Conditions: Beta Thalassemia Major Anemia Iron Overload
Keywords: thalassemia iron overload chelation deferiprone Ferriprox
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 64
Healthy volunteers: no

Brief summary:
This study is looking at the effects of giving early treatment of deferiprone to young children with beta thalassemia who have started receiving regular blood transfusions but have not yet reached the criteria for starting on iron chelation therapy. Half the patients in the study will receive deferiprone, and the other half will receive placebo, for up to 12 months.

Detailed description:
This study will give deferiprone to infants and young children with thalassemia who have started receiving regular blood transfusions but whose iron load is not yet at the level where chelation treatment would normally begin. The purpose is to see if doing this will postpone the build-up of iron without causing serious side effects. Half the children in the study will be given deferiprone at a dose that is lower than what is normally prescribed, and the other half will be given placebo. All patients will receive the assigned product three times a day for up to 12 months. Tests for signs of iron overload will be done monthly, and a patient whose iron load reaches the level where chelation therapy would normally begin will be immediately taken out of the study and started on standard chelation therapy.

Arms:
arm 1: Subjects in this group will receive deferiprone oral solution at a dosage up to 75 milligrams per kilogram of body weight (mg/kg) per day, divided into 3 equal doses arm 2: Subjects in this group will receive placebo solution at a volume equal to what they would receive if they were in the active arm, divided into 3 equal doses

Interventions: intervention 1: Deferiprone oral solution intervention 2: Placebo
Intervention descriptions: intervention 1: Liquid formulation of deferiprone, with a concentration of 80 mg/mL intervention 2: Liquid solution that matches deferiprone oral solution in appearance and taste

Protocol document:
ICF_002.pdf: 
 
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Parent’s or Guardian’s initials: _____ 
 
Informed Consent to Take Part in a Clinical Trial, Parent/Guardian Version 
Study Title:  Safety and efficacy of early-start deferiprone treatment in infants and young 
children newly diagnosed with transfusion-dependent beta thalassemia 
Study Code:  LA55-0417 
Sponsor:  ApoPharma Inc. 
200 Barmac Drive, Toronto, Ontario, Canada M9L 2Z7 
Investigator: [insert name] 
[insert name and address of study site]  
Telephone: [insert telephone number of investigator] 
 
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Dear Parent or Guardian, 
Your child (son, daughter, or ward) is invited to take part in a research study.  It is important that 
you fully understand what this participation will mean before you give your consent, so take your 
time to review this form, and ask the Investigator (study doctor) or other study staff to explain 
anything that is not clear. You may wish to discuss things with your child’s regular doctor and 
family members before making your decision. 
Having your child take part in this study is up to you. You do not have to say yes, and if you do 
agree, you may later change your mind at any time.  It is important to note that if you say yes but 
your child is old enough to be asked as well and says no, he/she will not be enrolled.  
This study is organized and paid for by the pharmaceutical company ApoPharma Inc. (the 
“Sponsor”).  The Investigator, Dr. [insert name], is being paid by the Sponsor to do this research. 
If there are any conflicts of interest affecting the investigator, identify them here. 
What is the purpose of this study? 
Your child has been diagnosed with beta thalassemia major, a genetic blood disorder.  People 
with this disease have an abnormal form of hemoglobin, the protein in red blood cells that carries 
oxygen throughout the body, and must therefore receive transfusions of healthy red blood cells 
for their entire lives. These transfusions are life-saving, but since each unit of transfused blood 
contains iron and the body has no natural way of getting rid of extra iron, over time there is a 
build-up of iron in blood and organs.  While a certain amount of iron is necessary, too much of it 


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is harmful and can lead to serious medical problems.  Patients who need frequent transfusions 
must therefore take drugs called iron chelators to help their bodies get rid of the extra iron. 
The iron build-up caused by blood transfusions is gradual, and according to medical guidelines, 
treatment to remove the extra iron from the body should not be started until a certain iron level is 
reached.  This delay is due to a concern that removing too much iron from the body may interfere 
with normal development in young children.  In fact, with the first iron chelator, deferoxamine, 
growth delays were often seen in children who were started on this drug while their level of iron 
overload was still mild, and postponing the start of iron-removal treatment was found to prevent 
that problem.  However, this delay may increase the risk of extra iron building up in glands and 
organs, which may cause health problems later in life. 
Deferiprone (brand name Ferriprox®) is an iron chelator that binds to iron less strongly than 
deferoxamine does and has a greater ability to redistribute it in the body, which may reduce the 
risk of reducing iron levels by too much when the build-up is not yet very high.   Therefore, it 
may be safe to start using this drug at a lower level of iron load than usual.  The purpose of this 
study is to give deferiprone to patients who are not yet eligible to start iron-removal treatment 
according to the guidelines, to see if doing so will postpone the build-up of iron without 
causing significant side effects. 
Deferiprone is produced by ApoPharma, the sponsor of this study, and is licensed for use in 
thalassemia patients who have a high level of iron overload. It has already been tested in an 
earlier study in 64 young children whose levels were too low to start iron-removal treatment in 
the standard way.  (Half the children in that study received deferiprone, while the other half did 
not receive any iron-removal treatment.)  The Investigator has received permission to give 
deferiprone to such children in this study as well. 
Where is the study being done, and how many children will take part in it? 
This study is expected to be done at treatment centers in North America, Europe, the Middle 
East, and Asia.  A total of 64 patients are expected to take part. 
Who can participate? 
Patients in this study must be between 6 months and 10 years of age, have a diagnosis of beta 
thalassemia major, and have started receiving regular red blood cell transfusions, but have an 
iron level that has not yet reached the point when iron-removal therapy is typically started. 
What drugs will be used? 
Patients will be assigned randomly (by chance) to receive either deferiprone or placebo, with an 
equal chance of being in each group.  Both these products are provided by ApoPharma. 


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• The form of deferiprone that is provided in this study is a liquid called deferiprone oral 
solution, which contains 80 milligrams of active medication per milliliter. 
• The placebo solution looks and tastes the same as deferiprone but does not contain any 
active medication.  By comparing patients who are getting the active medication to those 
who are getting placebo, we can tell if effects (both positive and negative) are due to the 
drug itself, and not to other factors. 
Both products are taken by mouth, using a syringe if necessary.  The total daily dose is divided 
into three equal amounts to be given in the morning, afternoon, and evening. 
What will be done during the study? 
If your child takes part in this study, you will both need to come to the treatment center about 
once a month for up to a year. Counting the screening visit, there will be a maximum of 14 clinic 
visits.  (For your convenience, we will try to schedule each of these visits on the same day on 
which your child will be coming in anyways for a blood transfusion.)  In addition, for as long as 
your child remains in the study, it will be necessary to have a blood test done once a week for the 
first 6 months and then once every 2 weeks for the next 6 months, but this can be done at a 
laboratory that is close to where you live. 
Before your child can be enrolled or undergo any procedures, you must sign and date this 
informed consent form, and if your child is old enough to understand what is happening, he or 
she will need to sign a separate assent form.  The Investigator will then ask you some questions 
and will carry out some tests to see if it would be appropriate for your child to take part.  If 
anything is found that raises concerns about safety or that might make the study findings harder 
to understand, your child will not be enrolled. 
The details of each study visit are described below.  Visits may take up to approximately 2 hours. 
Note:  At each visit, up to 11 milliliters (about 2 teaspoons) of blood will be taken for testing, so  
a patient who remains in the study for the full 12 months will be providing a total of about 208 
milliliters (about 40 teaspoons) of blood. This total does not include possible unscheduled visits 
at which there may be a request for additional blood, or the possibility that staff may need to take 
extra blood samples if any are damaged or handled incorrectly. 
Screening visit 
• 
You will be asked questions about your child’s medical history, medications, and blood 
transfusions. Genetic (DNA) proof of a diagnosis of beta thalassemia major is needed, so if 
this has not been done in the past, a blood sample for genetic testing will be taken at this visit. 
• 
Your child will be given a physical examination, including measurement of vital signs 
(blood pressure, heart rate, and temperature). 


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• 
Blood and urine samples will be taken for safety testing, and additional blood samples will 
be taken to check the levels of three different markers of iron overload. One of these is 
called serum ferritin. Ferritin is a protein that stores and transports iron in the body, and the 
amount of ferritin in the blood is used to determine when standard iron-removal therapy 
should begin.  Current guidelines state that treatment is to start when the serum ferritin level 
reaches 1000 micrograms per liter (μg/L).  To be eligible for this study, your child must 
(among other things) have a serum ferritin level that is between 200 and 600 μg/L at this 
time. 
A child who is found to be eligible once all the laboratory results are available may be enrolled, 
and the baseline visit will be scheduled. 
Baseline Visit 
• 
You will be asked questions about any health issues that have come up, medications taken, 
and transfusions received by your child since the screening visit. 
• 
Your child will be randomized to receive either deferiprone or placebo. There is an equal 
chance of receiving either product. Neither you nor any of the study staff will know which 
one is being given. 
• 
Blood samples will be taken for safety testing, including checking the level of prolactin 
(a protein in the body that plays an important role in metabolism), and to measure the three 
markers of iron load.   
• 
Your child’s weight, height, and vital signs will be measured. 
• 
The Investigator will calculate the amount of study drug that is to be given each day, based 
on your child’s weight: 
o For the first 2 weeks, the amount will be 25 milligrams of deferiprone per kilogram of 
body weight (mg/kg) per day. For example, for a child who weighs 10 kg, this works 
out to a volume of about 3 milliliters (mL) per day. Since the daily dosage is divided 
into 3 equal parts, each dose would be about 1 mL.  For patients who are getting 
placebo, the volumes will be the same as for the active product. 
o After 2 weeks, if there are no safety concerns, the dosage will be increased to 50 mg/kg 
per day. (Note that this is still lower than the usually prescribed dose of deferiprone, 
which is between 75 and 99 mg/kg per day.)  For example, a child weighing 10 kg at 
this time would now be given 6 mL per day, divided into three 2-mL doses. A staff 
member will tell you exactly how much to give your child at each dose for the first 
2 weeks, and how much to give after that. 


