Clinical trial NCT02041299
Conditions: Iron Overload Sickle Cell Disease Other Anemias
Keywords: sickle cell disease Iron overload Deferiprone Ferriprox deferoxamine Chelation
Sponsor: ApoPharma
Start date: 2014-04-17; Completion date: 2019-06-18
Enrollment: 230 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research is being done so that we can look at the safety and efficacy of deferiprone in people with sickle cell disease or other anemias. Deferiprone is a drug that removes iron from the body. We will be comparing deferiprone with deferoxamine, another drug that removes iron from the body.

Detailed description:
Deferiprone (brand name Ferriprox®) is an iron chelator that is approved in the United States and over 60 other countries for the treatment of iron overload in patients with thalassemia, when other treatments are inadequate. This study has been designed to evaluate the efficacy, safety, and tolerability of deferiprone vs. deferoxamine in patients who have SCD or other anemias, and who require chelation because of the extra iron they are taking in through blood transfusions.

About 300 people from North America, South America, Europe, and the Middle East will take part in this study. Participants will be randomized in a 2:1 ratio to receive therapy for 52 weeks with either deferiprone or deferoxamine, another type of iron chelator. Patients who are randomized to the deferiprone group can choose to get the drug as either tablets or liquid, and must take it three times daily. Patients who are randomized to the deferoxamine group will receive it as a subcutaneous infusion that lasts from 8 to 12 hours and is given 5 to 7 days per week. For both drugs, the starting dosage is based on how much extra iron they have taken in through transfusions in the last 3 months and on the severity of iron load, as measured by serum ferritin levels in the blood and by the amount of iron in the liver and the heart. For deferiprone, the starting dosage will be increased each week over the first 3 weeks; and for both drugs, the dosage may be adjusted up or down during the study based on the level of iron overload and on safety considerations.

Patients will need to have their blood count checked every week for the first 26 weeks, then every other week for the remaining 26 weeks; they will also have to give a blood sample for more detailed safety testing every month; and to give a blood sample for the measurement of serum ferritin every 3 months. Every six months, they will undergo an ECG and an MRI scan, and will be asked to complete a quality of life survey.

At the end of the 52 weeks, participants will be invited to enter a 2-year study in which all patients will receive deferiprone, including those who were randomized to receive deferoxamine in the first year.

Arms: arm 1: Patients randomized to the deferiprone arm will be prescribed either tablets or liquid medication. Deferiprone is taken orally, at a dosage that is calculated in terms of milligrams per kilogram of body weight (mg/kg) and is divided into 3 equal doses taken approximately 8 hours apart. The daily dosage is 75 mg/kg (25 mg/kg per dose) for patients with less severe iron load, and 99 mg/kg (33 mg/kg per dose) for those with more severe iron load. arm 2: Patients randomized to the deferoxamine arm will be prescribed the drug as per the approved US prescribing information. Deferoxamine is administered as a subcutaneous infusion over 8-12 hours, 5 to 7 days a week. The dosage is 20 mg/kg (children) or 40 mg/kg (adults) in patients with less severe iron load, and up to 40 mg/kg (children) or 50 mg/kg (adults) in those with more severe iron load.
Interventions: intervention 1: Deferiprone intervention 2: Deferoxamine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
PRODUCT: 
STUDY CODE: 
DATE: 
Deferiprone 
LA38-0411 
01 MAY 2017 
 
The information contained in this document is the property of ApoPharma Inc. and is 
confidential.  It may be submitted to a Registration Authority, an Ethics Committee, or an 
Investigator or a Pharmacist for the purpose of assessment in relation to registration of the 
product or initiation of a Clinical trial.  Reproduction or disclosure of the information in whole 
or in part is forbidden without the written consent of ApoPharma Inc.   
 
Clinical Study Protocol  
 (Ferriprox in patients with iron overload in 
sickle cell disease trial - FIRST) 
LA38-0411 
 
The efficacy and safety of Ferriprox® for the treatment of 
transfusional iron overload in patients with sickle cell disease 
or other anemias  
 
 
Version:  
 
 
Final version 10.1 (U.S. only) 
Date:  
 
 
 
01 MAY 2017 
 
 


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PROTOCOL SYNOPSIS 
Title of the Study: 
The efficacy and safety of Ferriprox® for the treatment of transfusional 
iron overload in patients with sickle cell disease or other anemias. 
Protocol Code: 
LA38-0411 
Development 
Phase: 
Phase IV  
Sponsor: 
ApoPharma Inc. 
Principal 
Investigator: 
Janet Kwiatkowski, MD 
The Children's Hospital of Philadelphia 
Philadelphia, PA, USA 
Study Center: 
Multicenter  
Planned Study 
Period: 
Individual patient treatment duration of 52 weeks. At the end of the 52 
weeks of treatment, patients will be invited to participate in a 2-year 
extension phase. 
Study Objectives: 
 
Primary: 
To determine the efficacy of deferiprone vs. deferoxamine in the 
treatment of iron overload in patients with sickle cell disease or other 
anemias. 
Secondary: 
o  To evaluate the effect of deferiprone vs. deferoxamine on the 
patients’ quality of life; 
o  To evaluate the safety and tolerability of deferiprone vs. 
deferoxamine. 
Study Design: 
 
This study is a 52-week, prospective, multi-center, two-arm, randomized, 
open-label, parallel design study of deferiprone vs. deferoxamine. 
Baseline Phase 
During the Baseline Phase, patients who sign an informed consent will 
undergo initial screening. On the final day of the Baseline Phase, patients’ 
eligibility will be determined, based on the inclusion/exclusion criteria, 
and qualified patients will enter the Treatment Phase. 
Treatment Phase 
At the beginning of the Treatment Phase, patients will be randomized in a 
2:1 ratio to receive (1) deferiprone or (2) deferoxamine. The Treatment 
Phase will be 52 weeks in duration. 


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Investigational 
Product: 
Ferriprox® (deferiprone) 500 mg tablets and/or deferiprone 80 mg/mL oral 
solution 
Comparator 
Product: 
Deferoxamine 2 g vial for injection 
Treatment 
(duration, 
treatment arm, 
dose, route): 
Deferiprone: 
During the study, patients will be prescribed Ferriprox 500 mg tablets or 
deferiprone 80 mg/mL oral solution, according to patient preference or 
product’s availability, for administration three times a day (tid).  The dose 
of deferiprone will be based on the transfusional iron input and the 
severity of iron load at baseline, and may be adjusted on the basis of the 
magnitude of change in iron overload during the study. 
Deferiprone 25 mg/kg tid: 
Patients with transfusional iron input ≤ 0.3 mg/kg/day in the 3 months 
prior to baseline 
AND 
Patients with a baseline measure of iron load of: 
- Serum ferritin <2500 μg/L  
AND 
- LIC <15 mg/g dry weight  
AND 
- Cardiac T2* > 20 ms 
 
Deferiprone 33 mg/kg tid: 
Patients with a transfusional iron input > 0.3 mg/kg/day in the 3 months 
prior to baseline 
OR  
Patients with at least one baseline measure of iron load as follows: 
- Serum ferritin ≥2500 μg/L  
OR  
- LIC ≥15 mg/g dry weight 
OR  
- Cardiac T2* ≤ 20 ms 
 
Dosing of all patients will be initially started at 15 mg/kg tid for 1 week, 
which will be increased to 20 mg/kg tid in Week 2 and to 25 mg/kg tid in 
Week 3, which will be the treatment dose for the remainder of the trial, 


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unless a patient meets the 33 mg/kg tid dosing criteria. In that case, the 
dose of deferiprone will be increased further to 33 mg/kg tid in Week 4 
and this dose will be the treatment dose for the remainder of the trial.  
The dose of deferiprone will also be increased to 33 mg/kg tid at any time 
during the trial if the mean daily transfusional iron input increases to more 
than 0.3 mg/kg body weight for at least 3 consecutive months OR at Week 
26 if there is less than 10% improvement from baseline to Week 26 in at 
least one of the measures indicative of iron overload (serum ferritin, 
cardiac MRI T2* or LIC). 
Dose reduction recommendations will be based on regular assessment of 
safety markers for adverse reactions that are possibly dose dependent, 
such as gastrointestinal upset, increases in serum liver enzyme levels and 
arthropathies. 
Deferoxamine:  
During the study, patients will be prescribed deferoxamine as per the 
approved US prescribing information at doses of 20 – 40 mg/kg/day in 
children (<16 years of age) and 40–50 mg/kg/day in adults (≥16 years of 
age) as 8 – 12 h subcutaneous infusion for 5 – 7 days per week.  The dose 
of deferoxamine will be based on the transfusional iron input, on the 
severity of iron load at baseline, and on the magnitude of its change during 
the study. 
Deferoxamine 20 mg/kg/day (children) or 40 mg/kg/day (adults): 
Patients with transfusional iron input ≤ 0.3 mg/kg/day in the 3 months 
prior to baseline 
AND 
Patients with a baseline measure of iron load of: 
- Serum ferritin <2500 μg/L * 
AND 
- LIC <15 mg/g dry weight  
AND 
- Cardiac T2* > 20 ms 
* If there is a delay in obtaining the results of the baseline serum 
ferritin assessment from the central laboratory, the most recent result 
(obtained within the last 3 months) should be used to calculate the 
starting DFO dosage. This dosage must remain in effect until the 
baseline serum ferritin results become available, at which time it is 
to be adjusted if necessary.  If no serum ferritin measure has been 
obtained within the last 3 months, the start of dosing must be 
deferred until the baseline results are available. 


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Deferoxamine up to 40 mg/kg (children) or 50 mg/kg (adults): 
Patients with a transfusional iron input > 0.3 mg/kg/day in the 3 months 
prior to baseline 
OR  
Patients with at least one baseline measure of iron load as follows: 
- Serum ferritin ≥2500 μg/L  
OR  
- LIC ≥15 mg/g dry weight  
OR  
- Cardiac T2* ≤ 20 ms 
Children (<16 years of age) 
The dose of deferoxamine will also be increased up to 40 mg/kg for 5 – 7 
days per week at any time during the trial if the mean daily transfusional 
iron input increases to more than 0.3 mg/kg body weight for at least 3 
consecutive months OR at Week 26 if there is less than 10% improvement 
from baseline to Week 26 in at least one of the measures of iron overload 
(serum ferritin, cardiac MRI T2* or LIC). 
Adults (≥16 years of age) 
The dose of deferoxamine will be increased up to 50 mg/kg for 5 – 7 days 
per week at any time during the trial if the mean daily transfusional iron 
input increases to more than 0.3 mg/kg body weight for at least 3 
consecutive months OR at Week 26 if there is less than 10% improvement 
from baseline to Week 26 in at least one of the measures of iron overload 
(serum ferritin, cardiac MRI T2* or LIC). 
Dose reduction recommendations will be based on regular assessment of 
safety markers. 
Target Population: 
 
Three hundred (300) male and female patients with sickle cell disease or 
other anemias will be enrolled and randomized to receive deferiprone or 
deferoxamine in a 2:1 ratio. At least 80% of the patients will have sickle 
cell disease. Stratified randomization based on disease category (sickle 
cell disease vs. other anemias) and on the transfusional iron input in the 3 
months prior to baseline (> 0.3 mg/kg/day vs. ≤ 0.3 mg/kg/day) will be 
employed to ensure that the 2:1 ratio is maintained within each of the 4 
strata: 1) sickle cell disease with transfusional iron input > 0.3 mg/kg/day, 
2) sickle cell disease with transfusional iron input ≤ 0.3 mg/kg/day, 3) 
other anemias with transfusional iron input > 0.3 mg/kg/day, and 4) other 
anemias with transfusional iron input ≤ 0.3 mg/kg/day. 


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Efficacy 
Endpoints: 
 
Primary: 
The change from baseline to Week 52 in liver iron 
concentration(measured by MRI). 
Secondary: 
1. Change from baseline to Week 52 in patient-reported quality of life 
(SF-36 or Child Health Questionnaire); 
2. Change from baseline to Week 52 in cardiac MRI T2*;  
3. Change from baseline to Week 52 in serum ferritin. 
Safety Endpoints: 
 
1. Frequency, severity and time to onset/duration of adverse events (AEs); 
2. Frequency of serious adverse events (SAEs); 
3. Discontinuation due to AEs; 
4. Hematology assessments;  
5. Blood clinical biochemistry assessments; 
6. 12-lead ECG. 
Sample Size: 
Three hundred (300) male and female patients will be enrolled into the 
study. In a randomized study of two iron chelators for the treatment of 
iron overload in patients with sickle cell disease (Vichinsky E et al. 2007), 
mean ±SD reductions of 4.0 ± 1.5 mg/g dw and 4.5 ± 2.0 mg/g dw in LIC, 
as measured by SQUID, were observed (Figure 1 of the article, numerical 
values obtained from the authors) in patients from the baseline LIC 
categories of >7-14 mg/g dw or >14 mg/g dw after they were treated with 
35-50 mg/kg or ≥50 mg/kg of deferoxamine respectively, for 52 weeks. 
Assuming the same mean reduction in LIC for deferiprone but a higher 
SD of ±4.0 mg/g dw for both treatments due to possibly higher variability 
associated with MRI measurement, the sample size of 300, with >80% 
being patients with sickle cell disease, will provide over 95% power for 
demonstrating non-inferiority of deferiprone to deferoxamine in patients 
with sickle cell disease.  
The sample size estimate is based on a non-inferiority margin of 2 mg/g 
dw for the reduction of LIC and an alpha of 0.05, two-sided (or an alpha 
of 0.025, one-sided). It has been reported that in a typical patient with 
thalassemia major, the LIC could increase by 5 mg/g dw after 1 year 
without chelation therapy. As the cause of iron overload is the same in 
thalassemia and sickle cell disease, the same increase in LIC may be 
expected if patients with sickle cell disease are transfused at the same rate 
and not treated with a chelator.  Hence, the difference in reduction of LIC 
between deferoxamine therapy and a placebo (effect size) can be 
estimated to be 9 (i.e., 4 – (-5)) mg/g dw. This means that the non-
inferiority margin of 2 mg/g dw would be about 20% of the effect size. 


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With the enrolment of 300 patients, there is a greater than 99% chance 
(power) of occurrence of at least 1 adverse event with an anticipated 
incidence rate of 2%, or greater than 95% chance for an anticipated 
incidence rate as low as 1%.  
Main Inclusion 
Criteria: 
 
1. 
Male or female ≥ 2 years of age; 
2. 
Have sickle cell disease (confirmed by Hb electrophoresis or more 
specific tests) or other conditions with iron overload from repeated 
blood transfusions (see exclusion criteria for exceptions); 
3. 
Baseline LIC >7 mg/g dw (measured by MRI); 
4. 
Patients who have received no less than 20 transfusions of RBCs; 
5. 
Patients who have received at least 1 transfusion per year in the last 2 
years and who are expected to have a continuing requirement (based 
on Investigator’s judgement) during the duration of the trial 
Main Exclusion 
Criteria: 
1. 
Thalassemia syndromes; 
2. 
Myelodysplastic syndrome (MDS) or myelofibrosis; 
3. 
Diamond Blackfan anemia; 
4. 
Primary bone marrow failure; 
5. 
Patients with a baseline LIC >30 mg/g dw (measured by MRI); 
6. 
Unable or unwilling to undergo a 7-day washout period if currently 
being treated with deferiprone or deferoxamine or deferasirox; 
7. 
Previous discontinuation of treatment with deferiprone or 
deferoxamine due to adverse events; 
8. 
History or presence of hypersensitivity or idiosyncratic reaction to 
deferiprone or deferoxamine; 
9. 
Treated with hydroxyurea within 30 days; 
10. History of malignancy; 
11. Evidence of abnormal liver function (serum ALT level(s) > 5 times 
upper limit of normal at screening or creatinine levels >2 times upper 
limit of normal at screening); 
12. A serious, unstable illness, as judged by the Investigator, during the 
past 3 months before screening/baseline visit including but not 
limited to: hepatic, renal, gastro-enterologic, respiratory, 
cardiovascular, endocrinologic, neurologic or immunologic disease; 
13. Clinically significant abnormal 12-lead ECG findings; 
14. Cardiac MRI T2* <10 ms 
15. Myocardial infarction, cardiac arrest or cardiac failure within 1 year 
before screening/baseline visit;  


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16. Unable to undergo MRI 
17. Presence of metallic objects such as artificial joints, inner ear 
(cochlear) implants, brain aneurysm clips, pacemakers, and metallic 
foreign bodies in the eye or other body areas that would prevent use 
of MRI imaging 
Schedule of Study 
Procedures: 
Following screening assessments, eligible patients will undergo baseline 
assessments within two months of the screening assessments.  
1. 
MRI scans will be performed at Screening/Baseline, and Weeks 26 
and 52 (End of Study) or Early Termination visits, whichever comes 
first for: 
- 
Liver MRI for LIC calculation; 
- 
Cardiac MRI T2* ; 
2. 
Serum ferritin will be measured at Baseline and Weeks 12, 26, 40 and 
52 (End of Study) or Early Termination visits, whichever comes first; 
3. 
Hematology assessments will be performed at Screening/Baseline, 
weekly until Week 26, and then  biweekly until Week 52 (End of 
Study) or Early Termination visits, whichever comes first; 
4. 
Chemistry assessments will be performed at Screening/Baseline, and 
monthly up to Week 52 (End of Study) or Early Termination visits, 
whichever comes first. 
5. 
Quality of life patient-reported questionnaire will be completed at 
Baseline and Weeks 26 and 52 (End of Study) or Early Termination 
visits, whichever comes first. 
Data Analysis: 
 
Primary Efficacy Endpoint 
The change from baseline to Week 52 in LIC will be compared between 
the two treatment groups using an analysis of covariance (ANCOVA) 
model including treatment variable as the main factor, and total 
transfusional iron input during the study and baseline LIC as covariates. 
The 95% confidence interval (CI) of the difference (deferiprone minus 
deferoxamine) in change of LIC from baseline to Week 52 between the 
two treatment groups will be computed. For the demonstration of non-
inferiority, the upper limit of the 95% CI should be no more than 
2 mg/g dw. 
 
Secondary Efficacy Endpoints 
The change from baseline to Week 52 in patients’ reported quality of life 
(SF-36 or Child Health Questionnaire) will be compared between the two 
treatment groups. Detailed information on the statistical method to be 
used will be provided in the statistical analysis plan. The change from 
baseline to Week 52 in cardiac MRI T2* and serum ferritin will be 


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compared between the two treatment groups, using an ANCOVA model 
including treatment variable as the main factor and total transfusional iron 
input during the study and baseline cardiac MRI T2* or serum ferritin as 
covariates. As with LIC, the 95% CI of the difference between the two 
treatment groups will be computed for both MRI T2* and serum ferritin. 
The MRI T2* data will be log-transformed before any statistical testing.   
The longitudinal data of patient-reported quality of life (SF-36 or Child 
Health Questionnaire), LIC, cardiac MRI T2*, and serum ferritin will also 
be analyzed for time trend by using the appropriate mixed model or its 
equivalent for the quality of life data. Transfusional iron input during the 
study will be assessed and compared among treatment groups and 
hematologic diagnoses.  
Subgroup Analysis 
The comparison of the two treatment groups for the primary and 
secondary efficacy endpoints will be performed in: 
- 
Patients with sickle cell disease (SCD) only; 
- 
non-SCD patients. 
Safety Analysis 
The safety data for continuous variables will be summarized using 
descriptive statistics, and the safety data for discrete variables will be 
presented as frequency tables. The proportions of drop-outs will be 
compared between the deferiprone group and the deferoxamine group 
using Fisher’s exact test.  
 


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CLINICAL STUDY ADMINISTRATIVE STRUCTURE 
 
Sponsor: 
ApoPharma Inc. 
200 Barmac Drive 
Toronto, Ontario 
Canada M9L 2Z7 
Tel: +1-416-749-9300 
Toll-free: 1-800-268-4623 
Fax: +1-416-401-3867 
Contract Research Organization: 
Parexel International  
195 West Street 
Waltham, MA 02451 USA 
Tel: 1-781-487-9900 
Fax: 1-781 -487 0525 
Email: info@parexel.com 
Web: www.parexel.com 
 
Contract Research Laboratories: 
Eurofins Global Central Laboratory 
Eurofins Global Central Laboratory    
Bergschot 71  
4817 PA   Breda  
The Netherlands 
Tel: +31 76 572 72 72 
Fax: +31 76 573 77 78 
Email: clinicaltrials@eurofins.com 
 
Eurofins Global Central Laboratory  
2430 New Holland Pike 
Building D, Suite 100 
Lancaster, PA 17601 
USA 
Tel: +1-717-656-2300 
Fax: +1-717-556-0367 
Email: clinicaltrials@eurofins.com 
Web: pharma.eurofins.com 


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Contract Research Imaging 
Laboratories:  
 
BioMed Informatics, LLC 
2801 Townsgate Road, Suite 212 
Westlake Village, California 91361 
USA 
Tel: +1-818-584-3560 
Fax: +1-818-475-1986 
Email: aaker@biomed-informatics.com 
CMR Core Lab Technologist 
Royal Brompton Hospital  
Sydney Street, London SW3 6NP  
United Kingdom 
 
Tel:  011-44-20-7351-8768 
Fax:  011-44-20-7351-881 
Email: g.smith@rbh.nthames.nhs.uk  


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Table of Contents 
Page No. 
1 
BACKGROUND AND RATIONALE .............................................................................. 18 
1.1 
SICKLE CELL DISEASE ................................................................................................... 18 
1.2 
FERRIPROX® ................................................................................................................... 19 
1.3 
DEFEROXAMINE ............................................................................................................. 21 
1.4 
STUDY RATIONALE ........................................................................................................ 22 
2 
OBJECTIVES ..................................................................................................................... 22 
2.1 
PRIMARY OBJECTIVE ..................................................................................................... 22 
2.2 
SECONDARY OBJECTIVES ............................................................................................... 22 
3 
INVESTIGATIONAL PLAN ............................................................................................ 23 
3.1 
OVERALL STUDY DESIGN .............................................................................................. 23 
3.2 
DISCUSSION OF STUDY DESIGN ...................................................................................... 23 
3.3 
STUDY SITES AND STUDY DURATION ............................................................................ 26 
4 
STUDY POPULATION ..................................................................................................... 26 
4.1 
NUMBER OF PATIENTS ................................................................................................... 26 
4.2 
INCLUSION CRITERIA ..................................................................................................... 26 
4.3 
EXCLUSION CRITERIA .................................................................................................... 27 
4.4 
ENROLMENT VIOLATIONS .............................................................................................. 29 
4.5 
WITHDRAWAL CRITERIA ................................................................................................ 29 
4.6 
TREATMENT INTERRUPTIONS ......................................................................................... 30 
4.7 
PREGNANCY ................................................................................................................... 30 
4.8 
ALLOCATION OF PATIENT NUMBERS.............................................................................. 31 
4.9 
METHOD OF ASSIGNMENT TO TREATMENT .................................................................... 31 
5 
STUDY PROCEDURES .................................................................................................... 31 
5.1 
ENTRY PROCEDURES ...................................................................................................... 31 
5.2 
SCREENING/BASELINE VISIT (DAY -60 TO DAY -1: VISIT -1) ......................................... 32 
5.3 
BASELINE VISIT (DAY 0, VISIT 0) .................................................................................. 33 
5.4 
WEEKLY OR BIWEEKLY ASSESSMENTS .......................................................................... 34 
5.5 
TELEPHONE CALLS (WEEKS 1, 2 AND 3) ........................................................................ 35 
5.6 
MONTHLY VISITS (WEEKS 4, 8, 16, 20, 32, 36, 44 AND 48 VISITS) ................................ 35 
5.7 
QUARTERLY VISITS (WEEKS 12 AND 40 VISITS) ............................................................ 37 
5.8 
SEMI-ANNUAL VISIT (WEEK 26 VISIT) .......................................................................... 38 
5.9 
END OF STUDY VISIT (WEEK 52 OR EARLY TERMINATION VISIT) ................................. 40 
5.10 
EARLY TERMINATION .................................................................................................... 41 
6 
TREATMENT ..................................................................................................................... 41 
6.1 
STUDY MEDICATION ...................................................................................................... 41 
6.2 
RATIONALE FOR SELECTION OF DOSES .......................................................................... 43 
6.3 
PRIOR AND CONCOMITANT MEDICATIONS ..................................................................... 44 
6.4 
RESCUE MEDICATION .................................................................................................... 44 
6.5 
TREATMENT COMPLIANCE ............................................................................................. 44 
7 
MATERIALS AND SUPPLIES......................................................................................... 45 


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7.1 
STUDY MEDICATION ...................................................................................................... 45 
7.2 
PACKAGING AND LABELLING ......................................................................................... 45 
7.3 
STORAGE AND DISPOSITION OF STUDY MEDICATIONS ................................................... 45 
7.4 
DRUG DISPENSING PROCEDURES ................................................................................... 46 
7.5 
STUDY MEDICATIONS ACCOUNTABILITY AND INVENTORY CONTROL ........................... 46 
7.6 
OTHER STUDY SUPPLIES ................................................................................................ 47 
8 
MEASUREMENTS AND EVALUATIONS .................................................................... 47 
8.1  
EFFICACY ....................................................................................................................... 47 
8.1.1 Primary Efficacy Measure ........................................................................................ 47 
8.1.1.1  Liver Iron Concentration................................................................................... 47 
8.1.2 Secondary Efficacy Measures ................................................................................... 48 
8.1.2.1  Patient Reported Quality of Life ....................................................................... 48 
8.1.2.2 
Cardiac MRI T2* .............................................................................................. 48 
8.1.2.3  Serum Ferritin ................................................................................................... 49 
8.2 
SAFETY .......................................................................................................................... 49 
8.2.1 Medical History, Physical Examination, Vital Signs and Prior and Concomitant 
Medication Use ..................................................................................................................... 49 
8.2.2 Clinical Laboratory Tests ......................................................................................... 50 
8.2.3 ECG........................................................................................................................... 51 
8.2.4 Adverse/Medical Events and Serious Adverse Events .............................................. 51 
8.2.4.1 
Definition of Medical/Adverse Events ............................................................. 51 
8.2.4.2 
Adverse/Medical Event Considerations ............................................................ 52 
8.2.4.3 
Procedures for Adverse/Medical Event Monitoring and Recording................. 53 
8.2.4.4 
Causality ........................................................................................................... 54 
8.2.4.5 
Severity ............................................................................................................. 54 
8.2.4.6 
Serious Adverse Event ...................................................................................... 55 
8.2.4.7 
Procedures for Serious Adverse Event Reporting ............................................ 56 
8.2.4.8 
Follow-up and Documenting of SAEs .............................................................. 56 
8.2.4.9 
Adverse Event of Special Interest – Neutropenia (Definitions and Management)
 
57 
9 
PROCEDURES IN CASE OF MEDICAL EMERGENCY ........................................... 59 
9.1 
PRECAUTIONS/OVERDOSE .............................................................................................. 59 
9.2 
PROCEDURES IN CASE OF PREGNANCY .......................................................................... 60 
10 STUDY COMMITTEE ...................................................................................................... 61 
10.1 
DATA SAFETY MONITORING BOARD.............................................................................. 61 
11 DATA HANDLING AND STATISTICAL ANALYSIS ................................................. 61 
11.1 
DATA COLLECTION AND HANDLING PROCEDURES ........................................................ 61 
11.1.1 
Documentation of Data ......................................................................................... 61 
11.1.2 
Corrections to Study Documentation .................................................................... 61 
11.1.3 
Data Processing .................................................................................................... 62 
11.1.4 
Coding ................................................................................................................... 62 
11.1.5 
Data Handling ...................................................................................................... 62 
11.1.6 
Missing, Unused and Spurious Data .................................................................... 62 
11.2 
STATISTICAL ANALYSIS ................................................................................................. 62 


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11.2.1 Primary Efficacy Endpoint ........................................................................................ 62 
11.2.2 Secondary Efficacy Endpoints ................................................................................... 62 
11.2.3 Safety Endpoints......................................................................................................... 63 
11.2.4 Determination of Sample Size .................................................................................... 63 
11.2.5 Study Populations ...................................................................................................... 63 
11.2.5.1 Intent-to-Treat ..................................................................................................... 64 
11.2.5.2 Per-Protocol ........................................................................................................ 64 
11.2.5.3 Safety .................................................................................................................. 64 
11.3 
STATISTICAL PLAN ........................................................................................................ 64 
11.4 
DEFINITION OF ANALYSIS .............................................................................................. 64 
11.4.1 Planned Analyses ....................................................................................................... 65 
11.4.1.1 Patient Disposition and Drug Exposure .............................................................. 65 
11.4.1.2 Patient Characteristics ......................................................................................... 65 
11.4.1.3 Efficacy Analyses ............................................................................................... 65 
11.4.1.4 Safety Analyses ................................................................................................... 66 
12 DATA MANAGEMENT CONSIDERATIONS............................................................... 68 
12.1 
DATA MANAGEMENT ..................................................................................................... 68 
12.2 
SOURCE DOCUMENTS .................................................................................................... 68 
12.3 
ELECTRONIC DATA CAPTURE (EDC) ............................................................................. 69 
13 MONITORING, AUDITS AND INSPECTIONS ............................................................ 69 
13.1 
MONITORING ................................................................................................................. 69 
13.2 
AUDITS AND INSPECTIONS ............................................................................................. 70 
14 REGULATORY REQUIREMENTS AND OBLIGATIONS ......................................... 70 
14.1 
INFORMED CONSENT/ASSENT ........................................................................................ 70 
14.2 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ............................ 71 
14.3 
PATIENT DATA PROTECTION .......................................................................................... 72 
14.4 
ASSUMPTION OF LIABILITY AND INDEMNIFICATION ....................................................... 72 
14.5 
COMPLIANCE ................................................................................................................. 73 
14.6 
AMENDMENTS TO THE PROTOCOL .................................................................................. 73 
14.7 
APOPHARMA INC. OBLIGATIONS ................................................................................... 74 
14.8 
INVESTIGATORS’ OBLIGATIONS ..................................................................................... 75 
14.9 
DATA QUALITY COMPLIANCE ........................................................................................ 76 
14.10 
STUDY REPORTS ........................................................................................................ 76 
14.11 
OWNERSHIP ............................................................................................................... 76 
14.12 
PUBLICATIONS/POSTER/PRESENTATION ..................................................................... 77 
14.13 
EARLY STUDY TERMINATION .................................................................................... 77 
15 CONFIDENTIALITY ........................................................................................................ 77 
16  REFERENCES ................................................................................................................... 78 
17 SIGNED AGREEMENT TO THE PROTOCOL ............................................................ 82 
17.1 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE ................................................................. 82 
17.2 
PROTOCOL APPROVAL SIGNATURE PAGE....................................................................... 83 
18 APPENDICES ..................................................................................................................... 84 
18.1 
SCHEDULE OF EVENTS ................................................................................................... 84 


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18.2 
ACCEPTABLE METHODS OF CONTRACEPTION AND DEFINITIONS RELATED TO 
CHILDBEARING POTENTIAL........................................................................................................ 86 
18.3 
LIST OF PROHIBITED DRUGS .......................................................................................... 87 
18.4 
SAMPLE SIZE CALCULATION OUTPUT ............................................................................ 88 
18.5 
QUESTIONNAIRES ........................................................................................................... 90 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADR  
 
 
Adverse Drug Reaction 
AE 
 
 
 
Adverse Event 
AF 
 
 
 
Assent Form 
ANC  
 
 
Absolute Neutrophil Count 
ANCOVA  
Analysis of Covariance 
ALT  
 
 
Alanine aminotransferase 
AST  
 
 
Aspartate aminotransferase 
AUC  
 
 
Area Under the Curve 
BUN  
 
 
Blood urea nitrogen 
CFR  
 
 
Code of Federal Regulations 
CI  
 
 
 
Confidence Interval 
CRA  
 
 
Clinical Research Associate 
CRF  
 
 
Case Report Form 
CRO  
 
 
Contract Research Organization  
CTCAE  
 
Common Terminology Criteria for Adverse Events 
DFO  
 
 
Deferoxamine 
DFX  
 
 
Deferasirox 
DSMB   
 
Data Safety Monitoring Board 
dw 
 
 
 
dry weight 
ECG  
 
 
Electrocardiogram 
eCRF 
 
 
electronic Case Report Form 
EDC  
 
 
Electronic Data Capture 
EMA  
 
 
European Medicines Agency 
FDA  
 
 
Food and Drug Administration 
GCP  
 
 
Good Clinical Practice 
GGT  
 
 
gamma-glutamyl transferase 
Hb 
 
 
 
Hemoglobin 
HbS  
 
 
Hemoglobin S   
HbSC 
 
 
Sickle-hemoglobin C disease 
HIV  
 
 
Human Immunodeficiency Virus 
HR  
 
 
Heart rate 
ICF  
 
 
Informed Consent Form 
ICH  
 
 
International Conference on Harmonisation 


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ID  
 
 
 
Identification 
IRB/IEC 
 
Institutional Review Board/Independent Ethics Committee 
ITT   
 
 
Intent to Treat 
IUD  
 
 
Intrauterine Device 
IVRS  
 
 
Interactive Voice Response System 
LIC  
 
 
Liver Iron Concentration 
LOCF  
 
Last Observation Carried Forward 
MDS  
 
 
Myelodysplastic Syndrome 
ME  
 
 
Medical Event 
MedDRA  
Medical Dictionary for Regulatory Activities 
mg 
 
 
 
milligram 
mg/g  
 
 
milligram per gram 
mg/kg/day  
milligram/kilogram/day 
mL  
 
 
millilitre 
MMRM  
 
Mixed-Effects Model for Repeated Measures 
MRI  
 
 
Magnetic Resonance Imaging 
NCI  
 
 
National Cancer Institute 
OC  
 
 
Observed Case 
OCRDC  
 
Oracle Clinical Remote Data Capture 
PDR  
 
 
Patient Data Report 
PP 
 
 
 
Per-Protocol 
RBCs 
 
 
Red Blood Cells 
SADR  
 
Serious Adverse Drug Reaction 
SAE  
 
 
Serious Adverse Event 
SAP  
 
 
Statistical Analysis Plan 
SCD  
 
 
Sickle Cell Disease 
SOC  
 
 
System Organ Class 
SOP  
 
 
Standard Operating Procedure 
tid  
 
 
 
three times a day 
UDP  
 
 
uridine 5’-diphosphate  
WHO 
 
 
World Health Organization 


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1 
BACKGROUND AND RATIONALE 
Pursuant to the Accelerated Approval of Ferriprox by the FDA in October 2011, 
ApoPharma committed to conduct a confirmatory trial of deferiprone in transfused 
patients, focussing primarily on transfused patients with sickle cell disease (SCD). This 
will be a 52-week, prospective, multi-center, two-arm, randomized, open-label, parallel 
design of deferiprone therapy vs. deferoxamine. At least 80% of the patients enrolled in 
the study will be patients with SCD, but patients with other anemias requiring blood 
transfusion and with iron overload will also be included. Excluded from the study will be 
patients with thalassemia syndromes, myelodysplastic syndrome (MDS), myelofibrosis, 
Diamond Blackfan Anemia, and primary bone marrow failure.  
 
