Clinical trial NCT03802916
Conditions: Iron Overload Due to Repeated Red Blood Cell Transfusions
Keywords: iron overload chelation deferiprone Ferriprox
Sponsor: ApoPharma
Start date: 2019-03-06; Completion date: 2019-12-19
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Safety, tolerability, and acceptability of twice-daily dosing with deferiprone delayed-release (DR) tablets in patients with systemic iron overload.

Detailed description:
This study is looking at the safety, tolerability, and acceptability of twice-daily dosing with deferiprone delayed-release (DR) tablets in patients with systemic iron overload who are currently taking deferiprone immediate-release tablets (Ferriprox) three times a day. Ferriprox doses range from 75 milligrams per kilogram of body weight (mg/kg) per day to 100 mg/kg per day. Half the patients in the study will be on a dosage that is closer to the low end of the range, and half will be on a dosage that is closer to the high end. Both groups will be switched for one month to deferiprone DR tablets at approximately the same total daily dosage that they have been taking for Ferriprox.

Arms: arm 1: Patients in this group will receive a total daily dosage of deferiprone DR tablets that is closer to 75 mg/kg/day. The total dosage will be divided into two equal parts, taken about 12 hours apart. arm 2: Patients in this group will receive a total daily dosage of deferiprone DR tablets that is closer to 100 mg/kg/day. The total dosage will be divided into two equal parts, taken about 12 hours apart.
Interventions: intervention 1: Deferiprone DR tablets 1000 mg (Low dosage) intervention 2: Deferiprone DR tablets 1000 mg (High dosage)
Intervention descriptions: intervention 1: Deferiprone DR tablets 1000 mg intervention 2: Deferiprone DR tablets 1000 mg

Protocol documents:
Prot_SAP_002.pdf: 
 
 
 
CONFIDENTIAL 
Page 1 of 58 
 
 
 
Safety and acceptability of deferiprone delayed release tablets in patients 
with systemic iron overload 
LA61-0218 
CLINICAL STUDY PROTOCOL 
 
IND Number: 
45724 
Investigational Product: 
Deferiprone delayed release 1000 mg tablets 
Development Phase: 
Phase 2 
Indication Studied: 
Systemic iron overload 
Study Design: 
Multi-center open-label study in patients with transfusion-
dependent blood disorders  
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 1.0, 10 OCT 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 delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 2 of 58 
 
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 acceptability of deferiprone delayed release tablets in 
patients with systemic iron overload 
Study Code: 
LA61-0218 
Version Number: 
1.0 
Version Date: 
10 OCT 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) 
 
 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 3 of 58 
 
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 acceptability of deferiprone delayed release 
tablets in patients with systemic iron overload 
Study Code: 
LA61-0218 
Version Number: 
1.0 
Version Date: 
10 OCT 2018 
Name of Principal Investigator: 
 
Name of Study Site: 
 
Location of Study Site: 
(City, region/province/state, 
country) 
 
 
 
 
Signature 
 
Date (DD MMM YYYY) 
 
 
 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 4 of 58 
 
 
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 
delayed release tablet 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Title of study: 
Safety and acceptability of deferiprone delayed release tablets in patients with 
systemic iron overload 
Study code: 
LA61-0218 
Phase of development: 
Phase 2 
Objectives: 
Primary objective:  To evaluate the safety of deferiprone delayed release (DR) 
tablets in two different dosage groups in patients with systemic iron overload. 
Secondary objectives: 
• To evaluate the tolerability of deferiprone DR tablets in two different 
dosage groups in patients with systemic iron overload 
• To evaluate the acceptability to patients of deferiprone DR 
Study design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multi-center open-label study in patients with transfusion-dependent blood disorders 
who are currently taking deferiprone immediate release tablets (Ferriprox®) for the 
treatment of systemic iron overload. There will be two treatment groups, defined as 
“low dosage” (Group A) and “high dosage” (Group B).  With Ferriprox, the 
recommended starting dosage is 75 milligrams per kilogram of body weight (mg/kg) 
per day and the recommended maximum is 100 mg/kg per day, but for most 
patients, the precise daily amount differs from either of these values since doses 
must be tailored to the individual patient’s response and therapeutic goals and 
rounded to the nearest half-tablet.  Study participants will be assigned to Group A or 
Group B depending on which end of the range their Ferriprox intake is closer to, 
with equal numbers of patients enrolled in each group: 
• 
Group A, low dosage:  Patients currently taking Ferriprox tablets at a 
dosage that is closer to 75 mg/kg/day (n=15) 
• 
Group B, high dosage:  Patients currently taking Ferriprox tablets at a 
dosage that is closer to 100 mg/kg/day (n=15) 
In each group, participants will be provided with deferiprone DR tablets to be 
taken twice daily (b.i.d.) for 28 days at a total daily dosage the matches the total 
amount of Ferriprox they have been taking three times daily (t.i.d.) as closely as 
possible. Individual doses will be rounded to the nearest 500 mg half-tablet.  
Doses are always to be taken with food.  Following the last dose, patients will 
return to their regular chelation regimen. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 5 of 58 
 
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 
delayed release tablet 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Study design (cont’d): 
Screening will be conducted within 14 days prior to the start of dosing, and with the 
exception of hematology, laboratory results obtained at that time will be treated as 
the baseline values. Blood samples will be collected for the assessment of 
biochemistry (screening and Days 3, 7, 14, 21, and 28), hematology (screening, 
baseline, and Days 7, 14, 21, and 28), serology (screening only), and other safety 
parameters (screening and Day 28); and urine samples will be collected for 
urinalysis (screening and Day 28).  For the Day 3, 7, 14, and 21 samples, patients 
may choose to visit a local laboratory instead of the study site; if this is done, they 
must use the same laboratory throughout the entire study.  If deemed necessary, 
patients with ongoing adverse events may be asked after the last dose to provide 
further blood samples until resolution. On Day 28, patients will be asked for their 
views on the acceptability of the delayed release formulation vs. the immediate 
release (Ferriprox) tablets.   
Any patient who withdraws before completing treatment will be requested to 
return for an Early Termination visit, at which time the procedures scheduled for 
the Day 28 visit will be conducted. 
As this will be the first time that deferiprone DR is administered to patients with 
iron overload, as a precaution, enrollment will be conducted progressively in small 
groups, and safety results will be reviewed following the enrollment of a limited 
number of patients. Decisions regarding continuation will be based on the findings. 
Duration of 
participation: 
The duration of participation will be 28 days, excluding the screening period. 
 
Criteria for 
evaluation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
In recognition of the variability of levels of the liver enzymes alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) in patients with 
iron overload, the criterion for deciding whether an individual patient’s increases 
for each of these enzymes during the study constitute a safety concern will be set as 
follows: 
• For a patient whose level is within the normal range at baseline, the criterion 
will be reaching a value of 5 times the upper limit of normal (ULN)  
• For a patient whose level is above the ULN at baseline, the criterion will be 
reaching a value of 5 times the baseline value or 10 x ULN 
For each dosage group, the following will be determined: 
• 
The number and percentage of patients with increased post-dose levels of 
ALT and/or AST that meet either of the criteria defined above 
• 
Adverse events (AEs):  Frequency, intensity, time to onset, duration, and 
relatedness to study drug 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 6 of 58 
 
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 
delayed release tablet 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Criteria for evaluation 
(cont’d): 
• 
Serious adverse events (SAEs):  Frequency, intensity, time to onset, duration, 
and relatedness to study drug 
• 
Number of discontinuations due to AEs 
 
Acceptability 
At the end of the treatment, patients will be asked to complete a questionnaire as 
to what their preference is between the two formulations (Ferriprox IR tablets vs. 
deferiprone DR tablets) with respect to scheduling, convenience of administration, 
and tolerability. 
Number of patients: 
A total of 30 patients will be enrolled in this study, 15 in each dosage group. 
Diagnosis and main 
criteria for inclusion: 
Main inclusion criteria 
• Male or female aged ≥ 18 years 
• Diagnosis of thalassemia syndrome, sickle cell disease, or other disorder 
requiring a regular regimen of red blood cell transfusions 
• On a stable regimen (≥3 months) of Ferriprox tablets for the treatment of 
systemic iron overload 
• A record of at least the last 12 measured ALT and AST levels prior to 
baseline  
Main exclusion criteria 
• ALT and/or AST value > 5 x ULN at screening  
• Active case of hepatitis B or C at screening 
Investigational 
product: 
Product: Deferiprone delayed release (DR) 1000 mg tablets  
Dose:  
All patients will receive deferiprone DR at approximately the same 
total daily dosage at which they were taking Ferriprox (Group A:  closer 
to 75 mg/kg/day; Group B:  closer to 100 mg/kg/day), approximately 
12 hours apart, rounded to the nearest 500 mg half-tablet 
Mode of administration: 
Oral 
Schedule of treatment 
and specimen 
collection: 
 
 
 
 
Schedule of Treatment 
Patients will receive 28 days of b.i.d. dosing with deferiprone DR tablets. 
• 
Biochemistry:  Screening and Days 3, 7, 14, 21, and 28 
• 
Hematology:  Screening, baseline, and Days 7, 14, 21, and 28  
• 
Coagulation:  Screening and Day 28 
• 
Serology: Screening 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 7 of 58 
 
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 
delayed release tablet 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Schedule of treatment 
and specimen 
collection (cont’d): 
 
• 
Urinalysis: Screening and Day 28 
• 
Physical examination: Screening and Day 28  
• 
Vital signs: Screening and Day 28  
• 
Serum pregnancy test (if applicable):  Screening and Day 28 
• 
Adverse events: Throughout the study 
• 
Prior and concomitant medications:  Throughout the study 
Notes: 
- With the exception of hematology, laboratory results obtained at screening 
will be treated as the baseline values. 
- There will be a window of ±1 day for assessments done at Days 3 and 7, 
and of ±2 days for assessments done at Days 14, 21, and 28. 
- The investigator may increase the frequency of safety evaluations if 
deemed appropriate for assessment of any clinically significant adverse 
event.  In the case of increases in liver enzymes that meet the criteria for 
being considered a safety concern, the patient is to be followed until 
resolution of the event, beyond Day 28 if necessary. 
- If a patient withdraws from the study, the End of Study procedures are to be 
performed at an early termination visit. 
Schedule of Evaluation of Acceptability  
Questionnaire on patient preference for IR vs. DR formulation:  Day 28 
Statistical methods: 
The Clopper-Pearson 95% confidence interval (CI) of the incidence of post-dose 
levels of ALT or AST that meet the criteria for being considered a safety concern 
will be calculated for each dosage group.  Similarly, the Clopper-Pearson 95% CI of 
the incidence of gastrointestinal (GI) distress reported by patients during the study 
will also be calculated. Other AEs will be summarized by using frequency tables. 
The incidence of abnormal data for safety measures will be presented for each 
dosage group. The continuous and discrete variables for safety data will be 
summarized with descriptive statistics (mean, median, standard deviation, 
minimum, and maximum) and frequency tables, respectively, at each assessment. 
For each dosage group, frequency tables will be used to summarize the response to 
each question of the questionnaire on treatment acceptability between Ferriprox 
IR vs. deferiprone DR. Based on the responses to the question on overall 
preference for one formulation or the other, a one-sample proportion test will be 
used to test if the overall preference for deferiprone DR is greater than 0.5 for 
each dosage group. 
Version and date of 
the protocol: 
 Version 1.0, 10 OCT 2018 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 8 of 58 
 