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• Your child will be given the first dose of study drug by a clinic staff member. 
• Exactly an hour and a half after the dose is given, a blood sample will be taken for a 
second measurement of prolactin.  (Prolactin will be measured again at the end of the study, 
to see if its level has changed from baseline.) 
• You will be given a quantity of the assigned study drug that will be enough to last until the 
next scheduled visit, along with instructions on how to administer it.  (Remember that the 
amount of study drug given will change after 2 weeks if there are no safety concerns.) At the 
next visit, you must bring back all medication containers, whether empty, partly used, or 
unopened. 
• You will be given a diary card in which you must keep track of the amount of study drug 
you give your child each day, the time at which you give it, any health problems your 
child experiences, and any medications taken other than the study drug. You must bring 
back the completed diary card at the next site visit. 
• We will give you a card that briefly describes this study and provides an emergency 
number which you can call at any time. You should carry this card at all times. If at any 
time during the study your child develops signs of infection, such as fever (a temperature 
greater than 38°C or 100.4°F), sore throat, or flu-like symptoms, you must stop treatment 
immediately and call the study center.  A thermometer will be provided to you for the 
measurement of temperature. 
From this visit until your child leaves the study, you are to administer the assigned study drug 
3 times daily, always at about the same times of day.  The only exceptions are that on days of 
study visits, 1) the evening before, you must give the third dose at least 12 hours before the 
expected start of the visit, and 2) the morning of the visit, do not give the first dose; it will be 
given at the site. 
Blood Draws 
For as long as your child is in the study, blood tests must be done once a week up to Month 6, 
and then once every 2 weeks until the end of the study.  On weeks that include a site visit, this 
testing will be done as part of the regular study procedures.  On other weeks, it may be done 
either at the site or at a laboratory that is near you.  The reason for these blood tests is explained 
in the section “What are the possible risks of taking part in the study?” 
Remaining Visits 
The rest of the visits will be scheduled approximately once a month, potentially up to Month 12.  
At each visit, the Investigator will check your child’s level of iron load, based on the now-
available results of the blood tests that were done at the last visit.  If the level of serum ferritin 
is found to be greater than 1000 μg/L at 2 consecutive visits, your child will be immediately 


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withdrawn from the study, and arrangements will be made to begin standard iron-removal 
therapy.  This ensures that any patient who was assigned to the placebo group, or who is not 
responding adequately to the dose of deferiprone being given, will start to receive the necessary 
treatment at the same point where this would have happened if he or she were not in the study. 
For as long as your child remains eligible to remain in the study, the following procedures will 
be done at each visit: 
• You will be asked questions about any health issues, medications taken, and transfusions 
received since the previous visit. 
• You will return all study drug containers that were given to you at the previous visit. 
• The diary card that you completed over the past month will be collected and reviewed, and 
(except at the final visit) you will be given a new one. 
• Your child’s weight, height, and vital signs will be measured. 
• Blood samples will be taken for safety testing and to check levels of iron load. 
• Except at the final visit, the Investigator will calculate the next month’s dosage, and will 
provide you with enough study drug to last until the next scheduled visit.  The dosage will 
now be based on two factors: 
o 
Body weight, as before 
o 
Level of iron load, based on the now-available results of the blood tests that were 
done at the previous visit.  If certain criteria are met for any of the three markers of 
iron load, the dosage will be increased to 75 mg/kg per day; otherwise, the dosage 
will remain at 50 mg/kg per day (and the same volumes for placebo). 
• A staff member will give your child the morning dose of study drug.  (Remember that on 
days of study visits, you are not to give this dose yourself before coming to the site.) 
The following additional procedures will be done only at some visits.  The visits that include 
more procedures will take a little longer than the others.  
• Months 1, 3, 6, 9, and 12:  Extra blood will be taken for additional safety tests 
• Months 1, 3, 6, 9, and 12:  A physical examination will be performed 
• Month 12:  A urine sample will be collected 
• Month 12:   A blood sample will be taken for measurement of prolactin, before dosing, 
and an hour and a half after the last dose was given 


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If at any time before Month 12 your child’s serum ferritin level is found to have been greater 
than 1000 μg/L at 2 consecutive visits, all the procedures scheduled for the Month 12 visit will 
be done at this visit instead, and participation in the study will be ended. 
Are there any medications that are not allowed during the study? 
There are some medications that may interact with the study drug. The Investigator will let you 
know which ones are not permitted.  
No iron chelators other than deferiprone, and no increase in the dose of study drug that your 
child is assigned, are permitted.  Patients whose iron load is not being well controlled by the 
product that they are receiving in the study will be withdrawn so that they can start on standard 
therapy. 
What are the possible benefits of taking part in this study? 
Deferiprone may prevent your child’s level of iron load from increasing. However, there is no 
guarantee that this will happen. 
Your child’s health will be monitored closely during the study, and there will be many chances 
to speak with the Investigator and other health care workers about any medical concerns that you 
may want to discuss. 
Apart from any direct benefit to your child, the information we get from his/her participation will 
add to our knowledge about the use of early iron-removal therapy in children with beta thalassemia 
major, and may help other patients in future. 
What are the possible risks of taking part in the study? 
Risks of receiving deferiprone 
With any medication, there is the possibility of experiencing unwanted side effects. If your child 
develops health problems at any time during the study or up to 30 days after completing or 
leaving the study, you should tell the Investigator or nurse about them. 
The most serious side effect of deferiprone is a sudden drop in neutrophils, a type of white 
blood cell that is a very important part of the immune system. A very low neutrophil count, 
which is called severe neutropenia or agranulocytosis, has occurred in 1 to 2 out of every 100 
people who have taken deferiprone in clinical studies. If your child develops agranulocytosis, it 
may be necessary to have a blood sample taken to be tested for evidence of infection. If he/she is 
being treated in hospital, there may also be a request to have a bone marrow sample taken for 
testing. Agranulocytosis can be successfully treated, and all patients who developed it while they 
were taking part in a clinical study recovered. There have been a few cases however where 
patients who were not in clinical studies (and therefore were not under such close observation) 
have died as a result of developing agranulocytosis. We cannot predict who is at risk for 


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agranulocytosis.  There are no symptoms before an infection develops, which is why it is so 
important to have your child’s white blood cell count checked regularly and to stop deferiprone 
immediately in case of fever, flu-like symptoms, or any other signs of infection. If the results of 
blood tests show that your child’s white blood cell count is too low, the Investigator will make 
sure that the right treatment is provided.  Patients who develop agranulocytosis will be withdrawn 
from the study, and will come back only for follow-up tests until the agranulocytosis is resolved.  
Other side effects that have been seen in patients taking deferiprone are the following: 
Very common (more than 1 user in 10): 
• Abdominal pain 
• Nausea 
• Vomiting 
• Reddish/brown discoloration of urine (this is due to iron leaving the body, and is harmless) 
 
Common (1 to 10 users in 100): 
• Low white blood cell count (agranulocytosis and neutropenia) 
• Headache 
• Diarrhea 
• Increase in liver enzymes 
• Fatigue 
• Increase in appetite 
• Fever 
 
Events of joint pain and swelling (5% to 12% of patients) have ranged from mild pain in one or 
more joints to severe disability. In most cases, the pain disappeared while patients continued 
taking deferiprone. 
Allergic reactions may occur with any product.  Common symptoms may include rash and 
itching. Rarely, a severe and possibly life-threatening allergic reaction can occur. Symptoms of a 
severe reaction include swelling of the face, difficulty breathing, and a sudden drop in blood 
pressure that may cause dizziness. If your child has any of these symptoms, call an emergency 
service at once, and let Dr. [name of investigator] know as soon as possible, at [telephone 
number].  
It is possible that your child could experience other side effects that have not previously been 
reported, particularly since he or she has a lower level of iron load than that seen in patients who 
take this drug under standard conditions.  If you notice any side effects not listed here, tell the 
Investigator or study staff immediately. 


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Risks of receiving placebo 
Patients who are assigned to get placebo will not be receiving any active medication, so if your 
child happens to be in this group, his/her level of iron load will increase with each blood 
transfusion received.  However, since only patients who are not yet eligible to start on iron-
removal therapy according to standard guidelines will be enrolled, this will not put your child at 
any risk compared to children with the same condition who are not in this trial. 
Risks of blood sampling 
Having blood taken may cause reactions of pain, swelling, bruising, minor bleeding at the site of 
the needle entry, redness, and occasionally fainting. In rare cases, an infection or small blood 
clots may result. 
Are there other treatments available? 
There are iron chelators other than deferiprone, but at this time your child is not eligible to 
receive any of them.  If you choose not to enroll your child in this study, he or she will be 
monitored for signs of iron overload until it is determined that it is time for iron-removal therapy 
to begin, at which point your doctor will suggest which product will be best. 
What will happen if new information becomes available? 
If any new information is discovered that may affect the risk to your child or may affect your 
willingness to let him or her stay in the study, you will be told about this as soon as possible. You 
will be given a new version of this informed consent form that explains the new findings, and you 
will need to sign the updated form in order for your child to continue in the study. 
What will happen if I don’t want my child to take part? 
Participation in this study is completely voluntary. If you do not wish to enroll your child (or if 
your child is old enough to express that he or she does not wish to enroll), or if you agree to the 
enrollment but later change your mind, there will be no penalty or loss of benefits to which your 
child is entitled. 
If you decide to withdraw your child from the study after enrolling, we ask that you let us know, 
and that your child return to have some final tests done so that we can do some safety checks and 
collect information that may help increase our understanding of the study product.  
If your child withdraws or is withdrawn from the study (see next section), any study information that 
was collected up to the date of leaving will still be used. 