1.1 
Sickle Cell Disease 
SCD is an inherited hemoglobinopathy, displaying a varied phenotypic expression as a 
result of diverse genetic and environmental factors.  It is determined by combinations of 
2 abnormal alleles of the beta globin gene, among which at least one carries the beta6 glu-
val mutation (Lal A & Vichinsky. 2005).  The disease is clinically silent until expression 
of the gamma genes is substituted by expression of the beta genes (at between 3 and 9 
months of age).   
Haemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood 
cells (RBCs) responsible for tissue oxygenation.  Normal RBCs contain mainly 
haemoglobin A; people with sickle cell conditions have the genetic variation HbS.  RBCs 
containing mostly HbS do not survive as long as normal RBCs (typically, about 16 days, 
compared to about 120 days for normal cells) (Lal A & Vichinsky. 2005).  The RBCs 
containing HbS can become crescent (sickle)-shaped, leading to loss of their mobility and 
flexibility (Kikuchi BA. 2003).  As a result, these RBCs have difficulty passing through 
small blood vessels.  This in turn leads to blood-cell agglomeration, impeding the 
circulation of blood and delivery of oxygen to vital tissues and organs (Kikuchi BA. 
2003).  Tissue that does not receive a normal blood flow eventually becomes ischemic 
(Hess DC et al. 1991). The anaemia and blockage of blood flow results in a variety of 
problems, such as painful crises, susceptibility to infection, priapism, skin ulcers, acute 
chest syndrome, acute splenic sequestration, pulmonary disease, renal and hepatic 
dysfunction, and cerebrovascular disease, ultimately causing premature death (Hess DC 
et al. 1991; Nathan DG & Orkin. 1998). Abnormal cardiac findings, with the notable 
development of a progressive proliferative systemic vasculopathy, pulmonary 
hypertension, and left ventricular diastolic dysfunction, are also present in most patients 
with sickle cell disease (SCD) and are primarily the result of chronic anaemia, cardiac 
chamber dilation, and compensatory increase in left and right ventricular mass (Gladwin 
MT & Sachdev. 2012; Knight-Perry JE et al. 2011). 
Some patients undergo transfusions to improve blood rheology by replacing sickled 
RBCs with normal RBCs.  Blood transfusions have been indicated for the prevention of 
and treatment of vaso-occlusive complications such as painful crisis, stroke, acute chest 
syndrome, acute multi-organ failure, acute splenic sequestration, or medical intervention 
(preoperative preparation) (Vichinsky E. 2001). Although chronic blood transfusions can 


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reduce the incidence of sickle cell–induced morbidity and mortality, repeated 
transfusions result in progressive accumulation of iron in the blood (Inati A et al. 2010).  
Excess iron accumulates in organs, particularly the liver and endocrine glands, generating 
iron-induced morbidity and eventually causing premature death if left untreated (Ballas 
SK. 2001). A study in transfusion-dependent patients with SCD demonstrated increased 
iron deposition, with mean liver iron of 13.68 mg/g dry weight (range of 2.9 to 26.19 
mg/g dry weight) and peak mean serum ferritin of 4614  1989 μg/L over a transfusion 
period of 57  35 months (range 12 to 146 months) (Harmatz P et al. 2000).  
In the sickle cell centres of the Cardeza Foundation and Thomas Jefferson University 
Hospital, approximately 50% of the patients with SCD admitted to the hospital received 
an average of 10 units of RBCs per year; 17% to 37% of these patients developed iron 
overload.  Compared to the non-iron-overloaded group, the iron-overloaded patients with 
serum ferritin level > 1,500 μg/L and transferrin saturation > 50% had a higher incidence 
of painful episodes per year (64% vs. 38%), organ failure (71% vs. 19%), and mortality 
(64% vs. 5%).  Patients who died had significantly higher mean levels of serum ferritin 
than the surviving patients (2,379 versus 597 μg/L, p<0.05).  The results of this study 
indicate that iron overload is a determinant of morbidity and mortality in adult patients 
with SCD (Ballas SK. 2001). Results from a natural history study demonstrated that the 
unadjusted death rate of transfused patients with SCD (7.0/100 person years) was even 
higher than in patients with thalassemia (2.2/100 person years) (Fung EB et al. 2007). 
Iron metabolism and trafficking in patients with SCD have some distinctive characteristics. 
The high levels of inflammatory cytokines in SCD may enhance macrophage/
reticuloendothelial cell iron and/or renal cell iron retention. This makes tissues that retain 
iron different in SCD, and thus the organs that fail due to excess iron load in patients with 
SCD are somewhat different from those of patients with thalassemia (Walter PB et al. 
2009).  Indeed, unlike thalassemia patients, cardiac iron overload is not frequently 
observed in patients with SCD (Kaushik N et al. 2012). Nonetheless, cardiac siderosis 
does occur in some transfused SCD patients who have been transfused for more than 10 
years (Wood JC. 2008).  
Care for SCD now commonly uses transfusion, which potentially results in iron overload 
and necessitates chelation (Walter PB et al. 2009). 
 
1.2 
Ferriprox® 
Ferriprox (deferiprone) is an iron chelator that was first approved for “Treatment of iron 
overload in patients with thalassemia major for whom deferoxamine therapy is 
contraindicated or who present serious toxicity with deferoxamine therapy” in 1999 by 
the European Medicines Agency (EMA), and it is currently approved in more than 60 
countries. It was approved by the Food and Drug Administration (FDA) of the USA in 
October 2011 for the treatment of patients with transfusional iron overload due to 
thalassemia syndromes when current chelation therapy is inadequate. The recommended 
initial dose of Ferriprox is 25 mg/kg, orally, three times per day for a total of 75 mg/kg/day. 
The maximum dose is 33 mg/kg, three times per day for a total of 99 mg/kg/day. 


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Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one) is a bidentate iron chelator that 
preferentially binds trivalent iron (Fe3+) in a 3:1 (deferiprone : iron) complex. The 
effectiveness of deferiprone has been assessed by urinary iron excretion, sequential 
measurements of serum ferritin levels, iron concentration in the liver and in the heart, and 
by clinical outcomes such as its ability to prevent iron-induced cardiac disease and 
prolong survival in transfused patients with thalassemia. The results of ApoPharma-
sponsored clinical studies and of independent trials have demonstrated that therapy with 
deferiprone is associated with good compliance and stabilization or decline of the body 
iron load. See clinical study reports LA01, LA02, LA03, LA04, LA06, LA10, LA11, 
LA12, LA15, LA16, and LA30 (ApoPharma Inc. 2006a; ApoPharma Inc. 2006b; 
ApoPharma Inc. 2006c; ApoPharma Inc. 2009; Apotex Research Inc. 1998; Apotex 
Research Inc. 2000a; Apotex Research Inc. 2000b; Apotex Research Inc. 2001; Apotex 
Research Inc. 2003; Apotex Research Inc. 2005; Apotex Research Inc. 2006). 
In humans, deferiprone is rapidly absorbed from the upper part of the gastrointestinal 
tract after oral administration and appears in blood within 5 to 10 minutes (min). The 
mean time for deferiprone concentrations to peak in serum is 45 to 60 min in fasting 
patients and approximately 2.2 h in non-fasting patients. Less than 20% of deferiprone is 
bound to serum proteins. The majority of the administered dose of deferiprone is 
metabolized, mainly via Phase II metabolism through O-glucuronidation. In vitro studies 
suggest that UDP glucuronosyltransferase 1A6 is primarily responsible for the 
glucuronidation of deferiprone. The predominant deferiprone metabolite is a 3-O-
glucuronide conjugate. Glucuronidation of deferiprone results in a loss of the iron 
binding capacity due to the inactivation of the 3-hydroxy functional group and facilitates 
elimination through increased hydrophilicity. In most patients, more than 90% of 
deferiprone is eliminated from serum within 5 to 6 hours. The elimination half-life of 
deferiprone is 2 to 3 hours, with about 75% to 90% of the total deferiprone excreted in 
urine in the first 24 hours in the form of free deferiprone, the 3-O-glucuronide metabolite 
and iron-deferiprone complex. Food decreased the rate of absorption of the parent drug 
and the subsequent rate of formation of deferiprone glucuronide in healthy patients, while 
the overall bioavailability (AUC) remained unchanged.   
The safety profile of deferiprone has been extensively characterized. The most significant 
serious adverse event (SAE) associated with deferiprone use is agranulocytosis, 
sometimes referred to as severe neutropenia, defined as a confirmed absolute neutrophil 
count less than 0.5 × 109/L.  
In pooled clinical trials, the incidence of agranulocytosis/severe neutropenia was 1.7% of 
patients. The mechanism of deferiprone-associated agranulocytosis is unknown. 
Agranulocytosis and neutropenia usually resolve upon discontinuation of deferiprone, but 
there have been post-marketing reports of agranulocytosis leading to death. A recent 
review of 20 years of data confirmed that deferiprone-induced agranulocytosis is not 
dose-related within the therapeutic range, and its occurrence peaks at 5 months after 
initiation of therapy, declining in frequency after that period (Tricta et al. 2016). 
The most common observed event reported during clinical trials was chromaturia, due to 
iron excretion. Nausea, vomiting, abdominal pain, alanine aminotransferase increased, 
arthralgia, and neutropenia were the most common adverse events. Please refer to the US 


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full prescribing information (USPI) and the Investigator’s Brochure for complete safety 
information. 
The table below lists the adverse events associated with deferiprone therapy that occurred 
in at least 1% of patients in the ApoPharma clinical trials. 
 
Body System  
     Preferred Term 
% Patients 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
       Neutropenia 
6.2 
       Agranulocytosis 
1.7 
GASTROINTESTINAL DISORDERS 
 
       Nausea 
12.6 
       Abdominal pain/discomfort 
10.4 
       Vomiting 
9.8 
       Diarrhea 
3.0 
       Dyspepsia 
2.0 
INVESTIGATIONS 
 
       Alanine Aminotransferase increased  
7.5 
       Neutrophil count decreased 
7.3 
       Weight increased 
1.9 
       Aspartate Aminotransferase increased 
1.2 
METABOLISM AND NUTRITION DISORDERS 
 
       Increased appetite 
4.0 
       Decreased appetite 
1.1 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
       Arthralgia 
9.8 
       Back pain 
2.0 
       Pain in extremity 
1.9 
       Arthropathy 
1.4 
NERVOUS SYSTEM DISORDERS 
 
       Headache 
2.5 
Data cut-off date: 31 August 2010 
 
1.3 
Deferoxamine 
Deferoxamine (DFO) was the first commercially available iron chelator, which was 
approved in 1968 for the treatment of acute iron intoxication and of chronic iron overload 
due to transfusion-dependent anemias.  To be effective, DFO must be delivered as a 
constant infusion, usually subcutaneously, for 8 to 12 hours a night, at least five days per 
week at recommended doses of 20-60 mg/kg/day. Deferoxamine chelates iron by forming 
a stable complex that prevents the iron from entering into further chemical reactions. It 
readily chelates iron from ferritin and hemosiderin but not readily from transferrin; it 
does not combine with the iron from cytochromes and hemoglobin. Long-term use of 
DFO is associated with stabilization or decline in all three measures of iron load and with 


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decreased iron-induced morbidity and with improved survival of transfusion-dependent 
thalassemia patients (Borgna-Pignatti C et al. 2004; Kwiatkowski JL. 2008).   
However, there are some important adverse reactions to deferoxamine.  These include 
local skin reactions which are almost universal, and auditory and visual disturbances.  
There is a susceptibility to certain gram-negative infections, in particular Yersinia 
enterocolitica, in patients who receive deferoxamine.   
 
1.4 
Study Rationale 
Deferiprone is an iron chelator that has been demonstrated to be effective in reducing iron 
load in transfusional siderosis. Its safety profile has been extensively characterized by 
more than 25 years of clinical experience, including 14 years of post-marketing 
experience outside of the US. The post-marketing experience with deferiprone exceeds 
44,000 patient years of drug exposure. The clinical trial and post-marketing populations 
comprise predominantly patients with thalassemia, although a small number of patients 
with sickle cell disease were included in clinical studies.  
Previous studies have shown that the iron excretion obtained with deferiprone at doses of 
75 and 100 mg/kg/day is sufficient to neutralize the iron accumulation that would 
inevitably occur in patients with SCD who are regularly transfused (Collins AF et al. 
1994).  In this study, deferiprone decreased the total body iron load significantly in 3 of 
the 4 patients with SCD. In a randomized clinical trial that included a total of 101 patients 
(60 patients with thalassemia intermedia and 41 patients with SCD), deferiprone was 
shown to reduce serum ferritin levels (information supplied by independent investigators; 
Maggio AF et al.).   
The current study is designed to collect additional information on the safety and efficacy 
of deferiprone in patients with sickle cell disease or other anemias (excluding thalassemia 
syndromes, MDS, myelofibrosis, Diamond Blackfan anemia and primary bone marrow 
failure) and transfusional hemosiderosis. As per the natural history study conducted by 
Fung et al. (Fung EB et al. 2007), the unadjusted death rate in transfused patients with 
SCD is 7.0/100 person years. Therefore, assuming that 100% of the patients enroll in this 
study are patients with SCD, 21 deaths are expected to occur during this 52-week study.  
  
2 
OBJECTIVES 
2.1 
Primary Objective 
To determine the efficacy of deferiprone vs. deferoxamine in the treatment of iron 
overload in patients with sickle cell disease or other anemias. 
2.2 
Secondary Objectives 
The secondary objectives are: 
o To evaluate the effect of deferiprone vs. deferoxamine on the patients’ quality of 
life; 
o To evaluate the safety and tolerability of deferiprone vs. deferoxamine. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design 
This study is a 52-week, prospective, multi-center, two-arm, randomized, open-label, 
parallel design of deferiprone therapy vs. deferoxamine. The study will consist of a 
Baseline Phase and a Treatment Phase. Three hundred (300) male and female patients 
with sickle cell disease (SCD) or other anemias requiring blood transfusion will be 
enrolled.  
 
3.2 
Discussion of Study Design 
This study has been designed to evaluate the efficacy, safety, and tolerability of 
deferiprone vs. deferoxamine in patients with SCD or other anemias requiring iron 
chelation. Patients will participate in a Baseline Phase followed by a Treatment Phase.  
Excluded from the study will be patients with thalassemia syndromes, myelodysplastic 
syndrome (MDS), myelofibrosis, Diamond Blackfan anemia and primary bone marrow 
failure.  
Baseline Phase: 
During the Baseline Phase, patients who sign an informed consent/assent form will 
undergo initial screening. On the final day of the Baseline Phase, patients’ eligibility will 
be determined, based on inclusion/exclusion criteria, and qualified patients will enter the 
Treatment Phase. 
 
Treatment Phase: 
At the beginning of the Treatment Phase, patients will be randomized in a 2:1 ratio to 
receive (1) deferiprone or (2) deferoxamine. The Treatment Phase will be 52 weeks in 
duration. At the end of the 52 weeks of treatment, patients will be invited to enter a 2-
year extension phase. 
Deferiprone treatment arm: 
During the study, patients will be prescribed Ferriprox 500 mg tablets or deferiprone 80 
mg/mL oral solution, according to patient preference or product’s availability, for 
administration three times a day (tid). The dose of deferiprone will be based on the 
transfusional iron input and the severity of iron load at baseline, and may be adjusted on 
the basis of the magnitude of change in iron overload during the study. 
Deferiprone 25 mg/kg tid: 
Patients with transfusional iron input ≤ 0.3 mg/kg/day in in the 3 months prior to 
baseline 
AND 
Patients with a baseline measure of iron load of: 
- Serum ferritin <2500 μg/L  


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AND 
- LIC <15 mg/g dry weight  
  
AND 
- Cardiac T2* > 20 ms 
 
Deferiprone 33 mg/kg tid: 
Patients with a transfusional iron input > 0.3 mg/kg/day in the 3 months prior to 
baseline 
OR  
 
Patients with at least one baseline measure of iron load as follows: 
- Serum ferritin ≥2500 μg/L  
OR  
- LIC ≥15 mg/g dry weight  
OR  
- Cardiac T2* ≤ 20 ms 
Dosing of all patients will be initially at 15 mg/kg tid for 1 week, which will be increased 
to 20 mg/kg tid in Week 2 and to 25 mg/kg tid in Week 3, which will be the treatment 
dose for the remainder of the trial, unless a patient meets the 33 mg/kg tid dosing criteria. 
In that case, the dose of deferiprone will be increased further to 33 mg/kg tid in Week 4, 
and this dose will be the treatment dose for the remainder of the trial.  
The dose of deferiprone will also be increased to 33 mg/kg tid at any time during the trial 
if the mean daily transfusional iron input increases to more than 0.3 mg/kg body weight 
for at least 3 consecutive months OR at Week 26 if there is less than 10% improvement 
from baseline to Week 26 in at least one of the measures indicative of iron overload 
(serum ferritin, cardiac MRI T2* or LIC). 
Dose reduction recommendations will be based on regular assessment of safety markers 
for adverse reactions that are possibly dose dependent, such as gastrointestinal upset, 
increases in serum liver enzyme levels, and arthropathies. 
Deferoxamine treatment arm: 
During the study, patients will be prescribed deferoxamine as per the approved US 
prescribing information at doses of 20 – 40 mg/kg/day for children (<16 years of age) and 
40–50 mg/kg/day in adults (≥16 years of age) as 8 – 12 h subcutaneous infusion for 5 – 7 
days per week.  The dose of deferoxamine will be based on the transfusional iron input, 
on the severity of iron load at baseline, and on the magnitude of its change during the study. 


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Deferoxamine 20 mg/kg/day (children) or 40 mg/kg/day (adults): 
Patients with transfusional iron input ≤ 0.3 mg/kg/day in the 3 months prior to baseline 
AND 
Patients with a baseline measure of iron load of: 
- Serum ferritin <2500 μg/L * 
AND 
- LIC <15 mg/g dry weight  
AND 
- Cardiac T2* > 20 ms 
* If there is a delay in obtaining the results of the baseline serum ferritin assessment 
from the central laboratory, the most recent result (obtained within the last 3 months) 
should be used to calculate the starting DFO dosage.  This dosage must remain in 
effect until the baseline serum ferritin results become available, at which time it is to 
be adjusted if necessary.  If no serum ferritin measure has been obtained within the last 
3 months, the start of dosing must be deferred until the baseline results are available. 
Deferoxamine up to 40 mg/kg/day (children) or 50 mg/kg/day (adults): 
Patients with a transfusional iron input > 0.3 mg/kg/day in the 3 months prior to baseline 
OR  
Patients with at least one baseline measure of iron load as follows: 
- Serum ferritin ≥2500 μg/L  
OR  
- LIC ≥15 mg/g dry weight  
OR  
- Cardiac T2* ≤ 20 ms 
Children (<16 years of age) 
The dose of deferoxamine will also be increased up to 40 mg/kg for 5 – 7 days per week 
at any time during the trial if the mean daily transfusional iron input increases to more 
than 0.3 mg/kg body weight for at least 3 consecutive months OR at Week 26 if there is 
less than 10% improvement from baseline to Week 26 in at least one of the measures of 
iron overload (serum ferritin, cardiac MRI T2* or LIC). 
Adults (≥16 years of age) 
The dose of deferoxamine will be increased up to 50 mg/kg for 5 – 7 days per week at 
any time during the trial if the mean daily transfusional iron input increases to more than 
0.3 mg/kg body weight for at least 3 consecutive months OR at Week 26 if there is less 


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than 10% improvement from baseline to Week 26 in at least one of the measures of iron 
overload (serum ferritin, cardiac MRI T2* or LIC). 
Dose reduction recommendations will be based on regular assessment of safety markers. 
Efficacy, safety and tolerability evaluations will occur according to the schedule of 
evaluation (Appendix 18.1). Rescue medication (intravenous administration of 
deferoxamine or combination of 2 iron chelators: deferiprone, deferoxamine or 
deferasirox) for the treatment of iron overload will not be allowed during the Treatment 
Phase. Should iron overload symptoms become intolerable for the patient despite dose 
adjustment, the Investigator should withdraw the patient from the study. 
If a patient withdraws early, he or she will return to the clinic for an Early Termination 
Visit as soon as possible, and no later than 1 month following treatment discontinuation. 
All of the efficacy and safety evaluations will be performed at the last study visit or the 
Early Termination visit, whichever comes first. 
 
3.3 
Study Sites and Study Duration 
Study sites will be located in but not limited to countries in North America, Europe, and 
the Middle East. While the goal will be to keep the number of sites to a minimum, it is 
expected that the study will engage sites worldwide due to the anticipated difficulty in 
enrolling patients with a 33% probability of being allocated to the deferoxamine 
treatment arm. 
Each patient is expected to participate in the study for approximately 60 weeks (from the 
Screening Visit to the End of Study Visit). 
 
4 
STUDY POPULATION 
4.1 
Number of Patients 
Three hundred (300) male and female patients with SCD disease or other anemias 
requiring blood transfusion will be enrolled in the study. Excluded from the study will be 
patients with thalassemia syndromes, MDS, myelofibrosis, Diamond Blackfan anemia, 
and primary bone marrow failure.  At least 80% of the enrolled patients will have sickle 
cell disease.  
Patients who withdraw from the study after starting study medication will not be replaced.  
 
4.2 
Inclusion Criteria 
Patients will be included in the study only if they meet all of the following criteria: 
1. Male or female ≥ 2 years of age; 
2. Have sickle cell disease (confirmed by Hb electrophoresis or more specific tests) 
or other conditions with iron overload from repeated blood transfusions (see 
exclusion criteria for exceptions); 


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3. Baseline LIC >7 mg/g dw (measured by MRI); 
4. Patients who have received no less than 20 transfusions of RBCs; 
5. Patients who have received at least 1 transfusion per year in the last 2 years and 
who are expected to have a continuing requirement (based on Investigator’s 
judgement) during the duration of the trial; 
6. Patients, and when applicable their legal representatives, will provide a signed and 
dated written assent/informed consent prior to the first study intervention; patients 
will be able to adhere to study restrictions, appointments and evaluation schedule. 
7. Female patients of childbearing potential must have a negative pregnancy test 
result at Screening and Baseline Visits. In addition, a female patient of 
childbearing age who is sexually active must confirm that during the study and for 
30 days following the completion of the study or early termination she: 
 will use an effective method of contraception, OR 
 has had a tubal ligation (supporting evidence required), OR 
 has had a hysterectomy (supporting evidence required), OR 
 participates in a non-heterosexual lifestyle, OR 
 indicates her only male sexual partner has been sterilized (supporting 
evidence required).  
Effective methods of contraception include oral contraceptives, intrauterine 
devices (IUDs) or condom, providing it is used with contraceptive foam or cream, 
or abstinence from sexual intercourse. Supporting evidence for sterilization 
consists of a surgical report or letter from the family physician; 
8. If the patient is a heterosexual sexually-active fertile male, patient must confirm, 
in writing, that he and/or his female partner will use an effective method of 
contraception for the length of the trial and for 30 days following completion of 
the study or early termination. Effective methods of contraception for males 
include condoms or sterilization or abstinence from sexual intercourse. 
 
4.3 
Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 
1. Thalassemia syndromes; 
2. Myelodysplastic syndrome (MDS) or myelofibrosis; 
3. Diamond Blackfan anemia; 
4. Primary bone marrow failure;  


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5. Patients with a baseline LIC >30 mg/g dw (measured by MRI); 
6. Unable or unwilling to undergo a 7-day washout period if currently being treated 
with deferiprone or deferoxamine or deferasirox; 
7. Previous discontinuation of treatment with deferiprone or deferoxamine due to 
adverse events; 
8. History or presence of hypersensitivity or idiosyncratic reaction to deferiprone or 
deferoxamine; 
9. Treated with hydroxyurea within 30 days; 
10. History of malignancy; 
11. Evidence of abnormal liver function (serum ALT level(s) > 5 times upper limit of 
normal at screening or creatinine levels >2 times upper limit of normal at 
screening); 
12. A serious, unstable illness, as judged by the Investigator, during the past 3 
months before screening/baseline visit including but not limited to: hepatic, 
renal, gastro-enterologic, respiratory, cardiovascular, endocrinologic, neurologic 
or immunologic disease. 
13. Clinically significant abnormal 12-lead ECG findings; 
14. Cardiac MRI T2* <10 ms  
15. Myocardial infarction, cardiac arrest or cardiac failure within 1 year before 
screening/baseline visit; 
16. Bowel disease causing malabsorption; 
17. HIV positive patient; 
18. Unable to undergo MRI; 
19. Presence of metallic objects such as artificial joints, inner ear (cochlear) 
implants, brain aneurysm clips, pacemakers, and metallic foreign bodies in the 
eye or other body areas that would prevent use of MRI imaging; 
20. History of alcohol or drug abuse; 
21. Treatment with an investigational drug within 30 days or 5 half-lives (whichever 
is longer) preceding the first dose of study medication; 
22. Participation in another clinical trial during the conduct of this study; 
23. Pregnant, nursing females and females of childbearing potential who are sexually 
active and unwilling, or unable, to use an acceptable method of contraception; 
24. Mental incapacity, unwillingness or language barriers precluding adequate 
understanding or co-operation; 
25. Any condition that, in the opinion of the Investigators, would adversely affect 
ability to complete the study or its assessments. 
 


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4.4 
Enrolment Violations 
The criteria for enrolment must be followed explicitly.  If there is inadvertent enrolment 
of patients who do not meet enrolment criteria, such patients should be withdrawn from 
the study. 
 
4.5 
Withdrawal Criteria 
A patient has 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. The reason for withdrawal 
will be sought. 
When a patient decides to withdraw from the study, he/she should always be contacted, 
not only to determine the reason(s) for withdrawing, but also to determine if there were 
any adverse events (AEs).  Whenever possible, the patient should return for a clinic visit 
at the time of or soon after discontinuation of study medication but no later than 1 month 
after treatment discontinuation.  All investigational products and materials should be 
returned.  If any AEs occurred, the Investigator must attempt to follow up with the 
outcome for 30 days post-study withdrawal. 
Data collected for patients who are withdrawn after receiving the study drug should be 
evaluated for efficacy and safety.  
If, for any reason, the Investigator decides to withdraw a patient before completing the 
study, the reason for withdrawal must be entered into the source document and the 
electronic case report form (eCRF). 
A patient may be withdrawn from the study at any time for any of the following reasons: 
 Patient request; 
 Medical reasons considered significant by the patient and/or Investigator;  
 Requirement for concomitant medication that may interfere with the evaluation of 
study medication, or may be contraindicated; 
 Occurrence of other illnesses that affect the patient’s further participation in the 
study or evaluation of study medication; 
 Significant changes in QTcF interval (defined as QTcF change of greater than 60 
ms) are detected; 
 Any other situation where, in the opinion of the Investigator, continuation of the 
study would not be in the best interest of the patient. 
A patient must be withdrawn from the study if any of the following conditions apply: 
 Pregnant or planning to become pregnant (see Section 9.2 Procedures in Case of 
Pregnancy); 
 Occurrence of any adverse reaction characterized as life-threatening or disabling;  


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 Non-compliance with blood counts.  During the first 6 months, if a patient misses a 
weekly ANC monitoring visit, then missing a further 3 of the next 5 visits (i.e., a 
total of 4 out of 6) will result in automatic withdrawal.  During the last 6 months, 
ANC monitoring will be done biweekly, and missing 3 consecutive biweekly blood 
counts will result in automatic withdrawal.  
 Termination of the study by the Sponsor; 
 Patient experiences severe neutropenia/ agranulocytosis (refer to Section 8.2.4.9 for 
definition and management). 
4.6 
Treatment Interruptions 
Study medication will be interrupted for ANY of the following reasons: 
 If the patient develops an infection during the study, deferiprone must be interrupted 
immediately and neutrophil count should be obtained and monitored more frequently 
(every 2 days if ANC <1.5 x 109/L). Patients should be advised to report immediately 
to their physician any symptoms indicative of infection such as fever, sore throat, and 
flu-like symptoms. They will be provided with a thermometer, and instructed to seek 
immediate medical attention at a hospital or clinic if they experience fever 
(temperature >38.0° C/100.4°F).  Body temperature may be measured at the mouth, 
axilla, or ear. Patients/legal guardians will be provided with an emergency services 
card with contact information, and will be advised to carry this card at all times. In 
presence of confirmed fever and/or infection, patients will be required to have their 
neutrophil counts tested as soon as possible and no later than 24 hours after the 
symptoms of infection are detected. Therapy with deferiprone can be re-initiated 
once all symptoms have been resolved and it is deemed safe by the Investigator.   
 If temperature is >38.0°C/100.4°F and ANC is ≤0.5 x 109/L, the following must be 
done: 
o 
Commence therapy with antibiotics immediately (treatment should depend on 
the site of the suspected infection and on local antibiotic policy) 
o 
Perform a chest x-ray, and collect blood and other relevant cultures (if possible, 
collect culture samples before initiating antibiotics)  
 If the patient develops moderate neutropenia while on deferiprone (refer to Section 
8.2.4.9 for definition), therapy must be interrupted immediately and neutrophil count 
must be obtained and monitored every 2 days.  Therapy with deferiprone can be 
re-initiated once two successive ANCs are >1.5 x 109/L and it is deemed safe by the 
Investigator. The patient will be withdrawn from the study if the ANC remains <1.5 
x 109/L by the end of a two-week period (14 days) (Section 8.2.4.9). 
4.7 
Pregnancy 
All female participants of childbearing potential will be administered a serum and urine 
pregnancy test prior to starting study medication. A negative test result will be required 
prior to study entry. Patients of childbearing potential should not become pregnant during 
the study and therefore must agree to use an approved method of contraception (as 


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defined in Appendix 18.2) for 30 days prior to Day 1 (at least 3 months for hormonal 
contraceptives), throughout the course of the trial, and for 30 days following early 
termination or the last visit. 
In the situation where a female patient is withdrawn prematurely from the study because 
of a pregnancy, study medication must be stopped immediately, the Sponsor must be 
informed immediately via the Pregnancy Report Form, and the patient must be closely 
followed up during her pregnancy, as much as possible. Update reports must be provided 
to the ApoPharma Medical Safety department at mid-pregnancy and at delivery or at 
termination of the pregnancy. 
Male patients must inform the Investigator if their female partner becomes pregnant 
during the trial or within one month after trial completion. 
4.8 
Allocation of Patient Numbers 
After signing of the Informed Consent/Assent Form (ICF/AF) by patients and/or patients’ 
legal representatives, if applicable, patients will be assigned a unique patient ID number. 
A patient ID number will consist of six digits.  The first three digits represent the site 
code (00X for the X site). These three digits will be used in combination with a three-
digit rolling number that will be sequentially assigned by the site to patients who sign the 
ICF/AF.  This number would start at 001 for each site.  For example, if site 001 has eight 
patients, the patient ID number would be 001001 to 001008. The patient ID number 
would start again for site 002 at 002001. If a patient is withdrawn after receiving his or 
her patient ID number, the number will not be reused.  For the purpose of the study, 
patients will be referred to by their patient ID number. 
4.9 
Method of Assignment to Treatment 
At the baseline visit, patients will be randomly assigned to receive deferiprone or 
deferoxamine in a 2:1 ratio.  Stratified randomization based on disease category (sickle 
cell disease vs. other anemias) and on the transfusional iron input in the 3 months prior to 
baseline (> 0.3 mg/kg/day vs. ≤ 0.3 mg/kg/day) will be employed to ensure that the 2:1 
ratio is maintained within each of the 4 strata: 1) sickle cell disease with transfusional 
iron input > 0.3 mg/kg/day, 2) sickle cell disease with transfusional iron input ≤ 0.3 
mg/kg/day, 3) other anemias with transfusional iron input > 0.3 mg/kg/day, and 4) other 
anemias with transfusional iron input ≤ 0.3 mg/kg/day.  A randomization list will be 
generated for each stratum, assigning study medication to individual randomization 
numbers in blocks of 6. Treatment assignment and drug allocation will be performed by 
an Interactive Voice Response System (IVRS). 
5 
STUDY PROCEDURES  
5.1 
Entry Procedures 
An Informed Consent Form (ICF)/assent form (AF) approved by a recognized IRB/IEC, 
and local regulatory bodies, if applicable, will be signed and dated by the patient and 
when applicable, the patient’s authorized legal representative prior to the patient’s 
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be provided with a copy of the signed ICF/AF. The original ICF/AF will be kept by the 
Investigator. Patients who sign an ICF/AF will undergo Baseline Phase procedures. 
All transfusions must be performed during a study visit (i.e., during weekly, biweekly, 
monthly, quarterly, or semi-annual visits) for the entire study duration, except for those 
patients who may require emergency transfusion. Data of all transfusions performed 
during the trial, including type of transfusion (simple, exchange, partial exchange), 
volume of blood that the patient received during the transfusion, and the mean hematocrit 
of the packed red blood cell units transfused, must be recorded in the eCRF and source 
documents. Iron input per transfusion will be calculated based on the information 
collected throughout the study. 
 
