Safety and Efficacy of Early-start Deferiprone Treatment in Infants and Young Children Newly Diagnosed With Transfusion-dependent Beta Thalassemia
Phase: PHASE4
Conditions: Beta Thalassemia Major Anemia, Iron Overload
Sponsor: Chiesi Canada Corp

 
 
 
CONFIDENTIAL 
Page 1 of 75 
Safety and efficacy of early-start deferiprone treatment in infants and young 
children newly diagnosed with transfusion-dependent beta thalassemia 
LA55-0417 
CLINICAL STUDY PROTOCOL 
 
  
IND Number: 
45724 
EudraCT Number: 
2017-002318-29 
Investigational Product: 
Deferiprone oral solution 
Development Phase: 
Phase 4 
Indication Studied: 
Transfusion-dependent beta-thalassemia 
Study Design: 
Multi-center, randomized, double-blind, placebo-
controlled study in infants and young children  
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 4.0, 12 DEC 2018 
 
The information contained in this document is the property of ApoPharma Inc. and is confidential. It may 
be submitted to a regulatory authority, an ethics committee, or an investigator for the purpose of 
initiation of a clinical study. Reproduction or disclosure of this information, in whole or in part, is 
forbidden without the written consent of ApoPharma Inc. 

ApoPharma Inc. 
Deferiprone Oral Solution 
LA55-0417    
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 2 of 75 
 
SIGNATURE PAGES 
 
Sponsor 
We, the undersigned, hereby declare that this study will be carried out under our supervision 
in accordance with the methods described herein. 
 
Study Title: 
Safety and efficacy of early-start deferiprone treatment in infants and 
young children newly diagnosed with transfusion-dependent beta 
thalassemia 
Study Code: 
LA55-0417 
Version Number: 
Version 4.0 
Version Date: 
12 DEC 2018 
 
 
 
Caroline Fradette, PhD 
Director of Clinical Research, ApoPharma Inc. 
 
Date (DD MMM YYYY) 
 
 
 
Anna Rozova, MD 
Director of Medical Safety, ApoPharma Inc. 
 
Date (DD MMM YYYY) 
 
 
 
Yu Chung Tsang, PhD 
Chief Scientific Officer, Biopharmaceutics & 
Biostatistics, Apotex Inc. 
 
Date (DD MMM YYYY) 
 
 

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Page 3 of 75 
 
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: 
Safety and efficacy of early-start deferiprone treatment in 
infants and young children newly diagnosed with 
transfusion-dependent beta thalassemia 
Study Code: 
LA55-0417 
Version Number: 
Version 4.0 
Version Date: 
12 DEC 2018 
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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Clinical Study Protocol, v 4.0 
 
 
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Page 4 of 75 
 
 
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 oral 
solution 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Title of study: 
Safety and efficacy of early-start deferiprone treatment in infants and young 
children newly diagnosed with transfusion-dependent beta thalassemia (START) 
Study code: 
LA55-0417 
Phase of 
development: 
Phase 4 
Objectives: 
Primary:  To evaluate the effect of early treatment with deferiprone on 
lessening progressive iron overload in infants and young children with 
transfusion-dependent β-thalassemia 
Secondary:  To evaluate the safety and tolerability of early treatment with 
deferiprone in infants and young children with transfusion-dependent β-
thalassemia 
Study design: 
Multi-center, randomized, double-blind, placebo-controlled study in infants and 
young children newly diagnosed with transfusion-dependent β-thalassemia.  
Patients will have started on a red blood cell (RBC) transfusion regimen 
designed to maintain a hemoglobin level > 9 g/dL but will still have a serum 
ferritin level well below 1000 μg/L, which current treatment guidelines state to 
be the threshold that should be reached before iron chelation therapy can begin. 
Screening will be conducted within 14 days prior to the start of dosing. At 
baseline, eligible participants will be randomized in a 1:1 ratio to receive 
either deferiprone oral solution 80 mg/mL or matching placebo. Visits will be 
scheduled approximately monthly (every 30 ±10 days) for the determination 
of levels of serum ferritin (SF), labile plasma iron (LPI), and transferrin saturation 
(TSAT), and for assessments of safety that include determination of liver enzymes 
(ALT and AST) and growth measurements. 
Dosage will begin at 25 mg/kg/day, divided into 3 doses (t.i.d.), and will be 
increased to 50 mg/kg/day (divided t.i.d.) after 2 weeks. After that, it will be 
increased to 75 mg/kg/day (divided t.i.d.) for patients who meet either of the 
following criteria: 
• 
An SF value ≥ 800 μg/L (but still below 1000 μg/L) and/or an LPI value 
≥ 0.6 µM and/or a TSAT value ≥ 60% at 2 consecutive visits, or 
• 
An increasing trend in any of the above 3 measures (SF, LPI, and/or 
TSAT) at 3 consecutive visits, regardless of value 

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Name of Sponsor: ApoPharma Inc. 
Individual Study Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For National 
Authority Use Only) 
Name of Finished Product: Deferiprone oral 
solution 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Study design 
(cont’d): 
If a single occurrence of any of the following is detected at any time, 
treatment will be interrupted: 
• 
SF value below the lower reference range for the child’s age  
• 
Mild neutropenia, defined as an absolute neutrophil count (ANC) 
< 1.5 x 109/L but ≥ 1.0 x 109/L  
• 
Fever or other signs of infection, prior to confirmation that ANC is 
≥ 1.5 x 109/L 
As these parameters are known to fluctuate, the assessment will be repeated 
as soon as possible to verify that treatment interruption is necessary. 
Treatment will be re-initiated after the abnormally low SF, LPI, TSAT, or 
ANC level has recovered, or when the fever or infection has resolved or has 
been determined to not be indicative of neutropenia.  
 If moderate neutropenia (ANC < 1.0 x 109/L) is confirmed, the patient will 
be withdrawn from the study.  
Patients will remain in the study for 12 months or until their SF level has 
been confirmed to be ≥1000 μg/L at 2 consecutive visits, whichever comes 
first. Those whose SF levels are still under 1000 μg/L at 12 months will be 
offered participation in an extension study, LA55-EXT, in which they will 
continue to receive their assigned study product for up to 2 more years. 
Those who are terminated early will not be eligible to enroll in the extension 
study.  
Duration of 
participation: 
The duration of participation in this study for each patient will be up to 
12 months. 
Criteria for 
evaluation: 
 
 
 
 
 
 
 
 
 
 
 
Efficacy: 
Primary efficacy endpoint:  The percentage of patients who still have a serum 
ferritin level < 1000 μg/L at Month 12. 
Secondary efficacy endpoints: 
• 
The percentage of patients whose serum ferritin level is still less than 
1000 μg/L at each visit 
• 
The percentage of patients whose LPI value is still less than 0.6 µM at 
each visit 
• 
The percentage of patients in each treatment arm whose TSAT value is 
still less than 60% at each visit 
• 
Time to reach a serum ferritin level ≥ 1000 μg/L 
• 
Time to reach an LPI value ≥ 0.6 µM 
• 
Time to reach a TSAT value ≥ 60% 

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CONFIDENTIAL 
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Name of Sponsor: ApoPharma Inc. 
Individual Study Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For National 
Authority Use Only) 
Name of Finished Product: Deferiprone oral 
solution 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Criteria for 
evaluation (cont’d): 
 
 
Safety: 
• 
Adverse events (AEs):  Frequency, intensity, time to onset, duration, and 
relatedness to study drug 
• 
Serious adverse events (SAEs):  Frequency, intensity, time to onset, 
duration, and relatedness to study drug 
• 
Number of discontinuations due to AEs 
• 
Growth parameters:  Weight, height, and height velocity, as classified 
using the Z-score system 
• 
Change in prolactin level from baseline to Month 12 
Number of patients: 
A planned total of 64 patients will be randomized in a 1:1 ratio to the two arms. 
Diagnosis and main 
criteria for inclusion: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main inclusion criteria 
• 
Male or female aged ≥ 6 months to < 10 years 
• 
Confirmed diagnosis of beta-thalassemia, as determined by high 
performance liquid chromatography (HPLC) or DNA testing 
• 
Started on a regular RBC transfusion regimen, with a minimum of 2 
transfusions already completed 
• 
Screening level of serum ferritin greater than >200 g/L but not more 
than 600 μg/L. Since SF level may be impacted by the presence of 
infection, it must additionally be verified that the child has had no signs 
of infection in the previous 7 days, including the day of screening, and 
that the level of C-reactive protein (CRP) is no greater than 20% higher 
than the normal range for the patient’s age.  If there are signs of infection 
and/or the CRP level is above this threshold, the SF level must be 
checked again a minimum of one week later. (Note:  If an investigator 
has valid reason to believe that an out-of-range SF level may be 
attributable to infection even if this is not indicated by the CRP result, 
SF may be rechecked once more a minimum of one week later.) 
Main exclusion criteria 
• 
Prior use of iron chelation 
• 
Diagnosis of hepatitis B or C, or HIV infection 
• 
Evidence of abnormal liver or kidney function at screening (serum ALT 
level > 5 times upper limit of normal or creatinine levels >2 times upper 
limit of normal) 
• 
Disorders associated with neutropenia (ANC < 1.5 x 109/L) prior to the 
initiation of study medication 

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Name of Sponsor: ApoPharma Inc. 
Individual Study Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For National 
Authority Use Only) 
Name of Finished Product: Deferiprone oral 
solution 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Diagnosis and main 
criteria for inclusion 
(cont’d): 
Exception: Patients whose neutropenia is attributed by the treating 
physician to episodes of infection or to drugs associated with a decline in 
the neutrophil count and in whom the ANC has returned to a normal level 
at the screening visit. 
Investigational 
product: 
Product: 
Deferiprone oral solution 80 mg/mL 
Dose:   
25, 50, or 75 mg/kg/day, divided t.i.d.  
Mode of administration:  Oral 
Reference product: 
Product: 
Placebo 
Dose: 
Volume of solution matching that required for a 25, 50, or 75 
mg/kg/day dose of active product, divided t.i.d. 
Mode of administration:  Oral 
Schedule of 
treatment and 
specimen collection: 
Treatment:  All patients will be administered the assigned study product 3 times 
daily for the duration of the study. 
Efficacy assessments:  Blood samples for the assessment of LPI, TSAT, and SF 
will be collected at screening/baseline and at each monthly visit until 
termination from the study. 
Safety assessments: 
• Hematology:  Screening, baseline, weekly after the start of dosing up to 
Month 6, then biweekly until Month 12 or early termination from the study 
• Blood chemistry:  Screening and Months 1, 3, 6, 9, and 12 or until early 
termination from the study 
• Prolactin:  Baseline and Month 12 
• Vital signs:  Each visit 
• Physical examination:  Screening and Months 1, 3, 6, 9, and 12 or until 
early termination from the study 
• Urinalysis:  Screening and Month 12 or early termination from the study 
• Weight and height:  Baseline and monthly until Month 12 or early 
termination from the study 
• Adverse events:  Collected throughout the study, from baseline until 
Month 12 or early termination from the study 

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Name of Sponsor: ApoPharma Inc. 
Individual Study Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For National 
Authority Use Only) 
Name of Finished Product: Deferiprone oral 
solution 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Statistical methods: 
 
Sample size:  With 64 patients, there will be over 90% power to detect a 
statistically significant difference ( = 0.05) between the two treatment groups 
in the percentage of patients who have a serum ferritin level < 1000 μg/L at 
Month 12 if the deferiprone arm and the placebo arm have an expected 
incidence of 70% and 20%, respectively.  
Efficacy evaluation:  The percentage of patients who have not reached levels of 
LPI ≥ 0.6 µM, TSAT ≥ 60%, and SF ≥ 1000 μg/L will be compared between 
the two treatment groups at each monthly time point as well as at the end of 
study, using the Fisher’s exact test. The effect of baseline value on each of the 
3 endpoints will be examined in a covariate analysis. The Kaplan-Meier 
survival curve for the time to reach a serum ferritin level ≥ 1000 μg/L, an LPI 
value ≥ 0.6 µM, and a TSAT value ≥ 60% will be generated for the two 
treatment groups. The log-rank test will be used for comparing the two 
survival curves for each of the 3 endpoints.  The trend analysis over time for 
LPI, TSAT, and SF measures will be performed to compare the rates of change 
in these measures between the two treatment groups.  
Safety evaluation:  Descriptive statistics (mean, standard deviation, minimum, 
and maximum) will be produced for continuous variables, and frequency tables 
will be produced for discrete variables by treatment group. Summaries of 
adverse events and serious adverse events will be produced by treatment group. 
Shift tables will be generated for comparing the screening/baseline values and 
end of study values of the relevant measures. 
For weight and height, the change from baseline to last assessment will be 
compared between the two treatment groups using an ANCOVA model with 
baseline value as a covariate and treatment as the main factor. The rate of 
change in height will be assessed using regression analysis. For prolactin, a 
similar ANCOVA model will be used for the evaluation of change in prolactin 
from baseline to Month 12.  
The appropriate procedures in SAS will be used for the efficacy and safety 
analyses. 
Version and date of 
the protocol 
 Version 4.0, 12 DEC 2018 