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Can my child be taken out of the study even if I don’t want that to happen? 
The Investigator may withdraw your child from the study at any time without your consent if you 
are not following instructions or if there are concerns about safety, including the development of 
other medical problems or of severe side effects from the study drug. 
Any patient whose serum ferritin level is found to be greater than 1000 μg/L at 2 visits in a row, 
or whose neutrophil count is found to be too low, will be automatically withdrawn. 
If the study is cancelled for administrative or other reasons, all patients will be withdrawn. 
What will happen if my child is harmed by being in this study? 
If your child is harmed as a result of being in this study, the Investigator will provide or will refer 
you for any necessary medical treatment. The Sponsor will pay for necessary medical costs not 
covered by your health care plan or private medical insurance (if any). 
Costs for medical care for injuries or illnesses that are not a direct result of research activities 
pertaining to this study will not be covered. 
Your signing this consent form does not mean that you waive your legal rights or release the 
Investigator, the institution, the Sponsor, or their representatives from legal responsibility of 
negligence. 
Will there be any costs or payments for being in this study? 
There will be no cost to you for any of your child’s study visits, examinations, tests, and drug 
supplies.  
Describe any compensation that participants will receive. Sample text:  As compensation for 
your child’s participation, at the end of the study, you will receive [insert amount] for each visit 
that you and your child attended.   If your child voluntarily withdraws or is withdrawn by the 
Investigator before the scheduled end of the study, you will be paid for the visits that were 
completed to date, unless the reason for withdrawal was because you or your child were not 
following the study instructions. OR: For each visit that your child attends, you will receive 
[insert amount] to compensate you for transportation and parking costs. 
If there will not be any compensation, include the following: You will not receive any 
compensation for enrolling your child in this study. 
Who has approved the study? 
The proposal for this research study was reviewed and approved by the research ethics committee 
[insert name of IRB or IEC] and by [insert name of regulatory body; e.g., the Food and Drug 
Administration, Health Canada, European Medicines Agency].  A research ethics committee is a 
group that is independent of a study’s sponsor and investigators and is responsible for protecting 
the rights and safety of subjects. 


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Who will be allowed to see my child’s information? 
Access to your child’s records at the study site will be given only to authorized persons.  
Members of the research team and representatives of the Sponsor, the research ethics committee, 
and government agencies may be given access, as permitted by laws and/or regulations, in order, 
for example, to check that the study information is being collected properly. Any information 
about your child that they are allowed to see will remain confidential. The findings of this study 
will be reported to the Sponsor, the [insert name of regulatory agency], and possibly other 
regulatory agencies; however, once information leaves the study site, it will not contain your 
child’s name or other details that could make it possible to identify your child.  Only the 
Investigator will have access to the code numbers that link your child’s study information to 
his/her identity. By signing this consent form, you agree to this disclosure. 
If the findings of this study are published or presented, your child’s identity will remain private. 
Once the trial is completed, the main results will be posted on the web site www.clinicaltrials.gov. 
Refer to other registries if applicable.  Only group findings will appear there; no participants will 
be identified.  
Your child’s information and results will be kept on file by the Investigator and Sponsor for at 
least 25 years, as required by local regulations, after which time they may be destroyed following 
the Sponsor’s written authorization.  
If you agree, we will tell your child’s primary care physician that he/she is taking part in this 
study. 
What will happen to my child’s blood samples? 
The blood samples that your child provides will be used only for this research study. After the 
study is completed, any leftover samples will be destroyed within 6 months. 
If it is necessary to do genetic testing to confirm that your child has a diagnosis of beta 
thalassemia major, this test will be performed by a local laboratory, and any leftover blood sample 
will be destroyed. 
There is a rare but dangerous side effect of deferiprone called agranulocytosis (described above 
under “What are the possible risks of taking part in the study?”). We are trying to find a way of 
predicting which patients are at higher risk for this, and there may possibly be a genetic cause. If 
your child develops agranulocytosis, and if you (and your child, if applicable) agree, we will take 
an additional blood sample for genetic testing.  You will need to sign a separate consent form for 
this testing to be done. Your child can still be in the study even if you do not sign that other 
consent form. 


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Whom should I contact if I have any questions? 
For any questions about this study, or if you need to report a health problem that may be related 
to your child’s participation, you may contact [name of individual] at [phone number].  If your 
question is urgent, you may call a 24-hour line at [phone number]. 
For any questions regarding your child’s rights as a study subject, you may contact the research 
ethics committee at [phone number of IRB/IEC]. 


ApoPharma Model ICF Version 3.0, 24 APR 2019 
Site-Specific ICF Version [x.x], DD MMM YYYY 
 
Study Code:  LA55-0417 
Page 13 of 15 
I have read this page 
 
 
 
Parent’s or Guardian’s initials: _____ 
CONSENT 
 
Please initial below 
 
I confirm that I have read and understood this informed consent form.  
I have had the opportunity to discuss it with Dr. [name of Investigator] 
and/or his/her study staff and to ask questions about it, and have had any 
questions answered satisfactorily. 
_ 
I confirm that I understand the research study and the nature and extent 
of participation, including the risks involved. 
_ 
I agree to let my child take part in this study and to follow the instructions 
I am given.  
_ 
I understand that my child’s participation is voluntary, and that he/she is 
free to leave the study at any time without any medical care or legal 
rights being affected. 
_ 
I agree that if my child does not have genetic proof of a diagnosis of 
beta thalassemia major at the time of enrollment, a blood sample will be 
taken for DNA testing.  I understand that the only test that will be done on 
this sample will be to look for the genes that cause beta thalassemia 
major, and that no other tests of any kind will be done on it. 
_ 
I understand that information collected about my child during the study 
may be looked at by representatives of the Sponsor, regulatory 
authorities, or the research ethics committee. I hereby give permission 
for these individuals to have access to my child’s records. 
_ 
I will contact the Investigator or clinical study staff immediately if my 
child experiences any unexpected or unusual health problems during the 
study, including any signs of infection. 
_ 
I understand that I will receive a photocopy of this informed consent 
form after it is signed and dated. 
_ 
 
 


ApoPharma Model ICF Version 3.0, 24 APR 2019 
Site-Specific ICF Version [x.x], DD MMM YYYY 
 
Study Code:  LA55-0417 
Page 14 of 15 
I have read this page 
 
 
 
Parent’s or Guardian’s initials: _____ 
I agree that the study site may inform my child’s primary care physician of his/her participation 
in this study (please check one):    
 
Yes  
 
 
No  
 
 
 
 
 
Name of patient (please print) 
 
 
 
/ 
:    hr 
Name of parent or legal 
guardian (please print) 
 
Signature of parent or legal 
guardian 
 
Date: (DD MMM YYYY) 
and time (24-hr clock) 
 
 
If signed by a legal representative, identify the authority to act on the parent/guardian’s behalf. 
 
Individual is:  
__ Incompetent 
 
 
__Disabled 
 
 
Authority: 
 
__ Power of Attorney Healthcare 
__Authorized Legal Representative  
   
 
 
__Other (specify): _________________ 
 
Signature of person authorized to obtain consent: 
I, the undersigned, acknowledge having provided all the necessary information for 
comprehension of this research study to the individual identified above. 
 
 
         
/      :      hr 
Name (please print) 
 
Signature 
 
Date: (DD MMM YYYY) 
and time (24-hr clock) 
 


ApoPharma Model ICF Version 3.0, 24 APR 2019 
Site-Specific ICF Version [x.x], DD MMM YYYY 
 
Study Code:  LA55-0417 
Page 15 of 15 
I have read this page 
 
 
 
Parent’s or Guardian’s initials: _____ 
Signature of Investigator: 
I acknowledge my responsibility for the care and well-being of the above patient, to respect the 
rights and wishes of the patient and his/her parent/guardian, and to conduct the study according 
to applicable Good Clinical Practice guidelines and regulations. 
 
         
/      :      hr 
Name (please print) 
 
Signature 
 
Date: (DD MMM YYYY) 
and time (24-hr clock) 
 

Prot_000.pdf: 
 
 
 
CONFIDENTIAL 
Page 1 of 75 
Safety and efficacy of early-start deferiprone treatment in infants and young 
children newly diagnosed with transfusion-dependent beta thalassemia 
LA55-0417 
CLINICAL STUDY PROTOCOL 
 
  
IND Number: 
45724 
EudraCT Number: 
2017-002318-29 
Investigational Product: 
Deferiprone oral solution 
Development Phase: 
Phase 4 
Indication Studied: 
Transfusion-dependent beta-thalassemia 
Study Design: 
Multi-center, randomized, double-blind, placebo-
controlled study in infants and young children  
Sponsor: 
ApoPharma Inc. 
200 Barmac Drive 
Toronto, Ontario M9L 2Z7, Canada 
Telephone:  +1-416-749-9300 
Toll-Free:  1-800-268-4623 (North America only) 
Fax:  +1-416-401-3867 
Sponsor’s Representative: 
Fernando Tricta, MD 
Vice President, Medical Affairs 
Tel: 
1-416-401-7332 
Fax: 1-416-401-3867 
Version and Date of Protocol: 
 Version 4.0, 12 DEC 2018 
 
The information contained in this document is the property of ApoPharma Inc. and is confidential. It may 
be submitted to a regulatory authority, an ethics committee, or an investigator for the purpose of 
initiation of a clinical study. Reproduction or disclosure of this information, in whole or in part, is 
forbidden without the written consent of ApoPharma Inc. 


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


ApoPharma Inc. 
Deferiprone Oral Solution 
LA55-0417    
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 3 of 75 
 
Principal Investigator 
I, the undersigned, hereby declare that I agree to assume responsibility for the proper conduct 
of the study at this site; and that I will conduct the study in compliance with this protocol, 
with any future amendments, and with any other written study conduct procedures provided, 
reviewed, and approved by the sponsor or its delegate. 
 