TABLE OF CONTENTS 
SIGNATURE PAGES .............................................................................................................2 
SYNOPSIS ................................................................................................................................4 
LIST OF IN-TEXT TABLES ...............................................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................12 
1 
INTRODUCTION......................................................................................................13 
1.1 
Background .............................................................................................................13 
1.2 
Rationale ..................................................................................................................15 
1.3 
Potential Risks and Benefits ....................................................................................16 
2 
STUDY OBJECTIVES ..............................................................................................17 
2.1 
Primary Objective ....................................................................................................17 
2.2 
Secondary Objectives ..............................................................................................17 
3 
STUDY DESIGN ........................................................................................................17 
3.1 
Description of Study Design ...................................................................................17 
3.1.1 
Precautions Regarding Enrollment ..................................................................18 
3.1.1.1 
Criteria for Safety Concerns .....................................................................18 
3.1.1.2 
 Rules for Enrollment................................................................................19 
3.2 
Rationale for Study Design .....................................................................................22 
3.3 
Rationale for Selection of Doses .............................................................................22 
4 
STUDY POPULATION ............................................................................................23 
4.1 
Number of Patients ..................................................................................................23 
4.2 
Inclusion Criteria .....................................................................................................23 
4.3 
Exclusion Criteria ....................................................................................................24 
4.4 
Enrolment Violations ..............................................................................................25 
4.5 
Patient Withdrawal ..................................................................................................25 
4.5.1.1 
Elevated Liver Enzymes ...........................................................................26 
4.5.1.2 
Neutropenia...............................................................................................26 
4.5.1.3 
Infection ....................................................................................................27 
4.6 
Prior and Concomitant Therapies ............................................................................28 
4.7 
Rescue Medication ..................................................................................................28 
5 
STUDY PROCEDURES ...........................................................................................28 
5.1 
Visit Procedures ......................................................................................................31 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 9 of 58 
 
5.2 
Method of Assignment to Treatment .......................................................................34 
5.3 
Blinding Procedures ................................................................................................34 
5.4 
Allocation of Patient Numbers ................................................................................34 
5.5 
Treatment Compliance ............................................................................................34 
6 
STUDY TREATMENTS ...........................................................................................35 
6.1 
Investigational Product ............................................................................................35 
6.2 
Packaging and Labeling ..........................................................................................35 
6.3 
Shipping and Storage ...............................................................................................36 
6.4 
Product Accountability ............................................................................................36 
6.5 
Replacement Doses .................................................................................................36 
6.6 
Disposition of Unused Product................................................................................36 
7 
MEASUREMENTS AND EVALUATIONS ...........................................................37 
7.1 
Safety Measurements ..............................................................................................37 
7.1.1.1 
Definition of Medical Events and Adverse Events...................................37 
7.1.1.2 
Monitoring and Documenting of Medical Events and Adverse 
Events .......................................................................................................38 
7.1.1.3 
Assessment of Causality ...........................................................................39 
7.1.1.4 
Assessment of Intensity ............................................................................40 
7.1.1.5 
Serious Adverse Events ............................................................................40 
7.1.1.6 
Reporting of Serious Adverse Events .......................................................41 
7.1.1.7 
Follow-up and Documentation of SAEs ...................................................41 
7.1.1.8 
Adverse Events of Special Interest ...........................................................42 
7.1.1.8.1 
Elevated Liver Enzymes .................................................................... 42 
7.1.1.8.2 
Neutropenia ....................................................................................... 42 
7.1.1.8.3 
Infections ........................................................................................... 44 
7.1.3.1 
Physical Examinations ..............................................................................46 
7.1.3.2 
Vital Signs ................................................................................................46 
7.1.3.3 
Concomitant Medications .........................................................................46 
7.2 
Acceptability Measurements ...................................................................................47 
8 
STUDY COMMITTEES ...........................................................................................47 
9 
STATISTICAL ANALYSIS .....................................................................................48 
9.1 
Endpoints .................................................................................................................48 
9.2 
Determination of Sample Size and Study Power ....................................................48 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 10 of 58 
 
9.3 
Study Populations ....................................................................................................49 
9.3.1 
Safety Population .............................................................................................49 
9.3.2 
Per Protocol Population ...................................................................................49 
9.4 
Data Analysis Plan ..................................................................................................49 
9.4.1.1 
Patient Disposition and Drug Exposure ....................................................49 
9.4.1.2 
Patient Characteristics ..............................................................................49 
9.4.1.3 
Analysis of Safety .....................................................................................49 
9.4.1.4 
Analysis of Acceptability .........................................................................49 
9.5 
Criteria for Evaluability of Patient Data ..................................................................50 
10 
DATA MANAGEMENT CONSIDERATIONS......................................................50 
10.1 
Data Management ....................................................................................................50 
10.2 
Case Report Forms ..................................................................................................51 
11 
MONITORING, AUDITS, AND INSPECTIONS ..................................................51 
11.1 
Source Documents ...................................................................................................51 
11.2 
Monitoring ...............................................................................................................51 
11.3 
Audits and Inspections ............................................................................................52 
11.4 
Site Closure .............................................................................................................52 
11.5 
Retention of Records ...............................................................................................53 
12 
ETHICAL CONSIDERATIONS ..............................................................................53 
12.1 
Informed Consent ....................................................................................................53 
12.2 
Institutional Review Board/Independent Ethics Committee ...................................54 
12.3 
Patient Confidentiality .............................................................................................54 
13 
REGULATORY REQUIREMENTS .......................................................................54 
13.1 
Regulatory Obligations ............................................................................................54 
13.2 
Amendments to the Protocol ...................................................................................55 
14 
EARLY STUDY TERMINATION ..........................................................................56 
15 
CONFIDENTIALITY ...............................................................................................56 
16 
DISPUTE RESOLUTION.........................................................................................56 
17 
OWNERSHIP .............................................................................................................56 
18 
PUBLICATION .........................................................................................................56 
19 
REFERENCES ...........................................................................................................57 
APPENDIX 1:  QUESTIONNAIRE ON TREATMENT ACCEPTABILITY ................58 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 11 of 58 
 
 
 
LIST OF IN-TEXT TABLES 
Table 5.1 
Table of study procedures ..................................................................................29 
 
 
 
 
 
 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 12 of 58 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase  
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase  
b.i.d. 
twice daily 
CS 
clinically significant 
CI 
confidence interval 
Cmax  
maximum observed plasma concentration over a dosing interval 
CRO 
contract research organization 
eCRF 
electronic case report form 
DR 
delayed release 
EDC 
electronic data capture 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IR 
immediate release 
IRB 
Institutional Review Board 
ME 
medical event 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
PK 
pharmacokinetics 
RBC 
red blood cell 
SAE 
serious adverse event 
t.i.d. 
three times daily 
ULN 
upper limit of normal 
WHO 
World Health Organization 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 13 of 58 
 
1 
INTRODUCTION 
1.1 
Background 
Beta thalassemia and certain other hereditary blood disorders are characterized by abnormal 
forms of hemoglobin that lead 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, endocrine glands, 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. 
Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one) is a bidentate iron chelator that binds 
ferric iron tightly in a 3:1 (deferiprone:iron) molar ratio and has markedly lesser affinity for 
other cations.  Deferiprone’s small molecular size, lack of charge at physiological pH, and 
balanced octanol:water partition coefficient support cell permeability and rapid access to 
both extracellular and intracellular labile iron stores.1 
Immediate-Release Deferiprone 
Three commercial oral formulations of immediate release (IR) deferiprone are currently 
marketed by ApoPharma Inc. under the brand name Ferriprox®:  500 mg film-coated tablets, 
1000 mg film-coated tablets, and a 100 mg/mL oral solution. In the European Union, all 
3 formulations have been approved by the European Medicines Agency (EMA) for the 
treatment of iron overload in patients with thalassemia major for whom deferoxamine 
therapy is contraindicated or causes serious toxicity. In the United States, the Food and Drug 
Administration (FDA) has approved the 500 mg tablets and the 100 mg/mL oral solution for 
the treatment of patients with transfusional iron overload due to thalassemia syndromes when 
current chelation therapy is inadequate; and in Canada, all three formulations of Ferriprox 
were approved in 2015 by Health Canada for the same indication.   
Ferriprox must be taken three times a day, at a total daily dosage of 75 up to 99 or 100 mg/kg 
(i.e., 3 equal doses of 25 to 33 mg/kg t.i.d.).  However, post-marketing feedback from both 
clinicians and patients has indicated that the number of tablets per day, as well as the need to 
take a dose in the middle of the day, creates a situation where the choice is sometimes made 
to forgo the mid-day dose, particularly in the case of school-age children.  The scale of this 
omission has not been formally assessed, but the frequency with which ApoPharma is asked 
if Ferriprox can be taken twice instead of three times daily supports the intuitive sense that 
mid-day dosing is a bona fide concern for a significant segment of the patient population.   


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 14 of 58 
 
Delayed-Release Deferiprone 
In an effort to improve patient compliance, ApoPharma Inc. has developed a 1000 mg 
delayed release (DR) deferiprone tablet that would support twice-daily (b.i.d.) administration 
instead of the t.i.d. regimen required for the IR tablets.  It contains an enteric coating to 
significantly decrease drug release in the stomach, and the composition of the core allows 
half-tablets to provide similar bioavailability of drug as that from a whole tablet.  To date, the 
DR formulation has been assessed in four ApoPharma-sponsored trials in healthy volunteers:  
two that looked at pharmacokinetics (PK) and two that looked at tolerability, with one of the 
tolerability studies adding a special focus on the effect of this formulation on liver enzyme 
levels. 
In the first PK study, LA53-0116 (N=28), healthy volunteers received a single 1000 mg dose 
of deferiprone DR (equivalent to about 15 mg/kg for a subject weighing 70 kg) in the forms 
of a whole tablet under fed conditions, a whole tablet under fasting conditions, and two half-
tablets under fed conditions. In the second, LA45-0116 (N=36), healthy volunteers subjects 
received a total daily dosage of 3000 mg of deferiprone DR (equivalent to about 45 mg/kg 
for an average-weight subject), divided into 2 equal doses per day, for 3 consecutive days, 
under fed conditions.  Both trials included a control treatment of the licensed Ferriprox IR 
tablets, administered as a single dose in the first trial and as a t.i.d. regimen in the second, 
and both involved a comparison of the safety and tolerability of the two formulations as 
well as of PK parameters.  It was demonstrated that the extent of drug exposure (i.e., AUC) 
of the DR formulation was equivalent to that of the IR tablet after a single dose. There were 
no significant food effects on the pharmacokinetics of the DR formulation. There were also 
no differences in drug exposure between a whole tablet and two half-tablets of the DR 
formulation. At steady state, the PK profile of the two dose administrations of DR over a 
24-hour period under fed conditions demonstrated a peak (i.e., Cmax) and extent of drug 
exposure that were equivalent to those of the three dose administrations of IR over a 24-
hour period.  With respect to safety, the DR tablet at this dosage was found to be safe and 
well tolerated. 
Study LA58-0117, with a planned sample size of 86, was a Phase I study that evaluated 
the gastrointestinal (GI) tolerance of deferiprone DR.  Healthy subjects were randomized to 
receive the highest approved dosage (100 mg/kg daily) of either deferiprone DR or 
Ferriprox IR for 3 days, with dosing conducted in the fasting state in order to assess 
tolerability under the conditions most likely to induce GI distress, even though the 24-hour 
bioequivalence of DR and IR tablets had been demonstrated only in the fed state in study 
LA45-0116.  Subjects randomized to deferiprone DR received 50 mg/kg b.i.d., while those 
randomized to Ferriprox received 33 mg/kg t.i.d. While the study was still in progress, it was 
observed that of the 19 participants at that time who had received the DR formulation, 31.6% 
experienced nausea and 26.3% experienced vomiting, compared to rates of 20.0% and 0.0%, 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 15 of 58 
 