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TABLE OF CONTENTS 
SIGNATURE PAGES .............................................................................................................2 
SYNOPSIS ................................................................................................................................4 
LIST OF IN-TEXT TABLES ...............................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................13 
1 
INTRODUCTION......................................................................................................14 
1.1 
Background of the Disease ......................................................................................14 
1.2 
Background of the Investigational Product .............................................................14 
1.3 
Rationale ..................................................................................................................15 
1.4 
Potential Risks and Benefits ....................................................................................15 
2 
STUDY OBJECTIVES ..............................................................................................17 
2.1 
Primary Objective ....................................................................................................17 
2.2 
Secondary Objective ................................................................................................17 
3 
STUDY DESIGN ........................................................................................................17 
3.1 
Description of Study Design ...................................................................................17 
3.2 
Rationale for Study Design .....................................................................................18 
3.3 
Rationale for Selection of Doses .............................................................................19 
4 
STUDY POPULATION ............................................................................................19 
4.1 
Number of Patients ..................................................................................................19 
4.2 
Inclusion Criteria .....................................................................................................19 
4.3 
Exclusion Criteria ....................................................................................................20 
4.4 
Enrolment Violations ..............................................................................................21 
4.5 
Patient Withdrawal ..................................................................................................21 
4.5.1 
Replacement of Patients Who Withdraw .........................................................22 
4.5.2 
Treatment Interruptions ...................................................................................22 
4.6 
Prior and Concomitant Therapies ............................................................................23 
4.7 
Rescue Medication ..................................................................................................23 
5 
STUDY PROCEDURES ...........................................................................................23 
5.1 
Visit Procedures ......................................................................................................27 
5.2 
Method of Assignment to Treatment .......................................................................48 
5.3 
Blinding Procedures ................................................................................................49 

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5.4 
Allocation of Patient Numbers ................................................................................49 
5.5 
Treatment Compliance ............................................................................................49 
6 
STUDY TREATMENTS ...........................................................................................50 
6.1 
Investigational Product ............................................................................................50 
6.1.1 
Dosage Form and Mode of Administration .....................................................50 
6.1.2 
Precautions for Use ..........................................................................................50 
6.2 
Reference Product ...................................................................................................50 
6.3 
Packaging and Labeling ..........................................................................................50 
6.4 
Shipping and Storage ...............................................................................................50 
6.5 
Product Accountability ............................................................................................51 
6.6 
Replacement Doses .................................................................................................52 
6.7 
Disposition of Unused Product................................................................................52 
6.8 
Other Study Supplies ...............................................................................................52 
7 
MEASUREMENTS AND EVALUATIONS ...........................................................52 
7.1 
Efficacy Measurements ...........................................................................................52 
7.1.1 
Serum Ferritin ..................................................................................................52 
7.1.2 
Transferrin Saturation ......................................................................................53 
7.1.3 
Labile Plasma Iron ...........................................................................................53 
7.2 
Safety Measurements ..............................................................................................53 
7.2.1 
Medical Events, Adverse Events, and Serious Adverse Events ......................53 
7.2.1.1 
Definition of Medical Events and Adverse Events...................................53 
7.2.1.2 
Monitoring and Documenting of Medical Events and Adverse 
Events .......................................................................................................54 
7.2.1.3 
Assessment of Causality ...........................................................................56 
7.2.1.4 
Assessment of Intensity ............................................................................56 
7.2.1.5 
Serious Adverse Events ............................................................................57 
7.2.1.6 
Reporting of Serious Adverse Events .......................................................57 
7.2.1.7 
Follow-up and Documentation of SAEs ...................................................58 
7.2.1.8 
Adverse Events of Special Interest ...........................................................59 
7.2.1.8.1 
Neutropenia ....................................................................................... 59 
7.2.1.8.2 
Infections ........................................................................................... 61 
7.2.2 
Laboratory Measurements ...............................................................................61 
7.2.3 
Other Safety Measurements .............................................................................62 

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7.2.3.1 
Physical Examinations ..............................................................................62 
7.2.3.2 
Vital Signs ................................................................................................62 
7.2.3.3 
Concomitant Medications .........................................................................63 
8 
STUDY COMMITTEES ...........................................................................................63 
9 
STATISTICAL ANALYSIS .....................................................................................64 
9.1 
Endpoints .................................................................................................................64 
9.1.1 
Primary Efficacy Endpoint ..............................................................................64 
9.1.2 
Secondary Efficacy Endpoints .........................................................................64 
9.1.3 
Safety Endpoints ..............................................................................................64 
9.2 
Determination of Sample Size and Study Power ....................................................64 
9.3 
Study Populations ....................................................................................................65 
9.3.1 
Intent-to-Treat Population ................................................................................65 
9.3.2 
Per Protocol Population ...................................................................................65 
9.3.3 
Safety Population .............................................................................................65 
9.4 
Data Analysis Plan ..................................................................................................65 
9.4.1 
Planned Analyses .............................................................................................65 
9.4.1.1 
Patient Disposition and Drug Exposure ....................................................65 
9.4.1.2 
Patient Characteristics ..............................................................................65 
9.4.1.3 
Analysis of Efficacy .................................................................................66 
9.4.1.4 
Analysis of Safety .....................................................................................66 
9.4.2 
Interim Analyses ..............................................................................................66 
9.5 
Criteria for Evaluability of Patient Data ..................................................................67 
10 
DATA MANAGEMENT CONSIDERATIONS......................................................67 
10.1 
Data Management ....................................................................................................67 
10.2 
Case Report Forms ..................................................................................................67 
11 
MONITORING, AUDITS, AND INSPECTIONS ..................................................68 
11.1 
Source Documents ...................................................................................................68 
11.2 
Monitoring ...............................................................................................................68 
11.3 
Audits and Inspections ............................................................................................68 
11.4 
Site Closure .............................................................................................................69 
11.5 
Retention of Records ...............................................................................................70 
12 
ETHICAL CONSIDERATIONS ..............................................................................70 

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12.1 
Informed Consent/Assent ........................................................................................70 
12.2 
Institutional Review Board/Independent Ethics Committee ...................................70 
12.3 
Patient Confidentiality .............................................................................................71 
13 
REGULATORY REQUIREMENTS .......................................................................71 
13.1 
Regulatory Obligations ............................................................................................71 
13.2 
Amendments to the Protocol ...................................................................................72 
14 
EARLY STUDY TERMINATION ..........................................................................72 
15 
CONFIDENTIALITY ...............................................................................................73 
16 
DISPUTE RESOLUTION.........................................................................................73 
17 
OWNERSHIP .............................................................................................................73 
18 
PUBLICATION .........................................................................................................73 
19 
REFERENCES ...........................................................................................................74 
 
 
LIST OF IN-TEXT TABLES 
Table 1.1  Adverse drug reactions seen in ≥ 1% deferiprone-treated patients with 
systemic iron overload........................................................................................16 
Table 5.1 
Table of study procedures ..................................................................................24 
 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate transaminase 
CS 
clinically significant 
CI 
confidence interval 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein  
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HPLC 
high performance liquid chromatography 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
LPI 
labile plasma iron 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
RBC 
red blood cell 
SAE 
serious adverse event 
SF 
serum ferritin 
TSAT 
transferrin saturation 
WHO 
World Health Organization 

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1 
INTRODUCTION 
1.1 
Background of the Disease 
Beta thalassemia major is a hereditary blood disorder characterized by a genetic deficiency in 
the synthesis of beta-globin chains, resulting in an abnormal form of hemoglobin.  This leads 
to excessive destruction of red blood cells and severe anemia, necessitating frequent and 
lifelong red blood cell (RBC) transfusions. As each RBC unit contains approximately 200 mg 
of iron and there is no natural mechanism for the excretion of extra iron, body iron 
accumulates rapidly in the absence of chelation treatment, with particular impact on the heart 
and liver. While iron plays an essential role in many metabolic pathways, free iron is toxic to 
cells, acting as a catalyst in the formation of free radicals and leading to morbidity and 
mortality. Accordingly, life-long iron chelation therapy is necessary for survival. 
In young children with a diagnosis of β-thalassemia major, current practice is to start this 
therapy only after 10 to 20 RBC transfusions have been received or when serum ferritin 
levels rise above 1000 μg/L.1 This delay is believed to be necessary in order to minimize the 
risk of toxicities due to excessive depletion of iron needed for normal biologic reactions.  
With the parenteral iron chelator deferoxamine, growth delays were commonly observed in 
children with mild iron overload who had started chelation at very young ages, and delaying 
the start of treatment was found to be effective in preventing that problem.2  However, this 
delay may also increase the risk of iron accumulation in endocrine glands such as the pancreas, 
pituitary, and thyroid, where toxicities could manifest later in life.3 
1.2 
Background of the Investigational Product 
Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one; brand name Ferriprox®) is a bidentate 
iron chelator that preferentially binds trivalent iron cations (Fe3+) in a 3:1 (deferiprone:iron) 
complex. It was first approved in 1999 by the European Medicines Agency for the treatment 
of iron overload in transfusion-dependent patients with thalassemia major, and is currently 
approved for that indication in over 60 countries. The effectiveness of deferiprone in 
reducing body iron in the case of systemic iron overload has been assessed by urinary iron 
excretion, by sequential measurements of serum ferritin levels, and by iron concentrations in 
the liver and heart, while clinical outcomes include reduction of iron-induced cardiac disease 
and prolongation of survival. 
Compared to deferoxamine, deferiprone has a lower physiological affinity for iron (pFe3+ 
log stability constants of 19.9 vs. 26.6 for deferoxamine), which reduces the risks of 
excessive iron depletion, particularly in conditions of only mild to moderate iron overload.4,5  
Data from clinical trials in young children with transfusion-dependent thalassemia and in 

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patients with local but not systemic iron overload support the safety profile for deferiprone in 
those conditions.6,7  Further, deferiprone has been shown to be more effective than 
deferoxamine in promoting iron release from iron-loaded macrophages, which is the initial 
site of iron overload in transfusional iron overload, and to make it accessible to biologic 
receptors, where it can then be used for protein biosynthesis.8,9,10,11,12  These characteristics 
of deferiprone support its use for initiation of chelation therapy in children with transfusion-
dependent thalassemia at a lower threshold of iron load than what is used for initiation of 
therapy with deferoxamine.  
1.3 
Rationale 
A recent investigator-led trial that explored whether early-start therapy with deferiprone 
could delay the progression of iron accumulation without inducing toxicity yielded promising 
results.13  Recently diagnosed thalassemia patients aged approximately 12 months were 
randomized to either start receiving deferiprone at a low dose of 50 mg/kg/day or to wait 
until their serum ferritin levels reached the threshold of 1000 μg/L recommended by current 
guidelines. All the subjects who were not receiving chelation reached this threshold at about 
6 months post-baseline, after receipt of about 10 transfusions; in comparison, for those on 
deferiprone, none had reached it by 6 months, only 10% had reached it by 9 months, and the 
remainder reached it only at 12 months, after 16 to 18 transfusions. Large group differences 
were seen for other indices of iron overload as well. With respect to safety, there were no 
unexpected, serious, or severe adverse events associated with deferiprone treatment. 
The current trial has been designed to further evaluate the early use of deferiprone in young 
children with newly diagnosed transfusion-dependent thalassemia. The objectives are to 
determine whether such a regimen can postpone saturation of transferrin and thus the 
appearance of labile plasma iron (considered the main source of iron overload in endocrine 
glands and myocytes) while maintaining a good safety profile.14 Participants in this trial will 
have already started on a transfusion regimen designed to maintain a hemoglobin level 
> 9 g/dL, but will still have a serum ferritin well below 1000 μg/L, which is the current 
standard for starting iron chelation therapy. 
1.4 
Potential Risks and Benefits 
Risks:  The safety profile of deferiprone in patients with systemic iron overload has been 
extensively characterized. The most serious adverse event associated with its use is severe 
neutropenia or agranulocytosis, defined as a confirmed absolute neutrophil count (ANC) less 
than 0.5 × 109/L.  In pooled clinical trials, agranulocytosis has been seen in about 2% of 
patients. The most common non-serious adverse reactions reported during clinical trials have 
been nausea, vomiting, abdominal pain, increased alanine aminotransferase, arthralgia, and mild 
or moderate neutropenia (ANC less than 1.5 × 109/L).15,16 

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Table 1.1 displays the most common adverse drug reactions associated with deferiprone that 
have been reported in the pooled database of patients with systemic iron overload. 
Table 1.1  Adverse drug reactions seen in ≥ 1% deferiprone-treated patients with 
systemic iron overload 
System Organ Class  
     Preferred Term 
N=860  
n (%) 
Blood and lymphatic system disorders 
 
       Neutropenia 
 54 (6.3) 
       Agranulocytosis 
 18 (2.1) 
Gastrointestinal disorders 
 
       Nausea 
 96 (11.2) 
       Vomiting 
 85 (9.9) 
       Abdominal pain upper 
 46 (5.3) 
       Abdominal pain 
 42 (4.9) 
       Diarrhea 
 22 (2.6) 
       Dyspepsia 
 13 (1.5) 
       Abdominal discomfort 
 10 (1.2) 
General disorders and administration site conditions 
 
       Pyrexia 
 12 (1.4) 
Investigations 
 
       Alanine aminotransferase increased 
 65 (7.6) 
       Neutrophil count decreased 
 55 (6.4) 
       Aspartate aminotransferase increased 
 22 (2.6) 
       Transaminases increased 
  15 (1.7) 
       Weight increased 
 12 (1.4) 
Metabolism and nutrition disorders 
 
       Increased appetite 
 26 (3.0) 
Musculoskeletal and connective tissue disorders 
 
       Arthralgia 
 79 (9.2) 
       Pain in extremity 
 14 (1.6) 
       Back pain 
 13 (1.5) 
       Arthropathy 
  11 (1.3) 
Nervous system disorders 
 