5.2 
Screening/Baseline Visit (Day -60 to Day -1: Visit -1) 
Assessment of eligibility: 
The following procedures will take place at the Screening/Baseline visit: 
 Explain the study to the patient and/or parent/legal representative, obtain written 
informed consent/assent, and give a copy to the patient and/or parent/legal 
representative; 
 Assign the patient ID number (see Section 4.8); 
 Review previous/current chelation therapy; 
 Record demographic information; 
 Obtain medical history; 
 Obtain transfusion history; 
 Record prior and current medication(s); 
 Collect blood sample for hematology, biochemistry (fasting glucose; patient must 
come to the site following a 10-hour fast), and serology (to be conducted within 
14 days of starting study medication; will be considered as the baseline 
procedures for biochemistry);  
 Collect blood sample for pregnancy testing for all females of childbearing 
potential. A negative result will be required for start of dosing; 
 Collect urine for urinalysis; 
 Perform physical examination (to be completed by Investigator or a  qualified 
delegate); 
 Take vital signs, weight, and height; 
 Perform 12-lead ECG; 
 If patient is identified as potentially eligible based on the available data (medical 
history, transfusional history, current  medication(s), physical examination, vital 
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o Liver, and transmit to a central laboratory for interpretation and LIC 
calculation (to be conducted within two months prior to starting study 
drug; will be considered as the baseline procedure);  
o Cardiac MRI T2*, and transmit to a central laboratory for interpretation 
(to be conducted within two months prior to starting study drug; will be 
considered as the baseline procedure); 
 Conduct contraceptive counselling for all sexually active patients; 
 Review inclusion/exclusion criteria; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that she/he must carefully keep track of medical events and medication used to 
treat them; 
 Instruct eligible patients to start washout of current chelation therapy (if required) 
7 days prior to the baseline visit, and washout of hydroxyurea (if required) 30 
days prior to the baseline visit; 
 Schedule next study visit. 
 
5.3 
Baseline Visit (Day 0, Visit 0) 
Enrolment and Baseline Assessments: 
Once the results of the screening/baseline visit procedures have been obtained, they 
should be reviewed against the inclusion/exclusion criteria to confirm the patient’s 
eligibility to enter the trial. If the patient is determined to be eligible, perform the 
following Baseline assessments: 
 Collect blood sample for hematology (the results of this procedure will be 
considered the baseline values). An ANC value of  >1.5 x 109/L will be required 
for start of dosing;  
 Collect blood sample for serum ferritin; 
 Collect blood and urine samples for pregnancy testing for all females of 
childbearing potential. A negative result of the urine test will be required for start 
of dosing. This result will have to be reconfirmed by the results of the serum 
pregnancy test; 
 Determine if patient has had any medical events or used any new medications/
changed medications or changed dose or frequency of medication since the 
screening visit. If so, document them as specified in Sections 8.2.1 and 8.2.4.3;  
 Confirm eligibility; 
 Randomize patient; 
 Take vital signs (including weight); 


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 Collect blood sample for assessing genetic polymorphism related to deferiprone -
induced agranulocytosis (optional); 
 Complete patient-reported  quality of life questionnaire (SF-36 or Child Health 
Questionnaire); 
 Review and update transfusion history; 
 Conduct contraceptive counselling for all sexually active patients; 
 Perform dose calculation; 
 Dispense study medication as per Section 7.4; 
 Instruct the patient, and/or if applicable patient’s authorized legal representative, 
how to take the medication; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that all used (empty bottles) and unused medication must be returned at each 
monthly study visit; 
 Provide a patient diary card, explain how to complete it, and remind patient to 
return completed card at next visit; 
 Remind patient to visit the site or a local laboratory for the weekly blood draws; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that she/he must carefully keep track of adverse events and medication used to 
treat them; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that if study medication is stopped early, she/he must return to the clinic for an 
Early Termination Visit as soon as possible, but no later than 1 month following 
study medication discontinuation;  
 Remind patient, and/or if applicable patient’s authorized legal representative, that 
if an infection develops, therapy must be interrupted immediately. Patients should 
be advised to report immediately to their physician any symptoms indicative of 
infection such as fever, sore throat, and flu-like symptoms. In presence of 
confirmed fever and/or infection, they will be required to have their neutrophil 
counts tested as soon as possible and no later than 24 hours after the symptoms of 
infection are detected;  
 Provide patient and/or if applicable patient’s authorized legal representative with 
an emergency card and advise her/him to carry this card at all times; 
 Schedule next study visit. 
 
5.4 
Weekly or Biweekly Assessments 
The hematology assessments that are required weekly (± 3 days) up to Week 26 and 
biweekly (± 3 days) thereafter can be conducted at local laboratories or study sites, and 
will consist of the following procedures:  


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 Collect blood sample for hematology. Hematology results should be reviewed by 
the Investigator as soon as they are received from the laboratory; 
 If a patient is receiving a blood transfusion during this visit or has received blood 
transfusions since the last visit (except for those patients who received an 
emergency transfusion), record the type of transfusion (simple, exchange, partial 
exchange), volume of blood that the patient received during the transfusions, and 
the mean hematocrit of the packed red blood cell units transfused (data obtained 
from the site’s blood bank).  
5.5 
Telephone Calls (Weeks 1, 2 and 3) 
The patient and/or legal representative must be contacted by telephone weekly (every 7 
 3 days) on Weeks 1, 2 and 3 to ensure that the titration of dose or treatment is 
proceeding satisfactorily. 
If the patient appears to be having difficulty with the treatment, patient and/or legal 
representative should be contacted again, as frequently as necessary. 
Remind the patient/legal representative that if treatment is stopped early, patient must 
return to the clinic for an Early Termination Visit as soon as possible, but no later than 1 
month following treatment discontinuation. 
Remind patients to interrupt therapy immediately if they develop an infection. Patients 
must be advised to report promptly to the Investigator any symptoms indicative of 
infection such as fever, sore throat, or flu-like symptoms. In presence of confirmed 
fever and/or infection, they will be required to have their neutrophil counts tested as 
soon as possible and no later than 24 hours after the symptoms of infection are detected. 
All telephone contacts must be fully documented as follows: 
 
Record date and time of contact; 
 
Record name of person contacted (patients, parent, legal representative); 
 
Remind the patient and/or legal representative of the study medication dose and 
instructions on how to take medication; 
  Record any adverse events 
 
Note if the patient has used any concomitant medications. If so, document them 
as specified in Sections 8.2.4.3, 8.2.4.8, and 8.2.1; 
 
Remind patient to visit the site or a local laboratory for the weekly blood draws; 
 
Reconfirm the next study visit; 
 
Include the name and signature of the person contacting the patient. 
 
5.6 
Monthly Visits (Weeks 4, 8, 16, 20, 32, 36, 44 and 48 Visits) 
Weeks 4, 8, 16, 20, 32, 36, 44 and 48 visits assessments will consist of the following 
procedures. Each visit could occur between -7 or +7 days from the indicated visit day. 


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 Take vital signs and weight; 
 Collect blood sample for hematology and biochemistry;  
 Collect blood sample for pregnancy testing for all females of childbearing 
potential. A negative result will be required for study continuation; 
 Review patient diary card with the patient, and/or if applicable patient’s 
authorized legal representative, then collect and file the diary card with the source 
documents; provide new diary card, and remind patient how to complete the diary 
card. 
 Determine if patient has had any AEs or SAEs or used any concomitant 
medications. If so, document them as specified in Sections 6.3 and 8.2.4;  
 Conduct contraceptive counselling for all sexually active patients; 
 Collect and account for the medication dispensed at the previous applicable visit; 
 Verify/adjust dose level, according to recommendations; 
 Dispense the study medication as per Section 7.4; 
 Instruct the patient, and/or if applicable patient’s authorized legal representative, 
how to take the medication; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that all used and unused medication bottles must be returned at the next monthly, 
quarterly or semi-annual study visit; 
 Provide a new patient diary card and explain how to complete it; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that she/he must carefully keep track of adverse events and medication used to 
treat them as well as any other medication taken; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that if study medication is stopped early, she/he must return to the clinic for an 
Early Termination Visit as soon as possible, but no later than 4 weeks following 
study medication discontinuation;  
 Remind patient, and/or if applicable patient’s authorized legal representative, if an 
infection develops, therapy must be interrupted immediately. Patients should be 
advised to report immediately to their physician any symptoms indicative of 
infection such as fever, sore throat, and flu-like symptoms In presence of 
confirmed fever and/or infection, they will be required to have their neutrophil 
counts tested as soon as possible and no later than 24 hours after the symptoms of 
infection are detected; 
 If the patient is receiving a blood transfusion during this visit or has received 
blood transfusions since the last visit (except for those patients who received an 
emergency transfusion), record the type of transfusion (simple, exchange, partial 
exchange), volume of blood that the patient received during the transfusions, and 


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the mean hematocrit of the packed red blood cell units transfused (data obtained 
from the site’s blood bank); 
 Remind patient to visit the site or a local laboratory for the weekly (applicable at 
Weeks 4, 8, 16, and 20) or biweekly (applicable at Weeks 32, 36, 44, and 48)  
blood draws; 
 Schedule next study visit. 
 
5.7 
Quarterly Visits (Weeks 12 and 40 Visits) 
Weeks 12 and 40 visits assessments will consist of the following procedures. Each visit 
could occur between -7 and +7 days from the indicated visit day. 
 Take vital signs and weight; 
 Collect blood sample for serum ferritin, hematology and biochemistry;  
 Collect blood sample for pregnancy testing for all females of childbearing 
potential. A negative result will be required for study continuation; 
 Review patient diary card with the patient, and/or if applicable patient’s 
authorized legal representative, then collect and file the diary cards with the 
source documents; provide new diary card, and remind patient how to complete 
the diary card. 
 Determine if patient has had any AEs or SAEs or used any concomitant 
medications. If so, document them as specified in Sections 6.3 and 8.2.4; 
 Conduct contraceptive counselling for all sexually active patients; 
 Collect and account for the medication dispensed at the previous applicable visit; 
 Verify/adjust dose level, according to recommendations; 
 Dispense the study medication as per Section 7.4; 
 Instruct the patient, and/or if applicable patient’s authorized legal representative, 
how to take the medication; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that all used and unused medication bottles must be returned at the next monthly 
or semi-annual study visit; 
 Provide a new patient diary card and explain how to complete it; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that she/he must carefully keep track of adverse events and medication used to 
treat them as well as any other medication taken; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that if study medication is stopped early, she/he must return to the clinic for an 
Early Termination Visit as soon as possible, but no later than 4 weeks following 
study medication discontinuation; 


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 Remind patient, and/or if applicable patient’s authorized legal representative, that 
if an infection develops, therapy must be interrupted immediately. Patients should 
be advised to report immediately to their physician any symptoms indicative of 
infection such as fever, sore throat, and flu-like symptoms In presence of 
confirmed fever and/or infection, they will be required to have their neutrophil 
counts tested as soon as possible and no later than 24 hours after the symptoms of 
infection are detected; 
 If the patient is receiving a blood transfusion during this visit or has received 
blood transfusions since the last visit (except for those patients who received an 
emergency transfusion), record the type of transfusion (simple, exchange, partial 
exchange), volume of blood that the patient received during the transfusions, and 
the mean hematocrit of the packed red blood cell units transfused (data obtained 
from the site’s blood bank); 
 
Remind patient to visit the site or a local laboratory for the weekly (applicable at 
Week 12) or biweekly (applicable at Week 40) blood draws; 
 Schedule next study visit. 
 
5.8 
Semi-Annual Visit (Week 26 Visit) 
Week 26 visits assessments will consist of the following procedures. This visit should 
occur between -7 and +7 days from the indicated visit day. 
 Perform physical examination; 
 Take vital signs (including weight and height); 
 Collect blood sample for serum ferritin, hematology, biochemistry and serology;  
 Collect blood sample for pregnancy testing for all females of childbearing 
potential. A negative result will be required for study continuation; 
 Collect urine for urinalysis; 
 Perform 12-lead ECG;  
 Perform MRI scan for: 
 Liver,  and  transmit to a central laboratory for interpretation and LIC 
calculation; 
 Cardiac MRI T2*, and transmit to a central laboratory for interpretation; 
 Complete patient-reported quality of life questionnaire (SF-36 or Child Health 
Questionnaire);  
 Review patient diary card with the patient, and/or if applicable patient’s 
authorized legal representative; then collect and file the diary card with the source 
documents, provide new diary card, and remind patient how to complete the diary 
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 Determine if patient has had any AEs or SAEs or used any concomitant 
medications. If so, document them as specified in Sections 6.3 and 8.2.4;  
 Receive and account for the medication dispensed at the previous applicable visit; 
 Conduct contraceptive counselling for all sexually active patients; 
 Verify/adjust dose level, according to recommendations; 
 Dispense the study medication as per Section 7.4; 
 Instruct the patient, and/or if applicable patient’s authorized legal representative, 
how to take the medication; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that all used and unused medication bottles must be returned at the next monthly 
or quarterly study visit; 
 Provide a new patient diary card and explain how to complete it; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that she/he must carefully keep track of adverse events and medication used to 
treat them as well as any other medication taken; 
 Remind the patient, and/or if applicable patient’s authorized legal representative, 
that if study medication is stopped early, she/he must return to the clinic for an 
Early Termination Visit as soon as possible, but no later than 4 weeks following 
study medication discontinuation;  
 Remind patient, and/or if applicable patient’s authorized legal representative, that 
if an infection develops, therapy must be interrupted immediately. Patients should 
be advised to report immediately to their physician any symptoms indicative of 
infection such as fever, sore throat, and flu-like symptoms In presence of 
confirmed fever and/or infection, they will be required to have their neutrophil 
counts tested as soon as possible and no later than 24 hours after the symptoms of 
infection are detected; 
 If the patient is receiving a blood transfusion during this visit or has received 
blood transfusions since the last visit (except for those patients who received an 
emergency transfusion), record the type of transfusion (simple, exchange, partial 
exchange), volume of blood that the patient received during the transfusions, and 
the mean hematocrit of the packed red blood cell units transfused (data obtained 
from the site’s blood bank); 
 
Remind patient to visit the site or a local laboratory for the biweekly blood 
draws; 
 Schedule next study visit. 
 


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5.9 
End of Study Visit (Week 52 or Early Termination Visit) 
The End of Study assessment (at 52 weeks  7 days from the start of study medication) or 
Early Termination will consist of the following procedures: 
 Perform physical examination; 
 Review medical history and concurrent medications; 
 Take vital signs, weight, and height; 
 Collect blood sample for serum ferritin, hematology, biochemistry (fasting 
glucose; patient must come to the site following a 10-hour fast), and serology;  
 Collect blood sample for pregnancy testing for all females of childbearing 
potential; 
 Collect urine for urinalysis; 
 Perform 12-lead ECG; 
 Perform MRI scan for: 
 Liver, and  transmit to a central laboratory for interpretation and LIC 
calculation; 
 Cardiac MRI T2* and transmit to a central laboratory for interpretation; 
 Complete patient-reported quality of life questionnaire (SF-36 or Child Health 
Questionnaire); 
 Review patient diary card with the patient, and/or if applicable patient’s 
authorized legal representative, then collect and file the diary card with the source 
documents; 
 Determine if patient has had any AEs or SAEs or used any concomitant 
medications. If so, document them as specified in Sections 6.3 and 8.2.4; 
 If the patient has received blood transfusions since the last visit (except for those 
patients who received an emergency transfusion), record the type of transfusion 
(simple, exchange, partial exchange), volume of blood that the patient received 
during the transfusions, and the mean hematocrit of the packed red blood cell 
units transfused (data obtained from the site’s blood bank); 
 Collect and account for the medication dispensed at the previous applicable visit; 
 Explain to the patient, and/or if applicable the patient’s authorized legal 
representative, that she or he should inform the site if she/he experiences any 
serious medical problems (SAEs) in the 30 days following the last dose; 
 Follow up on any continuing adverse events or serious adverse events until 
resolution, until the condition stabilizes, until the event is otherwise explained, or 
until the patient is lost to follow-up. 
 


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5.10 Early Termination 
Patients can be withdrawn from the study at any time. Reasons for withdrawal will be 
documented in the source document and eCRF, and early termination visit procedures 
should be performed within 1 month. 
These data should be recorded and entered in the eCRF, as they constitute essential data 
from an evaluation that should be conducted prior to discharging any patient from the 
study. 
6 
TREATMENT 
6.1 
Study Medication 
The treatment phase of the study will last 52 weeks, beginning on the day of the first dose 
of the study medication.  Dispense the study medication as per Section 7.4. As per 
Section 4.6.5 and 4.6.6 of the ICH Consolidated Guideline on GCP, the Investigator is 
responsible for ensuring that the investigational products are used only in accordance 
with the approved protocol, that the correct use of the medication has been clearly 
explained by the Investigator or delegate to each patient, and that the patient continues to 
take the medication according to those instructions throughout the trial. 
Deferiprone treatment arm: 
During the study, patients will be prescribed Ferriprox 500 mg tablets or deferiprone 80 
mg/mL oral solution, according to patient preference or product’s availability, for 
administration three times a day (tid). The dose of deferiprone will be based on the 
transfusional iron input and the severity of iron load at baseline, and may be adjusted on 
the basis of the magnitude of change in iron overload during the study. 
Deferiprone 25 mg/kg tid: 
Patients with transfusional iron input ≤ 0.3 mg/kg/day in the 3 months prior to baseline 
AND 
Patients with a baseline measure of iron load of: 
- Serum ferritin <2500 μg/L  
AND 
- LIC <15 mg/g dry weight  
AND 
- Cardiac T2* > 20 ms 
 
Deferiprone 33 mg/kg tid: 
Patients with a transfusional iron input > 0.3 mg/kg/day in the 3 months prior to 
baseline 
OR  


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Patients with at least one baseline measure of iron load as follows: 
- Serum ferritin ≥2500 μg/L  
OR  
- LIC ≥15 mg/g dry weight  
OR  
- Cardiac T2* ≤ 20 ms 
Dosing of all patients will be initially at 15 mg/kg tid for 1 week, which will be increased 
to 20 mg/kg tid in Week 2 and to 25 mg/kg tid in Week 3, which will be the treatment 
dose for the remainder of the trial, unless a patient meets the 33 mg/kg tid dosing criteria. 
In that case, the dose of deferiprone will be increased further to 33 mg/kg tid in Week 4 
and this dose will be the treatment dose for the remainder of the trial.  
The dose of deferiprone will also be increased to 33 mg/kg tid at any time during the trial 
if the mean daily transfusional iron input increases to more than 0.3 mg/kg body weight 
for at least 3 consecutive months OR at Week 26 if there is less than 10% improvement 
from baseline to Week 26 in at least one of the measures indicative of iron overload 
(serum ferritin, cardiac MRI T2* or LIC). 
Dose reduction recommendations will be based on regular assessment of safety markers 
for adverse reactions that are possibly dose dependent, such as gastrointestinal upset, 
increases in serum liver enzyme levels, and arthropathies. 
 
Deferoxamine treatment arm: 
During the study, patients will be prescribed deferoxamine as per the approved US 
prescribing information at doses of 20 – 40 mg/kg/day for children (<16 years of age) and 
40–50 mg/kg/day in adults (≥16 years of age) as 8 – 12 h subcutaneous infusion for 5 – 7 
days per week.  The dose of deferoxamine will be based on the transfusional iron input, 
on the severity of iron load at baseline, and on the magnitude of its change during the 
study. 
Deferoxamine 20 mg/kg/day (children) or 40 mg/kg/day (adults): 
Patients with transfusional iron input ≤ 0.3 mg/kg/day in the 3 months prior to baseline 
AND 
Patients with a baseline measure of iron load of: 
- Serum ferritin <2500 μg/L * 
AND 
- LIC <15 mg/g dry weight  
AND 
- Cardiac T2* > 20 ms 


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* 
If there is a delay in obtaining the results of the baseline serum ferritin 
assessment from the central laboratory, the most recent result (obtained within 
the last 3 months) should be used to calculate the starting DFO dosage.  This 
dosage must remain in effect until the baseline serum ferritin results become 
available, at which time it is to be adjusted if necessary.  If no serum ferritin 
measure has been obtained within the last 3 months, the start of dosing must 
be deferred until the baseline results are available. 
 
Deferoxamine up to 40 mg/kg/day (children) or 50 mg/kg/day (adults): 
Patients with a transfusional iron input > 0.3 mg/kg/day in the 3 months prior to 
baseline  
OR  
Patients with at least one baseline measure of iron load as follows: 
- Serum ferritin ≥2500 μg/L  
OR  
- LIC ≥15 mg/g dry weight  
OR  
- Cardiac T2* ≤ 20 ms 
 
Children (<16 years of age) 
The dose of deferoxamine will also be increased up to 40 mg/kg for 5 – 7 days per week 
at any time during the trial if the mean daily transfusional iron input increases to more 
than 0.3 mg/kg body weight for at least 3 consecutive months OR at Week 26 if there is 
less than 10% improvement from baseline to Week 26 in at least one of the measures of 
iron overload (serum ferritin, cardiac MRI T2* or LIC). 
Adults (≥16 years of age) 
The dose of deferoxamine will be increased up to 50 mg/kg for 5 – 7 days per week at 
any time during the trial if the mean daily transfusional iron input increases to more than 
0.3 mg/kg body weight for at least 3 consecutive months OR at Week 26 if there is less 
than 10% improvement from baseline to Week 26 in at least one of the measures of iron 
overload (serum ferritin, cardiac MRI T2* or LIC). 
Dose reduction recommendations will be based on regular assessment of safety markers. 
 
6.2 
Rationale for Selection of Doses 
Deferiprone: 
In thalassemia syndromes, the dose of 25 to 33 mg/kg body weight three times a day for a 
total daily dose of 75 to 99 mg/kg, seven days a week, has been approved on the basis 


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that it is able to reduce or control transfusional iron burden.  The transfusion regimen in 
SCD patients in this study is similar to that employed in patients with thalassemia major, 
and as such, is expected to be capable of offsetting iron accumulation in the majority of 
transfusion-dependent patients (Bansal RK. 2002; Longo F et al. 1999; Pennell DJ et al. 
2006; Piga A et al. 2003; Rombos Y et al. 2000; Taher A et al. 2005; Wonke B et al. 1998). 
The recommended initial dose of deferiprone is 25 mg/kg, orally, three times per day for 
a total of 75 mg/kg/day. The maximum dose is 33 mg/kg, three times per day for a total 
of 99 mg/kg/day.  
Deferoxamine: 
Initial and maximal doses recommendations for deferoxamine are based on its 
prescribing information. 
 
6.3 
Prior and Concomitant Medications 
All medications taken during the 3 months prior to dosing up to the end of the study 
(Week 52 or early termination) will be recorded and reviewed by the Investigator. 
Medications considered necessary for the patient’s welfare may be given at the discretion 
of the Investigator.  The administration of all medications (including study product, 
herbal medications, and over-the-counter medications) and nutrition supplements must be 
recorded in the source document and the appropriate sections of the eCRF.  During 
treatment with deferiprone, patients must not receive any other investigational product or 
any drugs that are known to cause neutropenia or agranulocytosis. See Appendix 18.3 for 
a list of prohibited drugs. 
 
6.4 
Rescue Medication 
Rescue medication (intravenous administration of deferoxamine or combination of 2 iron 
chelators: deferiprone, deferoxamine or deferasirox) for the treatment of iron overload 
will not be allowed during the study. Should symptoms become intolerable for the 
patient, dose adjustment should be attempted. If the treatment is unsuccessful, the 
Investigator may decide to withdraw the patient from the study to optimize treatment. 
 
6.5 
Treatment Compliance 
Patients will be instructed on how to take the study medication. A medication usage diary 
card will be provided to the patients by the study staff.  Patients will record the number of 
tablets or volume of oral solution taken, or the volume of injection solution administered 
and the time of injection. For deferiprone, compliance will be evaluated monthly by the 
Investigator or delegate by monthly pill counts or volume of drug returned by the patient. 
For deferoxamine, compliance will be evaluated by the number of infusions performed, 
which will be recorded monthly through the use of infusion pumps that keep records of 
those numbers, and by physical assessment of the infusion sites. 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 and, if applicable, 
his/her parent or legal representative, at each visit. 


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Compliance reported in the eCRF will be based on the patient’s diary and compliance 
calculation. If compliance is greater than 100% and the patient reports taking all doses as 
prescribed, compliance will be reported as 100% in the eCRF.  
Compliance <80% and an over-compliance of >120% will be reported as a protocol 
deviation. 
7 
MATERIALS AND SUPPLIES  
7.1 
Study Medication  
Deferiprone: 
Deferiprone will be supplied to the clinical sites by ApoPharma Inc. as 500 mg film-
coated scored tablets and/or 80 mg/mL oral solution. It will be manufactured by Apotex 
Inc., Toronto, Ontario, Canada, and will have been tested and released according to 
appropriate standards and regulations.  
 
Deferoxamine: 
Deferoxamine will be obtained from Hospira Inc.  It will be provided by ApoPharma Inc. 
to the clinical sites as 2 g vials of sterile deferoxamine mesylate. The vials are to be 
stored as per label requirement, and their contents are to be dissolved according to the 
instructions provided by the investigator or qualified designate. 
 
7.2 
Packaging and Labelling 
Study medication will be supplied by the Sponsor to the Investigator for each patient 
enrolled and randomized in the clinical trial. Study medication provided must only be 
used to treat patients enrolled in this clinical trial. 
 
Ferriprox tablets will be supplied in bottles of 100 tablets each, high-density polyethylene 
(HDPE) bottles with child-resistant closure and appropriately labelled. Deferiprone 80 
mg/mL oral solution will be supplied in 250 mL bottles with child-resistant closure and 
appropriately labelled. 
Deferoxamine will be supplied in vials of 2 g and appropriately labelled. 
The contents of the label will be in accordance with all applicable regulatory 
requirements. The label will include protocol number, expiry date, lot/batch number, 
investigational statement, storage temperature, dosage, direction for use, visit number, 
and name and address of the Sponsor. 
 
7.3 
Storage and Disposition of Study Medications 
The study medication will be stored in a locked room/cabinet at each site. The supply of 
study medication will be stored as per label requirements in a secure location under the 
control of the Investigator. The Sponsor will provide a digital temperature monitoring 
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of the study medication storage facility. The site must report temperature deviations 
immediately to the Sponsor and quarantine the product until the Sponsor deems it 
acceptably for human use. 
 
7.4 
Drug Dispensing Procedures  
Dispensing of study medication is to be done by appropriately qualified staff (e.g., 
physician, pharmacist, or nurse).  
At the baseline visit, any patient for whom all necessary dosage information is available 
will be dispensed enough study medication for the next 4 weeks. However, if (1) a 
patient’s baseline serum ferritin result is not yet available, AND (2) a higher dosage is not 
indicated on the basis of the other iron overload markers (transfusional iron input, LIC, 
and cardiac MRI T2*), dispensing will be done as follows: 
For patients randomized to DFP:  All participants will be dispensed a 3-week supply of 
medication based on the scheduled titration (15 mg/kg tid for the first week, 20 mg/kg tid 
for the second week, and 25 mg/kg tid for the third week).  At the Week 3 visit, at which 
time the baseline serum ferritin results will be available, they will be dispensed a 1-week 
supply at either 25 or 33 mg/kg tid as appropriate. 
For patients randomized to DFO: 
 
If a serum ferritin value from within the last 3 months is available, the patient will 
be dispensed enough medication for 1 week based on that earlier value, and must 
continue to be dispensed the same dose on a weekly basis (i.e., returning to the site 
each time for the next week’s supply) until the baseline serum ferritin result is 
available.  Once it is available, the dosage will either be left as is or adjusted 
accordingly. 
 
If no serum ferritin value has been obtained within the last 3 months, the start of 
DFO dosing must be deferred until the baseline result is available. 
At the Week 4 visit and thereafter, medication will be dispensed monthly for all patients.  
Patients reporting that their medication has been lost or misplaced will be asked to attend 
the study site to receive replacement medication. Requests for replacement must be made 
in writing to the Sponsor’s Project Leader (PL), Clinical Research by the appropriate 
clinical site (pharmacist/physician/Investigator), who will approve the request. The 
replacement will then be made through the IVRS system by the study coordinator. All 
information related to the lost/misplaced medication and the replacement medication 
must be recorded in the drug accountability forms. 
7.5 
Study Medications Accountability and Inventory Control 
A “Site Investigational Drug Inventory Record” and “Patient Investigational Drug 
Dispensing Record” form will be provided by the Sponsor to the Investigator.  


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Investigational product accountability lies with the Investigator at all times.  The 
Investigator must maintain an updated Site Investigational Drug Inventory Record at the 
study site.  This log will include at minimum: 
 Name of Sponsor 
 Name of Investigator 
 Study identifier 
 Date and quantity of investigational product received from Sponsor 
 Lot/Batch number 
For each patient, the Investigator must maintain an updated Patient Investigational Drug 
Dispensing Record. This log will include at a minimum: 
 Patient identification number 
 Date of dispensing and return 
 Dispenser’s initials 
 Quantity dispensed and returned 
At the conclusion of the study, a final inventory must be performed by the Investigator 
(or delegate). If any tablets are missing, this must be indicated on the study drug 
accountability form, together with an explanation of the discrepancy. These forms must 
be available for Sponsor clinical monitoring as well as for Sponsor audit and regulatory 
authority inspection purposes at any time.  
All investigational products that have been returned by the patient or that are unused for 
any other reasons will be returned to the Sponsor or discarded by the site according to 
internal procedures, which must include the issuance of appropriate signed destruction 
certificates including mode of destruction and complete drug accountability of destroyed 
materials. 
 
7.6 
Other Study Supplies 
All required study supplies including but not limited to infusion pumps, diary cards and 
laboratory kits will be provided to all sites.  
8 
MEASUREMENTS AND EVALUATIONS 
Efficacy and safety measurements/evaluations will be performed at visits outlined in 
Appendix 18.1 – Schedule of Study Procedures.  
 
8.1  
Efficacy 
8.1.1 
Primary Efficacy Measure 
8.1.1.1  
Liver Iron Concentration  


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The liver contains 70% or more of total body iron (Angelucci E et al. 2000), justifying 
the use of liver iron concentration (LIC) as a measure of body iron load (Brittenham GM 
et al. 2001; Olivieri NF & Brittenham. 1997; Overmoyer BA et al. 1987; St Pierre TG et 
al. 2005). In the absence of effective iron chelation therapy, transfusion-dependent 
patients experience a progressive increase in LIC (Cazzola M et al. 1983). Although liver 
iron concentrations may differ from the concentrations of iron in other organs, it has been 
reported that patients with LIC greater than 7 mg iron/g liver (dry weight; dw) are at 
increased risk of iron-induced toxicity such as cardiac disease, hepatic fibrosis, diabetes 
mellitus and death (Hoffbrand AV et al. 2003; Olivieri NF & Brittenham. 1997; Telfer 
PT et al. 2000). The current goal for chelation therapy in transfusion-dependent patients 
is to maintain an “optimal” body iron burden corresponding to hepatic storage 
concentrations of less than 7 mg/g dw (Olivieri NF & Brittenham. 1997). MRI scans will 
be performed at the screening/baseline, Week 26, and Week 52 (or early termination) 
visits, and will be transmitted to a central laboratory for interpretation and LIC 
calculation.  
 
8.1.2 
Secondary Efficacy Measures 
8.1.2.1  
Patient Reported Quality of Life 
SF36: 
The SF-36 is a multi-purpose, short-form health survey with only 36 questions. It yields 
an 8-scale profile of functional health and well-being scores as well as psychometrically-
based physical and mental health summary measures and a preference-based health utility 
index. It is a generic measure, as opposed to one that targets a specific age, disease, or 
treatment group. A sample of the questionnaire is included in Appendix 18.5. The SF-36 
Questionnaire will be completed by patients aged 18 years old and above at the baseline, 
Week 26, and Week 52 (or early termination) visits. 
Child Health Questionnaire: 
The Child Health Questionnaire™ (CHQ) is a family of generic quality of life 
instruments that have been designed and normed for children. The CHQ measures 14 
unique physical and psychosocial concepts. The versions to be used in this study are the 
Child Health Questionnaire-Parent Form 50 (CHQ-PF50), composed of 50 questions, and 
the Child Health Questionnaire Child Form 87 (CHQ-CF87), composed of 87 questions. 
Samples of the questionnaires are included in Appendix 18.5. When possible, both 
versions will be completed for patients aged 17 years and under at the baseline, Week 26, 
and Week 52 (or early termination) visits. 
8.1.2.2 
Cardiac MRI T2* 
Myocardial MRI T2* can be used to monitor the myocardial iron load resulting from 
chronic transfusions, with low T2* levels reflecting a high cardiac iron concentration and 
high T2* values reflecting low cardiac iron. This technique has been calibrated with 
cardiac iron concentration in post mortem hearts (Carpenter JP et al. 2011). Studies in 
non-iron-overloaded patients reveal that none have a cardiac T2* <20 ms, a value that is 


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now widely used clinically as the threshold for cardiac iron overload (Wood JC. 2007). 
The ability of cardiac MRI T2* to identify patients at risk of iron-induced cardiac disease 
and premature death has been reported (Kirk P et al. 2009), and its predictive value has 
been prospectively evaluated in 652 transfusion-dependent thalassemia patients from 21 
UK centers who had cardiac MRI T2* assessment and who had their cardiac status 
followed over time (Kirk P et al. 2009). The results of that study demonstrated that the 
lower the cardiac MRI T2* value (i.e., the higher the cardiac iron load), the higher the 
risk of developing iron-induced cardiac failure within the subsequent 12 months. MRI 
scans for the assessment of cardiac MRI T2* will be performed at the screening/baseline, 
Week 26, and Week 52 (or early termination) visits, and will be transmitted to a central 
laboratory for interpretation.  
 
8.1.2.3  
Serum Ferritin 
The most commonly used method for the assessment of body iron burden is the 
measurement of serum ferritin concentration (Borgna-Pignatti C & Castriota-Scanderbeg. 
1991; Brittenham GM et al. 1981; Brittenham GM et al. 1993; Finch C. 1994; Finch CA 
et al. 1986; Lipschitz DA et al. 1974; Worwood M et al. 1980).  Ferritin is the major 
storage protein for iron. It is present in low concentrations in the plasma and is a 
reflection of total body iron. Due to the continual transfusional iron input and the lack of 
a natural excretory pathway for the excess iron, a progressive increase in serum ferritin 
concentration occurs in transfusion-dependent patients in the absence of effective iron 
chelation therapy. Sequential measures of serum ferritin concentration remain the most 
common method for assessment of body iron burden, and in clinical practice it is the 
standard for identifying trends in iron status within individuals and across populations. 
For an individual, serum ferritin is therefore a useful index of changes in iron load status, 
and for decades, a serum ferritin level above 2,500 μg/L has been considered an 
important indicator of the relative risk of death (Hoffbrand AV et al. 2003; Olivieri NF et 
al. 1994; Telfer PT et al. 2000). Serum ferritin will be assessed at baseline and at the 
Weeks 12, 26, 40 and 52 (or early termination) visits. 
 
