Clinical trial NCT02174848
Conditions: Pantothenate Kinase-Associated Neurodegeneration
Keywords: Pantothenate Kinase-Associated Neurodegeneration PKAN Neurodegeneration with Brain Iron Accumulation NBIA Deferiprone Ferriprox
Sponsor: ApoPharma
Start date: 2014-06-01; Completion date: 2018-03-16
Enrollment: 68 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Patients with PKAN will be treated with the iron chelator deferiprone for 18 months. Only patients who have completed the earlier study TIRCON2012V1 (NCT01741532), a double-blind placebo-controlled trial in which participants were randomized to receive either deferiprone or placebo for 18 months, are eligible to enroll.

Detailed description:
TIRCON2012V1-EXT is a multi-center, single-arm, open-label study. All patients who completed the earlier study TIRCON2012V1 (NCT01741532) are eligible to take part. In the initial study, patients were randomized in a 2:1 ratio to receive 18 months of treatment with either the iron chelator deferiprone or placebo, respectively. In this extension study, all participants will receive deferiprone for 18 months. Thus, depending on which product was received earlier, patients will be on deferiprone for a total of either 1.5 years or 3 years. As in the earlier study, assessments will be carried out every six months to look at the safety of the drug and to see if patients are showing any improvement in dystonia and other symptoms of PKAN.

Arms: arm 1: All patients will receive deferiprone oral solution.
Interventions: intervention 1: Deferiprone oral solution
Intervention descriptions: intervention 1: Deferiprone oral solution at a dosage of up to 15 mg per kilogram of body weight, twice a day

Protocol documents:
Prot_001.pdf: 
 
 
Long-term Safety and Efficacy Study of  Deferiprone in Patients with 
Pantothenate Kinase-Associated Neurodegeneration (PKAN) 
TIRCON2012V1-EXT 
CLINICAL STUDY PROTOCOL 
 
 
EudraCT Number: 
2014-001427-79 
IND Number: 
104880   
Investigational Product: 
Deferiprone  
Development Phase: 
III 
Indication Studied: 
Pantothenate kinase-associated neurodegeneration (PKAN) 
Study Design: 
Multi-center, single-arm, open-label, 18-month extension 
of an earlier 18-month study assessing the safety and 
efficacy of deferiprone in patients with PKAN 
Sponsor: 
ApoPharma Inc. 
200 Barmac Drive 
Toronto, Ontario M9L 2Z7, Canada 
Telephone: 
1-416-749-9300 
Toll-Free: 
1-800-268-4623 (North America only) 
Fax: 
 
1-416-401-3867 
Sponsor’s Representative: 
Fernando Tricta, MD 
Vice President, Medical Affairs 
Tel: 
1-416-401-7332 
Fax: 1-416-401-3867 
Version and Date of Protocol: 
Version 2.0, 20 AUG 2014 
 
 
The information contained in this document is the property of ApoPharma Inc. and is 
confidential. It may be submitted to a regulatory authority, an ethics committee, or an 
investigator for the purpose of initiation of a clinical study. Reproduction or disclosure of this 
information, in whole or in part, is forbidden without the written consent of ApoPharma Inc. 


ApoPharma Inc. 
Deferiprone  
TIRCON2012V1-EXT 
Clinical Study Protocol v 2.0 
 
 
CONFIDENTIAL 
Page 2 of 75 
 
SIGNATURE PAGES 
 
Sponsor 
 
We, the undersigned, hereby declare that this study will be carried out under our supervision 
in accordance with the methods described herein. 
 
 
Study Title: 
Long-term safety and efficacy study of  deferiprone in patients 
with pantothenate kinase-associated neurodegeneration (PKAN) 
Study Code: 
TIRCON2012V1-EXT 
Version Number: 
2.0 
Version Date: 
20 AUG 2014 
 
 
 
Caroline Fradette, PhD 
Director of Clinical Research, ApoPharma Inc. 
 
Date (DD MMM YYYY) 
 
 
 
 
Anna Rozova, MD 
Director of Medical Safety, ApoPharma Inc. 
 
Date (DD MMM YYYY) 
 
 
 
 
Yu Chung Tsang, PhD 
Chief Scientific Officer, Biopharmaceutics & 
Biostatistics, Apotex Inc. 
 
Date (DD MMM YYYY) 
 
 


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Principal Investigator 
I, the undersigned, hereby declare that I agree to assume responsibility for the proper conduct 
of the study at this site; and that I will conduct the study in compliance with this protocol, 
with any future amendments, and with any other written study conduct procedures provided, 
reviewed, and approved by the sponsor or its delegate. 
 
Study Title: 
Long-term safety and efficacy study of  deferiprone in patients 
with pantothenate kinase-associated neurodegeneration (PKAN) 
Study Code: 
TIRCON2012V1-EXT 
Version Number: 
2.0 
Version Date: 
20 AUG 2014 
Name of Principal 
Investigator: 
 
Name of Study Site: 
 
Location of Study Site: 
(City, region/province/
state, country) 
 
 
 
 
 
Signature 
 
Date (DD MMM YYYY) 
 
 


ApoPharma Inc. 
Deferiprone  
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SYNOPSIS 
Name of Sponsor: ApoPharma Inc. 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Product:  Deferiprone  
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Title of study: 
Long-term safety and efficacy study of  deferiprone in patients with 
pantothenate kinase-associated neurodegeneration (PKAN) 
Study code: 
TIRCON2012V1-EXT 
Phase of development: 
Phase III 
Objectives: 
Primary: 
To evaluate the long-term safety and tolerability of deferiprone in patients 
with PKAN. 
Secondary: 
• 
To evaluate the change in severity of dystonia over time in patients with 
PKAN treated with deferiprone.  
• 
To evaluate global improvement over time in patients with PKAN treated 
with deferiprone  
Study design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study TIRCON2012V1-EXT is an 18-month, multi-center, single-arm, 
open-label extension of study TIRCON2012V1. In the initial study, patients 
with a diagnosis of PKAN are being randomized in a 2:1 ratio to receive 18 
months of treatment with either deferiprone or placebo, respectively.  All 
participants who complete TIRCON2012V1 will be offered the opportunity to 
continue in the extension study, with the final visit (Week 78) of the initial 
study being considered Visit 1 of the extension study. (A 4-week follow-up 
visit that is planned for the end of study TIRCON2012V1 will be cancelled for 
individuals who choose to continue.)   
Patients who were randomized to receive deferiprone in study TIRCON2012V1 
will continue to receive deferiprone in the extension study, while those who 
were randomized to receive placebo will be switched to deferiprone. Since the 
initial study will still be in progress at the time that the first patients enter the 
extension study, patients and study staff will remain blinded as to which 
product was received for the previous 18 months. 
In order to minimize the possible gastrointestinal upset that could result from 
starting deferiprone at too high a dose (and which might alert the former 
placebo recipients to the change in product), the dosing regimen will be titrated 
weekly for the first 3 weeks.   All patients, including those who were on 
deferiprone initially, will receive 5 mg/kg deferiprone twice a day (b.i.d.) for 
the first week. If this dose is tolerated and there are no signs of toxicity, the 
dose will be increased to 10 mg/kg b.i.d. for the next week; and if that dose is 
tolerated, it will be increased the following week to 15 mg/kg b.i.d. for the 
remainder of the study.  Individual dosages may be adjusted downward if 
necessary at any time for reasons of safety or tolerability. 


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Deferiprone  
TIRCON2012V1-EXT 
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Page 5 of 75 
 
Name of Sponsor: ApoPharma Inc. 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Product:  Deferiprone  
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Study design 
(cont’d): 
Patients will have their hematology blood counts monitored weekly, and will 
undergo safety and efficacy assessments at 6 months (Visit 2), 12 months 
(Visit 3), and 18 months (Visit 4).  
Duration of 
participation: 
The duration of participation in the extension study for each patient will be 
approximately 18 months. 
Criteria for 
evaluation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety: 
• 
Adverse events (AEs):  Frequency, severity, time to onset, duration, and 
relatedness to study product 
• 
Serious adverse events (SAEs): Frequency, severity, time to onset, 
duration, and relatedness to study product  
• 
Number of discontinuations due to AEs 
• 
Hematology assessments 
• 
Blood chemistry assessments 
• 
ECG assessments 
Efficacy: 
All patients: 
• 
Change in the Barry-Albright Dystonia Scale (BAD) total score from 
baseline (defined as prior to the start of deferiprone therapy) to Visit 4, as 
assessed by central evaluation of videotapes 
• 
Proportion of patients with improved or unchanged BAD scale total score 
between baseline and Visit 4 (responder analysis) 
• 
Change from baseline to Visit 4 in BAD scale score per body region (eyes, 
mouth, neck, trunk, and each upper and lower extremity), as assessed by 
central evaluation of videotapes 
• 
Change in score on the Patient Global Impression of Improvement (PGI-I) 
from Visit 1 to Visit 4 
• 
Proportion of patients showing an improvement on PGI-I at Visit 4 
(responder analysis) 
The time points for assessment of these efficacy endpoints are defined as 
follows: 
• 
For patients who received deferiprone in the earlier study, the baseline 
visit of that study will be treated as the baseline visit of TIRCON2012V1-
EXT as well.  Thus, Visit 1 of the extension study (Week 0) will be Year 
1.5, and Visit 4 (Week 78) will be Year 3. 
• 
For patients who received placebo in the earlier study, Visit 1 of the 
extension study (Week 0) will be the baseline visit. Thus, Visit 4 (Week 78) 
will be Year 1.5. 


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Deferiprone  
TIRCON2012V1-EXT 
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Name of Sponsor: ApoPharma Inc. 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Product:  Deferiprone  
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Criteria for 
evaluation (cont’d): 
Only patients who received placebo in initial study: 
For this group only, for each measure, the change seen between the start and 
completion of study TIRCON2012V1 (i.e., following 18 months on placebo) 
will be compared against the change seen between the start and completion of 
study TIRCON2012V1-EXT (i.e., following 18 months on deferiprone) as 
follows: 
• 
Comparison of change in BAD total score from baseline to completion of 
the initial study vs. change in BAD total score from baseline to completion 
of the extension study 
• 
Comparison of the proportion of patients with improved or unchanged 
BAD total score between baseline and completion of the initial study  vs. 
the proportion with improved or unchanged BAD total score from baseline 
to completion of the extension study (responder analysis) 
• 
Comparison of the change in BAD score per body region between baseline 
and completion of the initial study  vs. change in BAD score per body 
region between baseline and completion of the extension study   
• 
Comparison of change in PGI-I score from baseline to completion of the 
initial study vs. change in PGI-I score from baseline to completion of the 
extension study 
• 
Comparison of the proportion of patients showing an improvement on 
PGI-I at completion of the initial study vs. the proportion showing an 
improvement at completion of the extension study (responder analysis)  
Number of patients: 
A planned total of 90 patients will be enrolled in the TIRCON2012V1 study. 
All patients who complete that study will be invited to enroll in the extension 
study. 
Main criterion for 
inclusion: 
Completed study TIRCON2012V1 
Investigational 
product: 
Product:  Deferiprone oral solution (80 mg/mL)  
Dose:  Up to 15 mg/kg b.i.d. (based on tolerability) 
Mode of administration:  Oral 


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Name of Sponsor: ApoPharma Inc. 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Product:  Deferiprone  
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Schedule of 
treatment and 
specimen collection: 
All patients will be scheduled to take deferiprone daily, 2 times a day, for up to 
18 months. 
Safety and efficacy assessments will be conducted at the following time points: 
• 
Hematology: Weekly up to Visit 4 (End of Study) or early termination  
• 
Blood chemistry: Visits 1, 2, 3, and 4 or early termination  
• 
ECG:  Visits 1 and 4 or early termination 
• 
BAD:  Visits 1, 2, 3, and 4 or early termination 
• 
PGI-I: Visits  2, 3, and 4 or early termination * 
* The PGI-I will be conducted at Visit 1 as well, but its data on that day will be 
applicable only to the initial study (for which this is the last visit), not to the 
extension study. 
Statistical methods:  
 
Safety Analysis 
The incidences of AEs and SAEs reported during deferiprone therapy for all 
patients, from the start of TIRCON2012V1 to the completion of 
TIRCON2012V1-EXT, will be tabulated. Similar tables will be produced for 
the severity of AEs and for their relationship to the study medication. Time to 
onset and duration of all AEs with an incidence of >5%, and of any AEs of 
special interest (e.g., worsening of dystonia), will be summarized with 
descriptive statistics.  
The percentage of discontinuations due to AEs will be calculated, and the AEs 
leading to discontinuation will be summarized in a frequency table by 
preferred term. 
Laboratory data (hematology and blood chemistry) will be summarized using 
descriptive statistics for continuous variables and frequency tables for discrete 
variables.  The incidences of out-of-range data will be tabulated, and the 
changes from baseline to the end of study will be examined using shift tables.  
Efficacy Analysis 
For the efficacy measures of BAD (total score and by body region) and PGI-I, 
the change from baseline to each of the measurement time points will be 
determined and summarized using descriptive statistics. A paired t-test will be 
used to assess the statistical significance of the changes in these efficacy 
outcomes from baseline to Visit 4.  For the BAD total score and for PGI-I, the 
proportions of patients determined to be responders at Visit 4 will be 
calculated and presented along with 95% confidence intervals.  


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Deferiprone  
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Clinical Study Protocol v 2.0 
 
 
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Name of Sponsor: ApoPharma Inc. 
Individual Study Table Referring 
to Part of the Dossier 
Volume: 
Page: 
(For National Authority 
Use Only) 
Name of Finished Product:  Deferiprone  
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Statistical methods 
(cont’d): 
For patients who received placebo in study TIRCON2012V1, a paired t-test 
will be used to compare the change in BAD (total score and by body region) 
and PGI-I between the start and completion of the initial study and between the 
start and completion of the extension study. For the BAD total score and for 
PGI-I, McNemar’s test will be used to compare the proportion of responders in 
the initial study with the proportion of responders in the extension study. 
Version and date of 
protocol: 
Version 2.0, 20 AUG 2014 


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TABLE OF CONTENTS 
SIGNATURE PAGES .............................................................................................................2 
SYNOPSIS ................................................................................................................................4 
LIST OF IN-TEXT TABLES ...............................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................13 
1 
INTRODUCTION......................................................................................................15 
1.1 
Background .............................................................................................................15 
1.1.1 
Background of the Disease ..............................................................................15 
1.1.2 
Background of the Investigational Product......................................................16 
1.1.3 
Rationale for Deferiprone in the Treatment of PKAN .....................................17 
1.2 
Rationale ..................................................................................................................18 
1.3 
Potential Risks and Benefits ....................................................................................18 
2 
STUDY OBJECTIVES ..............................................................................................19 
2.1 
Primary Objective ....................................................................................................19 
2.2 
Secondary Objectives ..............................................................................................19 
3 
STUDY DESIGN ........................................................................................................19 
3.1 
Description of Study Design ...................................................................................19 
3.2 
Rationale for Study Design .....................................................................................20 
3.3 
Rationale for Selection of Doses .............................................................................20 
4 
STUDY POPULATION ............................................................................................20 
4.1 
Number of Patients ..................................................................................................20 
4.2 
Inclusion Criteria .....................................................................................................21 
4.3 
Exclusion Criteria ....................................................................................................22 
4.4 
Enrolment Violations ..............................................................................................22 
4.5 
Patient Withdrawal ..................................................................................................22 
4.5.1 
Follow-up of Patient Withdrawal Due to Pregnancy .......................................23 
4.5.2 
Replacement of Patients Who Withdraw .........................................................24 
4.5.3 
Treatment Interruptions ...................................................................................24 
4.6 
Prior and Concomitant Therapies ............................................................................24 
4.7 
Rescue Medication ..................................................................................................24 


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5 
STUDY PROCEDURES ...........................................................................................25 
5.1 
Visit Procedures ......................................................................................................27 
5.2 
Method of Assignment to Treatment .......................................................................34 
5.3 
Blinding Procedures ................................................................................................34 
5.4 
Allocation of Patient Numbers ................................................................................34 
5.5 
Treatment Compliance ............................................................................................34 
6 
STUDY TREATMENTS ...........................................................................................35 
6.1 
Investigational Product ............................................................................................35 
6.1.1 
Dosage Form and Mode of Administration .....................................................35 
6.1.2 
Precautions for Use ..........................................................................................35 
6.2 
Reference Product ...................................................................................................35 
6.3 
Packaging and Labeling ..........................................................................................35 
6.4 
Shipping and Storage ...............................................................................................35 
6.5 
Product Accountability ............................................................................................36 
6.6 
Replacement Doses .................................................................................................36 
6.7 
Disposition of Unused Product ................................................................................37 
7 
MEASUREMENTS AND EVALUATIONS ...........................................................37 
7.1 
Efficacy Measurements ...........................................................................................37 
7.1.1 
Barry-Albright Dystonia Scale ........................................................................37 
7.1.2 
Patient Global Impression of Improvement .....................................................37 
7.2 
Safety Measurements ..............................................................................................38 
7.2.1 
Adverse Events and Serious Adverse Events ..................................................38 
7.2.1.1 
Definition of Adverse Events ...................................................................38 
7.2.1.2 
Monitoring and Documenting of Adverse Events ....................................39 
7.2.1.3 
Assessment of Causality ...........................................................................40 
7.2.1.4 
Assessment of Intensity ............................................................................40 
7.2.1.5 
Serious Adverse Events ............................................................................41 
7.2.1.6 
Reporting of Serious Adverse Events .......................................................42 
7.2.1.7 
Follow-up and Documentation of SAEs ...................................................42 
7.2.1.8 
Adverse Events of Special Interest ...........................................................43 
7.2.2 
Laboratory Measurements ...............................................................................46 
7.2.3 
Other Safety Measurements .............................................................................47 


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7.2.3.1 
Physical Examinations ..............................................................................47 
7.2.3.2 
Vital Signs ................................................................................................47 
7.2.3.3 
Electrocardiogram .....................................................................................47 
7.2.3.4 
Concomitant Medications/Therapies ........................................................47 
7.2.4 
Procedures in Case of Pregnancy .....................................................................48 
8 
STUDY COMMITTEES ...........................................................................................48 
9 
STATISTICAL ANALYSIS .....................................................................................49 
9.1 
Endpoints .................................................................................................................49 
9.1.1 
Primary Endpoints ...........................................................................................49 
9.1.2 
Secondary Endpoints .......................................................................................50 
9.2 
Determination of Sample Size and Study Power ....................................................51 
9.3 
Study Populations ....................................................................................................51 
9.3.1 
Intent-to-Treat Population ................................................................................51 
9.3.2 
Per Protocol Population ...................................................................................51 
9.3.3 
Safety Population .............................................................................................52 
9.4 
Data Analysis Plan ..................................................................................................52 
9.4.1 
Planned Analyses .............................................................................................52 
9.4.1.1 
Patient Disposition and Drug Exposure ....................................................52 
9.4.1.2 
Patient Characteristics ..............................................................................52 
9.4.1.3 
Analysis of Efficacy .................................................................................52 
9.4.1.4 
Analysis of Safety .....................................................................................53 
9.4.2 
Interim Analyses ..............................................................................................55 
10 
DATA MANAGEMENT CONSIDERATIONS......................................................55 
10.1 
Data Management ....................................................................................................55 
10.2 
Case Report Forms ..................................................................................................56 
11 
MONITORING, AUDITS, AND INSPECTIONS ..................................................56 
11.1 
Source Documents ...................................................................................................56 
11.2 
Monitoring ...............................................................................................................57 
11.3 
Audits and Inspections ............................................................................................57 
11.4 
Site Closure .............................................................................................................58 
11.5 
Retention of Records ...............................................................................................58 
12 
ETHICAL CONSIDERATIONS ..............................................................................58 


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12.1 
Informed Consent ....................................................................................................58 
12.2 
Institutional Review Board/Independent Ethics Committee ...................................59 
12.3 
Patient Confidentiality .............................................................................................60 
13 
REGULATORY REQUIREMENTS .......................................................................60 
13.1 
Regulatory Obligations ............................................................................................60 
13.2 
Amendments to the Protocol ...................................................................................61 
14 
EARLY STUDY TERMINATION ..........................................................................61 
15 
CONFIDENTIALITY ...............................................................................................61 
16 
INDEMNIFICATION ...............................................................................................62 
17 
OWNERSHIP .............................................................................................................62 
18 
PUBLICATION .........................................................................................................62 
19 
REFERENCES ...........................................................................................................64 
APPENDIX 1:  CLINICAL STUDY ADMINISTRATIVE STRUCTURE .....................67 
APPENDIX 2:  LIST OF PROHIBITED DRUGS .............................................................68 
APPENDIX 3:  LIST OF RESCUE MEDICATIONS .......................................................69 
APPENDIX 4:  BARRY-ALBRIGHT DYSTONIA SCALE .............................................70 
APPENDIX 5:  PATIENT GLOBAL IMPRESSION OF IMPROVEMENT .................73 
APPENDIX 6:  SCIENTIFIC STEERING COMMITTEE ...............................................74 
 
 
LIST OF IN-TEXT TABLES  
Table 5.1 
Table of study procedures ..................................................................................25 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
BAD 
Barry Albright Dystonia 
b.i.d. 
bis in die (twice daily dosing) 
CBC 
complete blood count 
CRA 
clinical research associate 
CRF 
case report form 
CS 
clinically significant 
DBS 
Deep Brain Stimulation 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
LOCF 
last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed-effect model repeated measure 
NBIA 
neurodegeneration with brain iron accumulation 
NCS 
not clinically significant 
PGI-I 
Patient Global Impression of Improvement 
PKAN 
pantothenate kinase-associated neurodegeneration 


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Abbreviation 
Definition 
PP 
per protocol 
PRN 
pro re nata (as needed) 
QA 
Quality Assurance 
RDC 
remote data capture 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
WHO 
World Health Organization 


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1 
INTRODUCTION 
1.1 
Background 
1.1.1 
Background of the Disease 
Pantothenate kinase-associated neurodegeneration (PKAN) is a rare disorder characterized 
by progressive dystonia, parkinsonism, spasticity, and brain iron accumulation (1, 2). 
Clinically, the disease manifests as rigidity, dystonia, and chorea (3). PKAN is the most 
prevalent form of a group of progressive extrapyramidal disorders associated with iron 
accumulation in the brain, collectively called neurodegeneration with brain iron 
accumulation (NBIA) (4). With the advent of molecular genetic testing, it has become 
apparent that there are several genetically distinct disorders classified as NBIA, of which 
PKAN accounts for approximately 50% of cases (5).  
PKAN is an autosomal recessive inherited disorder caused by mutations in the pantothenate 
kinase 2 (PANK2) gene. PANK2 codes for the PANK2 enzyme, which phosphorylates 
pantothenate, the initial and rate-limiting step in coenzyme A biosynthesis.  Coenzyme A has 
a vital role in adenosine triphosphate synthesis and in fatty acid and neurotransmitter 
metabolism. Mitochondrial dysfunction is proposed to result from PANK2 mutations, leading 
to neurodegeneration. Abnormal PANK2 function will lead to accumulation of the 
neurotoxic metabolites cysteine and pantetheine (5). Although PANK2 is not directly 
involved in iron metabolism, its absence or abnormal function may contribute to iron 
accumulation in the brain, leading to neuronal death via a free-radical pathway. 
Because the basal ganglia are involved in mediating the initiation of movements, an 
accumulation of excess labile iron within this region would be expected to result in poor 
motor control, as a result of iron-related ROS-mediated damage, although proof that iron 
causes the neurodegeneration is lacking (6). Common physiological features include 
abnormal movements and posture (dystonia), muscular rigidity and sudden involuntary 
muscle spasms (spasticity). These features can result in clumsiness, problems with gait and 
posture, difficulty controlling movement, and problems with speech. Progressive generalized 
dystonia is a major clinical feature of PKAN and can result in life-threatening complications (7). 
Cranial and limb dystonia crises are frequent and are part of the natural history of the disease. 
These crises may lead to recurrent trauma to the tongue/mouth or to bone fractures, the latter 
being due to a combination of dystonic overstraining and inactivity-related osteopenia (3). 
Another common feature is degeneration of the retina, resulting in progressive night 
blindness and loss of peripheral vision. Hence, PKAN may manifest itself not only as 


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movement disorders but also as retinopathy, deterioration of cognition or hearing, or 
peripheral nerve changes. 
Historically, PKAN has been described as either classical or atypical. The majority of cases 
are classical and therefore relatively homogeneous in their phenotype (3). Classical PKAN 
usually develops before 6 years of age (average age at onset of symptoms is 3.5 years) (3, 5). 
Most patients with the classical form of PKAN lose the ability to walk independently 10–15 
years after the beginning of symptoms, and many require a wheelchair by their mid-teens; in 
some cases, earlier.  Individuals with classical PKAN are also more likely to have eye 
problems, with approximately two-thirds suffering from retinal degeneration resulting in 
tunnel vision, night blindness, and loss of peripheral vision. Loss of peripheral vision may 
contribute to the more frequent falls and gait disturbances in the early stages. Optic atrophy, 
a vision impairment caused by gradual degeneration of the nerves of the eyes, is found in 3% 
of patients (5).  
In contrast, atypical PKAN usually becomes evident after the age of ten years and progresses 
more slowly. The average age at which symptoms develop is 13 years. Loss of independent 
ambulation often occurs 15–40 years after the initial development of symptoms. In general, 
atypical disease is less severe and progresses more slowly than classical PKAN. It is 
hypothesized that classical PKAN results from complete absence of the enzyme pantothenate 
kinase whereas atypical disease results from a severe deficiency; i.e., individuals retain some 
level of enzyme activity.  
In the last decade, progress has been made in stratifying NBIA and PKAN according to gene 
mutations and phenotype. However, no genetic or other specific therapies are available for 
this condition (2, 8, 9). 
1.1.2 
Background of the Investigational Product 
Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one) is an oral bidentate iron chelator that 
preferentially binds trivalent iron cations (Fe3+) in a 3:1 (deferiprone:iron) complex. 
Ferriprox® is the ApoPharma formulation of deferiprone. It is available as immediate release 
500 mg or 1000 mg tablets and as an oral solution of 100 mg/mL. The effectiveness of 
deferiprone in reducing body iron in transfusional iron overload has been assessed by urinary 
iron excretion, sequential measurements of serum ferritin levels, and iron concentration in the 
liver and in the heart; and by clinical outcomes such as its ability to prevent iron-induced 
cardiac disease and prolong survival. The results of ApoPharma-sponsored clinical studies 
and of independent trials demonstrate that therapy with Ferriprox® is associated with good 
compliance and with stabilization or decline of body iron load. 