respectively, among the 20 subjects who had received Ferriprox. None of the events were 
deemed to be serious or severe, but in 2 cases they led to voluntary withdrawal. The study 
was terminated early as it was determined that sufficient information had been obtained on 
the GI tolerance of deferiprone DR in the fasting state. The subsequent study, LA60-0118 
(N=50), assessed the tolerability of deferiprone DR in healthy volunteers in the fed state, 
which is the condition under which iron-overloaded patients will be instructed to take it, as 
its 24-hour bioequivalence to Ferriprox IR tablets was demonstrated under fed conditions. 
In both study LA58-0117 and the subsequent study LA60-0118, the dosage of deferiprone DR 
was set at 100 mg/kg/day (50 mg/kg b.i.d.), which is the maximum recommended dose that 
would be prescribed to patients for the treatment of systemic iron overload.  While LA60-0118 
was in progress, it was observed that half the subjects dosed to date had asymptomatic 
elevated levels of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), 
with approximately 20% reaching values of approximately 5 times the upper limit of normal 
(ULN) and 1 subject reaching 8 x ULN.  Subjects remained asymptomatic, and liver enzyme 
levels returned to normal following the last dose.  The protocol was amended to reduce the 
dosage for the remaining subjects to 75 mg/kg/day (37.5 mg/kg b.i.d.), which is the dose 
normally prescribed for the treatment of iron-overload at the start of therapy, in order to 
evaluate if there is a dose-related effect with regard to elevation of liver enzymes in healthy 
volunteers.  That study is ongoing.  
1.2 
Rationale 
According to pharmacokinetic bioequivalence criteria, adverse events that depend on Cmax 
and/or AUC would be expected to be the same for two formulations that provide equivalent 
Cmax and AUC over a 24-hour period. While transient liver enzyme elevations are a known 
adverse event at initiation of therapy with Ferriprox IR, particular attention will be paid to 
this effect in the current study given the rate of elevated liver enzymes seen in the Phase I 
study. While the reason for that happening is unclear, it is hypothesized that this effect will 
be less prominent in iron-overloaded individuals, since with them, unlike in healthy 
volunteers, deferiprone will rapidly bind to excess iron and will thus be less available for 
involvement in other biochemical reactions. 
Previous clinical trials of deferiprone IR in patients with thalassemia have shown that ALT 
values in individual patients fluctuate, with declines from baseline of up to 369 U/L and 
increases from baseline of up to 564 U/L.2  ALT levels of at least twice the upper limit of the 
reference range have been observed in up to 60% of patients treated with deferiprone.3  In the 
majority of these patients, the increase is asymptomatic and returns to baseline levels without 
discontinuation or dose reduction of deferiprone. In ApoPharma clinical trials, elevations of 
liver enzymes led to discontinuation of deferiprone therapy in only 5 of 889 patients; 4 (0.4%) 
due to increased serum ALT levels and 1 (0.1%) due to an increase in both ALT and AST. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 16 of 58 
 
The current study will evaluate deferiprone DR in the target population of iron-overloaded 
patients. Participants must have been on Ferriprox IR tablets for at least 3 months at the time 
of enrollment, and will be switched to deferiprone DR tablets for 28 days at approximately 
the same daily dosage at which they have been taking Ferriprox IR.  The study will thus be 
able to evaluate if switching from the IR to the DR formulation will have an impact on liver 
enzyme levels. Some increases are to be expected in this population, due to liver iron 
overload and frequent blood transfusions, and may be considered acceptable.  In recognition 
of this, study participants’ past record of liver enzyme levels will be taken into account when 
assessing safety concerns.  With regard to other adverse effects, because of the higher than 
expected rates of gastrointestinal events that were observed in healthy volunteers (studies 
LA58-0117 and LA60-0118), attention will be paid to the occurrence of GI events as well. 
Finally, in addition to the assessments of safety and tolerability, the study will allow for 
patients’ input on the acceptability of this new formulation and of the change in dosing from 
t.i.d. to b.i.d.  
1.3 
Potential Risks and Benefits 
The safety profile of two formulations is expected to be the same since they provide 
equivalent drug exposure over a 24-hour period.  The elevations of ALT and AST that were 
seen in the Phase I subjects following b.i.d. dosing with deferiprone DR were not of clinical 
concern. However, it is possible that this formulation has a greater impact on liver enzymes 
than does t.i.d. dosing with the immediate-release formulation, at least in healthy volunteers.  
Whether this difference extends to patients with systemic iron overload is not yet known. 
Nevertheless, no other safety concerns were identified following a 3-day dosing period in 
healthy volunteers. 
Comprehensive safety information on Ferriprox is provided in the Investigator’s Brochure 
for that product.4 In clinical trials, the most common adverse reactions were nausea, 
vomiting, and chromaturia (seen in more than 10% of patients) and increased ALT, arthralgia, 
and neutropenia (seen in more than 1% of patients); and the most serious adverse reaction was 
agranulocytosis, defined as an absolute neutrophil count (ANC) less than 0.5 x 109/L.  
Agranulocytosis has been reported in approximately 2% of patients taking Ferriprox, and less 
severe episodes of neutropenia (ANC < 1.5 x 109/L but > 0.5 x 109/L) have been reported in 
approximately 6.4% of patients. In clinical trials, all events of agranulocytosis or neutropenia 
resolved upon discontinuation of Ferriprox. Because of this known risk, participants in the 
present study will undergo safety monitoring that includes a weekly blood count to ensure early 
detection in case of a significant drop in ANC.     
With respect to benefit, as bioequivalence of deferiprone DR tablets to Ferriprox IR tablets 
over a 24-hour period has been demonstrated, it is expected that study participants will 
achieve at least the same efficacy that they have been obtaining from Ferriprox.  Furthermore, 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 17 of 58 
 
given the recognized concerns associated with t.i.d. dosing, the opportunity to achieve the 
same control of iron overload through a less onerous regimen may be perceived as an 
advantage by some patients. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is to evaluate the safety of deferiprone DR tablets in two 
different dosage groups in patients with systemic iron overload. 
The endpoints for the primary objective are provided in Section 9.1.1. 
2.2 
Secondary Objectives 
• To evaluate the tolerability of deferiprone DR tablets in two different dosage groups 
in patients with systemic iron overload 
• To evaluate the acceptability to patients of deferiprone DR  
The endpoints for the secondary objectives provided in Section 9.1.2. 
3 
STUDY DESIGN 
3.1 
Description of Study Design 
This is a multi-center open-label study in patients with transfusion-dependent blood disorders 
who are currently taking deferiprone immediate release tablets (Ferriprox) for the treatment of 
systemic iron overload.   There will be two treatment groups, defined as “low dosage” (Group 
A) and “high dosage” (Group B).  With Ferriprox, the recommended starting dosage is 75 
milligrams per kilogram of body weight (mg/kg) per day and the recommended maximum is 
100 mg/kg per day, but for many patients, the precise daily amount differs from either of these 
values since doses must be tailored to the individual patient’s response and therapeutic goals 
and rounded to the nearest half-tablet. Study participants will be assigned to Group A or Group 
B depending on which end of the range their Ferriprox intake is closer to, with equal numbers 
of patients enrolled in each group: 
• Group A, low dosage:  Patients currently taking Ferriprox tablets at a dosage that is 
closer to 75 mg/kg/day (n=15) 
• Group B, high dosage:  Patients currently taking Ferriprox tablets at a dosage that is 
closer to 100 mg/kg/day (n=15) 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 18 of 58 
 
In each group, participants will be provided with deferiprone DR tablets to be taken twice 
daily (b.i.d.) for 28 days at a total daily dosage the matches the total amount of Ferriprox they 
have been taking three times daily (t.i.d.) as closely as possible. Individual doses will be 
rounded to the nearest 500 mg half-tablet.  Doses are always to be taken with food.  
Following the last dose, patients will return to their regular chelation regimen. 
Screening will be conducted within 14 days prior to the start of dosing, and with the exception 
of hematology, laboratory results obtained at that time will be treated as the baseline values. 
Blood samples will be collected for the assessment of biochemistry (screening and Days 3, 7, 
14, 21, and 28), hematology (screening, baseline, and Days 7, 14, 21, and 28), serology 
(screening only), and other safety parameters (screening and Day 28); and urine samples will 
be collected for urinalysis (screening and Day 28).  For the Day 3, 7, 14, and 21 samples, 
patients may choose to visit a local laboratory instead of the study site; if this is done, they 
must use the same laboratory throughout the entire study.  If deemed necessary, patients with 
ongoing adverse events may be asked after the last dose to provide further blood samples for 
up to 30 days or until resolution. On Day 28, patients will be asked for their views on the 
acceptability of the delayed release formulation vs. the immediate release (Ferriprox) tablets.   
Any patient who withdraws before completing treatment will be requested to return for an 
Early Termination visit, at which time the procedures scheduled for the Day 28 visit will be 
conducted. 
As this will be the first time that deferiprone DR is administered to patients with iron 
overload, as a precaution, enrollment will be conducted progressively in small groups, and 
safety results will be reviewed following the enrollment of a limited number of patients. 
Decisions regarding continuation will be based on the findings.  Details are provided in 
Section 3.1.1. 
3.1.1 
Precautions Regarding Enrollment 
The process to be followed with respect to enrollment is described below. 
3.1.1.1 
Criteria for Safety Concerns 
As a consequence of liver iron overload and frequent blood transfusions, patients in the target 
population may have fluctuations of AST and/or ALT that frequently exceed the reference 
ranges.  In recognition of this variability, for each of these enzymes, the criteria for deciding 
whether an individual patient’s increases during the current study is of concern will be set as 
follows: 
 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 19 of 58 
 
• For a patient whose baseline level is within the normal range, the criterion will be 
reaching a value of 5 times the ULN during the study. 
• For a patient whose baseline level is above the ULN, the criterion will be reaching a 
value of 5 times the baseline value during the study or 10 x ULN. 
All cases of patients meeting either of the above criteria at any point during the study must be 
reported to ApoPharma by the investigator within 24 hours of occurrence, using the sponsor’s 
SAE form.   
If at any time during the study a patient’s ALT and/or AST values reach a level of 10 x ULN, 
do the following: 
• If the patient is symptomatic and/or has any other clinically significant abnormal 
laboratory results, immediately withdraw the patient from the study. 
• If the patient is asymptomatic and has no other clinically significant abnormal 
laboratory results, interrupt treatment and obtain a confirmatory count the next day. 
• 
If the value is confirmed to be ≥10 x ULN: 
o 
Stop treatment, withdraw the patient and complete all end of study 
assessments scheduled for Day 28 
o 
Document the event and report it within 24 hours to ApoPharma 
o 
Monitor the patient daily until the elevated value returns to a level that is 
regarded as not clinically significant 
• 
If the confirmatory value is found to be < 10 x ULN, resume treatment as per 
protocol, and monitor liver enzyme levels within 3 days of resuming therapy. 
3.1.1.2  
Rules for Enrollment 
The rules that will be applied for enrolling patients in each group are described below, using 
the criteria provided in Section 3.1.1.1.  Decisions will be made by a safety committee 
whose composition is described in Section 8.  
Sites will enroll and start the dosing of patients in both groups. Once enrollment has 
reached 5 patients in either group, enrollment will be paused, the safety data of those 
5 patients will be reviewed by the safety committee after all 5 have completed at least one 
week of dosing, and further enrollment will depend on whether the findings are satisfactory 
or raise safety concerns. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 20 of 58 
 
