-like syndrome (MELAS); Kearn-Sayre syndrome; subacute necrotizing encephalopathy (Leigh Syndrome); polymerase gamma (POLG)-related disorders (Alpers-Huttenlocher Syndrome, Autosomal Dominant Progressive External Ophthalmoplegia, Autosomal Recessive Progressive External Ophthalmoplegia, Childhood Myocerebrohepatopathy Spectrum Disorders, Myoclonic Epilepsy Myopathy Sensory Ataxia, POLG-Related Ataxia Neuropathy Spectrum Disorders); Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), also called myoneurogastrointestinal encephalopathy syndrome or polyneuropathy-ophthalmoplegia-leukoencephalopathy- Intestinal pseudoobstruction (POLIP) syndrome; others, e.g., mitochondrial cardiomyopathies and other syndromes due to multiple mitochondrial DNA deletions.

Patients completing study RP103-MITO-001 (NCT02023866) are eligible for enrollment into the extension study RP103-MITO-002 if all inclusion and exclusion criteria are fulfilled. Subjects continue on the last total daily dose of cysteamine bitartrate delayed-release capsules taken during RP103-MITO-001. Dose-adjustments are permitted.

Study with completed results acquired from Horizon in 2024.

Arms: arm 1: Participants received cysteamine bitartrate delayed-release capsules (RP103) twice daily for up to 2 years. The starting dose was the same as the last dose received in study RP103-MITO-001, the maximum dose was 1.3 g/m²/day.
Interventions: intervention 1: Cysteamine Bitartrate
Intervention descriptions: intervention 1: Cysteamine Bitartrate Delayed-release capsules

Protocol documents:
Prot_000.pdf: 



































































































SAP_001.pdf: 
 
STATISTICAL ANALYSIS PLAN 
Protocol RP103-MITO-002 
A Long-Term Open-Label Extension Study of RP103-MITO-001 to Assess the Safety, 
Tolerability and Efficacy of Cysteamine Bitartrate Delayed-release Capsules (RP103) for 
Treatment of Children with Inherited Mitochondrial Disease 
 
Protocol Number: 
(Version Date) 
RP103-MITO-002 
December 16 , 2014 
 
Name of Test Drug: 
RP103 
 
Phase: 
2a 
 
Methodology: 
Open-Label, Extension 
Sponsor: 
Horizon Pharma USA, Inc. 
150 S. Saunders Road 
Lake Forest, IL 60045 
Sponsor Representative: 
,
 
Chief Medical Officer & Executive Vice President Research 
and Development 
Horizon Pharma Inc. 
 
 
 
Document Date: 
October 16, 2017 
 
Document Version: 
Version 1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality 