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Ferriprox® was first approved in 1999 by the European Medicines Agency (EMA) for the 
treatment of systemic iron overload in patients with thalassemia major, and it is currently 
approved in over 60 countries. It was approved by the Food and Drug Administration (FDA) 
in October 2011 for the treatment of patients with transfusional iron overload due to thalassemia 
syndromes when current chelation therapy is inadequate. The recommended initial dose of 
deferiprone in these patients is 25 mg/kg three times per day for a total of 75 mg/kg/day, and 
the maximum dose is 33 mg/kg three times per day for a total of 99 mg/kg/day. 
1.1.3 
Rationale for Deferiprone in the Treatment of PKAN  
While iron is essential for normal physiological function, excessive amounts of it or 
dysregulation of its metabolism is potentially toxic. Increased free iron levels in tissues lead 
to the formation of highly reactive oxygen species, including the extremely damaging 
hydroxyl radical, causing localized toxicity (10, 11).  
Neurodegeneration in patients with PKAN appears to be related to the intracellular 
mismanagement of iron, resulting in localized brain iron accumulation, iron toxicity, and 
eventually cell death. The regions of the brain with the highest amounts of iron accumulation 
include those that control motor output. Thus, motor impairments associated with PKAN are 
thought to be due, at least in part, to the oxidative damage/necrosis that occurs as a result of 
long-term localized iron-induced damage (12). In patients with Friedreich’s Ataxia, another 
neurodegenerative condition involving regional iron deposition in the brain, deferiprone has been 
shown to be able to reduce localized elevated levels of brain iron, as evidenced by MRI scans (13). 
If iron can be sequestered from brain regions with excess amounts of labile iron prior to cell 
death, the clinical symptoms of PKAN could be reduced. In conditions of iron overload, the 
accepted therapeutic strategy for dealing with accumulation of iron is administration of iron 
chelators, which both increases iron excretion and prevents the toxic effects of iron excess. 
Although patients with PKAN do not have generalized iron overload, they have a 
mismanagement of intracellular iron, which results in a misdistribution of iron at the local 
level. One strategy for treating PKAN might be iron redistribution by “reversed 
siderophores”. The aim of chelation with reversed siderophores would be to bind excess 
labile cell iron and transfer it, directly or indirectly, to endogenous acceptors, such as 
transferrin, for transport to other compartments inside or outside the cells (12).  
Deferiprone appears to fulfill at least some of the criteria required for a reversed siderophore: 
• Ability to cross the blood brain barrier (14, 15)  
• Ability to gain access to cells (16)  and effectively scavenge intracellular labile iron 
pools (17), exiting cells bound to the iron as an iron-chelate 


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• Ability to selectively bind iron in the various intracellular labile iron pools (18)  and 
thereby reduce iron-dependent free radical formation (14, 15, 19, 20, 21, 22) 
• Ability to spare extracellular transferrin-bound iron and potentially transfer chelated 
iron to apotransferrin (13, 18, 23, 24) 
• Ability to donate iron for metabolic reutilization (18) 
Because of its low molecular weight and favorable physicochemical properties, deferiprone 
has been shown to readily cross the blood-brain barrier in animal studies (25), and there is 
indirect evidence to suggest that it does so in humans as well (13). Pharmacokinetic studies 
have shown that deferiprone is rapidly absorbed, appearing in plasma within 5 to 10 minutes 
of ingestion, with a peak plasma level within 45–60 minutes. The 3:1 chelator:iron complex 
is excreted with the free drug and its glucuronide in the urine and feces. Because of its ability 
to penetrate the blood brain barrier, enter and exit cells, and allow iron to be passed to 
transferrin (and be subsequently used in normal endogenous processes), deferiprone could be 
exploited clinically for treating neurodegenerative diseases involving regional iron 
accumulation. Targeting the site of iron accumulation within the brain and removing excess 
iron may potentially slow or halt the debilitation that accompanies PKAN. 
1.2 
Rationale 
ApoPharma Inc. is currently conducting an 18-month trial, TIRCON2012V1, to assess the 
safety and efficacy of deferiprone in patients with PKAN.  In that study, a planned 90 
participants are being randomized in a 2:1 ratio to receive either deferiprone oral solution or 
placebo. Patients are scheduled to undergo weekly monitoring of absolute neutrophil count 
(ANC) and to undergo safety and efficacy assessments at Months 1.5, 3, 6, 12, and 18. 
Patients who complete TIRCON2012V1will be invited to enroll in the current study, in which 
all participants will receive deferiprone. Participants will thus receive deferiprone for a total of 
either 1.5 years or 3 years, depending on which treatment was assigned in the earlier study.  
The long-term data obtained will enable a better understanding of the use of deferiprone in 
this patient population.  
1.3 
Potential Risks and Benefits 
Risks: 
The safety profile of deferiprone has been extensively characterized in patients with systemic 
iron overload. The most serious adverse event associated with deferiprone use is 
agranulocytosis, defined as a confirmed absolute neutrophil count less than 0.5 × 109/L.  In 


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pooled clinical trials, agranulocytosis has been seen in about 1.7% of patients. The mechanism 
of deferiprone-associated agranulocytosis is unknown. Agranulocytosis usually resolves upon 
discontinuation of deferiprone, but there have been post-marketing reports of it leading to death. 
The most common adverse reactions reported during clinical trials have been chromaturia, 
nausea, vomiting, abdominal pain, alanine aminotransferase increased, arthralgia, and 
neutropenia (26).  
Benefits: 
The findings of preclinical research and case studies suggest that deferiprone has the potential 
to access pathologically relevant brain iron and to produce clinical benefit in patients with 
PKAN. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the long-term safety and tolerability of deferiprone in patients with PKAN. 
The endpoints for the primary objective are provided in Section 9.1.1. 
2.2 
Secondary Objectives 
• To evaluate the change in severity of dystonia over time in patients with PKAN treated 
with deferiprone.  
• To evaluate global improvement over time in patients with PKAN treated with deferiprone  
The endpoints for the secondary objectives are provided in Section 9.1.2. 
3 
STUDY DESIGN 
3.1 
Description of Study Design 
Study TIRCON2012V1-EXT is an 18-month, multi-center, single-arm, open-label extension 
of study TIRCON2012V1, which began in 2012 and is currently in progress.  In the initial 
study, patients with a diagnosis of PKAN are being randomized in a 2:1 ratio to receive 18 
months of treatment with either deferiprone or placebo, respectively.  All participants who 
complete TIRCON2012V1 will be offered the opportunity to continue in the extension 
study, with the final visit of the initial study being considered Visit 1 of the extension study.  
(The 4-week follow-up visit that is planned at the end of study TIRCON2012V1 will be 
cancelled for individuals who choose to continue.)  Patients who had been randomized to 


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receive deferiprone in study TIRCON2012V1 will continue to receive deferiprone in the 
extension study, while those who had been randomized to receive placebo will be switched 
to deferiprone. Since the initial study will still be in progress at the time that the first 
patients enter the extension study, patients and study staff will remain blinded until the 
initial study is over as to which product was received for the previous 18 months. 
Patients will have their hematology blood counts monitored weekly, and will return to the 
study site at 6 months (Visit 2), 12 months (Visit 3), and 18 months (Visit 4) for 
assessments of safety and efficacy.  Due to the difficulties that travel may pose for patients 
with PKAN, participants will have the option of arranging for the Visit 2 and Visit 3 
assessments to be done locally instead. Details are provided in Section 5.1. 
3.2 
Rationale for Study Design 
This single-arm, open-label extension study design has been primarily chosen to gather data 
on multiple patient-years of exposure to deferiprone in order to understand and gain 
confidence in its safety and efficacy profile in patients with PKAN. 
3.3 
Rationale for Selection of Doses 
The dosage of deferiprone for each patient will be the same as that being used in study 
TIRCON2012V1:  up to 15 mg/kg twice a day (b.i.d.), for a total daily dose of 30 mg/kg.   
In order to minimize the possible gastrointestinal upset that could result from starting 
deferiprone at too high a dose (and which might alert the former placebo recipients to the 
change in product), the dosing regimen will be titrated weekly for the first 3 weeks.  All 
patients, including those who were on deferiprone initially, will receive 5 mg/kg deferiprone 
twice a day (b.i.d.) for the first week. If this dose is tolerated and there are no signs of 
toxicity, the dose will be increased to 10 mg/kg b.i.d. for the next week; and if that dose is 
tolerated, it will be increased the following week to 15 mg/kg b.i.d. for the remainder of the 
study.  Individual dosages may be adjusted downward if necessary at any time for reasons of 
safety or tolerability. 
4 
STUDY POPULATION 
4.1 
Number of Patients 
A planned total of 90 patients will be enrolled in the TIRCON2012V1 study.  All patients 
who complete that study will be invited to enroll in the extension study. 


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4.2 
Inclusion Criteria 
Patients will be eligible to enroll in the study if they meet all the following criteria: 
1. Completed study TIRCON2012V1 
2. Sexually active females of childbearing potential, including those who are peri-
menopausal (defined as less than 2 years since last menstrual period) must have a negative 
pregnancy test result at Visit 1 (if applicable; in cases where the investigator determines 
there is no reasonable risk of pregnancy because of significant incapacity, pregnancy 
testing will not be performed). In addition, if applicable, they must meet at least one of the 
following criteria: 
• Use an effective method of contraception during the study and within 30 days 
following their last dose of study medication, OR 
• Participate in a non-heterosexual lifestyle, OR 
• Have a male sexual partner who has been sterilized (supporting evidence required) 
Approved methods of contraception will consist of the following or must follow local 
requirements: 
• Oral contraceptive used in conjunction with condom, diaphragm, or spermicide 
• Hormonal implant used in conjunction with condom, diaphragm, or spermicide 
• Injectable contraceptive used in conjunction with condom, diaphragm, or spermicide 
• Diaphragm or condom used with spermicide 
If a hormonal contraception is used, it should have a Pearl index <1%. 
Female patients who meet any of the following criteria are not of childbearing potential 
and therefore do not need to practice contraception: 
• Post-menopausal (last menstrual period > 2 years ago) 
• Had a tubal ligation (supporting evidence required) 
• Had a hysterectomy or oophorectomy (supporting evidence required) 
3. Fertile heterosexual males and/or their partners must agree to use an effective method of 
contraception during the study and for 30 days following the last dose of study medication 
4. Patients and/or their authorized legal representatives must provide signed and dated 
written informed consent prior to the first study intervention, and patients must be able to 
adhere to study restrictions, appointments, and evaluation schedules.  Patients who are 
minors must sign an assent form as per local regulatory requirements. 


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4.3 
Exclusion Criteria 
1. Withdrew from the study TIRCON2012V1 for reasons of safety  
2. Plan to participate in another clinical trial at any time from the day of enrolment until 30 
days post-treatment in the current study 
3. Presence of any medical, psychological, or psychiatric condition which in the opinion of 
the investigator would cause participation in the study to be unwise. 
4. Pregnant, breastfeeding, or planning to become pregnant during the study period. 
4.4 
Enrolment Violations 
The criteria for enrolment must be followed explicitly.  If there is inadvertent enrolment of 
patients who do not meet enrolment criteria, the investigator should consider withdrawing these 
individuals from the study. 
4.5 
Patient Withdrawal 
Patients have the right to withdraw from the study at any time and for any reason without 
consequence to future care by the investigator or study center.   
A patient may be withdrawn from the study at any time, at the discretion of the investigator, 
for any of the following reasons:   
• 
Medical or safety reasons considered significant by the patient and/or the investigator 
• 
Requirement for concomitant medication that might interfere with the evaluation of 
study treatment or may be contraindicated 
• 
Occurrence of other illnesses that might affect the patient’s further participation in 
the study or evaluation of study treatment 
• 
A protocol deviation that might interfere with study assessments, as judged by the 
investigator 
• 
Repetitive patient non-compliance with the protocol or with instructions of the 
investigator 
• 
Participation in another clinical trial at any time during the conduct of this study 
• 
Any other situation where, in the opinion of the investigator, continuation of the 
study would not be in the best interest of the patient 
A patient must be withdrawn from the study if any of the following conditions apply: 
• 
Pregnant or planning to become pregnant (see Section 7.2.4, Procedures in Case of 
Pregnancy) 


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• 
Occurrence of any adverse event characterized as life-threatening or disabling that is 
not associated with the patient’s primary diagnosis and that is assessed as at least 
possibly related to study drug by the investigator or the sponsor 
• 
Non-compliance with weekly hematology blood counts (3 or more consecutively 
missed visits will result in automatic withdrawal) 
• 
Termination of the study by the sponsor 
• 
Occurrence of moderate neutropenia or severe neutropenia/agranulocytosis (see 
Section 7.2.1.8, Adverse Events of Special Interest) 
Patients who decide to withdraw participation in the study should always be contacted, if 
possible, in order to ask about the reason for withdrawal, whether any adverse events (AEs) 
occurred, and use of concomitant medications.  A withdrawn patient should return for an 
Early Termination Visit. All investigational product and materials should be returned.  If any 
AEs occurred, the investigator must attempt to follow up the outcome for 30 days post-
termination. 
If a patient withdraws or is withdrawn before completing the study, the date and reason for 
the withdrawal must be entered on the source document and on the appropriate page of the 
electronic case report form (eCRF), and all other appropriate eCRF pages must be completed.  
4.5.1 
Follow-up of Patient Withdrawal Due to Pregnancy 
All sexually active female participants of childbearing potential will be administered a 
pregnancy test prior to drug treatment (if applicable; in cases where the investigator 
determines there is no reasonable risk of pregnancy because of significant incapacity, 
pregnancy testing will not be performed). A negative test will be required prior to study 
entry. Patients of childbearing potential should not become pregnant during the study and 
therefore must agree to use an approved method of contraception (as defined in inclusion 
criterion #2) throughout the course of the trial and for 30 days following receipt of the last 
dose of study medication. 
If a patient does become pregnant, the investigator must do the following upon becoming 
aware of the pregnancy: 
• Ensure that the study medication is stopped immediately  
• Inform the sponsor via the pregnancy report form  
• Follow the pregnancy closely, and provide reports to the sponsor until delivery or 
other resolution 
• Male patients must inform the investigator if their female partner becomes pregnant 
during the trial or within 30 days following the last dose of study medication.  As 


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with the pregnancy of a female subject, the site must inform the sponsor and, if the 
partner consents, will follow the pregnancy and provide the sponsor with a report on 
its outcome. 
4.5.2 
Replacement of Patients Who Withdraw 
Not applicable.  The only individuals eligible for enrolment are those who completed 
treatment in study TIRCON2012V1. 
4.5.3 
Treatment Interruptions 
As in the initial study, patients will be provided with a card containing contact information 
for emergency services which they are to carry at all times, and will be advised to promptly 
report any symptoms indicative of infection such as fever or flu-like symptoms. Treatment 
will be interrupted under the following circumstances: 
• If a patient develops an infection, therapy will be interrupted based on the 
investigator’s judgment.  If ANC <1.5 x 109/L., neutrophil count must be obtained 
and monitored more frequently.  
• If a patient develops a fever (defined as ≥38.5 ºC or 101.3 ºF), therapy must be 
interrupted immediately, and a CBC and differential count must be obtained. 
Therapy with study medication can be re-initiated once all symptoms have been resolved and 
it is deemed safe by the investigator. See Section 7.2.1.8, Adverse Events of Special Interest. 
4.6 
Prior and Concomitant Therapies 
Medications considered necessary for the patient’s welfare may be given at the discretion of 
the investigator.  The administration of all medication (including study product) must be 
recorded in the source document and the appropriate sections of the eCRF.  During treatment 
with deferiprone, patients must not receive any other investigational product or any drugs 
that are known to cause neutropenia or agranulocytosis.  A list of prohibited drugs is provided 
in Appendix 2. 
4.7 
Rescue Medication 
Rescue medication is defined as a newly prescribed medication or a change in dosage of a 
currently prescribed medication that has the potential to have an effect on dystonia symptoms 
and is provided because of a worsening of the patient’s condition.  
The use of rescue medication should be limited to circumstances judged as absolutely 
necessary by the investigator. Any use of a rescue medication must be documented, including 


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the reason.  If a patient uses rescue medication for more than 2 events, the investigator should 
notify the sponsor to discuss the patient’s continued participation in the study. 
Rescue medications for dystonia include, but are not limited to, the list of drugs provided in 
Appendix 3. 
5 
STUDY PROCEDURES 
The procedures and assessments to be conducted at each study visit are summarized in 
Table 5.1 and are detailed in the section that follows. 
 
Table 5.1 
Table of study procedures 
Procedure 
Visit 1 1 
Weekly 
Blood 
Draws 
Telephone 
Contact 
Visit 2 
Visit 3 
Visit 4 or 
Early 
Termination 
Week: 
0 
1 to 78 
1 and 2 
26 
52 
78 
Informed 
consent/assent 
X 
 
 
 
 
 
Confirmation of 
eligibility 
X 
 
 
 
 
 
Review of medical 
history 
X 
 
 
 
 
X 
Serum pregnancy 
testing2 
X 
 
 
X 
X 
X 
Physical examination 
X 
 
 
X 
X 
X 
Vital signs (including 
weight and height)3 
X 
 
 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
Contraceptive 
counseling 
X 
 
 
X 
X 
X 
Hematology 
X 
X 
 
X 
X 
X 
Blood chemistry 
X 
 
 
X 
X 
X 
Urinalysis 
X 
 
 
X 
X 
X 
BAD 
X 
 
 
X 
X 
X 
PGI-I 
 
 
 
X 
X 
X 


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Procedure 
Visit 1 1 
Weekly 
Blood 
Draws 
Telephone 
Contact 
Visit 2 
Visit 3 
Visit 4 or 
Early 
Termination 
Week: 
0 
1 to 78 
1 and 2 
26 
52 
78 
Dose calculation/verify 
and adjust dose level 
X 
 
 
X 
X 
 
Dispense study 
medication 
X 
 
 
X 
X 
 
Remind patient to 
adjust dosage 4 
 
 
X 
 
 
 
Collect used and 
unused study 
medication 
 
 
 
X 
X 
X 
Prior and concomitant 
medications 
Throughout the study 
Adverse events and 
serious adverse events 
Throughout the study 
 
1 
Visit 1 is the final visit (Month 18) of study TIRCON2012V1.  It serves as the screening visit for 
TIRCON2012V1-EXT for all patients, and as the baseline for those patients who received 
placebo in TIRCON2012V1 and will now be receiving deferiprone for the first time. (For patients 
who received deferiprone in TIRCON2012V1, the measures obtained at the baseline visit of the 
TIRCON2012V1 study will be used as the baseline measures for TIRCON2012V1-EXT as well.) 
2 
Sexually active females of childbearing potential only (if applicable; in cases where the 
investigator determines there is no reasonable risk of pregnancy because of significant 
incapacity, pregnancy testing will not be performed). 
3 
Height will be measured only at Visits 1 and 4 
4 
All patients, including those who were on deferiprone initially, will receive 5 mg/kg deferiprone 
b.i.d. for the first week. If the medication is tolerated and there are no signs of toxicity, the dose 
will be increased at Week 1 to 10 mg/kg b.i.d., and will be increased again at Week 2 to 15 mg/kg 
b.i.d. for the remainder of the study.  Patients will receive a telephone call at these times to 
remind them to implement the increase in dosage, provided there are no safety concerns in 
doing so. 


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5.1 
Visit Procedures 
Visit 1 (Week 0) 
This visit is the Month 18 visit of TIRCON2012V1: i.e., for patients who choose to 
continue on, the last visit of the initial study is considered the first of the extension study.  
For patients who had been on placebo and will now be receiving deferiprone for the first time, 
the data obtained at this visit will be treated as the baseline measures for TIRCON2012V1-EXT.  
The following procedures will be done: 
• Explain the extension study to the patient and/or authorized legal representative, and 
obtain written informed consent/assent 
• Confirm eligibility criteria 
• Review medical history 
• Collect information about concomitant medications 
• Ask patient about the use of any of the medications listed in Appendix 3 or any other 
medication that has the potential to affect dystonia symptoms (e.g., spasticity, muscular 
rigidity, and parkinsonism), as follows:  
o 
If patient has been on a regular dosing regimen of any of these medications since the 
start of study TIRCON2012V1, verify that the regimen has been stable 
o 
If patient has been taking any of these medications on a PRN (as needed) basis since 
the start of study TIRCON2012V1, verify that treatment was interrupted prior to the 
current visit according to the following timelines:  
Medication 
Treatment interruption period 
prior to current visit  
Baclofen 
30 days 
Trihexyphenidyl 
30 days 
Clonazepam 
30 days 
Tizanidine 
30 days 
Botox 
60 days 
Tetrabenazine 
90 days 
 
• If patient has a DBS system or Baclofen pump in place, verify that the DBS stimulation 
parameters or pump settings have been stable, as confirmed by the investigator 


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• Collect blood samples for the following assessments: 
o 
Hematology  
o 
Blood chemistry  
o 
Pregnancy testing for all sexually active females of childbearing potential (if 
applicable; in cases where the investigator determines there is no reasonable risk of 
pregnancy because of significant incapacity, pregnancy testing will not be 
performed) 
• Collect a urine sample for urinalysis 
• Measure vital signs, weight, and height 
• Perform a 12-lead ECG 
• Conduct contraceptive counseling for sexually active patients 
• The following must be performed by a qualified investigator or a qualified delegate:  
o 
Conduct a physical examination 
o 
Record administration of the BAD in a standardized manner on videotape, and 
transmit tape to the evaluation center 
• Verify dosage of study medication 
• Dispense a 6-month supply of study medication 
• Remind the patient/authorized legal representative to do the following: 
o 
Return all study medication containers at the next visit, whether empty or unused 
o 
Keep careful track of adverse events and medication(s) used 
o 
Interrupt therapy immediately in the event of fever (temperature ≥38.5 ºC/101.3 ºF), 
and promptly report any symptoms indicative of infection such as fever or flu-like 
symptoms 
o 
If patient is on a regular dosing regimen of any of the medications listed in 
Appendix 3 or of any other medication that has the potential to affect dystonia 
symptoms, to stay on the same regimen for the duration of the study. Any change 
in dose and dosing regimen should be limited to circumstances judged as 
absolutely necessary by the investigator. 
o 
If patient is being treated with any such medications on a PRN basis, to use them 
only under circumstances judged as absolutely necessary by the investigator, and to 
interrupt treatment prior to the next study visit according to the following timelines: 


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Medication 
Treatment interruption period 
prior to current visit  
Baclofen 
30 days 
Trihexyphenidyl 
30 days 
Clonazepam 
30 days 
Tizanidine 
30 days 
Botox 
60 days 
Tetrabenazine 
90 days 
 
o 
If patient has a DBS system or Baclofen pump in place, to make every effort to 
maintain the same DBS stimulation parameters or Baclofen pump settings for the 
duration of the study. Any changes in settings should be limited to circumstances 
judged as absolutely necessary by the investigator. 
o 
If leaving the study before completion, to return to the clinic for an Early 
Termination Visit as soon as possible and no later than  30 days following the last 
dose of study medication 
• Provide patient with card containing contact information for emergency services, and 
advise that this card should be carried at all times 
• Schedule next study visit 
Weekly Blood Draws (every 7 ± 3 days) 
Note: These blood draws can be conducted either at a local laboratory or at the study site.  
• Collect blood sample for hematology assessment.  The results are to be reviewed by the 
investigator in a timely manner when they are received from the laboratory. 
Telephone Contact ( Week 1 ±2 days and Week 2 ±2 days) 
A study staff member will contact the patient and/or legal representative by telephone at 
Week 1 and Week 2 with the following queries and reminders, and will document the 
responses: 
• Ask if treatment is proceeding satisfactorily.  If the patient appears to be having 
difficulty, the telephone calls should be repeated as frequently as necessary. 
• Remind the patient to increase the dosage of study medication at Week 1 from 
5 mg/kg to 10 mg/kg, and at Week 2 from 10 mg/kg to 15 mg/kg, provided there are 
no safety concerns in doing so 