Study Title: 
Safety and efficacy of early-start deferiprone treatment in 
infants and young children newly diagnosed with 
transfusion-dependent beta thalassemia 
Study Code: 
LA55-0417 
Version Number: 
Version 4.0 
Version Date: 
12 DEC 2018 
Name of Principal Investigator: 
 
Name of Study Site: 
 
Location of Study Site: 
(City, region/province/state, 
country) 
 
 
 
 
 
Signature 
 
Date (DD MMM YYYY) 
 


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


ApoPharma Inc. 
Deferiprone Oral Solution 
LA55-0417    
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 5 of 75 
 
Name of Sponsor: ApoPharma Inc. 
Individual Study Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For National 
Authority Use Only) 
Name of Finished Product: Deferiprone oral 
solution 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Study design 
(cont’d): 
If a single occurrence of any of the following is detected at any time, 
treatment will be interrupted: 
• 
SF value below the lower reference range for the child’s age  
• 
Mild neutropenia, defined as an absolute neutrophil count (ANC) 
< 1.5 x 109/L but ≥ 1.0 x 109/L  
• 
Fever or other signs of infection, prior to confirmation that ANC is 
≥ 1.5 x 109/L 
As these parameters are known to fluctuate, the assessment will be repeated 
as soon as possible to verify that treatment interruption is necessary. 
Treatment will be re-initiated after the abnormally low SF, LPI, TSAT, or 
ANC level has recovered, or when the fever or infection has resolved or has 
been determined to not be indicative of neutropenia.  
 If moderate neutropenia (ANC < 1.0 x 109/L) is confirmed, the patient will 
be withdrawn from the study.  
Patients will remain in the study for 12 months or until their SF level has 
been confirmed to be ≥1000 μg/L at 2 consecutive visits, whichever comes 
first. Those whose SF levels are still under 1000 μg/L at 12 months will be 
offered participation in an extension study, LA55-EXT, in which they will 
continue to receive their assigned study product for up to 2 more years. 
Those who are terminated early will not be eligible to enroll in the extension 
study.  
Duration of 
participation: 
The duration of participation in this study for each patient will be up to 
12 months. 
Criteria for 
evaluation: 
 
 
 
 
 
 
 
 
 
 
 
Efficacy: 
Primary efficacy endpoint:  The percentage of patients who still have a serum 
ferritin level < 1000 μg/L at Month 12. 
Secondary efficacy endpoints: 
• 
The percentage of patients whose serum ferritin level is still less than 
1000 μg/L at each visit 
• 
The percentage of patients whose LPI value is still less than 0.6 µM at 
each visit 
• 
The percentage of patients in each treatment arm whose TSAT value is 
still less than 60% at each visit 
• 
Time to reach a serum ferritin level ≥ 1000 μg/L 
• 
Time to reach an LPI value ≥ 0.6 µM 
• 
Time to reach a TSAT value ≥ 60% 


ApoPharma Inc. 
Deferiprone Oral Solution 
LA55-0417    
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 6 of 75 
 
Name of Sponsor: ApoPharma Inc. 
Individual Study Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For National 
Authority Use Only) 
Name of Finished Product: Deferiprone oral 
solution 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Criteria for 
evaluation (cont’d): 
 
 
Safety: 
• 
Adverse events (AEs):  Frequency, intensity, time to onset, duration, and 
relatedness to study drug 
• 
Serious adverse events (SAEs):  Frequency, intensity, time to onset, 
duration, and relatedness to study drug 
• 
Number of discontinuations due to AEs 
• 
Growth parameters:  Weight, height, and height velocity, as classified 
using the Z-score system 
• 
Change in prolactin level from baseline to Month 12 
Number of patients: 
A planned total of 64 patients will be randomized in a 1:1 ratio to the two arms. 
Diagnosis and main 
criteria for inclusion: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Main inclusion criteria 
• 
Male or female aged ≥ 6 months to < 10 years 
• 
Confirmed diagnosis of beta-thalassemia, as determined by high 
performance liquid chromatography (HPLC) or DNA testing 
• 
Started on a regular RBC transfusion regimen, with a minimum of 2 
transfusions already completed 
• 
Screening level of serum ferritin greater than >200 g/L but not more 
than 600 μg/L. Since SF level may be impacted by the presence of 
infection, it must additionally be verified that the child has had no signs 
of infection in the previous 7 days, including the day of screening, and 
that the level of C-reactive protein (CRP) is no greater than 20% higher 
than the normal range for the patient’s age.  If there are signs of infection 
and/or the CRP level is above this threshold, the SF level must be 
checked again a minimum of one week later. (Note:  If an investigator 
has valid reason to believe that an out-of-range SF level may be 
attributable to infection even if this is not indicated by the CRP result, 
SF may be rechecked once more a minimum of one week later.) 
Main exclusion criteria 
• 
Prior use of iron chelation 
• 
Diagnosis of hepatitis B or C, or HIV infection 
• 
Evidence of abnormal liver or kidney function at screening (serum ALT 
level > 5 times upper limit of normal or creatinine levels >2 times upper 
limit of normal) 
• 
Disorders associated with neutropenia (ANC < 1.5 x 109/L) prior to the 
initiation of study medication 


ApoPharma Inc. 
Deferiprone Oral Solution 
LA55-0417    
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 7 of 75 
 
Name of Sponsor: ApoPharma Inc. 
Individual Study Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For National 
Authority Use Only) 
Name of Finished Product: Deferiprone oral 
solution 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Diagnosis and main 
criteria for inclusion 
(cont’d): 
Exception: Patients whose neutropenia is attributed by the treating 
physician to episodes of infection or to drugs associated with a decline in 
the neutrophil count and in whom the ANC has returned to a normal level 
at the screening visit. 
Investigational 
product: 
Product: 
Deferiprone oral solution 80 mg/mL 
Dose:   
25, 50, or 75 mg/kg/day, divided t.i.d.  
Mode of administration:  Oral 
Reference product: 
Product: 
Placebo 
Dose: 
Volume of solution matching that required for a 25, 50, or 75 
mg/kg/day dose of active product, divided t.i.d. 
Mode of administration:  Oral 
Schedule of 
treatment and 
specimen collection: 
Treatment:  All patients will be administered the assigned study product 3 times 
daily for the duration of the study. 
Efficacy assessments:  Blood samples for the assessment of LPI, TSAT, and SF 
will be collected at screening/baseline and at each monthly visit until 
termination from the study. 
Safety assessments: 
• Hematology:  Screening, baseline, weekly after the start of dosing up to 
Month 6, then biweekly until Month 12 or early termination from the study 
• Blood chemistry:  Screening and Months 1, 3, 6, 9, and 12 or until early 
termination from the study 
• Prolactin:  Baseline and Month 12 
• Vital signs:  Each visit 
• Physical examination:  Screening and Months 1, 3, 6, 9, and 12 or until 
early termination from the study 
• Urinalysis:  Screening and Month 12 or early termination from the study 
• Weight and height:  Baseline and monthly until Month 12 or early 
termination from the study 
• Adverse events:  Collected throughout the study, from baseline until 
Month 12 or early termination from the study 


ApoPharma Inc. 
Deferiprone Oral Solution 
LA55-0417    
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 8 of 75 
 
Name of Sponsor: ApoPharma Inc. 
Individual Study Table 
Referring to Part of the 
Dossier 
Volume: 
Page: 
(For National 
Authority Use Only) 
Name of Finished Product: Deferiprone oral 
solution 
Name of Active Ingredient: 3-hydroxy-1,2-
dimethylpyridin-4-one 
Statistical methods: 
 
Sample size:  With 64 patients, there will be over 90% power to detect a 
statistically significant difference ( = 0.05) between the two treatment groups 
in the percentage of patients who have a serum ferritin level < 1000 μg/L at 
Month 12 if the deferiprone arm and the placebo arm have an expected 
incidence of 70% and 20%, respectively.  
Efficacy evaluation:  The percentage of patients who have not reached levels of 
LPI ≥ 0.6 µM, TSAT ≥ 60%, and SF ≥ 1000 μg/L will be compared between 
the two treatment groups at each monthly time point as well as at the end of 
study, using the Fisher’s exact test. The effect of baseline value on each of the 
3 endpoints will be examined in a covariate analysis. The Kaplan-Meier 
survival curve for the time to reach a serum ferritin level ≥ 1000 μg/L, an LPI 
value ≥ 0.6 µM, and a TSAT value ≥ 60% will be generated for the two 
treatment groups. The log-rank test will be used for comparing the two 
survival curves for each of the 3 endpoints.  The trend analysis over time for 
LPI, TSAT, and SF measures will be performed to compare the rates of change 
in these measures between the two treatment groups.  
Safety evaluation:  Descriptive statistics (mean, standard deviation, minimum, 
and maximum) will be produced for continuous variables, and frequency tables 
will be produced for discrete variables by treatment group. Summaries of 
adverse events and serious adverse events will be produced by treatment group. 
Shift tables will be generated for comparing the screening/baseline values and 
end of study values of the relevant measures. 
For weight and height, the change from baseline to last assessment will be 
compared between the two treatment groups using an ANCOVA model with 
baseline value as a covariate and treatment as the main factor. The rate of 
change in height will be assessed using regression analysis. For prolactin, a 
similar ANCOVA model will be used for the evaluation of change in prolactin 
from baseline to Month 12.  
The appropriate procedures in SAS will be used for the efficacy and safety 
analyses. 
Version and date of 
the protocol 
 Version 4.0, 12 DEC 2018 


ApoPharma Inc. 
Deferiprone Oral Solution 
LA55-0417    
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 9 of 75 
 