       Headache 
 21 (2.4) 
* Data cut-off date: 31 Aug 2016 
 

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Benefits:  The findings of the investigator-led study indicate that deferiprone has the potential 
to prevent early accumulation of iron toxicity in very young children who are transfusion-
dependent but not yet considered eligible to start conventional chelation therapy. Early-start 
chelation may possibly act to prevent accumulation of iron in organs and thereby avert 
long-term toxicity. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the effect of early treatment with deferiprone on lessening progressive iron 
overload in infants and young children with transfusion-dependent β-thalassemia.  The 
endpoints for the primary objective are provided in Section 9.1.1. 
2.2 
Secondary Objective 
To evaluate the safety and tolerability of early treatment with deferiprone in infants and 
young children with transfusion-dependent β-thalassemia.  
The endpoints for the secondary objective are provided in Section 9.1.2. 
3 
STUDY DESIGN 
3.1 
Description of Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled study in infants and 
young children newly diagnosed with transfusion-dependent β-thalassemia.  Patients will have 
started on a red blood cell (RBC) transfusion regimen designed to maintain a hemoglobin 
level > 9 g/dL, but still have a serum ferritin level well below the threshold that current 
treatment guidelines state should be reached before iron chelation therapy can begin. 
Screening will be conducted within 14 days prior to the start of dosing. At baseline, eligible 
participants will be randomized in a 1:1 ratio to receive either deferiprone oral solution 
80 mg/mL or matching placebo.  Visits will be scheduled approximately monthly (every 
30 ±10 days) for the determination of levels of serum ferritin (SF), labile plasma iron (LPI), 
and transferrin saturation (TSAT), and for assessments of safety that include determination of 
liver enzymes (ALT and AST) and growth measurements. 
Dosage will begin at 25 mg/kg/day, divided into 3 doses (t.i.d.), and will be increased to 
50 mg/kg/day (divided t.i.d.) after 2 weeks. After that, it will be increased to 75 mg/kg/day 
(divided t.i.d.) for patients who meet either of the following criteria: 

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• An SF value ≥ 800 μg/L (but still below 1000 μg/L) and/or an LPI value ≥ 0.6 µM 
and/or a TSAT value ≥ 60% at 2 consecutive visits, or 
• An increasing trend in any of the above 3 measures (SF, LPI, and/or TSAT) at 
3 consecutive visits, regardless of value 
If a single occurrence of any of the following is detected at any time, treatment will be 
interrupted: 
• SF value below the lower reference range for the child’s age  
• Mild neutropenia, defined as an absolute neutrophil count (ANC) < 1.5 x 109/L but 
≥ 1.0 x 109/L  
• Fever or other signs of infection, prior to confirmation that ANC is ≥ 1.5 x 109/L 
As these parameters are known to fluctuate, the assessment will be repeated as soon as 
possible to verify that treatment interruption is necessary.  Treatment will be re-initiated 
after the abnormally low SF or ANC level has recovered, or when the fever or infection has 
resolved or has been determined to not be indicative of neutropenia.  
If moderate neutropenia (ANC < 1.0 x 109/L) is confirmed, the patient will be withdrawn 
from the study. 
Patients will remain in the study for 12 months or until their SF level is found to be ≥ 1000 μg/L 
at 2 consecutive visits, whichever comes first.  Since SF level may be impacted by the 
presence of infection, it must additionally be verified that the child has had no signs of 
infection in the previous 7 days, including the day of the visit, and that the level of C-reactive 
protein (CRP) is no greater than 20% higher than the normal range for the patient’s age. If 
there are signs of infection and/or the CRP level is above this threshold, the SF level must be 
checked again a minimum of one week later. (Note:  If an investigator  has valid reason to 
believe that an SF level ≥ 1000 μg/L may be attributable to infection even if this is not 
indicated by the CRP result, SF may be rechecked once more a minimum of one week later.) 
Patients whose SF levels are still under 1000 μg/L at 12 months will be offered participation 
in an extension study, LA55-EXT, in which they will continue to receive their assigned study 
product for up to 2 more years. Those who are terminated early will not be eligible to enroll 
in the extension study.  
3.2 
Rationale for Study Design 
The study is placebo-controlled in order to compare the current standard of care of no chelation 
vs. early-start chelation, on both safety and efficacy measures. 
Apart from the use of placebo, the design is similar to that of the earlier investigator-led 
open-label study, in which the control group received no treatment.13  The same parameters 

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that were used in that study to measure iron overload—serum ferritin, transferrin saturation, 
and labile plasma iron—are used here, with the difference of applying a criterion of 60% 
rather than 70% for transferrin saturation.  The same criterion of discontinuing patients from 
the study when they reach a serum ferritin level ≥ 1000 μg/L at 2 consecutive visits is 
maintained, which ensures that patients who are ready to begin standard chelation therapy 
will not be delayed in doing so. 
3.3 
Rationale for Selection of Doses 
The earlier study used a low dose of 50 mg/kg/day, divided t.i.d., but iron balance studies 
have shown that such a dose is insufficient to neutralize the transfusional iron load in most 
patients with transfusion-dependent thalassemia.17,18 Here, dosing will start at an even lower 
level, 25 mg/kg/day, in order to minimize the gastrointestinal adverse events that are 
sometimes seen when deferiprone is first introduced, and will be raised to 50 mg/kg/day after 
2 weeks. Once a patient reaches any of several criteria based on indices of iron overload, the 
dose will be further increased to a therapeutic level of 75 mg/kg/day, to see if this will act to 
delay reaching the threshold of serum ferritin ≥ 1000 μg/L for a longer time. Strict criteria for 
treatment interruptions will be in place throughout the study to ensure patients’ safety. 
4 
STUDY POPULATION 
4.1 
Number of Patients 
A planned total of 64 patients will be enrolled in the study, 32 in each arm.  
4.2 
Inclusion Criteria 
Individuals will be eligible to enroll in the study if they meet all the following criteria: 
1. Male or female aged ≥ 6 months to < 10 years 
2. Confirmed diagnosis of beta-thalassemia, as determined by high performance liquid 
chromatography (HPLC) or DNA testing 
3. Started on a regular RBC transfusion regimen, with a minimum of 2 transfusions already 
completed 
4. Screening levels of serum ferritin greater than >200 g/L but not more than 600 μg/L. . 
Since SF level may be impacted by the presence of infection, it must additionally be 
verified that the child has had no signs of infection in the previous 7 days, including the 
day of screening, and that the level of C-reactive protein (CRP) is no greater than 20% 
higher than the normal range for the patient’s age.  If there are signs of infection and/or 
the CRP level is above this threshold, the SF level must be checked again a minimum of 

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one week later.  (Note:  If an investigator has valid reason to believe that an out-of-range 
SF level may be attributable to infection even if this is not indicated by the CRP result, 
SF may be rechecked once more a minimum of one week later.) 
5. Parent(s) or legal guardian (as per local requirements) must provide signed and dated 
written informed consent prior to the first study intervention, and must verify that patient 
will be able to adhere to study restrictions, appointments, and evaluation schedules.  If 
applicable, patients who are old enough will additionally provide assent. 
4.3 
Exclusion Criteria 
Individuals will be excluded from enrollment if they meet any of the following criteria: 
1. Prior use of iron chelation 
2. Diagnosis of hepatitis B or C, or HIV infection 
3. Evidence of abnormal liver or kidney function at screening (serum ALT level > 5 times 
upper limit of normal or creatinine levels >2 times upper limit of normal) 
4. Disorders associated with neutropenia (ANC < 1.5 x 109/L) prior to the initiation of study 
medication 
Exception: Patients whose neutropenia is attributed by the treating physician to episodes 
of infection or to drugs associated with a decline in the neutrophil count and in whom the 
ANC has returned to a normal level at the screening visit. 
6. A serious, unstable illness, as judged by the investigator, during the past 3 months before 
screening/baseline visit including but not limited to hepatic, renal, gastro-enterologic, 
respiratory, cardiovascular, endocrinologic, neurologic or immunologic disease. 
7. History of allergy or sensitivity to any components of the study product or related 
compounds. 
8. Receipt of any investigational products within the past 30 days or 5 half-lives (whichever 
is longer) preceding the first dose of study medication. 
9. Participation in any investigational clinical study, other than observational, within the 
past 30 days; or plans to participate in such a study at any time from the day of 
enrollment until 30 days post-treatment in the current study. 
10. Presence of any medical condition which in the opinion of the investigator would cause 
participation in the study to be unwise. 
11.  Identified as a child, either biological or legally adopted, of an investigator or other site 
staff directly affiliated with this study. 

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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. 
Exception:  A patient who does not have DNA confirmation of a diagnosis of beta-thalassemia 
available at the time of screening may be enrolled on the basis of HPLC results (see inclusion 
criterion #2). If subsequent DNA results are found to not confirm the diagnosis, the patient will 
still be permitted to remain in the study if all other eligibility criteria are met. 
4.5 
Patient Withdrawal 
Patients/parents have the right to withdraw/withdraw their child 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 parent/legal guardian (or 
patient, if applicable) and/or the investigator 
• 
Requirement for concomitant medication that might interfere with the evaluation of 
study treatment or may be contraindicated 
• 
Occurrence of other illnesses that might affect the patient’s further participation in 
the study or evaluation of study treatment 
• 
A protocol deviation that might interfere with study assessments, as judged by the 
investigator 
• 
Repetitive 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: 
• 
Attainment of a serum ferritin level ≥ 1000 μg/L at 2 consecutive visits (provided 
that the child has had no signs of infection in the previous 7 days and that CRP level 
is not greater than 20% higher than the normal range for the patient’s age) 
• 
Occurrence of moderate neutropenia or of severe neutropenia/agranulocytosis (see 
Section 7.2.1.8.1) 
• 
Occurrence of any adverse event characterized as life-threatening or disabling that is 
not associated with the patient’s condition 

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• 
Receipt of a rescue medication (see Section 4.7) 
• 
Termination of the study by the sponsor 
Parents/legal guardians who decide to withdraw their child from the study (or, in the case of 
a child who is able to communicate this, a patient who wishes to withdraw) should always be 
contacted, if possible, in order to ask about the reason for withdrawal, whether any adverse 
events (AEs) occurred, and use of concomitant medications.  A withdrawn patient should 
return for an Early Termination visit. All investigational product and materials should be 
returned.  If any AEs occurred, the investigator must attempt to follow up on the outcome 
until resolution or for 30 days post-termination, whichever comes first. 
If a patient withdraws or is withdrawn before completing the study, the date and reason for 
the withdrawal must be entered on the source document and on the appropriate page of the 
electronic case report form (eCRF), and all other appropriate eCRF pages must be completed. 
4.5.1 
Replacement of Patients Who Withdraw 
Patients who are withdrawn from the study will not be replaced. 
4.5.2 
Treatment Interruptions 
Study medication will be interrupted for ANY of the following reasons: 
• If a patient develops fever (≥ 38.0°C) or any sign 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.  Therapy with 
deferiprone can be re-initiated once all symptoms have been resolved, if the ANC is 
≥1.5 x 109/L. 
• Parents/guardians (and patients if applicable) are to be advised to immediately report 
any symptoms indicative of infection such as fever, sore throat, and flu-like symptoms. 
Participants will be provided with a thermometer, and will be instructed to seek 
immediate medical attention at a hospital or clinic if the patient experiences fever 
(temperature ≥38.0° C/100.4°F).  Body temperature may be measured at the ear, axilla, 
or mouth. In presence of confirmed fever and/or infection, patients 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 study drug can be re-initiated 
once all symptoms have been resolved and it is deemed safe by the investigator. 
• If a patient develops mild neutropenia during the study (ANC <1.5 x 109/L but ≥1.0 
x 109/L; see Section 7.2.1.8.1), therapy must be interrupted immediately, and neutrophil 
count must be obtained and monitored every 2 days.  Therapy can be re-initiated once 

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two successive ANCs are ≥1.5 x 109/L and it is deemed safe by the investigator.  If the 
ANC is still <1.5 x 109/L after 14 days, the patient will be withdrawn from the study. 
• A patient who develops neutropenia that is defined as moderate (ANC <1.0 x 109/L) or 
severe (ANC <0.5 x 109/L) is to be immediately withdrawn from the study. 
4.6 
Prior and Concomitant Therapies 
All medications taken during the 3 months prior to dosing up to the end of the study 
(Month 12 or early termination) will be recorded and reviewed by the investigator. 
Medications considered necessary for the patient’s welfare may be given at the discretion of 
the investigator.  The administration of 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 sections of the electronic case report form 
(eCRF).  During the study, patients must not receive any other investigational product or any 
drugs that are known to cause neutropenia or agranulocytosis.  
4.7 
Rescue Medication 
Administration of any other iron chelator (deferoxamine, deferasirox, or a combination of 
two chelators) or an increase in deferiprone dosage above the limit specified in the protocol 
will not be allowed. Patients who need higher doses of deferiprone than what is permitted in 
this study or a different chelator to control their iron overload will be withdrawn, as per protocol. 
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 
 
Day -14 to 
0 
(Screening) 
Month 0,  
Day 0 
(Baseline) 
Month 
1 1 
Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 
Month 
7 
Month 
8 
Month 
9 
Month 
10 
Month 
11 
Month 
12 or 
End of 
Study 2 
Informed consent/ 
assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
V 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 3 
X 
X 
Weekly (±3 days) after start of dosing up to Month 6 
Biweekly (±3 days) until termination from the study 
Blood chemistry 4,5 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
DNA testing (if 
applicable) 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 5,7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serology 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 5 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Labile plasma iron 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transferrin 
saturation 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum ferritin 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prolactin 12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 

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Day -14 to 
0 
(Screening) 
Month 0,  
Day 0 
(Baseline) 
Month 
1 1 
Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 
Month 
7 
Month 
8 
Month 
9 
Month 
10 
Month 
11 
Month 
12 or 
End of 
Study 2 
Dispense study 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Provide diary card 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing 13 
 
Three times daily from baseline until termination from the study 
Review and collect 
diary card 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect study 
medication containers 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess treatment 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior & concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical events 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
Throughout the study after start of dosing 
Transfusion history 
Throughout the study 
V: 
Verify 
1 
Visits will be scheduled every 30 days (± 10 days). 
2 
Patients will be terminated from the study at Month 12 or when they have been found to have a serum ferritin level ≥ 1000 μg/L at 2 consecutive visits, 
whichever comes first. 
3 
Hematology:  Hemoglobin, total WBC count, ANC, MCV, and platelet count. 
4 
Blood chemistry:  Total protein, GGT, glucose, bilirubin (total, direct, and indirect), AST, ALT, albumin, blood urea nitrogen, calcium, creatinine, total iron 
binding capacity, serum iron, zinc, and CRP. 
5 
The results obtained at screening for blood chemistry, physical examination, and urinalysis will be considered to be the baseline results.  These tests will not 
be repeated at Day 0. 