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• Remind the patient that if treatment is stopped early, to return to the clinic for an 
Early Termination Visit as soon as possible and no later than 1 month following 
treatment discontinuation 
• Remind patient to interrupt therapy immediately in the event of fever (temperature 
≥38.5 ºC/101.3 ºF), and to promptly report any symptoms indicative of infection such 
as fever or flu-like symptoms 
• Ask if the patient has experienced any AEs or SAEs or has taken any concomitant 
medications. If yes, document these as specified in Sections 7.2.1.2, 7.2.1.6, and 7.2.3.4. 
• Reconfirm the next study visit 
• Document the date and time of the contact; the person contacted (patient, parent, 
legal representative); and the name and signature of the staff member who conducted 
the call 
Visit 2 (Week 26 ± 14 days) and Visit 3 (Week 52 ± 14 days) 
The following procedures will be done: 
• Collect information about concomitant medications 
• Query patient about the use of any of the medications listed in Appendix 3 or any other 
medication that has the potential to affect dystonia symptoms, as follows:  
o 
If patient has been on a regular dosing regimen of any of these medications since the 
start of study TIRCON2012V1, verify that the regimen has been stable 
o 
If patient has been taking any of these medications on a PRN basis since the start of 
study TIRCON2012V1, verify that treatment was interrupted prior to the current 
visit according to the following timelines:  
Medication 
Treatment interruption period 
prior to current visit  
Baclofen 
30 days 
Trihexyphenidyl 
30 days 
Clonazepam 
30 days 
Tizanidine 
30 days 
Botox 
60 days 
Tetrabenazine 
90 days 
 
• If patient has a DBS system or Baclofen pump in place, verify that the DBS stimulation 
parameters or pump settings have been stable, as confirmed by the investigator 


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• Collect blood samples for the following assessments: 
o 
Hematology 
o 
Blood chemistry  
o 
Pregnancy testing for all sexually active females of childbearing potential (if 
applicable; in cases where the investigator determines there is no reasonable risk of 
pregnancy because of significant incapacity, pregnancy testing will not be 
performed) 
• Collect a urine sample for urinalysis 
• Measure vital signs and weight 
• Conduct contraceptive counseling for sexually active patients 
• The following must be performed by a qualified investigator or a qualified delegate:  
o 
Conduct a physical examination 
o 
 Record administration of the BAD in a standardized manner on videotape, and 
transmit tape to the evaluation center 
o 
Administer the Patient Global Impression of Improvement  
• Verify dosage of study medication 
• Dispense a 6-month supply of study medication 
• Collect any empty containers or unused medication from the previous 6 months, and 
perform drug accountability 
• Remind the patient/authorized legal representative to do the following: 
o 
Return all study medication containers at the next visit, whether empty or unused 
o 
Keep careful track of adverse events and medication used 
o 
Interrupt therapy immediately if an infection develops, and immediately report any 
symptoms indicative of infection such as fever,  or flu-like symptoms  
o 
If patient is on a regular dosing regimen of any of the medications listed in 
Appendix 3 or of any other medication that has the potential to affect dystonia 
symptoms, to stay on the same regimen for the duration of the study. Any change 
in dose and dosing regimen should be limited to circumstances judged as 
absolutely necessary by the investigator. 
o 
If patient is being treated with any such medication on a PRN basis, to use them 
only under circumstances judged as absolutely necessary by the investigator, and 
to interrupt treatment prior to the next study visit according to the following 
timelines: 


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Medication 
Treatment interruption period 
prior to next visit 
Baclofen 
30 days 
Trihexyphenidyl 
30 days 
Clonazepam 
30 days 
Tizanidine 
30 days 
Botox 
60 days 
Tetrabenazine 
90 days 
 
o 
If patient has a DBS system or Baclofen pump in place, to make every effort to 
maintain the same DBS stimulation parameters or Baclofen pump settings for the 
duration of the study. Any changes in settings should be limited to circumstances 
judged as absolutely necessary by the investigator. 
o 
If patient decides to leave the study before completion, return to the clinic for an 
Early Termination Visit as soon as possible and no later than 1 month following 
the last dose of study medication 
• Schedule next study visit 
 
Due to the difficulties that travel may pose for patients with PKAN, participants will have the 
option of arranging for the Visit 2 and Visit 3 assessments to be done locally instead, as follows: 
• At patient’s home, via telephone:  Collection of information on concomitant 
medications, use of medications with potential to affect dystonia symptoms, and 
stability of DBS stimulation parameters or pump settings; conducting of contraceptive 
counseling; administration of the PGI-I; verification of dosage of study medication; 
reminders to patient as detailed above  
• At a local doctor’s office:  Physical examination; measurement of weight; 
measurement of vital signs. 
• At a local laboratory:  Blood and urine samples for safety tests; blood sample for 
pregnancy test if applicable. 
• At patient’s home, via videoconferencing:  Video recording for BAD assessment.  
Patients and their family members who will not be travelling to the site for Visits 2 
and 3 will be provided with recording equipment and trained in how to operate it.  On 
the day of the assessment, the study doctor will connect to the patient’s home via 
videoconferencing, and will direct the patient what to do while the family member (or 
other appropriate individual) records it.  Instructions will be provided on how to 
upload the video for transmission to the site and to the central assessors. 


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• Via courier:  From patient to site:  Return of used and unused study medication 
containers from the past 6 months.  From site to patient:  Provision of study 
medication for the next 6 months. 
Visit 4 (Week 78 ± 14 days) / Early Termination Visit 
The following procedures will be done: 
• Review medical history 
• Collect information about concomitant medications 
• Query patient about the use of any of the medications listed in Appendix 3 or any other 
medication that has the potential to affect dystonia symptoms, as follows:  
o 
If patient has been on a regular dosing regimen of any of these medications since the 
start of study TIRCON2012V1, verify that the regimen has been stable 
o 
If patient has been taking any of these medications on a PRN basis since the start of 
study TIRCON2012V1, verify that treatment was interrupted prior to the current 
visit according to the following timelines:   
Medication 
Treatment interruption period 
prior to current visit  
Baclofen 
30 days 
Trihexyphenidyl 
30 days 
Clonazepam 
30 days 
Tizanidine 
30 days 
Botox 
60 days 
Tetrabenazine 
90 days 
 
• Collect blood samples for the following assessments: 
o 
Hematology 
o 
Blood chemistry  
o 
Pregnancy testing for all sexually active females of childbearing potential (if 
applicable; in cases where the investigator determines there is no reasonable risk of 
pregnancy because of significant incapacity, pregnancy testing will not be 
performed) 
• Collect a urine sample for urinalysis 
• Measure vital signs, weight, and height 
• Perform a 12-lead ECG 


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• Conduct contraceptive counseling for sexually active patients 
• The following must be performed by a qualified investigator or a qualified delegate:  
o 
Conduct a physical examination 
o 
Record administration of the BAD in a standardized manner on videotape, and 
transmit tape to the evaluation center 
o 
Administer the Patient Global Impression of Improvement 
• Collect any empty containers or unused medication from the previous 6 months, and 
perform drug accountability 
• Instruct the patient/authorized legal representative to report any AEs that occur in the 
next 14 days and any SAEs that occur in the next 30 days 
Any ongoing AE or SAE is to be followed until one of the following outcomes: 
• AE/SAE is resolved  
• Patient’s condition stabilizes  
• AE/SAE is otherwise explained  
• Patient is lost to follow-up 
5.2 
Method of Assignment to Treatment 
Not applicable.  All patients in the extension study will receive deferiprone. 
5.3 
Blinding Procedures 
This study is open-label, with all participants receiving deferiprone.  However, patients, 
study staff, and members of the ApoPharma study team will remain blinded during the 
extension study with regard to whether the patients had received deferiprone or placebo in the 
initial study.  The blind will be broken once the initial study is completed. 
5.4 
Allocation of Patient Numbers 
All patients who signed the ICF for study TIRCON2012V1 will have been assigned a unique 
6-digit number, where the first 3 digits represent the site code and the last 3 are sequentially 
assigned to each patient.  These assigned numbers will be maintained for patients who continue 
on to study TIRCON2012V1-EXT. 
5.5 
Treatment Compliance 
At each visit, patients will be instructed to bring empty and unused containers of study 
medication back to the study site.  Compliance will be evaluated by calculating the volume of 
medication dispensed and the volume of unused drug supply remaining in the bottle. 


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6 
STUDY TREATMENTS 
All patients in the extension study will receive deferiprone. 
6.1 
Investigational Product 
Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one) is manufactured by Apotex Inc.  The 
drug will be supplied to the clinical sites by ApoPharma Inc. 
6.1.1 
Dosage Form and Mode of Administration 
Deferiprone will be provided as an 80 mg/mL oral solution.  It is to be taken orally, twice a 
day, and can be taken with or without food, as per the investigator’s recommendation. 
6.1.2 
Precautions for Use 
Bottles should not be stored in direct light.  The contents of a bottle must be used within 8 
weeks of opening.  
6.2 
Reference Product 
Not applicable. All participants in study TIRCON2012V1-EXT will receive deferiprone. 
6.3 
Packaging and Labeling 
Deferiprone 80 mg/mL oral solution will be supplied in 500 mL amber-colored bottles with 
child-resistant closure and a tamper-evident seal.  The containers will be provided with labels 
whose content is in accordance with all applicable regulatory requirements. The label will 
include protocol number, expiry date, lot/batch number, investigational statement, storage 
temperature, dosage, direction for use, visit number, date dispensed, and name and address of 
the study sponsor. 
6.4 
Shipping and Storage 
A “Product Receipt Form and Temperature Verification Log” will be provided to the study 
sites by the sponsor with each shipment of investigational product.  The investigator or a 
designate is to sign and date this receipt form to acknowledge receiving the entire product 
shipment in good condition, and to record the time at which the “TempTale 4” (Sensitech 
Inc.) temperature-monitoring device was removed and stopped.  The site will fax a copy of 
this receipt form to the sponsor and retain the original in its Investigator Trial File. 
The study medication is to be stored in a secure location (a locked room or cabinet), under 
the control of the investigator and with access to authorized individuals only, at room 
temperature (15–30 ºC [59–86 ºF]).  The sites will use a digital temperature monitoring device 
and a temperature log to facilitate daily recording of the temperature of the storage facility.  


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6.5 
Product Accountability 
It is the responsibility of the investigator to ensure that all study drug received at the study 
center is inventoried and accounted for throughout the study. Records of receipt, storage and 
administration of the study drug supplied must be maintained, and the drug accountability 
will be verified by the sponsor or sponsor’s designee during on-site monitoring visits.  At the 
conclusion of the study, a final inventory must be performed by the investigator or delegate. 
The sponsor will be responsible for determining the specific conditions for destruction of 
unused product.   
The investigator must maintain logs of the quantity of product received from the sponsor and 
of the quantity dispensed to each patient, as follows: 
Site Investigational Drug Inventory Record: 
• Name of sponsor 
• Name of investigator 
• Study identifier 
• Date and quantity of investigational product received from the sponsor 
• Lot/batch number 
• Study medication bottle number 
Patient Investigational Drug Dispensing Record: 
• Patient identification number 
• Date of dispensing and return 
• Dispenser’s initials 
• Quantity dispensed and returned 
• Study medication bottle number 
6.6 
Replacement Doses 
Patients will be dispensed a 6-month supply of study medication at Visit 1 (Week 0), Visit 2 
(Week 26), and Visit 3 (Week 52).  Dispensing must be done by appropriately qualified staff 
(physician, pharmacist, or nurse).  
If a patient reports that medication has been lost or accidentally destroyed, the appropriate site 
staff member must make a request for replacement medication, in writing, to the Clinical Research 
Associate (CRA), who will review and forward the request to the sponsor. All information 
related to the replacement medication is to be recorded in the drug accountability forms. 


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6.7 
Disposition of Unused Product 
It is the responsibility of the investigator to ensure that all study drug received at the study 
center is inventoried and accounted for throughout the study. Records of receipt, storage and 
administration of the study drug supplied must be maintained, and the drug accountability 
will be verified by the sponsor or sponsor’s designee during on-site monitoring visits.  At the 
conclusion of the study, a final inventory must be performed by the investigator or delegate. 
The sponsor will be responsible for determining the specific conditions for destruction of 
unused product. 
7 
MEASUREMENTS AND EVALUATIONS 
7.1 
Efficacy Measurements 
7.1.1 
Barry-Albright Dystonia Scale 
Dystonia is a neurological movement disorder in which sustained muscle contractions cause 
twisting and repetitive movements or abnormal postures. The Barry-Albright Dystonia 
(BAD) scale is a reliable and responsive measure for rating the degree to which dystonia 
interferes with function (27). A 5-point ordinal scale is used to rate the severity of dystonia in 
8 body regions: eyes, mouth, neck, trunk, and each upper and each lower extremity. The 
individual scores are then summed to provide a total score that ranges from 0 to 32; the 
higher the score, the more severe the dystonia. See Appendix 4. 
For study TIRCON2012V1, a protocol was prepared by a group of experts to define a 
standardized way to administer and read the BAD scale, including a provocation test to better 
capture episodic or non-continuous symptoms. The administration of the BAD scale by the 
investigator or delegate is videotaped, and the videotape is sent to a central evaluator for 
objective assessment. The results will be sent back to the site, and will be entered by the 
study site staff into the eCRF. 
In study TIRCON2012V1-EXT, the BAD scale will be administered at Visits 1, 2, 3, and 4 
(or early termination visit). 
7.1.2 
Patient Global Impression of Improvement 
The Patient Global Impression of Improvement (PGI-I) is a global index used to rate the 
response of a condition to a therapy. Patients are asked at each post–Week 0 visit to rate their 
overall condition since Visit 1 of the extension study on a 7-point rating scale: 1 = very much 
improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 
6 = much worse, and 7 = very much worse. In cases where the patient cannot complete the 
scale by him/herself, the parent or legal representative will complete the scale. See Appendix 5. 
The PGI-I will be administered at Visits 2, 3, and 4 (or early termination). 


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7.2 
Safety Measurements 
7.2.1 
Adverse Events and Serious Adverse Events 
7.2.1.1 
Definition of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient who is administered 
a pharmaceutical or other therapeutic product in a clinical study, not necessarily having a 
causal relationship with the product. An AE can therefore be any unfavorable and unintended 
sign, symptom, or disease temporally associated with the use of a product, whether or not 
considered related to that product. 
AEs include: 
• Exacerbation of a pre-existing illness, including acute episodes/crisis of a chronic 
underlying condition 
• An increase in frequency or intensity of a pre-existing episodic event or condition 
• A condition detected or diagnosed after study treatment administration, even though it 
may have been present prior to the start of the study 
• A continuous persistent disease or symptom present at baseline that worsens following 
the start of the study 
• Accidents (e.g., involving a motor vehicle) 
• Reasons for changes in concomitant medication (type of drug and/or dose) 
• Medical, nursing, or pharmacy consultation 
• Admission to hospital and surgical operations 
• Abnormalities in laboratory findings (e.g., blood chemistry, hematology, urinalysis), 
ECG, or other assessments (e.g., vital signs) that are not part of a larger medical 
condition already recorded as an AE and which are judged by the investigator to be 
clinically significant. The investigator should exercise medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. 
 
AEs do not include: 
• A pre-existing disease or condition present or detected at the start of the study that does 
not worsen 
• Hospital admissions or surgical procedures that had been planned prior to enrolment into 
the study 


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• The disease or disorder being studied, or a sign or symptom associated with that disease 
or disorder, unless it has worsened 
• An overdose of either the study treatment or concurrent medication without any signs or 
symptoms 
Note:  A case of overdose that is not associated with an AE is to be documented as a protocol 
deviation and promptly reported to the Medical Monitor. 
7.2.1.2 
Monitoring and Documenting of Adverse Events 
AEs will be collected until 14 days after the last dose, and SAEs will be collected until 30 
days after the last dose.   
AEs and SAEs that are related to the underlying medical condition for which the patient 
enrolled in the clinical trial will be recorded separately from others. 
Patients will be instructed to report any AEs to the investigator or a delegate.  In addition, the 
investigator will solicit information about the occurrence of AEs through open-ended, non-
leading verbal questions such as: 
• How are you feeling? 
• Have you had any medical problems since the last visit? 
• Have you taken any new medications, other than those provided in this study, since 
the last visit? 
Based on the patient’s response to these questions, the investigator or delegate should ask 
additional questions relevant to the specific complaint, such as: 
• How severe is/was the symptom? 
• How often did the symptom occur? 
• How long did the symptom last? 
The patient should also be questioned about any previously reported AEs that have not 
resolved.  
The investigator will evaluate all AEs for their relationship to the investigational product 
(Section 7.2.1.3), intensity (Section 7.2.1.4), and seriousness (Section 7.2.1.5), and will 
document any measures taken to address the event.  There should be an attempt to establish a 
diagnosis of the AE based on signs, symptoms, and/or other clinical information. Wherever 
possible, a diagnosis should be documented, rather than the individual signs/symptoms. All 
information is to be clearly recorded in the source documents. 


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If the dosage of study drug is reduced or treatment is discontinued as a result of an AE, the 
circumstances leading to such reduction or discontinuation must be clearly documented. 
All AEs must be followed until resolution, the condition stabilizes, the event is otherwise 
explained, or the patient is lost to follow-up. The investigator is responsible for ensuring that 
follow-up includes any supplemental investigations that are needed to elucidate the nature 
and/or causality of the AE as completely as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 
7.2.1.3 
Assessment of Causality 
The relationship of an AE to the study drug should be determined by the investigator after 
thorough consideration of all available facts, including associative connections (time or place), 
pharmacological explanations, previous knowledge of the drug, presence of characteristic 
clinical or pathological phenomena, exclusion of other causes, and/or absence of alternative 
explanations. The causal relationship of an adverse event to study drug will be assessed 
according to the following criteria (based on World Health Organization definitions): 
• Not related: 
Temporal relationship to study drug administration is missing or 
implausible, or there is no evident cause. 
• Possibly related: 
Reasonable time sequence to administration of study drug, but 
event could also be explained by concurrent disease or other drugs 
or chemicals. 
• Probably related: 
Reasonable time sequence to administration of study drug, and 
unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). Re-challenge information is not required. 
• Definitely related: 
Plausible time relationship to study drug administration, and cannot 
be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug (de-challenge) should be 
clinically plausible. The event must be definitive pharmacologically 
or phenomenologically, using a satisfactory re-challenge procedure 
if necessary.  
7.2.1.4 
Assessment of Intensity 
Intensity refers to the degree of discomfort or impairment associated with an event. The 
intensity of AEs is to be reported on the eCRF as mild, moderate, or severe, according to the 
definitions provided below.  In addition, to maximize consistency in assessment, it is 


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recommended that the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) scale be used. 
 
Intensity 
Corresponding 
NCI CTCAE Grade 
Mild: awareness of a sign or symptom but easily tolerated 
1 
Moderate: discomfort sufficient to cause interference with 
normal daily activities 
2 
Severe: resulting in inability to do work or perform normal 
daily activities 
3–5 
 
7.2.1.5 
Serious Adverse Events 
An SAE is an adverse event occurring at any dose that results in any of the following 
outcomes: 
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability or incapacity 
• A congenital anomaly in the offspring of a patient who received the study treatment 
• An important medical event that does not result in death, is not life-threatening, and does 
not necessitate hospitalization but which in the investigator’s judgment may jeopardize 
the patient and may necessitate medical or surgical intervention to prevent one of those 
outcomes. Examples include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or treatment-related 
substance abuse.  
 
Clarifications: 
• “Life-threatening” means that the patient was, in the view of the investigator, at 
immediate risk of death from the event as it occurred. This definition does not include an 
event that, had it occurred in a more severe form, might have caused death. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
during the study is not considered an AE. 


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• Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, the event is considered an SAE. 
• “Inpatient” hospitalization means the patient has been formally admitted to a hospital for 
medical reasons. This may or may not be overnight. It does not include presentation at a 
casualty or emergency room unless the event meets one of the other criteria for being an SAE. 
• With regard to the criteria for an important medical event, medical and scientific judgment 
should be used in deciding whether prompt reporting is appropriate in this situation. 
7.2.1.6 
Reporting of Serious Adverse Events 
All SAEs occurring up to 30 days following completion of or discontinuation from the study 
must be reported to the sponsor, regardless of whether they are suspected of having a causal 
relationship with the study drug. Any SAEs for which the investigator does suspect a causal 
relationship must be reported to the sponsor regardless of the time elapsed since the last dose 
of the study drug. 
Patients will be instructed to report SAEs to the investigator within 24 hours, by telephone. 
In turn, the investigator must report all SAEs to the sponsor within 24 hours of notification 
by the patient, using the sponsor’s SAE form. The sponsor will provide the contact 
information for reporting SAEs. An assessment of causality must be provided at the time of 
the initial report. The investigator or delegate must then complete and submit a follow-up 
SAE form to the sponsor within 5 calendar days, and must submit further follow-up forms 
if additional relevant follow-up information becomes available.   
The sponsor will submit reports of SAEs to the appropriate regulatory agencies, in line with 
local regulatory requirements and timelines. 
Investigators must report all SAEs to their IRB/IEC as well as to the sponsor.  If any SAE 
that is considered at least possibly related to the study medication and is unexpected occurs at 
one site, the sponsor will promptly inform all other sites of this, and all investigators must 
then report this event to their own IRBs/IECs, following the same timelines as above or 
following local IRB/IEC policy, whichever takes precedence. 
7.2.1.7 
Follow-up and Documentation of SAEs 
SAEs that occur during the study and up to 30 days after the last dose of study drug must be 
documented in the patient’s medical record and on the SAE report form.  The investigator 
should attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis rather than the individual signs/symptoms 
should be documented as the SAE.   
All SAEs must be followed until resolution, the condition stabilizes, the event is otherwise 
explained, or the patient is lost to follow-up. The investigator is responsible for ensuring that 


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follow-up includes any supplemental investigations that may be indicated, in order to 
elucidate the nature and/or causality of the SAE as completely as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. The sponsor may request that the investigator perform or 
arrange for the conduct of supplemental measurements and/or evaluations. 
If a patient dies during participation in the study or during a specified follow-up period, the 
sponsor should be sent a copy of any post-mortem findings, including histopathology.  
New or updated information is to be recorded on the originally completed SAE report form, 
with all changes signed and dated by the investigator. 
The CRA will verify the original SAE report form against the source documents at the 
monitoring visit. 
7.2.1.8 
Adverse Events of Special Interest 
An important AE that has a known association with deferiprone is neutropenia, defined as 
an absolute neutrophil count (ANC) less than 1.5 x 109/L.  The severity of neutropenia is 
categorized as follows:  
Mild neutropenia: 
A confirmed ANC ≥1.0 x 109/L and < 1.5 x 109/L. 
Moderate neutropenia: 
A confirmed ANC ≥ 0.5 x 109/L and < 1.0 x 109/L. 
Severe neutropenia/agranulocytosis: 
A confirmed ANC < 0.5 x 109/L.  
“Confirmed” means that the ANC has been found to be within the specified range on 2 
consecutive measurements a maximum of 3 days apart.  If both consecutive counts are below 
1.5 x 109/L but are not within the same range, a third count is required to determine the 
severity category.  Neutropenia is considered to be resolved when ANC is ≥1.5 x 109/L on 
2 consecutive counts. 
Management of Neutropenia 
Patients will be scheduled for weekly hematology testing throughout the study, and the 
results will be forwarded to the investigator.  If an ANC < 1.5 x 109/L is detected, the patient 
and, if possible, the primary care physician, are to be promptly notified. In addition, since both 
fever and infection can be associated with neutropenia, patients will be instructed to do the 
following: 