8.2 
Safety 
The Investigator is responsible for monitoring the safety of patients who have entered the 
study.  Safety and tolerability of deferiprone will be assessed during the study by physical 
examinations, vital signs, clinical laboratory tests, spontaneous reporting of symptoms by 
patients, and by nurses’ and physicians’ observations. 
8.2.1 
Medical History, Physical Examination, Vital Signs and Prior and 
Concomitant Medication Use 
A medical history will be collected at screening/baseline, and reviewed at the end of 
study visit (Week 52 or early termination). A complete physical examination will be 
performed at screening/baseline, and Weeks 26 and 52 visits according to the schedule of 
events (Appendix 18.1). 
 


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 Vital signs (temperature, heart rate, respirations, blood pressure) and weight will 
be measured at screening/baseline, baseline and each monthly visit (Weeks 4, 8, 
12, 16, 20, 26, 32, 36, 40, 44, 48 and 52 (or early termination)). Height will be 
measured only at screening/baseline, semi-annual and week 52 (or early 
termination) visits. 
 
 Information about concomitant medications will be collected at screening/
baseline, baseline and each monthly visit (Weeks 4, 8, 12, 16, 20, 26, 32, 36, 40, 
44, 48 and 52 (or early termination)). The following must be recorded in the 
Source Documents and eCRFs: 
 All medications used during the 3 months prior to the screening/baseline 
visit; 
 Any previous use of deferiprone, deferoxamine and deferasirox; 
 Any medications that the patient continues to take during the trial; 
 Any medications which the patient starts to take during the trial. 
 The name, dose, route, frequency, indication, and start and stop dates of 
all medications used during the trial must be noted in the Source 
Documents and eCRFs as well as whether or not the medication was used 
to treat an medical events/adverse event. 
 
8.2.2 
Clinical Laboratory Tests 
Lab reports must be promptly interpreted by the Investigator. Any abnormal results 
should be assessed for clinical significance. Any clinically relevant abnormalities/changes 
which occur during the trial that are not part of a larger medical condition that is already 
recorded must be recorded on the source documents and the Adverse Events section of 
the eCRF.  
 
The following clinical laboratory tests will be performed. Analyses will be performed at a 
central laboratory, with the exception of the weekly or biweekly hematology assessments, 
which may be performed at a local laboratory. 
 
Hematology: 
Hematology assessments consisting of hemoglobin, total WBC, ANC and platelets will 
be performed at screening/baseline, baseline, weekly after start of dosing until Week 26, 
and then biweekly until Week 52 (or early termination). 
 
Biochemistry: 
Biochemistry assessments will be performed at the screening/baseline visit and then 
monthly: Weeks 4, 8, 12, 16, 20, 26, 32, 36, 40, 44, 48 and 52 (or early termination). 
Biochemistry evaluation will consist of total protein; GGT; lactate dehydrogenase 
(LDH); sodium, potassium, chloride, glucose (fasting at screening and Week 52 or early 
termination visits only); total, direct and indirect bilirubin; AST; ALT; albumin; blood 
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Serology: 
Serology assessments will be performed at the screening/baseline, Week 26, and end of 
study (Week 52 or early termination) visits. Serology evaluation will consist of Hepatitis 
B and C and HIV testing. 
 
Urinalysis: 
Urinalysis assessments will be performed at the screening, Week 26, and end of study 
(Week 52 or early termination) visits. Urinalysis by urine dipstick will consist of pH, 
specific gravity, glucose, protein, ketones, and blood. If indicated by the dipstick results, 
sediment microscopy will be performed.  If there is blood in the urine or three or more 
“plus signs” for protein, samples must be sent for microscopy. 
 
Pregnancy Test: 
Serum pregnancy tests will be performed at the screening/baseline and baseline visits and 
monthly (Weeks 4, 8, 12, 16, 20, 26, 32, 36, 40, 44, 48 and 52 (or early termination)). 
Urine pregnancy test will be performed at the baseline visit. 
 
8.2.3 
ECG 
A standard 12-lead ECG will be performed at the screening, Week 26, and end of study 
(Week 52 or early termination) visits. As a minimum, the following parameters will be 
assessed: HR, PR, QRS, QT, QTcF, and QTcB. Results will be interpreted by the 
Investigator. The overall interpretation will also be documented.  
 
8.2.4 
Adverse/Medical Events and Serious Adverse Events 
All adverse/medical events encountered during the study will be reported on the source 
documents and the eCRF, and will be carefully monitored and assessed with respect to 
seriousness, severity, and relationship to the study or study drug.  Adverse/medical events 
will be followed until the event is resolved, condition stabilizes (for conditions with long 
recovery period or those that progressed to chronic form) or the event is otherwise 
explained or the patient is lost to follow-up.  It is the responsibility of the Investigator to 
ensure that adequate medical care is provided to patients during the study.  All SAEs 
occurring within 30 days following the completion/discontinuation of the study must be 
reported to the Sponsor regardless of the suspected drug/event causal relationship.  SAEs 
for which the Investigator suspects a causal relationship to the study drug must be 
reported to the Sponsor irrespective of the time elapsed since the last dose of the study 
drug. 
8.2.4.1 
Definition of Medical/Adverse Events 
Medical Event: Any new untoward medical occurrence or worsening of a pre-existing 
condition in a patient that occurs after signing the ICF but before receiving an 
investigational product.  
 
Adverse Event:  An AE is any untoward medical occurrence in a clinical investigation in 
a patient administered a pharmaceutical or other therapeutic product, not necessarily 


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having a causal relationship with this treatment. An AE can therefore be any 
unfavourable and unintended sign, symptom or disease temporally associated with the 
use of a product, whether or not considered related to that product. 
 
An AE does include: 
 exacerbation of a pre-existing illness. This includes 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 
 
An AE does not include: 
 a pre-existing disease or condition present or detected at the start of the study that 
does not worsen 
 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 the 
disease or disorder, unless it has worsened 
 an overdose of either the study treatment or concurrent medication without any 
signs of symptoms 
 
8.2.4.2 
Adverse/Medical Event Considerations 
Note that the definition of AEs/MEs could include accidents (e.g., motor vehicle 
accidents) and the reasons for changes in concomitant medication (drug and/or dose), 
medical, nursing and/or pharmacy consultation, admission to hospital and surgical 
operations, and the worsening of a pre-existing medical condition. 
Planned hospital admissions and/or surgical operations/procedures for an illness or 
disease that existed before the investigational product was given or the patient was 
enrolled in a clinical trial are not to be considered AEs/MEs. 
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study 
site personnel must clearly document the circumstances and data leading to any such 
dosage reduction or discontinuation of treatment. 
Prior to enrolment, study site personnel will note the occurrence and nature of each 
patient’s medical condition(s) in the source documents and the appropriate section of the 
eCRF.  During the study, site personnel will again note any change in the condition(s) 
and the occurrence and nature of any AEs/MEs. 
Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis), 12-lead 
ECG abnormalities or other abnormal assessments (e.g. vital signs) which are not part of 
a larger medical condition which is already recorded as an adverse event and which are 
judged by the Investigator to be clinically significant must be recorded as AEs or SAEs if 
they meet the definition of an AE as defined in Section 8.2.4.1 or SAE as defined in 
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judgement in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant. 
8.2.4.3 
Procedures for Adverse/Medical Event Monitoring and Recording 
MEs will be collected from the time the ICF is signed, and AEs will be collected from the 
time the treatment starts.  The AEs and SAEs related to the underlying condition will be 
recorded separately. 
Patients will be instructed to report AEs/MEs to the Investigator.  Reports of adverse 
events will be elicited using a verbal probe and recorded in the source documentation and 
on the Adverse Event page of the eCRF. The Investigator or delegate should always ask 
the same open-ended and non-leading verbal questions of the patient to inquire about 
AE/ME occurrence.  Appropriate questions include: 
“How are you feeling?” or “How do you feel?” or for pediatric patients, “How does your 
child seem to feel?” 
“Have you had any (other) medical problems since your last visit/assessment?” or “Have 
you felt any different in any way since starting the new medication/treatment or since 
your last visit/assessment?” or for pediatric patients, “Has your child had any (other) 
medical problem or seemed to act differently in any way since his/her last 
visit/assessment?” 
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/assessment?” or for pediatric patients, “Has your child needed to take any 
medicines, other than those provided in this study, since his/her last visit/assessment?” 
Based on the patient’s response to these questions, the Investigator 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? 
 
All AEs/MEs will be recorded and evaluated by the Investigator for their seriousness, 
severity, and relationship to the investigational product or study.  
The Investigator should 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.  
The Investigator must also question the patient about any previously reported AEs that 
have not resolved.  
The Investigator will then rate the intensity, seriousness, and causality of the AEs and 
will also document any measures taken to address the AE. Causality should be rated in 
terms of relationship to the study medication as follows: not related, possibly related, 
probably related, definitely related. See Section 8.2.4.4 for further definitions of 


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relationship to study medication. All of this information should be clearly recorded in the 
source documents. 
The Investigator should employ this probe at each assessment. AEs will be collected 
throughout the study. 
All AEs must be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the patient is lost to follow-up. The Investigator is 
responsible to ensure that follow-up includes any supplemental investigations as may be 
indicated to elucidate as completely as practical the nature and/or causality of the AE. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
8.2.4.4 
Causality 
The relationship of an adverse event to study drug should be determined by the 
Investigator after thorough consideration of all facts that are available. Assessment of 
causality is based on considering 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 - information on drug withdrawal could also be lacking. 
 
Probably related:  Reasonable time sequence to administration of study drug, but 
unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and which follows a clinically reasonable response on 
withdrawal (de-challenge). Re-challenge information is not required. 
 
Definitely related: Plausible time relationship to study drug administration; event 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 rechallenge procedure if 
necessary.  
8.2.4.5 
Severity 
Severity refers to the accumulated intensity of discomfort/impairment of health since the 
last recording of AEs.  The Investigator will rate the intensity, seriousness, and causality 


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of the AEs. To achieve maximum consistency in the assessment of severity of adverse/
medical events, it is recommended that National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) scale be used whenever possible, to 
assist the Investigator in determining the severity of adverse/medical event.  Severity of 
adverse/medical events will be reported on the eCRF as mild, moderate, or severe 
according to the definitions provided below. Grading based on the CTCAE scale will not 
be entered into the eCRFs. 
 
Severity 
Corresponding 
NCI CTCAE Grade 
Mild: awareness of a sign or symptom but easily tolerated 
1 
Moderate: discomfort sufficient to cause interference with 
normal daily activities 
2 
Severe: resulting in inability to do work or perform normal 
daily activities 
3-5 
 
8.2.4.6 
Serious Adverse Event 
An SAE is any adverse event occurring at any dose that results in any of the following 
outcomes: 
1) Death 
2) A life-threatening adverse event 
3) Inpatient hospitalization or prolongation of existing hospitalization 
4) A persistent or significant disability or incapacity 
 
5) A congenital anomaly in the offspring of a patient who received the study 
treatment 
 
6) Important medical events that may not result in death, be life-threatening, or 
require hospitalization but which in the Investigator’s judgement may jeopardize 
the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events 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 
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 
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 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 a serious adverse event. 
 
With regard to the criteria in (6) above, medical and scientific judgement 
should be used in deciding whether prompt reporting is appropriate in this 
situation. 
 
8.2.4.7 
Procedures for Serious Adverse Event Reporting 
Patients will be instructed to report SAEs to the Investigator immediately (within 24 
hours) by telephone.  The Investigator must report all SAEs to the Sponsor within 24 
hours of occurrence or notification by the patient.  These events must be faxed to the 
Sponsor using the Sponsor’s standard SAE form.  The Sponsor will provide a list of 
project contacts for SAE receipt, fax numbers and telephone numbers. 
The Investigator will always provide an assessment of causality at the time of the initial 
report. 
A follow-up SAE form must be completed by the responsible Investigator/delegate and 
faxed to the Sponsor within 5 calendar days.  Furthermore, as additional relevant 
follow-up information becomes available, the Investigator must complete a follow-up 
SAE form and fax it to the Sponsor.  
The Sponsor will submit serious adverse drug events to the appropriate regulatory 
agencies, in line with local regulatory requirements and timelines. 
Investigators must also report all SAEs to their respective IRB/IEC responsible for the 
study.  The Sponsor will promptly inform all other sites of SAEs occurring at a single site 
that are at least possibly related to the study medication and are unexpected.  All site 
Investigators will report these events to their IRB/IEC following the same timelines as 
above or following local IRB/IEC policy, whichever takes precedence.  
8.2.4.8 
Follow-up and Documenting of SAEs 
SAEs that occur during the study and for 30 days after the patient takes the last dose of 
study medication must be documented in the patient’s medical record and on the SAE 
Report form. A separate SAE Report form should be used for each SAE. 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 and not the individual signs/
symptoms should be documented as the SAE.  
All SAEs must be followed until resolution, until the condition stabilizes, until the event 
is otherwise explained, or until the patient is lost to follow-up. The Investigator is 
responsible to ensure that follow-up includes any supplemental investigations as may be 


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indicated to elucidate as completely as practical the nature and/or causality of the SAE. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
The Sponsor may request that the Investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations. If a patient dies during participation in 
the study or during a recognized follow-up period, the Sponsor should be provided with a 
copy of any post-mortem findings, including histopathology. New or updated information 
should be recorded on the originally completed SAE page, with all changes signed and 
dated by the Investigator. 
The CRA will verify the original SAE Report form against the source documents at the 
next monitoring visit. 
8.2.4.9 
Adverse Event of Special Interest – Neutropenia (Definitions and 
Management) 
Definitions  
Mild Neutropenia: 
A confirmed ANC ≥1.0 x 109/L and < 1.5 x 109/L. 
Moderate Neutropenia: A confirmed ANC ≥ 0.5 x 109/L and < 1.0 x 109/L. 
 
Severe Neutropenia/Agranulocytosis: A confirmed ANC < 0.5 x 109/L.  
An absolute neutrophil count (ANC) is confirmed as being less than a specified value if 
two consecutive counts (maximum 3 days apart) are both less than the specified value. If 
both consecutive counts are below 1.5 x 109/L but not in the same severity category of 
neutropenia, a third count will be required to determine the severity. 
 
Management 
Mild Neutropenia (two consecutive Absolute Neutrophil Counts ≥1.0 x 109/L and 
<1.5 x 109/L): 
Patients receiving deferiprone treatment who experience mild neutropenia (ANC ≥1.0 x 
109/L and < 1.5 x 109/L) should continue treatment.  The patient’s ANC will be monitored 
every 2 days until resolution of the event, defined as two consecutive ANC ≥ 1.5 x 109/L. 
If the ANC remains ≥ 1.0x 109/L and < 1.5 x 109/L by the end of a two-week period (14 
days): 
 The patient will be withdrawn from the study and monitored until 
resolution of the event.  
 The patient will be advised regarding protective isolation. 
 The Investigator will notify ApoPharma Inc. by fax. 
 The Investigator will examine patient the same day (if possible) 
including drug history and physical examination. 
 


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However, if the patient has a mild neutropenia and develops an infection, therapy must be 
interrupted immediately and neutrophil count must be obtained and monitored more 
frequently (every 2 days if ANC <1.5 x 109/L) until resolution of the event, defined as 
two consecutive ANC ≥ 1.5 x 109/L. Patients should be advised to report immediately to 
their physician any symptoms indicative of infection such as fever, sore throat, and flu-
like symptoms. In presence of confirmed fever and/or infection, they will be required to 
have their neutrophil counts tested as soon as possible and no later than 24 hours after the 
symptoms of infection are detected. Patients will be provided with an emergency services 
card with contact information, and the patient/legal guardian will be advised to carry this 
card at all times. Therapy with deferiprone can be initiated once all symptoms have been 
resolved and it is deemed safe by the Investigator. 
Moderate Neutropenia (two consecutive Absolute Neutrophil Counts ≥ 0.5 x 109/L and < 
1.0 x 109/L): 
Patients receiving deferiprone treatment who experience moderate neutropenia (ANC ≥ 
0.5 x 109/L and < 1.0 x 109/L) will immediately interrupt treatment, and the patient’s 
ANC will be monitored every 2 days until resolution of the event, defined as two 
consecutive ANC ≥ 1.5 x 109/L. If the ANC remains < 1.5 x 109/L by the end of a two-
week period (14 days): 
 The patient will be withdrawn from the study and monitored until 
resolution of the event.  
 Provide protective isolation; if clinically indicated, admit patient to 
hospital and obtain q4h vital signs. 
 The Investigator will notify ApoPharma Inc. by fax. 
 The Investigator will examine the patient the same day, if possible, 
including drug history and physical examination. 
 If possible, obtain viral studies (CMV, parvovirus, hepatitis A/B/C), 
serum ALT, BUN, creatinine, and 10 mL serum split into two 5-mL 
aliquots for frozen storage, for future analysis. 
 
Severe Neutropenia/Agranulocytosis (two consecutive Absolute Neutrophil Counts < 0.5 
x 109/L): 
Patients receiving deferiprone and who experience severe neutropenia/agranulocytosis 
(ANC < 0.5 x 109/L) will immediately discontinue treatment. The patients will be 
withdrawn from the study and will be followed daily until two successive ANCs are ≥1.5 
x 109/L: 


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 The patient will be withdrawn from the study and monitored until 
resolution of the event.  
 Provide protective isolation; if clinically indicated, admit patient to 
hospital and obtain q4h vital signs. 
 The Investigator will notify ApoPharma Inc. by fax. 
 The Investigator will examine the patient the same day, if possible, 
including drug history and physical examination. 
 If possible, obtain viral studies (CMV, parvovirus, hepatitis A/B/C), 
serum ALT, BUN, creatinine, and 10 mL serum split into two 5-mL 
aliquots for frozen storage. 
 Collect a blood sample to attempt to identify genetic or other 
biomarkers related to agranulocytosis (optional). 
 If possible, obtain bone marrow aspirate for:  
o Histology 
o Progenitor culture 
o Frozen storage (1 mL sample) 
 If possible, obtain bone marrow biopsy (minimum length 3 mm). 
 Perform septic work-up including chest X-ray, blood, urine and throat 
cultures. 
 Obtain q4h temperatures from patient (monitored by family at home 
if patient is not in the hospital). 
 If warranted, administer granulocyte stimulating factors, such as G-CSF 
10 μg/kg, as an inpatient if possible, beginning the same day that the 
ANC is confirmed as < 0.5 x 109/L; administer daily until ANC is > 
1.5 x 109/L on two 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. 
 
9 
PROCEDURES IN CASE OF MEDICAL EMERGENCY 
The Investigator is responsible for ensuring that procedures and expertise are available to 
cope with medical emergencies during the study period.  An emergency may constitute 
an SAE. 
 
9.1 
Precautions/Overdose 
An overdose is defined as taking more than the prescribed individual dose or more than 
maximum daily dose. 


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Deferiprone: 
 
Deferiprone use can be associated with neutropenia, including agranulocytosis, the cause 
of which is currently unknown.  Because of the awareness of this risk, weekly monitoring 
for neutrophil count was proposed in the first marketing authorization application for 
deferiprone and has been in effect since. However, a recent review of both clinical and 
post-marketing data accumulated over the last two decades confirmed that deferiprone-
induced agranulocytosis is not dose-related within the therapeutic range, and its 
occurrence peaks at 5 months after initiation of therapy, declining in frequency after this 
period. It was concluded that weekly monitoring is a prudent approach but that it does not 
preclude agranulocytosis from occurring and it could even provide false security, as 
agranulocytosis could occur shortly after the finding of a normal neutrophil count. The 
relevance of weekly monitoring of the neutrophil count appears to decrease even further 
after the first six months of therapy, when agranulocytosis occurs less often. Based upon 
analysis of data collected over the past 20 years, it appears that patient education may be 
the key to minimizing risks associated with agranulocytosis during deferiprone therapy. 
A better approach to minimizing the risks in patients receiving long-term deferiprone 
therapy is for ANC monitoring to be done weekly only at the beginning of the treatment 
and to emphasize the importance of educating patients on the need to immediately stop 
deferiprone and to maintain ANC monitoring upon signs of infection. 
Neurological disorders such as cerebellar symptoms, diplopia, lateral nystagmus, 
psychomotor slowdown, hand movements, and axial hypotonia have been observed in 
children who were treated with deferiprone at doses more than twice the maximum 
recommended dose of 100 mg/kg/day for transfusion-related iron overload for up to 16 
months. The neurological disorders progressively regressed after deferiprone 
discontinuation. 
Deferoxamine: 
Inadvertent administration of an overdose or inadvertent intravenous bolus administration/
rapid intravenous infusion may be associated with hypotension, tachycardia, and 
gastrointestinal disturbances; acute but transient loss of vision, aphasia, agitation, 
headache, nausea, pallor, CNS depression including coma, bradycardia and acute renal 
failure have been reported. Acute respiratory distress syndrome has been reported 
following treatment with excessively high intravenous doses of deferoxamine in patients 
with acute iron intoxication and in patients with thalassemia. 
Overdose per se will not be reported as an AE.  The signs and symptoms or clinical 
sequelae resulting from overdose will be reported if they fulfill the AE or SAE definition. 
 
9.2 
Procedures in Case of Pregnancy 
If a female study patient becomes pregnant, or plans to become pregnant, during the 
course of the study, the patient must inform the Investigator, and deferiprone must be 
stopped and the patient will be immediately withdrawn from the clinical trial. The 
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after the last dose of study medication, using the Pregnancy Reporting Form and 
information collected in eCRF. The patient will be followed up and the pregnancy 
outcome will be reported.  Pregnancy outcomes include live birth, spontaneous abortions 
(loss of pregnancy before 20 weeks of gestation), elective termination, and fetal 
death/still births (loss of pregnancy after 20 weeks of gestation).  Within any of these 
categories, the fetus or infant must be evaluated for the presence of any congenital 
anomalies. Any maternal/fetal complications should be also reported.  If possible, the 
health of the child will be followed for 1 year. 
The same pregnancy and post-gestation monitoring procedures will also apply in the case 
where a male patient reports that his female partner has become pregnant. In this case, 
however, there will be no requirement for the patient to withdraw from the trial. 
10 
STUDY COMMITTEE 
10.1 Data Safety Monitoring Board  
An independent Data Safety Monitoring Board (DSMB) will be established to monitor 
the safety of patients during the course of the study. The DSMB will be responsible for 
overseeing the conduct of the trial, and will be empowered to recommend stopping the 
trial if in their judgement continuation is not ethically acceptable on the grounds of 
safety. 
The operating model and the frequency of the interim safety review meetings will be laid 
out in the DSMB charter.  The DSMB will be constituted prior to the enrolment of any 
patients into the study.  The DSMB will be notified of any changes to the protocol or the 
study conduct. All DSMB meeting minutes and board composition will be submitted to 
the regulatory authorities with the final clinical study report.   
11 
DATA HANDLING AND STATISTICAL ANALYSIS 
11.1 Data Collection and Handling Procedures 
11.1.1 
Documentation of Data 
All data obtained during this study are raw data and will be entered promptly by the 
Investigator or delegate in the source document. eCRF entries are derived from source 
documents. An explanation must be documented for any missing data. The Investigator 
will be required to place all source documents in the patients' medical record files. Details 
of the eCRF completion will be explained to the Investigator. 
11.1.2 
Corrections to Study Documentation 
Any errors in the study documentation must be crossed out with a single line, leaving the 
original entry legible. The correction must then be dated and initialled. Incorrect entries 
must not be covered with correcting fluid, obliterated, or made illegible in any way. 


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11.1.3 
Data Processing 
During the study, the study statistician will have read-only access to the data for program 
development. Integrity of the database will be assured by limiting access through 
passwords and account control and through regular, secure backups of both the clinical 
data management files and SAS-related files. 
 
11.1.4 
Coding 
The following coding dictionaries will be used: 
Diseases: 
Medical Dictionary for Regulatory Activities (MedDRA) 
Adverse events: 
MedDRA 
Drugs: 
World Health Organization (WHO) Drug Dictionary 
 
 
11.1.5 
Data Handling 
Discrepancies will be reviewed and resolved online by the clinical study site users or 
reviewed off-line by Clinical Data Management, the CRO and/or Clinical Research and 
sent to the study site. A Patient Data Report (PDR) is a generated compilation of data 
from the database that is presented in a PDF document. The PDR originates from the 
same HTML files as the eCRFs and can either be generated with no data, with patient and 
eCRF information (such as patient ID number #, site name, etc.), and/or with all collected 
response data. A copy of the final PDRs will be sent to the clinical study site after 
database freeze. 
11.1.6 
Missing, Unused and Spurious Data 
All missing data will be subject to data queries as specified above. All eCRF data will be 
entered into the electronic database and will be considered for analysis as specified in the 
statistical analysis plan. 
11.2 Statistical Analysis 
11.2.1 Primary Efficacy Endpoint 
The change from baseline to Week 52 in liver iron concentration (measured by MRI). 
11.2.2 Secondary Efficacy Endpoints 
- Change from baseline to Week 52 in patient-reported quality of life (SF-36 or Child 
Health Questionnaire); 
- Change from baseline to Week 52 in cardiac MRI T2*;  
- Change from baseline to Week 52 in serum ferritin. 


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11.2.3 Safety Endpoints 
- Frequency, severity and time to onset/duration of adverse events (AEs); 
- Frequency of serious adverse events (SAEs); 
- Discontinuation due to AEs; 
- Hematology assessments including hemoglobin, total WBC, ANC and platelets;  
-  Blood serum clinical biochemistry assessments; 
-  12-lead ECG. 
11.2.4 Determination of Sample Size 
Three hundred (300) male and female patients will be enrolled into the study. In a 
randomized study of two iron chelators for the treatment of iron overload in patients with 
sickle cell disease (Vichinsky et al., 2006), mean ±SD reductions of 4.0 ± 1.5 mg/g dw 
and 4.5 ± 2.0 mg/g dw were observed (Figure 1 of the article, numerical values obtained 
from the authors) in patients from the baseline LIC categories of >7-14 mg/g dw or >14 
mg/g dw after they were treated with 35-50 mg/kg or ≥50 mg/kg of deferoxamine 
respectively, for 52 weeks. Assuming the same mean reduction in LIC for deferiprone but 
a higher SD of ±4.0 mg/g dw for both treatments due to possibly higher variability 
associated with MRI measurement, the sample size of 300, with >80% being patients 
with sickle cell disease, will provide over 95% power for demonstrating non-inferiority 
of deferiprone to deferoxamine in patients with sickle cell disease.  
The sample size estimate is based on a non-inferiority margin of 2 mg/g dw for the 
reduction of LIC and an alpha of 0.05, two-sided (or an alpha of 0.025, one-sided, 
Appendix 18.5). It has been reported that in a typical patient with thalassemia major, the 
LIC could increase by 5 mg/g dw after 1 year without chelation therapy. As the cause of 
iron overload is the same in thalassemia and sickle cell disease, the same increase in LIC 
may be expected in patients with sickle cell disease who are transfused at the same rate 
and not treated with a chelator.  Hence, the difference in reduction of LIC between 
deferoxamine therapy and a placebo (effect size) can be estimated to be 9 (i.e., 4 – (-5)) 
mg/g dw. This means that the non-inferiority margin of 2 mg/g dw would be about 20% 
of the effect size. 
With the enrolment of 300 patients, there is also greater than 99% chance (power) of 
occurrence of at least 1 adverse event with an anticipated incidence rate of 2%, or greater 
than 95% chance for an anticipated incidence rate as low as 1%. 
11.2.5 Study Populations 
Study populations intended for analysis will be defined as follows: Intent-to-Treat (ITT), 
Per-Protocol (PP), and Safety. The ITT population will represent the primary analysis 
population to evaluate the treatment groups on all efficacy endpoints. The primary 
efficacy endpoint will also be analyzed for the PP population, which is the secondary 
analysis population. 


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11.2.5.1 Intent-to-Treat 
The ITT population will include all randomized patients who received at least one dose of 
study drug and have a baseline and at least one post-baseline efficacy assessment. All 
efficacy analyses will be based on the ITT population.  
11.2.5.2 Per-Protocol 
The Per-Protocol (PP) population will include all enrolled patients who complete the 
study, have no major protocol violations, and have an efficacy rating at the end of the 
study. Prior to database lock, major protocol violations will be reviewed and excluded 
from the PP population. Major protocol violations will include (but not be limited to) the 
following:  
 Patients who did not fulfill the LIC > 7 mg/g inclusion criterion. 
 Patients who were not compliant with the treatment (<80% compliance). 
 Patients who took iron chelator medications other than the assigned study 
medication during the course of the study. 
Only the primary efficacy analysis will be performed with the PP population. 
 
11.2.5.3 Safety 
The Safety population will include all enrolled patients who took at least one dose of 
study drug.  
 
11.3 Statistical Plan 
A separate detailed statistical analysis plan (SAP) will be prepared and approved before 
database lock. Any changes in the planned statistical methods after database lock will be 
documented in the final clinical study report. 
 
11.4 Definition of Analysis 
For patients who were terminated from the study prior to Month 12, if their last efficacy 
measures were obtained within 30 days of Month 12, the data obtained will be treated as 
the Month 12 data.  For early termination that occurred outside this window, the last 
observation carried forward (LOCF) method will be used to fill the missing data when the 
early termination was not caused by worsening of disease conditions or inadequate 
efficacy of the drug. For early termination due to worsening of disease conditions or 
inadequate efficacy of the drug, as indicated in the eCRF, the “worst value” method will 
be used.  That is, the worst value of all patients for the corresponding treatment group 
will be used to impute the missing data at that time point. For missing data due to missed 
visit, the LOCF method will be used to fill the void.  
As a sensitivity analysis, the analysis will be repeated with the LOCF method being used 
for all drop-out patients in the deferoxamine group.  Other sensitivity analyses, where 
appropriate, will be detailed in the SAP.  


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For safety data analysis, no imputation will be performed on the missing data, and 
analysis will be based on observed cases (OC).  
11.4.1 Planned Analyses 
11.4.1.1 Patient Disposition and Drug Exposure 
Patient disposition will be summarized and presented, including the number and 
percentages of patients who were screened, enrolled, received at least one dose of study 
medication, completed the study, and withdrew (including reasons for withdrawals). The 
proportions of drop-outs will be compared between the deferiprone group and the 
deferoxamine group using Fisher’s exact test. 
For each patient, the number of doses taken will be computed from the study drug 
dispensing and accountability eCRFs obtained at each visit. The extent of exposure to the 
study medication, the number of doses, and the total dose taken during the study will be 
summarized with descriptive statistics. 
11.4.1.2 Patient Characteristics 
Baseline characteristics will be summarized by: mean, standard deviation, minimum, 
median and maximum values (by ITT and PP populations). Medical history, prior and 
concomitant medications will be summarized descriptively (number of patients and 
percentage). 
11.4.1.3 Efficacy Analyses 
Primary Efficacy Endpoint 
The change from baseline to Week 52 in LIC will be compared between the two 
treatment groups using an analysis of covariance (ANCOVA) model, including treatment 
variable as the main factor and total transfusional iron input during the study and baseline 
LIC as covariates. The 95% confidence interval (CI) of the difference (deferiprone minus 
deferoxamine) in change of LIC from baseline to Week 52 between the two treatment 
groups will be computed. For the demonstration of non-inferiority, the upper limit of the 
95% CI should be no more than 2 mg/g dw. 
Secondary Efficacy Endpoints 
The change from baseline to Week 52 in patient-reported quality of life (SF-36 or Child 
Health Questionnaire) will be compared between the two treatment groups. Detailed 
information on the statistical method to be used will be provided in the statistical analysis 
plan. The change from baseline to Week 52 in cardiac MRI T2* and serum ferritin will be 
compared between the two treatment groups using an ANCOVA model, with treatment 
variable as the main factor and total transfusional iron input during the study and baseline 
cardiac MRI T2* or serum ferritin as covariates. As with LIC, the 95% CI of the 
difference between the two treatment groups will be computed for both MRI T2* and 
serum ferritin. The MRI T2* data will be log-transformed before any statistical testing.   
The longitudinal data of patient-reported quality of life, LIC, cardiac MRI T2*, and 
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or its equivalent for the quality of life data. Transfusional iron input will be assessed and 
compared among treatment groups and hematologic diagnoses. .  
Subgroup analysis: 
The comparison of the two treatment groups for the primary and secondary efficacy 
endpoints will be performed in: 
- SCD patients only; 
- non-SCD patients.  
More subgroup analysis, where appropriate, may be defined in the SAP. 
11.4.1.4 Safety Analyses 
All safety data collected will be presented in listings and summary tables to give an 
overview of the safety findings.  
Adverse Events 
A summary table of adverse events will include the following information: 
 number of patients exposed to study treatment, 
 number of patients experiencing at least one AE,  
 number of patients experiencing at least one severe AE,  
 number of patients experiencing at least one serious AE,  
 number of patients experiencing at least one drug-related AE, 
 number of deaths, 
 total number of patients withdrawn (and reason for withdrawal) and  
 number of withdrawals due to an AE.  
All adverse experiences will be coded using MedDRA. Adverse events will be defined 
as: 1) AEs that occurred or worsened (increased in severity and/or frequency) on or after 
the first dose of study medication. 2) AEs with a missing start date and a stop date on or 
after the first dose of study medication. 3) AEs with both a missing start and stop date. 
AEs will be summarized by treatment and by MedDRA system organ class (SOC) and 
Preferred Term. SAEs that occurred within 14 days after treatment discontinuation will 
be considered treatment-emergent AEs. Serious adverse events that occurred within 30 
days after treatment discontinuation will be included in the database.  
Adverse events will be summarized by treatment group using the total number of AEs, 
the total number and percent of patients who experience an AE, and the number and 
percent of patients who experienced an AE within each SOC (and preferred term within 
an SOC). AEs will also be presented by severity (mild, moderate, severe), by seriousness 
(serious, non-serious) and by relationship to study medication (at least possibly related, 
not related). The number of patients withdrawn will also be presented.  


