Long-term Safety and Efficacy Study of Ferriprox® for the Treatment of Transfusional Iron Overload in Patients With Sickle Cell Disease or Other Anemias
Phase: PHASE4
Conditions: Iron Overload, Sickle Cell Disease, Other Anemias
Sponsor: ApoPharma

 
 
 
CONFIDENTIAL 
Page 1 of 69 
 
 
Long-term Safety and Efficacy Study of Ferriprox® for the Treatment of 
Transfusional Iron Overload in Patients with Sickle Cell Disease 
or Other Anemias 
LA38-EXT 
CLINICAL STUDY PROTOCOL (U.S. ONLY) 
 
EudraCT Number: 
2014-005685-30 
IND Number 
IND 045724 
Investigational Product: 
Deferiprone 
Development Phase: 
Phase IV 
Indication Studied: 
Transfusional iron overload in patients with sickle cell 
disease or other anemias 
Study Design: 
Multi-center, 2-year prospective, single-arm, open-label 
extension study 
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 3.1, 01 MAY 2017 
 
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. 

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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 Ferriprox® for the 
Treatment of Transfusional Iron Overload in Patients With 
Sickle Cell Disease Or Other Anemias 
Study Code: 
LA38- EXT 
Version Number: 
3.1 
Version Date: 
01 MAY 2017 
Name of Principal Investigator: 
 
Name of Study Site: 
 
Location of Study Site: 
(City, region/province/state, 
country) 
 
 
 
 
 
Signature 
 
Date (DD MMM YYYY) 
 
 

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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 Ferriprox® for the treatment of 
transfusional iron overload in patients with sickle cell disease or other anemias 
Study code: 
LA38-EXT 
Phase of development: 
Phase IV 
Objectives: 
Primary: 
To evaluate the long-term safety and tolerability of deferiprone in iron-
overloaded patients with sickle cell disease or other anemias 
Secondary: 
To evaluate the efficacy of deferiprone in the treatment of iron overload in 
patients with sickle cell disease or other anemias who have received deferiprone 
for up to 3 years 
Study design: 
LA38-EXT is a 2-year prospective, multi-center, single-arm, open-label 
extension of study LA38-0411. All patients who complete the earlier study will 
be offered the opportunity to continue in the extension study, with the final 
visit of LA38-0411 being Visit 1 of LA38-EXT. Patients who had been treated 
with deferiprone during LA38-0411 (Group 1) will continue to receive 
deferiprone for an additional 2 years, while those who had been treated with 
deferoxamine (Group 2) will be switched to deferiprone.  Dosage will be 25–33 
mg/kg three times a day (t.i.d.). All patients will visit the site quarterly for 
assessments of safety and efficacy for up to 2 years.  Patients in Group 1 will 
additionally have blood counts monitored monthly, while those in Group 2 will 
have them monitored weekly for the first 6 months, biweekly for the next 6 
months, and monthly thereafter. 
Duration of 
participation: 
The duration of participation in the extension study for each patient (i.e., first 
visit to last visit) will be approximately 2 years. 
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 
Efficacy: 
The time points for the efficacy assessments are defined below.  Since the 
baseline measures are by definition those taken prior to the start of deferiprone 

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Criteria for 
evaluation (cont’d): 
 
therapy, “baseline” is defined differently for the two groups, as follows: 
 
Group 1: For patients who received deferiprone in LA38-0411, the baseline 
visit of that study will be treated as the baseline visit of LA38-EXT as 
well. Thus, Week 0 of the extension study will be Year 1 (i.e., the 
completion of one year of deferiprone treatment), Week 52 will be Year 2, 
and Week 104 will be Year 3. 
 
Group 2: For patients who received deferoxamine in LA38-0411, the start 
of the extension study (Week 0) will be treated as the baseline visit.  For 
this group, therefore, Week 52 will be Year 1, and Week 104 will be Year 2. 
Efficacy endpoints are provided below.  For Group 1, the change from baseline 
to Year 1 is derived from study LA38-0411. For Group 2, there is no Year 3 of 
deferiprone treatment. 
 
The change from baseline to Year 1 (both groups; Group 1 data are from 
LA38-0411), from baseline to Year 2 (both groups), and from baseline to 
Year 3  (Group 1 only) in liver iron concentration (LIC), as measured by 
magnetic resonance imaging (MRI) 
 
The change from baseline to Year 1 (both groups; Group 1 data are from 
LA38-0411), from baseline to Year 2 (both groups), and (Group 1 only) 
from baseline to Year 3 in cardiac MRI T2* 
 
The change from baseline to Year 1 (both groups; Group 1 data are from 
LA38-0411 data), from baseline to Year 2 (both groups), and from baseline 
to Year 3 (Group 1 only) in serum ferritin  
 
Responder analysis, defined as the percentage of patients who show a 
≥20% decline from baseline in LIC or serum ferritin or a ≥20% increase 
from baseline in cardiac MRI T2* at Year 1 (both groups; Group 1 data are 
from LA38-0411), at Year 2 (both groups), and at Year 3 (Group 1 only) 
Number of patients: 
In the LA38-0411 study, a planned total of 300 patients will be randomized to 
receive 1 year of treatment with either deferiprone or deferoxamine. All patients 
who complete that study will be invited to enroll in the extension study. 
Main criterion for 
inclusion: 
Completed study LA38-0411 
Investigational 
product: 
Product:  Ferriprox® (deferiprone) 500 mg tablets or deferiprone 80 mg/mL 
oral solution 
Dose:  25–33 mg/kg t.i.d. 
Mode of administration:  Oral 
Schedule of 
treatment and 
specimen collection: 
 
 
 
All patients will be scheduled to take deferiprone daily, 3 times a day, for up to 
2 years. 
Safety and efficacy assessments will be conducted at the following time points: 
 
Hematology:  
o 
Group 1: Monthly up to Visit 9 (End of Study) or the Early 

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Schedule of 
treatment and 
specimen collection 
(cont’d): 
Termination visit 
o 
Group 2:  Weekly up to Visit 3 (Week 26), then biweekly up to Visit 5 
(Week 52), then monthly up to Visit 9 (End of Study) or the Early 
Termination visit 
 
Biochemistry: Visit 1 and semi-annually up to Visit 9 or the Early 
Termination visit 
 
Serology:  Visits 1 and 9 
 
Serum ferritin: Visit 1 and quarterly up to Visit 9 or the Early Termination 
visit  
 
Liver MRI scan:  annually, at Visits 1, 5, and 9 or Early Termination visit 
 
Cardiac MRI T2* scan:  annually, at Visits 1, 5, and 9 or Early Termination visit 
Statistical methods:  
Safety Analysis 
The incidences of AEs and SAEs reported from the start of deferiprone therapy 
for all patients will be tabulated. For patients continuing on deferiprone, this 
time period will be from the start of LA38-0411 to the completion of LA38-EXT; 
while for those switching to deferiprone, it will be from the start of LA38-EXT 
to the completion of LA38-EXT. AEs will be summarized by worst severity 
and by relationship to the study medication. Time to onset and duration of all 
SAEs, of AEs of special interest such as neutropenia, agranulocytosis, 
increased ALT, and arthralgia, and of additional AEs that will be determined at 
the end of LA38-0411, will be analyzed as follows:  1) the mean time to the 
first onset and the mean time to the last recurrence will be calculated, and 
2) the mean duration for the first episode and the mean duration for any 
recurrent episodes, excluding the first episode, will be calculated for all SAEs 
and such AEs.  
The percentage of discontinuations due to AEs will be calculated, and the AEs 
leading to discontinuation will be summarized in a frequency table. 
Laboratory data (hematology and chemistry) will be summarized using 
descriptive statistics for continuous variables and frequency tables for 
discrete variables.  The incidences of out-of-range data that are seen for two 
consecutive measures will be tabulated, and the changes from baseline to the 
end of study will be presented in shift tables. 
Efficacy Analysis 
Changes in LIC, in cardiac MRI T2*, and in serum ferritin from baseline to 
Year 1(both groups; Group 1 data are from LA38-041), from baseline to Year 2 
(both groups), and from baseline to Year 3 (Group 1 only) will be summarized 
with descriptive statistics, and will be tested against no change using a one-
sample t-test.  The changes in these 3 efficacy measures from the start of 
deferiprone therapy to the last visit of LA38-EXT in all patients, irrespective 
of whether deferiprone therapy was initiated in LA38-0411 or in LA38-EXT, 
will also be tested using a one-sample t-test.  In addition, the percentages of 
responders will be tabulated for Year 1 (both groups; Group 1 data are from 
LA38-0411), for Year 2 (both groups), and for Year 3 (Group 1 only) of 

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deferiprone therapy.   
Additional statistical analysis may be performed if deemed necessary. Details 
will be provided in the statistical analysis plan.  
Version and date of 
the protocol: 
Version 3.1, 01 MAY 2017 

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TABLE OF CONTENTS 
SIGNATURE PAGES .............................................................................................................2 
SYNOPSIS ................................................................................................................................4 
LIST OF IN-TEXT TABLES ...............................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................12 
1 
INTRODUCTION......................................................................................................13 
1.1 
Background .............................................................................................................13 
1.1.1 
Sickle Cell Disease ..........................................................................................13 
1.1.2 
Ferriprox® ........................................................................................................14 
1.2 
Rationale ..................................................................................................................15 
1.3 
Potential Risks and Benefits ....................................................................................15 
2 
STUDY OBJECTIVES ..............................................................................................18 
2.1 
Primary Objective ....................................................................................................18 
2.2 
Secondary Objective ................................................................................................18 
3 
STUDY DESIGN ........................................................................................................18 
3.1 
Description of Study Design ...................................................................................18 
3.2 
Rationale for Study Design .....................................................................................18 
3.3 
Rationale for Selection of Doses .............................................................................18 
4 
STUDY POPULATION ............................................................................................20 
4.1 
Number of Patients ..................................................................................................20 
4.2 
Inclusion Criteria .....................................................................................................20 
4.3 
Exclusion Criteria ....................................................................................................20 
4.4 
Enrolment Violations ..............................................................................................21 
4.5 
Patient Withdrawal ..................................................................................................21 
4.5.1 
Follow-up of Patient Withdrawal Due to Pregnancy .......................................22 
4.5.2 
Replacement of Patients Who Withdraw .........................................................23 
4.5.3 
Treatment Interruptions ...................................................................................23 
4.6 
Prior and Concomitant Therapies ............................................................................24 
4.7 
Rescue Medication ..................................................................................................24 
5 
STUDY PROCEDURES ...........................................................................................24 
5.1 
Visit Procedures ......................................................................................................27 