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• 
In the event of a temperature ≥38.5 ºC/101.3 ºF, they are to immediately discontinue 
treatment and contact the investigator at the 24-hour number provided. The investigator 
will request that CBC and differential count be obtained.   
• 
If they develop any symptoms of infection, they are to promptly report this to the 
investigator at the 24-hour number provided. The investigator will then determine 
whether or not treatment should be interrupted. 
The management of neutropenia depends on its severity, as described below.  
Mild neutropenia: 
• 
Instruct patient to interrupt  deferiprone immediately. 
• 
Repeat the ANC count daily until resolution. 
• 
If possible, arrange for patient to be seen by a physician the same day for a physical 
examination, assessment of AEs, and a review of concomitant medications/therapies.  If 
this is not possible, contact patient by phone to obtain information on AEs and 
medications. 
• 
Advise patient to enter protective isolation, if possible. 
• 
Notify the sponsor of the event by submitting  the SAE form. 
• 
If patient is not febrile and does not have an infection, deferiprone therapy can be re-
initiated once 2 consecutive ANCs are ≥1.5 x 109/L and it is deemed safe by the 
investigator.  If patient is febrile and/or has an infection, therapy cannot be re-initiated 
until all symptoms have resolved.  
Moderate neutropenia: 
• 
Instruct patient to discontinue deferiprone immediately, and withdraw him/her from the 
study.  If this occurs, arrange for the patient to return to the site for an early termination 
visit. 
• 
Repeat the ANC count daily until resolution.   
• 
If possible, arrange for patient to be seen the same day by a physician for a physical 
examination, assessment of AEs, and a review of concomitant medications/therapies.  If 
this is not possible, contact patient by phone to obtain information on AEs and medications. 
• 
If clinically indicated, arrange for patient to be admitted to hospital and undergo q4h 
measurement of vital signs. Otherwise, advise him/her to enter protective isolation and 


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have a family member obtain q4h temperature.If patient has fever ≥38.5ºC/101.3 ºF, 
arrange for him/her to be seen by a physician within 4 hours and to undergo an 
evaluation, including at least a blood culture. Antibiotics are to be initiated prior to 
obtaining the culture results, and are to be maintained until the patient becomes afebrile, 
the neutropenia has resolved, and blood cultures have been negative for a minimum of 72 
hours. The antibiotics chosen should be based on local microbial prevalence and 
antibiotic sensitivity patterns. Broad spectrum antibiotics should be used in order to 
cover both gram negative and gram positive organisms.  
• 
If possible, obtain blood sample for viral studies (CMV, parvovirus, and hepatitis 
A/B/C); serum ALT, BUN, and creatinine; and 10 mL of serum split into two 5 mL 
aliquots for frozen storage. 
• 
Notify the sponsor of the event by submitting  the SAE form. 
Severe neutropenia/agranulocytosis: 
• 
Instruct patient to discontinue deferiprone immediately, and withdraw him/her from the 
study. 
• 
Repeat the ANC count daily until resolution.   
• 
If possible, arrange for patient to be seen the same day by a physician for a physical 
examination, assessment of AEs, and a review of concomitant medications/therapies.  If 
this is not possible, contact patient by phone to obtain information on AEs and 
medications. 
• 
If possible, arrange for patient to be admitted to hospital and to have vital signs 
monitored q4h. Otherwise, advise him/her to enter protective isolation and have a family 
member obtain q4h temperature. 
• 
If patient has fever ≥38.5ºC/101.3 ºF, arrange for him/her to be seen by a physician 
within 4 hours and to undergo an evaluation, including at least a blood culture. 
Antibiotics are to be initiated prior to obtaining the culture results, and are to be 
maintained until the patient becomes afebrile, the neutropenia has resolved, and blood 
cultures have been negative for a minimum of 72 hours. The antibiotics chosen should be 
based on local microbial prevalence and antibiotic sensitivity patterns. Broad spectrum 
antibiotics should be used in order to cover both gram negative and gram positive 
organisms.  
• 
Contact the treating physician at the hospital and arrange or request for the following to 
be done, if possible: 


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o 
 If possible, obtain blood sample for viral studies (CMV, parvovirus, and hepatitis 
A/B/C); serum ALT, BUN, and creatinine; and 10 mL of serum split into two 5 mL 
aliquots for frozen storage. 
o 
Collect a blood sample for use in attempting to identify genetic or other biomarkers 
related to agranulocytosis (separate patient consent needs to be obtained). 
o 
Obtain bone marrow aspirate for:  
• 
Histology 
• 
Progenitor culture 
• 
Frozen storage (1 mL sample) 
o 
Obtain bone marrow biopsy (minimum length 3 mm). 
o 
Perform septic work-up including chest x-ray and blood, urine, and throat cultures. 
o 
If warranted, administer granulocyte stimulating factor, such as G-CSF 10 μg/kg, 
beginning the day that the ANC is confirmed as < 0.5 x 109/L and continuing daily 
until ANC is ≥ 1.5 x 109/L on 2 consecutive days. 
o 
If ANC < 0.5 x 109/L for 7 days, repeat bone marrow biopsy and aspirate weekly 
during the period of agranulocytosis, if warranted. 
• 
Notify the sponsor of the event by submitting  the SAE form. 
7.2.2 
Laboratory Measurements 
Samples for laboratory safety assessments will be taken at the time points indicated below.  If 
a patient withdraws from the study, the End of Study procedures are to be performed at an 
early termination visit. 
Hematology:  Complete blood count (CBC), including total WBC, ANC, 
platelet count, and hemoglobin 
Weekly 
Blood chemistry:  Serum ferritin, total protein, GGT, LDH, sodium, 
potassium, chloride, glucose, total, bilirubin, AST, ALT, albumin, blood urea 
nitrogen, calcium, creatinine, uric acid, alkaline phosphatase, and amylase 
Visits 1, 2, 
3, and 4 
Urinalysis:  pH, specific gravity, glucose, protein, ketones, and blood. If 
indicated by the dipstick, sediment microscopy will be performed. 
Visits 1, 2, 
3, and 4 
Pregnancy testing:  Serum pregnancy tests will be performed for all sexually 
active females of childbearing potential (unless the investigator determines 
there is no reasonable risk of pregnancy because of significant incapacity) 
Visits 1, 2, 
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The investigator must review and interpret each laboratory report, and document the review 
by signing or initialing and dating the report. Any laboratory values that fall outside a 
clinically accepted range, or values that differ significantly from previous values, must be 
marked by the investigator as either “CS” (clinically significant) or “NCS” (not clinically 
significant).  Any that are marked as CS must be further explained and documented as an AE. 
7.2.3 
Other Safety Measurements 
7.2.3.1 
Physical Examinations 
Physical examination will consist of an examination of head, ears, eyes, nose, throat and 
neck, respiratory system, cardiovascular system, gastrointestinal system, musculoskeletal 
system, neurological systems (central and peripheral), skin, thyroid, and general constitution. 
Physical examination will be performed at each study visit. 
Body weight (without shoes) will be measured at each visit. Height will be measured at 
Visits 1 and 4 only.  
7.2.3.2 
Vital Signs 
Resting heart rate, resting blood pressure, respiration rate, and body temperature will be 
taken. Blood pressure should always be measured in the sitting position, after a minimum 3-
minute resting period, and using the same arm each time if possible. Systolic and diastolic 
blood pressures are to be recorded from one measurement.  
Vital signs will be measured at each site visit. Clinically significant out-of-range values for 
vital signs will be reported as AEs (see Section 7.2.1.1). 
7.2.3.3 
Electrocardiogram 
A standard 12-lead ECG will be performed at Visit 1 and Visit 4.  At a minimum, the 
following parameters will be assessed:  HR, PR, QRS, QT, QTcF, and QTcB.  The individual 
parameters and the overall interpretation will also be documented. 
7.2.3.4 
Concomitant Medications/Therapies 
Information about concomitant medications/therapies will be collected at each study visit, 
and the following information will be recorded in the source documents and eCRFs: 


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• All medications and therapies taken for dystonia symptoms, including DBS 
(including information about frequency of change and reason for change in dosage 
and settings)  
• Any other medications that the patient starts to take or continues to take during the 
trial 
• The name, dose, route, frequency, indication, and start and stop dates of all 
medications  
• Whether or not the medication was used to treat an adverse event 
7.2.4 
Procedures in Case of Pregnancy 
If a patient becomes pregnant during the course of the study, she will be immediately 
withdrawn. The pregnancy will be immediately reported to the sponsor, and information 
about the pregnancy is to be recorded on the appropriate form and in the patient’s eCRF. The 
patient will be followed to determine the outcome, and any premature termination of the 
pregnancy will be reported.  Upon delivery, the child will be examined for any adverse 
symptoms or congenital anomalies. Follow-up information on the status of the mother and 
child will be forwarded to  the sponsor no later than 8 weeks following the delivery.  
If the partner of a male patient becomes pregnant during the course of the study, or if the 
fetus may have been exposed to the patient’s study products either through maternal 
exposure or through transmission via semen following paternal exposure, the pregnancy must 
be reported to the sponsor, and information about the pregnancy must be recorded on the 
appropriate form and in the patient’s eCRF.  If the partner provides consent for follow-up of 
the pregnancy, she will be followed until the delivery of the child, and information on the 
delivery status of the mother and child will be forwarded to the sponsor no later than 8 weeks 
following the delivery date. 
Any SAE occurring as a result of a post-study pregnancy that the investigator believes may 
have been caused by the study product or by a protocol procedure will be reported to the 
sponsor as described in Section 7.2.1.6. 
8 
STUDY COMMITTEES 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) was established prior to the start of 
study TIRCON2012V1 to monitor patient safety, and will be maintained during the extension 
study. The DSMB is responsible for overseeing the conduct of the trial, and is empowered to 


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recommend stopping the trial if, in its members’ judgment, continuation is not ethically 
acceptable on the grounds of safety. 
The following will trigger an evaluation by the DSMB for recommending stopping the study 
at any time point: 
1. Death or life-threatening event that is deemed to be at least possibly related to the study 
medication by either the investigator or the sponsor  
2. Occurrence of serious adverse events that: 
• 
Are not associated with exacerbation of a pre-existing condition, and 
• 
Are deemed to be at least possibly related to the study medication by either the 
investigator or the sponsor, and 
• 
Affect at least 2 patients  
 
No study-stopping decision will be made without prior consultation with the sponsor, the 
FDA, and the EMA. 
The operating model and the frequency of the interim safety review meetings are laid out in 
the DSMB charter.    
The DSMB will be notified of any changes to the protocol or the study conduct, and will be 
included in the review of any substantive changes to the protocol that could affect patient 
safety prior to the submission of these changes to the IRB/IEC for implementation approval.  
All DSMB meeting minutes and board composition will be submitted to the regulatory 
authorities with the final clinical study report.  
Extension Study Scientific Steering Committee 
This committee was established to provide scientific guidance and to maintain control over 
the study data and its dissemination.  Details of the committee are provided in Appendix 6.  
9 
STATISTICAL ANALYSIS 
9.1 
Endpoints 
9.1.1 
Primary Endpoints 
• Adverse events (AEs):  Frequency, severity, time to onset, duration, and relatedness 
to study product 


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• Serious adverse events (SAEs): Frequency, severity, time to onset, duration, and 
relatedness to study product  
• Number of discontinuations due to AEs 
• Hematology assessments 
• Blood chemistry assessments 
• ECG assessments 
9.1.2 
Secondary Endpoints 
All patients: 
• Change in the BAD total score from baseline (defined as prior to the start of 
deferiprone therapy) to Visit 4, as assessed by central evaluation of videotapes 
• Proportion of patients with improved or unchanged BAD scale total score between 
baseline and Visit 4 (responder analysis) 
• Change from baseline to Visit 4 in BAD scale score per body region (eyes, mouth, 
neck, trunk, and each upper and lower extremity), as assessed by central evaluation of 
videotapes 
• Change in score on the PGI-I from baseline to Visit 4 
• Proportion of patients showing an improvement on PGI-I at Visit 4 (responder analysis) 
The time points for these efficacy endpoints are defined as follows: 
• For patients who received deferiprone in the earlier study, the baseline visit of that 
study will be treated as the baseline visit of TIRCON2012V1-EXT as well.  Thus, 
Visit 1 of the extension study (Week 0) will be Year 1.5, and Visit 4 (Week 78) will 
be Year 3. 
• For patients who received placebo in the earlier study, Visit 1 of the extension study 
(Week 0) will be the baseline visit. Thus, Visit 4 (Week 78) will be Year 1.5. 
Patients who received placebo in initial study: 
For this group only, for each measure, the changes seen between the start and completion of 
study TIRCON2012V1 (i.e., following 18 months on placebo) will be compared against the 
changes seen between the start and completion of study TIRCON2012V1-EXT (i.e., 
following 18 months on deferiprone), as follows: 


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• Comparison of change in BAD total score from baseline to completion of the initial 
study vs. change in BAD total score from baseline to completion of the extension study 
• Comparison of the proportion of patients with improved or unchanged BAD scale 
total score between baseline and completion of the initial study  vs. the proportion 
with improved or unchanged BAD scale total score from baseline to completion of 
the extension study (responder analysis) 
• Comparison of the change in BAD score per body region between baseline and 
completion of the initial study  vs. change in BAD score per body region between 
baseline and completion of the extension study   
• Comparison of change in PGI-I score from baseline to completion of the initial study 
vs. change in PGI-I score from baseline to completion of the extension study 
• Comparison of the proportion of patients showing an improvement on PGI-I at 
completion of the initial study vs. the proportion showing an improvement at 
completion of the extension study (responder analysis) 
9.2 
Determination of Sample Size and Study Power 
A planned total of 90 patients will be enrolled in the TIRCON2012V1 study, and all patients 
who complete that study will be invited to enroll in the extension study. 
9.3 
Study Populations 
The following study populations will be used for analysis:  Intent-to-Treat (ITT), Per-Protocol 
(PP), and Safety. The ITT population will represent the primary analysis population for the 
evaluation of efficacy endpoints, and the PP population will be the secondary efficacy 
analysis population. The safety population will be used for the analysis of safety endpoints.  
9.3.1 
Intent-to-Treat Population 
The ITT population will include all enrolled patients who received at least one dose of study 
drug and have a baseline and at least one post-baseline efficacy assessment. 
9.3.2 
Per Protocol Population 
The PP population will include all enrolled patients who complete the study, have no major 
protocol deviations, and have an efficacy assessment at the end of the study. Prior to database 
lock, protocol deviations will be reviewed for their seriousness, and patients with major 
deviations will be excluded from the PP population.  


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9.3.3 
Safety Population 
The Safety population will include all patients who took at least one dose of study drug. 
9.4 
Data Analysis Plan 
A separate statistical analysis plan (SAP) detailing the specifications given below will be 
prepared and approved prior to database lock. Any changes in the planned statistical methods 
will be documented in the final clinical study report. 
9.4.1 
Planned Analyses 
9.4.1.1 
Patient Disposition and Drug Exposure 
Patient disposition will be summarized and presented, including the number and percentages 
of patients who were enrolled, completed the study, and withdrew (including reasons for 
withdrawals). 
For each patient, the number of doses taken will be computed from the study drug dispensing 
and accountability eCRFs obtained at each visit. The extent of exposure to the study 
medication as well as the number of doses taken during the study will be summarized with 
descriptive statistics. 
9.4.1.2 
Patient Characteristics 
Baseline characteristics for continuous variables will be summarized by mean, standard 
deviation, minimum, median, and maximum values; and baseline characteristics for discrete 
variables will be summarized with frequency and percentages. 
9.4.1.3 
Analysis of Efficacy 
For the efficacy measures of BAD (total score and by body region) and PGI-I, the change 
from baseline to each of the measurement time points will be determined and summarized 
using descriptive statistics. A paired t-test will be used to assess the statistical significance of 
the changes in these efficacy outcomes from baseline to the end of study (Visit 4).  For the 
BAD total score and for PGI-I, the proportions of patients determined to be responders at the 
end of study (Visit 4) will be calculated and presented along with 95% confidence intervals.  
For patients who received placebo in study TIRCON2012V1, a paired t-test will be used to 
compare the change in BAD (total score and by body region) and PGI-I between the start and 
completion of the initial study and between the start and completion of the extension study. 
The incidence of changes in DBS settings and outcome impacting medication use as well as 
the frequency of PRN drug or rescue medication use will be compared between the initial 


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study and the extension study. If statistically significant imbalances are detected, they will be 
adjusted accordingly for the comparison of changes in BAD and PGI-I between the initial 
study and the extension study by using a modeling approach that is consistent with the 
planned analysis of the 2 efficacy measures in the initial study. The modeling approach will 
be detailed in the SAP. For the BAD total score and for PGI-I, McNemar’s test will be used 
to compare the proportion of responders in the initial study with the proportion of responders 
in the extension study. 
Additional statistical analyses may be performed if deemed necessary. Details will be 
provided in the SAP. 
9.4.1.4 
Analysis of Safety 
All safety data reported and collected during deferiprone therapy for all patients will be 
presented in listings and summary tables to give an overview of the safety findings. For 
patients continuing on deferiprone in the extension study, this time period will be from the 
start of TIRCON2012V1 to the completion of TIRCON2012V1-EXT;  for those who 
received placebo in the initial study and are switching to deferiprone in the extension study, it 
will be from the start to the completion of the extension study. 
Adverse Events: 
A summary table of adverse events will include the following information: 
• Number of patients exposed to study treatment 
• Number of patients experiencing at least one AE  
• Number of patients experiencing at least one severe AE  
• Number of patients experiencing at least one serious AE  
• Number of patients experiencing at least one drug-related AE 
• Number of deaths 
• Total number of patients withdrawn 
• Number of withdrawals due to AEs  
All adverse experiences will be coded using MedDRA (Medical Dictionary for Regulatory 
Activities) and will be summarized by MedDRA System Organ Class (SOC) and Preferred 
Term. Adverse events will be defined as: 1) AEs that occurred or worsened (increased in 
intensity and/or frequency) on or after the first dose of study medication, 2) AEs with a 


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missing start date and a stop date on or after the first dose of study medication, 3) AEs with 
both a missing start and stop date. Events that occur within 14 days after treatment 
discontinuation will also be considered AEs. Serious adverse events that occur within 30 
days after treatment discontinuation will be included in the database.  
Adverse events will be summarized using the total number of AEs, the total number and 
percent of patients who experience an AE, and the number and percent of patients who 
experienced an AE within each SOC (and preferred term within an SOC). AEs will also be 
presented by intensity (mild, moderate, severe), by seriousness (serious, non-serious), and by 
relationship to study medication (at least possibly related, not related). The number and 
percentage of patients who are withdrawn from the study due to AEs will be calculated, and 
the AEs involved will be summarized in a frequency table. Time to onset and duration of all 
AEs with an incidence of >5%, and of any AEs of special interest (e.g., worsening of 
dystonia), will be summarized with descriptive statistics.  
Patients who have experienced the same AE multiple times will be counted only once for the 
corresponding preferred term. Similarly, if a patient experiences multiple AEs within the 
same SOC, that patient will be counted only once for that SOC. AEs will be tabulated by 
presenting SOCs alphabetically and, within each SOC, presenting the preferred terms in 
decreasing order of the total number of patients who experienced each type of AE. In 
summaries presenting the incidence of AEs by intensity, seriousness, and relation to study 
medication, a patient with multiple events coded to a given preferred term or SOC will be 
counted only once for that preferred term or SOC according to the most severe event, the 
most serious event, or the event with the closest relationship to study medication. 
Listings of SAEs, of withdrawals due to AEs, and of deaths will be provided separately and 
described in patient narratives. 
ECG: 
Clinically significant ECG abnormalities will be reported. The number and percentage of 
patients with normal and abnormal ECG results will be provided. 
Vital Signs 
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will be 
presented for temperature, heart rate, respiratory rate, systolic blood pressure, diastolic blood 
pressure, weight, and height, at baseline and each relevant visit.  Data will also be presented 
graphically for examination of possible trends. 
Biochemistry and Hematology: 


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Descriptive statistics for each clinical laboratory test will be presented for each scheduled 
visit. According to the laboratory normal ranges, laboratory test results will be categorized as 
low (< lower normal limit), normal (within normal range), and high (> upper normal limit). 
Shift tables comparing the distributions of these 3 categories at baseline versus end of study 
will be presented. Continuous data will also be presented graphically for examination of 
possible trends. 
Clinically significant laboratory values will be reported in the AE analysis. 
Concomitant Medications 
Medications will be coded using the WHO Drug dictionary. Medications taken during the 
course of the trial (on or after the first study drug dose and before or on the study termination 
date) will be considered as concomitant medications. Medications started after the study 
termination date will not be reported in tables, but will be presented in patient data listings. 
Concomitant medications used to treat adverse events will be differentiated from others. 
Concomitant medications will be summarized according to the preferred terms only. To 
count the number of patients who took a medication, a patient taking the same medication 
multiple times will only be counted once for that medication. Medications will be tabulated 
in decreasing order of the total number of patients who took each medication. In addition, the 
total number of patients to ever take any concomitant medications will be presented. 
Concomitant medications will be presented based on the Safety population. 
9.4.2 
Interim Analyses 
No interim analysis is planned. 
10 
DATA MANAGEMENT CONSIDERATIONS 
10.1 
Data Management 
The sponsor’s Clinical Data Management group will be responsible for the processing, 
coding and validating/cleaning of clinical study data. Subject data will be entered by the 
investigator or designee using the electronic Case Report Forms (eCRFs) provided by the 
sponsor. Clinical data will be entered and stored into a validated database. The eCRFs will be 
provided in the Remote Data Capture (RDC) system hosted by the sponsor. Trained users 
will access the system via a secured gateway. Users will be only authorized to access data for 
their study site. Data will be entered directly into the system from the source documents in 
lieu of the paper CRFs. On-line and off-line edit checks will be used to prompt the user to 
provide clean and accurate data. Clinical Data Management will code and monitor the data 


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for accuracy. The data will be coded using the MedDRA (Medical Dictionary for Regulatory 
Activities) and WHODD (World Health Organization Drug Dictionary) dictionaries. An 
electronic signature will be required of the investigator on the eCRFs, and the monitor will 
verify the eCRFs on-line. 
Clinical data management activities will be performed by the sponsor in accordance with 
applicable standards and data cleaning procedures of the sponsor. An audit trail of all data 
processing will be stored in the database. The study biostatistician will be notified when all 
subject data are ready for analysis. 
Integrity of the database will be assured by limiting access through username/password 
combination and account control. Authorized access to the database will be provided to those 
individuals with an inspection/auditing function (Regulatory Authorities/Quality Assurance); 
“read only” access will be provided to avoid unintentional corruption of the database. 
The database will be backed up daily. 
10.2 
Case Report Forms 
Electronic CRFs may be generated and/or printed at any time using the sponsor’s RDC 
system.  These eCRFs may be used for electronic submission data archiving or data review. 
A copy of the final patient-specific eCRFs will be sent to the clinical study sites after 
database freeze. 
11 
MONITORING, AUDITS, AND INSPECTIONS 
11.1 
Source Documents 
The investigator or delegate will maintain adequately detailed source documents supporting 
significant source data for each patient. Source data are defined as all information in original 
records and/or certified copies of original records of clinical findings, observations, or other 
activities in a clinical study that are necessary for the reconstruction and evaluation of the 
study: e.g., medical history, physical examination, laboratory results, and x-ray or ultrasound 
results. The investigator will also retain all printouts/reports of tests or procedures performed 
as a requirement of the study. All source data that is printed on thermal paper, including 
laboratory printouts and ECGs scans, must be photocopied, initialed, and dated as authentic 
equivalents to the thermal paper documents to enable extended retention time. 
The source documents must be available at the time of an audit; a site visit from the sponsor, 
sponsor representatives, or IRB/IEC; and a regulatory authority inspection. 


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11.2 
Monitoring 
Monitoring of the investigational sites will be conducted by the sponsor or contracted to a 
qualified contract research organization (CRO).  The sponsor will determine the extent, 
nature, and frequency of on-site visits that are needed to ensure that the study is being 
conducted in accordance with the approved protocol (and any amendments), GCP, and all 
applicable regulatory requirements. At site visits, the monitor will, as required, assess the 
progress of the study; check that the study data chosen for verification are authentic, 
accurate, and complete; verify that the safety and rights of patients are being protected; 
compare original documents with data entered into the study database; and identify any 
issues and address their resolution. 
The investigator agrees to allow the monitor(s) direct access to all relevant documents, and to 
allocate his/her time and the time of staff to discuss findings, corrective actions and any 
relevant issues. In addition to contacts during the study, the monitor may also contact the site 
prior to the start of the study to discuss the protocol and data collection procedures with site 
personnel.  
11.3 
Audits and Inspections 
In accordance with the principles of ICH E6 Guideline for Good Clinical Practice, the study 
site may be inspected by regulatory authorities and/or audited by ApoPharma Quality 
Assurance (QA) or their designates. The investigator and relevant clinical support staff will 
be required to be actively involved in audits and inspections, including staff interviews, and 
to make all necessary documentation and data available upon request. 
During the course of the study and/or after it has been completed, one or more investigator 
site audits may be undertaken by auditors from ApoPharma QA or delegates. The purpose of 
these audits is to determine whether or not the study is being/has been conducted and monitored 
in compliance with recognized ICH E6 Guideline for Good Clinical Practice, protocol and 
approved amendment requirements, applicable local SOPs, and local laws and regulations. It 
is the responsibility of the investigator and site staff to promptly address, by coordinating 
with ApoPharma Clinical Research, any deficiencies stemming out of regulatory inspections 
and ApoPharma QA or delegate audits, and to ensure that agreed-upon corrective and 
preventive actions are implemented as soon as possible. 
An inspection by any regulatory authority may occur at any time during or after completion 
of the study. If an investigator is contacted by a regulatory authority for the purpose of 
conducting an inspection or to discuss any compliance issues, he/she is required to contact 
ApoPharma Clinical Research immediately. 