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To count the number of patients who experienced each AE, patients who experienced the 
same AE multiple times will only be counted once for the corresponding preferred term. 
Similarly, if a patient experiences multiple AEs within the same SOC, that patient will be 
counted only once for that SOC. AEs will be tabulated presenting the SOC 
alphabetically, and within each SOC, preferred terms will be presented in decreasing 
order of the total number of patients who experienced each AE. In summaries presenting 
the incidence of AEs by severity, seriousness, and relation to study medication, a patient 
with multiple events coded to a given preferred term or SOC will be counted once for that 
preferred term or SOC according to the most severe event, the most serious event, or the 
event with the closest relationship to study medication. 
A listing of serious adverse events and a listing of withdrawals due to AEs will be 
presented. Patient deaths will be listed separately and discussed with patient narratives. 
Vital Signs 
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will 
be presented for temperature, heart rate, respiratory rate, systolic blood pressure, diastolic 
blood pressure, and weight, at baseline and at each relevant visit. Changes from baseline 
to each post-baseline time-point will also be presented with descriptive statistics. 
ECGs 
Clinically significant 12-lead ECG abnormalities will be reported. The number and 
percentage of patients with normal and abnormal 12-lead ECG results will be provided 
for each scheduled visit. 
Biochemistry, Hematology and Urinalysis 
Descriptive statistics for each clinical laboratory test will be presented for each scheduled 
visit. Change from baseline to each visit will also be presented. According to the 
laboratory normal ranges, laboratory test results will be categorized as low (< lower 
normal limit), normal (within normal range), and high (> upper normal limit). Shift tables 
comparing the distributions of these three categories at baseline versus end of treatment 
will be presented. 
Clinically significant laboratory values will be reported in the AE analysis. 
Concomitant Medications 
Medications will be coded using the WHO Drug Dictionary. Medications taken during 
the course of the trial (on or after the first study drug dose and before or on the study 
termination date) will be considered as concomitant medications. Medications started 
after the study termination date will not be reported in tables, but will be presented in 
patient data listings. Concomitant medications used to treat AEs will be differentiated 
from others. 
Concomitant medications will be summarized by preferred term only. To count the 
number of patients who took a medication, a patient who took the same medication 
multiple times will only be counted once for that medication. Medications will be 
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In addition, the total number of patients to ever take any concomitant medications will be 
presented. 
Concomitant medications will be presented based on the Safety population. 
The safety analyses will be performed in: 
- SCD patients only; 
- non-SCD patients.  
12 
DATA MANAGEMENT CONSIDERATIONS  
12.1 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 eCRFs provided by the Sponsor.  Clinical data will be 
entered and stored into a validated database.  Data will be coded using MedDRA and the 
WHO Drug Dictionary .  The eCRFs will be provided in the Oracle Clinical Remote Data 
Capture (OCRDC) system hosted by the Sponsor. Trained users will access the system 
via a secured gateway.  Users will be authorized to access data for their study site only. 
Data will be entered directly into the system from the source documents. Online 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.  An electronic 
signature will be required by the Investigator on the eCRFs, and the monitor will verify 
the eCRFs on-line. 
Clinical data management activities will be performed by the Sponsor in accordance with 
applicable standards and data cleaning procedures of the Sponsor.  An audit trail of all 
data processing will be stored in the database.  The study biostatistician will be notified 
when all patient 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. 
 
12.2 Source Documents 
The Investigator 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, 
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evaluation of the trial.  Examples include medical history, physical examination, 
laboratory results, MRI scans, and 12-lead ECG results. 
The Investigator will also retain all patients’ specific printouts, reports of tests and 
procedures performed as requirements of the study.  The source documents must be 
available at the time of any site visit from the Sponsor/CRO and/or regulatory authorities.  
During monitoring visits, the monitor will need to validate data in the eCRFs against 
these sources of data. 
For every patient, the hospital/patient records should clearly indicate at least: 
 
That he/she participated in the study, e.g., by including patient identification 
(patient ID number) and study identification (study code or other). 
 
Diagnosis/indication under investigation. 
 
Medical history. 
 
A list of treatments withdrawn in order to meet inclusion criteria for participation in 
the study. 
 
A list of treatments, including investigational product(s), received or changed 
during the study. 
 
A record of all visits to the study site during the study period, including those for 
study purposes only. 
 
A list of all AEs, including SAEs, adverse drug reactions (ADRs), and serious 
adverse drug reactions (SADRs). 
 
12.3 Electronic Data Capture (EDC) 
ApoPharma will provide the Investigators with training on the EDC system. Data are 
entered by clinical study site personnel from the source data directly into the eCRF. 
Support is provided to data entry users at the site via a Help Desk. 
Discrepancies are reviewed and resolved on-line by the clinical study site users, or 
reviewed off-line by Clinical Data Management, a CRO, and/or Clinical Research, and 
sent to the study site.  
 
13 
MONITORING, AUDITS AND INSPECTIONS 
13.1 Monitoring 
The Sponsor has the obligation to follow this study closely throughout its course.  
Monitoring of the investigational sites will be conducted by the Sponsor and/or 
contracted to a qualified (through audit) CRO who will provide an appropriately trained 
Clinical Research Associate (CRA). The CRA will have regular contacts with the 
investigational site.  These contacts will include visits to confirm that facilities remain 
acceptable, that the investigational site is adhering to the protocol and that data are being 


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accurately recorded in the eCRFs, and to provide information and support to the 
Investigator.  The CRA will ensure that the investigational product is accounted for and 
that written informed consent/assent (where applicable) was obtained from each patient.  
Source data will be verified, and the data in the eCRF will be compared with the source 
data.  The source documents must be available at the time of the site visits. 
 
13.2 Audits and Inspections 
In accordance with the principles of ICH E6 Guideline for Good Clinical Practice, the 
study may be inspected by regulatory authorities and audited by the Sponsor or their 
designees. The Investigator and relevant clinical support staff will be required to attend 
audits and inspections and make all necessary documentation and data available upon 
request. 
During the course of the study or after study completion and site closure, one or more 
Investigator site audits may be undertaken by auditors from the Sponsor or their 
delegates. The purpose of these audits is to determine whether or not the study is 
being/has been conducted and monitored in compliance with the ICH E6 Guideline for 
Good Clinical Practice, approved protocol and amendment requirements, applicable local 
Standard Operating Procedures (SOPs) and local laws and regulations. It is the 
Investigator’s and his/her staff’s responsibility to promptly address deficiencies 
stemming out of regulatory inspections and the Sponsor’s or delegated audits, as well as 
to ensure that agreed-upon corrective and preventative actions are implemented promptly. 
An inspection by any regulatory authority or a Sponsor audit 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 inform the Sponsor immediately. 
14 
REGULATORY REQUIREMENTS AND OBLIGATIONS 
14.1 Informed Consent/Assent  
The Investigator will ensure that the patient and/or his/her legal representative is given 
full and adequate oral and written information about the nature, purpose, possible risks 
and possible benefits of the study. 
The Investigator must make a conscientious effort to be fully satisfied that the patient 
and/or his/her legal representative has truly understood that for which the consent has 
been given.  The patient and/or his/her legal representative must also be notified that 
he/she is free to withdraw his/her participation in the study at any time, and that such 
withdrawal will not affect his/her present or future care. 
The patient and/or his/her legal representative should be given ample opportunity to ask 
questions and discuss the study with the family.  The consent document signed by the 
patient must not be phrased in a manner that might be understood to abrogate the rights of 
the patient and/or his/her legal representative or the responsibility of the Investigator or 
Sponsor.  The consent/assent form used to obtain the patient’s consent must be the most 
up-to-date consent/assent form approved by the IRB/IEC. 


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Written informed consent/assent will be obtained from the study patient and/or legal 
representative as described in the Declaration of Helsinki, June 1964, as clarified by the 
World Medical Association (WMA) General Assembly, Washington 2002, CFR Part 50 
prior to entering the patient into the study.  The consent/assent form will be signed and 
dated by the patient or legal representative prior to the first study intervention.  A 
completed copy of each patient’s signed and dated consent/assent form will be retained in 
the patient’s chart. 
The patient will be provided with a copy of the signed and dated ICF/assent form.  Site 
variations may occur owing to the individual preferences of each ethics committee.  
Copies of the consent/assent form intended for use at each clinic will be forwarded to the 
Sponsor for approval prior to the submission of these documents to each ethics 
committee. 
Should a protocol amendment be made, the ICF/assent may need to be revised to reflect 
the changes to the protocol.  The revised consent/assent form will be forwarded to the 
Sponsor for approval prior to the submission to the IRB/IEC.  The Investigator must then 
ensure firstly that the revised consent/assent form is reviewed and receives favourable 
written approval from the IRB or IEC, and secondly that it is signed by all patients 
subsequently entered in the trial and those currently in the trial.  The Investigator must 
provide written approval from the IRB/IEC to the Sponsor. 
 
14.2 Institutional Review Board/Independent Ethics Committee 
The Investigators agree to provide the IRB/IEC with all appropriate documents, including 
a copy of the protocol/amendments, ICFs, advertising text (if any), Investigator’s 
Brochure (if any), and any written information to be given to the patient.  The 
Investigators must obtain IRB/IEC favourable written approvals for the protocol/
amendments, the ICFs and any applicable translations, and any written information to be 
given to the patient prior to their enrolment, and any advertising to be used for patient 
recruitment.  The Investigator must provide a copy of the written approval of the 
IRB/IEC to the Sponsor before commencement of the study.  The names of the members 
of IRB/IEC and their titles/institutional affiliations will be provided to the Sponsor and 
the Investigators prior to the start of the study.  The Sponsor further requires copies of all 
correspondence with the IRB/IEC. 
In the event that the protocol is amended, the protocol amendment must be approved by 
the IRB/IEC prior to its implementation, unless the changes are administrative in nature.  
If an ICF needs to be revised to reflect the changes to the protocol, the revised consent 
form will be forwarded to the Sponsor for approval prior to the submission to the IRB/IEC.  
The Investigator must then ensure firstly that the revised consent form is reviewed and 
receives favourable written approval from the IRB/IEC, and secondly that it is signed by 
all patients subsequently entered in the trial and those currently in the trial.  The 
Investigator must provide the written approval to the Sponsor. 
The Investigator is also obliged to report all SAEs to the IRB/IEC as per local 
requirements.  The Investigator must submit reports of the study at least annually to the 
IRB/IEC for review. 


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The Investigator must notify the IRB/IEC that the study has been completed within 3 
months of its completion.  A final clinical study report will be made available to the 
IRB/IEC.  The Investigator must maintain an accurate and complete record of all 
submissions made to the IRB/IEC, including a list of reports and documents. 
 
 
14.3 Patient Data Protection 
To ensure the patient’s identity remains unknown to the Sponsor, the Sponsor will 
identify all data by patient ID number. 
The Investigator must inform patients of the possibility that representatives from 
regulatory authorities and/or the Sponsor may require access to hospital or study site 
records for verification of data pertinent to the study, including medical history.  
The Investigator is responsible for keeping a patient identification list or form of all 
patients entered, including enrolment code, patient ID number, full name, and last known 
address and phone number. 
 
14.4 Assumption of Liability and Indemnification 
The Sponsor shall indemnify, defend, and hold harmless the Investigator(s) (which term 
includes the Investigator(s)’s institutions, employees, agents, representatives and 
associates) from and against any demands, claims, costs, judgments, liabilities, damages, 
losses and expenses, including reasonable legal fees (collectively, a “Loss”), that may be 
suffered or incurred by the Investigator(s) as a result of personal injuries or damage to 
property due to or arising out of the conduct of this clinical trial. 
Notwithstanding the foregoing, the Sponsor shall have no obligation or liability pursuant 
to the foregoing indemnity should the Loss result directly or indirectly from the 
Investigator(s)’s: 
a. negligence or wilful misconduct; 
b. failure to comply with the terms of the protocol or written instructions regarding 
the use of any product(s) used in this clinical trial; 
c. failure to adhere to any government regulations or requirements; or 
d. failure to conduct the study in accordance with standard medical practice. 
The Investigators shall promptly notify the Sponsor in writing of any demand, claim, 
proceeding or other matter (a “Claim”) for which indemnity may be claimed.  The 
notification shall specify the all known particulars of the Claim, including, if available, 
the amount of the Claim.  If the Investigator(s) fails to give timely notice of any Claim 
and as a result the Sponsor is prevented from effectively contesting liability for the 
Claim, the Sponsor shall be relieved of its obligations hereunder.  The Investigator(s) 
shall take all commercially reasonable action to preserve the right to object to and defend 
against any Claim. 
The Investigator(s) shall fully co-operate with the Sponsor with respect to all Claims and 
shall keep the Sponsor fully advised with respect thereto, including promptly supplying 
copies of all relevant documentation as it becomes available. 


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The Sponsor shall have the right but not the obligation, at its expense, and at any and all 
times participate in or assume control of the negotiation, settlement or defence of any 
Claim.  Should the Sponsor elect not to assume control of the negotiation, settlement or 
defence of a Claim, the Investigator shall not settle the Claim without the written consent 
of the Sponsor, which consent shall not be unreasonably withheld.  
If the Sponsor assumes control of the defence of a Claim, which it thereafter fails to 
defend, the Investigator shall be entitled to assume control thereof and the Sponsor shall 
be bound by the results obtained by the Investigator with respect to the Claim. 
14.5 Compliance 
This study will be conducted in compliance with the study protocol, ICH GCP E6, the 
Organization for Economic Co-operation and Development (OECD) Good Laboratory 
Practices and all applicable regulations, including the Federal Food, Drug and Cosmetic 
Act, U.S. applicable Code of Federal Regulations Title 21, Parts 11, 50, 54 (financial 
disclosure), 56, 312 and 314, Directive 2001/20/EC of the European Parliament and of 
the Council of 04 April 2001, on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the implementation of good 
clinical practices in the conduct of clinical trials on medicinal products for human use; 
any IRB requirements relative to clinical studies and the Declaration of Helsinki, June 
1964, as clarified by the WMA General Assembly, Washington 2002 and Directive 
2005/28/EC of the European Parliament and of the Council of 8 April 2005 laying down 
principles and detailed guidelines for good clinical practice as regards investigational 
medicinal products for human use, as well as the requirements for authorization of the 
manufacturing or importation of such products.  
14.6 Amendments to the Protocol 
No amendments may be made to this protocol without the agreement of both the Sponsor 
and the Investigators.  All changes to this protocol must be documented by signed 
protocol amendment. 
The amendment will be implemented by the study site from the day the document is 
signed by the Principal Investigator and the Sponsor, whichever comes later.  If the 
change affects the safety of patients or involves intervening in the patient’s treatment of 
care, the scope of the investigation or the scientific quality of the study, the amendment 
must also have IRB/IEC approval, and it also has to be notified to or approved by 
regulatory authorities before it is implemented.  Examples of these types of changes 
include: 
 Any change in drug dosage or duration of exposure of individual patients to the 
study agent beyond that in the current protocol, or any significant change in the 
number of patients under study. 
 Any significant change in the design of a protocol (such as the addition or dropping 
of a control group). 
 The addition or dropping of a test or procedure. 


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A change intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately and without written amendment to this protocol, provided that 
the regulatory authorities and the IRB/IEC are notified as soon as possible afterwards. 
When a proposed change to the protocol that meets the statutory criteria for amendment 
as defined by the FDA and EMA substantially alters the study design or potential risk to 
the patient, the patient’s re-consent to continue participation will be obtained.  This action 
will require a revised ICF.  The revised ICF will require approval from the Sponsor and 
the IRB/IEC. 
14.7 ApoPharma Inc. Obligations 
The obligations described below contain excerpts from the ICH guidelines (Good 
Clinical Practice: Consolidated Guidance: E6, 1996) and the Sponsor’s policy governing 
Sponsor and Investigator obligations. 
The Sponsor is responsible for implementing and maintaining quality assurance and 
quality control systems with written SOPs to ensure that trials are conducted and data are 
generated, documented (recorded) and reported in compliance with the protocol, GCP 
guidelines and the appropriate regulatory requirements. 
The Sponsor will have the ultimate and final authority in the trial on matters of policy and 
finance. At the time the study is initiated, the protocol and eCRFs will be reviewed 
thoroughly with the clinical Investigators and their staff. During the course of the study, 
the CRA and a Sponsor representative will be available to discuss by telephone, questions 
regarding AEs, removal of patients from the trial, conduct of the study and other clinical 
study matters. 
The Sponsor will be responsible for: 
1. Providing sufficient investigational product for all patients for the duration of the 
study. 
2. Providing all study-related supplies. 
3. Reporting the occurrence of SAEs to the Investigators and to regulatory agencies of 
findings that could affect adversely the safety of patients, impact the conduct of the 
trial, or alter the IRB/IEC approval/favourable opinion to continue the trial. 
4. Designing the study database, monitoring data entry, and ongoing validation of the 
database. 
5. Submitting data clarification forms that are generated as a result of data collected 
from the investigator sites.  
6. Providing adequate support to the Investigators so that the trial is conducted safely 
and effectively according to the standards of GCP. 
7. Reporting the findings of this study annually, or as required, to regulatory agencies 
and providing a written report of the study upon its completion. 
8. Retaining all documentation and records as required by the relevant regulatory 
agencies. 


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9. Monitoring and auditing of data at the clinical sites as well as staff interviews for the 
duration of the trial [or after study completion (e.g., for regulatory authority 
inspection readiness)] to ensure the study is being conducted according to ICH GCP 
E6 as well as any applicable local regulations and laws (e.g., adherence to the 
protocol, patient enrolment, investigational product accountability, and accuracy of 
data forms). 
 
14.8 Investigators’ Obligations 
1. Investigators must be registered clinical practitioners, qualified to carry out the study, 
taking into account the nature of the study and the particular phase and nature of the 
investigation undertaken. 
2. Investigators must provide the Sponsor with appropriate regulatory documentation 
and up-to-date curricula vitae for themselves and co-Investigators participating in the 
clinical trial. They must also furnish the Sponsor with the names of all ancillary staff 
(pharmacists, nurses, etc.) who are directly involved in the study. 
3. Investigators are responsible for providing suitable facilities to allow the study to be 
conducted efficiently and effectively. 
4. Investigators are responsible for obtaining written IRB/IEC approval before initiation 
of the study from their respective institutions. This also includes an IRB/IEC approval 
of the ICF and any applicable amendments. 
5. Investigators are responsible for obtaining written informed consent from the patients 
and/or legal representatives, prior to the initiation of any study procedures. The 
patient should receive a copy of the written ICF. 
6. Investigators are responsible for conducting the study according to the protocol for 
the accurate and complete reporting of results in accordance with GCP, and for 
maintaining accurate investigational product accountability records. 
7. Investigators must record in detail all AEs occurring during the course of the study.  
They must report all SAEs immediately to the Sponsor and the IRB/IEC, and notify 
the Sponsor immediately when a patient has been removed from the study because of 
a SAE. The responsible Investigators should institute appropriate diagnostic and 
therapeutic measures and should keep the patient under observation for as long as it is 
medically indicated. 
8. Investigators must provide completed eCRFs and resolve discrepancies in a timely 
manner. 
9. Investigators must ensure that the study documents are retained in a safe and secure 
location for 15 years following the completion of the study.  No documents may be 
destroyed without written permission of the Sponsor. 
 


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14.9 Data Quality Compliance 
To ensure accurate, complete, and reliable data, the Sponsor or its representatives will do 
the following: 
The Clinical Research Division will: 
 Provide instructional material to the study sites. 
 Sponsor a Start-up Training Session to instruct the Investigators and study 
coordinators. This session will give instruction on the protocol, the completion of 
the eCRFs, study procedures, GCP and ICH guidelines and the Operations Manual. 
 Make periodic visits to the study sites. 
 Be available for consultation and stay in contact with the study site personnel by 
mail, telephone and fax. 
The Clinical Data Management Division will: 
 Review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection. 
 Conduct a quality review of the database. 
The Quality Assurance Division will: 
 Audit all or parts of the study and all or parts of its documentation including those 
generated at investigators’ sites, local and central laboratories, and support sites. 
 Audit the final report to ensure that, as far as can be reasonably established, the 
methods described and the results reported accurately reflect the raw data generated 
during the study. 
 Conduct, if necessary, process audits including samples of data and documentation 
to assure compliance with ICH GCP E6, applicable local regulations, guidelines 
and laws as well as the study protocol and relevant Sponsor Policies, Standard 
Operating Procedures and Work Instructions. 
14.10 Study Reports 
One report on safety and efficacy will be prepared by the Sponsor at the completion of 
the study.  The lead Investigator may have an opportunity to review the study report.  
Appropriate Sponsor members will sign the study report to indicate approval. 
The Sponsor will be responsible for all submissions to the regulatory agencies. 
 
14.11 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 the whole as more fully 
described in the clinical trial agreement agreed upon with the Investigator and/or the site.  


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14.12 Publications/Poster/Presentation 
Data derived from the trial are the exclusive property of the Sponsor, and the Sponsor 
will be responsible for the primary publication of the trial data. The Investigators may, 
within 6 months of completion of the final report, indicate their interest in publishing the 
results of this study. No publication should be made by any Investigator prior to the 
publication of the study results, unless within 6 months of the final report the Sponsor 
declares no interest in the publication of the study results. 
The Sponsor reserves the right to receive any posters or abstracts a minimum of 30 days 
prior to submission for presentation and a minimum of 60 days for manuscripts prepared 
by the Investigator(s) based on data from this clinical trial, prior to submission for 
publication. The Sponsor also reserves the right to review and comment on any posters, 
abstracts, or publication intended for presentation or publication that are based on data 
from this clinical trial. 
 
14.13 Early Study Termination 
The Sponsor reserves the right to discontinue this trial at any time. The study may be 
terminated by the Investigator at his/her respective site following consultation with the 
Sponsor.  The Investigator will immediately, on discontinuance of the clinical trial, in its 
entirety or at a clinical trial site, inform both the clinical trial patients and the IRB/IEC 
responsible for the study of the discontinuance, provide them with the reasons for the 
discontinuance and advise them in writing of any potential risks to the health of clinical 
trial patients or other persons. It is the Sponsor’s responsibility to report discontinuance 
of the study to regulatory agencies, and provide them with the reasons for the 
discontinuance and advise them in writing of any potential risks to the health of clinical 
trial patients or other persons. The Sponsor must then inform the Investigators. 
In the event of a discontinuation, the Investigators will ensure return of all investigational 
products to the Sponsor with all outstanding investigational materials (e.g., eCRFs, SAE 
forms) within 1 month.  If possible, Investigators should complete all assessments as per 
the study termination assessments (see Section 5.8). 
15 
CONFIDENTIALITY 
Each Investigator must sign a confidentiality agreement, in form and content satisfactory 
to the Sponsor, concerning the protection of the Sponsor’s confidential and proprietary 
information disclosed to or obtained by the Investigator during the course of the study.  
Other than for study recruitment purposes and progress reports required by the regulatory 
agencies, the information contained in this document and all future information relating 
to this study is privileged, confidential, and proprietary and may not be used or disclosed 
without the express written consent of the Sponsor or unless otherwise required by law 
(in which case the requirement to make such disclosure shall be communicated to the 
Sponsor in advance and in writing).  All information provided to the Investigator by the 
Sponsor is to be considered strictly confidential unless otherwise specified. 


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16 
 REFERENCES 
  
1. 
Angelucci E, Brittenham GM, McLaren CE, Ripalti M, Baronciani D, Giardini C, 
et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J 
Med. 2000; 343(5):327-31. 
 
2. 
ApoPharma Inc. Clinical study report LA-01: Randomized trial of deferiprone 
(L1, Ferriprox) and deferoxamine (DFO) in thalassemia major. Toronto; Canada; 2006a. 
 
3. 
ApoPharma Inc. Clinical study report LA-03: The long term efficacy and safety 
of deferiprone in patients with thalassemia. Toronto; Canada; 2006b. 
 
4. 
ApoPharma Inc. Clinical study report LA-04: Compassionate use of deferiprone 
in patients with thalassemia. Toronto, Canada; 2006c. 
 
5. 
ApoPharma Inc. Clinical study report LA-30: A 24-week, open label, 
uncontrolled study of the safety and efficacy of Ferriprox (deferiprone) oral solution in 
iron-overloaded pediatric subjects with transfusion-dependent anemia. Toronto, Canada; 
2009. ApoPharma 
 
6. 
Apotex Research Inc. Clinical study report LA-02: Trial of deferiprone in 
thalassemia. Toronto; Canada; 1998. 
 
7.  
Apotex Research Inc. Clinical study report LA-06: Efficacy and safety data 
following 4 years of therapy with deferiprone in approximately 100 thalassemia major 
patients currently participating in the LA-06 trial. Specific obligation to the CPMP. 
Toronto, Canada; 2000a. 
 
8.  
Apotex Research Inc. Clinical study report LA10-9902: Results of prospective 
study assessing the lymphocyte clastogenicity in patients switching from deferoxamine 
therapy to deferiprone. Specific obligation to the CPMP. Toronto, Canada; 2000b. 
 
9.  
Apotex Research Inc. Clinical study report LA-12: Comparative data on survival 
and heart failure in thalassemia patients completing 4 or more years of therapy with 
deferoxamine and deferiprone. Follow-up March 2001. Specific obligation to the CPMP. 
Toronto, Canada; 2001. 
 
10.  
Apotex Research Inc. Clinical study report LA-15: Safety and efficacy of 
Ferriprox for the treatment of iron overload in subjects with transfusion-dependent 
thalassemia in Iran. Toronto, Canada; 2003. 
 
11.  
Apotex Research Inc. Clinical study report LA-16: Randomized trial comparing 
the relative efficacy of deferiprone to that of deferoxamine in removing excess cardiac 
iron in thalassemia major patients. Toronto, Canada; 2005. 
 
12.  
Apotex Research Inc. Clinical study report LA-11: Efficacy and safety of 
deferiprone (L1) in  thalassaemia/hemoglobin E diseases patients in Thailand. Toronto; 
Canada; 2006. 
 
13.  
Ballas SK. Iron overload is a determinant of morbidity and mortality in adult 
patients with sickle cell disease. Semin Hematol. 2001; 38(1 Suppl 1):30-6. 


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14.  
Bansal RK. Combined chelation with desferrioxamine and deferiprone in 
thalassemia major. Proceedings of the 12th International Conference on Oral Chelation in 
the Treatment of Thalassemia & Other Diseases; 2002 July 4-7; Santorini, Greece. p. 120.  
 
15.  
Borgna-Pignatti C, Castriota-Scanderbeg A. Methods for evaluating iron stores 
and efficacy of chelation in transfusional hemosiderosis. Haematologica. 1991; 76:409-13. 
 
16.  
Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del 
Vecchio GC, et al. Survival and complications in patients with thalassemia major treated 
with transfusion and deferoxamine. Haematologica. 2004; 89(10):1187-93. 
 
17.  
Brittenham GM, Cohen AR, McLaren CE, Martin MB, Griffith PM, Nienhuis 
AW, et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle 
cell anemia and thalassemia major. Am J Hematol. 1993; 42:81-5. 
 
18.  
Brittenham GM, Danish EH, Harris JW. Assessment of bone marrow and body 
iron stores: old techniques and new technologies. Semin Hematol. 1981; 18(3):194-221. 
 
19.  
Brittenham GM, Sheth S, Allen CJ, Farrell DE. Noninvasive methods for 
quantitative assessment of transfusional iron overload in sickle cell disease. Semin 
Hematol. 2001; 38(1 Suppl 1):37-56. 
 
20.  
Carpenter JP, He T, Kirk P, Roughton M, Anderson LJ, de Noronha SV, et al. On 
T2* Magnetic Resonance and Cardiac Iron. Circulation. 2011; 123:1519-28. 
 
21.  
Cazzola M, Borgna-Pignatti C, De Stefano P, Bergamaschi G, Bongo IG, Dezza 
L, et al. Internal Distribution of Excess Iron and Sources of Serum Ferritin in Patients 
with Thalassaemia. Scand J Haematol. 1983; 30:289-96. 
 
22.  
Collins AF, Fassos FF, Stobie S, Lewis N, Shaw D, Fry M, et al. Iron-balance and 
dose-response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) 
in iron-loaded patients with sickle cell disease. Blood. 1994; 83(8):2329-33. 
 
23.  
Finch C. Regulators of iron balance in humans. Blood. 1994; 84(6):1697-702. 
 
24.  
Finch CA, Bellotti V, Stray S, Lipschitz DA, Cook JD, Pippard MJ, et al. Plasma 
ferritin determination as a diagnostic tool. West J Med. 1986; 145(5):657-63. 
 
25.  
Fung EB, Harmatz P, Milet M, Ballas SK, De Castro L, Hagar W, et al. Morbidity 
and mortality in chronically transfused subjects with thalassemia and sickle cell disease: 
A report from the multi-center study of iron overload. Am J Hematol. 2007;  
 
26.  
Gladwin MT, Sachdev V. Cardiovascular abnormalities in sickle cell disease. J 
Am Coll Cardiol. 2012; 59(13):1123-33. 
 
27.  
Harmatz P, Butensky E, Quirolo K, Williams R, Ferrell L, Moyer T, et al. 
Severity of iron overload in patients with sickle cell disease receiving chronic red blood 
cell transfusion therapy. Blood. 2000; 96(1):76-9. 
 
28.  
Hess DC, Adams RJ, Nichols FT. Sickle cell anemia and other 
hemoglobinopathies. Semin Neurol. 1991; 11(4):314-28. 
 
29.  
Hoffbrand AV, Cohen A, Hershko C. Role of deferiprone in chelation therapy for 
transfusional iron overload. Blood. 2003; 102(1):17-24. 


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30.  
Inati A, Musallam KM, Wood JC, Taher AT. Iron overload indices rise linearly 
with transfusion rate in patients with sickle cell disease. Blood. 2010; 115(14):2980-1. 
 
31.  
Kaushik N, Eckrich MJ, Parra D, Yang E. Chronically Transfused Pediatric 
Sickle Cell Patients are Protected from Cardiac Iron Overload. Pediatr Hematol Oncol. 
2012;  
 
32.  
Kikuchi BA. Sickle Cell Disease. In: Livraria e Editora Saude Ltda., editor. Sickle 
Cell Disease - Manual for Health Workers and Educators in America. Sao Paulo: 2003. p. 
21-4.  
 
33.  
Kirk P, Roughton M, Porter JB, Walker JM, Tanner MA, Patel J, et al. Cardiac 
T2* Magnetic Resonance for Prediction of Cardiac Complications in Thalassemia Major. 
Circulation. 2009; 120:161-8. 
 
34.  
Knight-Perry JE, de Las FL, Waggoner AD, Hoffmann RG, Blinder MA, Davila-
Roman VG, et al. Abnormalities in cardiac structure and function in adults with sickle 
cell disease are not associated with pulmonary hypertension. J Am Soc Echocardiogr. 
2011; 24(11):1285-90. 
 
35.  
Kwiatkowski JL. Oral Iron Chelators. Pediatr Clin North Am. 2008; 55(2):461-82. 
 
36.  
Lal A, Vichinsky EP. Sickle Cell Disease. In: Postgraduate Haematology. Library 
of Congress Cataloging-In-Publication Data; 2005. p.  
 
37.  
Lipschitz DA, Cook JD, Finch CA. A clinical evaluation of serum ferritin as an 
index of iron stores. N Engl J Med. 1974; 290(22):1213-6. 
 
38.  
Longo F, Voi V, Gaglioti C, Engelhardt R, Fischer R, Piga A. Factors Influencing 
the Efficacy of Deferiprone Treatment. Proceedings of the 9th International Conference 
on Oral Chelation in the treatment of thalassaemia and other diseases; 1999 March 25-28; 
Hamburg, Germany.  
 
39.  
Nathan DG, Orkin SH. Nathan and Oski's hematology of infancy and childhood. 
5th Edition ed. 1998. p.  
 
40.  
Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of 
thalassemia. Blood. 1997; 89(3):739-61. 
 
41.  
Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu P, McGee A, et al. 
Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 
1994; 331(9):574-8. 
 
42.  
Overmoyer BA, McLaren CE, Brittenham GM. Uniformity of Liver Density and 
Nonheme (Storage) Iron Distribution. Arch Pathol Lab Med. 1987; 111:549-54. 
 
43.  
Pennell DJ, Berdoukas V, Karagiorga M, Ladis V, Piga A, Aessopos A, et al. 
Randomized controlled trial of deferiprone or deferoxamine in beta-thalassemia major 
patients with asymptomatic myocardial siderosis. Blood. 2006; 107(9):3738-44. 
 
44.  
Piga A, Gaglioti C, Fogliacco E, Tricta F. Comparative effects of deferiprone and 
deferoxamine on survival and cardiac disease in patients with thalassemia major: a 
retrospective analysis. Haematologica. 2003; 88(5):489-96. 


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45.  
Rombos Y, Tzanetea R, Konstantopoulos K, Simitzis S, Zervas C, Kyriaki P, et 
al. Chelation therapy in patients with thalassemia using the orally active iron chelator 
deferiprone (L1). Haematologica. 2000; 85(2):115-7. 
 
46.  
St Pierre TG, Clark PR, Chua-anusorn W, Fleming AJ, Jeffrey GP, Olynyk JK, et 
al. Noninvasive measurement and imaging of liver iron concentrations using proton 
magnetic resonance. Blood. 2005; 105(2):855-61. 
 
47.  
Taher A, Sheikh-Taha M, Sharara A, Inati A, Koussa S, Ellis G, et al. Safety and 
Effectiveness of 100 mg/kg/day Deferiprone in Patients with Thalassemia Major: A Two-
Year Study. Acta Haematol. 2005; 114(3):146-9. 
 
48.  
Telfer PT, Prestcott E, Holden S, Walker M, Hoffbrand AV, Wonke B. Hepatic 
iron concentration combined with long-term monitoring of serum ferritin to predict 
complications of iron overload in thalassaemia major. Br J Haematol. 2000; 110(4):971-7. 
 
49. 
Tricta F, Uetrecht J, Galanello R, Connelly J, Rozova A, Spino M, Palmblad J. 
Deferiprone-induced agranulocytosis: 20 years of clinical observations. Am J Hematol. 
2016 Oct;91(10):1026-31. 
 
50.  
Vichinsky E. Transfusion therapy in sickle cell disease. 2001;  
 
51.  
Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P, et al. A 
randomised comparison of deferasirox versus deferoxamine for the treatment of 
transfusional iron overload in sickle cell disease. Br J Haematol. 2007; 136(3):501-8. 
 