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5.2 
Method of Assignment to Treatment .......................................................................39 
5.3 
Blinding Procedures ................................................................................................39 
5.4 
Allocation of Patient Numbers ................................................................................39 
5.5 
Treatment Compliance ............................................................................................39 
6 
STUDY TREATMENTS ...........................................................................................39 
6.1 
Investigational Product ............................................................................................40 
6.1.1 
Dosage Form and Mode of Administration .....................................................40 
6.1.2 
Precautions for Use ..........................................................................................40 
6.2 
Reference Product ...................................................................................................40 
6.3 
Packaging and Labeling ..........................................................................................40 
6.4 
Shipping and Storage ...............................................................................................40 
6.5 
Product Accountability ............................................................................................40 
6.6 
Replacement Doses .................................................................................................41 
6.7 
Disposition of Unused Product ................................................................................42 
6.8 
Other Study Supplies ...............................................................................................42 
7 
MEASUREMENTS AND EVALUATIONS ...........................................................42 
7.1 
Efficacy Measurements ...........................................................................................42 
7.1.1 
Liver Iron Concentration..................................................................................42 
7.1.2 
Cardiac MRI T2* .............................................................................................42 
7.1.3 
Serum Ferritin ..................................................................................................43 
7.2 
Safety Measurements ..............................................................................................43 
7.2.1 
Adverse Events and Serious Adverse Events ..................................................43 
7.2.1.1 
Definition of Adverse Events ...................................................................43 
7.2.1.2 
Monitoring and Documenting of Adverse Events ....................................44 
7.2.1.3 
Assessment of Causality ...........................................................................45 
7.2.1.4 
Assessment of Intensity ............................................................................46 
7.2.1.5 
Serious Adverse Events ............................................................................46 
7.2.1.6 
Reporting of Serious Adverse Events .......................................................47 
7.2.1.7 
Follow-up and Documentation of SAEs ...................................................48 
7.2.1.8 
Adverse Events of Special Interest ...........................................................49 
7.2.1.8.1 
Neutropenia ....................................................................................... 49 
7.2.1.8.2 
Infections ........................................................................................... 51 

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7.2.2 
Laboratory Measurements ...............................................................................51 
7.2.3 
Other Safety Measurements .............................................................................52 
7.2.3.1 
Physical Examination ...............................................................................52 
7.2.3.2 
Vital Signs ................................................................................................52 
7.2.3.3 
Electrocardiogram .....................................................................................52 
7.2.3.4 
Concomitant Medications .........................................................................53 
7.2.4 
Procedures in Case of Pregnancy .....................................................................53 
8 
STUDY COMMITTEES ...........................................................................................53 
9 
STATISTICAL ANALYSIS .....................................................................................54 
9.1 
Endpoints .................................................................................................................54 
9.1.1 
Primary Endpoints ...........................................................................................54 
9.1.2 
Secondary Endpoints .......................................................................................54 
9.2 
Determination of Sample Size and Study Power ....................................................55 
9.3 
Study Populations ....................................................................................................55 
9.3.1 
Intent-to-Treat Population ................................................................................55 
9.3.2 
Per Protocol Population ...................................................................................55 
9.3.3 
Safety Population .............................................................................................55 
9.4 
Data Analysis Plan ..................................................................................................55 
9.4.1 
Planned Analyses .............................................................................................56 
9.4.1.1 
Patient Disposition and Drug Exposure ....................................................56 
9.4.1.2 
Patient Characteristics ..............................................................................56 
9.4.1.3 
Analysis of Efficacy .................................................................................56 
9.4.1.4 
Analysis of Safety .....................................................................................56 
9.4.2 
Interim Analyses ..............................................................................................57 
9.5 
Criteria for Evaluability of Patient Data ..................................................................57 
10 
DATA MANAGEMENT CONSIDERATIONS......................................................57 
10.1 
Data Management ....................................................................................................57 
10.2 
Case Report Forms ..................................................................................................58 
11 
MONITORING, AUDITS, AND INSPECTIONS ..................................................58 
11.1 
Source Documents ...................................................................................................58 
11.2 
Monitoring ...............................................................................................................58 

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11.3 
Audits and Inspections ............................................................................................59 
11.4 
Site Closure .............................................................................................................59 
11.5 
Retention of Records ...............................................................................................60 
12 
ETHICAL CONSIDERATIONS ..............................................................................60 
12.1 
Informed Consent ....................................................................................................60 
12.2 
Institutional Review Board/Independent Ethics Committee ...................................61 
12.3 
Patient Confidentiality .............................................................................................61 
13 
REGULATORY REQUIREMENTS .......................................................................61 
13.1 
Regulatory Obligations ............................................................................................61 
13.2 
Amendments to the Protocol ...................................................................................62 
14 
EARLY STUDY TERMINATION ..........................................................................63 
15 
CONFIDENTIALITY ...............................................................................................63 
16 
INDEMNIFICATION ...............................................................................................63 
17 
OWNERSHIP .............................................................................................................64 
18 
PUBLICATION .........................................................................................................64 
19 
REFERENCES ...........................................................................................................65 
APPENDIX 1:  CLINICAL STUDY ADMINISTRATIVE STRUCTURE .....................68 
APPENDIX 2:  LIST OF PROHIBITED DRUGS .............................................................69 
 
 
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 
AF 
assent form  
ANCOVA 
analysis of covariance 
CS 
clinically significant 
CI 
confidence interval 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
OCRDC 
Oracle Clinical Remote Data Capture 
PDR 
Patient Data Report 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCD 
sickle cell disease 
TEAE 
treatment-emergent adverse event 
t.i.d. 
three times daily 
ULN 
upper limit of normal 
WHO 
World Health Organization 

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1 
INTRODUCTION 
1.1 
Background 
Pursuant to the Accelerated Approval of Ferriprox by the FDA in October 2011, 
ApoPharma Inc. committed to conduct a confirmatory trial of Ferriprox (deferiprone) in 
transfused patients, focusing primarily on those with sickle cell disease (SCD). Study 
LA38-0411, currently in progress, is a 52-week, prospective, multi-center, 2-arm, randomized, 
parallel, open-label trial comparing deferiprone therapy to deferoxamine therapy.  Once 
patients in that trial have completed the last study visit (Week 52), they will be invited to 
enroll in LA38-EXT, a 2-year extension study in which all participants will receive 
deferiprone. 
1.1.1 
Sickle Cell Disease 
SCD is an inherited hemoglobinopathy determined by combinations of 2 abnormal alleles of 
the beta globin gene, among which at least one carries the beta6 glu-val mutation.(1) The 
disease is clinically silent until expression of the gamma genes is substituted by expression of 
the beta genes, at between 3 and 9 months of age.  There is a varied phenotypic expression as 
a result of diverse genetic and environmental factors. 
Hemoglobin is the iron-containing oxygen-transport metalloprotein in red blood cells (RBCs) 
responsible for tissue oxygenation.  Normal RBCs contain mainly hemoglobin A, while 
individuals with sickle cell conditions have the genetic variation hemoglobin S (HbS).  RBCs 
that contain mostly HbS do not survive as long as normal RBCs; typically about 16 days, 
compared to about 120 days for normal cells.(1) RBCs containing HbS can become crescent 
(sickle) shaped, leading to loss of their mobility and flexibility.(2) As a result, they have 
difficulty passing through small blood vessels.  This in turn leads to blood-cell agglomeration, 
impeding the circulation of blood and delivery of oxygen to vital tissues and organs.(2) Tissue 
that does not receive a normal blood flow eventually becomes ischemic.(3) The anemia and 
blockage of blood flow result in a variety of problems, such as sickle cell crisis (severe pain), 
susceptibility to infection, priapism, skin ulcers, acute chest syndrome, acute splenic 
sequestration, pulmonary disease, renal and hepatic dysfunction, and cerebrovascular disease, 
ultimately causing premature death.(3,4) Abnormal cardiac findings, with the notable 
development of a progressive proliferative systemic vasculopathy, pulmonary hypertension, 
and left ventricular diastolic dysfunction, are also present in most patients with SCD and are 
primarily the result of chronic anemia, cardiac chamber dilation, and compensatory increase 
in left and right ventricular mass.(5,6) 

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Some SCD patients undergo transfusions to improve blood rheology by replacing sickled 
RBCs with normal RBCs.  Blood transfusions have been indicated for the prevention and 
treatment of vaso-occlusive complications such as painful crisis, stroke, acute chest syndrome, 
acute multi-organ failure, acute splenic sequestration, and medical intervention (preoperative 
preparation).(7)However, while chronic blood transfusions can reduce the incidence of sickle 
cell–induced morbidity and mortality, repeated transfusions result in progressive accumulation 
of iron in the blood.(8) Excess iron accumulates in organs, particularly the liver and endocrine 
glands, generating iron-induced morbidity and eventually causing premature death if left 
untreated.(9) A study in transfusion-dependent patients with SCD demonstrated increased iron 
deposition, with mean liver iron of 13.68 mg/g dry weight (range of 2.9 to 26.19 mg/g dry 
weight) and peak mean serum ferritin of 4614  1989 μg/L over a transfusion period of 57  35 
months (range 12 to 146 months).(10) 
In the sickle cell centers of the Cardeza Foundation and Thomas Jefferson University Hospital, 
approximately 50% of the patients with SCD admitted to the hospital received an average of 
10 units of RBCs per year; of these, 17% to 37% developed iron overload.  Compared to the 
non-iron-overloaded group, the iron-overloaded patients with serum ferritin level >1,500 μg/L 
and transferrin saturation >50% had a higher incidence of painful episodes per year (64% vs. 
38%), organ failure (71% vs. 19%), and mortality (64% vs. 5%).  Patients who died had 
significantly higher mean levels of serum ferritin than those who survived (2379 versus 
597 μg/L, p<0.05).  The results of this study indicate that iron overload is a determinant of 
morbidity and mortality in adult patients with SCD.(9)Results from a natural history study 
demonstrated that the unadjusted death rate of transfused patients with SCD (7.0/100 person 
years) was even higher than in patients with thalassemia (2.2/100 person years).(11) Iron 
metabolism and trafficking in patients with SCD have some distinctive characteristics. The 
high levels of inflammatory cytokines in SCD may enhance macrophage/reticuloendothelial 
cell iron and/or renal cell iron retention. This makes tissues that retain iron different in SCD, 
and thus the organs that fail due to excess iron load in patients with SCD are somewhat 
different from those of patients with thalassemia.(12) Indeed, unlike thalassemia patients, 
cardiac iron overload is not frequently observed in patients with SCD.(13) Nonetheless, cardiac 
siderosis does occur in some SCD patients who have been transfused for more than 10 years.(14) 
Care for SCD now commonly uses transfusion, which potentially results in iron overload and 
necessitates chelation.(12) 
1.1.2 
Ferriprox® 
Ferriprox (deferiprone; active ingredient 3-hydroxy-1,2-dimethylpyridin-4-one) is a bidentate 
iron chelator that preferentially binds trivalent iron (Fe3+) in a 3:1 (deferiprone : iron) complex. 