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TABLE OF CONTENTS 
 
Section 
Page 
1. INTRODUCTION AND OBJECTIVES OF ANALYSIS ........................................................................................ 7 
1.1. 
Introduction ................................................................................................................................................ 7 
1.2. 
Study Objectives ......................................................................................................................................... 7 
2. STUDY DESIGN .......................................................................................................................................... 7 
2.1. 
Synopsis of Study Design ............................................................................................................................ 7 
2.2. 
Randomization Methodology .................................................................................................................... 8 
2.3. 
Stopping Rules ............................................................................................................................................ 8 
2.4. 
Study Procedures ........................................................................................................................................ 8 
2.5. 
Safety Variables ....................................................................................................................................... 10 
3. SUBJECT POPULATIONS .......................................................................................................................... 10 
3.1. 
Population Definitions .............................................................................................................................. 10 
3.1.1. 
Safety Analysis Set (SAF) ............................................................................................................. 10 
3.2. 
Protocol Deviations .................................................................................................................................. 10 
4. STATISTICAL METHODS ........................................................................................................................ 11 
4.1. 
Sample Size Justification .......................................................................................................................... 11 
4.2. 
General Statistical Methods and Data Handling ..................................................................................... 11 
4.2.1. 
General Methods .................................................................................................................... 11 
4.2.2. 
Computing Environment ............................................................................................................ 11 
4.2.3. 
Methods of Pooling Data ............................................................................................................ 11 
4.2.4. 
Adjustments for Covariates ........................................................................................................ 11 
4.2.5. 
Multiple Comparisons/Multiplicity ............................................................................................. 11 
4.2.6. 
Withdrawals, Dropouts, Loss to Follow-up ................................................................................ 11 
4.2.7. 
Missing, Unused, and Spurious Data .......................................................................................... 12 
4.2.8. 
Visit Windows ......................................................................................................................... 12 
4.2.9. 
Baseline Definitions .................................................................................................................... 12 
4.3. 
Interim Analyses ....................................................................................................................................... 12 
4.4. 
Subject Disposition ................................................................................................................................... 12 
4.5. 
Demographic and Baseline Characteristics ............................................................................................. 12 
4.6. 
Safety Analyses ........................................................................................................................................ 13 
4.6.1. 
Study Drug Exposure .................................................................................................................. 13 
4.6.2. 
Adverse Events ........................................................................................................................ 13 
4.6.3. 
Laboratory Data .......................................................................................................................... 14 
4.6.4. 
Vital Signs and Physical Examinations ..................................................................................... 14 
4.6.5. 
Neurological Examination ........................................................................................................... 14 
4.6.6. 
Electrocardiogram ...................................................................................................................... 14 
4.6.7. 
Concomitant Medications .......................................................................................................... 14 


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Section 
Page 
5. 
CHANGES TO PLANNED ANALYSES ....................................................................................................... 15 
6. 
List of tables and Listings......................................................................................................................... 16 


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LIST OF IN-TEXT TABLES 
Table 
Page 
 
Table 1 
Schedule of Assessments ................................................................................................... 9 


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ABBREVIATIONS 
 
Abbreviation 
Definition 
AE 
Adverse events 
ADL 
Activities of Daily Living 
BSA 
Body Surface Area 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
FARS 
Friedreich Ataxia Rating Scale 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FRDA 
Friedreich’s Ataxia 
GMFM 
Gross Motor Function Measure 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
LHON 
Leber’s Hereditary Optic Neuropathy 
MedDRA 
Medical Dictionary for Regulatory Activities 
NPMDS 
Newcastle Pediatric Mitochondrial Disease Scale 
NYHA 
New York Heart Association 
PT 
Preferred Term 
ROS 
Reactive Oxygen Species 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical analysis plan 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 
6MWT 
6-Minute Walk Test 
8MW 
8-Minute Walk 
9-HPT 
9-Hole Peg Test 


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1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
Study RP103-MITO-002 was closed prematurely after decision by the Sponsor to end 
development of RP103 for mitochondrial disease. This statistical analysis plan (SAP) describes 
the safety analyses that will be performed for Study RP103-MITO-002, based on the study 
protocol dated 16DEC2014. 
 
 
1.2. 
Study Objectives 
The primary objective is to assess safety, tolerability and efficacy of long-term repeat dosing of 
RP103 in subjects with inherited mitochondrial disease. 
The secondary objective is to assess the steady-state pharmacokinetics (PK) and 
pharmacodynamics (PD) of RP103 at steady state, in children with inherited mitochondrial 
disease. 
 
2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This is an open-label extension study of RP103-MITO-001 to assess the safety, tolerability, and 
efficacy of Cysteamine Bitartrate Delayed-release Capsules (RP103) for treatment of children 
with inherited mitochondrial disease. 
Subjects who have completed all visits associated with Study RP103-MITO-001 will be offered 
enrollment in this extension study. If enrolled in RP103-MITO-002, subjects will return to the 
clinic quarterly (every 3 months) for detailed assessments. 
 
Study visits will occur as follows: 
Day 1 (Baseline): is the day of enrollment, and will occur simultaneously with the RP103-MITO- 
001 Study Exit Visit. 
Quarterly Visits: will begin within 3 months (±7 days) of the RP103-MITO-002 Day 1 Visit and 
will continue quarterly (every 3 months). 
Study Exit Visit: will take place upon study completion (i.e. marketing approval has been granted 
for RP103 and the subject is able to obtain in commercially), study termination, or upon individual 
subject termination. 
 