TABLE OF CONTENTS 
SIGNATURE PAGES .............................................................................................................2 
SYNOPSIS ................................................................................................................................4 
LIST OF IN-TEXT TABLES ...............................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................13 
1 
INTRODUCTION......................................................................................................14 
1.1 
Background of the Disease ......................................................................................14 
1.2 
Background of the Investigational Product .............................................................14 
1.3 
Rationale ..................................................................................................................15 
1.4 
Potential Risks and Benefits ....................................................................................15 
2 
STUDY OBJECTIVES ..............................................................................................17 
2.1 
Primary Objective ....................................................................................................17 
2.2 
Secondary Objective ................................................................................................17 
3 
STUDY DESIGN ........................................................................................................17 
3.1 
Description of Study Design ...................................................................................17 
3.2 
Rationale for Study Design .....................................................................................18 
3.3 
Rationale for Selection of Doses .............................................................................19 
4 
STUDY POPULATION ............................................................................................19 
4.1 
Number of Patients ..................................................................................................19 
4.2 
Inclusion Criteria .....................................................................................................19 
4.3 
Exclusion Criteria ....................................................................................................20 
4.4 
Enrolment Violations ..............................................................................................21 
4.5 
Patient Withdrawal ..................................................................................................21 
4.5.1 
Replacement of Patients Who Withdraw .........................................................22 
4.5.2 
Treatment Interruptions ...................................................................................22 
4.6 
Prior and Concomitant Therapies ............................................................................23 
4.7 
Rescue Medication ..................................................................................................23 
5 
STUDY PROCEDURES ...........................................................................................23 
5.1 
Visit Procedures ......................................................................................................27 
5.2 
Method of Assignment to Treatment .......................................................................48 
5.3 
Blinding Procedures ................................................................................................49 


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


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Page 11 of 75 
 
7.2.3.1 
Physical Examinations ..............................................................................62 
7.2.3.2 
Vital Signs ................................................................................................62 
7.2.3.3 
Concomitant Medications .........................................................................63 
8 
STUDY COMMITTEES ...........................................................................................63 
9 
STATISTICAL ANALYSIS .....................................................................................64 
9.1 
Endpoints .................................................................................................................64 
9.1.1 
Primary Efficacy Endpoint ..............................................................................64 
9.1.2 
Secondary Efficacy Endpoints .........................................................................64 
9.1.3 
Safety Endpoints ..............................................................................................64 
9.2 
Determination of Sample Size and Study Power ....................................................64 
9.3 
Study Populations ....................................................................................................65 
9.3.1 
Intent-to-Treat Population ................................................................................65 
9.3.2 
Per Protocol Population ...................................................................................65 
9.3.3 
Safety Population .............................................................................................65 
9.4 
Data Analysis Plan ..................................................................................................65 
9.4.1 
Planned Analyses .............................................................................................65 
9.4.1.1 
Patient Disposition and Drug Exposure ....................................................65 
9.4.1.2 
Patient Characteristics ..............................................................................65 
9.4.1.3 
Analysis of Efficacy .................................................................................66 
9.4.1.4 
Analysis of Safety .....................................................................................66 
9.4.2 
Interim Analyses ..............................................................................................66 
9.5 
Criteria for Evaluability of Patient Data ..................................................................67 
10 
DATA MANAGEMENT CONSIDERATIONS......................................................67 
10.1 
Data Management ....................................................................................................67 
10.2 
Case Report Forms ..................................................................................................67 
11 
MONITORING, AUDITS, AND INSPECTIONS ..................................................68 
11.1 
Source Documents ...................................................................................................68 
11.2 
Monitoring ...............................................................................................................68 
11.3 
Audits and Inspections ............................................................................................68 
11.4 
Site Closure .............................................................................................................69 
11.5 
Retention of Records ...............................................................................................70 
12 
ETHICAL CONSIDERATIONS ..............................................................................70 


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Page 12 of 75 
 
12.1 
Informed Consent/Assent ........................................................................................70 
12.2 
Institutional Review Board/Independent Ethics Committee ...................................70 
12.3 
Patient Confidentiality .............................................................................................71 
13 
REGULATORY REQUIREMENTS .......................................................................71 
13.1 
Regulatory Obligations ............................................................................................71 
13.2 
Amendments to the Protocol ...................................................................................72 
14 
EARLY STUDY TERMINATION ..........................................................................72 
15 
CONFIDENTIALITY ...............................................................................................73 
16 
DISPUTE RESOLUTION.........................................................................................73 
17 
OWNERSHIP .............................................................................................................73 
18 
PUBLICATION .........................................................................................................73 
19 
REFERENCES ...........................................................................................................74 
 
 
LIST OF IN-TEXT TABLES 
Table 1.1  Adverse drug reactions seen in ≥ 1% deferiprone-treated patients with 
systemic iron overload........................................................................................16 
Table 5.1 
Table of study procedures ..................................................................................24 
 
 
 


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Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 13 of 75 
 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate transaminase 
CS 
clinically significant 
CI 
confidence interval 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein  
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
HPLC 
high performance liquid chromatography 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
LPI 
labile plasma iron 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
RBC 
red blood cell 
SAE 
serious adverse event 
SF 
serum ferritin 
TSAT 
transferrin saturation 
WHO 
World Health Organization 


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


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


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


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


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


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


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


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4.4 
Enrolment Violations 
The criteria for enrolment must be followed explicitly.  If there is inadvertent enrolment of 
patients who do not meet enrolment criteria, the investigator should consider withdrawing these 
individuals from the study. 
Exception:  A patient who does not have DNA confirmation of a diagnosis of beta-thalassemia 
available at the time of screening may be enrolled on the basis of HPLC results (see inclusion 
criterion #2). If subsequent DNA results are found to not confirm the diagnosis, the patient will 
still be permitted to remain in the study if all other eligibility criteria are met. 
4.5 
Patient Withdrawal 
Patients/parents have the right to withdraw/withdraw their child from the study at any time 
and for any reason without consequence to future care by the investigator or study center. 
A patient may be withdrawn from the study at any time, at the discretion of the investigator, 
for any of the following reasons: 
• 
Medical or safety reasons considered significant by the parent/legal guardian (or 
patient, if applicable) and/or the investigator 
• 
Requirement for concomitant medication that might interfere with the evaluation of 
study treatment or may be contraindicated 
• 
Occurrence of other illnesses that might affect the patient’s further participation in 
the study or evaluation of study treatment 
• 
A protocol deviation that might interfere with study assessments, as judged by the 
investigator 
• 
Repetitive non-compliance with the protocol or with instructions of the investigator 
• 
Participation in another clinical trial at any time during the conduct of this study 
• 
Any other situation where, in the opinion of the investigator, continuation of the 
study would not be in the best interest of the patient 
A patient must be withdrawn from the study if any of the following conditions apply: 
• 
Attainment of a serum ferritin level ≥ 1000 μg/L at 2 consecutive visits (provided 
that the child has had no signs of infection in the previous 7 days and that CRP level 
is not greater than 20% higher than the normal range for the patient’s age) 
• 
Occurrence of moderate neutropenia or of severe neutropenia/agranulocytosis (see 
Section 7.2.1.8.1) 
• 
Occurrence of any adverse event characterized as life-threatening or disabling that is 
not associated with the patient’s condition 


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• 
Receipt of a rescue medication (see Section 4.7) 
• 
Termination of the study by the sponsor 
Parents/legal guardians who decide to withdraw their child from the study (or, in the case of 
a child who is able to communicate this, a patient who wishes to withdraw) should always be 
contacted, if possible, in order to ask about the reason for withdrawal, whether any adverse 
events (AEs) occurred, and use of concomitant medications.  A withdrawn patient should 
return for an Early Termination visit. All investigational product and materials should be 
returned.  If any AEs occurred, the investigator must attempt to follow up on the outcome 
until resolution or for 30 days post-termination, whichever comes first. 
If a patient withdraws or is withdrawn before completing the study, the date and reason for 
the withdrawal must be entered on the source document and on the appropriate page of the 
electronic case report form (eCRF), and all other appropriate eCRF pages must be completed. 
4.5.1 
Replacement of Patients Who Withdraw 
Patients who are withdrawn from the study will not be replaced. 
4.5.2 
Treatment Interruptions 
Study medication will be interrupted for ANY of the following reasons: 
• If a patient develops fever (≥ 38.0°C) or any sign of infection during the study, 
deferiprone must be interrupted immediately, and neutrophil count should be obtained 
and monitored more frequently; every 2 days if ANC <1.5 x 109/L.  Therapy with 
deferiprone can be re-initiated once all symptoms have been resolved, if the ANC is 
≥1.5 x 109/L. 
• Parents/guardians (and patients if applicable) are to be advised to immediately report 
any symptoms indicative of infection such as fever, sore throat, and flu-like symptoms. 
Participants will be provided with a thermometer, and will be instructed to seek 
immediate medical attention at a hospital or clinic if the patient experiences fever 
(temperature ≥38.0° C/100.4°F).  Body temperature may be measured at the ear, axilla, 
or mouth. In presence of confirmed fever and/or infection, patients will be required to 
have their neutrophil counts tested as soon as possible and no later than 24 hours after 
the symptoms of infection are detected. Therapy with study drug can be re-initiated 
once all symptoms have been resolved and it is deemed safe by the investigator. 
• If a patient develops mild neutropenia during the study (ANC <1.5 x 109/L but ≥1.0 
x 109/L; see Section 7.2.1.8.1), therapy must be interrupted immediately, and neutrophil 
count must be obtained and monitored every 2 days.  Therapy can be re-initiated once 


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two successive ANCs are ≥1.5 x 109/L and it is deemed safe by the investigator.  If the 
ANC is still <1.5 x 109/L after 14 days, the patient will be withdrawn from the study. 
• A patient who develops neutropenia that is defined as moderate (ANC <1.0 x 109/L) or 
severe (ANC <0.5 x 109/L) is to be immediately withdrawn from the study. 
4.6 
Prior and Concomitant Therapies 
All medications taken during the 3 months prior to dosing up to the end of the study 
(Month 12 or early termination) will be recorded and reviewed by the investigator. 
Medications considered necessary for the patient’s welfare may be given at the discretion of 
the investigator.  The administration of all medications (including study product, herbal 
medications, and over-the-counter medications) and nutritional supplements must be 
recorded in the source document and the appropriate sections of the electronic case report form 
(eCRF).  During the study, patients must not receive any other investigational product or any 
drugs that are known to cause neutropenia or agranulocytosis.  
4.7 
Rescue Medication 
Administration of any other iron chelator (deferoxamine, deferasirox, or a combination of 
two chelators) or an increase in deferiprone dosage above the limit specified in the protocol 
will not be allowed. Patients who need higher doses of deferiprone than what is permitted in 
this study or a different chelator to control their iron overload will be withdrawn, as per protocol. 
5 
STUDY PROCEDURES 
The procedures and assessments to be conducted at each study visit are shown in Table 5.1.