52.  
Walter PB, Harmatz P, Vichinsky E. Iron metabolism and iron chelation in sickle 
cell disease. Acta Haematol. 2009; 122(2-3):174-83. 
 
53.  
Wonke B, Wright C, Hoffbrand AV. Combined therapy with deferiprone and 
desferrioxamine. Br J Haematol. 1998; 103(2):361-4. 
 
54.  
Wood JC. Magnetic resonance imaging measurement of iron overload. Curr Opin 
Hematol. 2007; 14(3):183-90. 
 
55.  
Wood JC. Cardiac iron across different transfusion-dependent diseases. Blood 
Rev. 2008; 22 Suppl 2:S14-S21. 
 
56.  
Worwood M, Cragg SJ, Jacobs A, McLaren C, Ricketts C, Economidou J. 
Binding of serum ferritin to concanavalin A: patients with homozygous beta thalassaemia 
and transfusional iron overload. Br J Haematol. 1980; 46(3):409-16. 
 


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17 
SIGNED AGREEMENT TO THE PROTOCOL 
17.1 Principal Investigator Signature Page 
I confirm that I have read this protocol and I understand it. I agree to conduct this study 
in accordance with ICH Good Clinical Practice guidelines, all of the specifications in this 
study protocol, and local regulatory requirements.  I will be responsible for obtaining 
approval from the IRB/IEC responsible for my institution before the start of the study.  I 
will adhere to the protocol and comply with the guidelines. I agree to fully co-operate 
with compliance checks by allowing access to all documentation by authorized 
individuals. 
Study Title: 
The efficacy and safety of Ferriprox® for the treatment of transfusional 
iron overload in patients with sickle cell disease or other anemias. 
Study Code: LA38-0411 
Study Site: 
 
 
 
Investigator Signature 
 
Investigator Name  
 
 
 
Investigator Signature  
 
Date: (DD MMM YYYY) 
 
Name of Facility 
 
 
 
Location of Facility 
 




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18 
APPENDICES 
18.1 Schedule of Events 
 
Baseline Phase 
Treatment Phase 
STUDY PROCEDURE 
Screening/ 
Baseline 
Baseline 
Hematology 
Assessments 1 
Telephone 
Calls 
(Week 1, 2, 3) 
Monthly 
Visits  (Week 
4, 8,16, 20, 32, 
36, 44, 48) 
Quarterly 
Visits  (Week 
12, 40) 
Semi-Annual 
Visit (Week 
26) 
End of Study / 
Early 
Termination 
Visit2 (Week 52) 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
Previous/current chelation therapy 
X 
 
 
 
 
 
 
 
Confirmation of eligibility 
 
X 
 
 
 
 
 
 
Demographic 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Medical history 
X 
V 
 
 
 
 
 
R 
Transfusion history 
X 
X 
 
 
 
 
 
 
Prior and Current medications 
X 
V 
 
 
 
 
 
X 
Hematology 
X3 
 X4 
X 
 
X 
X 
X 
X 
Biochemistry 
X3,4 
V 
 
 
X 
X 
X 
X 
Serum Pregnancy testing (females of 
childbearing potential only) 
X3 
X 
 
 
X 
X 
X 
X 
Urine Pregnancy testing (females of 
childbearing potential only) 
 
X 
 
 
 
 
 
 
Serology 
X3,4 
V 
 
 
 
 
X 
X 
Urinalysis  
X3,4 
V 
 
 
 
 
X 
X 
Physical examination 
X3,4 
V 
 
 
 
 
X 
X 
Vital signs (including weight and 
height)5 
X 
X4 
 
 
X 
X 
X 
X 
12-lead ECG 
X3,4 
V 
 
 
 
 
X 
X 
Blood sample for genetic 
polymorphism of agranulocytosis 
(optional) 
 
X 
 
 
 
 
 
 
Contraceptive counselling  
X 
X 
 
 
X 
X 
X 
 


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Baseline Phase 
Treatment Phase 
STUDY PROCEDURE 
Screening/ 
Baseline 
Baseline 
Hematology 
Assessments 1 
Telephone 
Calls 
(Week 1, 2, 3) 
Monthly 
Visits  (Week 
4, 8,16, 20, 32, 
36, 44, 48) 
Quarterly 
Visits  (Week 
12, 40) 
Semi-Annual 
Visit (Week 
26) 
End of Study / 
Early 
Termination 
Visit2 (Week 52) 
Quality of Life Questionnaire (SF-
36/ Child Health Questionnaire) 
 
X 
 
 
 
 
X 
X 
Serum Ferritin 
 
X 
 
 
 
X 
X 
X 
Liver MRI/LIC 
X4,6 
 
 
 
 
 
X 
X 
Cardiac MRI T2* 
X4,6 
 
 
 
 
 
X 
X 
Dose Calculation/Verify and adjust 
dose level 
 
X 
 
 
X 
X 
X 
 
Contact IVRS/IWRS 
 
X 
 
 
X 
X 
X 
X 
Dispense study medication 
 
X 
 
 
X 
X 
X 
 
Dispense Patient Diary Card 
 
X 
 
 
X 
X 
X 
 
Review and Collect Diary Card 
 
 
 
 
X 
X 
X 
X 
Medical events/Adverse events 
X 
X 
 
X 
X 
X 
X 
X 
Concomitant medications 
 
 
 
X 
X 
X 
X 
X 
Transfusion information (if 
applicable)7 
 
 
X 
 
X 
X 
X 
X 
Return used and unused study 
medication 
 
 
 
 
X 
X 
X 
X 
X- To do, V- To verify, R- To review 
 
1. 
Hematology testing is to be done weekly up to Week 26 and biweekly thereafter. 
2. 
Early Termination: if patient withdraws from the study prior to Week 52, the patient must be seen for an early termination visit. 
3. 
These evaluations must be done within 14 days prior to baseline visit. Females of childbearing potential must be making use of an approved birth control method at least 
one month prior to starting study medication. 
4. 
Results from these tests will be considered the baseline values. 
5. 
Height will only be measured at screening/baseline, semi-annual and Week 52 visits.  
6. 
These evaluations must be conducted within two months prior to starting study medication  
7. 
Collect volume of blood that the patient received during the transfusion and the mean hematocrit of the packed red blood cell units transfused. 


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18.2 Acceptable Methods of Contraception and Definitions Related to 
Childbearing Potential 
1. Approved methods of contraception will consist of the following for the purposes of this study 
or must follow local requirements: 
 Oral contraceptive medications with condom or spermicide 
 Hormonal implants with condom or spermicide 
 Injectable contraceptive medications with condom or spermicide 
 Condom used with spermicide. 
 
If the hormonal contraception is used, it should have a Pearl index <1%. 
 
2. Women who are not able to bear children and therefore do not need to practice a medically 
accepted method of contraception will include those who: 
 Have had a tubal ligation 
 Are post-menopausal (i.e. last menstrual period was more than 2 years ago) 
 Have had an hysterectomy or oophorectomy 
 Participate in a non-heterosexual lifestyle,  
 Have a male sexual partner has been sterilized (supporting evidence required).  
 
3. Patients who are peri-menopausal (i.e., less than 2 years since their last menstrual period), 
must have a pregnancy test and must use one of the medically accepted methods listed above 
(under point 1) if they wish to participate in the study. 
 


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18.3 List of Prohibited Drugs 
The use of the following medications is precluded by protocol. All exceptions must be approved by the 
Sponsor. 
1. Any investigational drug 
2. Chloramphenicol (CHLOROMYCETIN) 
3. Clozapine (CLOZARIL), Doxepin HCl (SINEQUAN), Amitriptyline HCl/Perphenazine (ETRAFON) 
and other tricyclic antidepressants 
4. Clomipramine hydrochloride (ANAFRANIL) 
5. Propranolol hydrochloride (INDERAL) 
6. Bepredil (VASCOR) 
7. Aminoglutethimide (CYTADREN) 
8. Interferon (INTRON A) 
9. Para-aminophenol or pyrazolone derivatives 
10. Phenytoin (DILANTIN), Carbamazepine 
11. Chlordiazepoxide (LIBRIUM) and other benzodiazepines 
12. Phenylbutazone 
13. Mefenamic Acid (PONSTAN) 
14. Metoclopramide  HCl (REGLAN) 
15. Chlorpromazine, prochlorperazine and other phenothiazines 
16. Procainamide 
17. Levamisole (ERGAMISOLE) 
18. Diclofenac Sodium (VOLTAREN) 
19. Hydroxyurea (Hydrea) 
20. Trimethoprim/sulfamethoxazole (Bactrim/Septra) 
21. Aminopyrine 
 


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18.4 Sample Size Calculation Output 
 
 
 
Power Analysis of a Non-Inferiority Test of The Difference of Two Means  
Page/Date/Time 
1    12/19/2012 4:32:13 PM 
 
Numeric Results for Non-Inferiority Test (H0: D <= -|E|; H1: D > -|E|) 
Test Statistic: T-Test 
 
 
 
Equivalence 
Margin 
Actual  
Difference 
Significance 
Level 
Standard 
Deviation1 
Standard 
Deviation2 
Power 
N1/N2 
(E) 
(D) 
(Alpha) 
Beta 
(SD1) 
(SD2) 
0.95017 
79/158 
-2.000 
0.000 
0.02500 
0.04983 
4.000 
4.000 
 
 
 
 
References 
Chow, S.C.; Shao, J.; Wang, H. 2003. Sample Size Calculations in Clinical Research. Marcel Dekker. 
New York. 
Julious, Steven A. 2004. 'Tutorial in Biostatistics. Sample sizes for clinical trials with Normal data.' 
     Statistics in Medicine, 23:1921-1986. 
 
Report Definitions 
Group 1 is the treatment group. Group 2 is the reference or standard group. 
Power is the probability of rejecting a false null hypothesis. Power should be close to one. 
N1 is the number of subjects in the first (treatment) group. 
N2 is the number of subjects in the second (reference) group. 
|E| is the magnitude of the margin of equivalence. It is the largest difference that is not of practical 
significance. 
D is the mean difference at which the power is computed. D = Mean1 - Mean2. 
Alpha is the probability of a false-positive result. 
Beta is the probability of a false-negative result. 
SD1 and SD2 are the standard deviations of groups 1 and 2, respectively. 
 
Summary Statements 
Group sample sizes of 79 and 158 achieve 95% power to detect non-inferiority using a one-sided, 
two-sample t-test. The margin of equivalence is -2.000. The true difference between the means 
is assumed to be 0.000. The significance level (alpha) of the test is 0.02500. The data are 
drawn from populations with standard deviations of 4.000 and 4.000. 
 
 
 


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Power Analysis of a Non-Inferiority Test of The Difference of Two Means  
Page/Date/Time 
2    12/19/2012 4:32:13 PM 
 
Chart Section 
 
 
 
N1 vs E with D=0.000 S1=4.000 S2=4.000 Alpha=0.025
Power=0.950 N2=2N1 1-Sided T-
N1
E
0
20
40
60
80
-0.5
-1.0
-1.5
-2.0
0.0


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18.5 Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Version Date: 01 MAY 2017 
 
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CHQ: Child Health Questionnaire   ( For content review only ) 
 
The Child Health Questionnaire™ (CHQ) is a family of generic quality of life instruments that have been designed and 
normed for children 5-to-18 years of age. The CHQ measures 14 unique physical and psychosocial concepts. The parent 
form is available in 2 lengths - 50 or 28 items. Scores can be analyzed separately, the CHQ Profile Scores, or combined to 
derive an overall physical and psychosocial score, the CHQ Summary Scores. In April 2008 HealthActCHQ released the 
first-ever electronic CHQ Scoring and Interpretation Manual. The 212-page Manual provides information about the 
conceptual framework and development of the CHQ, the proprietary scoring algorithms, norms and rules for interpretation. 
The interactive CD-rom features hyperlinks in both the Table of Contents and the Appendix of Tables for smooth navigation. 
 
Users can also click on URLs within the Manual to access the latest updates on translations and the online Bibliography at the 
 
HealthActCHQ website. The CHQ surveys and translations are made available upon approval of registration and payment. 
 
In the US, normative values and benchmarks for the parent-reported versions of the CHQ are available for some 
conditions. The CHQ has been extensively translated using rigorous international guidelines. The youth self-report version 
is 87 items, and was developed for ages 10 and older. Authorized translations are available from HealthActCHQ. Norms, 
benchmarks, and summary scoring for the youth version will be forthcoming upon the development and testing of a short-
form by the Principal Developer. 
 
Child Health Questionnaire Parent Form 28 Questions 
 
• In general, how would you rate your child's health?  
 
• Has your child been limited in any of the following activities due to health problems - doing things that take a lot 
of energy, such as playing soccer or running; doing things that take some energy such as riding a bike or 
skating; bending, lifting, or stooping  
 
• Has your child's been limited in the amount of time he/she could spend on schoolwork or activities with friends  
 
due to emotional difficulties or problems  with his/her behavior? 
 
• Has your child been limited in the kind of schoolwork or activities he/she could do with friends due to problems 
with his/her physical health?  
 
• How often has your child had bodily pain or discomfort?  
 
• How often did each of the following statements describe your child - argued a lot; had difficulty concentrating or 
paying attention; lied/cheated?  
 
• Compared to other children your child's age, in general how would you rate his/her behavior?  
 
• How much of the time do you think your child: felt lonely; acted nervous; bothered or upset?  
 
• How satisfied do you think your child has felt about: his/her school ability; friendships; life overall? 
 
• My child seems to be less healthy than other children I know; My child has never been seriously ill; I worry more 
about my child's health than other people.  
 
• Compared to one year ago, how would you rate your child's health now?  
 
• How much emotional worry or concern did each of the following cause you - your child's physical health; 
emotional well-being or behavior?  
 
• Were you limited in the amount of time you had for your own needs because of your child's - physical 
health; emotional well-being or behavior?  
 
• How often has your child's health or behavior - limited the types of activities you could do as a family; 
interrupted various everyday family activities (eating meals, watching tv)?  
 
• In general, how would you rate your family's ability to get along with one another?  
 
 
 
HealthActCHQ Inc. CHQ: Child Health Questionnaire 
© Copyright 2013 HealthActCHQ Inc. All Rights Reserved. 
 


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Child Health Questionnaire Parent Form 50 Questions 
 
• In general, how would you rate your child's health?  
 
• Has your child been limited in any of the following activities due to health problems - doing 
things that take  
a lot of energy, such as playing soccer or running; doing things that take some energy such as riding 
a bike or skating; ability (physically) to get around the neighborhood, playground, or school; walking 
one block or climbing  
one flight of stairs; bending, lifting,/stooping; taking care of him/herself? 
 
• Has your child's school work or activities with friends been limited in any of the following ways 
due to emotional difficulties or problems with his/her behavior - limited in the kind of 
schoolwork or activities with friends he/she could do; limited in the amount of time he/she 
could spend on schoolwork or activities with friends; limited in performing schoolwork or 
activities with friends? 
 
• Has your child's school work or activities with friends been limited in any of the following ways 
due to problems with his/her physical health - limited in the kind of schoolwork or activities with 
friends he/she could do; limited in the amount of time he/she could spend on schoolwork or 
activities with friends?  
 
• How much bodily pain or discomfort has your child had?  
 
• How often has your child had bodily pain or discomfort?  
 
• How often did each of the following statements describe your child - argued a lot; had difficulty 
concentrating or paying attention; lied/cheated; stole things; had tantrums?  
 
• Compared to other children your child's age, in general how would you rate his/her behavior?  
 
• How much of the time do you think your child: felt like crying; felt lonely; acted 
nervous; bothered or upset; cheerful?  
 
• How satisfied do you think your child has felt about: his/her school ability; athletic 
ability; friendships; looks/appearance; family relationships; life overall?  
 
• My child seems to be less healthy than other children I know; My child has never been 
seriously ill; When there is something going around my child usually catches it; I expect 
my child will have a very healthy life; I worry more about my child's health than other 
people.  
 
• Compared to one year ago, how would you rate your child's health now?  
 
• How much emotional worry or concern did each of the following cause you - your child's 
physical health; emotional well-being or behavior; attention or learning abilities?  
 
• Were you limited in the amount of time you had for your own needs because of your child's - 
physical health; emotional well-being or behavior; attention or learning abilities?  
 
• How often has your child's health or behavior - limited the types of activities you could do as a 
family; interrupted various everyday family activities; limited your ability as a family to "pick up 
and go"; caused tension or conflict; been a source of disagreements or arguments in your 
family; caused you to cancel or change plans (personal or work) at the last minute?  
 
• In general, how would you rate your family's ability to get along with one another?  
 
Child Health Questionnaire Child Form 87 Questions 
 
• In general, how would you say your health is? 
 
• Has it been difficult for you to do the following activities due to health problems - doing 
things that take a lot of energy, such as playing soccer or running; doing things that take 
some energy such as riding a bike or 
 
skating; walk several blocks or climb several flights of stairs; ability (physically) to get around 
the neighborhood, playground, or school; walk one block or climbing one flight of stairs; do your 
tasks around the house; bend, lift or stoop; eat, dress, bathe or go to the toilet by yourself; get 
in/out of bed? 
 


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HealthActCHQ Inc. CHQ: Child Health Questionnaire                           © Copyright 2013 HealthActCHQ Inc. All Rights Reserved. 
 
 
 
• Has it been difficult to do certain kinds of schoolwork or activities with friends because of problems like 
feeling sad or worried; spend the usual amount of time on schoolwork or activities with friends; get 
schoolwork done at all or do any activities with friends? 
 
• Has it been difficult to do certain kinds of schoolwork or activities  with friends because of problems  with 
 
your behavior; spend the usual amount of time on schoolwork or activities with friends; get schoolwork 
done at all or do any activities with friends? 
• Has it been difficult to do certain kinds of schoolwork or activities with friends because of problems with 
your physical health; spend the usual amount of time on schoolwork or activities with friends; get 
schoolwork done at all or do any activities with friends? 
 
• How much bodily pain or discomfort have you had? 
• How often have you had bodily pain or discomfort?  
• How often did each of the following statements describe you; acted too young for your age; argued; had  
 
a hard time paying attention; did not do what your teacher or parent asked you to do; wanted to be 
alone;  
 
lied/cheated; had a hard time getting others to like you; felt clumsy; ran away from home; had speech 
problems; stole things at home or outside the home; acted mean or moody if you did not get what you 
wanted; got really mad when you did not get what you wanted; found it hard to be with others; had a 
hard time getting along 
 
with others. 
 
• Compared to other children your age, in general how would you rate your behavior?  
 
• How much of the time do you: feel sad; feel like crying; feel afraid or scared; worry about things; feel 
lonely; feel unhappy; feel nervous; feel bothered or upset; feel happy; feel cheerful; enjoy the things you 
do; have fun; feel jittery or restless; have trouble sleeping; have headaches; like yourself?  
 
• How good or bad have you felt about: yourself; your school work; your ability to play sports; your 
friendships; the things you can do; the way you get along with others; your body and your looks; the way 
you seem to feel most of the time; the way you get along with your family; the way life seems to be for 
you; your ability to be a friend to others; the way others seem to feel about you; your ability to talk with 
others; your health in general?  
 
• My health is excellent; I was so sick once I thought I might die; I do not seem to get very sick; I seem to 
be less healthy than other kids I know; I have never been very, very sick; I always seem to get sick; I 
think I will be less healthy when I get older; I think I will be very healthy when I get older; I never worry 
about my health; I think I am healthy now; I think I worry more about my health than other kids my age.  
 
• Compared to one year ago, how would you rate your health now?  
 
• How often has your health or behavior - limited the types of activities you could do as a family; 
interrupted various everyday family activities; limited your ability as a family to "pick up and go"; 
caused tension or  
conflict; been a source of disagreements or arguments in your family; caused your family to cancel or 
change 
 
plans at the last minute? 
 
• In general, how would you rate your family's ability to get along with one another? 
 
 
HealthActCHQ Inc. CHQ: Child Health Questionnaire                       © Copyright 2013 HealthActCHQ Inc. All Rights Reserved. 
 

SAP_001.pdf: 




ApoPharma Inc. 
Statistical Analysis Plan 
 
Protocol LA38-0411 
 
 
CONFIDENTIAL INFORMATION 
3
 
Table of Contents 
 
 
Title page.......................................................................................................................1 
 
Approvals ......................................................................................................................2 
 
List of Abbreviations ...................................................................................................5 
1 INTRODUCTION........................................................................................................7 
2 OBJECTIVES ..............................................................................................................7 
2.1 
Primary Objective ..............................................................................................7 
2.2 
Secondary Objectives .........................................................................................7 
3 METHODS ...................................................................................................................7 
3.1 
Study Design .......................................................................................................7 
3.2 
Number of Patients .............................................................................................7 
3.3 
Treatment ............................................................................................................9 
3.4 
Study Sites and Study Duration ......................................................................12 
3.5 
Schedule of Study Procedures .........................................................................12 
3.6 
Method of Assignment to Treatment ..............................................................15 
3.7 
Interim Analysis ...............................................................................................15 
4 STUDY POPULATIONS ..........................................................................................16 
4.1 
Intent-to-Treat Population ..............................................................................16 
4.2 
Per-Protocol Population ..................................................................................16 
4.3 
Safety Population ..............................................................................................16 
5. HANDLING OF MISSING DATA ..........................................................................16 
6  PATIENT DISPOSTION AND BASELINE CHARACTERISTICS ...................17 
6.1 
Patient Disposition ............................................................................................17 
6.2 
Demographics ...................................................................................................17 
6.3 
LIC, Cardiac MRI T2*, and Serum Ferritin at Baseline .............................17 
6.4 
Prior and Concomitant Medications ..............................................................17 
6.5 
Medical History ................................................................................................18 
6.6 
Physical Examinations .....................................................................................18 
6.7 
Vital Signs, Weight and Height .......................................................................18 
7 EFFICAY ANALYSES .............................................................................................18 
7.1 
Primary Efficacy Endpoint .............................................................................18 
7.2 
Secondary Efficacy Endpoints ........................................................................19 
7.3 
Trend Analysis for LIC, cardiac MRI T2*, and Serum Ferritin .................21 
7.4 
Subgroup Analysis ............................................................................................22 
7.5 
Sensitivity Analysis ...........................................................................................22 
7.6 
Exploratory Analysis ........................................................................................22 
8 SAFETY ANALYSES ...............................................................................................23 
8.1 
Adverse Events .................................................................................................23 
8.2 
Physical Examination .......................................................................................24 
8.3 
Vital Signs, Weight and Height .......................................................................24 
8.4 
12-Lead ECG ....................................................................................................24 


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8.5 
Biochemistry, Hematology and Urinalysis .....................................................24 
8.6 
Concomitant Medications ................................................................................25 
8.7 
Pregnancy test ...................................................................................................25 
9 OTHER ANALYSES .................................................................................................25 
9.1 
Drug Exposure ..................................................................................................25 
9.2 
Treatment compliance .....................................................................................25 
9.3 
Transfusional Iron Input .................................................................................26 
14 SUMMARY TABLES AND FIGURES ...................................................................28 
14.1 
Demographics and Baseline Data ...................................................................28 
14.2 
Efficacy Analyses ..............................................................................................28 
14.2.1 
LIC ......................................................................................................28 
14.2.2 
Cardiac MRI T2* ...............................................................................28 
14.2.3 
Serum Ferritin ....................................................................................29 
14.3 
Safety Analyses .................................................................................................29 
14.3.1 
Adverse Events ...................................................................................29 
14.3.2 
Vital Signs ...........................................................................................29 
14.3.3 
Weight and Height .............................................................................29 
14.3.4 
Concomitant Medications .................................................................29 
14.3.5 
12-Lead ECG ......................................................................................30 
14.3.6 
Laboratory Data.................................................................................30 
14.3.6.1 Hematology ..........................................................................................30 
14.3.6.2 Biochemistry ........................................................................................30 
14.3.6.3 Serology ...............................................................................................30 
14.3.7 
Pregnancy test ....................................................................................31 
14.4 
Treatment compliance .....................................................................................31 
14.5 
 Transfusion information .................................................................................31 
14.6 
Total daily dose .................................................................................................31 
FIGURES ..........................................................................................................................31 
14.2 
Efficacy ..............................................................................................................31 
14.3 
Safety .................................................................................................................31 
14.3.1 
Hematology .........................................................................................31 
14.3.2 
Biochemistry .......................................................................................32 
16 DATA LISTINGS ......................................................................................................32 
16.2 
Patient Data Listings ........................................................................................32 
17 TABLE SHELLS .......................................................................................................33 


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Protocol LA38-0411 
 
 
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5
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 α                                 Type I error rate 
AE 
 
 
Adverse Event 
ANC  
 
Absolute Neutrophil Count 
ANCOVA 
 
Analysis of Covariance 
ALT 
 
 
Alanine aminotransferase 
AST 
 
 
Aspartate aminotransferase 
ATC  
 
Anatomical Therapeutic Chemical  
CHQ   
 
Child Health Questionnaire 
CI 
 
 
Confidence Interval 
CRF 
 
 
Case Report Form 
CRO  
 
Contract Research Organization  
CTCAE 
 
Common Terminology Criteria for Adverse Events 
DFO  
 
Deferoxamine 
DFP                             Deferiprone 
DFX  
 
Deferasirox 
dw 
 
 
dry weight 
ECG  
 
Electrocardiogram 
eCRF  
 
electronic Case Report Form 
EDC  
 
Electronic Data Capture 
GCP  
 
Good Clinical Practice 
GGT  
 
gamma-glutamyl transferase 
Hb 
 
 
Hemoglobin 
HIV 
 
 
Human Immunodeficiency Virus 
HR 
 
 
Heart rate 
ICF 
 
 
Informed Consent Form 
ICH 
 
 
International Conference on Harmonisation 
ID 
 
 
Identification 
ITT  
 
 
Intent to Treat 
IVRS  
 
Interactive Voice Response System 
LIC 
 
 
Liver Iron Concentration 
LOCF  
 
Last Observation Carried Forward 
MDS  
 
Myelodysplastic Syndrome 
ME 
 
 
Medical Event 


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Statistical Analysis Plan 
 
Protocol LA38-0411 
 
 
CONFIDENTIAL INFORMATION 
6
MedDRA 
 
Medical Dictionary for Regulatory Activities 
mg 
 
 
milligram 
mg/g  
 
milligram per gram 
mg/kg/day 
 
milligram/kilogram/day 
 
mL 
 
 
millilitre 
MRI 
 
 
Magnetic Resonance Imaging 
NCI 
 
 
National Cancer Institute 
NDA                           New Drug Application 
OC 
 
 
Observed Case 
PP 
 
 
Per-Protocol 
PT 
 
 
Preferred Term 
RBCs  
 
Red Blood Cells 
SADR  
 
Serious Adverse Drug Reaction 
SAE 
 
 
Serious Adverse Event 
SAP 
 
 
Statistical Analysis Plan 
SCD  
 
Sickle Cell Disease 
SD 
 
 
Standard Deviation 
SE 
                        Standard Error 
SOC  
 
System Organ Class 
SOP 
 
 
Standard Operating Procedure 
tid 
 
 
three times a day 
WHO  
 
World Health Organization 


ApoPharma Inc. 
Statistical Analysis Plan 
 
Protocol LA38-0411 
 
 
CONFIDENTIAL INFORMATION 
7
1 INTRODUCTION 
 
This document outlines the statistical analysis plan (SAP) for the efficacy and safety data 
of clinical study LA38-0411, entitled “The efficacy and safety of Ferriprox for the 
treatment of transfusional iron overload in patients with sickle cell disease or other 
anemias”. The SAP for the quality of life data from SF-36 or Child Health Questionnaire 
(CHQ) has been prepared by QualityMetric Inc.. 
2 OBJECTIVES 
2.1 
Primary Objective 
• To determine the efficacy of deferiprone vs. deferoxamine in the treatment of iron 
overload in patients with sickle cell disease (SCD) or other anemias. 
2.2 
Secondary Objectives 
• To evaluate the effect of deferiprone vs. deferoxamine on the patients’ quality of 
life; 
• To evaluate the safety and tolerability of deferiprone vs. deferoxamine. 
3 METHODS 
3.1 
Study Design 
This study is a 52-week, prospective, multi-center, two-arm, randomized, open-label, 
parallel design study of deferiprone (Ferriprox) vs. deferoxamine.   
 
3.2 
Number of Patients 
Originally, three hundred (300) male and female patients were planned to be enrolled into 
the study (200 patients for Ferriprox and 100 patients for deferoxamine in a 2:1 ratio for 
randomization). In a randomized study of two iron chelators for the treatment of iron 
overload in patients with sickle cell disease (Vichinsky E et al. 2007), mean ±SD 
reductions of 4.0 ± 1.5 mg/g dw and 4.5 ± 2.0 mg/g dw in LIC, as measured by SQUID, 
were observed (Figure 1 of the article, numerical values obtained from the authors) in 
patients from the baseline LIC categories of >7-14 mg/g dw or >14 mg/g dw after they 
were treated with 35-50 mg/kg or ≥50 mg/kg of deferoxamine respectively, for 52 weeks. 
Assuming the same mean reduction in LIC for Ferriprox but a higher SD of ±4.0 mg/g 


ApoPharma Inc. 
Statistical Analysis Plan 
 
Protocol LA38-0411 
 
 
CONFIDENTIAL INFORMATION 
8
dw for both treatments due to possibly higher variability associated with MRI 
measurement, the sample size of 300, with >80% being patients with sickle cell disease, 
will provide over 95% power for demonstrating non-inferiority of Ferriprox to 
deferoxamine in patients with sickle cell disease.  
 
The sample size estimate is based on a non-inferiority margin of 2 mg/g dw for the 
reduction of LIC and α of 0.05, two-sided (or α of 0.025, one-sided). It has been reported 
that in a typical patient with thalassemia major, the LIC could increase by 5 mg/g dw 
after 1 year without chelation therapy. As the cause of iron overload is the same in 
thalassemia and sickle cell disease, the same increase in LIC may be expected if patients 
with sickle cell disease are transfused at the same rate and not treated with a chelator.  
Hence, the difference in reduction of LIC between deferoxamine therapy and a placebo 
(effect size) can be estimated to be 9 (i.e., 4 – (-5)) mg/g dw. This means that the non-
inferiority margin of 2 mg/g dw would be about 20% of the effect size. With the 
enrolment of 300 patients, there is a greater than 99% chance (power) of occurrence of at 
least 1 adverse event with an anticipated incidence rate of 2%, or greater than 95% 
chance for an anticipated incidence rate as low as 1%. 
 
However, patient’s recruitment in this study has proceeded at a very slow pace and 
despite all our efforts over the past 4 years, the goal of enrolling a total of 300 patients 
has not been reached. A total of 213 patients (142 patients for Ferriprox and 71 patients 
for deferoxamine) are projected to have either completed the study or been withdrawn 
from the study by November 30, 2018. An interim analysis is planned to be performed on 
the data of these 213 patients. Based on the same values of non-inferiority margin and SD 
of the LIC measurement, but an α level of 0.0399, two-sided (Pocock’s α spending 
method, see section 3.7 for details), this sample size (213 patients) will provide 89% 
power to demonstrate non-inferiority of Ferriprox to deferoxamine in this interim 
analysis, assuming no real difference in efficacy between the two treatments. For the 
subgroup analysis of only patients with sickle cell disease, the power will be 82% as there 
are 178 SCD patients (119 patients for Ferriprox and 59 patients for deferoxamine), 
which is approximately 84% of 213 patients. With the safety data of 213 patients, there is 
98% chance (power) of occurrence of at least 1 SAE with an anticipated incidence rate of 
2%, or 88% chance for an anticipated incidence rate of as low as 1%. 
 
During this interim analysis, while patient enrollment has been put on hold, there will still 
be 17 patients who are on-going with their assigned drug treatment. All are projected to 
have completed the study by October, 2019. If the results of the interim analysis lead to 
the conclusion of non-inferiority of Ferriprox to deferoxamine, considerations will be 
given on early termination of the study, to avoid unnecessary exposure of patients to a 
clinical trial that has reached its objectives. The data from those patients up to the time of 


ApoPharma Inc. 
Statistical Analysis Plan 
 
Protocol LA38-0411 
 
 
CONFIDENTIAL INFORMATION 
9
study closure will be added to the interim dataset for the final statistical analysis of the 
study based on the same statistical analyses in this SAP.  
 
 
3.3 
Treatment 
Baseline Phase: 
 
During the baseline phase, patients who sign an informed consent form will 
undergo initial screening. On the final day of the baseline phase, patients’ eligibility will 
be determined, based on inclusion/exclusion criteria, and qualified patients will enter the 
treatment phase. 
 
Treatment Phase: 
 
At the beginning of the treatment phase, patients will be randomized in a 2:1 ratio to 
receive either deferiprone or deferoxamine. The treatment phase will be 52 weeks in 
duration.  
Deferiprone Treatment Arm: 
 
Patients will be prescribed Ferriprox 500 mg tablets and/or 80 mg/mL oral solution, 
according to patient preference or product’s availability, for administration three times a 
day (tid). The dose of Ferriprox will be based on the transfusional iron input and the 
severity of iron overload at baseline, and may be adjusted on the basis of the magnitude 
of change in iron overload during the study. 
 
Ferriprox 25 mg/kg tid: 
 
Patients with transfusional iron input ≤ 0.3 mg/kg/day in the 3 months prior to baseline 
 
AND 
 
Patients with a baseline measure of iron load of: 
 
- 
Serum ferritin < 2500 μg/L  
 
AND 
- 
LIC < 15 mg/g dry weight 
 
AND 
- 
Cardiac T2* > 20 ms 


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Ferriprox 33 mg/kg tid: 
 
Patients with a transfusional iron input > 0.3 mg/kg/day in the 3 months prior to baseline 
 
OR  
 
 
Patients with at least one baseline measure of iron load as follows: 
 
- 
Serum ferritin ≥ 2500 μg/L 
 
OR  
- 
LIC ≥ 15 mg/g dry weight  
 
OR  
- 
Cardiac T2* ≤ 20 ms 
 
Dosing of all patients will be initially at 15 mg/kg tid for 1 week, which will be increased 
to 20 mg/kg tid in Week 2 and to 25 mg/kg tid in Week 3, which will be the treatment 
dose for the remainder of the trial, unless a patient meets the 33 mg/kg tid dosing criteria. 
In that case, the dose of Ferriprox will be increased further to 33 mg/kg tid in Week 4, 
and this dose will be the treatment dose for the remainder of the trial.  
 