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Its effectiveness has been assessed by urinary iron excretion, sequential measurements of 
serum ferritin levels, iron concentration in the liver and in the heart, and clinical outcomes 
such as the ability to prevent iron-induced cardiac disease and prolong survival in transfused 
patients with thalassemia. Ferriprox was first approved in 1999 by the European Medicines 
Agency (EMA), and is currently approved in more than 60 countries.  In the USA, it was 
approved in 2011 by the Food and Drug Administration (FDA) for the treatment of patients 
with transfusional iron overload due to thalassemia syndromes when current chelation therapy 
is inadequate. 
1.2 
Rationale 
ApoPharma Inc. is currently conducting a 12-month trial, study LA38-0411, to assess the safety 
and efficacy of deferiprone in patients with SCD or other anemias that necessitate regular 
blood transfusions (excluding thalassemia syndromes, MDS, myelofibrosis, Diamond Blackfan 
anemia, and primary bone marrow failure).  In that study, a planned 300 participants will be 
randomized in a 2:1 ratio to receive either deferiprone or deferoxamine. Assessments include 
weekly, biweekly, or monthly monitoring of absolute neutrophil count (ANC); monthly 
assessments of adverse events, hematology, biochemistry, and vital signs; quarterly 
assessments of serum ferritin; and semi-annual serology, ECG, liver iron concentration (LIC) 
as measured by MRI, cardiac MRI T2*, and quality-of-life questionnaires. 
Patients who complete study LA38-0411will be invited to enroll in the current study, 
LA38-EXT, in which all participants will receive deferiprone. Participants will thus receive 
deferiprone for a total of either 2 years or 3 years, depending on which treatment was 
assigned in the earlier study.  The long-term data obtained will provide additional 
information on the safety and efficacy of deferiprone in patients with sickle cell disease or 
other anemias.  
1.3 
Potential Risks and Benefits 
The safety profile of deferiprone in patients with thalassemia has been extensively 
characterized. Apart from chromaturia, which is due to iron excretion and is harmless, the 
most commonly reported adverse events seen in clinical trials have been nausea, vomiting, 
abdominal pain, increased alanine aminotransferase, arthralgia, and neutropenia. Comprehensive 
safety information is provided in the US full prescribing information (USPI) and the 
Investigator’s Brochure. 
The most significant serious adverse event (SAE) 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, the incidence of agranulocytosis was approximately 2% of patients. The 
mechanism of deferiprone-associated agranulocytosis is unknown. Agranulocytosis and 
neutropenia usually resolve upon discontinuation of deferiprone, but there have been some 
post-marketing reports of agranulocytosis leading to death.  
Because of the awareness of this risk, weekly monitoring for neutrophil count was proposed 
in the first marketing authorization application for deferiprone and has been in effect since. 
However, a recent review of both clinical and post-marketing data accumulated over the last 
two decades confirmed that deferiprone-induced agranulocytosis is not dose-related within 
the therapeutic range, and its occurrence peaks at 5 months after initiation of therapy, 
declining in frequency after this period.(15)  It was concluded that weekly monitoring is a 
prudent approach but that it does not preclude agranulocytosis from occurring and it could 
even provide false security, as agranulocytosis could occur shortly after the finding of a 
normal neutrophil count. The relevance of weekly monitoring of the neutrophil count appears 
to decrease even further after the first six months of therapy, when agranulocytosis occurs 
less often. Based upon analysis of data collected over the past 20 years, it appears that patient 
education may be the key to minimizing risks associated with agranulocytosis during 
deferiprone therapy. A better approach to minimizing the risks in patients receiving long-
term deferiprone therapy is for ANC monitoring to be done weekly only at the beginning of 
the treatment and to emphasize the importance of educating patients on the need to 
immediately stop deferiprone and to maintain ANC monitoring upon signs of infection. 
Based on the conclusions of this review, the frequency of monitoring in this study is reduced: 
patients who have already been on deferiprone for 12 months in the earlier study, LA38-
0411, will now only need to undergo hematology testing monthly, while those who had been 
on deferoxamine and are now receiving deferiprone for the first time will have their 
neutrophil count monitored weekly for the first 6 months, biweekly for the next 6 months,  
and monthly thereafter. Neutropenia management directives (as per Section 7.2.1.8) must be 
followed at the first sign of neutropenia. Treatment with deferiprone should not be initiated 
in patients with a history of recurrent neutropenia or an episode of agranulocytosis.  
The most common adverse reactions (adverse events assessed as at least possibly related to 
deferiprone use) seen among the 712 patients treated with deferiprone in ApoPharma 
clinical trials carried out for the indication of systemic iron overload are listed in the table 
below.  For detailed information on adverse events (AEs) associated with deferiprone, see the 
Investigator’s Brochure. (16) 

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Adverse drug reactions occurring in ≥ 1% of 712 deferiprone-treated patients 
System Organ Class  
 
Preferred Term 
Patients 
n (%) 
Blood and lymphatic system disorders 
 
 
Neutropenia 
49 (6.9) 
 
Agranulocytosis 
15 (2.1) 
Gastrointestinal disorders 
 
 
Nausea 
89 (12.5) 
 
Vomiting 
69 (9.7) 
 
Abdominal pain upper 
39 (5.5) 
 
Abdominal pain 
23 (3.2) 
 
Diarrhoea 
21 (2.9) 
 
Dyspepsia 
13 (1.8) 
 
Abdominal discomfort 
10 (1.4) 
Investigations 
 
 
Alanine aminotransferase increased 
54 (7.6) 
 
Neutrophil count decreased 
50 (7.0) 
 
Weight increased 
12 (1.7) 
 
Aspartate aminotransferase increased 
11 (1.5) 
Metabolism and nutrition disorders 
 
 
Increased appetite 
26 (3.7) 
 
Decreased appetite 
8 (1.1) 
Musculoskeletal and connective tissue disorders 
 
 
Arthralgia 
75 (10.5) 
 
Back pain 
13 (1.8) 
 
Pain in extremity 
12 (1.7) 
 
Arthropathy 
9 (1.3) 
Nervous system disorders 
 
 
Headache 
17 (2.4) 
Renal and urinary disorders 
 
 
Chromaturia 
95 (13.3) 
Data cut-off date: 31 August 2014 
 
Currently, deferoxamine and deferasirox are the only iron chelators licensed for use in 
patients with sickle cell disease.  The benefit to participants in this trial is that they will have 
the option of being treated with a third chelator. 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the long-term safety and tolerability of deferiprone in iron-overloaded patients 
with sickle cell disease or other anemias. The endpoints for the primary objective are 
provided in Section 9.1.1. 
2.2 
Secondary Objective 
To evaluate the efficacy of deferiprone in the treatment of iron overload in patients with 
sickle cell disease or other anemias who have received deferiprone for up to 3 years. 
The endpoints for the secondary objectives are provided in Section 9.1.2. 
3 
STUDY DESIGN 
3.1 
Description of Study Design 
LA38-EXT is a 2-year prospective, multi-center, single-arm, open-label extension of study 
LA38-0411. All patients who complete the earlier study will be offered the opportunity to 
continue in the extension study, with the final visit of LA38-0411 being Visit 1 of LA38-EXT. 
Patients who had been treated with deferiprone during LA38-0411 (Group 1) will continue to 
receive deferiprone for an additional 2 years, while those who had been treated with 
deferoxamine (Group 2) will be switched to deferiprone. Dosage will be 25–33 mg/kg three 
times a day (t.i.d.). 
Patients will have blood counts monitored regularly (monthly throughout the study for 
patients in Group 1;  weekly for the first 6 months, biweekly for the next 6 months, and 
monthly thereafter for patients in Group 2), and will visit the site quarterly for assessments of 
safety and efficacy for up to 2 years.  The schedule of study procedures is shown in Table 5.1, 
and 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 
information on the safety and efficacy of deferiprone in iron-overloaded patients with SCD 
or other anemias who have been treated with this chelator for up to 3 years. 
3.3 
Rationale for Selection of Doses 
The dosage of deferiprone for each patient will be between 25 and 33 mg/kg t.i.d., for a total 
daily dose of 75 to 99 mg/kg.  This is the approved therapeutic dose range, and the same as 

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that being used in study LA38-0411. 
Dosing will be as follows: 
 Patients who were treated with deferiprone in LA38-0411 will continue on the same 
dosing regimen in LA38-EXT, unless there has been less than 10% improvement in 
the last 6 months in at least one of the measures indicative of iron overload (serum 
ferritin, LIC, or cardiac MRI T2*), in which case the dose can be increased up to 33 
mg/kg t.i.d. for patients who were receiving lower doses.  If a patient who is already 
at that dose level is not showing improvement but has consented to participate in the 
extension study, he/she must remain at 33 mg/kg t.i.d. since that is the maximum 
permitted. 
 For patients who were treated with deferoxamine in LA38-0411, the initial dose of 
deferiprone will be 15 mg/kg t.i.d. through Week 1, increasing to 20 mg/kg t.i.d. at 
Week 2 and then to 25 mg/kg t.i.d. at Week 3. It may be further increased to up to a 
limit of 33 mg/kg t.i.d. if any of the following is true: 
o 
Transfusional iron input > 0.3 mg/kg/day in the 3 months prior to Visit 1 
o 
Serum ferritin ≥2500 μg/L at Visit 1 
o 
LIC ≥15 mg/g dry weight at Visit 1 
o 
Cardiac T2* ≤ 20 ms at Visit 1 
Since the Visit 1 results for the above parameters may not be immediately available, 
the dosage beyond Week 3 cannot be confirmed at the time when the first supply of 
drug is dispensed. Details of how dispensing is to be handled at Visit 1 are provided 
in Section 5.1. 
 For any patient, the dose can be increased up to a limit of 33 mg/kg t.i.d. if any of the 
following is true:  
o 
At any time during the trial if mean daily transfusional iron input increases to 
more than 0.3 mg/kg body weight for at least 3 consecutive months 
o 
If in the past 6 months there has been less than 10% improvement in at least one of 
the measures indicative of iron overload (serum ferritin, LIC, or cardiac MRI T2*) 
 For any patient, the dose can be decreased at any time during the trial based on 
assessment of safety markers for adverse reactions that are possibly dose dependent 
(e.g., gastrointestinal upset, increases in serum liver enzyme levels, and arthropathies). 