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Table 5.1 
Table of study procedures 
 
Day -14 to 
0 
(Screening) 
Month 0,  
Day 0 
(Baseline) 
Month 
1 1 
Month 
2 
Month 
3 
Month 
4 
Month 
5 
Month 
6 
Month 
7 
Month 
8 
Month 
9 
Month 
10 
Month 
11 
Month 
12 or 
End of 
Study 2 
Informed consent/ 
assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
V 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 3 
X 
X 
Weekly (±3 days) after start of dosing up to Month 6 
Biweekly (±3 days) until termination from the study 
Blood chemistry 4,5 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
DNA testing (if 
applicable) 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 5,7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serology 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 5 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Labile plasma iron 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Transferrin 
saturation 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum ferritin 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prolactin 12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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5.3 
Blinding Procedures 
The placebo solution will have the same appearance and flavor as deferiprone oral solution, and 
will be administered at a volume matching that required for a 25, 50, or 75 mg/kg/day dose of 
active product. 
Sites will be provided with code-breaking instructions.  In the event of an emergency, the 
randomization code may be broken only if knowledge of the respective treatment is necessary for 
adequate treatment of the emergency.  The sponsor must be contacted within 24 hours in case 
of unblinding. Randomization information will be held by designated individual(s). The 
date and reason for breaking the blind must be documented. 
5.4 
Allocation of Patient Numbers 
After provision of informed consent (and assent if applicable), each patient will be assigned a 
unique ID number, and will be identified in all study data by this number rather than by 
name. The ID number will consist of 6 digits, where the first 3 digits represent the site code 
(001 for site #1, 002 for site #2, etc.) and the next 3 digits (separated from the first 3 by a 
hyphen) are assigned sequentially for each individual enrolled at that site.  For example, if 
site #1 enrolls 8 patients, the ID numbers will be 001-001 to 001-008. The assigned ID 
numbers of patients who are screening failures or who withdraw from the study will not be 
reused. 
5.5 
Treatment Compliance 
Compliance will be determined as follows: 1) participants will use the daily diary card to 
record the amount of study medication administered, and 2) at each visit, the investigator or 
delegate will collect the medication containers, whether empty, partly used, or unopened, and 
will check the volume of solution remaining by weighing the bottles.  Compliance will be 
calculated by the volume of solution taken divided by the volume of solution prescribed as 
per the dosing frequency and length of treatment.  Any discrepancies must be discussed with 
participants and documented in the source documents.  Reasons for non-compliance with the 
treatment will be recorded in the source document and in the eCRFs. The investigator should 
discuss treatment compliance at each visit. 
If the volume of returned solution is less than it should be but the parent/guardian (or patient, 
as applicable) reports having administered or taken the correct amount of medication, the site 
will report compliance as 100% in the eCRF, and will provide the reason for the apparent 
over-compliance (e.g., solution was accidentally spilled), along with the actual percentage. 
Both under-compliance < 80% and over-compliance >120% will be reported as a protocol 
deviation, unless under-compliance is due to treatment interruption because of infection or 
neutropenia or other extenuating circumstances (see Section 7.2.1.8). 


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


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A receipt form will be provided to the study sites by the sponsor with each shipment of 
investigational product.  The investigator or a designate is to sign and date this receipt form 
to acknowledge receiving the entire product shipment in good condition, and to record the 
time at which the temperature-monitoring device was removed and stopped.  The site will fax 
or email a copy of this receipt form to the sponsor and retain the original in its Investigator 
Trial File. 
6.5 
Product Accountability 
The investigator must maintain an updated Site Investigational Drug Inventory Record at the 
study site.  This log will include at a minimum: 
• 
Name of sponsor 
• 
Name of investigator 
• 
Study identifier 
• 
Date and quantity of investigational product received from sponsor 
• 
Lot/batch number 
 
For each patient, the investigator must maintain an updated Patient Investigational Drug 
Dispensing Record. This log will include at a minimum: 
• 
Patient identification number 
• 
Date of dispensing and return 
• 
Dispenser’s initials 
• 
Quantity dispensed and returned 
 
At the conclusion of the study, a final inventory must be performed by the investigator (or 
delegate). If any bottles are missing, this must be indicated on the study drug accountability 
form, together with an explanation of the discrepancy. These forms must be available for 
sponsor clinical monitoring as well as for sponsor audit and regulatory authority inspection 
purposes at any time. 
It is the responsibility of the investigator to ensure that all study drug received at the site is 
inventoried and accounted for throughout the study. Records of receipt, storage, and 
administration of the study drug supplied must be maintained, and the drug accountability 
will be verified by the sponsor or sponsor’s designee during on-site monitoring visits.  The 
sponsor will be responsible for determining the specific conditions for destruction of unused 
product. 


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


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7.1.2 
Transferrin Saturation 
Transferrin is a protein that combines with ferritin and transports it where iron is required.  
When its capacity to bind incoming iron is exceeded, excess iron circulates as free non-
transferrin-bound iron (NTBI), and is taken up by tissues where it can cause cell and organ 
damage. Transferrin saturation, defined as the percentage of the iron-binding sites of transferrin 
that are already occupied, is easily measured and hence serves as a marker for NTBI.  High 
levels of transferrin saturation are associated with iron toxicity.  As this measure is highly 
variable, the blood samples for its assessment will always be collected at approximately the 
same time of day and at approximately the same amount of time after the last dose of study 
medication, in an attempt to decrease variability as much as possible. 
Transferrin saturation will be measured at each visit, and the time to reach a level ≥ 60% will 
be compared between the treatment arms. 
7.1.3 
Labile Plasma Iron 
Labile plasma iron is a component of NTBI, and is the most toxic form of iron since it acts as 
a catalyst in the formation of harmful free hydroxyl radicals which can damage cellular DNA, 
proteins, and membrane lipids. High levels of this form of iron may be found in individuals 
with conditions of iron overload.  As this measure is highly variable, the blood samples for 
its assessment will always be collected at approximately the same time of day and at 
approximately the same amount of time after the last dose of study medication, in an attempt 
to decrease variability as much as possible. 
Labile plasma iron will be measured at each visit, and the time to reach a level ≥0.6 µM will 
be compared between the treatment arms. 
7.2 
Safety Measurements 
7.2.1 
Medical Events, Adverse Events, and Serious Adverse Events 
7.2.1.1 
Definition of Medical Events and Adverse Events 
Medical Event (ME): Any new untoward medical occurrence or worsening of a pre-existing 
condition in a clinical trial participant that occurs after signing the informed consent form 
(ICF) but before receiving the first dose of study drug. 
Adverse Event (AE): Any untoward medical occurrence in a patient who is administered a 
pharmaceutical or other therapeutic product in a clinical study, not necessarily having a 
causal relationship with the product. An AE can therefore be any unfavorable and unintended 
sign, symptom, or disease temporally associated with the use of a product, whether or not 
considered related to that product. 


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AEs include: 
• Exacerbation of a pre-existing illness, including acute episodes/crisis of a chronic 
underlying condition 
• An increase in frequency or intensity of a pre-existing episodic event or condition 
• A condition detected or diagnosed after study treatment administration, even though it 
may have been present prior to the start of the study 
• A continuous persistent disease or symptom present at baseline that worsens following 
the start of the study 
• Accidents (e.g., involving a motor vehicle) 
• Reasons for changes in concomitant medication (type of drug and/or dose) 
• Medical, nursing, or pharmacy consultation 
• Admission to hospital and surgical operations 
• Abnormalities in laboratory findings (e.g., clinical chemistry, hematology, urinalysis), 
other assessments (e.g., vital signs) that are not part of a larger medical condition already 
recorded as an AE and which are judged by the investigator to be clinically significant. 
The investigator should exercise medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
 
AEs do not include: 
• A pre-existing disease or condition present or detected at the start of the study that does 
not worsen 
• Hospital admissions or surgical procedures that had been planned prior to enrolment into 
the study 
• The disease or disorder being studied, or a sign or symptom associated with that disease 
or disorder, unless it has worsened 
• An overdose of either the study treatment or concurrent medication without any signs or 
symptoms 
7.2.1.2 
Monitoring and Documenting of Medical Events and Adverse Events 
Prior to enrolling a patient, study site personnel will note the occurrence and nature of any 
medical condition(s) in the source documents and the appropriate section of the eCRF. 
During the study, they will note any change in the condition(s), and the occurrence and 
nature of any MEs/AEs. MEs will be collected from the time the ICF is signed until the first 
dose of study drug, and AEs will be collected from the time the treatment starts until 30 days 


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 after the last dose. 
AEs and SAEs that are related to the underlying medical condition for which the patient 
enrolled in the clinical trial will be recorded separately from others. 
Participants will be instructed to report any MEs/AEs to the investigator or a delegate.  In 
addition, the investigator will solicit information about the occurrence of MEs/AEs through 
open-ended, non-leading verbal questions such as: 
• How is your child feeling? 
• Has your child had any medical problems since the last visit? 
• Has your child taken any new medications, other than those provided in this study, 
since the last visit? 
Based on the responses to these questions, the investigator or delegate should ask additional 
questions relevant to the specific complaint, such as: 
• How severe is/was the symptom? 
• How often did the symptom occur? 
• How long did the symptom last? 
Participants should also be questioned about any previously reported AEs that have not 
resolved. 
The investigator will evaluate all AEs/MEs for their relationship to the investigational 
product (Section 7.2.1.3), intensity (Section 7.2.1.4), and seriousness (Section 7.2.1.5), and 
will document any measures taken to address the event.  There should be an attempt to 
establish a diagnosis of the AE based on signs, symptoms, and/or other clinical information. 
Wherever possible, a diagnosis should be documented, rather than the individual signs/
symptoms. All information is to be clearly recorded in the source documents. 
If the dosage of study drug is reduced or treatment is discontinued as a result of an AE, the 
circumstances leading to such reduction or discontinuation must be clearly documented. 
All AEs must be followed until resolution, the condition stabilizes, the event is otherwise 
explained, or the patient is lost to follow-up. The investigator is responsible for ensuring that 
follow-up includes any supplemental investigations that are needed to elucidate the nature 
and/or causality of the AE as completely as possible. This may include additional laboratory 
tests or investigations, histopathological examinations, or consultation with other health care 
professionals. 