The maximum treatment time in the study is estimated to be 24 months. 
 
Upon RP103-MITO-002 study entry, subjects will continue on the last total daily dose of RP103 
taken during the previous RP103-MITO-001 study. Subsequent RP103 dose adjustments are 
permitted (e.g. as the subject grows, or if deemed necessary by the Investigator for tolerability 
reasons). 
 
The Sponsor’s medical officer may be consulted for assistance making RP103 dose adjustment 
decisions at any time during the study. NOTE: For each subject, when calculating the number of 


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capsules to be taken every 12 hours (i.e. half of the prescribed total daily dose), if rounding is 
required to get a whole number of capsules to be taken, then rounding should be down and not 
up. 
 
 
2.2. 
Randomization Methodology 
As this is an open label study with a single test drug, no randomization methodology is 
employed. 
 
2.3. 
Stopping Rules 
Close monitoring of the subjects during the study is performed.  Any decision to stop the 
clinical trial is immediately communicated to all Investigators and to the United States FDA and 
regulatory authorities of any other participating countries. 
 
Individual subject dosing is stopped if: 
• A subject exhibits a treatment-emergent adverse event of Common Terminology 
Criteria for Adverse Events (CTCAE) Grade 3 or higher and not likely related to the 
underlying disease, and possibly, probably or definitely related to study drug. 
 
A subject is discontinued if they exhibit an: 
• Unexplained fever (> 38.5°C) for > 24 hours. 
 
The study is halted and FDA (or participating regulatory authority) will be consulted if: 
• Two or more subjects develop the same CTCAE Grade 3 adverse event; 
• One subject develops a CTCAE Grade 4 adverse event; 
• One or more unexpected drug-related deaths. 
• Onset of one or more drug-related cases of: 
- 
Heart failure (NYHA Class II or greater); 
- 
Respiratory failure (Type 1 or Type 2); 
- 
Acute liver failure (associated with an international normalized ratio (INR) of 
greater than 1.5, and any degree of mental alteration (encephalopathy) in a 
subject without preexisting cirrhosis); 
- 
Malignant hypertension (i.e., Diastolic blood pressure > 140 mmHg); 
- 
Nephrotic syndrome which includes protein in the urine (more than 3.5 grams per 
day) and one or more of the following clinically significant symptoms: low blood 
protein levels and/or high cholesterol levels and/or high triglyceride levels and/or 
edema. 
 
2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Table 1. 


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Table 1 
Schedule of Assessments 
PROCEDURE 
Baseline 
Day 1 
Quarterly Visits 
Every 3 months 
Study Exit 
Allowable Visit Window 
None 
+/- 7 days 
+/- 7 days 
Informed Consent 
X 
Assess/Confirm Eligibility 
X 
Enrollment 
X 
Medical and Medication Histories 
X 
Monitoring of Adverse Events 
X 
X 
X 
Adverse Events Checklist 
X 
X 
X 
Review of Concomitant Meds 
X 
X 
X 
Vital Signsa (including body temperature) 
X 
X 
X 
Height, Weight, Head Circumferencea 
X 
X 
X 
BMI / BSA Calculationsa 
X 
X 
X 
12-lead ECGa 
X 
X 
X 
Physical Examinationa 
X 
X 
X 
Clinical Laboratory Testsa,b 
X 
X 
X 
Serum Pregnancy Test a(if applicable) 
X 
X 
X 
Breath Samples for Hydrogen Sulfidea 
X 
X 
X 
PD Biomarker Sample Collection b,c 
X 
X 
X 
PK Sample Collection c 
X 
X 
X 
Record Seizure Activityd 
X 
X 
X 
Subject Diary Training/Dispense 
X 
X 
Subject Diary Collect/Review/Sign 
X 
X 
X 
RP103 Administration 
X 
X 
X 
Dispense and / or Collect RP103e 
X 
X 
X 
Administer age-specific NPMDS 
X 
X 
X 
Conduct two of the following assessments, 
already specified during participation in previous Study RP103-MITO-001: 
6-minute Walk Test ; 
Jama Dynamometer 
X 
X 
X 
Barry-Albright Dystonia Scale 
X 
X 
X 
Friedreich Ataxia Rating Scale 
X 
X 
X 
Modified Lansky Play Performance 
Scale 
X 
X 
X 
Gross Motor Function Measure 
X 
X 
X 
Vision/Eye Examination 
X 
X 
X 
Schedule of Events Footnotes 
a 
 RP103-MITO-001 Study Exit is to take place on the same day as RP103-MITO-002 Day 1 (Baseline). Data 
collected from the RP103-MITO-001 study (i.e. medical history, ongoing adverse events, concomitant 