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4 
STUDY POPULATION 
4.1 
Number of Patients 
A total of 300 patients are planned to be enrolled in study LA38-0411, and all patients who 
complete that study will be invited to enroll in the extension study. 
4.2 
Inclusion Criteria 
Patients will be eligible to enroll in study LA38-EXT if they meet all the following criteria: 
1. Completed study LA38-0411 
2. Females of childbearing potential must have a negative pregnancy test result at Visit 1. In 
addition, if applicable, they must: 
 Use an effective method of contraception according to local requirements, during the 
study and within 30 days following their last dose of study medication, OR 
 Have had a tubal ligation (supporting evidence required), OR 
 Have had a hysterectomy (supporting evidence required), OR 
 Participate in a non-heterosexual lifestyle, OR 
 Have a male sexual partner who has been sterilized (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. All patients and/or their authorized legal representatives must provide signed and dated 
written informed consent prior to the first study intervention, and assent will be obtained 
from patients who are considered to be minors.  Patients must be able to adhere to study 
restrictions, appointments, and evaluation schedules.  
4.3 
Exclusion Criteria 
Patients will be excluded from enrollment in study LA38-EXT if they meet any of the 
following criteria: 
1. Plan to participate in another clinical trial at any time from the day of enrollment until 30 
days post-treatment in the current study 
2. For only those patients who were treated with deferoxamine in study LA38-0411 (Group 2):  
Presence of any medical condition (including clinically significant laboratory 
abnormalities, such as ALT ≥ 5 x ULN or creatinine ≥ 2 x ULN), psychological 
condition, or psychiatric condition which in the opinion of the investigator would cause 
participation in the study to be unwise. 

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3. Pregnant, breastfeeding, or planning to become pregnant during the study period. 
4. Treatment failure after 1 year on deferiprone which in the investigator’s judgment 
indicates the need for the patient to be started on a different iron chelator 
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 
 
Receipt of a rescue medication 
 
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 condition 
 
A confirmed ANC < 0.5 x 109/L. (For the potential withdrawal of patients with 
ANC between 0.5 and 1.5 x 109/L, see Section 7.2.1.8.) 
 
Non-compliance with blood counts: 
o Group 1: Missing 2 consecutive monthly blood counts will result in automatic 
withdrawal. If a patient misses one of the scheduled quarterly visits at which 
hematology testing would normally be done, an unscheduled visit for hematology 
testing must be completed within 10 days of the missed visit.  
o Group 2:  For the first 6 months, if a patient misses a weekly blood count visit, 
then missing a further 3 of the next 5 visits (i.e., a total of 4 out of 6) will result 
in automatic withdrawal. For the next 6 months, missing 3 consecutive 
biweekly blood counts will result in automatic withdrawal.  For the remainder 
of the study, missing 2 consecutive monthly blood counts will result in 
automatic withdrawal. As with Group 1 patients, if a patient misses one of the 
scheduled quarterly visits, an unscheduled visit for hematology testing must be 
completed within 10 days of the missed visit. 
 
Termination of the study by the sponsor 
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 and a follow-up 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 
case report form (CRF), and all other appropriate CRF pages must be completed. 
4.5.1 
Follow-up of Patient Withdrawal Due to Pregnancy 
All females of childbearing potential must have a negative serum pregnancy test prior to 
study entry and prior to first administration of the study drug, and must agree to use an 
approved method of contraception (as defined in inclusion criterion # 2 throughout the course 
of the trial.  If a patient does become pregnant, the investigator must do the following upon 
becoming aware of the pregnancy: 

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 Ensure that the study medication is stopped immediately 
 Inform the sponsor via the pregnancy report form 
 With the patient’s consent, 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 1 month following the last dose of study medication. As with the 
pregnancy of a female subject, the site must inform the sponsor and, if the partner consents, 
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 enrollment are those who completed 
treatment in study LA38-0411. 
4.5.3 
Treatment Interruptions 
Study medication will be interrupted for ANY of the following reasons: 
Infection, fever, or decrease in ANC: 
 If the patient develops an infection during the study, deferiprone must be interrupted 
immediately and neutrophil count should be obtained and monitored more frequently 
(every 2 days if ANC <1.5 x 109/L). Patients should be advised to report immediately 
to their physician any symptoms indicative of infection such as fever, sore throat, and 
flu-like symptoms. They will be provided with a thermometer, and instructed to seek 
immediate medical attention at a hospital or clinic if they experience fever 
(temperature >38.0° C/100.4°F).  Body temperature may be measured at the mouth, 
axilla, or ear. Patients/legal guardians will be provided with an emergency services 
card with contact information, and will be advised to carry this card at all times. In 
presence of confirmed fever and/or infection, they will be required to have their 
neutrophil counts tested as soon as possible and no later than 24 hours after the 
symptoms of infection are detected. Therapy with deferiprone can be re-initiated once 
all symptoms have been resolved and it is deemed safe by the investigator. 
 If temperature is >38.0°C/100.4°F and ANC is ≤0.5 x 109/L, the following must be 
done: 
o Commence therapy with antibiotics immediately (treatment should depend on 
the site of the suspected infection and on local antibiotic policy) 
o Perform a chest x-ray, and collect blood and other relevant cultures (if 
possible, collect culture samples before initiating antibiotics)  

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 If the patient develops moderate neutropenia while on deferiprone, therapy must be 
interrupted immediately and neutrophil count must be obtained and monitored every 
2 days.  Therapy with deferiprone can be re-initiated once two successive ANCs are 
>1.5 x 109/L and it is deemed safe by the investigator. The patient will be withdrawn 
from the study if the ANC remains <1.5 x 109/L by the end of a 2-week period (14 
days). 
For definitions of and further detail on the management of neutropenia, see Section 7.2.1.8.1. 
Increase in ALT: 
If a patient whose ALT level was normal at baseline is confirmed to have serum ALT levels 
≥ 5 x ULN on 2 consecutive assessments, deferiprone treatment may be interrupted based on 
investigator judgment.  
4.6 
Prior and Concomitant Therapies 
All medications taken from 3 months prior to Week 0 up to the end of the study (Week 104 
or early termination) will be recorded and reviewed by the investigator. For medications that 
were ongoing at the final visit of LA38-0411, the site is to update the status if necessary 
during LA38-EXT (e.g., note if use of the medication stops). 
Medications considered necessary for the patient’s welfare may continue to be taken at the 
discretion of the investigator. All medications (including study product, herbal medications, 
and over-the-counter medications) and nutritional supplements must be recorded in the 
source document and the appropriate section of the eCRF.  Patients must not take any other 
investigational product, or any drugs that are known to cause neutropenia or agranulocytosis, 
with the exception of hydroxyurea. See Appendix 2 for a list of prohibited drugs. 
4.7 
Rescue Medication 
Rescue medication (deferoxamine, or a combination of 2 iron chelators: deferiprone, 
deferoxamine, or deferasirox) for the treatment of iron overload will not be allowed during 
the study. Should symptoms become intolerable for a patient, dose adjustment should be 
attempted. If the treatment is unsuccessful, the investigator may decide to withdraw the 
patient from the study in order to optimize treatment. 
5 
STUDY PROCEDURES 
The procedures and assessments to be conducted at each study visit are shown in Table 5.1.

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Table 5.1 
Table of study procedures 
Procedure 
Visit 1 1 
Blood 
Draws 2 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
or Early 
Termination 
Week: 
0 
 
13 
26 
39 
52 
65 
78 
91 
104 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Transfusion information 
(if applicable) 3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy 
testing (if applicable) 4 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
X 
 
 
 
X 
Vital signs (including 
weight and height) 5 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
 
X 
 
 
 
X 
Contraceptive 
counseling 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Serology 
X 
 
 
 
 
 
 
 
 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 6 
X 
 
 
X 
 
X 
 
X 
 
X 
Serum ferritin 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
X 
Liver MRI 
X 
 
 
 
 
X 
 
 
 
X 
Cardiac MRI T2* 
X 
 
 
 
 
X 
 
 
 
X 

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Procedure 
Visit 1 1 
Blood 
Draws 2 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Visit 9 
or Early 
Termination 
Week: 
0 
 
13 
26 
39 
52 
65 
78 
91 
104 
Dose calculation/verify 
and adjust dose level 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Collect used and unused 
study medication 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense study 
medication 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Dispense patient diary 
card 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Review and collect 
diary card 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
1 
Visit 1 of study LA38-EXT is also the final visit of study LA38-0411.  It serves as the baseline visit for those patients who received 
deferoxamine in LA38-0411 and will now be receiving deferiprone for the first time. (For patients who received deferiprone in LA38-
0411, the measures obtained at the baseline visit of the LA38-0411 study will be used as the baseline measures for LA38-EXT as well.) 
2 
For Group 1, hematology testing is to be done monthly throughout the study.  For Group 2, it is to be done weekly up to Visit 3 (Week 26), 
biweekly up to Visit 5 (Week 52), and monthly thereafter.  At the quarterly site visits, this testing will be done as part of the routine 
procedures, and at the other time points it can be done at a local laboratory instead of at the site. 
3 
Record volume of blood that the patient received during the transfusion, and the mean hematocrit of the packed red blood cell units transfused 
5 
Females of childbearing potential only 
5 
Height will be measured only at Visits 1, 5, and 9 
6 
At Visits 1, 3, 5, 7, and 9, the blood sample must be drawn following a 10-hour fast 
 

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5.1 
Visit Procedures 
All transfusions must be performed during a study visit or during the weekly, biweekly, or 
monthly blood assessments conducted at the study site for the entire study duration, except 
for those patients who require an emergency transfusion. Data on all transfusions performed 
during the trial, including the type of transfusion (simple, exchange, partial exchange), 
volume of blood received, and the mean hematocrit of the packed red blood cell units 
transfused (data obtained from the site’s blood bank) must be recorded in the eCRF and 
source documents. Iron input per transfusion will be calculated based on the information 
collected throughout the study. 
Visit 1  
Note:  1) Many of the procedures listed below are already scheduled as end-of-study 
procedures for study LA38-0411.  2) For patients who will be receiving deferiprone for the 
first time, the data obtained at this visit will be treated as the baseline measures. 
 