If the first group to reach an N of 5 is Group A (low-dosage): 
• If there are no safety concerns after one week of dosing, the safety committee will 
issue approval for enrollment of all remaining patients in Group A and enrollment in 
Group B up to 5 patients. (The criteria for enrollment in Group B are described below.) 
• If 2 or more of the first 5 patients in Group A reach the criteria defined in Section 3.1.1.1,  
the committee will issue approval for enrollment of just 5 more patients in Group A, 
and enrollment in Group B will be put on hold. Dosing of the first 5 Group A patients 
will continue, and the committee will review the data of the 10 Group A patients once 
all of them have completed at least 1 week of dosing. 
o At this point, if there are no safety concerns, the committee will issue approval for 
enrollment of the final 5 patients in Group A and for enrollment of Group B to 
resume, as per the criteria described for that group. 
o If 4 or more of the 10 patients in Group A who have been dosed to date reach the 
criteria defined in Section 3.1.1.1, enrollment of additional patients in both groups 
will be put on hold, and the following processes are to be conducted:  
▪ 
Any patients who have reached the criterion and are symptomatic and/or 
have other associated abnormal laboratory values are to be withdrawn 
from the study. 
▪ 
Patients who did not reach the criterion and for whom there are no other 
safety concerns should continue dosing. 
▪ 
Patients who did reach the criterion but are asymptomatic and do not have 
any other associated abnormal laboratory values should continue dosing, 
but must have their enzyme levels monitored every 2 days: 
• 
If just one patient experiences a confirmed elevation of ALT and/or 
AST ≥10 x ULN, that patient is to be withdrawn from the study, but 
enrollment of the final 5 Group A patients may proceed.  
• 
If two or more patients experience a confirmed elevation of ALT 
and/or AST ≥10 x ULN, treatment is to be interrupted for all 
patients, and the safety committee must promptly meet to review all 
available safety data and recommend whether or not the study should 
continue.  
 
 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 21 of 58 
 
If the first group to reach an N of 5 is Group B (high-dosage): 
• If there are no safety concerns after one week of dosing, enroll all remaining patients in 
the study. 
• If 2 or more of the first 5 patients in Group B reach the criteria defined in Section 3.1.1.1, 
the committee will issue approval for enrollment of just 5 more patients in Group B.   
Dosing of the first 5 Group B patients will continue, and the committee will review the 
data of the 10 patients once all of them have completed at least 1 week of dosing.  
(Enrollment may continue in the meantime in Group A, provided the stopping criteria 
defined for that group are not met.) 
o 
At this point, if there are no safety concerns, the committee will issue approval for 
enrollment of the final 5 patients in Group B. 
o 
If 4 or more of the 10 patients in Group B who have been dosed to date reach the 
criteria defined in Section 3.1.1.1, enrollment of additional patients in Group B will 
be put on hold, and as the processes described below are to be conducted. 
(Enrollment may continue in the meantime in Group A, provided the stopping 
criteria defined for that group are not met.) 
▪ 
Any patients who have reached the criterion and are symptomatic and/or 
have other associated abnormal laboratory values are to be withdrawn 
from the study. 
▪ 
Patients who did not reach the criterion and for whom there are no other 
safety concerns should continue dosing. 
▪ 
Patients who did reach the criterion but are asymptomatic and do not have 
any other associated abnormal laboratory values should continue dosing 
but must have their enzyme levels monitored every 2 days: 
• If just one patient experiences a confirmed elevation of ALT and/or 
AST ≥10 x ULN, that patient is to be withdrawn from the study, but 
enrollment of the final Group B patients may proceed.  
• If two or more patients experience a confirmed elevation of ALT 
and/or AST ≥10 x ULN, treatment is to be interrupted for all 
patients, and the safety committee must promptly meet to review all 
available safety data and recommend whether or not the study should 
continue 
 
Repeat assessments to confirm laboratory results may be performed. The decision on whether 
to put the study on hold or terminate it will be made by the safety committee.   


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 22 of 58 
 
If a confirmed elevation of ALT and/or AST > 10 x ULN is experienced by two subjects in 
the same dosage group, a review of the data must immediately take place to decide whether 
or not the study should continue.  The investigator must report any occurrence of this to the 
sponsor within 24 hours of occurrence, using the sponsor’s SAE form. 
3.2 
Rationale for Study Design 
Study population: To date, four Phase I trials have been or are currently being conducted to 
assess the safety, tolerability, and pharmacokinetics of deferiprone delayed release tablets in 
healthy volunteers.  This study will be the first to look at the DR formulation in the population 
for which it is intended. It is possible that the rates of adverse events that were seen in healthy 
subjects would occur at different rates in patients, due to the different action of an iron chelator 
in iron-overloaded vs. non-iron-loaded recipients. 
Dosages:  Patients with systemic iron overload are usually prescribed deferiprone at a dosage 
ranging from 75 mg/kg/day to 100 mg/kg/day.  Dosages within both the upper half and the 
lower half of this range will be investigated, to determine if there is a dose effect on the 
adverse events that were seen in healthy subjects (due to tailoring of dosages to individual 
patient needs and to rounding, most potential subjects will not be on a dosage of 
Ferriprox that is exactly 75 mg/kg/day or exactly 100 mg/kg/day).  In all cases, the total 
daily dosage of deferiprone DR will be made to match that of Ferriprox IR as closely as 
possible. Since dosages will be rounded to the nearest 500 mg and body weights of participants 
will differ, some variability is unavoidable. 
Safety Precautions:  The findings from the first 5 participants to be enrolled in either dosage 
group will be assessed before enrollment can continue. Details are provided in Section 3.1.1. 
As a further precaution, alert events have been defined that will mandate extra monitoring or 
termination from the study in any patient in whom they are observed.  Information on alert 
events is provided in Section 4.5.1. 
Endpoints:  The endpoints are safety and acceptability.  No endpoints for efficacy have been 
included, as bioequivalence of deferiprone DR tablets to Ferriprox IR tablets over a 24-hour 
period has already been demonstrated. 
3.3 
Rationale for Selection of Doses 
For Ferriprox, dosages of 75 mg/kg/day and 100 mg/kg/day represent the most common 
starting dose and the maximum recommended dose, respectively, of the therapeutic dose 
range approved for patients with systemic iron overload.  The dosage groups in this study 
will be within either the upper half or the lower half of this range. 
The Phase I studies LA58-0118 and LA60-0118, conducted in healthy volunteers, both evaluated 
the maximum recommended dose of deferiprone (100 mg/kg/day) without the titration that is 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 23 of 58 
 
normally recommended for initiation of treatment in patients with iron overload. In both 
studies, following receipt of deferiprone DR, there were higher than expected percentages of 
subjects with GI events and elevated liver enzymes.  It is possible that starting the dosing 
directly at 100 mg/kg/day with no titration may have been a factor in the occurrence of both 
types of events. It is also known that healthy volunteers are more adversely impacted by an 
iron chelator in ways that iron-overloaded patients would not be.  That is, these events may 
prove to be less prominent in the latter since with them, deferiprone will rapidly bind to 
excess iron and will thus be less available for involvement in other biochemical reactions.  
As the maximum recommended dosage of deferiprone is essential in some patients, it is 
important to assess dosages at the high end of the range in the target population, with safety 
measures in place to ensure that participants are not placed at undue risk. In the case of liver 
enzymes, increases in ALT and AST are commonly observed in patients with transfusion-
dependent thalassemia, irrespective of deferiprone therapy, and thus the clinical significance of 
any increase needs to be evaluated in individual patients based on their medical history.   
Comparison of the low and high dosages will allow for assessment of a dose effect of 
deferiprone.  In healthy volunteers, in contrast to the elevated ALT and AST levels seen at 
100 mg/kg/day, no such concerns were observed in the earlier study LA45-0116, which 
employed a fixed dosage of 1500 mg b.i.d., the equivalent of about 20 mg/kg in an average-
weight (70 kg) person. There would be no purpose in assessing a sub-therapeutic dosage in 
patients, but it will be of interest to see if there are fewer or less severe liver enzyme 
elevations in the lower dosage group. 
4 
STUDY POPULATION 
4.1 
Number of Patients 
A total of 30 patients will be enrolled in this study, 15 in each dosing dosage group.   
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 ≥ 18 years. 
2. Diagnosis of thalassemia syndrome, sickle cell disease, or other disorder requiring a 
regular regimen of red blood cell transfusions. 
3. On a stable regimen (≥3 months) of Ferriprox tablets for the treatment of systemic iron 
overload. 
4. Absolute neutrophil count ≥1.5 x 109/L at screening. 
5. A record of at least 12 measured ALT and AST levels.  


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 24 of 58 
 
6. A female volunteer must meet one of the following criteria: 
• If of childbearing potential, have a negative pregnancy test result at screening.  In 
addition, she must: 
a. Agree to use an effective method of contraception according to local 
requirements, during the study and afterwards, OR 
b. Have undergone a tubal ligation (supporting evidence required), OR 
c. Abstain from heterosexual intercourse, OR 
d. Have a male sexual partner who has been sterilized (supporting evidence required) 
• 
Be of non-childbearing potential, defined as surgically sterile, having undergone 
complete hysterectomy or bilateral oophorectomy (supporting evidence required) or 
being in a menopausal state (at least 1 year without menses) 
 
7. Fertile heterosexual males and/or their partners must agree to use an effective method of 
contraception during the study and afterwards. 
8. All patients and/or their authorized legal representatives must provide signed and dated 
written informed consent prior to the first study intervention, and patients must be able to 
adhere to study restrictions, appointments, and evaluation schedules.  
4.3 
Exclusion Criteria 
Individuals will be excluded from enrollment if they meet any of the following criteria: 
1. Receipt of any iron chelator other than Ferriprox (i.e., combination therapy) in the last 3 
months, or planning to receive it at any time during the period of the study. 
2. ALT and/or AST value > 5 times the upper limit of normal (ULN) at screening  
3. Active case of hepatitis B or C at screening. 
4. Positive for HIV at screening. 
5. 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, gastroenterologic, 
respiratory, cardiovascular, endocrinologic, neurologic, or immunologic disease. 
6. Evidence of abnormal kidney function at screening (creatinine levels >2 x ULN). 
7. Myocardial infarction, cardiac arrest or cardiac failure within 1 year before screening/
baseline visit. 
8. Bowel disease causing malabsorption. 
9. History of allergy or sensitivity to the study product or related compounds or to other 
components of the formulation. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 25 of 58 
 