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6 
A blood sample for DNA testing is to be taken only if DNA confirmation of a diagnosis of beta-thalassemia is not available at the time of screening.  
7 
Urinalysis:  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. 
8  
Hepatitis B, hepatitis C, and HIV. 
9  
Heart rate, blood pressure, and body temperature.  At the time of these measurements, the child must be calm and not crying. 
10 
For infants not yet able to stand upright, stature will be measured as recumbent length. 
11 
For TSAT and SF, the values obtained at the screening visit (not those obtained at baseline) will be used for the eligibility criteria. 
12 
Blood samples for the assessment of prolactin will be taken pre-dose and at + 1.5 h +/- 5 minutes post-dose. The second set of samples will be taken only 
from patients who are still in the study at Month 12; they will not be taken from patients who are terminated before that time. 
13 
Dosing:  Deferiprone oral solution 80 mg/mL or matching placebo solution. 
 

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5.1 
Visit Procedures 
Details on the procedures to be carried out at each study visit are provided below. 
Note:  If possible, blood transfusions should be conducted on the same days as the study 
visits.  Data on all transfusions performed during the trial period, including type of 
transfusion, volume of blood received, and the mean hematocrit of the packed red blood cell 
units transfused, must be recorded in the eCRF and source documents. Iron input per 
transfusion will be calculated based on the information collected throughout the study. 
Screening Visit (Day -14 to Day 0) 
• Explain the study to the parent/legal guardian (and patient if applicable), and obtain 
written informed consent, and assent from the patient if applicable 
• Collect demographic information 
• Collect medical history 
• Check eligibility criteria 
Note:  If DNA confirmation of the diagnosis of beta-thalassemia is not available at 
this time, the patient may be enrolled on the basis of HPLC results, and a blood 
sample will be taken for later DNA testing. 
• Collect blood samples for assessment of the following: 
o 
Hematology 
o 
Blood chemistry 
o 
Serology 
o 
Labile plasma iron 
o 
Transferrin saturation 
o 
Serum ferritin 
o 
C-reactive protein 
o 
DNA testing if applicable 
Note:  A patient whose SF level is outside of the specified range will not be 
enrolled; however, since SF levels may be impacted by the presence of 
infection, it must additionally be verified that the child has had no signs of 
infection in the previous 7 days, including the day of screening, and that the 
level of CRP is no greater than 20% higher than the normal range for the 
patient’s age.  If there are signs of infection and/or the CRP level is above this 
threshold, the SF level must be checked again a minimum of one week later. 
(If an investigator  has valid reason to believe that an SF level ≥ 1000 μg/L 

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may be attributable to infection even if this is not indicated by the CRP result, 
SF may be rechecked once more a minimum of one week later.) 
• Collect a urine specimen for urinalysis 
• Perform a physical examination (to be completed by the investigator or a qualified delegate) 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Obtain transfusion history 
• Collect information on prior and concomitant medications 
• Record any medical events that have occurred after the consent form was signed 
• Schedule baseline visit if all eligibility criteria are met 
Baseline Visit (Month 0, Day 0) 
Notes: 
o For blood chemistry, physical examination, and urinalysis, the results obtained at 
screening will be considered to be the baseline results, and these tests will not be 
repeated at Day 0. 
o All of the post-baseline visits will need to be timed early enough in the day so that 
blood samples for the assessment of serum ferritin, LPI, and TSAT (as well as 
prolactin, at Month 12) will be drawn approximately 12 hours after the last dose of 
study drug and prior to administration of the next. Accordingly, the baseline visit must 
be scheduled early in the day as well, and the samples collected at approximately the 
same time at each visit, to ensure consistency across the study. 
• Verify eligibility criteria 
Notes: 
o For TSAT and SF, the values obtained at the screening visit (not those obtained at 
baseline) will be used for the eligibility criteria. 
o In the case of a patient who did not have DNA confirmation of diagnosis available 
at screening but was enrolled based on HPLC results, if the results of the DNA 
testing done post-screening are found not to confirm beta thalassemia major, such a 
patient will be permitted to remain in the study if all other eligibility criteria are met. 
• Contact the Interactive Voice (or Web) Randomization System (IVRS/IWRS) to have 
the patient randomized to receive either active product or placebo  

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• Collect pre-dose blood samples for assessment of the following: 
o 
Hematology 
o 
Prolactin (pre-dose sample) 
o 
Labile plasma iron 
o 
Transferrin saturation 
o 
Serum ferritin 
o 
C-reactive protein 
Notes:   
- 
Since SF level may be impacted by the presence of infection, it must 
additionally be verified that the child has had no signs of infection in the 
previous 7 days, including the day of the visit, and that the level of CRP is 
no greater than 20% higher than the normal range for the patient’s age.  If 
there are signs of infection and/or the CRP level is above this threshold, 
the SF level must be checked again a minimum of one week later.  (If an 
investigator has valid reason to believe that an out-of-range SF level may 
be attributable to infection even if this is not indicated by the CRP result, 
SF may be rechecked once more a minimum of one week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
SF, LPI, and TSAT must be collected before the transfusion is performed. 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Measure weight and height 
Note:  For infants not yet able to stand upright, stature will be measured as recumbent 
length. 
• Review and update transfusion history  
• Collect information on concomitant medications 
• Collect information on any medical events that have occurred since the screening visit 
• Calculate the amount of study medication required, based on a dosage of 25 mg/kg/day 
(divided t.i.d.) for the first 2 weeks and 50 mg/kg/day (divided t.i.d.) for the next 
2 weeks (± 10 days) 
• Dispense enough study medication to last until the next scheduled visit, with an 
allowance for the visit window of ± 10 days, and provide the parent/guardian (and 
patient, if applicable) with instructions on how to administer it 

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• Provide parent/guardian (or patient, if applicable) with a diary card and explain how to 
complete it 
• Administer the first dose of study medication, and note the time at which it is given 
• Collect a blood sample for the assessment of prolactin at 1.5 hours (± 5 min) post-dose  
• Provide parent/guardian (and patient, if applicable) with an emergency card containing 
contact information, and explain that it is to be carried at all times 
• Provide parent/guardian with a thermometer 
• Instruct parent/guardian (and patient, if applicable) to do the following: 
o 
Bring the patient to either the study site or a local laboratory for a weekly 
blood draw 
o 
In the event of any symptoms indicative of infection such as fever, sore throat, 
or flu-like symptoms, immediately interrupt therapy and contact the clinic 
o 
At the next site visit, bring back the completed diary card plus all medication 
containers, whether empty, partly used, or unopened 
o 
In the event of a decision to withdraw from the study before completion, bring 
the patient to the clinic for an Early Termination Visit as soon as possible, and 
no later than one month following the last dose of study medication 
• Schedule next study visit, and instruct the parent/guardian that: 1) on the preceding day, 
the evening dose of study medication must be administered at least 12 hours before the 
start of the visit, and 2) on the day of the visit, the morning dose must not be taken 
beforehand; it will be administered at the site. 
From this day until study termination, the patient is to receive the assigned study medication 
3 times daily. On days of study visits, the morning dose will be administered at the site. 
Blood Draws for Hematology 
Hematology testing is to be done weekly (every 7 ±3 days) after start of dosing up to 
Month 6, and then biweekly (every 14 ±3 days) until termination from the study.  On weeks 
that include a site visit, this testing will be done as part of the regular study procedures.  On 
other applicable weeks, it may be done either at the site or at a local laboratory. The results 
are to be reviewed by the investigator as soon as they are received, preferably within 24 hours. 

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Month 1 (± 10 days) 
• Collect blood samples for the following assessments (at approximately the same time 
that this was done at baseline): 
o 
Hematology 
o 
Blood chemistry 
o 
Labile plasma iron 
o 
Transferrin saturation 
o 
Serum ferritin 
o 
C-reactive protein 
Notes:   
- 
Since SF level may be impacted by the presence of infection, it must 
additionally be verified that the child has had no signs of infection in the 
previous 7 days, including the day of the visit, and that the level of CRP is 
no greater than 20% higher than the normal range for the patient’s age.  If 
there are signs of infection and/or the CRP level is above this threshold, 
the SF level must be checked again a minimum of one week later.  (If an 
investigator has valid reason to believe that an SF level ≥ 1000 μg/L may 
be attributable to infection even if this is not indicated by the CRP result, 
SF may be rechecked once more a minimum of one week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
serum ferritin, LPI, and TSAT must be collected before the transfusion is 
performed. 
• Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Measure weight and height/length 
• Review and update transfusion history  
• Ask the parent/guardian (and patient, if applicable) about any adverse events that have 
occurred and concomitant medications that have been taken since the last site visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them in order to calculate treatment 
compliance 

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• Dispense enough study medication to last until the next scheduled visit, with an 
allowance for the visit window of ± 10 days, along with a reminder if necessary on 
how to administer it 
• Administer the morning dose of study medication 
• Provide the parent/guardian (or patient, if applicable) with a new diary card, along 
with a reminder if necessary about how to complete it  
• Instruct parent/guardian (and patient, if applicable) to do the following: 
o 
Bring the patient to either the study site or a local laboratory for a weekly 
blood draw 
o 
In the event of any symptoms indicative of infection such as fever, sore throat, 
or flu-like symptoms, immediately interrupt therapy and contact the clinic 
o 
At the next site visit, bring back the completed diary card plus all medication 
containers, whether empty, partly used, or unopened 
o 
In the event of a decision to withdraw from the study before completion, bring 
the patient to the clinic for an Early Termination visit as soon as possible, and 
no later than one month following the last dose of study medication 
• Schedule next study visit, and instruct the parent/guardian that: 1) on the preceding day, 
the evening dose of study medication must be administered at least 12 hours before the 
start of the visit, and 2) on the day of the visit, the morning dose must not be taken 
beforehand; it will be administered at the site 
Month 2 (± 10 days) 
• Collect blood samples for the following assessments (at approximately the same time 
that this was done at baseline): 
o 
Hematology 
o 
Labile plasma iron 
o 
Transferrin saturation 
o 
Serum ferritin 
o 
C-reactive protein 
Notes:   
- 
A patient whose SF level is found to be ≥1000 μg/L at 2 consecutive visits 
is to be withdrawn; however, since SF level may be impacted by the 
presence of infection, it must additionally be verified that the child has had 

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no signs of infection in the previous 7 days, including the day of the visit, 
and that the level of CRP is no greater than 20% higher than the normal 
range for the patient’s age.  If there are signs of infection and/or the CRP 
level is above this threshold, an SF level ≥1000 μg/L must be checked 
again a minimum of a week later before the patient’s study status can be 
determined. (If an investigator has valid reason to believe that an SF level 
≥ 1000 μg/L may be attributable to infection even if this is not indicated 
by the CRP result, SF may be rechecked once more a minimum of one 
week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
serum ferritin, LPI, and TSAT must be collected before the transfusion is 
performed. 
• Measure vital signs (heart rate, blood pressure, and body temperature)  
• Measure weight and height/length 
• Review and update transfusion history  
• Ask about any adverse events that have occurred and concomitant medications that 
have been taken since the last site visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them in order to calculate treatment 
compliance 
• Check the laboratory results from the previous 2 visits (baseline and Month 1) to 
verify whether the patient has had an SF value ≥ 800 μg/L (but still below 1000 μg/L) 
and/or an LPI value ≥ 0.6 µM and/or a TSAT value ≥ 60% at both these visits.  If none 
of these criteria are met, the dosage is to remain at 50 mg/kg/day; if any of them are 
met, the dosage is to be increased to 75 mg/kg/day. 
• Dispense enough study medication to last until the next scheduled visit, with an 
allowance for the visit window of ± 10 days, along with a reminder if necessary on 
how to administer it 
• Administer the morning dose of study medication 
• Provide parent/guardian (or patient, if applicable) with a new diary card, along with a 
reminder if necessary about how to complete it  
• Instruct parent/guardian (or patient, if applicable) to do the following: 