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11.4 
Site Closure 
Upon completion of the study, the investigator must conduct the following activities, when 
applicable: 
• Return all study data and equipment to the sponsor 
• Complete  data clarifications and/or resolutions 
• Perform accountability, reconciliation, and final disposition of used and unused study 
drug, ensuring that unused medication is either destroyed or returned to the sponsor, as 
instructed 
• Review site study records for completeness 
 
The sponsor reserves the right to temporarily suspend or prematurely discontinue this study 
at any time and for any reason. If such action is taken, the sponsor will discuss this with the 
investigator (including the reasons for taking such action) at that time. The sponsor will 
promptly inform all other investigators conducting the study if the study is suspended or 
terminated for safety reasons, and will also inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by 
applicable regulations, the investigator must inform the IRB/IEC promptly and provide the 
reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the sponsor. In 
addition, the site must conduct final disposition of all unused study medication in accordance 
with the study procedures. 
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
11.5 
Retention of Records 
In accordance with applicable regulatory requirements, following closure of the study, the 
investigator will maintain a copy of all site study records in a safe and secure location. The 
sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. 
12 
ETHICAL CONSIDERATIONS 
12.1 
Informed Consent 
Prior to entering a patient into the study, the investigator or a designate must obtain written 
informed consent from the patient and/or where applicable the patient’s legally authorized 
representative, according to the sponsor’s procedures and as described in the Declaration of 
Helsinki, the Federal Food, Drug and Cosmetic Act, and U.S. applicable Code of Federal 


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Regulations Title 21, Part 50.  The investigator will ensure that the patient and/or legal 
representative is given full and adequate verbal and written information about the nature, 
purpose, and possible risks and benefits of the study, and is given ample opportunity to ask 
questions and to discuss the study with family members. The investigator must make a 
conscientious effort to be fully satisfied that the patient and/or legal representative has truly 
understood that for which the consent has been given. The patient and/or the legal 
representative must be notified that he/she is free to discontinue participation in the study at 
any time, and that such withdrawal will not affect present or future care. In the case of a 
minor or an incapacitated adult who is capable of forming an opinion and assessing the study 
information, the investigator must ensure that this individual’s decision to not participate or to 
withdraw from the study will be respected even if consent is given by the legal representative. 
The sponsor will provide a model version of the informed consent form to the sites as a 
separate document. Each site may then revise this version according to the requirements of 
its individual IRB/IEC. 
The patient and/or legal representative will sign and date the consent form prior to the first 
study intervention, and will be provided with a copy of the signed and dated ICF. Should a 
protocol amendment be made, the ICF may need to be revised to reflect the changes to the 
protocol. The investigator must then ensure that the revised ICF is signed by all patients 
currently enrolled as well as those subsequently entered in the study. 
12.2 
Institutional Review Board/Independent Ethics Committee 
It is the investigator’s responsibility to ensure that the protocol is reviewed and approved by 
a properly constituted IRB or IEC (according to ICH GCP guidelines, Section 3.2). The 
IRB/IEC must also review and approve the site’s ICF and any other written information that 
will be provided to patients, prior to any enrolment and the release of any advertisements for 
patient recruitment. Prior to the start of the study, the investigator or designee must forward 
copies of the IRB/IEC approval and the approved ICF materials to the sponsor. 
If it is necessary to amend either the protocol or the ICF during the study, the investigator 
will be responsible for ensuring that the IRB/IEC reviews these amended documents, and that 
once their approval is obtained, that any new patients are enrolled under the amended 
protocol. Copies of the amended ICF and of the IRB/IEC’s approval of it must be forwarded 
to the sponsor as soon as they are available. 


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12.3 
Patient Confidentiality 
To ensure that patients’ identities remain unknown to the sponsor, all data will be identified 
by patient ID. 
The investigator must inform patients of the possibility that representatives from regulatory 
authorities and/or the sponsor may require access to hospital or clinic records for verification 
of data pertinent to the study, including medical history. 
The investigator is responsible for keeping a list of all patients entered, including patient 
code, patient ID, full name, and last known address. 
13 
REGULATORY REQUIREMENTS  
13.1 
Regulatory Obligations 
This trial is to be conducted in accordance with the Declaration of Helsinki, the ICH 
Consolidated Guidelines for Good Clinical Practice (GCP), FDA regulations, and any local 
regulatory requirements. The trial will not begin at any given site until the site has provided 
the following documents to the sponsor or its delegate, as per the ICH Consolidated 
Guideline on GCP (Section 8.2): 
1. Signed and dated IRB/IEC approval indicating review and approval of each the following 
documents: 
• Protocol and any amendments 
• Patient Informed Consent Form 
• Any written information to be provided to patients 
• Any advertisements for patient recruitment 
• Any compensation to patients 
2. Membership of the IRB/IEC, to document that the committee is constituted in agreement 
with GCP 
3. Regulatory authority approval of the protocol  
4. Curriculum vitae of the investigator, sub-investigator(s), study coordinator, and 
pharmacist if applicable (updated within the last 2 years) 
5. For any laboratory evaluations performed at locations other than the study central 
laboratory: 


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• Accreditation, certification, established quality control, or external quality assessment 
of the laboratory 
• Normal ranges or values for all laboratory test or procedures conducted during the trial 
6. Financial Disclosure Forms (where applicable) 
7. Regulatory Authority statement of investigator forms (e.g., FDA form 1572 where 
applicable) 
8. Signed Clinical Trial Agreement 
13.2 
Amendments to the Protocol 
No amendments to this protocol will be made without consultation with and the agreement of 
the sponsor. Any amendment to the trial that seems indicated as the trial progresses must be 
discussed between the investigator and sponsor concurrently. If agreement is reached 
concerning the need for an amendment, this amendment will be produced in writing by the 
sponsor and will be made a formal part of the protocol. 
The investigator is responsible for ensuring that changes in the approved research project, 
during the period for which IRB/IEC approval has already been given, are not initiated 
without review and approval of the IRB/IEC except where necessary to eliminate apparent 
immediate hazards to the patients. 
14 
EARLY STUDY TERMINATION 
The sponsor reserves the right to discontinue this study at any time; or, an investigator may 
terminate it at his/her respective site following consultation with the sponsor. On 
discontinuance of the study, in its entirety or at a specific site, the investigator(s) will inform 
the study patients, the relevant clinical study staff, and the respective IRB/IEC of the 
discontinuance; provide them with the reasons for the discontinuance; and advise them in 
writing of any potential risks to the health of the study patients. It is the sponsor’s 
responsibility to report discontinuance of the study to regulatory agencies, to provide them 
with the reasons for the discontinuance, and to advise them in writing of any potential risks 
to the health of the study patients. 
15 
CONFIDENTIALITY 
 The confidentiality agreement signed by each investigator for the initial study concerning 
the protection of the sponsor’s confidential and proprietary information will apply to the 


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extension study as well.  Other than for study recruitment purposes and progress reports 
required by the regulatory agencies, the information contained in this document and all future 
information relating to this study is privileged, confidential, and proprietary, and may not be 
used or disclosed without the expressed written consent of the sponsor or unless otherwise 
required by law (in which case the requirement to make such disclosure shall be 
communicated to the sponsor in advance and in writing). All information provided to the 
investigator by the sponsor is to be considered strictly confidential unless otherwise specified. 
16 
INDEMNIFICATION 
Indemnification will be made in accordance with the terms and conditions set forth in the 
Clinical Trial Agreement agreed upon with the sponsor or its delegate. 
During the course of the clinical study, patients may not participate in any other study.  
Any deterioration in a patient’s health during or directly after the clinical study must be 
reported to the investigator at once. 
Should the patient receive any medical care not pertaining to the study in question, this must 
be reported to the investigator. 
Any legal dispute that may arise in respect of the interpretation of this protocol will be settled 
definitively in accordance with the applicable law in accordance with the terms and conditions 
set forth in the Clinical Trial Agreement agreed upon with the sponsor or its delegate. 
17 
OWNERSHIP 
All data generated during the study (other than patients’ medical records) are the property of 
the sponsor and the Extension Study Scientific Steering Committee (see Appendix 6), and all 
inventions discovered in the course of conducting the study are the exclusive property of the 
sponsor. The sponsor retains exclusive property of all “Background”, as defined in the 
TIRCON FP7 Grant Agreement No. 277984 and the TIRCON Consortium Agreement, and 
this “Background” will continue to apply for the TIRCON2012V1-EXT study. Details are 
provided in the Clinical Trial Agreement that was completed by the sponsor and the 
investigator and/or site.  
18 
PUBLICATION 
Data derived from the study are the property of the sponsor and the Extension Study 
Scientific Steering Committee, both of which will be responsible for the primary publication 
of the data.  


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Investigators may publish or otherwise disclose (e.g., present at a conference or use for 
instructional purposes) data from the trial solely in accordance with the terms and conditions 
described in the Clinical Trial Agreement. 


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19 
REFERENCES 
1. 
Hayflick SJ, Westaway SK, Levinson B, Zhou B, Johnson MA, Ching KH, et al. 
Genetic, clinical, and radiographic delineation of Hallervorden-Spatz syndrome. N 
Engl J Med. 2003; 348(1):33-40. 
2. 
Zorzi G, Zibordi F, Chiapparini L, Bertini E, Russo L, Piga A, et al. Iron-related 
MRI images in patients with pantothenate kinase-associated neurodegeneration 
(PKAN) treated with deferiprone: Results of a phase II pilot trial. Mov Disord. 
2011; 26(2):1756-9. 
3. 
Gregory A, Polster BJ, Hayflick SJ. Clinical and genetic delineation of 
neurodegeneration with brain iron accumulation. J Med Genet. 2009; 46(2):73-80. 
4. 
Hayflick SJ. Unraveling the Hallervorden-Spatz syndrome: pantothenate kinase-
associated neurodegeneration is the name. Curr Opin Pediatr. 2003; 15(6):572-7. 
5. 
Kurian MA, McNeill A, Lin JP, Maher ER. Childhood disorders of 
neurodegeneration with brain iron accumulation (NBIA). Dev Med Child Neurol. 
2011; 53(5):394-404. 
6. 
Hayflick SJ, Hogarth P. As iron goes, so goes disease? Haematologica. 2011; 
96(11):1571-2. 
7. 
Castelnau P, Cif L, Valente EM, Vayssiere N, Hemm S, Gannau A, DiGiorgio A, 
Coubes P. Palladial stimulation improves Pantothenate Kinase-Associated 
Neurodegeneration. Annals of Neurology. 2005; 57(5):738-741. 
8. 
Gregory A, Hayflick SJ. Pantothenate Kinase-Associated Neurodegeneration. In: 
1993-2002 Aug 13 [updated 2010 Mar 23] In: Pagon RA, Bird TD, Dolan CR, 
Stephens K editors Gene Reviews[Internet] Seattle (WA): University of 
Washington, Seattle. 1993; 
http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=pkan 
9. 
Hayflick SJ. Hallervorden-Spatz Syndrome (PKAN). 2010; Encyclopedia of 
Movement Disorders:1-3. 
10. Poulsen HE. Oxidative DNA modifications. Exp Toxicol Pathol. 2005; 57 Suppl 
1:161-9. 
11. Singh KK. Mitochondria damage checkpoint, aging, and cancer. Ann N Y Acad Sci. 
2006; 1067:182-90. 
12. Kakhlon O, Breuer W, Munnich A, Cabantchik ZI. Iron redistribution as a 
therapeutic strategy for treating diseases of localized iron accumulation. Can J 
Physiol Pharmacol. 2010; 88(3):187-96. 


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13. Boddaert N, Quan Sang KH, Rotig A, Leroy-Willig A, Gallet S, Brunelle F, et al. 
Selective iron chelation in Friedreich ataxia. Biological and clinical implications. 
Blood. 2007; 110(1):401-8. 
14. Arthur AS, Fergus AH, Lanzino G, Mathys J, Kassell NF, Lee KS. Systemic 
administration of the iron chelator deferiprone attenuates subarachnoid hemorrhage-
induced cerebral vasospasm in the rabbit. Neurosurg. 1997; 41(6):1385-91. 
15. Roy S, Preston JE, Hider RC, Ma YM. Glucosylated deferiprone and its brain 
uptake: implications for developing glucosylated hydroxypyridinone analogues 
intended to cross the blood-brain barrier. J Med Chem. 2010; 53(15):5886-9. 
16. Shanzer A, Libman J, Lytton SD, Glickstein H, Cabantchik ZI. Reversed 
siderophores act as antimalarial agents. Proc Natl Acad Sci U S A. 1991; 
88(15):6585-9. 
17. Zanninelli G, Choudury R, Loreal O, Guyader D, Lescoat G, Arnaud J, et al. Novel 
orally active iron chelators (3-hydroxypyridin-4-ones) enhance the biliary excretion 
of plasma non-transferrin-bound iron in rats. J Hepatol. 1997; 27(1):176-84. 
18. Sohn YS, Breuer W, Munnich A, Cabantchik ZI. Redistribution of accumulated cell 
iron. A modality of chelation with therapeutic implications. Blood. 2008; 111:1690-9. 
19. Dexter DT, Statton SA, Whitmore C, Freinbichler W, Weinberger P, Tipton KF, et 
al. Clinically available iron chelators induce neuroprotection in the 6-OHDA model 
of Parkinson's disease after peripheral administration. J Neural Transm. 2011; 
118:223-31. 
20. Glickstein H, Ben El R, Shvartsman M, Cabantchik ZI. Intracellular labile iron 
pools as direct targets of iron chelators. A fluorescence study of chelator action in 
living cells. Blood. 2005; 106(9):3242-50. 
21. Glickstein H, El RB, Link G, Breuer W, Konijn AM, Hershko C, et al. Action of 
chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and 
functional consequences. Blood. 2006; 108(9):3195-203. 
22. Molina-Holgado F, Hider RC, Gaeta A, Williams R, Francis P. Metals ions and 
neurodegeneration. Biometals. 2007; 20(3-4):639-54. 
23. Breuer W, Ermers MJ, Pootrakul P, Abramov A, Hershko C, Cabantchik ZI. 
Desferrioxamine-chelatable iron, a component of serum non-transferrin- bound iron, 
used for assessing chelation therapy. Blood. 2001; 97(3):792-8. 
24. Evans RW, Sharma M, Ogwang W, Patel KJ, Bartlett AN, Kontoghiorghes GJ. The 
effect of alpha-ketohydroxypyridine chelators on transferrin saturation in vitro and 
in vivo. Drugs of Today. 1992; 28(Suppl. A):19-23. 
 


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25. Waldmeier PC, Buchle AM, Steulet AF. Inhibition of catechol-O-methyltransferase 
(COMT) as well as tyrosine and tryptophan hydroxylase by the orally active iron 
chelator, 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20), in rat brain in vivo. 
Biochem Pharmacol. 1993; 45(12):2417-24. 
26. ApoPharma Inc. Deferiprone - Summary of Product Characteristics. 2009. 
27. Barry MJ, VanSwearingen JM, Albright AL. Reliability and responsiveness of the 
Barry-Albright Dystonia Scale. Dev Med Child Neurol. 1999; 41(6):404-11. 
 


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APPENDIX 1:  CLINICAL STUDY ADMINISTRATIVE STRUCTURE 
 
Function 
Name of Organization 
Address and Contact 
Information 
Study monitoring  
TheraGenesis GmbH 
 
Bruehlstrasse 50 
D-76297 Stutensee 
Germany 
Tel: +49-7249-952-063 
Main contact: Erik Hesse 
Centralized BAD score 
evaluation 
Klinikum der Universitaet 
Muenchen 
 Friedrich-Baur Institute, 
Department of Neurology, 
University of Munich 
 
Dr. Boriana Buechner 
Ziemssenstr. 1, 80336 Munich, 
Germany 
Tel: +49-89-4400-5-7443 
Fax: +49-89-4400-5-7402 
Email: Boriana.Buechner@med.uni- 
muenchen.de 


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APPENDIX 2:  LIST OF PROHIBITED DRUGS 
Use of the following medications is precluded by protocol TIRCON2012V1-EXT. 
All exceptions must be approved by the sponsor. 
 
1. 
Any investigational drug 
2. 
Chloramphenicol (CHLOROMYCETIN) 
3. 
Clozapine (CLOZARIL), Doxepin HCl (SINEQUAN), Amitriptyline 
HCl/Perphenazine (ETRAFON) and other tricyclic antidepressants 
4. 
Clomipramine hydrochloride (ANAFRANIL) 
5. 
Propranolol hydrochloride (INDERAL) 
6. 
Bepredil (VASCOR) 
7. 
Aminoglutethimide (CYTADREN) 
8. 
Interferon (INTRON A) 
9. 
Para-aminophenol,  with the following exception:  paracetamol/acetaminophen 
(TYLENOL) may be used with caution * 
10. 
Pyrazolone derivatives 
11. 
Phenytoin (DILANTIN), Carbamazepine 
12. 
Chlordiazepoxide (LIBRIUM) and other benzodiazepines 
13. 
Phenylbutazone 
14. 
Mefenamic Acid (PONSTAN) 
15. 
Metoclopramide  HCl (REGLAN) 
16. 
Chlorpromazine, prochlorperazine and other phenothiazines 
17. 
Procainamide 
18. 
Levamisole (ERGAMISOLE) 
19. 
Diclofenac Sodium (VOLTAREN) 
20. 
Hydroxyurea (HYDREA) 
21. 
Trimethoprim/sulfamethoxazole (BACTRIM/SEPTRA) 
22. 
Aminopyrine 
 
* In years of experience with Ferriprox for a different indication (thalassemia), no safety concerns have been 
reported that are related to concomitant use of this drug, and there are no restrictions on this drug in the 
Ferriprox prescribing information. Hence, paracetamol/acetaminophen may be taken by PKAN patients in 
this study under close supervision. 


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APPENDIX 3:  LIST OF RESCUE MEDICATIONS 
Rescue medication is defined as a newly prescribed medication or a change in dosage of a 
currently prescribed medication that has the potential to have an effect on dystonia symptoms 
and is provided because of a worsening of the patient’s condition.  
The use of rescue medication should be limited to circumstances judged as absolutely 
necessary by the investigator. Any use of a rescue medication must be documented, including 
the reason.  If a patient uses rescue medication for more than 2 events, the investigator should 
notify the sponsor to discuss the patient’s continued participation in the study. 
Rescue medications for dystonia include, but are not limited to, the following: 
 
• Baclofen 
• Trihexyphenidyl 
• Clonazepam 
• Tizanidine 
• Tetrabenazine 
• Botox 


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APPENDIX 4:  BARRY-ALBRIGHT DYSTONIA SCALE 
 
Permission granted by Blackwell Publishing Ltd.  
 
 
Barry-Albright Dystonia Scale 
Patient’s Number:__________________________________   Date: _____________ 
 
Directions: Assess the patient for dystonia in each of the following regions: eyes, 
mouth, neck, trunk, each upper and lower extremity (8 body regions). Write the scores 
on the lines provided (whole numbers only). Rate severity based only on dystonia as 
evidenced by abnormal movements or postures. 
 
Dystonia: sustained muscle contractions causing twisting and repetitive movements or 
abnormal postures. 
Spasticity: velocity-dependent resistance to passive stretch. 
Athetosis: distal writhing or contorting movements. 
Chorea: brief, rapid, unsustained, irregular movements. 
Ataxia: incoordination of movement characterized by wide-based unsteady gait, falling 
movements. 
 
 
Eyes: Signs of dystonia of the eyes include: Prolonged eyelid spasms and/or forced eye 
deviations. 
0____ Absence of eye dystonia. 
1____ Slight. Dystonia less than 10% of the time. 
2____ Mild. Frequent blinking without prolonged spasms of eye closure and/or eye 
movements less than 50% of the time. 
3____ Moderate. Prolonged spasms of eyelid closure, but eyes open most of the time. 
4____ Severe. Prolonged spasms of eyelid closure, with eyes closed at least 30% of the 
time. 
*____ Unable to assess eye movements. 
 
Eyes: ______ 
 
 
Mouth: Signs of dystonia of the mouth include: Grimacing, clenched or deviated jaw, 
forced open mouth, and/or forceful tongue thrusting. 
0____ Absence of mouth dystonia. 
1____ Slight. Dystonia less than 10% of the time and does not interfere with speech or 
feeding. 


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2____ Mild. Dystonia less than 50% of the time and does not interfere with speech or 
feeding. 
3____ Moderate. Dystonia more than 50% of the time, or dystonia that interferes with 
speech or feeding. 
4____ Severe. Dystonia more than 50% of the time or dystonia that prevents speech or 
feeding. 
*____ Unable to assess mouth movements. 
 
Mouth: ______ 
 
 
Neck: Signs of dystonia of the neck include: Pulling of the neck into any plane of 
motion: Extension, flexion, lateral flexion or rotation. 
0____ Absence of neck dystonia. 
1____ Slight. Pulling less than 10% of the time and does not interfere with lying, 
sitting, standing or walking. 
2____ Mild. Pulling less than 50% of the time and does not interfere with lying, 
sitting, standing or walking. 
3____ Moderate. Pulling more than 50% of the time or dystonia that interferes with 
lying, sitting, standing or walking. 
4____ Severe. Pulling more than 50% of the time or dystonia that prevents sitting in 
standard wheelchair, standing or walking (i.e. requires more than standard head 
rest for seating). 
*____ Unable to assess neck movements. 
 
Neck: ______ 
 
 
Trunk: 
0____ Absence of trunk dystonia. 
1____ Slight. Pulling less than 10% of the time and does not interfere with lying, 
sitting, standing or walking. 
2____ Mild. Pulling less than 50% of the time and does not interfere with lying, 
sitting, standing or walking. 
3____ Moderate. Pulling more than 50% of the time or dystonia that interferes with 
lying, sitting, standing or walking. 
4____ Severe. Pulling more than 50% of the time or dystonia that prevents sitting in 
standard wheelchair, standing or walking. 
*____ Unable to assess trunk movements. 
 
Trunk: ______ 
 
 


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Upper Extremities: 
0____ Absence of upper extremity dystonia. 
1____ Slight. Dystonia less than 10% of the time and does not interfere with normal 
positioning or functional activities. 
2____ Mild. Dystonia less than 50% of the time and does not interfere with normal 
positioning or functional activities. 
3____ Moderate. Dystonia more than 50% of the time or dystonia that interferes with 
normal positioning or upper extremity function. 
4____ Severe. Dystonia more than 50% of the time or dystonia that prevents normal 
positioning or upper 
extremity function; i.e., arms restrained in wheelchair to prevent injury. 
*____ Unable to assess upper extremity movements. 
 
Left Upper Extremity: ______ 
Right Upper Extremity: ______ 
 
 
Lower Extremities: 
0____ Absence of lower extremity dystonia. 
1____ Slight. Dystonia less than 10% of the time and does not interfere with normal 
positioning or functional activities. 
2____ Mild. Dystonia less than 50% of the time and does not interfere with normal 
positioning or functional activities. 
3____ Moderate. Dystonia more than 50% of the time or dystonia that interferes with 
normal positioning or lower extremity weight bearing or function. 
4____ Severe. Dystonia more than 50% of the time or dystonia that prevents normal 
positioning or lower extremity weight bearing or function. 
*____ Unable to assess lower extremity movements. 
 
Left Lower Extremity: ______ 
Right Lower Extremity: ______ 
 
 
Total Score: ________  
 
Rater’s Initials: _______ 
 


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APPENDIX 5:  PATIENT GLOBAL IMPRESSION OF IMPROVEMENT 
The Patient Global Impression of Improvement (PGI-I) is a global index used to rate the 
response of a condition to a therapy. Patients are asked to rate their total improvement since 
the beginning of the study. A 7 point rating scale is used as:  
 
1, very much improved;  
2, much improved;  
3, minimally improved;  
4, no change;  
5, minimally worse;  
6, much worse; or  
7, very much worse  
 


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APPENDIX 6:  SCIENTIFIC STEERING COMMITTEE 
 
Composition of the Committee  
The Extension Study Scientific Steering Committee includes the following members: 
 
Michael Spino, PhD 
President, ApoPharma Inc. 
Fernando Tricta, MD 
Vice President of Medical Affairs, ApoPharma Inc. 
Elliott Vichinsky, MD 
UCSF Benioff Children's Hospital Oakland 
Oakland, California, USA 
Thomas Klopstock, MD 
Klinikum der Universität München 
Munich, Germany   
Nardo Nardocci, MD 
Foundation Neurological Institute C. Besta 
Milan, Italy  
Patrick Chinnery, MD 
Newcastle University Institute of Human Genetics 
Newcastle Upon Tyne, United Kingdom 
 
Responsibilities  
• 
Provide scientific advice and guidance  
• 
Maintain exclusive ownership of the TIRCON2012V1-EXT study data 
• 
Oversee primary publication of the TIRCON2012V1-EXT study results 
• 
Review and approve  all publications, abstracts, presentations, or manuscripts that contain 
TIRCON2012V1-EXT study data 


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Signatures 
 
 
 
Michael Spino 
ApoPharma Inc.  
 