10. Receipt of any investigational products within the past 30 days or 5 half-lives (whichever 
is longer) preceding the first dose of study medication. 
11. 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. 
12. History of drug or alcohol abuse within the last 6 months. 
13. Presence of any medical, psychological, or psychiatric condition which in the opinion of 
the investigator would cause participation in the study to be unwise. 
14. Pregnant, breastfeeding, or planning to become pregnant during the study period. 
15. Identified as an investigator or other site staff directly affiliated with this study, or an 
immediate family member (spouse, parent, child, or sibling, whether biological or legally 
adopted) of either of the above. 
4.4 
Enrolment Violations 
The criteria for enrolment must be followed explicitly.  If there is inadvertent enrolment of 
patients who do not meet enrolment criteria, the investigator should consider withdrawing these 
individuals from the study. 
4.5 
Patient Withdrawal 
Patients have the right to withdraw from the study at any time and for any reason without 
consequence to future care by the investigator or study center. 
A patient may be withdrawn from the study at any time, at the discretion of the investigator, 
for any of the following reasons: 
• 
Medical or safety reasons considered significant by the patient and/or the investigator 
• 
Requirement for concomitant medication that might interfere with the evaluation of 
study treatment or may be contraindicated 
• 
Receipt of a rescue medication 
• 
Occurrence of other illnesses that might affect the patient’s further participation in 
the study or evaluation of study treatment 
• 
A protocol deviation that might interfere with study assessments, as judged by the 
investigator 
• 
Repetitive patient non-compliance with the protocol or with instructions of the 
investigator 
• 
Participation in another clinical trial at any time during the conduct of this study 
• 
Any other situation where, in the opinion of the investigator, continuation of the 
study would not be in the best interest of the patient 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 26 of 58 
 
A patient must be withdrawn from the study if any of the following conditions apply: 
• 
Pregnant or planning to become pregnant (see Section 7.1.4) 
• 
A confirmed ALT or AST value >10 x ULN (see Sections 4.5.1.1 and 7.1.1.8.1) 
• 
A confirmed ANC value < 0.5 x 109 (see Sections 4.5.1.2 and 7.1.1.8.2) 
• 
Occurrence of any adverse event characterized as life-threatening or disabling that is 
not associated with the patient’s condition 
• 
Termination of the study by the sponsor 
Patients who decide to withdraw participation in the study should always be contacted, if 
possible, in order to ask about the reason for withdrawal, whether any adverse events (AEs) 
occurred, and use of concomitant medications.  A withdrawn patient should return for an 
early termination visit and a follow-up visit. All investigational product and materials should 
be returned.  If any AEs occurred, the investigator must attempt to follow up the outcome 
until resolution. 
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 
Alert Events and Individual Stopping Rules 
Certain events are defined in this study as alerts, meaning that any occurrence must be 
carefully monitored, and in some cases may mandate withdrawal of a patient or even early 
termination of the study. 
4.5.1.1 Elevated Liver Enzymes 
A patient who reaches an ALT and/or AST value ≥10 x ULN at any time during the study is 
to be immediately withdrawn if he or she is additionally symptomatic and/or has any other 
clinically significant abnormal laboratory results. If there are no other signs of concern, a 
confirmatory count is to be obtained the next day.  If the value is confirmed, the patient is 
to be withdrawn; if it is not, the patient is to be closely monitored.  Details are provided in 
Section 3.1.1.1. 
4.5.1.2 Neutropenia 
A sudden drop in absolute neutrophil count (ANC) is a reaction that has been associated with 
deferiprone treatment and is considered an adverse event of special interest.  ANC values 
will be monitored throughout the study.  For a case of mild, moderate, or severe neutropenia 
to be confirmed, there must be 2 consecutive counts of ANC, a maximum of 3 days apart, 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 27 of 58 
 
that are both less than a specific value. If at any time, a patient’s confirmed ANC level is 
found to be below < 1.5 x 109/L, the investigator is to do the following: 
• 
Mild neutropenia:  If the confirmed ANC is < 1.5 x 109/L but ≥1.0 x 109/L, continue 
treatment without interruption, but monitor ANC every 2 days until resolution. 
• 
Moderate neutropenia: If the confirmed ANC is < 1.0 x 109/L but ≥ 0.5 x 109/L, 
interrupt treatment and monitor ANC every 2 days until resolution. The patient should 
re-initiate treatment once the event is resolved. If ANC is still < 1.5 x 109/L after 14 
days, withdraw patient from the study and monitor until resolution of the event. 
• 
Severe neutropenia / agranulocytosis: If a single ANC is < 0.5 x 109/L, immediately 
interrupt treatment without waiting for confirmation of the count and obtain a second 
measurement the following day.  If the second ANC is still < 0.5 x 109/L, permanently 
withdraw the patient from the study and follow the procedures for the management 
of agranulocytosis. 
Details on the management of each category of neutropenia are provided in Section 7.1.1.8.2. 
4.5.1.3 Infection 
If a patient reports any symptoms indicative of infection such as fever, sore throat, or flu-like 
symptoms, interrupt treatment immediately and obtain an ANC measurement, and monitor 
ANC more frequently; every 2 days if it is below <1.5 x 109/L but ≥ 0.5 x 109/L.  Therapy 
can be re-initiated once all symptoms have been resolved and it is deemed safe by the 
investigator.  (If ANC is found to be above 1.5 x 109/L, treatment can be continued if the 
investigator assesses the patient and considers continuation to be safe. Treatment should be 
interrupted in any case of fever of 38.5°C or greater.)  
4.5.2 
Follow-up of Patient Withdrawal Due to Pregnancy 
All females of childbearing potential must have a negative serum pregnancy test prior to 
study entry and prior to first administration of the study drug, and must agree to use an 
approved method of contraception (as defined in inclusion criterion #5) throughout the 
course of the trial.  If a patient does become pregnant, the investigator must do the following 
upon becoming aware of the pregnancy: 
• Ensure that the study medication is stopped immediately 
• Inform the sponsor via the pregnancy report form 
• With the patient’s consent, follow the pregnancy closely, and provide reports to the 
sponsor until delivery or other resolution 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 28 of 58 
 
A male patient must inform the investigator if his female partner becomes pregnant during 
the trial or within 1 month following the last dose of study medication. As with the 
pregnancy of a female subject, the site must inform the sponsor and, if the partner consents, 
follow the pregnancy and provide the sponsor with a report on its outcome. 
4.5.3 
Replacement of Patients Who Withdraw 
Patients who are withdrawn from the study will not be replaced. 
4.6 
Prior and Concomitant Therapies 
To be considered for enrollment, patients cannot be taking any iron chelator other than 
Ferriprox.  Those who are on a combination regimen of Ferriprox and another product are not 
eligible. 
In addition, during the trial, they may not take any other investigational product, or any drugs 
that are known to cause agranulocytosis. Medications that are being taken on a stable regimen 
and that are considered necessary for the subject’s welfare may continue to be taken, at the 
discretion of the investigator.  All medications (including study product, herbal medications, 
and over-the-counter medications) and nutritional supplements taken from 3 months prior to 
screening up to the end of the study (Day 28 or early termination) must be reviewed by the 
investigator and recorded in the source document and in the appropriate section of the eCRF. 
4.7 
Rescue Medication 
Patients will be assigned to Group A or Group B based on the total daily dosage of Ferriprox 
they have been taking for the last 3 months (i.e., closer to 75 mg/kg/day or closer to 100 
mg/kg/day) and must remain on their assigned dosage for the duration of the study.  If it is 
determined during the study that a change in dosage or the addition of another chelator is 
required to control iron load, that patient will be withdrawn from the trial. 
5 
STUDY PROCEDURES 
The procedures and assessments to be conducted at each study visit are shown in Table 5.1.


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 29 of 58 
 
Table 5.1 
Table of study procedures 
Study Procedure 
Screening 
Day -14 to -1 
Baseline 
Day 0 
Day 3 
(±1 day) 
Day 7 
(±1 day) 
Day 14 
(±2 days) 
Day 21 
(±2 days) 
Day 28 
(±2 days) or early 
termination 1 
Informed consent 
X 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
Medical history 2 
X 
 
 
 
 
 
 
Medication history 
X 
X 
 
 
 
 
 
Eligibility criteria 
X 
V 
 
 
 
 
 
Biochemistry 3 
X 
 
X 
X 
X 
X 
X 
Hematology 4 
X 
X 
 
X 
X 
X 
X 
Coagulation 5 
X 
 
 
 
 
 
X 
Serology 6 
X 
 
 
 
 
 
 
Urinalysis 7 
X 
 
 
 
 
 
X 
Physical examination 8 
X 
 
 
 
 
 
X 
Vital signs 
X 
 
 
 
 
 
X 
Serum pregnancy test 9 
X 
 
 
 
 
 
X 
Dispense study medication 
 
X 
 
 
 
 
 
Dosing  
 
Twice-daily from Day 1 to Day 28 
Collect study medication containers 
 
 
 
 
 
 
X 
Treatment compliance 
 
 
 
 
 
 
X 
Medical events 
X 
X 
 
 
 
 
 
Adverse events/ serious adverse events 
 
 
Throughout the study 
Concomitant medications 
 
 
Throughout the study 
Acceptability questionnaire 
 
 
 
 
 
 
X 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 30 of 58 
 
V:  Verify 
 
1. 
If deemed necessary, patients with ongoing adverse events may be asked after the last dose to provide further blood samples 
until resolution 
2. 
Medical history is to include a record of at least 10 measured ALT and AST levels  
3. 
Biochemistry:  Total protein, gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), sodium, potassium, chloride, 
glucose, bilirubin (total, direct, and indirect), alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, blood 
urea nitrogen, calcium, creatinine, uric acid, alkaline phosphatase, amylase, serum ferritin, and blood iron 
4. 
Hematology:  Hemoglobin, total WBC count, ANC, MCV, and platelet count 
5. 
Coagulation:   Prothrombin Time (PT), Partial Thromboplastin Time (PTT), and International Normalized Ratio (INR) 
6. 
Serology:   HIV Ag/Ab Combo, hepatitis B (HBsAg (B)), and hepatitis C (anti-HCV (C))  
7. 
Urinalysis:  Color, appearance, specific gravity, pH, leukocyte, protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen. 
Microscopic examination must be performed if dipstick test is outside the reference range for leukocyte, blood, nitrite or 
protein.  (Note:  for patients with sickle cell disease, samples are to be sent for microscopy if there is blood in the urine or three 
or more “plus signs” for protein.)  
8. 
At screening, a full physical examination will be performed, including measurement of weight.  At Day 28 (or early termination), 
only a symptom-oriented examination will be performed. 
9. 
Pregnancy testing (females only):  Beta-HCG qualitative serum pregnancy test 
 
 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 31 of 58 
 
5.1 
Visit Procedures 
Details on the procedures to be carried out at each study day are provided below. For details 
of the safety assessments, see Section 7.1. 
Note:  The procedures at screening, baseline, and Day 28 must be conducted at the study site.  
The procedures on all other study days may be handled via a telephone call (for collection of 
information on adverse events and concomitant medications) and at a local laboratory (for 
collection of blood samples for safety assessments).  If a patient chooses to go to a local 
laboratory, the same one must be used throughout the entire study. 
Screening Visit (Day -14 to Day -1) 
• Explain the study to the prospective participant, and obtain written informed consent 
• Collect demographic information 
• Collect medical history  
• Collect history of the last 12 or more ALT and AST results 
• Collect information on prior and concomitant medications including current chelation 
therapy 
• Collect blood samples for assessment of the following: 
o 
Biochemistry 
o 
Hematology 
o 
Coagulation 
o 
Serology 
o 
Pregnancy testing (women of childbearing potential only) 
• Collect a urine sample for urinalysis. Microscopic examination must be performed if 
dipstick test is outside the reference range for leukocyte, blood, nitrite or protein.  (Note:  
for patients with sickle cell disease, samples are to be sent for microscopy if there is 
blood in the urine or three or more “plus signs” for protein.)  
• Perform a physical examination (to be completed by the principal investigator or a 
qualified delegate), including weight 
• Measure vital signs (heart rate, blood pressure, and body temperature) 
• Record any medical events that have occurred after the consent form was signed 
Patients who are found to be eligible will complete the procedures below. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 32 of 58 
 