The dose of Ferriprox will also be increased to 33 mg/kg tid at any time during the trial if 
the mean daily transfusional iron input increases to more than 0.3 mg/kg body weight for 
at least 3 consecutive months OR at Week 26 if there is less than 10% improvement from 
baseline to Week 26 in at least one of the measures indicative of iron overload (serum 
ferritin, cardiac MRI T2* or LIC). 
 
Dose reduction recommendations will be based on regular assessment of safety markers 
for adverse reactions that are possibly dose dependent, such as gastrointestinal upset, 
increases in serum liver enzyme levels, and arthropathies. 
 
Deferoxamine Treatment Arm: 
 
Patients will be prescribed deferoxamine as per the approved US prescribing information 
at doses of 20 – 40 mg/kg/day for children (<16 years of age) and 40–50 mg/kg/day in 
adults (≥16 years of age) as 8 – 12 h subcutaneous infusion for 5 – 7 days per week.  The 
dose of deferoxamine will be based on the transfusional iron input, on the severity of iron 
overload at baseline, and on the magnitude of its change during the study. 


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Deferoxamine 20 mg/kg/day (children) or 40 mg/kg/day (adults): 
 
Patients with transfusional iron input ≤ 0.3 mg/kg/day in the 3 months prior to baseline 
 
AND 
 
Patients with a baseline measure of iron load of: 
 
- 
Serum ferritin < 2500 μg/L 
 
AND 
- 
LIC < 15 mg/g dry weight 
 
AND 
- 
Cardiac T2 > 20 ms 
 
Deferoxamine up to 40 mg/kg/day (children) or 50 mg/kg/day (adults): 
 
Patients with a transfusional iron input > 0.3 mg/kg/day in the 3 months prior to baseline 
 
OR  
 
Patients with at least one baseline measure of iron load as follows: 
 
- 
Serum ferritin ≥ 2500 μg/L 
 
OR  
- 
LIC ≥ 15 mg/g dry weight  
 
OR  
- 
Cardiac T2* ≤ 20 ms 
 
Children (<16 years of age). 
The dose of deferoxamine will also be increased up to 40 mg/kg for 5 – 7 days per week 
at any time during the trial if the mean daily transfusional iron input increases to more 
than 0.3 mg/kg body weight for at least 3 consecutive months OR at Week 26 if there is 
less than 10% improvement from baseline to Week 26 in at least one of the measures of 
iron overload (serum ferritin, cardiac MRI T2* or LIC). 
 
 


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Adults (≥16 years of age) 
The dose of deferoxamine will be increased up to 50 mg/kg for 5 – 7 days per week at 
any time during the trial if the mean daily transfusional iron input increases to more than 
0.3 mg/kg body weight for at least 3 consecutive months OR at Week 26 if there is less 
than 10% improvement from baseline to Week 26 in at least one of the measures of iron 
overload (serum ferritin, cardiac MRI T2* or LIC). 
 
Dose reduction recommendations will be based on regular assessment of safety markers. 
Efficacy, safety and tolerability evaluations will occur according to the schedule of 
evaluation (Table 1). Rescue medication (intravenous administration of deferoxamine or 
combination of 2 iron chelators: Ferriprox, deferoxamine or deferasirox) for the treatment 
of iron overload will not be allowed during the Treatment Phase. Should iron overload 
symptoms become intolerable for the patient despite dose adjustment, the Investigator 
should withdraw the patient from the study. 
If a patient withdraws early, he or she will return to the clinic for an Early Termination 
Visit as soon as possible, and no later than 1 month following treatment discontinuation.  
 
All of the efficacy and safety evaluations will be performed at the last study visit or the 
Early Termination visit, whichever comes first. 
3.4 
Study Sites and Study Duration 
Study sites have been located in USA, Canada, Brazil, United Kingdom, Egypt, Saudi 
Arabia, Tunisia, and Turkey. Each patient is expected to participate in the study for 
approximately 60 weeks (from the Screening Visit to the End of Study Visit). 
3.5 
Schedule of Study Procedures 
The efficacy and safety measurements/evaluations will be performed at visits outlined in 
Table 1 – Schedule of Study Procedures.  
 


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Table 1. Schedule of Study Procedures 
 
Baseline Phase 
Treatment Phase 
STUDY PROCEDURE 
Screening/ 
Baseline 
Baseline 
Hematology 
Assessments 1 
Telephone 
Calls 
(Week 1, 2, 3) 
Monthly 
Visits  (Week 
4, 8,16, 20, 
32, 36, 44, 48) 
Quarterly 
Visits  (Week 
12, 40) 
Semi-Annual 
Visit (Week 
26) 
End of Study / 
Early 
Termination 
Visit2 (Week 52) 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
Eligibility Criteria 
X 
 
 
 
 
 
 
 
Previous/current chelation therapy 
X 
 
 
 
 
 
 
 
Confirmation of eligibility 
 
X 
 
 
 
 
 
 
Demographic 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Medical history 
X 
V 
 
 
 
 
 
R 
Transfusion history 
X 
X 
 
 
 
 
 
 
Prior and Current medications 
X 
V 
 
 
 
 
 
X 
Hematology 
X3 
 X4 
X 
 
X 
X 
X 
X 
Biochemistry 
X3,4 
V 
 
 
X 
X 
X 
X 
Serum Pregnancy testing (females 
of childbearing potential only) 
X3 
X 
 
 
X 
X 
X 
X 
Urine Pregnancy testing (females of 
childbearing potential only) 
 
X 
 
 
 
 
 
 
Serology 
X3,4 
V 
 
 
 
 
X 
X 
Urinalysis  
X3,4 
V 
 
 
 
 
X 
X 
Physical examination 
X3,4 
V 
 
 
 
 
X 
X 
Vital signs (including weight and 
height)5 
X 
X4 
 
 
X 
X 
X 
X 
12-lead ECG 
X3,4 
V 
 
 
 
 
X 
X 
Blood sample for genetic 
polymorphism of agranulocytosis 
(optional) 
 
X 
 
 
 
 
 
 


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Baseline Phase 
Treatment Phase 
STUDY PROCEDURE 
Screening/ 
Baseline 
Baseline 
Hematology 
Assessments 1 
Telephone 
Calls 
(Week 1, 2, 3) 
Monthly 
Visits  (Week 
4, 8,16, 20, 
32, 36, 44, 48) 
Quarterly 
Visits  (Week 
12, 40) 
Semi-Annual 
Visit (Week 
26) 
End of Study / 
Early 
Termination 
Visit2 (Week 52) 
Contraceptive counselling  
X 
X 
 
 
X 
X 
X 
 
Quality of Life Questionnaire (SF-
36/ Child Health Questionnaire) 
 
X 
 
 
 
 
X 
X 
Serum Ferritin 
 
X 
 
 
 
X 
X 
X 
Liver MRI/LIC 
X4,6 
 
 
 
 
 
X 
X 
Cardiac MRI T2* 
X4,6 
 
 
 
 
 
X 
X 
Dose Calculation/Verify and adjust 
dose level 
 
X 
 
 
X 
X 
X 
 
Contact IVRS/IWRS 
 
X 
 
 
X 
X 
X 
X 
Dispense study medication 
 
X 
 
 
X 
X 
X 
 
Dispense Patient Diary Card 
 
X 
 
 
X 
X 
X 
 
Review and Collect Diary Card 
 
 
 
 
X 
X 
X 
X 
Medical events/Adverse events 
X 
X 
 
X 
X 
X 
X 
X 
Concomitant medications 
 
 
 
X 
X 
X 
X 
X 
Transfusion information (if 
applicable)7 
 
 
X 
 
X 
X 
X 
X 
Return used and unused study 
medication 
 
 
 
 
X 
X 
X 
X 
X- To do, V- To verify, R- To review 
1. 
Hematology testing is to be done weekly up to Week 26 and biweekly thereafter. 
2. 
Early Termination: if patient withdraws from the study prior to Week 52, the patient must be seen for an early termination visit. 
               3. 
These evaluations must be done within 14 days prior to baseline visit. Females of childbearing potential must be making use of an approved birth control method at  
                            least one month prior to starting study medication. 
4. 
Results from these tests will be considered the baseline values. 
5. 
Height will only be measured at screening/baseline, semi-annual and Week 52 visits.  
6. 
These evaluations must be conducted within two months prior to starting study medication  
7. 
Collect volume of blood that the patient received during the transfusion and the mean hematocrit of the packed red blood cell units transfused.


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3.6 
Method of Assignment to Treatment 
At the baseline visit, patients will be randomly assigned to receive Ferriprox or deferoxamine in a 2:1 ratio.  
Stratified randomization based on disease category (sickle cell disease vs. other anemias) and on the 
transfusional iron input in the 3 months prior to baseline (> 0.3 mg/kg/day vs. ≤ 0.3 mg/kg/day) will be 
employed to ensure that the 2:1 ratio is maintained within each of the 4 strata: 1) sickle cell disease with 
transfusional iron input > 0.3 mg/kg/day, 2) sickle cell disease with transfusional iron input ≤ 0.3 
mg/kg/day, 3) other anemias with transfusional iron input > 0.3 mg/kg/day, and 4) other anemias with 
transfusional iron input ≤ 0.3 mg/kg/day.  Treatment assignment and drug allocation will be performed by 
an Interactive Voice Response System (IVRS). 
3.7 
Interim Analysis 
An interim analysis will be performed with the data of patients who will have either completed or been 
withdrawn from the study by November 30, 2018. The Pocock’s α spending function (Lan and DeMets, 
Discrete sequential boundaries for clinical trials. Biometrika, 1983; 70:659-663) will be used for assigning 
α for this interim analysis. The Pocock’s α spending function is: 
α(t) = α x ln [1 + (e – 1) x t]  
where α = 0.05 and t = information fraction  
                                   = number of patients at the interim analysis / total number of patients  
                                   = 213 patients / 300 patients  
                                   = 0.71 
Substituting the values of α = 0.05, t = 0.71, and e = 2.718 into the Pocock’s α spending function gives  
α(t) = 0.05 x ln [1 + (2.718 – 1) x 0.71] 
        = 0.05 x ln [2.21978] 
        = 0.0399  
Therefore, α = 0.0399 will be used for the interim analysis. 
A study report will be prepared with the results of the interim analysis and the decision to re-start patient 
enrollment will be based on the advice of the Data and Safety Monitoring Board (DSMB) after their review 
of the interim analysis results.  
 


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4 STUDY POPULATIONS 
Study populations intended for analysis will be defined as follows: Intent-to-Treat (ITT), Per-Protocol (PP), 
and Safety. The ITT population will represent the primary analysis population to evaluate the treatment 
groups on all efficacy endpoints. The primary efficacy endpoint will also be analyzed for the PP population, 
which is the secondary analysis population. 
4.1 
Intent-to-Treat Population 
The ITT population will include all randomized patients who received at least one dose of study drug and 
have a baseline and at least one post-baseline efficacy assessment.  There can be a different number of 
patients (N) in the ITT population for each of the four efficacy measures (LIC, serum ferritin, cardiac T2*, 
and quality of life) if some of the patients don’t have post-baseline data on all of the three efficacy 
measures. All efficacy analyses will be based on the ITT population.   
  
4.2 
Per-Protocol Population 
The Per-Protocol (PP) population will include all enrolled patients who will have completed the study, have 
no major protocol violations, and have an efficacy measure by the end of the study.  Prior to database lock, 
major protocol violations will be determined and the affected patients will be excluded from the PP 
population. Major protocol violations will include (but not be limited to) the following:  
• 
Patients who did not fulfill the LIC > 7 mg/g inclusion criterion. 
• 
Patients who were not compliant with the treatment (< 80% compliance). 
• 
Patients who took iron chelator medications other than the assigned study medication during the 
course of the study. 
Only the primary efficacy measure, which is LIC, will be performed with the PP population. 
4.3 
Safety Population 
The Safety population will include all enrolled patients who took at least one dose of study drug.  
5. HANDLING OF MISSING DATA 
In the efficacy analyses, for patients who were terminated from the study prior to Month 12, if their last 
efficacy measures were obtained within 30 days of Month 12, the data obtained will be treated as the 
Month 12 data.  For early termination that occurred outside this window, the last observation carried 
forward (LOCF) method will be used to fill the missing data when the early termination was not caused by 
worsening of disease conditions or inadequate efficacy of the drug. For early termination due to worsening 


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of disease conditions or inadequate efficacy of the drug, as judged by assessing the AE log, the “worst 
value” method will be used.  That is, the worst value of all patients from the corresponding treatment group 
will be used to impute the missing data at that time point. For missing data due to missed visit, the LOCF 
method will be used to fill the void.  
 
For safety data analysis, no imputation will be performed on the missing data, and analysis will be based on 
observed cases (OC).  
 
6  PATIENT DISPOSTION AND BASELINE CHARACTERISTICS 
A two-sided p-value of 0.05 will be used as the significance level for the determination of statistical 
significance in the statistical tests with the data from patient disposition and baseline characteristics. 
6.1 
Patient Disposition 
Patient disposition will be summarized with the number and percent of patients who were enrolled, 
received at least one dose of study medication, completed the study, and were withdrawn from the study 
(including reasons for withdrawals). The proportions of drop-outs will be compared between the Ferriprox 
group and the deferoxamine group using Fisher’s exact test. 
6.2 
Demographics  
Demographics data such as age, sex, ethnicity, and race will be summarized by treatment group with 
descriptive statistics (mean, standard deviation, minimum, and maximum) for continuous variables and 
with frequency tables for discrete variables.  
6.3 
LIC, Cardiac MRI T2*, and Serum Ferritin at Baseline 
The baseline data of LIC, cardiac MRI T2*, and serum ferritin will be summarized using descriptive 
statistics by treatment group. If there are multiple baseline values, then the value that was measured closest 
prior to the treatment will consider to be the baseline value.  
6.4 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded and classified by the Anatomical Therapeutic Chemical 
(ATC) coding scheme of the World Health Organization (WHO), using the WHO Drug Dictionary Format 
B – March 2018 or newer.  The number and percent of patients who took a concomitant medication in each 
treatment group will be presented using frequency tables. 


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6.5 
Medical History 
Medical history for current and historical diagnoses and co-morbidities will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) Version 21.0 or higher and summarized by treatment 
group. They will be displayed by MedDRA System Organ Class (SOC) and Preferred Term (PT) and 
current status will be derived as “Resolved” if the stop date is reported and “Ongoing” if the stop data is 
missing, and will be presented in descending order of the most frequent Ongoing PT.  
6.6 
Physical Examinations 
A physical examination including head, ears, eyes, nose, throat, neck, respiratory system, general 
appearance, cardiovascular system, abdominal system, skin, and nervous system will be conducted and any 
clinically significant findings will be recorded on the medical history log (if the findings are of a pre-
existing condition) and the medical events log (if the findings are new untoward medical occurrence or 
worsening of a pre-existing condition that occurs after ICF singing but before dosing). 
6.7 
Vital Signs, Weight and Height 
Vital signs (temperature, resting heart rate, respiration, and blood pressure), weight and height at baseline 
will be summarized using descriptive statistics by treatment group.   
 
7 EFFICAY ANALYSES 
All statistical analyses will be performed using SAS (version 9.3 or higher) on the Windows operating 
system.  
7.1 
Primary Efficacy Endpoint 
Primary efficacy endpoint is the change from baseline to Week 52 in LIC. Primary efficacy endpoint will 
be compared between the two treatment groups using an analysis of covariance (ANCOVA) model 
including treatment variable as the main factor, and overall average transfusional iron input during the 
study, baseline LIC, and stratification factors (disease category and transfusional iron input in the 3 months 
prior to baseline) as covariates. The 96.01% (1 – α, where α = 0.0399 based on the Pocock’s α spending 
function for interim analysis) confidence interval (CI) of the difference (Ferriprox minus deferoxamine) in 
change of LIC from baseline to Week 52 (i.e., Week 52 minus baseline) between the two treatment groups 


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will be computed. For the demonstration of non-inferiority, the upper limit of the 96.01% CI should be no 
more than 2 mg/g dw. 
The following SAS codes of MIXED procedure will be used to produce the differences in Least Squares 
(LS) Mean of change in LIC at Month 6 and Month 12 between Ferriprox and deferoxamine groups and the 
corresponding 96.01% confidence intervals. In the mixed model, AR (1) (autoregressive of order 1) will be 
used for the covariance structure, and Kenward and Roger’s method will be used to estimate the 
denominator degrees of freedom (SAS model statement option, DDFM = KR). 
 
 
proc mixed data=LIC; 
  class patient treat disease prior_iron month 
  model LIC_change = treat overall_iron base_LIC disease prior_iron 
                     month treat*month / noint solution ddfm=kr; 
  repeated month / subject=patient(treat) type=ar(1); 
  lsmeans treat*month; 
  estimate 'Ferriprox - Deferoxamine at Month 6'  treat -1 1 
  treat*month -1 0 1 0 / cl alpha=0.0399; 
  estimate 'Ferriprox - Deferoxamine at Month 12' treat -1 1 
  treat*month 0 -1 0 1 / cl alpha=0.0399; 
run; 
 
Definition of the variables in the statistical model: 
  LIC_change  : Change in LIC from baseline to Week 5 
treat              : Ferriprox or Deferoxamine 
month           : Duration of treatment in month 
  overall_iron : Overall total transfusional iron input (mg/kg/day) during the study  
  base_LIC      : LIC at baseline 
  disease          : Sickle cell disease or other anemias 
  prior_iron     : transfusional iron input in 3 months prior to baseline (≤0.3mg/kg/day or >0.3 mg/kg/day)  
7.2 
Secondary Efficacy Endpoints 
- Change from baseline to Week 52 in patient-reported quality of life (SF-36 or Child Health 
Questionnaire); 
- Change from baseline to Week 52 in cardiac MRI T2*;  
- Change from baseline to Week 52 in serum ferritin. 
- 
Detailed information on the statistical analyses of the SF-36 or CHQ data is in a separate SAP 
prepared by QualityMetric Inc.. 
- 
The changes from baseline to Week 52 in cardiac MRI T2* and serum ferritin will be compared 
between the two treatment groups, using an ANCOVA model including treatment variable as the 


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main factor, and overall average transfusional iron input during the study, baseline cardiac MRI T2* 
or serum ferritin, and stratification factors (disease category and transfusional iron input in the 3 
months prior to baseline) as covariates. As with LIC, the 96.01% CI of the difference between the 
two treatment groups will be computed for both cardiac MRI T2* and serum ferritin. The cardiac 
MRI T2* data will be log-transformed before any statistical evaluation. Since cardiac MRI T2* will 
be measured at baseline, Week 26, and Week 52 as with LIC, the SAS codes for LIC data, with the 
exception of baseline MRI T2* instead of baseline LIC being included as the covariate, will be used 
for cardiac MRI T2* data as well. 
- 
The following SAS codes of MIXED procedure will be used to produce the differences in Least 
Squares (LS) Mean of change in serum ferritin at Months 3, 6, 9, and 12 between Ferriprox and 
deferoxamine groups and the corresponding 96.01% confidence intervals.  
proc mixed data=SF; 
  class patient treat disease prior_iron month; 
  model SF_change = treat overall_iron base_SF disease prior_iron  
                    month treat*month /  
  noint solution ddfm=kr; 
  repeated month / subject=patient(treat) type=ar(1); 
  lsmeans treat*month; 
  estimate 'Ferriprox - Deferoxamine at Month 3'  treat -1 1  
  treat*month -1 0 0 0 1 0 0 0 / cl alpha=0.0399; 
  estimate 'Ferriprox - Deferoxamine at Month 6'  treat -1 1  
  treat*month 0 -1 0 0 0 1 0 0 / cl alpha=0.0399; 
  estimate 'Ferriprox - Deferoxamine at Month 9'  treat -1 1  
  treat*month 0 0 -1 0 0 0 1 0 / cl alpha=0.0399; 
  estimate 'Ferriprox - Deferoxamine at Month 12' treat -1 1 
  treat*month 0 0 0 -1 0 0 0 1 / cl alpha=0.0399; 
run; 
 
Definition of the variables in the statistical model: 
  SF_change   : Change in SF from baseline to Week 5 
treat              : Ferriprox or Deferoxamine 
month           : Duration of treatment in month 
  overall_iron  : Overall total     transfusional iron input (mg/kg/day) during the study  
  base_LIC      : LIC at baseline 
  disease          : Sickle cell disease or other anemias 
  prior_iron     : transfusional iron input in 3 months prior to baseline (≤0.3mg/kg/day or >0.3 mg/kg/day)  
 


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7.3 
Trend Analysis for LIC, cardiac MRI T2*, and Serum Ferritin 
The longitudinal data of LIC, cardiac MRI T2*, and serum ferritin will be analyzed for time trend by using 
PROC MIXED procedure in SAS. The observed data of LIC, log-transformed cardiac MRI T2*, and serum 
ferritin will be used in this analysis. The following two statistical models will be fitted:  
• Model 1: Efficacy value = Intercept + Treatment + Time + Treatment × Time 
• Model 2: Efficacy value = Intercept + Treatment + Time 
Treatment will be treated as a categorical variable, and Time will be the time in month at each time point. 
Model 1 is the full model with the main effect of Treatment and Time, and the interaction effect of 
Treatment × Time. Model 2 is the reduced model with the main effect of Treatment and Time without the 
interaction term. If the interaction of Treatment × Time in Model 1 is not significant (p > 0.05), the reduced 
Model 2 will be used as the final model for trend analysis. 
The following SAS codes will be used:  
proc mixed data=efficacy_data; 
  class patient treat; 
  model measure = treat month treat*month / solution ddfm=kr; 
  repeated / subject=patient(treat) type=ar(1); 
run; 
 
Definition of the variables in the statistical model: 
  measure:  LIC or log-transformed cardiac MRI T2*, or SF 
treat      : Ferriprox or Deferoxamine 
month   : Duration of treatment in month 
 


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7.4 
Subgroup Analysis 
The comparison of the two treatment groups for the primary and secondary efficacy endpoints will be 
performed by disease type. The same ANCOVA models without disease factor as used in the main 
analyses will be used.  
• Patients with sickle cell disease (SCD) only 
• Non- SCD patients.  
7.5 
Sensitivity Analysis 
Sensitivity analyses will be performed on the primary efficacy measure, LIC. As a sensitivity analysis, the 
missing data imputation will be repeated with the LOCF method being used for all drop-out patients in the 
deferoxamine group and the “worst value” method being used for all drop-out patients in the Ferriprox 
group. This imputation approach will result in the worst case scenario for the Ferrirox group. In addition, 
the primary efficacy analysis will be repeated on a dataset involving only patients who have at least 6-
month LIC data in the ITT population to assess the impact of early patient withdrawal on the results of the 
ITT analysis. 
 
 
 
7.6 
Exploratory Analysis 
The following success criteria in LIC were used for the submission of Exjade’s NDA. 
LIC at Baseline 
Success, if LIC at the last measure is 
2 to < 7 mg Fe/g dw 
1 to < 7 mg Fe/g dw 
≥ 7 to < 10 mg Fe/g dw 
1 to 7 mg Fe/g dw 
≥ 10 mg Fe/g dw 
Decrease in LIC ≥ 3 mg Fe/g dw 
The success rates for Ferriprox and deferoxamine groups will be calculated based on these success criteria 
and will be compared using Fisher’s exact test. It is noted that there should be no patients in the first 
category of 2 to < 7 mg Fe/g dw at baseline LIC because one of the inclusion criteria for this study is 
baseline LIC >7 mg/g dw (measured by MRI). 


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In addition to the statistical analyses that have been specified in the SAP, any other exploratory analyses 
will be performed, if warranted, as post hoc analyses.  
8 SAFETY ANALYSES 
The safety data for continuous variables will be summarized using descriptive statistics, and the safety data 
for discrete variables will be presented as frequency tables.  
The safety analyses will be performed by disease category as well: SCD patients and non-SCD patients. 
8.1 
Adverse Events 
A summary table of adverse events will include the following information: 
• number of patients exposed to study treatment 
• number of patients experiencing at least one AE  
• number of patients experiencing at least one severe AE  
• number of patients experiencing at least one serious AE  
• number of patients experiencing at least one drug-related AE 
• number of deaths 
• total number of patients withdrawn (and reason for withdrawal)  
• number of withdrawals due to an AE  
Adverse events will be coded using MedDRA. Adverse events are defined as AEs that occurred or 
worsened (increased in severity and/or frequency) on or after the first dose of study medication. Serious 
adverse events (SAEs) that occurred within 14 days after treatment discontinuation will be considered to be 
SAEs. Serious adverse events that occurred within 30 days after treatment discontinuation will be included 
in the database.  
Adverse events will be summarized by treatment group using the total number of AEs and total exposure to 
the treatment, the total number and percent of patients who experience an AE, and the number and percent 
of patients who experienced an AE within each SOC (and preferred term within an SOC). AEs will also be 
presented by severity (mild, moderate, severe), by seriousness (serious, non-serious) and by relationship to 
study medication (at least possibly related, not related). The number of patients withdrawn will also be 
presented.  
To count the number of patients who experienced each AE, patients who experienced the same AE multiple 
times will only be counted once for the corresponding preferred term. Similarly, if a patient experiences 
multiple AEs within the same SOC, that patient will be counted only once for that SOC. AEs will be 
tabulated presenting the SOC alphabetically, and within each SOC, preferred terms will be presented in 
decreasing order of the total number of patients who experienced each AE. In summaries presenting the 


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incidence of AEs by severity, seriousness, and relation to study medication, a patient with multiple events 
coded to a given preferred term or SOC will be counted once for that preferred term or SOC according to 
the most severe event, the most serious event, or the event with the closest relationship to study medication. 
A listing of serious adverse events and a listing of withdrawals due to AEs will be presented. Patient deaths 
will be listed separately and discussed with patient narratives. 
8.2 
Physical Examination 
A physical examination including head, ears, eyes, nose, throat, neck, respiratory system, general 
appearance, cardiovascular system, abdominal system, skin, and nervous system will be conducted any 
clinically significant findings will be recorded as adverse events. 
8.3 
Vital Signs, Weight and Height 
Descriptive statistics will be presented for temperature, resting heart rate, respiratory rate, systolic blood 
pressure, diastolic blood pressure, weight and height  at each  visit. Changes from baseline to each follow-
up assessment will be also summarized using descriptive statistics by treatment group. 
8.4 
12-Lead ECG 
ECG data will be summarized using descriptive statistics at each assessment by treatment group. Change 
from baseline to each follow-up assessment will be also summarized using descriptive statistics by 
treatment group. Shift tables for clinically significant abnormality between baseline and the last assessment 
will be constructed by treatment group. 
8.5 
Biochemistry, Hematology and Urinalysis 
All analyses of laboratory data will be based on the planned visits. Laboratory data collected at 
unscheduled visits will be available in the data listings but not included in summary tables. 
Descriptive statistics for each clinical laboratory test will be presented for each scheduled visit. Change 
from baseline to each follow-up assessment will be also presented. According to the laboratory normal 
ranges, laboratory test results will be categorized as low (< lower normal limit), normal (within normal 
range), and high (> upper normal limit). Shift tables comparing the distributions of these three categories at 
baseline versus end of treatment will be presented. 
Urinalysis assessments will consist of pH, specific gravity, ketones, blood, glucose, and protein. The raw 
data listings for each individual patient will be produced for further evaluation, whenever needed. 


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Clinically significant laboratory values will be reported as AEs.  
8.6 
Concomitant Medications 
Medications will be coded using the WHO Drug Dictionary. Medications taken during the course of the 
trial (on or after the first study drug dose and before or on the study termination date) will be considered as 
concomitant medications. Medications started after the study termination date will not be reported in tables, 
but will be presented in patient data listings. Concomitant medications used to treat AEs will be 
differentiated from others. 
Concomitant medications will be summarized by preferred term only. To count the number of patients who 
took a medication, a patient who took the same medication multiple times will only be counted once for 
that medication. Medications will be tabulated in decreasing order of the total number of patients who took 
each medication. In addition, the total number of patients to ever take any concomitant medications will be 
presented. 
8.7 
Pregnancy test 
Any female patients with positive pregnancy test during the study period will be listed by treatment group. 
 
9 OTHER ANALYSES 
9.1 
Drug Exposure 
The total daily dose taken during the study will be summarized with descriptive statistics by treatment 
group. 
 
9.2 
Treatment compliance 
Patients will be instructed on how to take the study medication. A medication usage diary card will be 
provided to the patients by the study staff.  Patients will record the number of tablets or volume of oral 
solution taken, or the volume of injection solution administered and the time of injection. For Ferriprox, 
compliance will be evaluated monthly by the Investigator or delegate by monthly pill counts or volume of 
drug returned by the patient. For deferoxamine, compliance will be evaluated by the number of infusions 
performed, which will be recorded monthly through the use of infusion pumps that keep records of those 
numbers, and by physical assessment of the infusion sites. Reasons for non-compliance with the treatment 
will be recorded in the source document and in the eCRFs. Compliance reported in the eCRF will be based 
on the patient’s diary and compliance calculation. If compliance is greater than 100% and the patient 
reports taking all doses as prescribed, compliance will be reported as 100% in the eCRF.  


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Compliance <80% and an over-compliance of >120% will be reported as a protocol deviation. The number 
and percent of patients who had compliance <80% or >120% during the study will be presented by 
treatment group. 
9.3 
Transfusional Iron Input 
It is noted that transfusional iron input (mg/kg/day) for the 3 months prior to baseline, which is one of the 
stratification factors of randomization in this study, has been calculated, for example, as follow:  


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Assumption: 1 mg iron / 1 mL packed Red Blood Cells (pRBCs) 
If partial or exchange transfusions 
Type of 
transfusion 
Volume of 
blood 
transfused 
(mL) 
Average mean 
hematocrit of 
pRBC transfused 
(%) for the site 
Volume 
of blood 
removed 
(mL) 
Average mean 
hematocrit of 
pRBC removed 
(%) for the site (as 
we do not collect 
hematocrit, we use 
hemoglobin*3 = 
hematocrit as 
assumption) 
Iron in pRBC  
(volume blood 
transfused*mean 
hematocrit 
transfused – 
volume blood 
removed*mean 
hematocrit 
removed) 
Simple 
1200 
65 
780 
Exchange 
1250 
65 
1016 
80 
0 
Partial 
exchange 
2500 
65 
1000 
80 
825 
Simple 
1000 
65 
  
  
650 
Total iron transfused 
2255 mg 
Body weight at 
baseline 
54 kg 
3 months*30.5 days 
91.5 days 
 
Hence, transfusional iron input (mg/kg/day) for the 3 months = 2255 mg/54 kg/91.5 days = 0.46 
mg/kg/day. 
Transfusional iron input will be calculated monthly during the study in the same way above. Overall total 
transfusional iron input (mg/kg/day) during the study will be calculated by summing up monthly 
transfusional iron input. As the total transfusional iron input depends on the length of time a patient remains 
in the study, the total transfusional iron input will be divided by the total number of days involved in the 
months where blood transfusion data was obtained and will be compared between the two treatment 
groups; the same data will be used for the ANCOVA.  
 
 
 
 


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14 SUMMARY TABLES AND FIGURES 
Summary tables and figures are numbered following ICH structure. 
Note: The final numberings for tables and/or figures in the clinical study report can be changed if more tables and/or 
figures are made in the addition to those in the SAP.  
TABLES 
14.1 
Demographics and Baseline Data 
Table 14.1.1 Patient disposition 
Table 14.1.2 Number of patients in the efficacy and safety populations 
Table 14.1.3 Number of patients by study site 
Table 14.1.4 Reasons for not completing the study 
Table 14.1.5 Demographics data 
Table 14.1.6 Liver iron concentration (LIC), cardiac MRI T2*, serum ferritin at baseline 
Table 14.1.7 Prior chelation therapy 
Table 14.1.8 Transfusion iron input (mg/kg/day) in the 3 months prior to baseline 
Table 14.1.9 Medical history 
Table 14.1.10 Vital signs at baseline  
Table 14.1.11 Weight and height at baseline 
14.2 
Efficacy Analyses 
Note: Similar tables will be produced for SCD patients only and Non-SCD patients. 
14.2.1 
LIC  
Table 14.2.1.1 LIC at each assessment 
Table 14.2.1.2 Change in LIC at each follow-up assessment 
Table 14.2.1.3 LS Means of change in LIC from ANCOVA model at each follow-up assessment 
Table 14.2.1.4 Trend analysis for LIC over time 
14.2.2 
Cardiac MRI T2* 
Table 14.2.2.1 Cardiac MRI T2* at each assessment 
Table 14.2.2.2 Change cardiac MRI T2* at each follow-up assessment 
Table 14.2.2.3 LS Means of change in cardiac MRI T2* from ANCOVA model at each follow-up 
assessment  
Table 14.2.2.4 Trend analysis for cardiac MRI T2* over time 
 


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14.2.3 
Serum Ferritin 
Table 14.2.3.1 Serum ferritin at each assessment 
Table 14.2.3.2 Change in serum ferritin at each follow-up assessment 
Table 14.2.3.3 LS Means of change in serum ferritin from ANCOVA model at each follow-up assessment  
Table 14.2.3.4 Trend analysis for serum ferritin over time 
 
14.3 
Safety Analyses 
Note: Similar tables will be produced for SCD patients only and Non-SCD patients. 
14.3.1 
Adverse Events 
Table 14.3.1.1 Overall summary of adverse events  
Table 14.3.1.2 Adverse events 
Table 14.3.1.3 Most common adverse events (≥5% in total)  
Table 14.3.1.4 Adverse drug reactions  
Table 14.3.1.5 Most common adverse drug reactions (≥5% in total)  
Table 14.3.1.6 Serious adverse events  
Table 14.3.1.7 Serious adverse drug reactions  
Table 14.3.1.8 Adverse events by causality 
14.3.2 
Vital Signs 
Table 14.3.2.1 Temperature at each assessment 
Table 14.3.2.2 Change in temperature from baseline to each follow-up assessment 
Note: Similar tables will be produced for resting heart rate, respiration, systolic blood pressure, and diastolic blood 
pressure. 
14.3.3 
Weight and Height 
Table 14.3.3.1 Weight at each assessment 
Table 14.3.3.2 Change in weight from baseline to last assessment 
Table 14.3.3.1 Height at each assessment 
Table 14.3.3.2 Change in height from baseline to last assessment 
 
14.3.4 
Concomitant Medications 
Table 14.3.4.1 Concomitant medications 


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14.3.5 
12-Lead ECG 
Table 14.3.5.1 Heart rate of 12-Lead ECG at each assessment 
Table 14.3.5.2 Change in heart rate of 12-Lead ECG from baseline to each follow-up assessment 
Note: Similar tables will be produced for PR, QRS, QT, QTcF, and QTcB. 
 