 Explain the extension study to the patient and/or authorized legal representative, and 
obtain written informed consent/assent.  (This step may also be done prior to Visit 1; 
i.e., before the end of study LA38-0411.) 
 Ask patient or legal guardian if he/she would agree for a blood sample for genetic testing 
to be collected should an event of agranulocytosis occur, and if yes, obtain 
consent/assent. (As such a sample would only be obtained after detection of 
agranulocytosis, the decision about this consent could be deferred until then.) 
 Determine patient’s eligibility 
 Collect and review new information about concomitant medications 
 Obtain the results of the following tests and procedures which were done as part of the 
end-of-study visit in LA38-0411: 
o Hematology and biochemistry (Note:  blood sample must be drawn following a 
10-hour fast) 
o Serology 
o Serum ferritin 
o Pregnancy testing 
o Urinalysis 
o Physical examination 
o Vital signs, weight, and height 
o 12-lead ECG 

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o MRI scan of the liver, for LIC calculation 
o Cardiac MRI T2*  
 If the patient is receiving a blood transfusion during this visit or has received a blood 
transfusion since the last visit, record the type of transfusion (simple, exchange, partial 
exchange), the volume of blood patient received, and the mean hematocrit of the packed 
red blood cell units transfused (data obtained from the site’s blood bank) 
 Conduct contraceptive counseling for sexually active patients 
 Verify or determine dosage of study medication 
o 
For patients who received deferiprone in LA38-0411 (Group 1), the dosage will be 
the same as at the completion of that study, unless the LIC, MRI T2*, and serum 
ferritin results obtained at this visit indicate the need for an increase, as per the 
criteria listed in Section 3.3. 
o 
For patients who received deferoxamine in LA38-0411 (Group 2), the initial dose of 
deferiprone will be 15 mg/kg t.i.d. through Week 1, increasing to 20 mg/kg t.i.d. at 
Week 2 and then to 25 mg/kg t.i.d. at Week 3.  Based on the LIC, MRI T2*, and 
serum ferritin results obtained at this visit, the dose will either remain at 25 mg/kg 
t.i.d. or  be further increased up to a limit of 33 mg/kg t.i.d., as per the criteria listed 
in Section 3.3. 
 Dispense a 3-month supply of study medication, instruct patient how to take it. However, 
because there might be a delay in obtaining the Visit 1 results that are needed for dose 
determination, it may not be possible to provide the appropriate 3-month supply at this 
time.  In that case, do one of the following, based on patient preference:  
o 
Dispense a 3-month quantity that is sufficient to meet the requirements of the highest 
possible dosage (for Group 1, this will only be done in cases where the investigator 
suspects that an increase in dosage may be necessary); instruct the patient to start on 
whatever dosage is currently verified; then, once the Visit 1 results are available, call 
to let the patient know what dosage to continue taking. A written confirmation of the 
dosage to be administered will be provided to the patient as well. 
OR: 
o 
Dispense only a 3-week supply (for Group 1, the dosage will be the same that it was 
in LA38-0411; for Group 2, it will be based on the required 3-week titration); and 
have the patient return to the site once the Visit 1 results are available, to obtain the 
remainder.  

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 Provide the patient or authorized legal representative with a diary card in which to keep 
daily track of study drug taken, adverse events, and any medication used to treat them; 
and explain how to complete it if necessary 
 Remind the patient/authorized legal representative of the following: 
o To visit the site or a local laboratory for the weekly (Group 2) or monthly (Group 1) 
blood draws 
o To return the completed diary card at the next quarterly visit 
o To return all medication containers at the next quarterly visit, whether empty or 
unused 
o To interrupt therapy immediately if an infection develops, and to immediately 
report any symptoms indicative of infection such as fever, sore throat, or flu-like 
symptoms. In presence of confirmed fever and/or infection, they will be required to 
have their neutrophil counts tested as soon as possible and no later than 24 hours 
after the symptoms of infection are detected.  
o If patient decides to leave the study before completion, to 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 
 Provide patient or authorized legal representative with an emergency card, and advise 
her/him to carry this card at all times 
 Schedule next study visit 
Regular Blood Draws 
Notes:  
o These blood draws can be conducted either at a local laboratory or at the study site.  
o For patients in Group 1, the blood draws will be done monthly. For patients in 
Group 2, they will be done weekly for the first 6 months (up to Week 26), biweekly 
for the next 6 months (up to Week 52), and monthly thereafter. In all cases, the 
window is ± 3 days. 
 Collect blood sample for hematology. Hematology results should be reviewed by the 
investigator as soon as they are received from the laboratory (within 24 hours if 
possible). 
 If the patient receives a blood transfusion (either at one of these visits or at any other 
time during the study) , record the type of transfusion (simple, exchange, partial 

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exchange; and if exchange or partial exchange, what was the volume of blood removed 
and the average mean hematocrit of the packed red blood cells removed), volume of 
blood that the patient received during the transfusions, and the mean hematocrit of the 
packed red blood cell units transfused (data obtained from the site’s blood bank).  
Visit 2 (Week 13 ±7 days) 
 Review patient diary card, and file it with the source documents 
 Document information on adverse events, use of concomitant medications, and treatment 
compliance 
 Collect blood samples for the following assessments: 
o Hematology  
o Serum ferritin 
Pregnancy  
o testing for all females of childbearing potential. A negative result is required for 
study continuation. 
 Measure vital signs and weight 
 If the patient receives a blood transfusion at this visit (or at any other time during the 
study), record the type of transfusion (simple, exchange, partial exchange), volume of 
blood received, and the mean hematocrit of the packed red blood cell units transfused 
(data obtained from the site’s blood bank) 
 Conduct contraceptive counseling for sexually active patients 
 Collect and account for the medication dispensed at the previous visit 
 Give patient a new diary card, along with a reminder if necessary about how to complete it  
 Verify or adjust dosage of study medication 
 Dispense the next 3-month supply of study medication, along with instructions if 
necessary on how to take it 
 Remind the patient/authorized legal representative of the following: 
o To visit the site or a local laboratory for the weekly (Group 2) or monthly (Group 1) 
blood draws 
o To return the completed diary card at the next quarterly visit 
o To return all medication containers at the next quarterly visit, whether empty or 
unused 

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o To interrupt therapy immediately if an infection develops, and to immediately 
report any symptoms indicative of infection such as fever, sore throat, or flu-like 
symptoms. In presence of confirmed fever and/or infection, they will be required to 
have their neutrophil counts tested as soon as possible and no later than 24 hours 
after the symptoms of infection are detected.  
o If patient decides to leave study before completion, to 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 
Visit 3 (Week 26 ±7 days) 
 Review patient diary card, and file it with the source documents 
 Document information on adverse events, use of concomitant medications, and treatment 
compliance 
 Collect blood samples for the following assessments: 
o Hematology and biochemistry (Note:  blood sample must be drawn following a 
10-hour fast) 
o Serum ferritin 
o Pregnancy testing for all females of childbearing potential. A negative result is 
required for study continuation. 
 Measure vital signs and weight 
 If the patient receives a blood transfusion at this visit (or at any other time during the 
study), record the type of transfusion (simple, exchange, partial exchange), volume of 
blood received, and the mean hematocrit of the packed red blood cell units transfused 
(data obtained from the site’s blood bank) 
 Conduct contraceptive counseling for sexually active patients 
 Collect and account for the medication dispensed at the previous visit 
 Give patient a new diary card, along with a reminder if necessary about how to complete it  
 Verify or adjust dosage of study medication 
 Dispense the next 3-month supply of study medication, along with instructions if 
necessary on how to take it 
 Remind the patient/authorized legal representative of the following: 
o To visit the site or a local laboratory for the biweekly (Group 2) or monthly (Group 1) 
blood draws 

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o To return the completed diary card at the next quarterly visit 
o To return all medication containers at the next quarterly visit, whether empty or 
unused 
o To interrupt therapy immediately if an infection develops, and to immediately 
report any symptoms indicative of infection such as fever, sore throat, or flu-like 
symptoms In presence of confirmed fever and/or infection, they will be required to 
have their neutrophil counts tested as soon as possible and no later than 24 hours 
after the symptoms of infection are detected.  
o If patient decides to leave study before completion, to 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 
Visit 4 (Week 39 ±7 days) 
 Review patient diary card, and file it with the source documents 
 Document information on adverse events, use of concomitant medications, and treatment 
compliance 
 Collect blood samples for the following assessments: 
o Hematology 
o Serum ferritin 
o Pregnancy testing for all females of childbearing potential. A negative result is 
required for study continuation. 
 Measure vital signs and weight 
 If the patient receives a blood transfusion at this visit (or at any other time during the 
study), record the type of transfusion (simple, exchange, partial exchange), volume of 
blood received, and the mean hematocrit of the packed red blood cell units transfused 
(data obtained from the site’s blood bank) 
 Conduct contraceptive counseling for sexually active patients 
 Collect and account for the medication dispensed at the previous visit 
 Give patient a new diary card, along with a reminder if necessary about how to complete it  
 Verify or adjust dosage of study medication 
 Dispense the next 3-month supply of study medication, along with instructions if 
necessary on how to take it 

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 Remind the patient/authorized legal representative of the following: 
o To visit the site or a local laboratory for the biweekly (Group 2) or monthly (Group 1) 
blood draws 
o To return the completed diary card at the next quarterly visit 
o To return all medication containers at the next quarterly visit, whether empty or 
unused 
o To interrupt therapy immediately if an infection develops, and to immediately report 
any symptoms indicative of infection such as fever, sore throat, or flu-like symptoms. 
In presence of confirmed fever and/or infection, they will be required to have their 
neutrophil counts tested as soon as possible and no later than 24 hours after the 
symptoms of infection are detected.  
o If patient decides to leave study before completion, to 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 
Visit 5 (Week 52 ±7 days) 
 Review patient diary card, and file it with the source documents 
 Document information on adverse events, use of concomitant medications, and treatment 
compliance 
 Collect blood samples for the following assessments: 
o Hematology and biochemistry (Note:  blood sample must be drawn following a 
10-hour fast) 
o Serum ferritin 
o Pregnancy testing for all females of childbearing potential. A negative result is 
required for study continuation. 
 Collect urine for urinalysis 
 Measure vital signs, weight, and height 
 Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
 Administer a 12-lead ECG 
 Perform an MRI scan of the liver, and arrange for the results to be transmitted to a 
central laboratory for interpretation and LIC calculation 

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 Perform a cardiac MRI T2*, and arrange for the results to be transmitted to a central 
laboratory for interpretation 
 If the patient receives a blood transfusion at this visit (or at any other time during the 
study), record the type of transfusion (simple, exchange, partial exchange), volume of 
blood received, and the mean hematocrit of the packed red blood cell units transfused 
(data obtained from the site’s blood bank) 
 Conduct contraceptive counseling for sexually active patients 
 Collect and account for the medication dispensed at the previous visit 
 Give patient a new diary card, along with a reminder if necessary about how to 
complete it  
 Verify or adjust dosage of study medication 
 Dispense the next 3-month supply of study medication, along with instructions if 
necessary on how to take it 
 Remind the patient/authorized legal representative of the following: 
o To visit the site or a local laboratory for the monthly blood draws 
o To return the completed diary card at the next quarterly visit 
o To return all empty and unused medication containers at the next quarterly visit 
o To interrupt therapy immediately if an infection develops, and to immediately 
report any symptoms indicative of infection such as fever, sore throat, or flu-like 
symptoms. In presence of confirmed fever and/or infection, they will be required to 
have their neutrophil counts tested as soon as possible and no later than 24 hours 
after the symptoms of infection are detected.  
o If patient decides to leave study before completion, to 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 
Visit 6 (Week 65 ±7 days) 
 Review patient diary card, and file it with the source documents 
 Document information on adverse events, use of concomitant medications, and treatment 
compliance 
 Collect blood samples for the following assessments: 