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o 
Bring the patient to either the study site or a local laboratory for a weekly 
blood draw 
o 
In the event of any symptoms indicative of infection such as fever, sore throat, 
or flu-like symptoms, immediately interrupt therapy and contact the clinic 
o 
At the next site visit, bring back the completed diary card plus all medication 
containers, whether empty, partly used, or unopened 
o 
In the event of a decision to withdraw from the study before completion, bring 
the patient to the clinic for an Early Termination visit as soon as possible, and 
no later than one month following the last dose of study medication 
• Schedule next study visit, and instruct the parent/guardian that: 1) on the preceding day, 
the evening dose of study medication must be administered at least 12 hours before the 
start of the visit, and 2) on the day of the visit, the morning dose must not be taken 
beforehand; it will be administered at the site 
As soon as the SF results from this visit are available, check to see if the SF level was 
≥ 1000 μg/L (taking the factor of possible infection into account, as described above) at 
both this and the previous visit.  If no, have the patient continue; if yes, immediately 
terminate the patient from the study and schedule an early termination visit. 
Month 3 (± 10 days) 
• Collect blood samples for the following assessments (at approximately the same time 
that this was done at baseline): 
o 
Hematology 
o 
Blood chemistry 
o 
Labile plasma iron 
o 
Transferrin saturation 
o 
Serum ferritin 
o 
C-reactive protein 
Notes:   
- 
A patient whose SF level is found to be ≥1000 μg/L at 2 consecutive visits 
is to be withdrawn; however, since SF level may be impacted by the 
presence of infection, it must additionally be verified that the child has had 
no signs of infection in the previous 7 days, including the day of the visit, 
and that the level of CRP is no greater than 20% higher than the normal 
range for the patient’s age.  If there are signs of infection and/or the CRP 

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level is above this threshold, an SF level ≥1000 μg/L must be checked 
again a minimum of a week later before the patient’s study status can be 
determined.  (If an investigator has valid reason to believe that an SF level 
≥ 1000 μg/L may be attributable to infection even if this is not indicated 
by the CRP result, SF may be rechecked once more a minimum of one 
week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
serum ferritin, LPI, and TSAT must be collected before the transfusion is 
performed. 
• Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Measure weight and height/length 
• Review and update transfusion history  
• Ask the parent/guardian (and patient, if applicable) about any adverse events that have 
occurred and concomitant medications that have been taken since the last site visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them in order to calculate treatment 
compliance 
• Check the laboratory results from the previous 3 visits (baseline, Month 1, and Month 2) 
to verify whether: 
o The patient has had an SF value ≥ 800 μg/L (but still below 1000 μg/L) and/or an 
LPI value ≥ 0.6 µM and/or a TSAT value ≥ 60% at 2 consecutive visits, or 
o An increasing trend in any of the above 3 measures at 3 consecutive visits, 
regardless of value 
If none of these criteria are met, the dosage is to remain at 50 mg/kg/day; if any of 
them are met, the dosage is to be increased to 75 mg/kg/day. 
• Dispense enough study medication to last until the next scheduled visit, with an 
allowance for the visit window of ± 10 days, along with a reminder if necessary on 
how to administer it 
• Administer the morning dose of study medication 
• Provide the parent/guardian (or patient, if applicable) with a new diary card, along 
with a reminder if necessary about how to complete it  

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• Instruct parent/guardian (and patient, if applicable) to do the following: 
o 
Bring the patient to either the study site or a local laboratory for a weekly 
blood draw 
o 
In the event of any symptoms indicative of infection such as fever, sore throat, 
or flu-like symptoms, immediately interrupt therapy and contact the clinic 
o 
At the next site visit, bring back the completed diary card plus all medication 
containers, whether empty, partly used, or unopened 
o 
In the event of a decision to withdraw from the study before completion, bring 
the patient to the clinic for an Early Termination visit as soon as possible, and 
no later than one month following the last dose of study medication 
• Schedule next study visit, and instruct the parent/guardian that: 1) on the preceding 
day, the evening dose of study medication must be administered at least 12 hours 
before the start of the visit, and 2) on the day of the visit, the morning dose must not be 
taken beforehand; it will be administered at the site. 
As soon as the SF results from this visit are available, check to see if the SF level was ≥ 
1000 μg/L (taking the factor of possible infection into account, as described above) at 
both this and the previous visit.  If no, have the patient continue; if yes, immediately 
terminate the patient from the study and schedule an early termination visit. 
Month 4 and Month 5 (± 10 days) 
• Collect blood samples for the following assessments (at approximately the same time 
that this was done at baseline): 
o 
Hematology 
o 
Labile plasma iron 
o 
Transferrin saturation 
o 
Serum ferritin 
o 
C-reactive protein 
Notes:   
- 
A patient whose SF level is found to be ≥1000 μg/L at 2 consecutive visits 
is to be withdrawn; however, since SF level may be impacted by the 
presence of infection, it must additionally be verified that the child has had 
no signs of infection in the previous 7 days, including the day of the visit, 
and that the level of CRP is no greater than 20% higher than the normal 
range for the patient’s age.  If there are signs of infection and/or the CRP 

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level is above this threshold, an SF level ≥1000 μg/L must be checked 
again a minimum of a week later before the patient’s study status can be 
determined. (If an investigator has valid reason to believe that an SF level 
≥ 1000 μg/L may be attributable to infection even if this is not indicated 
by the CRP result, SF may be rechecked once more a minimum of one 
week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
serum ferritin, LPI, and TSAT must be collected before the transfusion is 
performed. 
• Measure vital signs (heart rate, blood pressure, and body temperature)  
• Measure weight and height/length 
• Review and update transfusion history  
• Ask about any adverse events that have occurred and concomitant medications that 
have been taken since the last site visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them in order to calculate treatment 
compliance 
• Check the laboratory results from the previous 3 visits (Months 1, 2, and 3 or Months 
2, 3, and 4) to verify whether: 
o The patient has had an SF value ≥ 800 μg/L (but still below 1000 μg/L) and/or 
an LPI value ≥ 0.6 µM and/or a TSAT value ≥ 60% at 2 consecutive visits, or 
o An increasing trend in any of the above 3 measures at 3 consecutive visits, 
regardless of value 
If none of these criteria are met, the dosage is to remain at 50 mg/kg/day; if any of 
them are met, the dosage is to be increased to 75 mg/kg/day. 
• Dispense enough study medication to last until the next scheduled visit, with an 
allowance for the visit window of ± 10 days, along with a reminder if necessary on 
how to administer it 
• Administer the morning dose of study medication 
• Provide parent/guardian (or patient, if applicable) with a new diary card, along with a 
reminder if necessary about how to complete it  
• Instruct parent/guardian (or patient, if applicable) to do the following: 

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o 
Bring the patient to either the study site or a local laboratory for a weekly 
blood draw 
o 
In the event of any symptoms indicative of infection such as fever, sore throat, 
or flu-like symptoms, immediately interrupt therapy and contact the clinic 
o 
At the next site visit, bring back the completed diary card plus all medication 
containers, whether empty, partly used, or unopened 
o 
In the event of a decision to withdraw from the study before completion, bring 
the patient to the clinic for an Early Termination visit as soon as possible, and 
no later than one month following the last dose of study medication 
• Schedule next study visit, and instruct the parent/guardian that: 1) on the preceding 
day, the evening dose of study medication must be administered at least 12 hours 
before the start of the visit, and 2) on the day of the visit, the morning dose must not be 
taken beforehand; it will be administered at the site. 
As soon as the SF results from this visit are available,  check to see if the SF level was 
≥ 1000 μg/L (taking the factor of possible infection into account, as described above) at 
both this and the previous visit.  If no, have the patient continue; if yes, immediately 
terminate the patient from the study and schedule an early termination visit. 
Month 6 (± 10 days) 
• Collect blood samples for the following assessments (at approximately the same time 
that this was done at baseline): 
o Hematology 
o Blood chemistry 
o Labile plasma iron 
o Transferrin saturation 
o Serum ferritin 
o C-reactive protein 
Notes:   
- 
A patient whose SF level is found to be ≥1000 μg/L at 2 consecutive visits 
is to be withdrawn; however, since SF level may be impacted by the 
presence of infection, it must additionally be verified that the child has had 
no signs of infection in the previous 7 days, including the day of the visit, 
and that the level of CRP is no greater than 20% higher than the normal 
range for the patient’s age.  If there are signs of infection and/or the CRP 

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level is above this threshold, an SF level ≥1000 μg/L must be checked 
again a minimum of a week later before the patient’s study status can be 
determined. (If an investigator has valid reason to believe that an SF level 
≥ 1000 μg/L may be attributable to infection even if this is not indicated 
by the CRP result, SF may be rechecked once more a minimum of one 
week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
serum ferritin, LPI, and TSAT must be collected before the transfusion is 
performed. 
• Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Measure weight and height/length 
• Review and update transfusion history  
• Ask the parent/guardian (and patient, if applicable) about any adverse events that 
have occurred and concomitant medications that have been taken since the last site 
visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them in order to calculate treatment 
compliance 
• Check the laboratory results from the previous 3 visits (Months 3, 4, and 5) to verify 
whether: 
o The patient has had an SF value ≥ 800 μg/L (but still below 1000 μg/L) and/or 
an LPI value ≥ 0.6 µM and/or a TSAT value ≥ 60% at 2 consecutive visits, or 
o An increasing trend in any of the above 3 measures at 3 consecutive visits, 
regardless of value 
If none of these criteria are met, the dosage is to remain at 50 mg/kg/day; if any of 
them are met, the dosage is to be increased to 75 mg/kg/day. 
• Dispense enough study medication to last until the next scheduled visit, with an 
allowance for the visit window of ± 10 days, along with a reminder if necessary on 
how to administer it 
• Administer the morning dose of study medication 

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• Provide the parent/guardian (or patient, if applicable) with a new diary card, along 
with a reminder if necessary about how to complete it  
• Instruct parent/guardian (and patient, if applicable) to do the following: 
o Bring the patient to either the study site or a local laboratory for a biweekly 
blood draw (as of Month 6, this is reduced from weekly) 
o In the event of any symptoms indicative of infection such as fever, sore throat, 
or flu-like symptoms, immediately interrupt therapy and contact the clinic 
o At the next site visit, bring back the completed diary card plus all medication 
containers, whether empty, partly used, or unopened 
o In the event of a decision to withdraw from the study before completion, bring 
the patient to the clinic for an Early Termination visit as soon as possible, and 
no later than one month following the last dose of study medication 
• Schedule next study visit, and instruct the parent/guardian that: 1) on the preceding 
day, the evening dose of study medication must be administered at least 12 hours 
before the start of the visit, and 2) on the day of the visit, the morning dose must not 
be taken beforehand; it will be administered at the site. 
As soon as the SF results from this visit are available, check to see if the SF level was ≥ 1000 
μg/L (taking the factor of possible infection into account, as described above) at both this 
and the previous visit.  If no, have the patient continue; if yes, immediately terminate the 
patient from the study and schedule an early termination visit. 
Month 7 and Month 8 (± 10 days) 
• Collect blood samples for the following assessments (at approximately the same time 
that this was done at baseline): 
o Hematology 
o Labile plasma iron 
o Transferrin saturation 
o Serum ferritin 
o C-reactive protein 
Notes:   
- 
A patient whose SF level is found to be ≥1000 μg/L at 2 consecutive visits 
is to be withdrawn; however, since SF level may be impacted by the 
presence of infection, it must additionally be verified that the child has had 

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no signs of infection in the previous 7 days, including the day of the visit, 
and that the level of CRP is no greater than 20% higher than the normal 
range for the patient’s age.  If there are signs of infection and/or the CRP 
level is above this threshold, an SF level ≥1000 μg/L must be checked 
again a minimum of a week later before the patient’s study status can be 
determined. (If an investigator has valid reason to believe that an SF level 
≥ 1000 μg/L may be attributable to infection even if this is not indicated 
by the CRP result, SF may be rechecked once more a minimum of one 
week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
serum ferritin, LPI, and TSAT must be collected before the transfusion is 
performed. 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Measure weight and height/length 
• Review and update transfusion history  
• Ask the parent/guardian (and patient, if applicable) about any adverse events that have 
occurred and concomitant medications that have been taken since the last site visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them in order to calculate treatment 
compliance 
• Check the laboratory results from the previous 3 visits (Months 4, 5, and 6 or 
Months 5, 6, and 7) to verify whether: 
o The patient has had an SF value ≥ 800 μg/L (but still below 1000 μg/L) and/or 
an LPI value ≥ 0.6 µM and/or a TSAT value ≥ 60% at 2 consecutive visits, or 
o An increasing trend in any of the above 3 measures at 3 consecutive visits, 
regardless of value 
If none of these criteria are met, the dosage is to remain at 50 mg/kg/day; if any of 
them are met, the dosage is to be increased to 75 mg/kg/day. 
• Dispense enough study medication to last until the next scheduled visit, with an 
allowance for the visit window of ± 10 days, along with a reminder if necessary on 
how to administer it 
• Administer the morning dose of study medication 