 
Date (DD MMM YYYY) 
 
 
 
Fernando Tricta 
ApoPharma Inc.  
 
Date (DD MMM YYYY) 
 
 
 
Elliott Vichinsky 
Principal Investigator 
 
 
Date (DD MMM YYYY) 
 
 
 
 
Thomas Klopstock 
Principal Investigator 
 
 
Date (DD MMM YYYY) 
 
 
 
Nardo Nardocci 
Principal Investigator 
 
 
Date (DD MMM YYYY) 
 
 
 
Patrick Chinnery 
Principal Investigator 
 
 
Date (DD MMM YYYY) 
 

SAP_000.pdf: 




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Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
CONFIDENTIAL INFORMATION 
3
 
Table of Contents 
 
 
Title page.......................................................................................................................1 
 
Approvals ......................................................................................................................2 
 
Table of Contents .........................................................................................................3 
 
List of Abbreviations ...................................................................................................5 
1 Introduction ..................................................................................................................6 
2 Study Objectives...........................................................................................................6 
2.1 
Primary Objective ..............................................................................................6 
2.2 
Secondary Objective ..........................................................................................6 
3 Methods .........................................................................................................................6 
3.1 
Study Design .......................................................................................................6 
3.2 
Determination of Sample Size and Study Power .............................................7 
3.3 
Analysis Populations ..........................................................................................7 
3.4 
Interim Analysis .................................................................................................7 
3.5 
Missing Data Handling and Derivation Rules .................................................7 
3.6 
Statistical Software and Level of Significance .................................................8 
4 Statistical Analyses.......................................................................................................8 
4.1 
Patient Dispositions and Drug Exposure .......................................................13 
4.2 
Patient Characteristics .....................................................................................14 
4.2.1 
Demographics and Baseline Characteristics ........................................14 
4.3 
Efficacy Analyses ..............................................................................................14 
4.3.1 
Efficacy Endpoints ...............................................................................14 
4.3.2 
Exploratory Analyses/Sensitivity Analysis..........................................15 
4.4 
Safety Analyses .................................................................................................15 
4.4.1 
Adverse Events ....................................................................................16 
4.4.2 
Laboratory Data ...................................................................................18 
4.4.3 
Vital Signs, Weight and Height ...........................................................18 
4.4.4 
12-Lead ECG .......................................................................................18 
4.4.5 
Treatment Compliance .........................................................................18 
4.4.6 
Concomitant Medications ....................................................................18 
5 Listing of Tables and Figures....................................................................................20 
6 Data Listings and Individual Subject Graphs .........................................................26 
7 Table Shells .................................................................................................................29 


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List of Abbreviations 
 
 
%  
Percentage 
<  
Less than 
>  
Greater than 
≥ 
Greater than or equal to 
≤ 
Less than or equal to 
ADR  
Adverse Drug Reaction 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase or serum glutamic pyruvic 
transaminase (SGPT) 
ANC 
Absolute Neutrophil Count 
AR 
Autoregressive of Order 
AST 
Aspartate aminotransferase or serum glutamic oxaloacetic 
transaminase (SGOT) 
BAD Scale 
Barry Albright Dystonia Scale 
BID 
Twice Daily Dosing 
BUN 
Blood Urea Nitrogen 
cm 
Centimetre 
CRF 
Case Report Form 
DDFM 
Denominator Degrees of Freedom Method 
DBS 
Deep Brain Stimulation 
DFP 
Deferiprone 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
GGT 
Gamma-glutamyl Transferase 
ITT 
Intent-to-treat 
kg 
Kilogram 
KR 
Kenward and Roger’s method 
LDH 
Lactate Dehydrogenase 
LSM 
Least Square Mean 
LV 
Left Ventricular 
MedDRA  
The Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mmHg 
Millimetres of mercury 
MMRM 
Mixed-Effect Model Repeated Measure 
NRBC 
Nucleated Red Blood Cell 
OC 
Observed Cases 
PGI-I 
Patient’s Global Impression of Improvement 
PKAN 
Pantothenate kinase-associated neurodegeneration 
PP 
Per protocol 
PT 
Preferred Terms 


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SADR  
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOC 
System Organ Class 
WBC 
White Blood Cell 
WHO 
World Health Organization 
WHODD 
World Health Organization Drug Dictionary 


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1 Introduction 
This document outlines the statistical analysis plan for the clinical trial TIRCON2012V1-
EXT at ApoPharma Inc. 
2 Study Objectives 
2.1 
Primary Objective 
To evaluate the long-term safety and tolerability of deferiprone in patients with PKAN. 
2.2 
Secondary Objective 
The secondary objectives are: 
 To evaluate the change in severity of dystonia over time in patients with PKAN 
treated with deferiprone; 
 To evaluate global improvement over time in patients with PKAN treated with 
deferiprone. 
3 Methods 
3.1 
Study Design 
Study TIRCON2012V1-EXT is an 18-month, multi-center, single-arm, open-label 
extension of study TIRCON2012V1.  In the initial study, patients with a diagnosis of 
PKAN were being randomized in a 2:1 ratio to receive 18 months of treatment with either 
deferiprone or placebo, respectively.  All participants who completed TIRCON2012V1 
were offered the opportunity to continue in the extension study, with the final visit of the 
initial study being considered Visit 1 of the extension study.  Patients who had been 
randomized to receive deferiprone in study TIRCON2012V1  continued to receive 
deferiprone in the extension study, while those who had been randomized to receive 
placebo were switched to deferiprone. Since the initial study were still in progress at the 
time that the first patients entered the extension study, patients and study staff  remained 
blinded until the initial study was over as to which product was received for the previous 
18 months. 
In the TIRCON-EXT study, patients will have their hematology blood counts monitored 
weekly, and will return to the study site at 6 months (Visit 2), 12 months (Visit 3), and 18 
months (Visit 4) for assessments of safety and efficacy. 


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3.2 
Determination of Sample Size and Study Power 
There was no formal sample size and power calculation for this study.  All patients who 
completed TIRCON2012V1 study were invited to enroll in the extension study. Among 
the 89 subjects randomized in TIRCON2012V1 study, 76 completed the study and 68 
subjects were subsequently enrolled in this extension study (44 originally randomized to 
the deferiprone group and 24 in the placebo group). 
3.3 
Analysis Populations 
The following study populations will be used for analysis:  Safety, Intent-to-Treat (ITT), 
and Per-Protocol (PP). The safety population will be used for the analysis of safety 
endpoints. The ITT population will represent the primary analysis population for the 
evaluation of efficacy endpoints, and the PP population will be the secondary efficacy 
analysis population.  
Safety Population 
The Safety population will include all patients who took at least one dose of study drug in 
the extension study.  
ITT Population  
The ITT population will include all enrolled patients who received at least one dose of 
study drug and have a baseline and at least one post-baseline efficacy assessment in the 
extension study.  
PP Population  
The PP population will include all enrolled patients who complete the extension study 
and have an efficacy assessment at the end of the study, have no major protocol 
violations, and have no change in DBS and baclofen pump settings or medications that 
could have an impact on dystonia. Prior to database lock, protocol deviations and 
medications that could have an impact on dystonia will be reviewed for their seriousness, 
and patients with major deviations will be excluded from the PP population. 
3.4 
Interim Analysis 
No interim analysis is planned.   
3.5 
Missing Data Handling and Derivation Rules 
For safety data analysis, no imputation will be performed on the missing data and 
analysis will be based on observed cases.  


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For efficacy endpoints, the continuous variables will be summarized and analyzed as 
recorded on the case report forms (CRFs).  If statistically significant imbalances are 
detected in the incidence of changes in DBS settings and outcome impacting medication 
use as well as the frequency of PRN drug or rescue medication between the initial study 
and the extension study, a Mixed-Effect Model Repeated Measure (MMRM) model will 
be used as the analysis method to compare the change in score from baseline between the 
initial study and the extension study for patients who received placebo in initial study 
(TIRCON2012V1) and the analysis will be based on observed cases. If no significant 
imbalance was detected, the paired t-test will be used as the analysis method and the last 
observed data will be used. 
For the efficacy analysis on all patients who received DFP during the initial and the 
extension study, the last observation will be used to calculate the change from baseline 
for patients terminated early.  As a sensitivity analysis, for early termination due to 
worsening of disease conditions or inadequate efficacy of the drug, as indicated in the 
CRF, the “worst score” method will be used for data imputation.  That is, for continuous 
variables such as BAD total score at a particular time point, the worst score of all patients 
will be used to impute the missing data at that time point. For categorical variable such as 
responder, the worst category (treatment failure) will be assigned. For missing data due to 
missed visit, the last observation will be used to fill the void.   
For BAD total score, if one or several component scores cannot be measured, then the 
same component score from the last visit will be carried forward and if it is also missing, 
the score from the next visit will be carried backward to fill the missing component 
score(s) before the total score is calculated.   
Date of exposure will be defined as day 1 for all duration calculations. For example, age 
at entry will be calculated as the integer value of the expression: (date of exposure – date 
of birth) / 365.25. For patients on DFP in the initial study, the date of exposure during the 
initial study (TIRCON2012V1) will be used while for those switched from placebo to 
DFP in the extension study (TIRCON2012V1-EXT), the date of exposure during the 
extension study will be used. 
3.6 
Statistical Software and Level of Significance 
All statistical analyses will be performed using SAS (version 9.3 or higher) on Windows 
operating system. Null hypotheses tested are that there are no differences in true 
parameter between comparison groups, unless otherwise stated. A two-sided p-value of 
0.05 will be used as the significance level for the determination of statistical significance 
in all statistical tests.   
4 Statistical Analyses 
The efficacy endpoints are defined as follows:  


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All patients: 
 Change in the BAD total score from baseline (defined as prior to the start of 
deferiprone therapy) to Visit 4, as assessed by central evaluation of videotapes 
 Proportion of patients with improved or unchanged BAD scale total score 
between baseline and Visit 4 (responder analysis, responders defined as change in 
BAD total score to be ≤0) 
 Change from baseline to Visit 4 in BAD scale score per body region (eyes, mouth, 
neck, trunk, and each upper and lower extremity), as assessed by central 
evaluation of videotapes 
 PGI-I score at Visit 4 
 Proportion of patients showing an improvement on PGI-I at Visit 4 (responder 
analysis, responders are defined as patients whose conditions have not 
deteriorated; patients who have “no change”, or are “minimally improved”, 
“much improved” or “very much improved” in the PGI-I questionnaire at the last 
study visit) 
The time points for these efficacy endpoints are defined as follows: 
 For patients who received deferiprone in the initial study, the baseline visit of that 
study will be treated as the baseline visit of TIRCON2012V1-EXT as well.  Thus, 
Visit 1 of the extension study (Week 0)  will be Year 1.5 (month 18), and Visit 4 
(Week 78) will be Year 3 (month 36). 
 For patients who received placebo in the initial study, Visit 1 of the extension 
study (Week 0) will be the baseline visit. Thus, Visit 4 (Week 78) will be Year 
1.5 (month 18). 
Patients who received placebo in initial study: 
For this group only, for each measure, the changes seen between the start and completion 
of the initial study (TIRCON2012V1) (i.e., following 18 months on placebo) will be 
compared against the changes seen between the start and completion of extension study 
(TIRCON2012V1-EXT) (i.e., following 18 months on deferiprone), as follows: 
 Comparison of change in BAD total score from baseline to completion of the 
initial study vs. change in BAD total score from baseline to completion of the 
extension study 
 Comparison of the proportion of patients with improved or unchanged BAD scale 
total score between baseline and completion of the initial study  vs. the proportion 


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with improved or unchanged BAD scale total score from baseline to completion 
of the extension study (responder analysis) 
 Comparison of the change in BAD score per body region between baseline and 
completion of the initial study  vs. change in BAD score per body region between 
baseline and completion of the extension study   
 Comparison of PGI-I score at the completion of the initial study vs. PGI-I score at 
the completion of the extension study 
 Comparison of the proportion of patients showing an improvement on PGI-I at 
completion of the initial study vs. the proportion showing an improvement at 
completion of the extension study (responder analysis) 
The following time window will be employed to classify the efficacy data into each 
scheduled visit according to the time elapsed from the first medication date (date of 
exposure) to the assessment date: 
 
Month 6 visit:  3 to <9 months 
 
Month 12 visit: 9 to <15 months 
 
Month 18 visit: 15 to <21 months 
Month 24 visit:  21 to <27 months 
 
Month 30 visit: 27 to <33 months 
 
Month 36 visit: 33 to <39 months 
The exact calculation of time elapsed from the date of exposure to the sample assessment 
date is: Time elapsed = (date of sample assessment) – (date of exposure) +1. The 
resulting time elapsed will be expressed in months and will be used for data tabulation 
and trend analysis. If multiple measurements for an outcome are available at the same 
visit for a subject, the average value will be used for that outcome for this subject at that 
visit. 
A paired t-test will be used to assess the statistical significance of the changes in the 
efficacy outcomes from baseline to the end of study.  For the BAD total score and for 
PGI-I, the proportions of patients determined to be responders at the end of study will be 
calculated and presented along with 95% confidence intervals.  
The incidence of changes in DBS settings and outcome impacting medication use as well 
as the frequency of PRN drug or rescue medication use will be tabulated by visit and 
treatment group for patients on placebo in the initial study. The incidence of changes in 
DBS settings and outcome impacting medication use as well as the frequency of PRN 
drug or rescue medication use will be compared between the initial study and the 


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extension study. Continuous variables will be compared by paired t-tests while 
proportions by McNemar’s test. If statistically significant imbalances are detected, they 
will be adjusted accordingly for the comparison of changes in BAD and PGI-I between 
the initial study and the extension study by using a MMRM model approach that is 
consistent with the analysis of these two efficacy measures in the initial study. The 
MMRM model is specified below. 
The MMRM model will be applied to non-imputed data from the observed cases (OC) 
data set. Let 
iy  denote the vector of 
in  continuous post-baseline measurements observed 
for study patient i. Each response (i.e., each element of 
iy ) will be defined as the 
patient’s score at that occasion minus the baseline score. 
The model will assume that the distribution of
iy is multivariate normal, 
)
,
(
~
i
i
i
X
N
y


, 
where 
i
X  is a design matrix of dimensions
p
ni 
,  is a vector of coefficients of length 
p , and 
i is an 
i
i
n
n 
 covariance matrix. 
The MMRM model will include baseline value of the outcome as a covariate and 
treatment group as the main factor in the model. A change in DBS settings or use of 
medications that have the potential to affect dystonia symptoms during the study may 
confound the treatment effect assessment (named outcome impacting medication use 
hereafter) for DFP vs. placebo between the initial study and the extension study for 
patients who were on placebo in the initial study. Hence, both variables will also be 
included in the MMRM model as visit-dependent covariates.  
The visit-dependent covariate for DBS settings change is defined as follows: for patients 
with DBS at enrollment, if there is any DBS setting change since the previous visit, it will 
be coded as ‘DBS Setting Change’ for the current visit or ‘No DBS Setting Change’ 
otherwise. For example, if a patient has a DBS setting change between the outcome 
assessment dates at month 6 visit and month 12 visit, it will be coded as ‘DBS Setting 
Change’ for month 12 visit in the model. For those patients without DBS at enrollment, it 
will be coded as ‘No DBS’. A discrete variable, DBSCHG, with three categories will be 
included in the MMRM model. 
The visit-dependent covariate for the outcome impacting medication use will be defined 
according to whether the patient is on a regular dosing regimen or on a PRN (as needed) 
dosing regimen between two visits. For patients treated on a regular dosing regimen, if 
there is a dose change or starting of new medication since the previous visit, it will be 
coded as ‘Yes’ for the current visit and the future follow-up visits or ‘No’ otherwise in 
the model. For patients who do not use any outcome impacting medication, it will be 
coded as ‘No’.  
For patients on a PRN (as needed) dosing regimen, the visit-dependent covriate will be 
defined according to the treatment impact period in the following table. 


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Medication 
Treatment impact period 
Baclofen 
30 days  
Trihexyphenidyl 
30 days 
Clonazepam 
30 days 
Tizanidine 
30 days 
Botox 
60 days 
Tetrabenazine 
90 days 
 
If the PRN drug is started within the treatment impact period prior to the assessment date 
of an outcome for a visit, it will be coded as ‘Yes’ for that visit. If the drug is started 
outside this time window but is not interrupted within this period, it will also be coded as 
‘Yes’ for that visit. Under other conditions, it will coded as ‘No’ in the model. A binary 
variable for the outcome impacting medication use, RESMED, will be included in the 
MMRM model. 
The frequency of PRN drug or rescue medication use between two outcome assessment 
dates of current visit and the previous visit will also be included in the MMRM model as 
a quantitative visit-dependent covariate, NDRUG, for the current visit. 
The MIXED procedure in SAS will be used for the MMRM model analysis. Data within 
each patient at different visits will be considered repeated measures. AR(1) 
(autoregressive of order 1) covariance structure will be used to model the correlation 
between repeated measures within the same patient and Kenward and Roger’s method 
will be used to estimate the denominator degrees of freedom. The 95% confidence 
interval (CI) for the difference between the two treatments will be calculated by the 
LSMEANS statement.  
A sample SAS code for the MMRM model is presented in the box below: 
proc mixed; 
  class TREAT USUBJID VISIT DBSCHG RESMED; 
  model CHG=TREAT VISIT TREAT*VISIT BASE DBSCHG RESMED 
NDRUG/solution ddfm=kr; 
  repeated VISIT/ subject=USUBJID type=ar(1); 
  lsmeans TREAT*VISIT / diff cl; 
run; 
where TREAT is the indicator variable for treatment group (DFP vs. Placebo), USUBJID 
represents the patient ID, VISIT is the discrete variable representing the scheduled study 
visit after the baseline visit, DBSCHG is the discrete variable with three categories for 


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DBS settings change (DBS Setting Change, No DBS Setting Change, No DBS), 
RESMED is the binary variable for outcome impacting medication use (Yes vs. No), 
CHG is the change in value of efficacy outcome from baseline to the scheduled visit, 
BASE is the baseline value of efficacy outcome, and NDRUG is the frequency of PRN 
drug or rescue medication use. 
PGI-I is already a measurement of change from baseline and thus will be used directly as 
the outcome variable and baseline BAD score will be included as the baseline value in all 
models. 
McNemar’s test will be used to compare the proportion of responders in the initial study 
with the proportion of responders in the extension study.  
For all patients who were on DFP in both studies, the longitudinal response profile for 
BAD score will be explored by a MMRM mdoel with time modelled as a continuous 
variable. 
For this model, AR(1) (autoregressive of order 1) covariance structure will be used to 
model the correlation between repeated measures within the same patient and Kenward 
and Roger’s method will be used to estimate the denominator degrees of freedom.  
A sample SAS code for this MMRM model is presented in the box below: 
proc mixed; 
  class USUBJID VISIT; 
  model BAD= TIME /solution ddfm=kr; 
  repeated VISIT/ subject=USUBJID type=ar(1); 
run; 
where USUBJID represents the patient ID, VISIT is the discrete variable representing the 
scheduled study visit after the baseline visit, BAD is the value of BAD score at each time 
point, and TIME is the time in months at each time point corresponding to each visit. 
4.1 
Patient Dispositions and Drug Exposure 
Patient disposition, based on the ITT population , will be summarized and presented, 
including the number and percentages of patients who were enrolled, completed the 
study, and withdrew (including reasons for withdrawals).  
For each patient, the compliance on the study drug will be computed from the study drug 
dispensing and accountability eCRFs obtained at each visit. The extent of exposure to the 
study medication taken during the study and the compliance will be summarized with 
descriptive statistics. 


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The number of enrolled patients for each study site will be presented and the number of 
subjects included in each population will be tabulated. 
4.2 
Patient Characteristics 
Baseline characteristics for continuous variables will be summarized by mean, standard 
deviation, minimum, median, and maximum values; and baseline characteristics for 
discrete variables will be summarized with frequency and percentages. 
4.2.1 Demographics and Baseline Characteristics 
Demographic data such as age, sex, ethnicity, and race will be summarized. Baseline 
characteristics at the initial study will also be tabulated. 
4.3 
Efficacy Analyses 
All efficacy endpoints will be analyzed based on the ITT population. The analyses will be 
repeated for PP population for outcomes defined for BAD total score and PGI-I as 
sensitivity analyses. Detailed definition of BAD scale and PGI-I can be found in section 
7.1 of the study protocol. 
4.3.1 Efficacy Endpoints 
All patients: 
For the efficacy measures of BAD (total score and by body region) and PGI-I, the value 
at each of the measurement time points defined in section 4 will be determined and 
summarized using descriptive statistics for all patients on DFP treatment. Similar data 
will also be presented by the treatment group received in initial study.  
A paired t-test will be used to assess the statistical significance of the changes in these 
efficacy outcomes from baseline to the end of study (Visit 4, month 18 or 36 as defined in 
section 4).  
For the BAD total score and for PGI-I, the proportions of patients determined to be 
responders at the end of study (Visit 4) will be calculated and presented along with 95% 
confidence intervals. 
The mean trajectory of BAD (total score and by body region) and PGI-I by time will be 
plotted. The longitudinal trend for BAD total score and by body region will be explored 
by the MMRM mdoel with time modelled as a continuous variable as defined in section 4 
for all time points where patients were on DFP. 
Patients who received placebo in initial study: 


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For the efficacy measures of BAD (total score and by body region) and PGI-I, the value 
at each of the measurement time points defined in section 4 will be determined and 
summarized using descriptive statistics for each study period.  
A paired t-test will be used to compare the change in BAD (total score and by body 
region) between the start and completion of the initial study to that between the start and 
completion of the extension study. The same test will be repeated for the PGI-I data. 
The incidence of changes in DBS settings and outcome impacting medication use as well 
as the frequency of PRN drug or rescue medication use will be tabulated and compared 
between the initial study and the extension study. If statistically significant imbalances 
are detected, they will be adjusted accordingly for the comparison of changes in BAD 
and PGI-I between the initial study and the extension study by using the MMRM model 
as defined in section 4.  
For the BAD total score and for PGI-I, McNemar’s test will be used to compare the 
proportion of responders in the initial study with the proportion of responders in the 
extension study. 
4.3.2 Exploratory Analyses/Sensitivity Analysis 
In order to explore potential differences in the change in BAD from baseline to Visit 4 
and PGI-I at Visit 4 across population subgroups, subgroup analyses will be performed 
for the ITT population on the following factors assessed at the baseline of the initial 
study: Age at onset of motor symptoms (<6  years vs. ≥6 years), DBS (Deep Brain 
Stimulation, Yes vs. No), Region (US vs. Europe), and Duration of disease (>5 years vs. 
<=5 years).    
Besides analysis for the ITT population, the efficacy analyses will also be repeated for 
outcomes defined based on BAD total score and PGI-I for the PP population as 
sensitivity analyses. 
As a sensitivity analysis, the statistical analysis on the change in the BAD total score 
from baseline to Visit 4 and PGI-I at Visit 4 will be repeated with the missing data being 
imputed as described in section 3.5 based on the ITT population. 
4.4 
Safety Analyses 
The safety endpoints include: 
 Adverse events (AEs):  Frequency, severity, time to onset, duration, and 
relatedness to study product 
 Serious adverse events (SAEs): Frequency, severity, time to onset, duration, and 
relatedness to study product  


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 Number of discontinuations due to AEs 
 Hematology assessments 
 Blood chemistry assessments 
 ECG assessments 
All safety data collected will be presented in listings and summary tables or graphs to 
give an overview of the safety findings. All safety endpoints will be analyzed based on 
the safety population. For patients continuing on deferiprone in the extension study, this 
time period will be from the start of TIRCON2012V1 to the completion of 
TIRCON2012V1-EXT;  for those who received placebo in the initial study and are 
switching to deferiprone in the extension study, it will be from the start to the completion 
of the extension study. 
For those patients who do not follow the scheduled time window exactly for each visit or 
withdraw from the study early, the following time window will be employed to classify 
the safety data into each scheduled visit according to the time elapsed from the first 
medication date (date of exposure) to the assessment date: 
Month 1.5 visit:  0.75 to <2.25 months 
 
Month 3 visit: 2.25 to <4.5 months 
 
Month 6 visit:  4.5 to <9 months 
 
Month 12 visit: 9 to <15 months 
 
Month 18 visit: 15 to <21 months 
Month 24 visit:  21 to <27 months 
 
Month 30 visit: 27 to <33 months 
 
Month 36 visit: 33 to <39 months 
4.4.1 Adverse Events 
A summary table of adverse events will include the following information: 
 number of patients exposed to study treatment, 
 number of patients experiencing at least one AE,  
 number of patients experiencing at least one severe AE,  


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 number of patients experiencing at least one serious AE,  
 number of patients experiencing at least one drug-related AE, 
 number of deaths, 
 total number of patients withdrawn,   
 number of withdrawals due to AEs.  
All adverse experiences will be coded using MedDRA (Medical Dictionary for 
Regulatory Activities) and will be summarized by MedDRA System Organ Class (SOC) 
and Preferred Term. Adverse events will be defined as: 1) AEs that occurred or worsened 
(increased in intensity and/or frequency) on or after the first dose of study medication, 2) 
AEs with a missing start date or a stop date on or after the first dose of study medication, 
3) AEs with both a missing start and stop date. Events that occur within 14 days after 
treatment discontinuation will also be considered AEs. Serious adverse events that occur 
within 30 days after treatment discontinuation will be included in the database.  
Adverse events will be summarized using the total number of AEs, the total number and 
percent of patients who experience an AE, and the number and percent of patients who 
experienced an AE within each SOC (and preferred term within an SOC). The rate of 
each AE (per 100 patient years) will also be calculated. AEs will also be presented by 
intensity (mild, moderate, severe), by seriousness (serious, non-serious), and by 
relationship to study medication (at least possibly related, not related). The number and 
percentage of patients who are withdrawn from the study due to AEs will be calculated, 
and the AEs involved will be summarized in a frequency table. Time to onset and 
duration of all AEs with an incidence of >5%, and of any AEs of special interest (e.g., 
worsening of dystonia), will be summarized with descriptive statistics.  
Patients who have experienced the same AE multiple times will be counted only once for 
the corresponding preferred term. Similarly, if a patient experiences multiple AEs within 
the same SOC, that patient will be counted only once for that SOC. AEs will be tabulated 
by presenting SOCs alphabetically and, within each SOC, presenting the preferred terms 
in decreasing order of the total number of patients who experienced each type of AE. In 
summaries presenting the incidence of AEs by intensity, seriousness, and relation to 
study medication, a patient with multiple events coded to a given preferred term or SOC 
will be counted only once for that preferred term or SOC according to the most severe 
event, the most serious event, or the event with the closest relationship to study 
medication. 
Listings of SAEs, of withdrawals due to AEs, and of deaths will be provided separately 
and described in patient narratives. 