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o Hematology  
o Serum ferritin 
o Pregnancy testing for all females of childbearing potential. A negative result is 
required for study continuation. 
 Measure vital signs and weight 
 If the patient receives a blood transfusion at this visit (or at any other time during the 
study), record the type of transfusion (simple, exchange, partial exchange), volume of 
blood received, and the mean hematocrit of the packed red blood cell units transfused 
(data obtained from the site’s blood bank) 
 Conduct contraceptive counseling for sexually active patients 
 Collect and account for the medication dispensed at the previous visit 
 Give patient a new diary card, along with a reminder if necessary about how to complete it  
 Verify or adjust dosage of study medication 
 Dispense the next 3-month supply of study medication, along with instructions if 
necessary on how to take it 
 Remind the patient/authorized legal representative of the following: 
o To visit the site or a local laboratory for the monthly blood draws 
o To return the completed diary card at the next quarterly visit 
o To return all medication containers at the next quarterly visit, whether empty or 
unused 
o To interrupt therapy immediately if an infection develops, and to immediately 
report any symptoms indicative of infection such as fever, sore throat, or flu-like 
symptoms. In presence of confirmed fever and/or infection, they will be required to 
have their neutrophil counts tested as soon as possible and no later than 24 hours 
after the symptoms of infection are detected.  
o If patient decides to leave study before completion, to 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 
Visit 7 (Week 78 ±7 days) 
 Review patient diary card, and file it with the source documents 

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 Document information on adverse events, use of concomitant medications, and treatment 
compliance 
 Collect blood samples for the following assessments: 
o Hematology and biochemistry (Note:  blood sample must be drawn following a 
10-hour fast) 
o Serum ferritin 
o Pregnancy testing for all females of childbearing potential. A negative result is 
required for study continuation. 
 Measure vital signs and weight 
 If the patient receives a blood transfusion at this visit (or at any other time during the 
study), record the type of transfusion (simple, exchange, partial exchange), volume of 
blood received, and the mean hematocrit of the packed red blood cell units transfused 
(data obtained from the site’s blood bank) 
 Conduct contraceptive counseling for sexually active patients 
 Collect and account for the medication dispensed at the previous visit 
 Give patient a new diary card, along with a reminder if necessary about how to complete it  
 Verify or adjust dosage of study medication 
 Dispense the next 3-month supply of study medication, along with instructions if 
necessary on how to take it 
 Remind the patient/authorized legal representative of the following: 
o To visit the site or a local laboratory for the monthly blood draws 
o To return the completed diary card at the next quarterly visit 
o To return all medication containers at the next quarterly visit, whether empty or 
unused 
o To interrupt therapy immediately if an infection develops, and to immediately 
report any symptoms indicative of infection such as fever, sore throat, or flu-like 
symptoms. In presence of confirmed fever and/or infection, they will be required to 
have their neutrophil counts tested as soon as possible and no later than 24 hours 
after the symptoms of infection are detected.  
o If patient decides to leave study before completion, to 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 

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Visit 8 (Week 91 ±7 days) 
 Review patient diary card, and file it with the source documents 
 Document information on adverse events, use of concomitant medications, and treatment 
compliance 
 Collect blood samples for the following assessments: 
o Hematology 
o Serum ferritin 
o Pregnancy testing for all females of childbearing potential. A negative result is 
required for study continuation. 
 Measure vital signs and weight 
 If the patient receives a blood transfusion at this visit (or at any other time during the 
study), record the type of transfusion (simple, exchange, partial exchange), volume of 
blood received, and the mean hematocrit of the packed red blood cell units transfused 
(data obtained from the site’s blood bank) 
 Conduct contraceptive counseling for sexually active patients 
 Collect and account for the medication dispensed at the previous visit 
 Give patient a new diary card, along with a reminder if necessary about how to complete it  
 Verify or adjust dosage of study medication 
 Dispense the next 3-month supply of study medication, along with instructions if 
necessary on how to take it 
 Remind the patient/authorized legal representative of the following: 
o To visit the site or a local laboratory for the monthly blood draws 
o To return the completed diary card at the next quarterly visit 
o To return all medication containers at the next quarterly visit, whether empty or 
unused 
o To interrupt therapy immediately if an infection develops, and to immediately 
report any symptoms indicative of infection such as fever, sore throat, or flu-like 
symptoms. In presence of confirmed fever and/or infection, they will be required to 
have their neutrophil counts tested as soon as possible and no later than 24 hours 
after the symptoms of infection are detected.  

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o If patient decides to leave study before completion, to 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 
Visit 9 (Week 104 ±7 days) or Early Termination Visit 
 Review patient diary card, and file it with the source documents 
 Document information on adverse events, use of concomitant medications, and treatment 
compliance 
 Collect blood samples for the following assessments: 
o Hematology and biochemistry (Note:  blood sample must be drawn following a 
10-hour fast) 
o Serology 
o Serum ferritin 
o Pregnancy testing for all females of childbearing potential. A negative result is 
required for study continuation. 
 Collect urine for urinalysis 
 Measure vital signs, weight, and height 
 Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
 Administer a 12-lead ECG 
 Perform an MRI scan of the liver, and arrange for the results to be transmitted to a 
central laboratory for interpretation and LIC calculation 
 Perform a cardiac MRI T2*, and arrange for the results to be transmitted to a central 
laboratory for interpretation 
 If the patient receives a blood transfusion at this visit (or at any other time during the 
study), record the type of transfusion (simple, exchange, partial exchange), volume of 
blood received, and the mean hematocrit of the packed red blood cell units transfused 
(data obtained from the site’s blood bank) 
 Conduct contraceptive counseling for sexually active patients 
 Collect and account for the medication dispensed at the previous visit 
 Instruct patient to inform the site if he/she experiences any SAEs in the 30 days 
following the last dose. If any are reported, follow up on any continuing AEs or SAEs 

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until resolution, until the condition stabilizes, until the event is otherwise explained, or 
until the 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 
Not applicable. 
5.4 
Allocation of Patient Numbers 
All participants in study LA38-0411 will have been assigned a unique 6-digit number, where 
the first 3 digits represent the site code and the last 3 were sequentially assigned to each 
patient who signed the ICF.  These assigned numbers will be maintained when patients 
continue on to study LA38-EXT. 
Patients will be identified in all study data by this number rather than by name. 
5.5 
Treatment Compliance 
Patients will be provided with a diary card in which they will daily record the number of 
Ferriprox tablets or volume of deferiprone oral solution taken. Compliance will be evaluated 
quarterly by the investigator or delegate by monthly pill counts or volume of drug returned. 
Reasons for non-compliance with the treatment will be recorded in the source document and in 
the eCRFs. The investigator should discuss treatment compliance with the patient at each visit. 
Compliance reported in the eCRF will be based on the patient’s diary and on the return of 
used and unused medication containers.  If compliance is greater than 100% and the patient 
reports taking all doses as prescribed, compliance will be reported as 100% in the eCRF. 
Under-compliance < 80% and over-compliance >120% will be reported as a protocol 
deviation, unless under-compliance is due to treatment interruption because of infection or 
neutropenia or other extenuating circumstances (see Section 7.2.1.8). 
6 
STUDY TREATMENTS 
All patients in the extension study will receive deferiprone. 

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6.1 
Investigational Product 
Deferiprone is manufactured by Apotex Inc., and will be supplied to the clinical sites by 
ApoPharma Inc. 
6.1.1 
Dosage Form and Mode of Administration 
Deferiprone is provided as 500 mg film-coated scored tablets or 80 mg/mL oral solution.  
The tablets are marketed under the brand name Ferriprox®.  Both forms are taken orally, 
3 times a day. 
6.1.2 
Precautions for Use 
Deferiprone can be taken with or without food, as per the investigator’s recommendation. 
6.2 
Reference Product 
Not applicable.  All participants in study LA38-EXT will receive deferiprone. 
6.3 
Packaging and Labeling 
Ferriprox tablets will be supplied in bottles of 100 tablets each, high-density polyethylene 
(HDPE) bottles with child-resistant closure. Deferiprone oral solution will be supplied in 
250 mL bottles with child-resistant closure. 
Both the tablet containers and oral solution 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 sponsor. 
6.4 
Shipping and Storage 
The study medication at each site will be kept in a secure location under adequate storage 
conditions, as per label requirements, with access to authorized individuals only. The room 
must have a calibrated digital temperature-monitoring device, and site personnel must use a 
temperature log to facilitate daily recording of the temperature of the storage facility. The site 
must report temperature deviations immediately to the sponsor, and quarantine the product 
until the sponsor deems it acceptable for use. 
6.5 
Product Accountability 
 Each site must maintain a record of inventory and a record of dispensing for the 
investigational product.Investigational product accountability lies with the investigator at all 

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times.  The investigator must maintain an updated Site Investigational Drug Inventory 
Record at the study site.  This log will include at a minimum: 
 Name of sponsor 
 Name of investigator 
 Study identifier 
 Date and quantity of investigational product received from sponsor 
 Lot/batch number 
For each patient, the investigator must maintain an updated Patient Investigational Drug 
Dispensing Record. This log will include at a minimum: 
 Patient identification number 
 Date of dispensing and return 
 Dispenser’s initials 
 Quantity dispensed and returned 
At the conclusion of the study, a final inventory must be performed by the investigator (or 
delegate). If any tablets or bottles are missing, this must be indicated on the study drug 
accountability form, together with an explanation of the discrepancy. These forms must be 
available for sponsor clinical monitoring as well as for sponsor audit and regulatory authority 
inspection purposes at any time.  
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. 
6.6 
Replacement Doses 
Patients will be dispensed study medication at the start of the extension study and quarterly 
thereafter. Dispensing of study medication must be done by appropriately qualified staff (e.g., 
physician, pharmacist, or nurse). 
Patients reporting that their medication has been lost or misplaced will be asked to attend the 
study site to receive replacement medication. Requests for replacement must be made in 

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writing by the appropriate clinical site member (pharmacist/physician/investigator) to the 
sponsor’s Project Leader, Clinical Research, who will approve the request. All information 
related to the lost/misplaced medication and the replacement medication must be recorded in 
the drug accountability forms. 
6.7 
Disposition of Unused Product 
All investigational product that has been returned by the patient or that is unused for any 
other reasons will be returned to the sponsor or discarded by the site according to internal 
procedures, which must include the issuance of appropriate signed destruction certificates 
including mode of destruction and complete drug accountability of destroyed materials. 
6.8 
Other Study Supplies 
All required study supplies, including but not limited to diary cards and laboratory kits, will 
be provided to the sites. 
7 
MEASUREMENTS AND EVALUATIONS 
7.1 
Efficacy Measurements 
7.1.1 
Liver Iron Concentration 
The liver contains 70% or more of total body iron,(17) justifying the use of liver iron 
concentration (LIC) as a measure of body iron load.(18,19,20,21) In the absence of effective iron 
chelation therapy, transfusion-dependent patients experience a progressive increase in 
LIC.(22)Although liver iron concentrations may differ from the concentrations of iron in other 
organs, it has been reported that patients with LIC greater than 7 mg iron/g liver (dry weight; 
dw) are at increased risk of iron-induced toxicity such as cardiac disease, hepatic fibrosis, 
diabetes mellitus and death.(19,23,24)The current goal for chelation therapy in transfusion-
dependent patients is to maintain an “optimal” body iron burden corresponding to hepatic 
storage concentrations of less than 7 mg/g dw.(19) 
MRI scans for liver iron will be performed at Visit 1, Visit 5, and Visit 9 (or early termination), 
and will be transmitted to a central laboratory for interpretation and LIC calculation.  
7.1.2 
Cardiac MRI T2* 
Myocardial MRI T2* can be used to monitor the myocardial iron load resulting from chronic 
transfusions, with low T2* levels reflecting a high cardiac iron concentration and high T2* 
values reflecting low cardiac iron. This technique has been calibrated with cardiac iron 
concentration in post mortem hearts.(25) Studies in non-iron-overloaded patients reveal that 