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• Provide the parent/guardian (or patient, if applicable) with a new diary card, along 
with a reminder if necessary about how to complete it  
• Instruct parent/guardian (and patient, if applicable) to do the following: 
o Bring the patient to either the study site or a local laboratory for a biweekly 
blood draw 
o In the event of any symptoms indicative of infection such as fever, sore throat, 
or flu-like symptoms, immediately interrupt therapy and contact the clinic 
o At the next site visit, bring back the completed diary card plus all medication 
containers, whether empty, partly used, or unopened 
o In the event of a decision to withdraw from the study before completion, bring 
the patient to the clinic for an Early Termination visit as soon as possible, and 
no later than one month following the last dose of study medication 
• Schedule next study visit, and instruct the parent/guardian that: 1) on the preceding 
day, the evening dose of study medication must be administered at least 12 hours 
before the start of the visit, and 2) on the day of the visit, the morning dose must not 
be taken beforehand; it will be administered at the site. 
As soon as the SF results from this visit are available, check to see if the SF level was ≥ 1000 
μg/L (taking the factor of possible infection into account, as described above) at both this 
and the previous visit.  If no, have the patient continue; if yes, immediately terminate the 
patient from the study and schedule an early termination visit. 
Month 9 (± 10 days) 
• Collect blood samples for the following assessments (at approximately the same time 
that this was done at baseline): 
o Hematology 
o Blood chemistry 
o Labile plasma iron 
o Transferrin saturation 
o Serum ferritin 
o C-reactive protein 

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Notes:   
- 
A patient whose SF level is found to be ≥1000 μg/L at 2 consecutive visits 
is to be withdrawn; however, since SF level may be impacted by the 
presence of infection, it must additionally be verified that the child has had 
no signs of infection in the previous 7 days, including the day of the visit, 
and that the level of CRP is no greater than 20% higher than the normal 
range for the patient’s age.  If there are signs of infection and/or the CRP 
level is above this threshold, an SF level ≥1000 μg/L must be checked 
again a minimum of a week later before the patient’s study status can be 
determined. (If an investigator has valid reason to believe that an SF level 
≥ 1000 μg/L may be attributable to infection even if this is not indicated 
by the CRP result, SF may be rechecked once more a minimum of one 
week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
serum ferritin, LPI, and TSAT must be collected before the transfusion is 
performed. 
• Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Measure weight and height/length 
• Review and update transfusion history  
• Ask the parent/guardian (and patient, if applicable) about any adverse events that have 
occurred and concomitant medications that have been taken since the last site visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them in order to calculate treatment 
compliance 
• Check the laboratory results from the previous 3 visits (Months 6, 7, and 8) to verify 
whether: 
o The patient has had an SF value ≥ 800 μg/L (but still below 1000 μg/L) and/or 
an LPI value ≥ 0.6 µM and/or a TSAT value ≥ 60% at 2 consecutive visits, or 
o An increasing trend in any of the above 3 measures at 3 consecutive visits, 
regardless of value 
If none of these criteria are met, the dosage is to remain at 50 mg/kg/day; if any of 
them are met, the dosage is to be increased to 75 mg/kg/day. 

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• Dispense enough study medication to last until the next scheduled visit, with an 
allowance for the visit window of ± 10 days, along with a reminder if necessary on 
how to administer it 
• Administer the morning dose of study medication 
• Provide the parent/guardian (or patient, if applicable) with a new diary card, along 
with a reminder if necessary about how to complete it  
• Instruct parent/guardian (and patient, if applicable) to do the following: 
o Bring the patient to either the study site or a local laboratory for a biweekly 
blood draw 
o In the event of any symptoms indicative of infection such as fever, sore throat, or 
flu-like symptoms, immediately interrupt therapy and contact the clinic 
o At the next site visit, bring back the completed diary card plus all medication 
containers, whether empty, partly used, or unopened 
o In the event of a decision to withdraw from the study before completion, bring 
the patient to the clinic for an Early Termination visit as soon as possible, and no 
later than one month following the last dose of study medication 
• Schedule next study visit, and instruct the parent/guardian that: 1) on the preceding 
day, the evening dose of study medication must be administered at least 12 hours 
before the start of the visit, and 2) on the day of the visit, the morning dose must not 
be taken beforehand; it will be administered at the site. 
As soon as the SF results from this visit are available, check to see if the SF level was ≥ 
1000 μg/L (taking the factor of possible infection into account, as described above) at both 
this and the previous visit.  If no, have the patient continue; if yes, immediately terminate the 
patient from the study and schedule an early termination visit. 
Months 10 and Month 11 (± 10 days) 
• Collect blood samples for the following assessments (at approximately the same time 
that this was done at baseline): 
o Hematology 
o Labile plasma iron 
o Transferrin saturation 
o Serum ferritin 
o C-reactive protein 

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Notes:   
- 
A patient whose SF level is found to be ≥1000 μg/L at 2 consecutive visits 
is to be withdrawn; however, since SF level may be impacted by the 
presence of infection, it must additionally be verified that the child has had 
no signs of infection in the previous 7 days, including the day of the visit, 
and that the level of CRP is no greater than 20% higher than the normal 
range for the patient’s age.  If there are signs of infection and/or the CRP 
level is above this threshold, an SF level ≥1000 μg/L must be checked 
again a minimum of a week later before the patient’s study status can be 
determined. (If an investigator has valid reason to believe that an SF level 
≥ 1000 μg/L may be attributable to infection even if this is not indicated 
by the CRP result, SF may be rechecked once more a minimum of one 
week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
serum ferritin, LPI, and TSAT must be collected before the transfusion is 
performed. 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Measure weight and height/length 
• Review and update transfusion history  
• Ask the parent/guardian (and patient, if applicable) about any adverse events that have 
occurred and concomitant medications that have been taken since the last site visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them in order to calculate treatment 
compliance 
• Check the laboratory results from the previous 3 visits (Months 7, 8, and 9 or Months 
8, 9, and 10) to verify whether: 
o The patient has had an SF value ≥ 800 μg/L (but still below 1000 μg/L) and/or 
an LPI value ≥ 0.6 µM and/or a TSAT value ≥ 60% at 2 consecutive visits, or 
o An increasing trend in any of the above 3 measures at 3 consecutive visits, 
regardless of value 
If none of these criteria are met, the dosage is to remain at 50 mg/kg/day; if any of 
them are met, the dosage is to be increased to 75 mg/kg/day. 

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• Dispense enough study medication to last until the next scheduled visit, with an 
allowance for the visit window of ± 10 days, along with a reminder if necessary on 
how to administer it 
• Administer the morning dose of study medication 
• Provide the parent/guardian (or patient, if applicable) with a new diary card, along 
with a reminder if necessary about how to complete it  
• Instruct parent/guardian (and patient, if applicable) to do the following: 
o Bring the patient to either the study site or a local laboratory for a biweekly 
blood draw 
o In the event of any symptoms indicative of infection such as fever, sore throat, 
or flu-like symptoms, immediately interrupt therapy and contact the clinic 
o At the next site visit, bring back the completed diary card plus all medication 
containers, whether empty, partly used, or unopened 
o In the event of a decision to withdraw from the study before completion, bring 
the patient to the clinic for an Early Termination visit as soon as possible, and 
no later than one month following the last dose of study medication 
• Schedule next study visit, and instruct the parent/guardian that: 1) on the preceding 
day, the evening dose of study medication must be administered at least 12 hours 
before the start of the visit, and 2) on the day of the visit, the morning dose must not 
be taken beforehand; it will be administered at the site. 
As soon as the SF results from this visit are available, check to see if the SF level was 
≥ 1000 μg/L (taking the factor of possible infection into account, as described above) at both 
this and the previous visit.  If no, have the patient continue; if yes, immediately terminate the 
patient from the study and schedule an early termination visit. 
Month 12 (± 10 days) (End of Study Visit) 
Note:  A study staff member is to call the patient’s home prior to this visit with a reminder to 
not administer the morning dose before coming to the site. 
• Collect blood samples for the following assessments (at approximately the same time 
that this was done at baseline): 
o 
Hematology 
o 
Blood chemistry 
o 
Prolactin (pre-dose sample) 

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o 
Labile plasma iron 
o 
Transferrin saturation 
o 
Serum ferritin 
o 
C-reactive protein 
Notes:   
- 
Since SF level may be impacted by the presence of infection, it must 
additionally be verified that the child has had no signs of infection in the 
previous 7 days, including the day of the visit, and that the level of CRP is 
no greater than 20% higher than the normal range for the patient’s age.  .  
If there are signs of infection and/or the CRP level is above this threshold, 
an SF level ≥ 1000 μg/L must be checked again a minimum of a week 
later.  (If an investigator has valid reason to believe that an SF level 
≥ 1000 μg/L may be attributable to infection even if this is not indicated 
by the CRP result, SF may be rechecked once more a minimum of one 
week later.) 
- 
If a transfusion is scheduled on the day of the visit, the blood samples for 
serum ferritin, LPI, and TSAT must be collected before the transfusion is 
performed. 
• Collect a urine specimen for urinalysis 
• Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Measure weight and height/length 
• Review and update transfusion history  
• Ask about any adverse events that have occurred and concomitant medications that 
have been taken since the last site visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them to calculate treatment compliance 
• Administer the final dose of study medication, ensuring that this is done at 
approximately the same time as at baseline, and note the exact time at which it is given 
• Collect a blood sample for the assessment of prolactin at 1.5 hours (± 5 min) post-dose 

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Early termination visit (if applicable) 
From Month 2 to Month 11, a patient who is determined to have had a serum ferritin level 
≥1000 μg/L at 2 consecutive visits will be terminated from the study, and is to return for an 
early termination visit as soon as possible.  The following procedures will be done: 
• Collect blood samples for hematology and blood chemistry assessments 
• Collect a urine specimen for urinalysis 
• Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Measure weight and height/length 
• Review and update transfusion history  
• Ask about any adverse events that have occurred and concomitant medications that 
have been taken since the last site visit 
• Additionally review the diary card for information on adverse events and use of 
concomitant medications, and file the diary card with the source documents 
• Collect study medication containers, and check them to calculate treatment compliance 
 
For patients who withdraw early for reasons other than reaching the serum ferritin threshold, 
the early termination visit will include all procedures done at the Month 12 visit except for 
measurement of prolactin. 
Participation in the study is now complete. Patients whose SF level is still below 1000 μg/L at 
12 months will be offered participation in an extension study, LA55-EXT, in which they will 
continue to receive their assigned study product for up to 2 more years.  Patients who are 
terminated early because they have already reached the 1000 μg/L threshold will not be 
eligible to enroll in the extension study.  
5.2 
Method of Assignment to Treatment 
A total of 64 participants will be randomized, 32 to receive placebo and 32 to receive 
deferiprone. 
The sponsor will generate the randomization codes according to the study design. Once 
generated, the randomization codes will be final and will not be modifiable. An Interactive 
Voice (or Web) Response System (IVRS/IWRS) will be used to perform the randomization 
in this study. 

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5.3 
Blinding Procedures 
The placebo solution will have the same appearance and flavor as deferiprone oral solution, and 
will be administered at a volume matching that required for a 25, 50, or 75 mg/kg/day dose of 
active product. 
Sites will be provided with code-breaking instructions.  In the event of an emergency, the 
randomization code may be broken only if knowledge of the respective treatment is necessary for 
adequate treatment of the emergency.  The sponsor must be contacted within 24 hours in case 
of unblinding. Randomization information will be held by designated individual(s). The 
date and reason for breaking the blind must be documented. 
5.4 
Allocation of Patient Numbers 
After provision of informed consent (and assent if applicable), each patient will be assigned a 
unique ID number, and will be identified in all study data by this number rather than by 
name. The ID number will consist of 6 digits, where the first 3 digits represent the site code 
(001 for site #1, 002 for site #2, etc.) and the next 3 digits (separated from the first 3 by a 
hyphen) are assigned sequentially for each individual enrolled at that site.  For example, if 
site #1 enrolls 8 patients, the ID numbers will be 001-001 to 001-008. The assigned ID 
numbers of patients who are screening failures or who withdraw from the study will not be 
reused. 
5.5 
Treatment Compliance 
Compliance will be determined as follows: 1) participants will use the daily diary card to 
record the amount of study medication administered, and 2) at each visit, the investigator or 
delegate will collect the medication containers, whether empty, partly used, or unopened, and 
will check the volume of solution remaining by weighing the bottles.  Compliance will be 
calculated by the volume of solution taken divided by the volume of solution prescribed as 
per the dosing frequency and length of treatment.  Any discrepancies must be discussed with 
participants and documented in the source documents.  Reasons for non-compliance with the 
treatment will be recorded in the source document and in the eCRFs. The investigator should 
discuss treatment compliance at each visit. 
If the volume of returned solution is less than it should be but the parent/guardian (or patient, 
as applicable) reports having administered or taken the correct amount of medication, the site 
will report compliance as 100% in the eCRF, and will provide the reason for the apparent 
over-compliance (e.g., solution was accidentally spilled), along with the actual percentage. 
Both 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). 