Baseline Visit (Day 0) 
• Verify that the patient has met all inclusion/exclusion criteria 
• Collect information on prior and concomitant medications 
• Collect a blood sample for hematology 
• Collect any medical events that have occurred since the previous visit 
• Conduct contraceptive counseling if applicable 
• Dispense an appropriate supply of deferiprone DR tablets at the specified dosage (see 
Section 6.1.1), along with instructions on how to take them.  The first dose is to be 
taken the next day, in the morning.  Patients are to be instructed to always take the 
medication with food. 
• Provide patient with an emergency card with contact information, and explain that it is 
to be carried at all times 
• Instruct patient to do the following: 
o Keep a record of all dosing, any concomitant medications that are taken, and any 
health problems that occur 
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 final visit, bring back the completed notes plus all medication containers, 
whether empty, partly used, or unopened 
o In the event of a decision to withdraw from the study before completion, return 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 
Day 3 (±1 day) 
• Collect a blood sample for assessment of biochemistry (site visit or local laboratory) 
• Collect information on concomitant medications (site visit or telephone call) 
• Collect information on any adverse events that have occurred since the previous visit 
(site visit or telephone call) 
• Remind the patient to keep a record of all dosing, any concomitant medications that 
are taken, and any health problems that occur 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 33 of 58 
 
Days 7, 14, and 21 (±1 day for Day 7, ±2 days for the remainder) 
• Collect blood samples for assessment of the following (site visit or local laboratory): 
o Biochemistry 
o Hematology 
• Collect information on any adverse events that have occurred since the previous 
contact (site visit or telephone call) 
• Collect information on concomitant medications (site visit or telephone call) 
• Remind the patient to do the following: 
o Keep a record of all dosing, any concomitant medications that are taken, and 
any health problems that occur 
o Day 21 only:  Bring back the completed notes plus all medication containers, 
whether empty, partly used, or unopened 
Day 28 (±2 days) or Early Termination 
• Collect blood samples for assessment of the following: 
o Biochemistry 
o Hematology 
o Coagulation 
o Pregnancy testing (women of childbearing potential only) 
• Collect a urine sample for urinalysis. Microscopic examination must be performed if 
dipstick test is outside the reference range for leukocyte, blood, nitrite or protein. 
(Note:  for patients with sickle cell disease, samples are to be sent for microscopy if 
there is blood in the urine or three or more “plus signs” for protein.)  
• Perform a symptom-oriented physical examination (to be completed by the principal 
investigator or a qualified delegate) 
• Measure vital signs (heart rate, blood pressure, and body temperature). 
• Review information that has been noted by the patient about doses taken, concomitant 
medications, and adverse events  
• Collect medication containers 
• Verify treatment compliance through tablet count and review of information in the 
patient’s notes 
• Collect information on any adverse events that have occurred since the previous contact 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 34 of 58 
 
• Collect information on concomitant medications 
• Administer questionnaire on the acceptability of deferiprone DR vs. that of Ferriprox  
 
If deemed necessary, patients with ongoing laboratory-related events may be asked after the 
last dose to provide further blood samples until resolution. 
5.2 
Method of Assignment to Treatment 
All patients must have been on a stable regimen of Ferriprox IR tablets for at least the 
past 3 months, and will be assigned to take deferiprone DR at approximately the same 
daily dosage that they are currently on.  Those who are presently on Ferriprox at a dosage 
closer to 75 mg/kg/day will be assigned to Group A, and those who are presently on 
Ferriprox at a dosage closer to 100 mg/kg/day will be assigned to Group B.  In both cases, the 
total dosage of deferiprone DR will be as close as possible to that of Ferriprox, but divided 
b.i.d. instead of t.i.d. 
5.3 
Blinding Procedures 
Not applicable.  This study is open label. 
5.4 
Allocation of Patient Numbers 
After provision of informed consent, 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 are assigned sequentially for each individual enrolled at that site.  
For example, if site #1 enrolls 8 patients, the ID numbers will be 001001 to 001008.  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) the patient will keep a daily record of the 
number of tablets taken, and 2) at Day 28, the investigator or a delegate will inspect the 
medication containers, whether empty, partly used, or unopened, and will check the number 
of tablets remaining.  Compliance will be calculated by the number of tablets taken divided 
by the number of tablets prescribed.  Any discrepancies must be discussed with the patient 
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 with the patient at each visit or during each telephone call. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 35 of 58 
 
If the number of returned tablets is less than it should be but the patient reports having 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., tablets were accidentally 
spoiled and could not be ingested), 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 7.1.1.8). 
6 
STUDY TREATMENTS 
All patients will be treated with deferiprone delayed release 1000 mg tablets at approximately 
the same total daily dosage that they had been prescribed for Ferriprox . 
6.1 
Investigational Product 
Deferiprone delayed release (DR) 1000 mg is a white to off-white, capsule-shaped, beveled 
edge, biconvex coated tablet, engraved with “FPX” score “DR” on one side and “APO” score 
“1000” on the other side. The tablets are manufactured by Apotex Inc., and will be supplied 
to the clinical site by ApoPharma Inc. 
6.1.1 
Dosage Form and Mode of Administration 
Deferiprone DR tablets are to be taken twice a day, approximately 12 hours apart.  The route 
of administration is oral.  All patients will take approximately the same total daily dosage 
that they were taking three times a day with Ferriprox IR, whether that dosage was closer to 
75 mg/kg/day (Group A) or closer to 100 mg/kg/day (Group B). The dosage for each subject 
will be rounded to the nearest multiple of 500 mg. The tablets are scored in a way that they 
can be split into two halves that maintain the release characteristics of the whole tablets. 
6.1.2 
Precautions for Use 
The tablets are to be kept in a tightly closed bottle in order to protect them from moisture. 
The bottles are to be kept out of the sight and reach of children. 
6.2 
Packaging and Labeling 
The tablets are packaged in 75 cc opaque, white, round high-density polyethylene (HDPE) 
bottles with induction seals and child-resistant caps. The bottles contain 50 tablets and a 
desiccant bag, and will bear a label whose content is in accordance with all applicable 
regulatory requirements. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 36 of 58 
 
6.3 
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 site personnel must use a temperature log to facilitate daily recording 
of the temperature of the storage facility. Temperature deviations must be immediately 
reported to the sponsor for investigation and determination of impact on the study medication. 
Each shipment of investigational product will include shipment documents, which the 
investigator or a designate must complete as per the provided instructions and retain the 
original copies in the Investigator Trial File. 
6.4 
Product Accountability 
It is the responsibility of the investigator to ensure that all study drug received at the study 
center is inventoried and accounted for throughout the study. Records of receipt, storage and 
administration of the study drug supplied must be maintained, and drug accountability will be 
performed. At the conclusion of the study, a final inventory must be performed by the 
investigator or delegate. The sponsor will be responsible for determining the specific 
conditions for destruction of unused product. 
6.5 
Replacement Doses 
Patients who report that their medication has been lost or damaged will need to return to the 
study site to receive replacement tablets. 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. 
6.6 
Disposition of Unused Product 
All investigational product (IP) 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.  Destruction certificates for the completed destructions (or proof that IP was sent 
for destruction) will be obtained.  The destruction may take place only after written approval 
by the sponsor. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 37 of 58 
 
7 
MEASUREMENTS AND EVALUATIONS 
7.1 
Safety Measurements 
7.1.1 
Medical Events, Adverse Events, and Serious Adverse Events 
7.1.1.1 
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. 
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), 
ECG, or other assessments (e.g., vital signs) that are not part of a larger medical 
condition already recorded as an AE and which are judged by the investigator to be 
clinically significant. The investigator should exercise medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. 
 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 38 of 58 
 
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 
7.1.1.2 
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 
after the last dose. 
AEs and SAEs that are related to the underlying medical condition for which the patient 
enrolled in the clinical trial will be recorded separately from others. 
Patients will be instructed to report any MEs/AEs to the investigator or a delegate.  In 
addition, at site visits and telephone calls, the investigator will solicit information about the 
occurrence of MEs/AEs through open-ended, non-leading verbal questions such as: 
• How are you feeling? 
• Have you had any medical problems since the last visit? 
• Have you taken any new medications, other than that provided in this study, since the 
last visit? 
Based on the patient’s response to these questions, the investigator or delegate should ask 
additional questions relevant to the specific complaint, such as: 
• How severe is/was the symptom? 
• How often did the symptom occur? 
• How long did the symptom last? 
The patient should also be questioned about any previously reported AEs that have not 
resolved. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 39 of 58 
 
The investigator will evaluate all AEs/MEs for their relationship to the investigational 
product (Section 7.1.1.3), intensity (Section 7.1.1.4), and seriousness (Section 7.1.1.5), and 
will document any measures taken to address the event.  There should be an attempt to 
establish a diagnosis of the AE based on signs, symptoms, and/or other clinical information. 
Wherever possible, a diagnosis should be documented, rather than the individual signs/
symptoms. All information is to be clearly recorded in the source documents. 
If the dosage of study drug is reduced or treatment is discontinued as a result of an AE, the 
circumstances leading to such reduction or discontinuation must be clearly documented. 
All AEs must be followed until resolution, the condition stabilizes, the event is otherwise 
explained, or the patient is lost to follow-up. The investigator is responsible for ensuring that 
follow-up includes any supplemental investigations that are needed to elucidate the nature 
and/or causality of the AE as completely as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 
7.1.1.3 
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. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 40 of 58 
 
7.1.1.4 
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 eCRF. To maximize consistency in assessment, 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) scale is to be used. 
7.1.1.5 
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. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 41 of 58 
 
• 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. 
7.1.1.6 
Reporting of Serious Adverse Events 
All SAEs occurring up to 30 days following completion of or discontinuation from the study 
must be reported to the sponsor, regardless of whether they are suspected of having a causal 
relationship with the study drug. Any SAEs for which the investigator does suspect a causal 
relationship must be reported to the sponsor regardless of the time elapsed since the last dose 
of the study drug. 
Patients will be instructed to report SAEs to the investigator within 24 hours, by telephone. 
In turn, the investigator must report all SAEs to the sponsor within 24 hours of occurrence 
or notification by the patient, using the sponsor’s SAE form. The sponsor will provide 
contact information for reporting SAEs. An assessment of causality must be provided at the 
time of the initial report. In the case of an SAE that is fatal or life-threatening, 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. 
7.1.1.7 
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 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 42 of 58 
 