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none have a cardiac T2* <20 ms, a value that is now widely used clinically as the threshold 
for cardiac iron overload.(26)The ability of cardiac MRI T2* to identify patients at risk of 
iron-induced cardiac disease and premature death has been reported,(27) and its predictive 
value has been prospectively evaluated in 652 transfusion-dependent thalassemia patients 
from 21 UK centers who had cardiac MRI T2* assessment and who had their cardiac status 
followed over time.(27) The results of this study demonstrate that the lower the cardiac MRI 
T2* value, i.e., the higher the cardiac iron load, the higher is the risk of developing iron-
induced cardiac failure within the subsequent 12 months.  
MRI scans for the assessment of cardiac MRI T2* will be performed at Visit 1, Visit 5, and 
Visit 9 (or early termination), and will be transmitted to a central laboratory for interpretation. 
7.1.3 
Serum Ferritin 
The most commonly used method for the assessment of body iron burden is the measurement 
of serum ferritin concentration.(28,29,30,31,32,33,34) Ferritin is the major storage protein for iron. It 
is present in low concentrations in the plasma and is a reflection of total body iron. In 
transfusion-dependent patients, due to continual transfusional iron input and the lack of a 
natural excretory pathway for excess iron, a progressive increase in serum ferritin 
concentration occurs in the absence of effective iron chelation therapy. Sequential 
measurement of serum ferritin concentration remains the most common method for 
assessment of body iron burden, and in clinical practice it is the standard for identifying 
trends in iron status within individuals and across populations. Serum ferritin is therefore a 
useful index of changes in iron load status. For decades, a serum ferritin level above 2,500 
μg/L has been considered an important indicator of the relative risk of death.(23,24,35) 
Serum ferritin will be assessed at the start of the extension study and quarterly thereafter. 
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: 

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 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., clinical 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 
 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 
7.2.1.2 
Monitoring and Documenting of Adverse Events 
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: 

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 How are you feeling / How does your child seem to be feeling? 
 Have you/ has your child had any medical problems since the last visit? 
 Have you / has your child 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. 
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): 

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 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 CRF as mild, moderate, or severe, according to the 
definitions provided below.  In addition, to maximize consistency in assessment, it is 
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: 

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 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 adverse 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. 
 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 adverse 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. 

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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 occurrence 
or notification by the patient, using the sponsor’s SAE form. The sponsor will provide 
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 
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 clinical research associate (CRA) will verify the original SAE report form against the 
source documents at the next monitoring visit. 

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7.2.1.8 
Adverse Events of Special Interest 
7.2.1.8.1 
Neutropenia 
Patients taking deferiprone must be monitored for neutropenia, defined as a confirmed 
absolute neutrophil count (ANC) less than 1.5 x 109/L.  Categories of neutropenia are as 
follows: 
 
 
Mild: 
A confirmed ANC < 1.5 x 109/L but ≥1.0 x 109/L 
 
Moderate: 
A confirmed ANC < 1.0 x 109/L but ≥ 0.5 x 109/L 
 
Severe: 
A confirmed ANC < 0.5 x 109/L. Severe neutropenia is also 
referred to as agranulocytosis. 
For a case of neutropenia to be confirmed, there must be 2 consecutive counts, a maximum 
of 3 days apart, that are both less than the specified value. If both counts are below 1.5 x 
109/L but are not in the same severity category, a third count will be required to determine 
the severity. 
The management of different severities of neutropenia is described below.  In addition to 
having ANC monitored, patients or authorized legal guardians will be advised to 
immediately report any symptoms indicative of infection such as fever, sore throat, and flu-
like symptoms; and will be provided with an emergency services card with contact 
information which they are advised to carry with them at all times. In presence of confirmed 
fever and/or infection, they will be required to have their neutrophil counts tested as soon as 
possible and no later than 24 hours after the symptoms of infection are detected. 
Mild neutropenia:  The patient should continue deferiprone treatment, and ANC will be 
monitored every 2 days until resolution of the event, defined as 2 consecutive ANC ≥ 1.5 
x 109/L. If ANC is still < 1.5 x 109/L after 14 days, the investigator is to do the following: 
 Withdraw patient from the study and monitor him/her until resolution of the event 
 Advise patient regarding protective isolation 
 Examine patient the same day (if possible), including drug history and physical 
examination 
 Notify ApoPharma Inc. by fax 
If a patient with mild neutropenia develops an infection, deferiprone therapy must be 
interrupted immediately, and neutrophil count will continue to be monitored every 2 days 

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until resolution. Therapy can be re-initiated once all symptoms have been resolved and it is 
deemed safe by the investigator. 
Moderate neutropenia:  Patient will immediately interrupt treatment, and ANC will be 
monitored every 2 days until resolution of the event. If ANC is still < 1.5 x 109/L after 14 
days, the investigator is to do the following: 
 Withdraw patient from the study and monitor him/her until resolution of the event 
 Provide protective isolation; if clinically indicated, admit patient to hospital and 
obtain vital signs every 4 hours 
 Examine the patient the same day, if possible, including drug history and physical 
examination 
 If possible, obtain viral studies (CMV, parvovirus, hepatitis A/B/C), serum ALT, 
BUN, creatinine, and 10 mL serum split into two 5-mL aliquots for frozen storage, 
for future analysis 
 Notify ApoPharma Inc. by fax 
 
Severe neutropenia/agranulocytosis:  Patient will immediately discontinue treatment and 
will be permanently withdrawn from the study, and ANC will be monitored daily until 
resolution of the event. The following procedures should be done by the investigator or the 
treating physician, as appropriate: 
 Provide protective isolation; if clinically indicated, admit patient to hospital and 
obtain vital signs every 4 hours 
 Examine the patient the same day, if possible, including drug history and physical 
examination 
 If possible, obtain viral studies (CMV, parvovirus, hepatitis A/B/C), serum ALT, 
BUN, creatinine, and 10 mL serum split into two 5-mL aliquots for frozen storage 
 With the patient’s consent, collect a blood sample to attempt to identify genetic or 
other biomarkers related to agranulocytosis (refer to the operations manual for further 
instructions) 
 If possible, consider obtaining bone marrow aspirate for:  
o Histology 
o Progenitor culture 

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o Frozen storage (1 mL sample) 
 If possible, consider obtaining bone marrow biopsy (minimum length 3 mm) 
 Perform septic work-up including chest X-ray, blood, urine and throat cultures 
 Obtain q4h temperatures from patient (monitored by family at home if patient is not 
in the hospital) 
 If warranted, administer granulocyte stimulating factors, such as G-CSF 10 μg/kg, as 
an inpatient if possible, beginning the same day that the ANC is confirmed as < 0.5 x 
109/L; administer daily until ANC is > 1.5 x 109/L on 2 consecutive days 
 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 ApoPharma Inc. by fax 
7.2.1.8.2 
Infections 
If the patient develops fever or any type of infection during the study, deferiprone must be 
interrupted immediately and neutrophil count should be obtained and monitored more 
frequently (every 2 days if ANC <1.5 x 109/L). Patients should be advised to report 
immediately to their physician any symptoms indicative of infection such as fever, sore 
throat, and flu-like symptoms. Patients will be provided with an emergency services card 
with contact information, and the patient/legal guardian will be advised to carry this card at 
all times. In presence of confirmed fever and/or infection, they will be required to have their 
neutrophil counts tested as soon as possible and no later than 24 hours after the symptoms of 
infection are detected. Therapy with deferiprone can be re-initiated once all symptoms have 
been resolved and it is deemed safe by the investigator. 
7.2.2 
Laboratory Measurements 
Analyses will be performed at a central laboratory, with the exception of the weekly, 
biweekly, or monthly hematology assessments which may be performed at a local laboratory. 
Investigators must interpret each report promptly (preferably within 24 hours) and must 
document their review by signing or initialing and dating it. Any laboratory values that fall 
outside a clinically accepted range, or values that differ significantly from previous values, 
must be assessed for clinical significance, and must be marked by the investigator as either 
“CS” (clinically significant) or “NCS” (not clinically significant).  Any clinically significant 
abnormalities or changes that are not part of a larger medical condition that is already 

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recorded must be further explained on the laboratory report and documented as an adverse 
event in the eCRF.  
The following laboratory tests will be performed: 
 Hematology (for Group 1, monthly throughout the study; for Group 2, weekly for the 
first 6 months, biweekly for the next 6 months, and monthly thereafter):  hemoglobin, 
total WBC count, ANC, and platelet count 
 Biochemistry (semi-annually; Visits 1, 3, 5, 7, and 9):  total protein, GGT, lactate 
dehydrogenase (LDH), sodium, potassium, chloride, fasting glucose, total and direct 
bilirubin (indirect bilirubin will be calculated by the sponsor), AST, ALT, albumin, 
blood urea nitrogen, calcium, creatinine, uric acid, alkaline phosphatase, and amylase 
 Serology (Visits 1 and 9):  Hepatitis B and C and HIV testing 
 Urinalysis (annually; Visits 1, 5, and 9):  pH, specific gravity, glucose, protein, 
ketones, blood, and (if indicated by the dipstick results), sediment microscopy.  If 
there is blood in the urine or three or more “plus signs” for protein, samples must be 
sent for microscopy. 
 Pregnancy (quarterly; Visits 1–9):  serum pregnancy test 
7.2.3 
Other Safety Measurements 
7.2.3.1 
Physical Examination 
At Visits 1, 5, and 9, the investigator or a qualified delegate will perform a physical 
examination of the following organs and systems:  head, ears, eyes, nose, throat and neck, 
respiratory system, cardiovascular system, gastrointestinal system, musculoskeletal system, 
central and peripheral nervous system, skin, thyroid, and general constitution. 
7.2.3.2 
Vital Signs 
Temperature, heart rate, respiration rate, and systolic and diastolic blood pressure will be 
measured at each visit.  
Weight will be measured at each visit, and height will be measured at Visits 1, 5, and 9. 
7.2.3.3 
Electrocardiogram 
A standard 12-lead ECG will be performed at Visits 1, 5, and 9. As a minimum, the 
following parameters will be assessed:  HR, PR, QRS, QT, QTcF, QTcB. The results will be 
interpreted by the investigator, and the overall interpretation will be documented. 