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medications, Study Exit vital signs) may be carried forward to the extension study clinical database. Data 
recording and entry instructions will be supplied via the electronic CRF instructions. 
b 
 Clinical Laboratory Tests and PD Biomarkers are specified in Protocol Table 2; Samples for Clinical 
Laboratory Tests and PD Biomarkers should be collected at the same time as PK blood samples. 
c 
PK blood samples will be collected within 30 minutes before or after the RP103 morning dose. 
d 
Seizure activity may be recorded by patients/caregivers using a paper seizure diary handed out by the site, 
or the form provided on www.seizuretracker.com website. If patients use the web-based form, it must be 
printed out and used as source documentation for any associated CRF data entry. 
e 
RP103 from the previous Study RP103-MITO-001 must be taken for the morning dose and associated PK 
blood draws on the day of Study Exit. Then, RP103 for Study RP103-MITO-002 is to be dispensed for the 
evening dose (RP103-MITO-002 Day 1) and to be taken every 12 hours for the remainder of participation 
in Study RP103-MITO-002. 
 
 
 
 
2.5. 
Safety Variables 
 
The safety profile of RP103 will be investigated through analysis of the following safety 
assessments: clinical laboratory tests, vital signs, physical examination, 12-lead ECG, urinalysis, 
serum pregnancy, concomitant medications, and subject incidence of treatment-emergent 
adverse events. 
 
3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
The following analysis population will be used. 
 
3.1.1. 
Safety Analysis Set (SAF) 
The safety analysis set (SAF) is defined as all subjects who received at least one dose of study 
drug (RP103). 
The SAF is the primary population for the analysis of safety endpoints. 
 
 
 
3.2. 
Protocol Deviations 
The following protocol deviations will be recorded and summarized in the final report: 1) eligibility 
(inclusion/exclusion) violations, 2) study drug dosing violations, 3) excluded medication violations, 
4) procedures performed outside the protocol-specified window, 5) procedures not done, 6) subject 
non-compliance and 7) other, to be specified by the Investigator. All protocol deviations will be 
presented in a by-subject data listing. 


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4. 
STATISTICAL METHODS 
4.1. 
Sample Size Justification 
The sample size will be up to 35 subjects (the number of subjects dosed in study RP103-MITO- 
001). 
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
Tabulations will be produced for appropriate demographic, baseline, and safety parameters. For 
categorical variables, summary tabulations of the number and percentage within each category 
(with a category for missing data) of the parameter will be presented. For continuous variables, 
the mean, median, standard deviation, minimum and maximum values will be presented. 
Additional statistics may be presented for certain endpoints as described in the sections below. 
All output will be incorporated into Microsoft Excel or Word files, sorted and labeled according 
to the International Conference on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
4.2.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.2 
or later), unless otherwise noted. Adverse Events will be coding using MedDRA version 17.0 
or later. Concomitant medications will be coded using World Health Organization (WHO) 
Drug (June 2013). 
4.2.3. 
Methods of Pooling Data 
Not applicable to the present study. 
4.2.4. 
Adjustments for Covariates 
No formal statistical analysis that adjusts for possible covariate effects is planned. 
4.2.5. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this exploratory study with a descriptive interpretation. 
4.2.6. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects will be informed that they are free to withdraw from the study at any time and for any 
reason. The Investigator may withdraw a subject from the study if, in the Investigator’s opinion, 
it is not in their best interest to continue participation. Notification of early termination will 
immediately be made to the Sponsor’s representative(s). 
In case of early termination the subject must return to the clinical for a Study Exit visit within 4 
weeks after last dosing (28 days +/- 7 days) and perform all assessments detailed in the Schedule 
of Events (Table 1). The reason for discontinuation will be recorded in source documentation and 
the eCRF. 
Subjects may be withdrawn from the study for the following reasons: 
• Adverse event(s); 
• Pregnancy; 
• Withdrawal of consent; 