Table 14.3.5.3 Shift table for clinically significant abnormality for 12-Lead ECG: Feriprox group 
Table 14.3.5.4 Shift table for clinically significant abnormality for 12-Lead ECG: Deferoxaome group 
 
14.3.6 
Laboratory Data 
14.3.6.1 Hematology 
Table 14.3.6.1.1 Hemoglobin at each assessment  
Table 14.3.6.1.2 Change in hemoglobin from baseline to each follow-up assessment 
Table 14.3.6.1.3 Shift table for hemoglobin in abnormal range at baseline vs. last assessment: Ferriprox 
group 
Table 14.3.6.1.4 Shift table for hemoglobin in abnormal range at baseline vs. last assessment: 
Deferoxamine group 
Note: Similar tables will be produced for total white blood cell (WBC), absolute neutrophil count (ANC), and platelets. 
  
14.3.6.2 Biochemistry 
Table 14.3.6.2.1 Total protein at each assessment 
Table 14.3.6.2.2 Change in total protein from baseline to each follow-up assessment 
Table 14.3.6.2.3 Shift table for total protein in abnormal range at baseline vs. last assessment: Ferriprox 
group 
Table 14.3.6.2.4 Shift table for total protein in abnormal range at baseline vs. last assessment: 
Deferoxamine group 
Note: Similar tables will be produced for GGT, lactate dehydrogenase (LDH), sodium, potassium, chloride, glucose 
(fasting at screening visit only), total, direct and indirect bilirubin, AST, ALT, albumin; blood urea nitrogen, calcium, 
creatinine, uric acid, alkaline phosphatase, and amylase. 
 
14.3.6.3 Serology 
Table 14.3.6.3.1 HIV at each assessment 
Note: Similar tables will be produce for Hepatitis B and C. 
 


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14.3.7 
Pregnancy test 
Table 14.3.7.1 List of patients with positive pregnancy test during the study 
14.4 
Treatment compliance 
Table 14.4.1 Treatment compliance at each visit 
 
14.5 
 Transfusion information 
Table 14.5.1 Mean transfusional iron input (mg/kg/day) during the study 
 
14.6 
Total daily dose 
Table 14.6.1 Summary of total daily dose 
 
FIGURES 
14.2 
Efficacy 
Figure 14.2.1 Mean line graph for LIC over time 
Figure 14.2.2 Mean line graph for cardiac MRI T2* over time 
Figure 14.2.3 Mean line graph for serum ferritin over time 
Figure 14.2.4 Bar graph for the change in LIC from baseline to the end of study 
Figure 14.2.5 Bar graph for the change in cardiac MRI T2* from baseline to the end of study 
Figure 14.2.6 Bar graph for the change in serum ferritin from baseline to the end of study 
 
14.3 
Safety 
14.3.1 
Hematology 
Figure 14.3.1.1 Mean line graph for hemoglobin over visit 
Figure 14.3.1.2 Proportion of patients with abnormal hemoglobin at each assessment 
Note: Similar graphs will be produced for total white blood cell (WBC), absolute neutrophil count (ANC), and platelets. 
  


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14.3.2 
Biochemistry 
Figure 14.3.2.1 Mean line graph for total protein over visit 
Figure 14.3.2.2 Proportion of patients with abnormal total protein at each assessment  
Note: Similar tables will be produced for GGT, lactate dehydrogenase (LDH), sodium, potassium, chloride, glucose 
(fasting at screening visit only), total, direct and indirect bilirubin, AST, ALT, albumin; blood urea nitrogen, calcium, 
creatinine, uric acid, alkaline phosphatase, and amylase. 
16 DATA LISTINGS  
Data listings are numbered following ICH structure. 
Note: The final numberings for patient data listings in the clinical study report can be changed if more patient data 
listings are made in the addition to those in the SAP. 
16.2 
Patient Data Listings 
16.2.1 Listing of informed consent 
16.2.2 Listing of demographics 
16.2.3 Listing of primary diagnosis 
16.2.4 Listing of prior chelation 
16.2.5 Listing of hydroxyurea history 
16.2.6 Listing of transfusion history 
16.2.7 Listing of vital signs including height, weight 
16.2.8 Listing of physical examination 
16.2.9 Listing of 12-lead electrocardiogram 
16.2.10 Listing of urinalysis 
16.2.11 Listing of hematology 
16.2.12 Listing of blood sample collection dates 
16.2.13 Listing of LIC 
16.2.14 Listing of cardiac MRI T2* 
16.2.15 Listing of chemistry 
16.2.16 Listing of serology 
16.2.17 Listing of pregnancy 
16.2.18 Listing of urine microscopy 
16.2.19 Listing of blood sample for genetic polymorphism 
16.2.20 Listing of randomization 
16.2.21 Listing of serum ferritin 
16.2.22 Listing of dose verification 
16.2.23 Listing of disposition 


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16.2.24 Listing of compliance 
16.2.25 Listing of medical history 
16.2.26 Listing of medication 
16.2.27 Listing of medical events 
16.2.28 Listing of adverse events 
16.2.29 Listing of exposure – DFP 
16.2.30 Listing of exposure – DFO 
16.2.31 Listing of local labs 
16.2.32 Listing of transfusion information 
16.2.33 Listing of SAEs 
16.2.34 Listing of withdrawals due to AEs 
 
17 TABLE SHELLS 
The following table shells provide a framework for the display of data from this study.  These tables may 
not be produced exactly as shown in the shells, but are intended to reflect the general layout of the data that 
will be included in the clinical study report. 
Note that ‘c’ in the table shells indicates an alphanumeric character and ‘x’ indicates a number from 0 to 9.  
If the same data points are collected at more than one visit, the results will be summarized in Table x.x for 
baseline, x.x-1 for visit 1, x.x-2 for visit 2 and so on. 
 


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Table 14.1.1 Patient disposition 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
P-value (Fisher’s exact test) 
Randomized 
xxx 
xxx 
 
Exposed* 
xxx (xx%) 
xxx (xx%) 
0.xxxx 
Completed* 
xxx (xx%) 
xxx (xx%) 
0.xxxx 
Withdrawn* 
xxx (xx%) 
xxx (xx%) 
0.xxxx 
Data source: 16.2.23 Listing of disposition 
Note: *Percentages are based on the number of randomized patients in each treatment group.  
 
Table 14.1.2 Number of patients in the ITT, PP, and safety populations 
 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
ITT population 
LIC 
xxx 
xxx 
Serum Ferritin 
xxx 
xxx 
Cardiac MRI T2* 
xxx 
xxx 
 
PP population 
LIC 
xxx 
xxx 
Serum Ferritin 
xxx 
xxx 
Cardiac MRI T2* 
xxx 
xxx 
Safety population 
 
xxx 
xxx 
Data source: 16.2.20 Listing of randomization 
  


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Table 14.1.3 Number of patients by study site 
 
Treatment 
Study Site 
Deferiprone 
Deferoxamine 
001 
xxx 
xxx 
002 
xxx 
xxx 
… 
… 
… 
Total 
xxx 
xxx 
Data source: 16.2.2 Listing of demographics 
Table 14.1.4 Reasons for not completing the study  
 
 
Treatment 
 
 
 
Deferiprone 
Deferoxamine 
P-value (Fisher’s exact test) 
N (%) 
 
xx (100) 
xx (100) 
 
Reason 
Detail 
 
 
 
Adverse event 
Ccccc 
xx (xx) 
xx (xx) 
0.xxxx 
Ccccc 
xx (xx) 
xx (xx) 
Voluntary withdrawal 
Ccccc 
xx (xx) 
xx (xx) 
0.xxxx 
Ccccc 
xx (xx) 
xx (xx) 
Lost to follow-up 
Ccccc 
xx (xx) 
xx (xx) 
0.xxxx 
Ccccc 
xx (xx) 
xx (xx) 
Investigator decision 
Ccccc 
xx (xx) 
xx (xx) 
0.xxxx 
Ccccc 
xx (xx) 
xx (xx) 
Protocol violation 
Ccccc 
xx (xx) 
xx (xx) 
0.xxxx 
Ccccc 
xx (xx) 
xx (xx) 
Other 
Ccccc 
xx (xx) 
xx (xx) 
0.xxxx 
Ccccc 
xx (xx) 
xx (xx) 
Total 
 
xx (xx) 
xx (xx) 
 
Data source: 16.2.23 Listing of disposition 


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Table 14.1.5 Demographics data   
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
N 
Xxx 
xxx 
p-value§ 
Age (years): 
Mean ± SD 
(Min, Max) 
 
xx.x ± xx.x 
(xx.x, xx.x) 
 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Sex: n (%)  
   Female 
   Male 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
0.xxxx 
Ethnic Origin: n (%) 
   Hispanic/Latino 
   Other 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
0.xxxx 
Racial Origin: n (%) 
   White 
   Black 
   Asian 
   Native American 
   Native Hawaiian/Other Pacific Islander 
   Multi-Racial 
 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx(xx) 
 
 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx(xx) 
 
0.xxxx 
 
§ T-test for age; Fisher’s exact test for sex, ethnic origin, and racial origin      
Data source: 16.2.2 Listing of demographics 


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Table 14.1.6 LIC, cardiac MRI T2*, and serum ferritin at baseline 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
N 
xxx 
xxx 
 
 
Mean ± SD 
(Min, Max) 
Mean ± SD 
(Min, Max) 
P-value (t-test) 
LIC (mg/g dw) 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Cardiac MRI T2* (ms) 
xx.x ± xx.x 
(xx.x, x.xx) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Serum Ferritin (µg/L) 
xxxx ± xxxx 
(xxxx, xxxx) 
xxxx ± xxxx 
(xxxx, xxxx) 
0.xxxx 
Data source: 16.2.13 Listing of LIC, 16.2.14 Listing of cardiac MRI T2*, 16.2.21 Listing of serum ferritin 
 
Table 14.1.7 Prior chelation therapy 
 
Treatment 
 
Deferiprone 
Deferoxamine 
Deferiprone 
xx (xx%) 
xx (xx%) 
Deferoxamine 
xx (xx%) 
xx (xx%) 
Deferasirox 
xx (xx%) 
xx (xx%) 
Data source: 16.2.4 Listing of prior chelation  
 
 
 
 
 
 


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Table 14.1.8 Transfusion iron input (mg/kg/day) in the 3 months prior to baseline 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
 
Mean ± SD 
(Min, Max) 
Mean ± SD 
(Min, Max) 
P-value (T-test) 
Transfusion iron input (mg/kg/day) 
x.xx ± x.xx 
(x.xx, x.xx) 
x.xx ± x.xx 
(x.xx, x.xx) 
0.xxxx 
Data source: 16.2.6 Listing of transfusion history 
 
Table 14.1.9 Medical history  
 
Treatment 
 
Deferiprone 
Deferoxamine 
N 
xxx 
xxx 
Illness/Event by 
MedDRA Primary 
System Organ Class and Preferred Term 
Resolved 
n (%) 
Ongoing 
n (%) 
Resolved 
n (%) 
Ongoing 
n (%) 
cccccc 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 cccccc 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 cccccc 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 cccccc 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
Data source: 16.2.25 Listing of medical history  


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 Table 14.1.10 Vital signs at baseline  
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
N 
xxx 
xxx 
Vital Sign: 
Mean ± SD 
(Min, Max) 
Mean ± SD 
(Min, Max) 
P-value (T-test) 
Temperature (ºC) 
xx.x ± xx.x 
(xx, xx) 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Resting Heart Rate (/min) 
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
0.xxxx 
Respiration (/min) 
xx.x ± xx.x 
(xx, xx) 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Systolic Blood Pressure (mmHg)  
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
0.xxxx 
Diastolic Blood Pressure (mmHg)  
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
0.xxxx 
Data source: 16.2.7 Listing of vital signs including height and weight 
 
Table 14.1.12 Weight and height at baseline  
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
N 
xxx 
xxx 
 
Mean ± SD 
(Min, Max) 
Mean ± SD 
(Min, Max) 
P-value (T-test) 
Weight (kg) 
xx.x ± xx.x 
(xx, xx) 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Height (cm) 
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
0.xxxx 
§For patients who had separate screening and baseline visits, height was measured only at screening                              
Data source: 16.2.7 Listing of vital signs including height and weight 


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Table 14.2.1.1 LIC at each assessment  
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
N 
 
xxx 
xxx 
P-value (T-test) 
 
Visit 
Mean ± SD 
(Min, Max) 
Mean ± SD 
(Min, Max) 
 
LIC (mg/g dw) 
Baseline 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
. 
Month 6 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Data source: 16.2.13 Listing of LIC 
Table 14.2.1.2 Change in LIC at each follow-up assessment 
 
 
Treatment 
 
Test 
Visit 
Deferiprone 
Deferoxamine 
 
N 
 
xxx 
xxx 
P-value (T-test) 
Change in LIC (mg/g dw) 
Mean ± SD 
(Min, Max) 
Month 6 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12  
 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Data source: 16.2.13 Listing of LIC 
Table 14.2.1.3 LS Means of change in LIC from ANCOVA model at each follow-up assessment  
 
Treatment 
 
 
 
Deferiprone 
Deferoxamine 
Deferiprone 
minus 
Deferoxamine 
96.01% C.I. 
N 
 
xxx 
xxx 
xxx 
 
 
Visit 
LS Mean ± SE 
LS Mean ± SE 
LS Mean ± SE 
 
LIC (mg/g 
dw) 
Month 6 
xx.x ± xx.x 
 
xx.x ± xx.x 
 
xx.x ± xx.x 
 
(xx.x, xx.x) 
Month 12 
xx.x ± xx.x 
 
xx.x ± xx.x 
 
xx.x ± xx.x 
 
(xx.x, xx.x) 
Data source: 16.2.13 Listing of LIC 


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Table 14.2.1.4 Trend analysis for LIC over time 
 
 
 
 
 
 
Deferiprone 
Deferoxamine 
      Deferiprone             
minus Deferoxamine 
       P-value 
     Slope: Mean ± SE 
xx.x ± xx.x 
xx.x ± xx.x 
xx. x ± xx.x  
         0.xxxx 
Data source: 16.2.13 Listing of LIC 
 
Table 14.2.1.5 Success rate in LIC based on the submission of Exjade’s NDA. 
 
             Treatment 
 
 
    Deferiprone 
   Deferoxamine 
P-value (Fisher’s exact test) 
Success rate 
        xx.x % 
      xx.x% 
0.xxxx 
Data source: 16.2.13 Listing of LIC 
 
 
Table 14.2.2.1 Cardiac MRI T2* at each assessment  
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
N 
 
xxx 
xxx 
P-value (T-test) 
 
Visit 
Mean ± SD 
(Min, Max) 
Mean ± SD 
(Min, Max) 
 
Cardiac MRI T2* (ms) 
Baseline 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
. 
Month 6 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Data source: 16.2.14 Listing of cardiac MRI T2* 
 
 
 


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Table 14.2.2.2 Change in cardiac MRI T2* at each follow-up assessment 
 
 
Treatment 
 
Test 
Visit 
Deferiprone 
Deferoxamine 
 
N 
 
xxx 
xxx 
P-value (T-test) 
Change in cardiac MRI T2* (ms) 
Mean ± SD 
(Min, Max) 
Month 6 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12  
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Data source: 16.2.14 Listing of cardiac MRI T2* 
Table 14.2.2.3 LS Means of change in cardiac MRI T2* from ANCOVA model at each follow-up assessment  
 
Treatment 
 
 
 
Deferiprone 
Deferoxamine 
Deferiprone 
minus 
Deferoxamine 
96.01% C.I. 
N 
 
Xxx 
xxx 
xxx 
 
 
Visit 
LS Mean ± SE 
LS Mean ± SE 
LS Mean ± SE 
 
Cardiac MRI T2* (ms) 
Month 6 
xx.x ± xx.x 
xx.x ± xx.x 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
Month 12 
xx.x ± xx.x 
xx.x ± xx.x 
 
(xx.x, xx.x) 
(xx.x, xx.x) 
Data source: 16.2.14 Listing of cardiac MRI T2* 
 
Table 14.2.2.4 Trend analysis for cardiac MRI T2* over time 
 
 
 
 
 
 
Deferiprone 
Deferoxamine 
      Deferiprone             
minus Deferoxamine 
       P-value 
     Slope: Mean ± SE 
xx.x ± xx.x 
xx.x ± xx.x 
xx. x ± xx.x  
         0.xxxx 
Data source: 16.2.14 Listing of cardiac MRI T2* 
 
 
 


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Table 14.2.3.1 Serum ferritin each assessment  
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
N 
 
xxx 
xxx 
P-value (T-test) 
 
Visit 
Mean ± SD 
(Min, Max) 
Mean ± SD 
(Min, Max) 
 
Serum Ferritin (µg/L) 
Baseline 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
. 
Month 3 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 6 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 9 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Data source: 16.2.21 Listing of serum ferritin 
 
Table 14.2.3.2 Change in serum ferritin at each follow-up assessment 
 
 
Treatment 
 
Test 
Visit 
Deferiprone 
Deferoxamine 
 
N 
 
xxx 
xxx 
P-value (T-test) 
Change in serum ferritin (µg/L) 
Mean ± SD 
(Min, Max) 
Month 3 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 6 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 9  
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 12 
xx.x ± xx.x 
(xx.x, xx.x) 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Data source: 16.2.21 Listing of serum ferritin 


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Table 14.2.3.3 LS Means of change in serum ferritin from ANCOVA model at each follow-up assessment  
 
Treatment 
 
 
 
Deferiprone 
Deferoxamine 
Deferiprone      
minus        
Deferoxamine 
96.01% CI 
N 
 
Xxx 
xxx 
xxx 
 
 
Visit 
LS Mean ± SE 
LS Mean ± SE 
LS Mean ± SE 
 
 
Serum ferritin (µg/L) 
Month 3 
xx.x ± xx.x 
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Month 6 
xx.x ± xx.x 
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Month 9 
xx.x ± xx.x 
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Month 12 
xx.x ± xx.x 
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Data source: 16.2.21 Listing of serum ferritin 
Table 14.2.3.4 Trend analysis for serum ferritin over time 
 
 
 
 
 
 
Deferiprone 
Deferoxamine 
      Deferiprone             
minus Deferoxamine 
       P-value 
     Slope: Mean ± SE 
xx.x ± xx.x 
xx.x ± xx.x 
xx. x ± xx.x  
         0.xxxx 
Data source: 16.2.21 Listing of serum ferritin 
 


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Table 14.3.1.1 Overall summary of adverse events  
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
N 
xxx 
xxx 
P-value 
Number of patients experiencing at least one AE 
xx (xx%) 
xx (xx%) 
0.xxxx 
Number of patients experiencing at least one severe AE 
xx (xx%) 
xx (xx%) 
0.xxxx 
Number of patients experiencing at least one serious AE 
xx (xx%) 
xx (xx%) 
0.xxxx 
Number of patients experiencing at least one related* AE 
xx (xx%) 
xx (xx%) 
0.xxxx 
Number of patient deaths 
xx (xx%) 
xx (xx%) 
0.xxxx 
Number of patient withdrawals due to AEs 
xx (xx%) 
xx (xx%) 
0.xxxx 
*Includes possibly, probably, and definitely related. Worst case scenario of causality between the investigator 
and company’s assessment. 
Data source: 16.2.28 Listing of adverse events  


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Table14.3.1.2 Adverse events  
 
Treatment 
 
  
  
  
  
Deferiprone 
(N=xxx) 
Deferoxamine 
(N=xxx) 
  
 
 
 
Exposure  
(patient-years): x.xx 
Exposure  
(patient-years):x.xx 
Total Events: xxx 
Total Events: xxx 
System Organ Class 
  Preferred Term 
n Patients (%)  
n Patients (%)  
P-value (Fisher’s exact 
test) 
CCCCCC 
x (x.x) 
x (x.x) 
0.xxxx 
  Cccccc 
x (x.x) 
x (x.x) 
0.xxxx 
  Cccccc 
x (x.x) 
x (x.x) 
0.xxxx 
  Cccccc 
x (x.x) 
x (x.x) 
0.xxxx 
……... 
……... 
……... 
……... 
Note: Similar tables will be produced from Table 14.3.1.3 to Table 14.3.1.7      
Data source: 16.2.28 Listing of adverse events 
 
Table 14.3.1.8 Adverse events by causality 
Treatment 
Deferiprone 
(N=xxx) 
Deferoxamine 
(N=xxx) 
System Organ Class  
     Preferred Term 
Relatedness  
(worst case) 
Patients reporting 
(n=xx) 
Patients reporting 
(n=xx) 
CCCCCCCC 
 
x (x.x) 
x (x.x) 
      cccccc 
Not Related 
x (x.x) 
x (x.x) 
 
Related*  
x (x.x) 
x (x.x) 
      cccccc 
Not Related 
x (x.x) 
x (x.x) 
 
Related*  
x (x.x) 
x (x.x) 
……… 
……. 
….. 
….. 
*Possibly, Probably, or Definitely Related 
Data source: 16.2.28 Listing of adverse events 


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Table 14.3.2.1 Temperature at each assessment 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
Visit 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
P-value (T-test) 
Baseline  
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 1 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 2 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 3 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 4 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
… 
… 
… 
… 
… 
… 
Month 10 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 11 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 12 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Note: Similar tables will be produced for resting heart rate, respiration, systolic and diastolic blood pressures. 
Data source: 16.2.7 Listing of vital signs including height and weight  


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Table 14.3.2.2 Change in temperature from baseline to each follow-up assessment 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
Visit 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
P-value (T-test) 
Month 1 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 2 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 3 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 4 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
… 
… 
… 
… 
… 
… 
Month 10 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 11 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 12 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Note: Similar tables will be produced for resting heart rate, respiration, systolic and diastolic blood pressures. 
Data source: 16.2.7 Listing of vital signs including height and weight  


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Table 14.3.3.1 Weight (kg) at each assessment 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
Visit 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
P-value (T-test) 
Baseline  
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Month 1 
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Month 2 
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Month 3 
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Month 4 
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
… 
… 
… 
… 
… 
… 
Month 10 
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Month 11 
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Month 12 
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Data source: 16.2.7 Listing of vital signs including height and weight 


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Table 14.3.3.2 Change in weight from baseline to last assessment 
 
 
Treatment 
 
 
 
Deferiprone 
Deferoxamine 
 
 
 
N 
xxx 
xxx 
P-value (T-test) 
Change in weight (kg) 
Mean ± SD 
(Min, Max) 
Baseline 
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
0.xxxx 
Last assessment 
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
0.xxxx 
Change at last assessment 
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
 
0.xxxx 
Data source: 16.2.7 Listing of vital signs including height and weight 
 
Table 14.3.3.1 Height (cm) at each assessment 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
Visit 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
P-value (T-test) 
Baseline  
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Week 26 
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Week 52 
xxx 
xxx ± xxx 
(xxx, xxx) 
xxx 
xxx ± xxx 
(xxx, xxx) 
0.xxxx 
Data source: 16.2.7 Listing of vital signs including height and weight 
Table 14.3.3.4 Change in height from baseline to last assessment 
 
 
Treatment 
 
 
 
Deferiprone 
Deferoxamine 
 
 
 
N 
xxx 
xxx 
P-value (T-test) 
Height (cm): 
Mean ± SD 
(Min, Max) 
Baseline 
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
0.xxxx 
Last assessment 
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
0.xxxx 
Change at last assessment 
xxx.x ± xxx.x 
(xxx, xxx) 
xxx.x ± xxx.x 
(xxx, xxx) 
0.xxxx 
Data source: 16.2.7 Listing of vital signs including height and weight 


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Table 14.3.4.1 Concomitant medications 
 
Treatment 
 
  
  
  
Deferiprone 
(N) 
Deferoxamine 
(N) 
 
Exposure (patient-years): x.xx 
Exposure (patient-years): x.xx 
Total Patients Reporting: xx 
Total Patients Reporting: xx 
Preferred Name 
n Patients (%)  
n Patients (%)  
 
  cccccc 
x (x.x) 
x (x.x) 
 
  cccccc 
x (x.x) 
x (x.x) 
 
  cccccc 
x (x.x) 
x (x.x) 
 
……... 
……... 
……... 
 
Data source: 16.2.26 Listing of medication 
 
Table 14.3.5.1 Heart rate of 12-lead ECG at each assessment 
 
Treatment 
 
Heart Rate (bpm) 
Deferiprone 
Deferoxamine 
P-value (T-test) 
 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
 
Baseline 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 6 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 12  
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Note: Similar tables will be produced for PR (ms), QRS (ms), QT (ms), QTcF (ms), and QTcB (ms), 
respectively. 
Data source: 16.2.9 Listing of 12-lead electrocardiogram  
 
 
 
 
 
 


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Table 14.3.5.2 Change in heart rate of 12-lead ECG at each follow-up assessment 
 
Treatment 
 
Heart Rate (bpm) 
Deferiprone 
Deferoxamine 
P-value (T-test) 
 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
 
Month 6 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 12  
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Note: Similar tables will be produced for PR (ms), QRS (ms), QT (ms), QTcF (ms), and QTcB (ms), 
respectively. 
Data source: 16.2.9 Listing of 12-lead electrocardiogram  
 
Table 14.3.5.3 Shift table for clinically significant abnormality for 12-lead ECG: Deferiprone group  
 
 
Last Assessment 
 
 
n (%) 
Normal 
Abnormal 
P-value (McNemar’s test) 
Baseline 
Normal 
xx (xx) 
xx (xx) 
0.xxxx 
Abnormal 
xx (xx) 
xx (xx) 
P-value = Data source: 16.2.9 Listing of 12-lead electrocardiogram 
 
Table 14.3.5.4 Shift table for clinically significant abnormality for 12-lead ECG: Deferoxamine group  
 
 
          Last Assessment 
 
 
n (%) 
Normal 
Abnormal 
P-value (McNemar’s test) 
Baseline 
Normal 
xx (xx) 
xx (xx) 
0.xxxx 
Abnormal 
xx (xx) 
xx (xx) 
P-value = Data source: 16.2.9 Listing of 12-lead electrocardiogram 


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Table 14.3.6.1.1 Hemoglobin at each assessment 
 
Treatment 
 
Hemoglobin 
Deferiprone 
Deferoxamine 
P-value (T-test) 
Visit 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
0.xxxx 
Baseline 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 1 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 2 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 3 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 4 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
… 
… 
… 
… 
… 
… 
Week 49 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 50 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 51 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 52 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Note: Similar tables will be produced for total white blood cell (WBC), absolute neutrophil count (ANC), and 
platelets. 
Data source: 16.2.11 Listing of hematology 


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Table 14.3.6.1.2 Change in hemoglobin at each follow-up assessment 
 
Treatment 
 
Hemoglobin 
Deferiprone 
Deferoxamine 
P-value (T-test) 
Visit 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
0.xxxx 
Week 1 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 2 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 3 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 4 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
… 
… 
… 
… 
… 
… 
Week 49 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 50 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 51 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Week 52 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Note: Similar tables will be produced for total white blood cell (WBC), absolute neutrophil count (ANC), and 
platelets. 
Data source: 16.2.11 Listing of hematology 


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Table 14.3.6.1.3 Shift table for hemoglobin in abnormal range at baseline vs last assessment: Deferiprone group  
 
 
                                    Last Assessment 
 
            n (%) 
Low 
  Normal 
             High 
P-value 
(McNemar’s test) 
    Baseline 
Low 
xx (xx) 
xx (xx) 
xx (xx) 
0.xxxx 
Normal 
xx (xx) 
xx (xx) 
xx (xx) 
High 
xx (xx) 
xx (xx) 
xx (xx) 
Note: Similar tables will be produced for total white blood cell (WBC), absolute neutrophil count (ANC), and 
platelets. 
Data source: 16.2.11 Listing of hematology 
 
Table 14.3.6.1.4 Shift table for hemoglobin in abnormal range at baseline vs last assessment: Deferoxamine group  
 
 
                                    Last Assessment 
 
            n (%) 
Low 
  Normal 
             High 
P-value 
(McNemar’s test) 
    Baseline 
Low 
xx (xx) 
xx (xx) 
xx (xx) 
0.xxxx 
Normal 
xx (xx) 
xx (xx) 
xx (xx) 
High 
xx (xx) 
xx (xx) 
xx (xx) 
Note: Similar tables will be produced for total white blood cell (WBC), absolute neutrophil count (ANC), and 
platelets. 
Data source: 16.2.11 Listing of hematology 
 
 
 


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Table 14.3.6.2.1 Total protein at each assessment 
 
Treatment 
 
Hemoglobin 
Deferiprone 
Deferoxamine 
P-value (T-test) 
Visit 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
0.xxxx 
Baseline 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 1 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 2 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 3 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 4 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
… 
… 
… 
… 
… 
… 
Month 10 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 11 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 12 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Note: Similar tables will be produced for GGT, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
glucose (fasting at screening visit only), total, direct and indirect bilirubin, AST, ALT, albumin; blood urea 
nitrogen, calcium, creatinine, uric acid, alkaline phosphatase, and amylase. 
Data source: 16.2.15 Listing of chemistry 


ApoPharma Inc. 
Statistical Analysis Plan 
 
Protocol LA38-0411 
 
 
CONFIDENTIAL INFORMATION 
57
Table 14.3.6.2.2 Change in total protein at each follow-up assessment 
 
Treatment 
 
Hemoglobin 
Deferiprone 
Deferoxamine 
P-value (T-test) 
Visit 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
0.xxxx 
Month 1 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 2 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 3 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 4 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
… 
… 
… 
… 
… 
… 
Month 10 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 11 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Month 12 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Note: Similar tables will be produced for GGT, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
glucose (fasting at screening visit only), total, direct and indirect bilirubin, AST, ALT, albumin; blood urea 
nitrogen, calcium, creatinine, uric acid, alkaline phosphatase, and amylase. 
Data source: 16.2.15 Listing of chemistry 


ApoPharma Inc. 
Statistical Analysis Plan 
 
Protocol LA38-0411 
 
 
CONFIDENTIAL INFORMATION 
58
Table 14.3.6.2.3 Shift table for total protein in abnormal range at baseline vs last assessment: Deferiprone group  
 
 
                                    Last Assessment 
 
            n (%) 
Low 
  Normal 
             High 
P-value 
(McNemar’s test) 
    Baseline 
Low 
xx (xx) 
xx (xx) 
xx (xx) 
0.xxxx 
Normal 
xx (xx) 
xx (xx) 
xx (xx) 
High 
xx (xx) 
xx (xx) 
xx (xx) 
Note: Similar tables will be produced for GGT, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
glucose (fasting at screening visit only), total, direct and indirect bilirubin, AST, ALT, albumin; blood urea 
nitrogen, calcium, creatinine, uric acid, alkaline phosphatase, and amylase. 
Data source: 16.2.15 Listing of chemistry 
 
Table 14.3.6.2.4 Shift table for total protein in abnormal range at baseline vs last assessment: Deferoxamine group  
 
 
                                    Last Assessment 
 
            n (%) 
Low 
  Normal 
             High 
P-value 
(McNemar’s test) 
    Baseline 
Low 
xx (xx) 
xx (xx) 
xx (xx) 
0.xxxx 
Normal 
xx (xx) 
xx (xx) 
xx (xx) 
High 
xx (xx) 
xx (xx) 
xx (xx) 
Note: Similar tables will be produced for GGT, lactate dehydrogenase (LDH), sodium, potassium, chloride, 
glucose (fasting at screening visit only), total, direct and indirect bilirubin, AST, ALT, albumin; blood urea 
nitrogen, calcium, creatinine, uric acid, alkaline phosphatase, and amylase. 
Data source: 16.2.15 Listing of chemistry 


ApoPharma Inc. 
Statistical Analysis Plan 
 
Protocol LA38-0411 
 
 
CONFIDENTIAL INFORMATION 
59
Table 14.3.6.3.1 HIV Antibody at each assessment  
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
P-value (Fisher’s exact test) 
 
Positive 
N (%) 
Negative 
N (%) 
Positive 
N (%) 
Negative 
N (%) 
 
Baseline 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
0xxxx 
 Week 26 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
0.xxxx 
 Week 52 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
0.xxxx 
Note: Similar tables will be produced for Hepatitis B and C. 
Data source: 16.2.16 Listing of serology  
 
Table 14.3.7.1 Female patients with positive pregnancy test during the study 
 
Treatment 
Pregnancy test: Positive 
Deferiprone 
Deferoxamine 
 
 
Patient ID 
xxxxxx 
 xxxxxx 
xxxxxx 
xxxxxx 
…… 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxxx 
…… 
Data source: 16.2.17 Listing of pregnancy 


ApoPharma Inc. 
Statistical Analysis Plan 
 
Protocol LA38-0411 
 
 
CONFIDENTIAL INFORMATION 
60
Table 14.3.8.1 The number and percent of patients who had compliance <80% or >120% during the study 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
Compliance 
N 
Percent 
N 
Percent 
P-value (Fisher’s exact test) 
< 80% 
xx 
xx.x% 
xx 
xx.x% 
0.xxxx 
> 120% 
xx 
xx.x% 
xx 
xx.x% 
0.xxxx 
Data source: 16.2.24 Listing of compliance 
 
Table 14.5.1 Transfusional iron input (mg/kg/day) during the study 
 
Treatment 
 
 
Deferiprone 
Deferoxamine 
 
 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
P-value (T-test) 
Transfusional iron input (mg/kg/day) 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
0.xxxx 
Data source: 16.2.32 Listing of transfusion information 
 
 
Table 14.6.1 Summary of total daily dose 
 
Treatment 
 
Deferiprone 
Deferoxamine 
 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
Total daily dose (mg/kg/day) 
xxx 
xx.x ± xx.x 
(xx, xx) 
xxx 
xx.x ± xx.x 
(xx, xx) 
Data source: 16.2.22 Listing of dose verification