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. 
7.1.1.8 
Adverse Events of Special Interest 
7.1.1.8.1 
Elevated Liver Enzymes 
Due to the rate of elevated levels of ALT and AST seen in healthy volunteers in study 
LA60-0118, particular attention will be paid to these measures in the current study to 
determine if their rates are higher than expected in patients with systemic iron overload.  
Investigators are to review all laboratory reports promptly, and are to report any increases in 
ALT or AST that meet the criteria described in Section 3.1.1 to the sponsor within 24 hours 
of occurrence, using the sponsor’s SAE form. 
7.1.1.8.2 
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: 
A confirmed ANC < 1.5 x 109/L but ≥1.0 x 109/L  
Moderate: 
A confirmed ANC < 1.0 x 109/L but ≥ 0.5 x 109/L 
Severe / 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 eCRF 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, patients will be advised to immediately report any 
symptoms indicative of infection such as fever (≥ 38.5°C), sore throat, and flu-like symptoms 
at any time during treatment or during the first week following treatment. They will be 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 43 of 58 
 
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 and moderate neutropenia: 
A patient who develops mild neutropenia is to continue treatment without interruption, but 
ANC is to be monitored every 2 days until resolution.  
A patient who develops moderate 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 
• Advise patient 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 the following day. 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 
• Notify ApoPharma Inc. using the SAE form. 
The following additional measures describe a suggested medical management and 
monitoring: 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 44 of 58 
 
• 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) 
• 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 
7.1.1.8.3 
Infections 
If a patient develops fever (≥ 38.5°C) or symptoms and signs of that indicate systemic 
infection (e.g., chills, sore throat, mouth ulcers) during the study, deferiprone must be 
interrupted immediately, and neutrophil count should be obtained and monitored more 
frequently; every 2 days if ANC is <1.5 x 109/L.  Therapy with deferiprone can be 
re-initiated once all symptoms have been resolved and it is deemed safe by the investigator. 
7.1.2 
Laboratory Measurements 
Samples for laboratory safety assessments will be taken at the time points indicated below.   
Biochemistry:  Total protein, gamma-glutamyl 
transferase (GGT), lactate dehydrogenase (LDH), 
sodium, potassium, chloride, glucose, bilirubin 
(total, direct, and indirect), alanine 
aminotransferase (ALT), aspartate 
aminotransferase (AST), albumin, blood urea 
nitrogen, calcium, creatinine, uric acid, alkaline 
phosphatase, amylase, serum ferritin, and blood 
iron 
Screening and Days 3, 7, 14, 21, 
and 28 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 45 of 58 
 
Hematology:  Hemoglobin, total WBC count, 
ANC, MCV, and platelet count 
Screening, baseline, and Days 7, 14, 
21, and 28 
Coagulation:   Prothrombin Time (PT), Partial 
Thromboplastin Time (PTT), and International 
Normalized Ratio (INR) 
Screening and Day 2 
Serology:   HIV Ag/Ab Combo, hepatitis B 
(HBsAg (B)), and hepatitis C (anti-HCV (C))  
Screening 
Urinalysis:  Color, appearance, specific gravity, 
pH, leukocyte, protein, glucose, ketones, bilirubin, 
blood, nitrite, urobilinogen. Microscopic 
examination must be performed if dipstick test is 
outside the reference range for leukocyte, blood, 
nitrite or protein.  (Note: For patients with sickle 
cell disease, samples are to be sent for microscopy 
if there is blood in the urine or three or more “plus 
signs” for protein.)  
Screening and Day 28 
 
Pregnancy testing:  Beta-HCG qualitative serum 
pregnancy test 
Screening and Day 28 
 
Notes: 
• With the exception of hematology, laboratory results obtained at screening will be 
treated as the baseline values. 
• There will be a window of ±1 day for assessments done at Days 3 and 7, and of 
±2 days for assessments done at Days 14, 21, and 28. 
• The investigator may increase the frequency of safety evaluations if deemed 
appropriate for assessment of any clinically significant adverse event.  In the case of 
increases in liver enzymes that meet the criteria for being considered a safety concern, 
the patient is to be followed until resolution of the event, beyond Day 28 if necessary. 
• If a patient withdraws from the study, the End of Study procedures are to be 
performed at an early termination visit. 
 
Investigators must document their review of each laboratory report by signing or initialing 
and dating it. Any laboratory values that fall outside a clinically accepted range, or values 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 46 of 58 
 
that differ significantly from previous values, must be marked by the investigator as either 
“CS” (clinically significant) or “NCS” (not clinically significant).  Any that are marked as 
CS must be further explained and documented as an AE. 
7.1.3 
Other Safety Measurements 
7.1.3.1 
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. A 
complete examination will be performed at screening, and a symptom-oriented examination 
will be performed at Day 28. Any abnormalities noted prior to the first dose of study 
medication will be recorded as either medical history or a medical event (depending on time 
of occurrence), while any that are noted at the end of the study will be recorded as AEs. 
Body weight (without shoes) will be measured at screening only. 
7.1.3.2 
Vital Signs 
Resting heart rate, resting blood pressure, and body temperature will be taken.  Blood 
pressure should always be measured in the sitting position, after a minimum 3-minute resting 
period, and using the same arm each time if possible. Systolic and diastolic blood pressures 
are to be recorded from one measurement. 
Vital signs will be measured at screening and Day 28. Clinically significant out-of-range 
values for vital signs will be reported as AEs (see Section 7.1.1.1). 
7.1.3.3 
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 eCRFs, 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 or telephone 
contact. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 47 of 58 
 
7.1.4 
Procedures in Case of Pregnancy 
If a patient becomes pregnant during the course of the study, she will be immediately 
withdrawn. The pregnancy will be immediately reported to the sponsor, and information 
about the pregnancy is to be recorded on the appropriate form and in the patient’s eCRF. The 
patient will be followed to determine the outcome, and any premature termination of the 
pregnancy will be reported.  Upon delivery, the child will be examined for any adverse 
symptoms or congenital anomalies. Follow-up information on the status of the mother and 
child will be forwarded to the sponsor no later than 8 weeks following the delivery. 
If the partner of a male patient becomes pregnant during the course of the study, or if the 
fetus may have been exposed to the patient’s study products either through maternal 
exposure or through transmission via semen following paternal exposure, the pregnancy must 
be reported to the sponsor, and information about the pregnancy must be recorded on the 
appropriate form and in the patient’s eCRF.  If the partner provides consent for follow-up of 
the pregnancy, she will be followed until the delivery of the child, and information on the 
delivery status of the mother and child will be forwarded to the sponsor no later than 8 weeks 
following the delivery date. 
Any SAE occurring as a result of a post-study pregnancy that the investigator believes may 
have been caused by the study product or by a protocol procedure will be reported to the 
sponsor as described in Section 7.1.1.6. 
7.2 
Acceptability Measurements 
On Day 28, following completion of study treatment, patients will be asked what their 
preference is between the two formulations (Ferriprox IR vs. deferiprone DR) with respect to 
scheduling, ease of administration, and tolerability.  The questionnaire is provided in 
Appendix 1.   
8 
STUDY COMMITTEES 
A safety committee will be set up that is composed of representatives from ApoPharma Inc. 
(the Vice President of Medical Affairs, the Director of Medical Safety, and the Director of 
Clinical Research) and the principal investigators.  Other experts may be included as needed. 
This committee will review the available safety data at specified time points, with a 
particular emphasis on the number of patients with ALT and/or AST levels that meet the 
criteria described in Section 3.1.1.1, to confirm if enrollment may continue. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 48 of 58 
 
9 
STATISTICAL ANALYSIS 
SAS Windows version 9.3 or higher will be used for statistical analysis. The safety population, 
defined in Section 9.3.1, will be the primary population for this study.  
The continuous and discrete variables for safety data will be summarized with descriptive 
statistics (mean, median, standard deviation, minimum, and maximum) and frequency tables, 
respectively, at each assessment. 
9.1 
Endpoints 
9.1.1 
Primary Endpoint 
The primary endpoint is the incidence of any post-dose occurrence of increases in ALT 
and/or ALT levels that meet one of the criteria for being considered a safety concern.  The 
safety criteria are: 
• 
For a patient whose baseline level is within the normal range, the criterion will be 
reaching a value of 5 times the ULN during the study. 
• 
For a patient whose baseline level is above the ULN, the criterion will be reaching a 
value of 5 times the baseline value during the study or >10 x ULN.  
9.1.2 
Secondary Endpoints 
Secondary endpoints are as follows: 
• The assessment of tolerability will be based on the incidence of gastrointestinal (GI) 
distress reported by patients during the study. 
• The assessment of acceptability will be based on the number of patients who indicate 
that they prefer the DR formulation over Ferriprox IR after considering their 
preference with respect to scheduling, ease of administration, and tolerability. 
9.2 
Determination of Sample Size and Study Power 
This is the first study of the safety, tolerability, and acceptability of deferiprone DR tablets in 
patients with systemic iron overload. No formal power calculation can be performed. It is 
believed that the data that will be obtained in this study will be adequate to evaluate the 
effect of the DR formulation on liver enzymes. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 49 of 58 
 
9.3 
Study Populations 
9.3.1 
Safety Population 
The primary analysis population used in this study will be the safety population, which will 
include all patients who received at least one dose of deferiprone DR tablets. 
9.3.2 
Per Protocol Population 
The per protocol population, which includes all patients who completed the study without 
major study deviations, will be the secondary population for the assessment of the primary 
endpoint. 
9.4 
Data Analysis Plan 
9.4.1 
Planned Analyses 
9.4.1.1 
Patient Disposition and Drug Exposure 
The number of patients who were exposed to the study medication, who completed the study, 
and who withdrew from the study will be presented, along with reasons for withdrawals. 
9.4.1.2 
Patient Characteristics 
Patients characteristics 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). 
9.4.1.3 
Analysis of Safety 
The Clopper-Pearson 95% confidence interval (CI) of the incidence of post-dose levels of 
ALT or AST that meet the criterion for being considered a safety concern will be calculated 
for each dosage group. Similarly, the Clopper-Pearson 95% CI of the incidence of GI distress 
reported by patients during the study will also be calculated. Other AEs will be summarized 
by using frequency tables. The incidence of abnormal data for safety measures will be 
presented for each dosage group.  
9.4.1.4 
Analysis of Acceptability 
For each dosage group, frequency tables will be used to summarize the response to each 
question of the questionnaire in Appendix 1 on treatment acceptability between Ferriprox IR 
vs. deferiprone DR.  Based on the response to the question on overall preference for one 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 50 of 58 
 
formulation or the other (Question #4), a one-sample proportion test will be used to test if the 
overall preference of deferiprone DR is greater than 0.5 for each dosage group. 
9.4.2 
Interim Analyses 
No interim analysis is planned. 
9.5 
Criteria for Evaluability of Patient Data 
All patients who received at least one dose of study product will be eligible for evaluation of 
safety. 
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. Trained users 
will access the system via a secured gateway. Users will be only authorized to access data for 
their study site. Data will be entered directly into the system from the source documents in 
lieu of the paper CRFs. On-line and off-line edit checks will be used to prompt the user to 
provide clean and accurate data. Clinical Data Management will code and monitor the data 
for accuracy. The data will be coded using the 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 (Regulatory Authorities/Quality Assurance); 
“read only” access will be provided to avoid unintentional corruption of the database. 
The database will be backed up daily. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 51 of 58 
 