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7.2.3.4 
Concomitant Medications 
Information about prior and concomitant medications will be collected at each visit. The 
following must be recorded in the source documents and eCRFs: 
 Any medications that the patient continues to take during the trial 
 Any medications that the patient starts to take during the trial 
The name, dose, route, frequency, indication, and start and stop dates of all medications used 
during the trial, as well as whether or not the medication was used to treat an adverse event, 
must be noted in the source documents and eCRFs. 
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 CRF. 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 CRF.  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 
A Data Safety Monitoring Board (DSMB) will be set up to oversee the safety of the patients 
enrolled in the study. 

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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 
 Serious adverse events (SAEs): Frequency and relatedness to study product 
 Number of discontinuations due to AEs 
9.1.2 
Secondary Endpoints 
The time points for the efficacy assessments are defined below.  Since the baseline measures 
are by definition those taken prior to the start of deferiprone therapy, “baseline” is defined 
differently for the two groups, as follows: 
 Group 1: For patients who received deferiprone in LA38-0411, the baseline visit of that 
study will be treated as the baseline visit of LA38-EXT as well. Thus, Week 0 of the 
extension study will be Year 1 (i.e., the completion of one year of deferiprone treatment), 
Week 52 will be Year 2, and Week 104 will be Year 3. 
 Group 2: For patients who received deferoxamine in LA38-0411, the start of the 
extension study (Week 0) will be treated as the baseline visit.  For this group, therefore, 
Week 52 will be Year 1, and Week 104 will be Year 2. 
Efficacy endpoints are provided below.  For Group 1, the change from baseline to Year 1 is 
derived from study LA38-0411. For Group 2, there is no Year 3 of deferiprone treatment. 
 The change from baseline to Year 1 (both groups; Group 1 data are from LA38-0411), 
from baseline to Year 2 (both groups), and from baseline to Year 3  (Group 1 only) in liver 
iron concentration (LIC), as measured by magnetic resonance imaging (MRI) 
 The change from baseline to Year 1 (both groups; Group 1 data are from LA38-0411), 
from baseline to Year 2 (both groups), and (Group 1 only) from baseline to Year 3 in 
cardiac MRI T2* 
 The change from baseline to Year 1 (both groups; Group 1 data are from LA38-0411 data), 
from baseline to Year 2 (both groups), and from baseline to Year 3 (Group 1 only) in 
serum ferritin  
 Responder analysis, defined as the percentage of patients who show a ≥20% decline from 
baseline in LIC or serum ferritin or a ≥20% increase from baseline in cardiac MRI T2* at 

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Year 1 (both groups; Group 1 data are from LA38-0411), at Year 2 (both groups), and at 
Year 3 (Group 1 only) 
9.2 
Determination of Sample Size and Study Power 
A planned total of 300 patients will be randomized in the LA38-0411 study to receive 1 year 
of either deferiprone or deferoxamine, and all patients who complete that study will be 
invited to enroll in the extension study. 
9.3 
Study Populations 
Study populations intended for analysis will be defined as follows: Intent-to-Treat (ITT), Per-
Protocol (PP), and Safety. The ITT population will represent the primary analysis population 
to evaluate all efficacy endpoints. The efficacy endpoints will also be analyzed for the PP 
population, which is the secondary analysis population. 
9.3.1 
Intent-to-Treat Population 
The ITT population will include all randomized 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 Per-Protocol (PP) population will include all enrolled patients who complete the study, 
have no major protocol violations, and have an efficacy assessment at the end of the study. 
Prior to database lock, patients with major protocol violations will be reviewed and excluded, 
where appropriate, from the PP population. Major protocol violations will include (but not be 
limited to) the following:  
 Patients who were not compliant with the treatment (<80% compliance) 
 Patients who took iron chelator medications other than the assigned study medication 
during the course of the study 
9.3.3 
Safety Population 
The safety population will include all enrolled patients who took at least one dose of study 
drug.  
9.4 
Data Analysis Plan 
A separate detailed statistical analysis plan (SAP) will be prepared and approved before 
database lock. Any changes in the planned statistical methods after database lock will be 
documented in the final clinical study report. 

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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, received at least one dose of study medication, 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, the number of doses, 
and the total dose taken during the study will be summarized with descriptive statistics. 
9.4.1.2 
Patient Characteristics 
Baseline characteristics for continuous variables will be summarized with descriptive 
statistics such as mean, standard deviation, minimum, median and maximum values.  
Baseline characteristics for discrete variables will be summarized with frequency tables.  
9.4.1.3 
Analysis of Efficacy 
Changes in LIC, in cardiac MRI T2*, and in serum ferritin from baseline to Year 1(both 
groups; Group 1 data are from LA38-041), from baseline to Year 2 (both groups), and from 
baseline to Year 3 (Group 1 only) will be summarized with descriptive statistics, and will be 
tested against no change using a one-sample t-test.  The changes in these 3 efficacy measures 
from the start of deferiprone therapy to the last visit of LA38-EXT in all patients, irrespective 
of whether deferiprone therapy was initiated in LA38-0411 or in LA38-EXT, will also be 
tested using a one-sample t-test.  In addition, the percentages of responders will be tabulated 
for Year 1 (both groups; Group 1 data are from LA38-0411), for Year 2 (both groups), and for 
Year 3 (Group 1 only) of deferiprone therapy.   
9.4.1.4 
Analysis of Safety 
The incidences of AEs and SAEs reported from the start of deferiprone therapy for all 
patients will be tabulated. For patients continuing on deferiprone, this time period will be 
from the start of LA38-0411 to the completion of LA38-EXT; for those switching to 
deferiprone, it will be from the start of LA38-EXT to the completion of LA38-EXT. AEs will 
be summarized by worst severity and by relationship to the study medication.  Time to onset 
and duration of all SAEs, of AEs of special interest such as neutropenia, agranulocytosis, 
increased ALT, and arthralgia, and of additional AEs that will be determined at the end of 
LA38-0411, will be analyzed as follows:  1) the mean time to the first onset and the mean 
time to the last recurrence will be calculated, and 2) the mean duration for the first episode 
and the mean duration for any recurrent episodes, excluding the first episode, will be 
calculated for all SAEs and such AEs.  

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The percentage of discontinuations due to AEs will be calculated, and the AEs leading to 
discontinuation will be summarized in a frequency table. 
Laboratory data (hematology and chemistry) will be summarized using descriptive statistics 
for continuous variables and frequency tables for discrete variables.  The incidences of out-
of-range data   that are seen for two consecutive measures will be tabulated, and the changes 
from baseline to the end of study will be presented in shift tables.  
9.4.2 
Interim Analyses 
There will be no interim analysis. 
9.5 
Criteria for Evaluability of Patient Data 
All patients who were enrolled and treated with the study drug, including those who 
withdrew early, will be eligible for inclusion in the safety and efficacy analyses. 
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 
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 

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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. 
11.2 
Monitoring 
Monitoring of the investigational sites will be conducted by the sponsor or contracted to a 
qualified 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 

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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. 
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 
 Ensure that drug accountability is completed and 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 

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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 
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. 

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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 enrollment 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 
IRB/IEC approval of the amended ICF is obtained before any additional patients are enrolled. 
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. 
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): 

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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: 
 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. 

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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 
Each investigator must sign a confidentiality agreement, in form and content satisfactory to 
the sponsor, concerning the protection of the sponsor’s confidential and proprietary 
information disclosed to or obtained by the investigator during the course of the study. 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. 

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17 
OWNERSHIP 
All data and records provided by the sponsor or its delegate or generated during the study 
(other than a patient’s medical records) and all inventions discovered in the course of 
conducting the study are the exclusive property of the sponsor. Details are provided in the 
Clinical Trial Agreement completed by the sponsor and the investigator and/or site. 
18 
PUBLICATION 
Data derived from the study are the exclusive property of the sponsor, and the sponsor will 
be responsible for the primary publication of the data. 
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 
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Worwood M, Cragg SJ, Jacobs A, McLaren C, Ricketts C, Economidou J. Binding of 
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APPENDIX 1:  CLINICAL STUDY ADMINISTRATIVE STRUCTURE 
 
Function 
Name of Organization 
Address and Contact Information 
Study monitoring  
 ApoPharma Inc. 
200 Barmac Drive 
Toronto, Ontario 
Canada M9L 2Z7 
Tel: +1-416-749-9300 
Toll-free: 1-800-268-4623 
Fax: +1-416-401-3867 
Laboratory measures 
 Eurofins Global Central 
Laboratory 
 
2430 New Holland Pike 
Building D, Suite 100 
Lancaster, PA 17601 
USA 
Tel: +1-717-656-2300 
Fax: +1-717-556-0367 
Email: clinicaltrials@eurofins.com 
Web: pharma.eurofins.com 
Imaging Laboratories 
BioMed Informatics, LLC 2801 Townsgate Road, Suite 212 
Westlake Village, California 91361 
USA 
Tel: +1-818-584-3560 
Fax: +1-818-475-1986 
Email: aaker@biomed-
informatics.com 
CMR Core Lab 
Technologist 
Royal Brompton Hospital  
Sydney Street, London SW3 6NP  
United Kingdom 
Tel:  011-44-20-7351-8768 
Fax:  011-44-20-7351-881 
Email: g.smith@rbh.nthames.nhs.uk 
 

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APPENDIX 2:  LIST OF PROHIBITED DRUGS 
The use of the following medications is precluded by protocol. All exceptions must be 
approved by the sponsor. 
 Any investigational drug 
 Chloramphenicol (CHLOROMYCETIN) 
 Clozapine (CLOZARIL), doxepin HCl (SINEQUAN), amitriptyline HCl/
perphenazine (ETRAFON), and other tricyclic antidepressants 
 Clomipramine hydrochloride (ANAFRANIL) 
 Propranolol hydrochloride (INDERAL) 
 Bepredil (VASCOR) 
 Aminoglutethimide (CYTADREN) 
 Interferon (INTRON A) 
 Para-aminophenol or pyrazolone derivatives 
 Phenytoin (DILANTIN), carbamazepine 
 Chlordiazepoxide (LIBRIUM) and other benzodiazepines 
 Phenylbutazone 
 Mefenamic acid (PONSTAN) 
 Metoclopramide HCl (REGLAN) 
 Chlorpromazine, prochlorperazine, and other phenothiazines 
 Procainamide 
 Levamisole (ERGAMISOLE) 
 Diclofenac sodium (VOLTAREN) 
 Trimethoprim/sulfamethoxazole (BACTRIM/SEPTRA) 
 Aminopyrine