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• Subject non-compliance; 
• Investigator decision; 
• Sponsor decision, i.e., cancellation of drug development; 
• Request from regulatory agency (e.g. FDA), Institutional Review Board, or Ethics 
Committee. 
4.2.7. 
Missing, Unused, and Spurious Data 
In general, there will be no substitutions made to accommodate missing data points. All data 
recorded on the CRF will be included in data listings that will accompany the clinical study 
report. 
4.2.8. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data will be 
tabulated per the nominal visit as recorded in the database.  In data listings, the relative day of 
all dates will be presented. Relative days will be calculated relative to the first dose of study drug. 
Day 1 will be the first day of study drug administration in the study, and the day prior to the first dose of 
study drug administration will be Day -1. There will be no Day 0. 
4.2.9. 
Baseline Definitions 
For all endpoints involving a baseline measure, baseline will be the value obtained at day 1. 
4.3. 
Interim Analyses 
No interim analyses are planned for this study. 
 
4.4. 
Subject Disposition 
Subject disposition will be tabulated, including the number of subjects enrolled and treated, the 
number of subjects that withdrew prior to completing the study and primary reasons for 
withdrawal, as well as the number of subjects in the Safety Analysis Set. 
A by-subject listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented. 
 
 
4.5. 
Demographic and Baseline Characteristics 
Demographic, baseline characteristics, mitochondrial disease subtype, and medical history is 
summarized using descriptive statistics and presented for the SAF. 
Age, height, weight, body mass index (BMI), and body surface area (BSA) will be summarized 
using descriptive statistics (number of subjects, mean, standard deviation, median, minimum, 
and maximum). The number and percentage of subjects by sex and racial/ethnic category will 
also be presented. 
All collected demographic, baseline characteristic, and medical history data will be provided in 
data listings. 


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4.6. 
Safety Analyses 
Safety analyses will be conducted using the Safety Analysis Set. 
4.6.1. 
Study Drug Exposure 
Descriptive statistics will be presented for total duration of exposure in days, computed as the 
last dose - first dose + 1. Duration of exposure will also be summarized in weeks by dividing the 
exposure in days by 7. Additionally, the number and percent of subjects completing dosing 
through duration categories (>= 1 day, >= 12 weeks, >= 24 weeks, etc.) will be presented. 
Dosing compliance will be assessed by tabulating the number of days in which a subject missed 
a dose up through date of study discontinuation. All dosing data will be presented in a data 
listing with a record for each dosing event as documented on the subject daily diaries and in- 
clinic administration records. 
4.6.2. 
Adverse Events 
Adverse events will be coded using the MedDRA (version 17.0) coding system and displayed in 
tables and data listings using system organ class (SOC) and preferred term (PT). 
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where a treatment-emergent adverse event (TEAE) is defined as any AE with onset after Day 1 
of drug administration.  TEAEs will also be summarized. If the start date of an AE is partially or 
completely missing, the date will be compared as far as possible with the date of the start of 
administration of study drug.  If the start date/time of an AE is partially or completely missing, 
the date/time will be compared as far as possible with the date/time of the start of administration 
of study drug.  The AE will be assumed to be treatment emergent if it cannot be definitely 
shown that the AE did not occur or worsen during the treatment-emergent period (worst case 
approach).  The following approach will be taken: 
• 
If the start time of an AE is missing but the start date is complete, an AE will only be 
excluded as being treatment emergent if the start date is before the date of Day 1 study drug 
administration or if the stop date/time is before Day 1 study drug administration. 
• 
If the start time and day are missing but the start month and year are complete, an AE will 
only be excluded as being treatment emergent if the start month/year is before the 
month/year of Day 1 study drug administration or if the stop date/time is before Day 1 study 
drug administration. 
• 
If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment emergent if start year is before the year of Day 1 study drug 
administration or if the stop date/time is before Day 1 study drug administration. 
• 
If the start date is completely missing, an AE will be considered treatment-emergent unless 
the stop date/time is before Day 1 study drug administration. 
These imputations will be used for determining treatment emergence for adverse events; the un- 
imputed partial dates will be included in the data listings. 
Adverse events are summarized by subject incidence rates; therefore, in any tabulation, a subject 
contributes only once to the count for a given SOC or preferred term. 
The number and percentage of patients with any treatment-emergent AE (TEAE) and with any 
related TEAE, with any Grade >= 3 TEAE, with any serious TEAE, and with any TEAE leading 