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6 
STUDY TREATMENTS 
Patients will receive either deferiprone oral solution 80 mg/mL or matching placebo solution. 
6.1 
Investigational Product 
Deferiprone oral solution (3-hydroxy-1,2-dimethylpyridin-4-one) is manufactured by Apotex 
Inc., and will be supplied to the clinical sites by ApoPharma Inc.  
The 80 mg/mL formulation used in this study is a clear reddish solution with a bubble gum–
flavored aroma. 
6.1.1 
Dosage Form and Mode of Administration 
Deferiprone oral solution is to be administered orally, using a syringe, three times a day. It 
can be given with or without food, as per the investigator’s recommendation. 
6.1.2 
Precautions for Use 
Deferiprone oral solution 80 mg/mL is to be stored at 15–30°C in the container in which it is 
supplied.  Bottles should not be stored in direct light. 
6.2 
Reference Product 
The placebo product will be matched to deferiprone oral solution for color and flavor, and 
will be provided in the same type of bottle and with the same label. 
6.3 
Packaging and Labeling 
The product will be supplied in 250 mL amber-colored bottles with child-resistant closure 
and a tamper-evident seal.  The containers will be provided with labels whose content is in 
accordance with all applicable regulatory requirements and includes details such as protocol 
number, expiry date, lot/batch number, investigational statement, storage temperature, dosage, 
direction for use, visit number, date dispensed, and name and address of the study sponsor. 
6.4 
Shipping and Storage 
The study medication at each site will be kept in a secure location (a locked room or cabinet) 
under adequate storage conditions, as per label requirements, under the control of the 
investigator and with access to authorized individuals only. Product is to be kept at room 
temperature (15–30 ºC / 59–86 ºF). The room must have a calibrated digital temperature-
monitoring device, and daily recordings of the storage facility temperature must be available.  
Temperature excursions must be immediately reported to the sponsor for investigation and 
determination of impact on the study medication. 

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A receipt form will be provided to the study sites by the sponsor with each shipment of 
investigational product.  The investigator or a designate is to sign and date this receipt form 
to acknowledge receiving the entire product shipment in good condition, and to record the 
time at which the temperature-monitoring device was removed and stopped.  The site will fax 
or email a copy of this receipt form to the sponsor and retain the original in its Investigator 
Trial File. 
6.5 
Product Accountability 
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 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 site 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.  The 
sponsor will be responsible for determining the specific conditions for destruction of unused 
product. 

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6.6 
Replacement Doses 
If medication has been lost or damaged, participants will need to return to the study site to 
receive replacement bottles. Requests for replacement must be made in writing to the sponsor 
by the qualified staff member. All information related to the lost or damaged medication and 
the replacement medication is to be recorded in the drug accountability forms and patient 
source data. 
6.7 
Disposition of Unused Product 
All investigational product that has been returned by participants or that is unused for any 
other reasons will be returned to the sponsor or discarded by the site according to internal 
procedures, if approved, in writing, by the sponsor. The destruction procedures must include 
the issuance of appropriate signed destruction certificates including mode of destruction and 
complete drug accountability of destroyed materials. The destruction may take place only 
after written approval by the sponsor. 
6.8 
Other Study Supplies 
All required study supplies, including but not limited to diary cards and laboratory kits, will 
be provided by the sponsor to the sites. 
7 
MEASUREMENTS AND EVALUATIONS 
7.1 
Efficacy Measurements 
Efficacy will be measured by monitoring levels of serum ferritin, transferrin saturation, and 
labile plasma iron. 
7.1.1 
Serum Ferritin 
Ferritin is a protein that stores iron in a non-toxic form, transports it to areas where it is 
required, and releases it in a controlled manner, thereby acting as a buffer against iron 
deficiency and iron overload. It is mainly found in tissues, but small amounts are secreted 
into the serum, where it can serve as an indirect but easily measurable marker of the total 
amount of iron stored in the body.  (Drawbacks of using it as a marker include lack of 
specificity, as disorders other than iron overload can cause large amounts of ferritin to be 
released into the circulation, and inter-patient variability.)  Levels of serum ferritin above 
1000 ng/mL are often considered to be associated with iron toxicity.  In young children who 
have only recently begun an RBC transfusion regimen, it takes some time for this level to be 
reached, but in the absence of chelation it inevitably is reached. 
Serum ferritin will be measured at each visit, and the time to reach a level ≥ 1000 μg/L will 
be compared between the treatment arms. 

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7.1.2 
Transferrin Saturation 
Transferrin is a protein that combines with ferritin and transports it where iron is required.  
When its capacity to bind incoming iron is exceeded, excess iron circulates as free non-
transferrin-bound iron (NTBI), and is taken up by tissues where it can cause cell and organ 
damage. Transferrin saturation, defined as the percentage of the iron-binding sites of transferrin 
that are already occupied, is easily measured and hence serves as a marker for NTBI.  High 
levels of transferrin saturation are associated with iron toxicity.  As this measure is highly 
variable, the blood samples for its assessment will always be collected at approximately the 
same time of day and at approximately the same amount of time after the last dose of study 
medication, in an attempt to decrease variability as much as possible. 
Transferrin saturation will be measured at each visit, and the time to reach a level ≥ 60% will 
be compared between the treatment arms. 
7.1.3 
Labile Plasma Iron 
Labile plasma iron is a component of NTBI, and is the most toxic form of iron since it acts as 
a catalyst in the formation of harmful free hydroxyl radicals which can damage cellular DNA, 
proteins, and membrane lipids. High levels of this form of iron may be found in individuals 
with conditions of iron overload.  As this measure is highly variable, the blood samples for 
its assessment will always be collected at approximately the same time of day and at 
approximately the same amount of time after the last dose of study medication, in an attempt 
to decrease variability as much as possible. 
Labile plasma iron will be measured at each visit, and the time to reach a level ≥0.6 µM will 
be compared between the treatment arms. 
7.2 
Safety Measurements 
7.2.1 
Medical Events, Adverse Events, and Serious Adverse Events 
7.2.1.1 
Definition of Medical Events and Adverse Events 
Medical Event (ME): Any new untoward medical occurrence or worsening of a pre-existing 
condition in a clinical trial participant that occurs after signing the informed consent form 
(ICF) but before receiving the first dose of study drug. 
Adverse Event (AE): 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. 

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AEs include: 
• Exacerbation of a pre-existing illness, including acute episodes/crisis of a chronic 
underlying condition 
• An increase in frequency or intensity of a pre-existing episodic event or condition 
• A condition detected or diagnosed after study treatment administration, even though it 
may have been present prior to the start of the study 
• A continuous persistent disease or symptom present at baseline that worsens following 
the start of the study 
• Accidents (e.g., involving a motor vehicle) 
• Reasons for changes in concomitant medication (type of drug and/or dose) 
• Medical, nursing, or pharmacy consultation 
• Admission to hospital and surgical operations 
• Abnormalities in laboratory findings (e.g., clinical chemistry, hematology, urinalysis), 
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 Medical Events and Adverse Events 
Prior to enrolling a patient, study site personnel will note the occurrence and nature of any 
medical condition(s) in the source documents and the appropriate section of the eCRF. 
During the study, they will note any change in the condition(s), and the occurrence and 
nature of any MEs/AEs. MEs will be collected from the time the ICF is signed until the first 
dose of study drug, and AEs will be collected from the time the treatment starts until 30 days 

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 after the last dose. 
AEs and SAEs that are related to the underlying medical condition for which the patient 
enrolled in the clinical trial will be recorded separately from others. 
Participants will be instructed to report any MEs/AEs to the investigator or a delegate.  In 
addition, the investigator will solicit information about the occurrence of MEs/AEs through 
open-ended, non-leading verbal questions such as: 
• How is your child feeling? 
• Has your child had any medical problems since the last visit? 
• Has your child taken any new medications, other than those provided in this study, 
since the last visit? 
Based on the responses 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? 
Participants should also be questioned about any previously reported AEs that have not 
resolved. 
The investigator will evaluate all AEs/MEs 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. 

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7.2.1.3 
Assessment of Causality 
The relationship of an AE to the study drug should be determined by the investigator after 
thorough consideration of all available facts, including associative connections (time or place), 
pharmacological explanations, previous knowledge of the drug, presence of characteristic 
clinical or pathological phenomena, exclusion of other causes, and/or absence of alternative 
explanations. The causal relationship of an adverse event to study drug will be assessed 
according to the following criteria (based on World Health Organization definitions): 
• Not related: 
Temporal relationship to study drug administration is missing or 
implausible, or there is no evident cause. 
• Possibly related: 
Reasonable time sequence to administration of study drug, but 
event could also be explained by concurrent disease or other drugs 
or chemicals. 
• Probably related: 
Reasonable time sequence to administration of study drug, and 
unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). Re-challenge information is not required. 
• Definitely related: 
Plausible time relationship to study drug administration, and cannot 
be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug (de-challenge) should be 
clinically plausible. The event must be definitive pharmacologically 
or phenomenologically, using a satisfactory re-challenge procedure 
if necessary. 
7.2.1.4 
Assessment of Intensity 
Intensity refers to the degree of discomfort or impairment associated with an event. The 
intensity of MEs/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 perform normal daily activities 
3–5 

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7.2.1.5 
Serious Adverse Events 
An SAE is an adverse event occurring at any dose that results in any of the following 
outcomes: 
• Death 
• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability or incapacity 
• A congenital anomaly in the offspring of a patient who received the study treatment 
• An important medical event that does not result in death, is not life-threatening, and does 
not necessitate hospitalization but which in the investigator’s judgment may jeopardize 
the patient and may necessitate medical or surgical intervention to prevent one of those 
outcomes. Examples include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or treatment-related 
substance abuse. 
 
Clarifications: 
• “Life-threatening” means that the patient was, in the view of the investigator, at 
immediate risk of death from the event as it occurred. This definition does not include an 
event that, had it occurred in a more severe form, might have caused death. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
during the study is not considered an AE. 
• Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, the event is considered an SAE. 
• “Inpatient” hospitalization means the patient has been formally admitted to a hospital for 
medical reasons. This may or may not be overnight. It does not include presentation at a 
casualty or emergency room unless the event meets one of the other criteria for being an 
SAE. 
• With regard to the criteria for an important medical event, medical and scientific 
judgment should be used in deciding whether prompt reporting is appropriate in this 
situation. 
7.2.1.6 
Reporting of Serious Adverse Events 
All SAEs occurring up to 30 days following completion of or discontinuation from the study 
must be reported to the sponsor, regardless of whether they are suspected of having a causal 

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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. 
Participants 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 participant, 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 
Individuals 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 neutropenia  
A confirmed ANC < 1.5 x 109/L but ≥1.0 x 109/L 
Moderate neutropenia  
A confirmed ANC < 1.0 x 109/L but ≥ 0.5 x 109/L 
Severe neutropenia / agranulocytosis 
A confirmed ANC < 0.5 x 109/L 
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 the 2 counts are not in the same 
severity category, a third count will be required to determine the severity. If a patient has just 
a single ANC value less than 1.5 x 109/L, this is to be documented in the CRF as an AE of 
“decreased ANC”, but is not to be defined as neutropenia.  The investigator is to use judgment 
as to whether the decrease is clinically significant. 
In addition to having ANC monitored, participants will be advised to immediately report any 
symptoms indicative of infection such as fever (≥ 38.0°C), sore throat, and flu-like symptoms 
at any time during the study and for one week following the last dose. They will be provided 
with an emergency services card with contact information, and advised to carry it with them 
at all times. 
Depending of the severity of neutropenia, patients will either remain in or be withdrawn 
from the study. The management of different severities of neutropenia is described below. 
Mild neutropenia:  A patient who develops mild neutropenia is to interrupt treatment as 
soon as the neutropenia is confirmed, and ANC is to be monitored every 2 days until 
resolution. 
The patient should re-initiate treatment once the event is resolved, 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 
• Provide advice regarding protective isolation 
• Examine patient the same day (if possible), including drug history and physical 
examination 

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• Notify ApoPharma Inc. using the SAE form 
Moderate neutropenia:  A patient in whom a single ANC measurement <1.0 x 109/L but 
≥ 0.5 x 109/L is detected is to immediately stop treatment, without waiting for confirmation 
of the count, and a second measurement is to be done within 48 hours. If the second ANC 
is still < 1.0 x 109/L, the investigator is to do the following: 
• Withdraw patient permanently from the study and monitor ANC daily until resolution  
• Provide advice regarding protective isolation 
• Examine patient the same day (if possible), including drug history and physical 
examination 
• Notify ApoPharma Inc. using the SAE form 
Severe neutropenia/agranulocytosis:  A patient in whom a single ANC measurement 
< 0.5 x 109/L is detected is to immediately stop treatment, without waiting for confirmation 
of the count, and a second measurement is to be done within 48 hours. If the second ANC 
is still < 0.5 x 109/L, the patient is to be permanently withdrawn from the study, and ANC is 
to be monitored daily until resolution. 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 
• With the consent of the parent/guardian (or patient, if applicable), collect a blood 
sample to attempt to identify genetic or other biomarkers related to agranulocytosis 
• Notify ApoPharma Inc. using the SAE form. 
The following additional measures describe a suggested medical management and 
monitoring: 
• If possible, consider obtaining bone marrow aspirate for: 
o Histology 
o Progenitor culture 
o Frozen storage (1 mL sample) 
• If possible, consider obtaining bone marrow biopsy (minimum length 3 mm) 

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• 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, on 
an in-patient basis 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 
7.2.1.8.2 
Infections 
If a patient develops fever (≥ 38.0°C) or any sign of infection during the study, study product 
must be interrupted immediately, and neutrophil count should be obtained and monitored 
more frequently; every 2 days if ANC <1.5 x 109/L.  Therapy can be re-initiated once all 
symptoms have been resolved, if the ANC is ≥1.5 x 109/L. 
7.2.2 
Laboratory Measurements 
Analyses will be performed at a central laboratory, with the exception of the weekly or 
biweekly 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 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 
recorded must be further explained on the laboratory report and documented as an adverse 
event in the eCRF. 
Samples for laboratory safety assessments will be taken at the time points indicated below.  If 
a patient withdraws from the study, the End of Study procedures are to be performed at an 
early termination visit. 