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7.2.1.3 
Assessment of Causality 
The relationship of an AE to the study drug should be determined by the investigator after 
thorough consideration of all available facts, including associative connections (time or place), 
pharmacological explanations, previous knowledge of the drug, presence of characteristic 
clinical or pathological phenomena, exclusion of other causes, and/or absence of alternative 
explanations. The causal relationship of an adverse event to study drug will be assessed 
according to the following criteria (based on World Health Organization definitions): 
• Not related: 
Temporal relationship to study drug administration is missing or 
implausible, or there is no evident cause. 
• Possibly related: 
Reasonable time sequence to administration of study drug, but 
event could also be explained by concurrent disease or other drugs 
or chemicals. 
• Probably related: 
Reasonable time sequence to administration of study drug, and 
unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). Re-challenge information is not required. 
• Definitely related: 
Plausible time relationship to study drug administration, and cannot 
be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug (de-challenge) should be 
clinically plausible. The event must be definitive pharmacologically 
or phenomenologically, using a satisfactory re-challenge procedure 
if necessary. 
7.2.1.4 
Assessment of Intensity 
Intensity refers to the degree of discomfort or impairment associated with an event. The 
intensity of MEs/AEs is to be reported on the CRF as mild, moderate, or severe, according to 
the definitions provided below.  In addition, to maximize consistency in assessment, it is 
recommended that the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) scale be used. 
 
Intensity 
Corresponding 
NCI CTCAE Grade 
Mild: awareness of a sign or symptom but easily tolerated 
1 
Moderate: discomfort sufficient to cause interference with 
normal daily activities 
2 
Severe: resulting in inability to perform normal daily activities 
3–5 


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


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relationship with the study drug. Any SAEs for which the investigator does suspect a causal 
relationship must be reported to the sponsor regardless of the time elapsed since the last dose 
of the study drug. 
Participants will be instructed to report SAEs to the investigator within 24 hours, by 
telephone. In turn, the investigator must report all SAEs to the sponsor within 24 hours of 
occurrence or notification by the participant, using the sponsor’s SAE form. The sponsor will 
provide contact information for reporting SAEs. An assessment of causality must be 
provided at the time of the initial report. The investigator or delegate must then complete and 
submit a follow-up SAE form to the sponsor within 5 calendar days, and must submit 
further follow-up forms if additional relevant follow-up information becomes available. 
The sponsor will submit reports of SAEs to the appropriate regulatory agencies, in line with 
local regulatory requirements and timelines. 
Investigators must report all SAEs to their IRB/IEC as well as to the sponsor.  If any SAE 
that is considered at least possibly related to the study medication and is unexpected occurs at 
one site, the sponsor will promptly inform all other sites of this, and all investigators must 
then report this event to their own IRBs/IECs, following the same timelines as above or 
following local IRB/IEC policy, whichever takes precedence. 
7.2.1.7 
Follow-up and Documentation of SAEs 
SAEs that occur during the study and up to 30 days after the last dose of study drug must be 
documented in the patient’s medical record and on the SAE report form. The investigator 
should attempt to establish a diagnosis of the event based on signs, symptoms, and/or other 
clinical information. In such cases, the diagnosis rather than the individual signs/symptoms 
should be documented as the SAE. 
All SAEs must be followed until resolution, the condition stabilizes, the event is otherwise 
explained, or the patient is lost to follow-up. The investigator is responsible for ensuring that 
follow-up includes any supplemental investigations that may be indicated, in order to 
elucidate the nature and/or causality of the SAE as completely as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. The sponsor may request that the investigator perform or 
arrange for the conduct of supplemental measurements and/or evaluations. 
If a patient dies during participation in the study or during a specified follow-up period, the 
sponsor should be sent a copy of any post-mortem findings, including histopathology. 
New or updated information is to be recorded on the originally completed SAE report form, 
with all changes signed and dated by the investigator. 
The clinical research associate (CRA) will verify the original SAE report form against the 
source documents at the next monitoring visit. 


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7.2.1.8 
Adverse Events of Special Interest 
7.2.1.8.1 
Neutropenia 
Individuals taking deferiprone must be monitored for neutropenia, defined as a confirmed 
absolute neutrophil count (ANC) less than 1.5 x 109/L. Categories of neutropenia are as follows: 
Mild neutropenia  
A confirmed ANC < 1.5 x 109/L but ≥1.0 x 109/L 
Moderate neutropenia  
A confirmed ANC < 1.0 x 109/L but ≥ 0.5 x 109/L 
Severe neutropenia / agranulocytosis 
A confirmed ANC < 0.5 x 109/L 
For a case of neutropenia to be confirmed, there must be 2 consecutive counts, a maximum 
of 3 days apart, that are both less than the specified value. If the 2 counts are not in the same 
severity category, a third count will be required to determine the severity. If a patient has just 
a single ANC value less than 1.5 x 109/L, this is to be documented in the CRF as an AE of 
“decreased ANC”, but is not to be defined as neutropenia.  The investigator is to use judgment 
as to whether the decrease is clinically significant. 
In addition to having ANC monitored, participants will be advised to immediately report any 
symptoms indicative of infection such as fever (≥ 38.0°C), sore throat, and flu-like symptoms 
at any time during the study and for one week following the last dose. They will be provided 
with an emergency services card with contact information, and advised to carry it with them 
at all times. 
Depending of the severity of neutropenia, patients will either remain in or be withdrawn 
from the study. The management of different severities of neutropenia is described below. 
Mild neutropenia:  A patient who develops mild neutropenia is to interrupt treatment as 
soon as the neutropenia is confirmed, and ANC is to be monitored every 2 days until 
resolution. 
The patient should re-initiate treatment once the event is resolved, defined as 2 consecutive 
ANC ≥ 1.5 x 109/L. If ANC is still < 1.5 x 109/L after 14 days, the investigator is to 
do the following: 
• Withdraw patient from the study and monitor him/her until resolution of the event 
• Provide advice regarding protective isolation 
• Examine patient the same day (if possible), including drug history and physical 
examination 


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• Notify ApoPharma Inc. using the SAE form 
Moderate neutropenia:  A patient in whom a single ANC measurement <1.0 x 109/L but 
≥ 0.5 x 109/L is detected is to immediately stop treatment, without waiting for confirmation 
of the count, and a second measurement is to be done within 48 hours. If the second ANC 
is still < 1.0 x 109/L, the investigator is to do the following: 
• Withdraw patient permanently from the study and monitor ANC daily until resolution  
• Provide advice regarding protective isolation 
• Examine patient the same day (if possible), including drug history and physical 
examination 
• Notify ApoPharma Inc. using the SAE form 
Severe neutropenia/agranulocytosis:  A patient in whom a single ANC measurement 
< 0.5 x 109/L is detected is to immediately stop treatment, without waiting for confirmation 
of the count, and a second measurement is to be done within 48 hours. If the second ANC 
is still < 0.5 x 109/L, the patient is to be permanently withdrawn from the study, and ANC is 
to be monitored daily until resolution. The following procedures should be done by 
the investigator or the treating physician, as appropriate: 
• Provide protective isolation; if clinically indicated, admit patient to hospital and 
obtain vital signs every 4 hours 
• Examine the patient the same day, if possible, including drug history and physical 
examination 
• With the consent of the parent/guardian (or patient, if applicable), collect a blood 
sample to attempt to identify genetic or other biomarkers related to agranulocytosis 
• Notify ApoPharma Inc. using the SAE form. 
The following additional measures describe a suggested medical management and 
monitoring: 
• If possible, consider obtaining bone marrow aspirate for: 
o Histology 
o Progenitor culture 
o Frozen storage (1 mL sample) 
• If possible, consider obtaining bone marrow biopsy (minimum length 3 mm) 