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to withdrawal of study drug, and will be tabulated.  In these tabulations, related is defined as any 
TEAE deemed possibly, probably or definitely related to study drug by the investigator. 
Tabulations by SOC and PT will also be produced for all treatment-emergent AEs and for 
serious TEAEs, presented in alphabetical order by SOC and PT. 
No formal hypothesis-testing analysis of adverse events incidence rates will be performed. 
All adverse events occurring on study will be listed in subject data listings. By-subject listings 
also will be provided for the following: subject deaths; serious adverse events; and adverse 
events leading to treatment withdrawal or death. 
4.6.3. 
Laboratory Data 
Clinical laboratory values will be expressed using the International System of Units (SI) units. 
The actual value and change from baseline to each on study evaluation will be summarized at all 
visits using descriptive statistics for each clinical laboratory parameter, including hematology, 
clinical chemistry and urinalysis. 
All laboratory data including hematology, chemistry, urinalysis and serum pregnancy will be 
provided in data listings. 
4.6.4. 
Vital Signs and Physical Examinations 
The actual value and change from baseline to each on study evaluation will be summarized for 
vital signs. By-subject listings of vital sign measurements will be presented in data listings. 
All abnormal physical examination findings will be presented in a data listing. 
4.6.5. 
Neurological Examination 
Individual subject changes will be summarized by shift tables. These tables will show the 
number of subjects who had values that shifted from normal, abnormal – not clinically 
significant, or abnormal – clinically significant at baseline to normal, abnormal – not clinically 
significant, or abnormal – clinically significant at the last observed value. 
Abnormal neurological examination findings will be provided in a data listing. 
4.6.6. 
Electrocardiogram 
Individual subject changes will be summarized by shift tables. These tables will show the 
number of subjects who had values that shifted from normal, abnormal – not clinically 
significant, or abnormal – clinically significant at baseline to normal, abnormal – not clinically 
significant, or abnormal – clinically significant at each visit and the last observed value. 
All ECG data for each subject will be provided in data listings. 
4.6.7. 
Concomitant Medications 
Concomitant medications will be coded using the WHO Drug dictionary. The use of 
concomitant medications will be included in by-subject data listing. 


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5. 
CHANGES TO PLANNED ANALYSES 
The study was closed prematurely and results will be summarized in an abbreviated clinical 
study report.  Thus, certain analyses described in the protocol (all efficacy analyses, 
pharmacokinetic and pharmacodynamic analyses, analysis of seizure activity, summaries of AEs 
by severity, AEs by relationship to study drug, and AE method of collection) will not be 
performed. 




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Horizon Pharma USA, Inc. 
Confidential 
Cysteamine Bitartrate DR Capsules 
Protocol RP103-MITO-002 
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