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4.4.2 Laboratory Data 
Descriptive statistics for each clinical laboratory test will be presented for each visit as 
defined above for hematology and for blood biochemistry. For each test, if multiple 
measurements are taken on the same scheduled visit for a subject, average value will be 
used for this subject at that visit.  According to the laboratory normal ranges, laboratory 
test results will be categorized as low (< lower normal limit), normal (within normal 
range), and high (> upper normal limit). Shift tables comparing the distributions of these 
three categories at baseline versus end of study for parameters of interest will be 
presented. 
Continuous data will also be presented graphically for examination of possible trends. 
Clinically significant laboratory values will be reported in the adverse event analysis. 
4.4.3 Vital Signs, Weight and Height 
Descriptive statistics will be presented for temperature, heart rate, respiratory rate, 
systolic blood pressure, diastolic blood pressure, weight, height, at baseline and each 
relevant visit. Data will also be presented graphically for examination of possible trends. 
4.4.4 12-Lead ECG 
Clinically significant ECG abnormalities will be reported. The number and percentage of 
patients with normal and abnormal ECG results will be provided. 
Descriptive statistics will be presented for 12-lead ECG parameters at each relevant visit.  
4.4.5 Treatment Compliance 
Patients will be instructed on how to take the study medication. Compliance will be 
evaluated  by calculating the volume of medication dispensed and the amount of unused 
drug supply remaining in the bottle. The compliance to the study medication at each visit 
will be summarized descriptively in a table. 
4.4.6 Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. Medications taken during the course of the trial (on or after the first study 
drug dose and before or on the study termination date) will be considered as concomitant 
medications. Medications started after the study termination date will not be reported in 
tables, but will be presented in patient data listings. Concomitant medications used to 
treat adverse events will be differentiated from others. 


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Concomitant medications will be summarized according to the preferred terms only. To 
count the number of patients who took a medication, a patient taking the same medication 
multiple times will only be counted once for that medication. Medications will be 
tabulated in decreasing order of the total number of patients who took each medication. 
In addition, the total number of patients to ever take any concomitant medications will be 
presented. 
Concomitant medications will be presented based on the Safety population.  


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5 Listing of Tables and Figures 
The listing of tables and figures shows the summary tables and figures that will be produced 
based on the statistical analysis detailed in this document. Summary tables and figures are 
numbered following ICH structure but the final numberings for tables and/or figures in the 
clinical study report can be changed if more tables and/or figures are added. 
 
Tables Listing: 
 
14.1 
Disposition, Demographics and Baseline Data 
 
Table 14.1.1 
Number of patients in different populations 
Table 14.1.2 
Subject disposition – ITT population 
Table 14.1.3 
Subject exposure to study medication – ITT population 
Table 14.1.4 
Number of patients enrolled by study site – ITT population 
Table 14.1.5 
Summary of the reasons for not completing the study – ITT population 
Table 14.1.6 
Summary of demographics data at baseline of initial study – ITT 
population 
Table 14.1.6a 
Summary of demographics data at baseline of initial study – PP 
population 
Table 14.1.7 
Summary of baseline characteristics at the initial study – ITT population 
Table 14.1.7a 
Summary of baseline characteristics at the initial study – PP population 
 
14.2 
Efficacy Analyses 
 
14.2.1 Analysis for All Patients on DFP 
 
Table 14.2.1.1 
BAD score at each follow-up visit by treatment group in initial study 
– ITT population 
Table 14.2.1.1a 
BAD score at each follow-up visit by treatment group in initial study  
– PP population 
Table 14.2.1.2 
BAD score at each follow-up visit for all patients on DFP – ITT 
population 
Table 14.2.1.2a 
BAD score at each follow-up visit for all patients on DFP – PP 
population 
Table 14.2.1.3 
Change in BAD score at each follow-up visit by treatment group in 
initial study – ITT population 
Table 14.2.1.3a 
Change in BAD score at each follow-up visit by treatment group in 
initial study  – PP population 
Table 14.2.1.4 
Change in BAD score from baseline at each follow-up visit for all 
patients on DFP – ITT population 
Table 14.2.1.4a 
Change in BAD score from baseline at each follow-up visit for all 
patients on DFP – PP population 
Table 14.2.1.5 
BAD score per body region at each follow-up visit by treatment 


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group in initial study – ITT population 
Table 14.2.1.6 
BAD score per body region at each follow-up visit for all patients on 
DFP – ITT population 
Table 14.2.1.7 
Change in BAD score per body region from baseline at each follow-
up visit by treatment group in initial study – ITT population 
Table 14.2.1.8 
Change in BAD score per body region from baseline at each follow-
up visit for all patients on DFP – ITT population 
Table 14.2.1.9 
Proportions of responders in BAD total score at each follow-up visit 
by treatment group in initial study – ITT population 
Table 14.2.1.9a 
Proportions of responders in BAD total score at each follow-up visit 
by treatment group in initial study – PP population 
Table 14.2.1.10 
Proportions of responders in BAD total score at each follow-up visit 
for all patients on DFP – ITT population 
Table 14.2.1.10a 
Proportions of responders in BAD total score at each follow-up visit 
for all patients on DFP – PP population 
Table 14.2.1.11 
PGI-I score at each follow-up visit by treatment group in initial study 
– ITT population 
Table 14.2.1.11a 
PGI-I score at each follow-up visit by treatment group in initial study 
– PP population 
Table 14.2.1.12 
PGI-I score at each follow-up visit for all patients on DFP – ITT 
population 
Table 14.2.1.12a 
PGI-I score at each follow-up visit for all patients on DFP – PP 
population 
Table 14.2.1.13 
Proportions of responders in PGI-I at each follow-up visit by 
treatment group in initial study – ITT population 
Table 14.2.1.13a 
Proportions of responders in PGI-I at each follow-up visit by 
treatment group in initial study – PP population 
Table 14.2.1.14 
Proportions of responders in PGI-I at each follow-up visit for all 
patients on DFP – ITT population 
Table 14.2.1.14a 
Proportions of responders in PGI-I at each follow-up visit for all 
patients on DFP – PP population 
Table 14.2.1.15 
Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – ITT population 
Table 14.2.1.15a 
Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – PP population 
Table 14.2.1.15s 
Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) with imputed data – ITT population 
Table 14.2.1.15.1 Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – ITT population and age at onset < 6 
years  
Table 14.2.1.15.2 Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – ITT population and age at onset ≥ 6 
years 
Table 14.2.1.15.3 Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – ITT population and DBS = Yes 


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Table 14.2.1.15.4 Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – ITT population and DBS = No 
Table 14.2.1.15.5 Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – ITT population and Region = US 
Table 14.2.1.15.6 Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – ITT population and Region = Europe 
Table 14.2.1.15.7 Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – ITT population and Duration of disease 
> 5 years 
Table 14.2.1.15.8 Efficacy endpoints analysis for all patients on DFP: change in value 
at the end of study (Visit 4) – ITT population and Duration of disease 
<= 5 years 
Table 14.2.1.16 
Efficacy endpoints analysis for all patients on DFP: proportions of 
responders in BAD total score and PGI-I at the end of study (Visit 4) 
– ITT population 
Table 14.2.1.16a 
Efficacy endpoints analysis for all patients on DFP: proportions of 
responders in BAD total score and PGI-I at the end of study (Visit 4) 
– PP population 
Table 14.2.1.16s 
Efficacy endpoints analysis for all patients on DFP: proportions of 
responders in BAD total score and PGI-I at the end of study (Visit 4) 
with imputed data – PP population 
Table 14.2.1.17 
Trend analysis by MMRM model on BAD total score and by body 
region for all patients – ITT population 
 
14.2.2 Analysis for Patients on Placebo in Initial Study 
 
Table 14.2.2.1 
BAD total score at each follow-up visit for patients on placebo in initial 
study – ITT population 
Table 14.2.2.1a BAD total score at each follow-up visit for patients on placebo in initial 
study – PP population 
Table 14.2.2.2 
Change in BAD total score from baseline at each follow-up visit for 
patients on placebo in initial study – ITT population 
Table 14.2.2.2a Change in BAD total score from baseline at each follow-up visit for 
patients on placebo in initial study – PP population 
Table 14.2.2.3 
BAD score per body region at each follow-up visit for patients on 
placebo in initial study – ITT population 
Table 14.2.2.4 
Change in BAD score per body region from baseline at each follow-up 
visit for patients on placebo in initial study – ITT population 
Table 14.2.2.5 
Proportions of responders in BAD total score at each follow-up visit for 
patients on placebo in initial study – ITT population 
Table 14.2.2.5a Proportions of responders in BAD total score at each follow-up visit for 
patients on placebo in initial study – PP population 
Table 14.2.2.6 
PGI-I score at each follow-up visit for patients on placebo in initial 
study – ITT population 
Table 14.2.2.6a PGI-I score at each follow-up visit for patients on placebo in initial 


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study – PP population 
Table 14.2.2.7 
Proportions of responders in PGI-I at each follow-up visit for patients 
on placebo in initial study – ITT population 
Table 14.2.2.7a Proportions of responders in PGI-I at each follow-up visit for patients 
on placebo in initial study – PP population 
Table 14.2.2.8 
Summary of DBS settings change and outcome impacting medication 
use for patients on placebo in initial study – ITT population 
Table 14.2.2.9 
Efficacy endpoints analysis with MMRM model: Least square mean 
(LSM) change in score from baseline to Visit 4 for patients on placebo 
in initial study – ITT population 
 
14.2.3 Analysis for Patients on DFP in Initial Study and the extension study 
 
Table 14.2.3.1 
Comparison of change in BAD total score from baseline to month 18 
for patients on DFP in initial study and patients on placebo in initial 
study but switched to DFP in the extension study  – ITT population 
 
14.3 
Safety Analyses 
 
14.3.1 Adverse Events 
 
Table 14.3.1.1 Overall summary of adverse events – safety population 
Table 14.3.1.2 Summary of adverse events – safety population 
Table 14.3.1.3 Summary of adverse events related to iron deficiency – safety 
population 
Table 14.3.1.4 Summary of adverse events related to PKAN – safety population 
Table 14.3.1.5 All adverse events by severity – safety population 
Table 14.3.1.6 All adverse events by seriousness – safety population 
Table 14.3.1.7 All adverse events by relatedness to study medication – safety 
population 
Table 14.3.1.8 Summary of most common (>5%) adverse drug reactions – safety 
population 
 
 14.3.2 Hematology and Biochemistry and Urinalysis 
 
Table 14.3.2.1.1 Hematology at each follow-up visit – safety population 
Table 14.3.2.1.2 Hematology analysis: change in value at the end of study (Visit 4) – 
safety population 
Table 14.3.2.1.3 Shift table comparing three laboratory value categories at baseline and 
end of study: Hematology – safety population 
Table 14.3.2.2.1 Blood biochemistry at each follow-up visit – safety population 
Table 14.3.2.2.2 Blood biochemistry analysis: change in value at the end of study (Visit 
4) – safety population 
Table 14.3.2.2.3 Shift table comparing three laboratory value categories at baseline and 
end of study: Blood biochemistry – safety population 


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Table 14.3.2.3.1 Proportions of abnormal urinalysis results in each visit – safety 
population 
 
14.3.3 Vital Signs, Weight and Height 
 
Table 14.3.3.1 
Summary of vital signs at each follow-up visit – safety population 
Table 14.3.3.2 
Summary of weight at each follow-up visit – safety population 
Table 14.3.3.3 
Summary of height at each follow-up visit – safety population 
 
14.3.4 12-Lead ECG 
 
Table 14.3.4.1 
Summary of 12-lead ECG parameters at each follow-up visit – safety 
population 
Table 14.3.4.2 
Proportions of normal and abnormal ECG results in each visit – safety 
population 
 
14.3.5 Treatment Compliance 
 
Table 14.3.5.1 
Treatment compliance (%) by visit – safety population 
 
14.3.6 Concomitant Medications 
 
Table 14.3.6.1 
Concomitant Medications – safety population 
Table 14.3.6.2 
Rescue Medications – safety population 
Table 14.3.6.3 
PRN Medications – safety population 
 
Figures Listing: 
 
14.2 
Efficacy 
 
Figure 14.2.1.1 
Mean line graph for BAD score over time – ITT population 
Figure 14.2.1.2 
Mean line graph for PGI-I over time – ITT population 
Figure 14.2.1.3 
Mean line graph for BAD eyes score over time – ITT population 
Figure 14.2.1.4 
Mean line graph for BAD mouth score over time – ITT population 
Figure 14.2.1.5 
Mean line graph for BAD neck score over time – ITT population 
Figure 14.2.1.6 
Mean line graph for BAD trunk score over time – ITT population 
Figure 14.2.1.7 
Mean line graph for BAD left upper extremity score over time – ITT 
population 
Figure 14.2.1.8 
Mean line graph for BAD right upper extremity score over time – ITT 
population 
Figure 14.2.1.9 
Mean line graph for BAD left lower extremity score over time – ITT 
population 
Figure 14.2.1.10 Mean line graph for BAD right lower extremity score over time – ITT 
population 
 


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14.3 
Safety 
 
14.3.1 Hematology 
 
Figure 14.3.1.1 
Mean line graph for hemoglobin over time – safety population 
Figure 14.3.1.2 
Mean line graph for total WBC over time – safety population 
Figure 14.3.1.3 
Mean line graph for ANC over time – safety population 
Figure 14.3.1.4 
Mean line graph for platelets over time – safety population 
Figure 14.3.1.5 
Mean line graph for MCV over time – safety population 
 
14.3.2 Biochemistry 
 
Figure 14.3.2.1 
Mean line graph for serum ferritin over time – safety population 
Figure 14.3.2.2 
Mean line graph for total protein over time – safety population 
Figure 14.3.2.3 
Mean line graph for gamma-glutamyl transferase (GGT) over time – 
safety population 
Figure 14.3.2.4 
Mean line graph for lactate dehydrogenase (LDH) over time – safety 
population 
Figure 14.3.2.5 
Mean line graph for sodium over time – safety population 
Figure 14.3.2.6 
Mean line graph for potassium over time – safety population 
Figure 14.3.2.7 
Mean line graph for chloride over time – safety population 
Figure 14.3.2.8 
Mean line graph for glucose over time – safety population 
Figure 14.3.2.9 
Mean line graph for total bilirubin over time – safety population 
Figure 14.3.2.10 Mean line graph for aspartate aminotransferase (AST) over time – 
safety population 
Figure 14.3.2.11 Mean line graph for alanine transaminase (ALT) over time – safety 
population 
Figure 14.3.2.12 Mean line graph for albumin over time – safety population 
Figure 14.3.2.13 Mean line graph for blood urea nitrogen (BUN) over time – safety 
population 
Figure 14.3.2.14 Mean line graph for calcium over time – safety population 
Figure 14.3.2.15 Mean line graph for creatinine over time – safety population 
Figure 14.3.2.16 Mean line graph for uric acid over time – safety population 
Figure 14.3.2.17 Mean line graph for alkaline phosphatase (ALP) over time – safety 
population 
Figure 14.3.2.18 Mean line graph for amylase over time – safety population 
 
14.3.3 Vital signs, Weight and Height 
 
Figure 14.3.3.1 
Mean line graph for temperature over time – safety population 
Figure 14.3.3.2 
Mean line graph for resting heart rate over time – safety population 
Figure 14.3.3.3 
Mean line graph for respiration rate over time – safety population 
Figure 14.3.3.4 
Mean line graph for systolic blood pressure over time – safety 
population 
Figure 14.3.3.5 
Mean line graph for diastolic blood pressure over time – safety 


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population 
Figure 14.3.3.6 
Mean line graph for weight over time – safety population 
Figure 14.3.3.7 
Mean line graph for height over time – safety population 
 
6 Data Listings and Individual Subject Graphs 
Data listings are numbered following ICH structure. The final numberings for subject data 
listings in the clinical study report can be changed if more subject data listings are made in 
the addition to those in the SAP. 
 
16.2 
Subject Data Listings 
16.2.1 Subject Disposition 
 
16.2.1.1 
Listing of Disposition 
 
16.2.2 Protocol Deviations 
 
16.2.2.1 
Listing of Protocol Deviations 
 
16.2.3 Subjects Excluded from the Efficacy Analysis 
 
16.2.3.1 
Assignment of Subjects to Analysis Sets 
 
16.2.4 Demographic Data and Medical History 
 
16.2.4.1 
Listing of Informed Consent Form 
16.2.4.2 
Listing of Demographics 
16.2.4.3 
Listing of PKAN History 
16.2.4.4 
Listing of PKAN Symptoms 
16.2.4.5 
Listing of Physical Exam 
16.2.4.6 
Listing of Medical History 
 
16.2.5 Compliance and/or Drug Concentration Data 
 
16.2.5.1 
Listing of Compliance 
16.2.5.2 
Listing of Exposure 
16.2.5.3 
Listing of Changes to Exposure 
 
16.2.6 Efficacy Data 
 
16.2.6.1 
Listing of  Barry Albright Dystonia (BAD) score 
16.2.6.2 
Listing of Patient’s Global Impression of Improvement (PGI-I) 
 


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16.2.7 Adverse Events Listing 
 
16.2.7.1 
Listing of Medical Events 
16.2.7.2 
Listing of Adverse Events 
16.2.7.3 
Listing of Adverse Drug Reactions 
16.2.7.4 
Listing of Serious Adverse Events 
16.2.7.5 
Listing of Serious Adverse Drug Reactions 
 
 16.2.8 Listing of Individual Laboratory Measurements by Subjects 
 
16.2.8.1 
Listing of Hematology 
16.2.8.2 
Listing of Biochemistry 
16.2.8.3 
Listing of Urinalysis 
16.2.8.4 
Listing of Pregnancy Test 
 
16.2.9 Other Listings 
 
16.2.9.1 
Listing of Vital Signs 
16.2.9.2 
Listing of Height and Weight 
16.2.9.3 
Listing of Concomitant Medications 
16.2.9.4 
Listing of Deep Brain Stimulator (DBS) / Baclofen Pump Setting 
Changes 
16.2.9.5 
Listing of Telephone Contacts 
16.2.9.6 
Listing of Bottle Numbers 
 
 
 
16.3 
Individual Subject Graphs 
 
16.3.1 
Line plot of ANC over time by patient 
16.3.2 
Line plot of  haemoglobin over time by patient 
16.3.3 
Line plot of platelets over time by patient 
16.3.4 
Line plot of total WBC over time by patient 
16.3.5 
Line plot of MCV over time by patient 
16.3.6 
Line plot of alanine transferase over time by patient 
16.3.7 
Line plot of albumin over time by patient 
16.3.8 
Line plot of alkaline phosphatase over time by patient 
16.3.9 
Line plot of amylase over time by patient 
16.3.10 
Line plot of aspartate transaminase over time by patient 
16.3.11 
Line plot of total bilirubin over time by patient 
16.3.12 
Line plot of blood urea nitrogen over time by patient 
16.3.13 
Line plot of calcium over time by patient 
16.3.14 
Line plot of chloride over time by patient 
16.3.15 
Line plot of creatinine over time by patient 


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16.3.16 
Line plot of gamma-glutamyltransferase over time by patient 
16.3.17 
Line plot of glucose over time by patient 
16.3.18 
Line plot of lactate dehydrogenase over time by patient 
16.3.19 
Line plot of potassium over time by patient 
16.3.20 
Line plot of total protein over time by patient 
16.3.21 
Line plot of serum ferritin over time by patient 
16.3.22 
Line plot of sodium over time by patient 
16.3.23 
Line plot of uric acid over time by patient 
16.3.24 
Line plot of BAD total score over time by patient 
16.3.25 
Line plot of PGI-I score over time by patient 
 


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7 Table Shells 
The following table shells provide a framework for the display of data from this study.  These tables may not be designed exactly 
as shown in the shells, but are intended to reflect the general layout of the data that will be included in the clinical study report. 
Note that ‘c’ in the table shells indicates an alphanumeric character and ‘x’ indicates a number from 0 to 9. The analysis 
population will be indicated at the end of table title. Some tables will be based on both ITT and PP populations, and those tables 
for PP population will have a ‘a’ added to the table number so that Table x.x for ITT population and Table x.xa for PP population. 
Tables generated as sensitivity analyses will have a ‘s’ added to the table number, such as Table x.xs. 
 
Disposition tables 
 
Table 14.1.1 Number of patients in different populations  
Population 
Placebo-DFP 
DFP-DFP 
Overall 
ITT 
xx 
xx 
xx 
PP 
xx 
xx 
xx 
Safety 
xx 
xx 
xx 
 
 


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Table 14.1.2 Subject disposition – ITT population 
 
Placebo-DFP 
DFP-DFP 
Overall 
Enrolled 
xx 
xx 
xx 
Exposed 
xx 
xx 
xx 
Completed 
xx 
xx 
xx 
Withdrawn 
xx 
xx 
xx 
 


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Table 14.1.3 Subject exposure to study medication – ITT population 
 
Group 
Placebo-DFP 
(N=xx) 
DFP-DFP 
(N=xx) 
Overall 
(N=xx) 
Subjects Exposed 
xx 
xx 
xx 
Total Exposure (person-years) 
xxx.x 
xxx.x 
xxx.x 
Length of Exposure (years) 
Mean (SD) 
Median 
(Min, Max) 
 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Duration of Exposure [n(%)] 
>= 1 month 
>= 6 months 
Repeat for 9, 12,15, 18 months 
 
 
xx (xx) 
xx (xx) 
…. 
 
xx (xx) 
xx (xx) 
…. 
 
xx (xx) 
xx (xx) 
…. 