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Hematology:  Hemoglobin, total WBC count, 
ANC, MCV, and platelet count 
Screening and weekly after start of dosing up 
to Month 6 visit, then biweekly until Month 12 
or early termination from the study 
Blood chemistry:  Total protein, GGT, glucose, 
bilirubin (total, direct, and indirect), AST, ALT, 
albumin, blood urea nitrogen, calcium, creatinine, 
total iron binding capacity, serum iron, zinc, and 
C-reactive protein (CRP) 
Screening and Months 1, 3, 6, 9, and 12 (or end 
of study)  
Urinalysis:  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. 
Screening and Month 12 (or end of study) 
Serology: Hepatitis B, hepatitis C, HIV 
Screening 
Other: Prolactin 
Baseline and Month 12 
 
7.2.3 
Other Safety Measurements 
7.2.3.1 
Physical Examinations 
Physical examination will consist of an examination of head, ears, eyes, nose, throat and 
neck, respiratory system, cardiovascular system, gastrointestinal system, musculoskeletal 
system, neurological systems (central and peripheral), and skin, nails, hair, and scalp. 
Physical examination will be performed at screening and at Months 1, 3, 6, 9, and 12 (or end 
of study). Any clinically significant abnormalities noted prior to the screening visit will be 
recorded as medical history, any noted between screening and the first dose of study 
medication will be recorded as medical events, and any that are noted post–Dose 1 will be 
recorded as AEs. 
The growth parameters of body weight and height (or length, in infants not yet able to stand 
upright) which are separate safety endpoints, will be measured at each post-screening visit. 
7.2.3.2 
Vital Signs 
Resting heart rate, resting blood pressure, and body temperature will be taken.  (“Resting” 
implies that the child must be calm and not crying.) Blood pressure should always be 
measured after a minimum 3-minute resting period, and using the same arm each time if 
possible. Systolic and diastolic blood pressures are to be recorded from one measurement. 

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Vital signs will be measured at each site visit. Clinically significant out-of-range values for 
vital signs will be reported as AEs (see Section 7.2.1.1). 
7.2.3.3 
Concomitant Medications 
The following information about prior and concomitant medications is to be recorded: 
• All medications used within the 3 months prior to baseline 
• Any medications that the patient continues to take during the study 
• Any medications that the patient starts to take during the study 
The name, dose, route, frequency, indication, and stop and start dates of all medications used 
during the study must be noted in the source documents and CRFs, as well as whether or not 
the medication was used to treat an AE. 
Information on concurrent medications will be obtained at every site visit. 
8 
STUDY COMMITTEES 
An independent Data Safety Monitoring Board (DSMB) will be established to monitor the 
safety of patients during the course of the study.  Members of the DSMB will be responsible 
for overseeing the conduct of the trial, and will be empowered to recommend stopping the 
trial if, in their judgment, continuation is not ethically acceptable on the grounds of safety. 
Death or a life-threatening event in any study patient which is deemed by either the 
investigator or the sponsor to be at least possibly related to the study medication will trigger 
an evaluation by the DSMB for recommending stopping the study.  Details will be provided 
in the DSMB charter. No study-stopping decision will be made without prior consultation 
with the sponsor. 
The operating model and the frequency of the interim safety review meetings will be laid out 
in the DSMB charter. The DSMB will be constituted prior to the enrolment of any patients 
into the study, and its members will be notified of any changes to the protocol or the study 
conduct. The DSMB will be informed of any substantive changes to the protocol that could 
affect patient safety prior to their implementation. 

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9 
STATISTICAL ANALYSIS 
9.1 
Endpoints 
9.1.1 
Primary Efficacy Endpoint 
The primary endpoint is the percentage of patients who still have a serum ferritin level 
< 1000 μg/L at Month 12. 
9.1.2 
Secondary Efficacy Endpoints 
The secondary endpoints are: 
 
• The percentage of patients whose serum ferritin level is still less than 1000 μg/L at each visit 
• The percentage of patients whose LPI value is still less than 0.6 µM at each visit 
• The percentage of patients in each treatment arm whose TSAT value is still less than 
60% at each visit 
• Time to reach a serum ferritin level ≥ 1000 μg/L 
• Time to reach an LPI value ≥ 0.6 µM 
• Time to reach a TSAT value ≥ 60% 
9.1.3 
Safety Endpoints 
• Adverse events (AEs):  Frequency, intensity, time to onset, duration, and relatedness to 
study drug 
• Serious adverse events (SAEs):  Frequency, intensity, time to onset, duration, and 
relatedness to study drug 
• Number of discontinuations due to AEs 
• Growth parameters:  Weight, height, and height velocity, as classified using the Z-score 
system 
• Change in prolactin level from baseline to Month 12 
9.2 
Determination of Sample Size and Study Power 
The sample size for this study is 64 patients, randomized in a 1:1 ratio to the two arms. With 
this number of patients, there will be over 90% power to detect a statistically significant 
difference ( = 0.05) between the two treatment groups in the percentage of patients who 
have a serum ferritin level < 1000 μg/L at Month 12 if the deferiprone arm and the placebo 
arm have an expected incidence of 70% and 20%, respectively.  

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9.3 
Study Populations 
9.3.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will be composed of patients who have been randomized, 
have received at least one dose of study medication, and have had at least one post-baseline 
measurement on the efficacy variables.  All efficacy endpoints will be analyzed for the ITT 
population, which represents the primary analysis population. 
9.3.2 
Per Protocol Population 
The per protocol (PP) population represents the secondary analysis population, and will be 
composed of patients who have completed the study and have an assessment for the primary 
efficacy measure at the end of the study. Patients with major protocol deviations will be 
excluded from the PP population. The primary efficacy endpoint will be analyzed for this 
population as well. 
9.3.3 
Safety Population 
The safety population will be composed of subjects who have received at least one dose of 
study medication.  
9.4 
Data Analysis Plan 
SAS Windows Version 9.3 or higher will be used for all statistical analyses. 
9.4.1 
Planned Analyses 
9.4.1.1 
Patient Disposition and Drug Exposure 
The number of subjects who were randomized, who were exposed to the study medication, 
who completed the study, and who withdrew from the study (along with reasons for 
withdrawals) will be presented. 
9.4.1.2 
Patient Characteristics 
Subject characteristics at baseline, including demographics, will be summarized with 
descriptive statistics for continuous variables and with frequency tables for categorical 
variables. Medical history will be summarized using the Medical Dictionary for Regulatory 
Activities (MedDRA).  Prior and concomitant medications will be summarized using the 
WHO Drug Dictionary (WHO-DD). 

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9.4.1.3 
Analysis of Efficacy 
The percentage of patients who have not reached levels of LPI ≥ 0.6 µM, TSAT ≥ 60% and 
SF ≥ 1000 μg/L will be compared between the two treatment groups at each monthly time 
point as well as at the end of study, using the Fisher’s exact test. The effect of baseline value 
on each of the 3 endpoints will be examined in a covariate analysis. The Kaplan-Meier 
survival curve for the time to reach a serum ferritin level ≥ 1000 μg/L, an LPI value ≥ 0.6 
µM, and a TSAT value ≥ 60% will be generated for the two treatment groups. The log-rank 
test will be used for comparing the two survival curves for each of the 3 endpoints.  The 
trend analysis over time for LPI, TSAT, and SF measures will be performed to compare the 
rate of change in these measures between the two treatment groups. 
9.4.1.4 
Analysis of Safety 
Descriptive statistics (mean, standard deviation, minimum, and maximum) will be produced 
for continuous variables, and frequency tables will be produced for discrete variables by 
treatment group. Summaries of adverse events and serious adverse events will be produced 
by treatment group. Shift tables will be generated for comparing the screening/baseline 
values and end of study values of the relevant measures. 
For weight and height, the change from baseline to last assessment will be compared between 
the two treatment groups using an ANCOVA model with baseline value as a covariate and 
treatment as the main factor. A similar ANCOVA model will be used for the analysis of the 
z-scores for height. The rate of change in height will be assessed using regression analysis. 
The following safety data will be summarized by treatment group: 
• Adverse events (AEs), adverse drug reactions (ADRs), serious adverse events 
(SAEs), and serious adverse drug reactions (SADRs)  
• Number of discontinuations due to AEs 
• Hematology assessments 
• Biochemistry assessments 
• Vital signs 
• Urinalysis 
• Prior and concomitant medications 
Prolactin will be measured at baseline and Month 12. The change in prolactin level from 
baseline to Month 12 will be compared between the two treatment groups using an 
ANCOVA model with baseline value as a covariate and treatment as the main factor. 
9.4.2 
Interim Analyses 
There is no interim analysis planned for this study. 

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9.5 
Criteria for Evaluability of Patient Data 
Patients with protocol deviations will be assessed, and the deviations will be determined as 
minor or major before the randomization codes are broken. Patients with major protocol 
deviations will be excluded from the PP population. 
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. Patient 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 Electronic Data Capture (EDC) system hosted by the sponsor or the sponsor’s 
vendor. Trained users will access the system via a secured gateway. Users will only be 
authorized to access data for their study site. Data will be entered directly into the system 
from the source documents in lieu of 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 current versions of 
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 study monitor will verify the eCRFs on-line. 
Clinical data management activities will be performed by the sponsor in accordance with 
applicable standards and data cleaning procedures of the sponsor. An audit trail of all data 
processing will be stored in the database. The study biostatistician will be notified when all 
subject data are ready for analysis. 
Integrity of the database will be assured by limiting access through username/password 
combination and account control. Authorized access to the database will be provided to those 
individuals with an inspection/auditing function (e.g., Quality Assurance); “read only” access 
will be provided to avoid unintentional corruption of the database. 
The database will be backed up regularly. 
10.2 
Case Report Forms 
Electronic CRFs may be generated and/or printed at any time using the sponsor’s EDC 
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. 

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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 ECG 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 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, study sites 
may be inspected by regulatory authorities and/or audited by ApoPharma Quality 
Assurance (QA) or their third-party 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. 

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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 third-party 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 
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. 

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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/Assent 
Prior to entering a patient into the study, the investigator or a designate must obtain written 
informed consent from the parent/guardian and/or where applicable a 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.  In the case of patients who are capable of assenting, 
informed assent is to be obtained as well. The investigator will ensure that the 
parent/guardian/patient/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 other family members. 
The investigator must make a conscientious effort to be fully satisfied that this individual has 
truly understood that for which the consent has been given. The parent/guardian/ legal 
representative must be notified that he/she is free to discontinue the patient’s participation in 
the study at any time, and that such withdrawal will not affect present or future care. In the 
case of a child 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 model versions of the informed consent/assent forms to the sites as 
separate documents. Each site may then revise these versions according to the requirements 
of its individual IRB/IEC. 
The parent/guardian 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 the parent/
guardian of 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 

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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 the parent/guardian (and patient, if applicable) 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 their child’s 
medical history. 
The investigator is responsible for keeping a list of all patients entered, including patient 
code, patient ID, full name, and last known address. 
13 
REGULATORY REQUIREMENTS 
13.1 
Regulatory Obligations 
This trial is to be conducted in accordance with the Declaration of Helsinki, the ICH 
Consolidated Guidelines for Good Clinical Practice (GCP), FDA regulations, and any local 
regulatory requirements. The trial will not begin at any given site until the site has provided 
the following documents to the sponsor or its delegate, as per the ICH Consolidated 
Guideline on GCP (Section 8.2): 
1. Signed and dated IRB/IEC approval indicating review and approval of each the following 
documents: 
• Protocol and any amendments 
• Patient Informed Consent Form 
• Any written information to be provided to patients 
• Any advertisements for patient recruitment 
• Any compensation to patients 
2. Membership of the IRB/IEC, to document that the committee is constituted in agreement 
with GCP 

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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 Study Agreement 
13.2 
Amendments to the Protocol 
No amendments to this protocol will be made without consultation with and the agreement of 
the sponsor. Any amendment to the trial that seems indicated as the trial progresses must be 
discussed between the investigator and sponsor concurrently. If agreement is reached 
concerning the need for an amendment, this amendment will be produced in writing by the 
sponsor and will be made a formal part of the protocol. 
The investigator is responsible for ensuring that changes in the approved research project, 
during the period for which IRB/IEC approval has already been given, are not initiated 
without review and approval of the IRB/IEC except where necessary to eliminate apparent 
immediate hazards to the patients. 
14 
EARLY STUDY TERMINATION 
The sponsor reserves the right to discontinue this study at any time; or, an investigator may 
terminate it at his/her respective site following consultation with the sponsor. On 
discontinuance of the study, in its entirety or at a specific site, the investigator(s) will inform 
the study patients, the relevant clinical study staff, and the respective IRB/IEC of the 
discontinuance; provide them with the reasons for the discontinuance; and advise them in 
writing of any potential risks to the health of the study patients. It is the sponsor’s 
responsibility to report discontinuance of the study to regulatory agencies, to provide them 
with the reasons for the discontinuance, and to advise them in writing of any potential risks 
to the health of the study patients. 

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15 
CONFIDENTIALITY 
Each investigator, co-investigator, and institution’s representative 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. Otherwise, matters of confidentiality will be 
governed by the Clinical Study Agreement.  
16 
DISPUTE RESOLUTION  
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 Study Agreement. 
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 Study 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 Study Agreement. 

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19 
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