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. 
11 
MONITORING, AUDITS, AND INSPECTIONS 
11.1 
Source Documents 
The investigator or delegate will maintain adequately detailed source documents supporting 
significant source data for each patient. Source data are defined as all information in original 
records and/or certified copies of original records of clinical findings, observations, or other 
activities in a clinical study that are necessary for the reconstruction and evaluation of the 
study: e.g., medical history, physical examination, laboratory results, and x-ray or ultrasound 
results. The investigator will also retain all printouts/reports of tests or procedures performed 
as a requirement of the study. All source data that is printed on thermal paper, including 
laboratory printouts and ECGs scans, must be photocopied, initialed, and dated as authentic 
equivalents to the thermal paper documents to enable extended retention time. 
The source documents must be available at the time of an audit; a site visit from the sponsor, 
sponsor representatives, or IRB/IEC; and a regulatory authority inspection. 
11.2 
Monitoring 
Monitoring of the investigational sites will be conducted by the sponsor or contracted to a 
qualified CRO.  The sponsor will determine the extent, nature, and frequency of on-site visits 
that are needed to ensure that the study is being conducted in accordance with the approved 
protocol (and any amendments), GCP, and all applicable regulatory requirements. At site 
visits, the monitor will, as required, assess the progress of the study; check that the study data 
chosen for verification are authentic, accurate, and complete; verify that the safety and rights 
of patients are being protected; compare original documents with data entered into the study 
database; and identify any issues and address their resolution. 
The investigator agrees to allow the monitor(s) direct access to all relevant documents, and to 
allocate his/her time and the time of staff to discuss findings, corrective actions and any 
relevant 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. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 52 of 58 
 
11.3 
Audits and Inspections 
In accordance with the principles of ICH E6 Guideline for Good Clinical Practice, the study 
site may be inspected by regulatory authorities and/or audited by ApoPharma Quality 
Assurance (QA) or their designates. The investigator and relevant clinical support staff will 
be required to be actively involved in audits and inspections, including staff interviews, and 
to make all necessary documentation and data available upon request. 
During the course of the study and/or after it has been completed, one or more investigator 
site audits may be undertaken by auditors from ApoPharma QA or delegates. The purpose of 
these audits is to determine whether or not the study is being/has been conducted and monitored 
in compliance with recognized ICH E6 Guideline for Good Clinical Practice, protocol and 
approved amendment requirements, applicable local SOPs, and local laws and regulations. It 
is the responsibility of the investigator and site staff to promptly address, by coordinating 
with ApoPharma Clinical Research, any deficiencies stemming out of regulatory inspections 
and ApoPharma QA or delegate audits, and to ensure that agreed-upon corrective and 
preventive actions are implemented as soon as possible. 
An inspection by any regulatory authority may occur at any time during or after completion 
of the study. If an investigator is contacted by a regulatory authority for the purpose of 
conducting an inspection or to discuss any compliance issues, he/she is required to contact 
ApoPharma Clinical Research immediately. 
11.4 
Site Closure 
Upon completion of the study, the investigator must conduct the following activities, when 
applicable: 
• Return all study data and equipment to the sponsor 
• Complete data clarifications and/or resolutions 
• Ensure that drug accountability is completed and that unused medication is either 
destroyed or returned to the sponsor, as instructed 
• Review site study records for completeness 
 
The sponsor reserves the right to temporarily suspend or prematurely discontinue this study 
at any time and for any reason. If such action is taken, the sponsor will discuss this with the 
investigator (including the reasons for taking such action) at that time. The sponsor will 
promptly inform all other investigators conducting the study if the study is suspended or 
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 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 53 of 58 
 
applicable regulations, the investigator must inform the IRB/IEC promptly and provide the 
reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the sponsor. In 
addition, the site must conduct final disposition of all unused study medication in accordance 
with the study procedures. 
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
11.5 
Retention of Records 
In accordance with applicable regulatory requirements, following closure of the study, the 
investigator will maintain a copy of all site study records in a safe and secure location. The 
sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. 
12 
ETHICAL CONSIDERATIONS 
12.1 
Informed Consent 
Prior to entering a patient into the study, the investigator or a designate must obtain written 
informed consent from the patient and/or where applicable the patient’s legally authorized 
representative, according to the sponsor’s procedures and as described in the Declaration of 
Helsinki, the Federal Food, Drug and Cosmetic Act, and U.S. applicable Code of Federal 
Regulations Title 21, Part 50.  The investigator will ensure that the patient and/or legal 
representative is given full and adequate verbal and written information about the nature, 
purpose, and possible risks and benefits of the study, and is given ample opportunity to ask 
questions and to discuss the study with family members. The investigator must make a 
conscientious effort to be fully satisfied that the patient and/or legal representative has truly 
understood that for which the consent has been given. The patient and/or the legal 
representative must be notified that he/she is free to discontinue participation in the study at 
any time, and that such withdrawal will not affect present or future care. In the case of a 
minor or an incapacitated adult who is capable of forming an opinion and assessing the study 
information, the investigator must ensure that this individual’s decision to not participate or to 
withdraw from the study will be respected even if consent is given by the legal representative. 
The sponsor will provide a model version of the informed consent form to the sites as a 
separate document. Each site may then revise this version according to the requirements of 
its individual IRB/IEC. 
The patient and/or legal representative will sign and date the consent form prior to the first 
study intervention, and will be provided with a copy of the signed and dated ICF. Should a 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 54 of 58 
 
protocol amendment be made, the ICF may need to be revised to reflect the changes to the 
protocol. The investigator must then ensure that the revised ICF is signed by all patients 
currently enrolled as well as those subsequently entered in the study. 
12.2 
Institutional Review Board/Independent Ethics Committee 
It is the investigator’s responsibility to ensure that the protocol is reviewed and approved by 
a properly constituted IRB or IEC (according to ICH GCP guidelines, Section 3.2). The 
IRB/IEC must also review and approve the site’s ICF and any other written information that 
will be provided to patients, prior to any enrollment and the release of any advertisements for 
patient recruitment. Prior to the start of the study, the investigator or designee must forward 
copies of the IRB/IEC approval and the approved ICF materials to the sponsor. 
If it is necessary to amend either the protocol or the ICF during the study, the investigator 
will be responsible for ensuring that the IRB/IEC reviews these amended documents, and that 
IRB/IEC approval of the amended ICF is obtained before any additional patients are enrolled. 
Copies of the amended ICF and of the IRB/IEC’s approval of it must be forwarded to the 
sponsor as soon as they are available. 
12.3 
Patient Confidentiality 
To ensure that patients’ identities remain unknown to the sponsor, all data will be identified 
by patient ID. 
The investigator must inform patients of the possibility that representatives from regulatory 
authorities and/or the sponsor may require access to hospital or clinic records, including 
signed ICFs that contain patients’ names and IDs, for verification of data pertinent to the 
study, including medical history. 
The investigator is responsible for keeping a list of all patients entered, including patient 
code, patient ID, full name, and last known address. 
13 
REGULATORY REQUIREMENTS 
13.1 
Regulatory Obligations 
This trial is to be conducted in accordance with the Declaration of Helsinki, the ICH 
Consolidated Guidelines for Good Clinical Practice (GCP), FDA regulations, and any local 
regulatory requirements. The trial will not begin at any given site until the site has provided 
the following documents to the sponsor or its delegate, as per the ICH Consolidated 
Guideline on GCP (Section 8.2): 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 55 of 58 
 
1. Signed and dated IRB/IEC approval indicating review and approval of each the following 
documents: 
• Protocol and any amendments 
• Patient Informed Consent Form 
• Any written information to be provided to patients 
• Any advertisements for patient recruitment 
• Any compensation to patients 
2. Membership of the IRB/IEC, to document that the committee is constituted in agreement 
with GCP 
3. Regulatory authority approval of the protocol 
4. Curriculum vitae of the investigator, sub-investigator(s), study coordinator, and 
pharmacist if applicable (updated within the last 2 years) 
5. For any laboratory evaluations performed at locations other than the study central 
laboratory: 
• Accreditation, certification, established quality control, or external quality assessment 
of the laboratory 
• Normal ranges or values for all laboratory test or procedures conducted during the 
trial 
6. Financial Disclosure Forms (where applicable) 
7. Regulatory Authority statement of investigator forms (e.g., FDA form 1572 where 
applicable) 
8. Signed Clinical 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. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 56 of 58 
 
14 
EARLY STUDY TERMINATION 
The sponsor reserves the right to discontinue this study at any time; or, an investigator may 
terminate it at his/her respective site following consultation with the sponsor. On 
discontinuance of the study, in its entirety or at a specific site, the investigator(s) will inform 
the study patients, the relevant clinical study staff, and the respective IRB/IEC of the 
discontinuance; provide them with the reasons for the discontinuance; and advise them in 
writing of any potential risks to the health of the study patients. It is the sponsor’s 
responsibility to report discontinuance of the study to regulatory agencies, to provide them 
with the reasons for the discontinuance, and to advise them in writing of any potential risks 
to the health of the study patients. 
15 
CONFIDENTIALITY 
Each investigator, 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. 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 57 of 58 
 
19 
REFERENCES 
1. 
United States Prescribing Information for Ferriprox 500 mg Tablets, February 2015. 
2. 
Cohen AR, Galanello R, Piga A, DiPalma A, Vullo C, Tricta F. Safety profile of the oral 
iron chelator deferiprone: a multicentre study. BrJ Haematol. 2000;108:305-12.  
3. 
Al-Refaie FN, Hershko C, Hoffbrand AV, Kosaryan M, Olivieri NF, Töndury P, et al. 
Results of long-term deferiprone (L1) therapy: A report by the international study group 
on oral iron chelators. British Journal of Haematology. 1995;91:224-9. 
4. 
ApoPharma Inc.  Investigator’s Brochure for Ferriprox® (deferiprone) for transfusional 
iron overload, Edition 12.0, Release date 11 May 2018. 
 


ApoPharma Inc. 
Deferiprone delayed release 1000 mg tablets 
LA61-0218 
Clinical Study Protocol, v 1.0 
 
 
CONFIDENTIAL 
Page 58 of 58 
 
APPENDIX 1:  QUESTIONNAIRE ON TREATMENT ACCEPTABILITY 
 
Patient Number: 
____________________ 
Site Number:  
____________________ 
Date:  
 
____________________ 
 
1. 
What is your preference between deferiprone delayed release (DR) tablets and Ferriprox 
tablets with respect to the dosing schedule (twice a day vs. three times a day)? 
 
 
 
 
 
 
Much prefer 
deferiprone DR 
Somewhat prefer 
deferiprone DR 
No preference 
Somewhat prefer 
Ferriprox 
Much prefer Ferriprox 
 
2. 
What is your preference between deferiprone DR and Ferriprox with respect to taking 
the tablets (ease of swallowing, feel of tablet, aftertaste, or any other factors)? 
 
 
 
 
 
 
Much prefer 
deferiprone DR 
Somewhat prefer 
deferiprone DR 
No preference 
Somewhat prefer 
Ferriprox 
Much prefer Ferriprox 
 
3. 
What is your preference between deferiprone DR and Ferriprox with respect to any 
side effects (upset stomach, joint pain, or any other problems)? 
 
 
 
 
 
 
Much prefer 
deferiprone DR 
Somewhat prefer 
deferiprone DR 
No preference 
Somewhat prefer 
Ferriprox 
Much prefer Ferriprox 
 
4. 
After considering the above factors, if you had the choice of which formulation to take in 
future, which one would you prefer? 
 
 
 
Deferiprone DR 
Ferriprox