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Table 14.1.4 Number of patients enrolled by study site – ITT population 
Country 
Site 
Group 
Placebo-DFP 
DFP-DFP 
Overall 
xxx 
000x 
xx 
xx 
xx 
… 
… 
xx 
xx 
xx 
Total 
x 
xx 
xx 
xx 
 
 


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 Table 14.1.5 Summary of the reasons for not completing the study – ITT population 
 
 
Group 
Placebo-DFP (N=xx) 
 
DFP-DFP (N=xx) 
Overall (N=xx) 
Reason 
Detail 
n (%) 
n (%) 
n (%) 
Adverse event 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Voluntary withdrawal 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Lost to follow up 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Investigator decision 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Protocol violation 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Worsening of the disease/ 
Lack of efficacy 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Other 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Total 
 
xx (xx) 
xx (xx) 
xx (xx) 
 


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Demographics and baseline characteristics tables 
Table 14.1.6 Summary of demographics data at baseline of initial study – ITT population 
 
Group 
Placebo-DFP 
(N=xx) 
DFP-DFP 
(N=xx) 
Overall 
(N=xx) 
DFP vs 
Placebo 
p-value§ 
Age (years) 
(Mean ± SD) 
(Minimum, Median, Maximum) 
 
xx.x ± xx.x 
(xx.x, xx.x, xx.x) 
 
xx.x ± xx.x 
(xx.x, xx.x, xx.x) 
 
xx.x ± xx.x 
(xx.x, xx.x, xx.x) 
0.xxxx 
Sex: n (%)  
   Female 
   Male 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
0.xxxx 
Racial Origin: n (%) 
   White 
   Black 
   Asian 
   Native American 
   Native Hawaiian or Other Pacific Islander 
   Multi-Racial 
 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 
 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 
0.xxxx 
Ethnic Origin: n (%) 
   Hispanic/Latino 
   Other 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
0.xxxx 
§ T-test for means and Fisher’s exact test for percentages  
Similar Table 14.1.6a will be based on PP population  
 


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Table 14.1.7 Summary of baseline characteristics at the initial study  – ITT population 
 
Group 
Placebo-DFP 
(N=xx) 
DFP-DFP 
(N=xx) 
Overall 
(N=xx) 
DFP vs Placebo 
p-value§ 
Age (years) at onset of motor symptoms 
n 
(Mean ± SD) 
(Minimum,  Median, Maximum) 
 
xx 
xx.x ± xx.x 
(xx.x, xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
(xx.x, xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
(xx.x, xx.x, xx.x) 
0.xxxx 
Duration of disease (years) 
n 
(Mean ± SD) 
(Minimum,  Maximum) 
 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
DBS: n (%)  
   Yes 
   No 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
0.xxxx 
Baclofen pump: n (%)  
   Yes 
   No 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
0.xxxx 
BAD 
n 
(Mean ± SD) 
(Minimum,  Maximum) 
 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
§ T-test for means and Fisher’s exact test for percentages 
Similar Table 14.1.7a will be based on PP population  


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Efficacy outcomes tables 
Table 14.2.1.1 BAD score at each follow-up visit by treatment group in initial study – ITT population 
 
Visit 
Placebo-DFP§ 
(N=xx) 
DFP-DFP§ 
(N=xx) 
 
BAD 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Similar Table 14.2.1.1a will be based on PP population  


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§ Placebo-DFP group includes all patients who took Placebo during initial study and switched to DFP during the extension study; 
DFP-DFP group includes all patients who took DFP during initial study and continued on DFP during the extension study. These 
definitions are applicable to all tables with these treatment groups. 


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Table 14.2.1.2 BAD score at each follow-up visit for all patients on DFP – ITT population 
 
Visit 
DFP§ 
(N=xx) 
 
BAD 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Similar Table 14.2.1.2a will be based on PP population  
 


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§ DFP group includes all patients who ever took DFP during initial and extension study. This definition is applicable to all tables 
with this treatment group. 


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Table 14.2.1.3 Change in BAD score at each follow-up visit by treatment group in initial study – ITT population 
 
Visit 
Placebo-DFP 
(N=xx) 
DFP-DFP 
(N=xx) 
 
Change in BAD 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 


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Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
§ p-value from paired t-test 
Similar Table 14.2.1.3a will be based on PP population  


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Table 14.2.1.4 Change in BAD score from baseline at each follow-up visit for all patients on DFP – ITT population 
 
Visit 
DFP 
(N=xx) 
 
Change in BAD 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 


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Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
§ p-value from paired t-test 
Similar Table 14.2.1.4a will be based on PP population  


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Table 14.2.1.5 BAD score per body region at each follow-up visit by treatment group in initial study – ITT population 
Body Region 
Visit 
Placebo-DFP 
(N=xx) 
DFP-DFP 
(N=xx) 
 
Eyes 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for Mouth, Neck, Trunk, Left 
and right upper extremity, Left and 
right lower extremity 
… 
… 
… 


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Table 14.2.1.6 BAD score per body region at each follow-up visit for all patients on DFP – ITT population 
Body Region 
Visit 
DFP 
(N=xx) 
 
Eyes 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for Mouth, Neck, Trunk, Left 
and right upper extremity, Left and 
right lower extremity 
… 
… 


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Table 14.2.1.7 Change in BAD score per body region from baseline at each follow-up visit by treatment group in initial study – 
ITT population 
 
Visit 
Placebo-DFP 
(N=xx) 
DFP-DFP 
(N=xx) 
 
Change in Eyes Score 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 


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Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Repeat for Mouth, Neck, Trunk, Left 
and right upper extremity, Left and 
right lower extremity 
… 
… 
… 
§ p-value from paired t-test 


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Table 14.2.1.8 Change in BAD score per body region from baseline at each follow-up visit for all patients on DFP – ITT 
population 
 
Visit 
DFP 
(N=xx) 
 
Change in Eyes Score 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 


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Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Repeat for Mouth, Neck, Trunk, Left 
and right upper extremity, Left and 
right lower extremity 
… 
… 
§ p-value from paired t-test 
 
 


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Table 14.2.1.9 Proportions of responders in BAD total score at each follow-up visit by treatment group in initial study – ITT 
population 
 
Visit 
Placebo-DFP 
(N=xx) 
DFP-DFP 
(N=xx) 
Responder in BAD total score 
n (%) 
Month 6 
xx (xx.x) 
xx (xx.x) 
Month 12 
xx (xx.x) 
xx (xx.x) 
Month 18 
xx (xx.x) 
xx (xx.x) 
Month 24 
xx (xx.x) 
xx (xx.x) 
Month 30 
xx (xx.x) 
xx (xx.x) 
Month 36 
xx (xx.x) 
xx (xx.x) 
Similar Table 14.2.1.9a will be based on PP population 


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Table 14.2.1.10 Proportions of responders in BAD total score at each follow-up visit for all patients on DFP – ITT population 
 
Visit 
DFP 
(N=xx) 
Responder in BAD total score 
n (%) 
Month 6 
xx (xx.x) 
Month 12 
xx (xx.x) 
Month 18 
xx (xx.x) 
Month 24 
xx (xx.x) 
Month 30 
xx (xx.x) 
Month 36 
xx (xx.x) 
Similar Table 14.2.1.10a will be based on PP population  
 
 


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Table 14.2.1.11 PGI-I score at each follow-up visit by treatment group in initial study – ITT population 
 
Visit 
Placebo - DFP 
(N=xx) 
DFP - DFP 
(N=xx) 
PGI-I 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
§ p-value from paired t-test  


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Similar Table 14.2.1.11a will be based on PP population  


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Table 14.2.1.12 PGI-I score at each follow-up visit for all patients on DFP – ITT population 
 
Visit 
DFP 
(N=xx) 
PGI-I 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
§ p-value from paired t-test 


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Similar Table 14.2.1.12a will be based on PP population  
 


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Table 14.2.1.13 Proportions of responders in PGI-I at each follow-up visit by treatment group in initial study – ITT population 
 
Visit 
Placebo-DFP 
(N=xx) 
DFP-DFP 
(N=xx) 
Responder in PGI-I 
n (%) 
Month 6 
xx (xx.x) 
xx (xx.x) 
Month 12 
xx (xx.x) 
xx (xx.x) 
Month 18 
xx (xx.x) 
xx (xx.x) 
Month 24 
xx (xx.x) 
xx (xx.x) 
Month 30 
xx (xx.x) 
xx (xx.x) 
Month 36 
xx (xx.x) 
xx (xx.x) 
Similar Table 14.2.1.13a will be based on PP population  


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Table 14.2.1.14 Proportions of responders in PGI-I at each follow-up visit for all patients on DFP – ITT population 
 
Visit 
DFP 
(N=xx) 
Responder in PGI-I 
n (%) 
Month 6 
xx (xx.x) 
Month 12 
xx (xx.x) 
Month 18 
xx (xx.x) 
Month 24 
xx (xx.x) 
Month 30 
xx (xx.x) 
Month 36 
xx (xx.x) 
Similar Table 14.2.1.14a will be based on PP population  


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Table 14.2.1.15 Efficacy endpoints analysis for all patients on DFP: change in value at the end of study (Visit 4) – ITT population 
 
Visit 
Score 
n 
Mean (SD) 
Change from Baseline 
n 
Mean (SD) 
p-value§ 
BAD Total Score 
 
Baseline 
xx 
xx.xx (xx.x) 
 
 
 
Visit 4 
 
xx 
xx.xx (xx.x) 
xx 
xx.xx (xx.x) 
0.xxxx 
PGI-I 
Visit 4 
 
 
xx 
xx.xx (xx.x) 
0.xxxx 
Eyes score 
Baseline 
xx 
xx.xx (xx.x) 
 
 
 
Visit 4 
 
xx 
xx.xx (xx.x) 
xx 
xx.xx (xx.x) 
0.xxxx 
Repeat for other body 
regions 
…. 
…. 
…. 
…. 
§ p-value from paired t-test 
Similar Table 14.2.1.15a will be based on PP population 
Similar Table 14.2.1.15s will be based on missing data imputed as sensitivity analysis 
 
Similar Tables 14.2.1.15.1 and 14.2.1.15.2 will be based on ITT population and Age at onset of motor symptoms (Age <6 vs. Age 
≥6) 
Similar Tables 14.2.1.15.3 and 14.2.1.15.4 will be based on ITT population and DBS (Deep Brain Stimulation Yes vs. No) 
Similar Tables 14.2.1.15.5 and 14.2.1.15.6 will be based on ITT population and Region (US vs. Europe) 
Similar Tables 14.2.1.15.7 and 14.2.1.15.8 will be based on ITT population and Duration of disease at baseline (>5 years vs. <=5 
years) 


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Table 14.2.1.16 Efficacy endpoints analysis for all patients on DFP: proportions of responders in BAD total score and PGI-I at the 
end of study (Visit 4) – ITT population 
 
Visit 
(N=xx) 
Responder in BAD total score 
n (%) 
(95% CI) 
Visit 4 
 
 
xx  (xx.x) 
(xx.x, xx.x) 
Responder in PGI-I 
n (%) 
(95% CI) 
Visit 4  
 
xx  (xx.x) 
(xx.x, xx.x) 
Similar Table 14.2.1.16a will be based on PP population 
Similar Table 14.2.1.16s will be based on missing data imputed as sensitivity analysis 


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Table 14.2.1.17 Trend analysis by MMRM model on BAD total score and by body region for all patients – ITT population 
Dependent Variable 
Time slope 
95% CI of the Slope 
p-value 
BAD Total Score 
xx.x 
(xx.xx xx.x) 
0.xxxx 
Eyes 
xx.x 
(xx.xx xx.x) 
0.xxxx 
Repeat for Mouth, Neck, Trunk, Left and right 
upper extremity, Left and right lower extremity 
…. 
…. 
…. 
 


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Table 14.2.2.1 BAD total score at each follow-up visit for patients on placebo in initial study – ITT population 
 
Visit 
Placebo in TIRCON 
(N=xx) 
DFP in TIRCON-
EXT 
(N=xx) 
 
BAD 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Similar Table 14.2.2.1a will be based on PP population  


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 Table 14.2.2.2 Change in BAD total score from baseline at each follow-up visit for patients on placebo in initial study – ITT 
population 
 
Visit 
Placebo in TIRCON 
(N=xx) 
DFP in TIRCON-
EXT 
(N=xx) 
DFP 
Vs. 
Placebo 
p-value§ 
 
BAD 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
§ Paired T-test 
Similar Table 14.2.2.2a will be based on PP population  


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Table 14.2.2.3 BAD score per body region at each follow-up visit for patients on placebo in initial study – ITT population 
 
Visit 
Placebo in TIRCON 
(N=xx) 
DFP in TIRCON-
EXT 
(N=xx) 
 
Eyes 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for other body regions 
…. 
…. 
…. 
 


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Table 14.2.2.4 Change in BAD score per body region from baseline at each follow-up visit for patients on placebo in initial study 
– ITT population 
 
Visit 
Placebo in TIRCON 
(N=xx) 
DFP in TIRCON-
EXT 
(N=xx) 
DFP 
Vs. 
Placebo 
p-value§ 
 
Eyes 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
Repeat for other body regions 
…. 
…. 
…. 
 
§ Paired T-test 


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Table 14.2.2.5 Proportions of responders in BAD total score at each follow-up visit for patients on placebo in initial study – ITT 
population 
 
Visit 
Placebo in 
TIRCON 
(N=xx) 
DFP in TIRCON-
EXT 
(N=xx) 
DFP 
Vs. 
Placebo 
p-value§ 
Responder in BAD total score 
n (%) 
Month 6 
xx (xx.x) 
xx (xx.x) 
0.xxxx 
Month 12 
xx (xx.x) 
xx (xx.x) 
0.xxxx 
Month 18 
xx (xx.x) 
xx (xx.x) 
0.xxxx 
§ McNemar’s test 
 
Similar Table 14.2.2.5a will be based on PP population  
 
 


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Table 14.2.2.6 PGI-I score at each follow-up visit for patients on placebo in initial study – ITT population 
 
Visit 
Placebo in TIRCON 
(N=xx) 
DFP in TIRCON-
EXT 
(N=xx) 
DFP 
Vs. 
Placebo 
p-value§ 
 
PGI-I  
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
§ Paired T-test 
Similar Table 14.2.2.6a will be based on PP population  


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Table 14.2.2.7 Proportions of responders in PGI-I at each follow-up visit for patients on placebo in initial study – ITT population 
 
Visit 
Placebo in 
TIRCON 
(N=xx) 
DFP in 
TIRCON-EXT 
(N=xx) 
DFP 
Vs. 
Placebo 
p-value§ 
Responder in PGI-I 
n (%) 
Month 6 
xx (xx.x) 
xx (xx.x) 
0.xxxx 
Month 12 
xx (xx.x) 
xx (xx.x) 
0.xxxx 
Month 18 
xx (xx.x) 
xx (xx.x) 
0.xxxx 
§ McNemar’s test 
 
Similar Table 14.2.2.7a will be based on PP population  
 


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Table 14.2.2.8 Summary of DBS settings change and medication use with a potential outcome impact for patients on placebo in 
initial study – ITT population 
Visit 
 
Group 
Placebo in 
TIRCON 
(N=xx) 
DFP in TIRCON-
EXT 
(N=xx) 
Month 6 
DBS Settings: n (%)  
   DBS Setting Change 
   No DBS Setting Change 
   No DBS 
 
xx (xx) 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
xx (xx) 
Outcome Impacting Medication Use: n (%) 
   Yes 
   No 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
Frequency of PRN drug or rescue medication use 
(Mean ± SD) 
Median 
(Minimum, Maximum) 
 
xx ± xx.x 
xx 
(xx, xx) 
 
xx ± xx.x 
xx 
(xx, xx) 
Repeat for other 
visits 
… 
… 
… 
Overall 
… 
… 
… 
 
 
  


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Table 14.2.2.9 Efficacy endpoints analysis with MMRM model: Least square mean (LSM) change in score from baseline to Visit 4 
for patients on placebo in initial study – ITT population 
 
Visit 
Placebo in 
TIRCON 
(N=xx) 
DFP in TIRCON-
EXT 
(N=xx) 
 
DFP - Placebo 
LSM Difference 
(95% CI) 
 
 
p-value 
 
BAD 
 
Change from baseline to 
Visit 4  
 
Mean (SD) 
 
 
xx.xx (xx.x) 
 
 
xx.xx (xx.x) 
 
xx 
(xx.x xx.x) 
 
0.xxxx 
PGI-I 
Score at Visit 4 
 
Mean (SD) 
 
 
xx.xx (xx.x) 
 
 
xx.xx (xx.x) 
 
xx 
(xx.x xx.x) 
 
0.xxxx 
BAD Eyes 
Change from baseline to 
Visit 4  
 
Mean (SD) 
 
 
xx.xx (xx.x) 
 
 
xx.xx (xx.x) 
 
xx 
(xx.x xx.x) 
 
0.xxxx 
Repeat for other 
body regions 
…. 
…. 
…. 
…. 
…. 
 


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Table 14.2.3.1 Comparison of change in BAD total score from baseline to month 18 for patients on DFP in initial study and 
patients on placebo in initial study but switched to DFP in the extension study  – ITT population 
 
Visit 
DFP in TIRCON 
(N=xx) 
DFP in TIRCON-
EXT 
(N=xx) 
p-value§ 
 
BAD 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value§ 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
0.xxxx 
§ T-test 


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  Safety outcomes tables 
 
Table 14.3.1.1 Overall summary of adverse events – safety population 
 
Treatment Group 
DFP 
(N=xx) 
Number of subjects with at least one AE 
xx (xx%) 
Number of subjects with at least one SAE 
xx (xx%) 
Number of subjects with at least one severe AE 
xx (xx%) 
Number of subjects with at least one ADR 
xx (xx%) 
Number of deaths 
xx (xx%) 
Number of subject withdrawn 
xx (xx%) 
Number of subject withdrawals due to AE 
xx (xx%) 
 
 


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Table 14.3.1.2 Summary of adverse events – safety population 
  
  
  
  
DFP 
Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Events: xxx 
Total Subjects Reporting: xx 
System 
Organ Class 
  Preferred Term 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
CCCCCC 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
……... 
x (x.x) 
x (x.xx) 
 


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Table 14.3.1.3 Summary of adverse events related to iron deficiency – safety population 
  
  
  
  
DFP 
Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Events: xxx 
Total Subjects Reporting: xx 
  Preferred Term 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
  Cccccc 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
……... 
x (x.x) 
x (x.xx) 
 


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Table 14.3.1.4 Summary of adverse events related to PKAN – safety population 
  
  
  
  
DFP 
Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Events: xxx 
Total Subjects Reporting: xx 
  Preferred Term 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
  Cccccc 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
……... 
x (x.x) 
x (x.xx) 


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Table 14.3.1.5 All adverse events by severity – safety population 
  
  
  
  
DFP 
Mild 
Moderate 
Severe 
Exposure (subject-years): x.xx Exposure (subject-years): x.xx Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Events: xxx 
Total Events: xxx 
Total Events: xxx 
Total Subjects Reporting: xx 
Total Subjects Reporting: xx 
Total Subjects Reporting: xx 
System 
Organ Class 
  Preferred Term 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
CCCCCC 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
……... 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
 


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Table 14.3.1.6 All adverse events by seriousness – safety population 
  
  
  
  
DFP 
Non-serious 
Serious 
Exposure (subject-years): x.xx Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Events: xxx 
Total Events: xxx 
Total Subjects Reporting: xx 
Total Subjects Reporting: xx 
System 
Organ Class 
  Preferred Term 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
CCCCCC 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
……... 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
 


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Table 14.3.1.7 All adverse events by relatedness to study medication – safety population 
  
  
  
  
DFP 
Related 
Unrelated 
Exposure (subject-years): x.xx Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Events: xxx 
Total Events: xxx 
Total Subjects Reporting: xx 
Total Subjects Reporting: xx 
System 
Organ Class 
  Preferred Term 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
CCCCCC 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
……... 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
 


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Table 14.3.1.8 Summary of most common (>5%) adverse drug reactions – safety population 
  
  
  
  
DFP 
Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Events: xxx 
Total Subjects Reporting: xx 
System 
Organ Class 
  Preferred Term 
N Subjects 
(%)  
N Events 
(Rate/100 patient 
years) 
Time to onset (Days) 
Mean (SD) 
Median 
(Min, Max) 
Duration (Days) 
Mean (SD) 
Median 
(Min, Max) 
CCCCCC 
x (x.x) 
x (x.xx) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
  Cccccc 
x (x.x) 
x (x.xx) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
……... 
x (x.x) 
x (x.xx) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
 


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Table 14.3.2.1.1 Hematology at each visit – safety population 
Test 
Visit 
DFP 
(N=xx) 
 
Hemoglobin (g/L)  
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 1.5 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 3 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 


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Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for other hematology 
parameters 
… 
… 
 


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Table 14.3.2.1.2  Hematology analysis: change in value at the end of study (Visit 4) – safety population 
 
Visit 
n 
Mean (SD) 
Change from Baseline 
n 
Mean (SD) 
p-value§ 
Hemoglobin (g/L)  
 
Baseline 
xx 
xx.xx (xx.x) 
 
 
 
Visit 4 
 
xx 
xx.xx (xx.x) 
xx 
xx.xx (xx.x) 
0.xxxx 
Repeat for other 
hematology parameters 
…. 
…. 
…. 
…. 
§ p-value from paired t-test 


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Table 14.3.2.1.3 Shift table comparing three laboratory value categories at baseline and end of study: Hematology – safety 
population 
Laboratory Test 
Treatment 
Baseline 
End of study 
Total 
Low 
Normal 
High 
Hemoglobin 
 
DFP 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
Repeat for other tests 
of interest 
 
 
 
 
 
 
 
 


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Table 14.3.2.2.1 Blood biochemistry at each visit – safety population 
Test 
Visit 
DFP 
(N=xx) 
 
Seum Ferritin (ug/L)  
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 1.5 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 3 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 


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Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for other biochemistry 
parameters 
… 
… 
 


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Table 14.3.2.2.2  Blood biochemistry analysis: change in value at the end of study (Visit 4) – safety population 
 
Visit 
n 
Mean (SD) 
Change from Baseline 
n 
Mean (SD) 
p-value§ 
Seum Ferritin (ug/L)  
Baseline 
xx 
xx.xx (xx.x) 
 
 
 
Visit 4 
 
xx 
xx.xx (xx.x) 
xx 
xx.xx (xx.x) 
0.xxxx 
Repeat for other 
biochemistry parameters 
…. 
…. 
…. 
…. 
§ p-value from paired t-test 


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Table 14.3.2.2.3 Shift table comparing three laboratory value categories at baseline and end of study: Blood biochemistry – safety 
population 
 
Laboratory Test 
Treatment 
Baseline 
End of study 
Total 
Low 
Normal 
High 
Seum Ferritin  
DFP 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
Repeat for other tests 
of interest 
 
 
 
 
 
 


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CONFIDENTIAL INFORMATION 
87
Table 14.3.2.3.1 Proportions of abnormal urinalysis results in each visit – safety population 
Test 
Visit 
DFP 
(N=xx) 
 
Abnormal Urinalysis 
n 
Abnormal (n (%)) 
 
Baseline 
xx 
xx (xx) 
 
Month 1.5 
xx 
xx (xx) 
 
Month 3 
xx 
xx (xx) 
 
Month 6 
xx 
xx (xx) 
 
Month 12 
xx 
xx (xx) 
 
Month 18 
xx 
xx (xx) 
 
Month 24 
xx 
xx (xx) 
 
Month 30 
xx 
xx (xx) 
 
Month 36 
xx 
xx (xx) 
 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
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Table 14.3.3.1 Summary of vital signs at each visit – safety population 
Test 
Visit 
DFP 
(N=xx) 
 
Resting Heart Rate 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 1.5 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 3 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
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Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for respiratory rate, systolic 
blood pressure, diastolic blood 
pressure  
… 
… 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
CONFIDENTIAL INFORMATION 
90
Table 14.3.3.2 Summary of weight at each visit – safety population 
Test 
Visit 
DFP 
(N=xx) 
 
Weight 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 1.5 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 3 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
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Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
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92
Table 14.3.3.3 Summary of height at each visit – safety population 
Test 
Visit 
DFP 
(N=xx) 
 
Height 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
CONFIDENTIAL INFORMATION 
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Table 14.3.4.1 Summary of 12-lead ECG parameters at each visit – safety population 
Test 
Visit 
DFP 
(N=xx) 
Heart Rate (bpm)  
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for PR Interval, QRS 
Interval, QT Interval, QTcB 
Interval,and QTcF Interval 
… 
… 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
CONFIDENTIAL INFORMATION 
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Table 14.3.4.2 Proportions of normal and abnormal ECG results in each visit – safety population 
Test 
Visit 
DFP 
(N=xx) 
 
ECG 
n 
Abnormal (n (%)) 
Normal (n (%)) 
Baseline 
xx 
xx (xx) 
xx (xx) 
Month 18 
xx 
xx (xx) 
xx (xx) 
Month 36 
xx 
xx (xx) 
xx (xx) 
 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
CONFIDENTIAL INFORMATION 
95
Table 14.3.5.1 Treatment compliance (%) by visit – safety population 
Parameter 
Visit 
DFP 
(N=xx) 
 
Compliance (%) 
n 
Mean (SD) 
Median 
(Min, Max) 
Month 1.5 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 3 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 6 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 12 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 18 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 24 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 30 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
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Month 36 
xx 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
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Table 14.3.6.1 Concomitant Medications – safety population 
  
  
  
DFP 
Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Subjects Reporting: xx 
Preferred Name 
N Subjects (%) 
  Cccccc 
x (x.x) 
  Cccccc 
x (x.x) 
……... 
x (x.x) 
 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
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Table 14.3.6.2 Rescue Medications – safety population 
  
  
  
DFP 
Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Subjects Reporting: xx 
Preferred Name 
N Subjects (%) 
  Baclofen 
x (x.x) 
  Diazepam 
x (x.x) 
……... 
x (x.x) 
 


ApoPharma Inc. 
Deferiprone in PKAN 
Statistical Analysis Plan: Protocol TIRCON2012V1-EXT 
 
 
CONFIDENTIAL INFORMATION 
99
Table 14.3.6.3 PRN Medications – safety population 
  
  
  
DFP 
Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Subjects Reporting: xx 
Preferred Name 
N Subjects (%) 
  Botulinum toxin type A 
x (x.x) 
  Baclofen 
x (x.x) 
  Clonazepam 
x (x.x) 
……... 
x (x.x)