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• Perform septic work-up including chest X-ray, blood, urine, and throat cultures 
• Obtain q4h temperatures from patient (monitored by family at home if patient is not 
in the hospital) 
• If warranted, administer granulocyte stimulating factors, such as G-CSF 10 μg/kg, on 
an in-patient basis if possible, beginning the same day that the ANC is confirmed as 
< 0.5 x 109/L; administer daily until ANC is > 1.5 x 109/L on 2 consecutive days 
• If ANC < 0.5 x 109/L for 7 days, repeat bone marrow biopsy and aspirate weekly 
during the period of agranulocytosis, if warranted 
7.2.1.8.2 
Infections 
If a patient develops fever (≥ 38.0°C) or any sign of infection during the study, study product 
must be interrupted immediately, and neutrophil count should be obtained and monitored 
more frequently; every 2 days if ANC <1.5 x 109/L.  Therapy can be re-initiated once all 
symptoms have been resolved, if the ANC is ≥1.5 x 109/L. 
7.2.2 
Laboratory Measurements 
Analyses will be performed at a central laboratory, with the exception of the weekly or 
biweekly hematology assessments which may be performed at a local laboratory.  
Investigators must interpret each report promptly (preferably within 24 hours) and must 
document their review by signing or initialing and dating it. Any laboratory values that fall 
outside a clinically accepted range, or that differ significantly from previous values, must be 
assessed for clinical significance, and must be marked by the investigator as either “CS” 
(clinically significant) or “NCS” (not clinically significant).  Any clinically significant 
abnormalities or changes that are not part of a larger medical condition that is already 
recorded must be further explained on the laboratory report and documented as an adverse 
event in the eCRF. 
Samples for laboratory safety assessments will be taken at the time points indicated below.  If 
a patient withdraws from the study, the End of Study procedures are to be performed at an 
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Hematology:  Hemoglobin, total WBC count, 
ANC, MCV, and platelet count 
Screening and weekly after start of dosing up 
to Month 6 visit, then biweekly until Month 12 
or early termination from the study 
Blood chemistry:  Total protein, GGT, glucose, 
bilirubin (total, direct, and indirect), AST, ALT, 
albumin, blood urea nitrogen, calcium, creatinine, 
total iron binding capacity, serum iron, zinc, and 
C-reactive protein (CRP) 
Screening and Months 1, 3, 6, 9, and 12 (or end 
of study)  
Urinalysis:  pH, specific gravity, glucose, protein, 
ketones, blood, and (if indicated by the dipstick 
results), sediment microscopy.  If there is blood in 
the urine or three or more “plus signs” for protein, 
samples must be sent for microscopy. 
Screening and Month 12 (or end of study) 
Serology: Hepatitis B, hepatitis C, HIV 
Screening 
Other: Prolactin 
Baseline and Month 12 
 
7.2.3 
Other Safety Measurements 
7.2.3.1 
Physical Examinations 
Physical examination will consist of an examination of head, ears, eyes, nose, throat and 
neck, respiratory system, cardiovascular system, gastrointestinal system, musculoskeletal 
system, neurological systems (central and peripheral), and skin, nails, hair, and scalp. 
Physical examination will be performed at screening and at Months 1, 3, 6, 9, and 12 (or end 
of study). Any clinically significant abnormalities noted prior to the screening visit will be 
recorded as medical history, any noted between screening and the first dose of study 
medication will be recorded as medical events, and any that are noted post–Dose 1 will be 
recorded as AEs. 
The growth parameters of body weight and height (or length, in infants not yet able to stand 
upright) which are separate safety endpoints, will be measured at each post-screening visit. 
7.2.3.2 
Vital Signs 
Resting heart rate, resting blood pressure, and body temperature will be taken.  (“Resting” 
implies that the child must be calm and not crying.) Blood pressure should always be 
measured after a minimum 3-minute resting period, and using the same arm each time if 
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Vital signs will be measured at each site visit. Clinically significant out-of-range values for 
vital signs will be reported as AEs (see Section 7.2.1.1). 
7.2.3.3 
Concomitant Medications 
The following information about prior and concomitant medications is to be recorded: 
• All medications used within the 3 months prior to baseline 
• Any medications that the patient continues to take during the study 
• Any medications that the patient starts to take during the study 
The name, dose, route, frequency, indication, and stop and start dates of all medications used 
during the study must be noted in the source documents and CRFs, as well as whether or not 
the medication was used to treat an AE. 
Information on concurrent medications will be obtained at every site visit. 
8 
STUDY COMMITTEES 
An independent Data Safety Monitoring Board (DSMB) will be established to monitor the 
safety of patients during the course of the study.  Members of the DSMB will be responsible 
for overseeing the conduct of the trial, and will be empowered to recommend stopping the 
trial if, in their judgment, continuation is not ethically acceptable on the grounds of safety. 
Death or a life-threatening event in any study patient which is deemed by either the 
investigator or the sponsor to be at least possibly related to the study medication will trigger 
an evaluation by the DSMB for recommending stopping the study.  Details will be provided 
in the DSMB charter. No study-stopping decision will be made without prior consultation 
with the sponsor. 
The operating model and the frequency of the interim safety review meetings will be laid out 
in the DSMB charter. The DSMB will be constituted prior to the enrolment of any patients 
into the study, and its members will be notified of any changes to the protocol or the study 
conduct. The DSMB will be informed of any substantive changes to the protocol that could 
affect patient safety prior to their implementation. 


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


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


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


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9.5 
Criteria for Evaluability of Patient Data 
Patients with protocol deviations will be assessed, and the deviations will be determined as 
minor or major before the randomization codes are broken. Patients with major protocol 
deviations will be excluded from the PP population. 
10 
DATA MANAGEMENT CONSIDERATIONS 
10.1 
Data Management 
The sponsor’s Clinical Data Management group will be responsible for the processing, 
coding, and validating/cleaning of clinical study data. Patient data will be entered by the 
investigator or designee using the electronic Case Report Forms (eCRFs) provided by the 
sponsor. Clinical data will be entered and stored into a validated database. The eCRFs will be 
provided in the Electronic Data Capture (EDC) system hosted by the sponsor or the sponsor’s 
vendor. Trained users will access the system via a secured gateway. Users will only be 
authorized to access data for their study site. Data will be entered directly into the system 
from the source documents in lieu of paper CRFs. On-line and off-line edit checks will be 
used to prompt the user to provide clean and accurate data. Clinical Data Management will 
code and monitor the data for accuracy. The data will be coded using the current versions of 
the MedDRA (Medical Dictionary for Regulatory Activities) and WHODD (World Health 
Organization Drug Dictionary) dictionaries. An electronic signature will be required of the 
investigator on the eCRFs, and the study monitor will verify the eCRFs on-line. 
Clinical data management activities will be performed by the sponsor in accordance with 
applicable standards and data cleaning procedures of the sponsor. An audit trail of all data 
processing will be stored in the database. The study biostatistician will be notified when all 
subject data are ready for analysis. 
Integrity of the database will be assured by limiting access through username/password 
combination and account control. Authorized access to the database will be provided to those 
individuals with an inspection/auditing function (e.g., Quality Assurance); “read only” access 
will be provided to avoid unintentional corruption of the database. 
The database will be backed up regularly. 
10.2 
Case Report Forms 
Electronic CRFs may be generated and/or printed at any time using the sponsor’s EDC 
system.  These eCRFs may be used for electronic submission data archiving or data review. 
A copy of the final patient-specific eCRFs will be sent to the clinical study sites after 
database freeze. 


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11 
MONITORING, AUDITS, AND INSPECTIONS 
11.1 
Source Documents 
The investigator or delegate will maintain adequately detailed source documents supporting 
significant source data for each patient. Source data are defined as all information in original 
records and/or certified copies of original records of clinical findings, observations, or other 
activities in a clinical study that are necessary for the reconstruction and evaluation of the 
study: e.g., medical history, physical examination, laboratory results, and x-ray or ultrasound 
results. The investigator will also retain all printouts/reports of tests or procedures performed 
as a requirement of the study. All source data that is printed on thermal paper, including 
laboratory printouts and ECG scans, must be photocopied, initialed, and dated as authentic 
equivalents to the thermal paper documents to enable extended retention time. 
The source documents must be available at the time of an audit; a site visit from the sponsor, 
sponsor representatives, or IRB/IEC; and a regulatory authority inspection. 
11.2 
Monitoring 
Monitoring of the investigational sites will be conducted by the sponsor or contracted to a 
qualified CRO.  The sponsor will determine the extent, nature, and frequency of on-site visits 
that are needed to ensure that the study is being conducted in accordance with the approved 
protocol (and any amendments), GCP, and all applicable regulatory requirements. At site 
visits, the monitor will, as required, assess the progress of the study; check that the study data 
chosen for verification are authentic, accurate, and complete; verify that the safety and rights 
of patients are being protected; compare original documents with data entered into the study 
database; and identify any issues and address their resolution. 
The investigator agrees to allow the monitor(s) direct access to all relevant documents, and to 
allocate his/her time and the time of staff to discuss findings, corrective actions and any 
relevant issues. In addition to contacts during the study, the monitor may also contact the site 
prior to the start of the study to discuss the protocol and data collection procedures with site 
personnel. 
11.3 
Audits and Inspections 
In accordance with the principles of ICH E6 Guideline for Good Clinical Practice, study sites 
may be inspected by regulatory authorities and/or audited by ApoPharma Quality 
Assurance (QA) or their third-party designates. The investigator and relevant clinical support 
staff will be required to be actively involved in audits and inspections, including staff 
interviews, and to make all necessary documentation and data available upon request. 


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During the course of the study and/or after it has been completed, one or more investigator 
site audits may be undertaken by auditors from ApoPharma QA or delegates. The purpose of 
these audits is to determine whether or not the study is being/has been conducted and monitored 
in compliance with recognized ICH E6 Guideline for Good Clinical Practice, protocol and 
approved amendment requirements, applicable local SOPs, and local laws and regulations. It 
is the responsibility of the investigator and site staff to promptly address, by coordinating 
with ApoPharma Clinical Research, any deficiencies stemming out of regulatory inspections 
and ApoPharma QA or third-party audits, and to ensure that agreed-upon corrective and 
preventive actions are implemented as soon as possible. 
An inspection by any regulatory authority may occur at any time during or after completion 
of the study. If an investigator is contacted by a regulatory authority for the purpose of 
conducting an inspection or to discuss any compliance issues, he/she is required to contact 
ApoPharma Clinical Research immediately. 
11.4 
Site Closure 
Upon completion of the study, the investigator must conduct the following activities, when 
applicable: 
• Return all study data and equipment to the sponsor 
• Complete data clarifications and/or resolutions 
• Ensure that drug accountability is completed and that unused medication is either 
destroyed or returned to the sponsor, as instructed 
• Review site study records for completeness 
 
The sponsor reserves the right to temporarily suspend or prematurely discontinue this study 
at any time and for any reason. If such action is taken, the sponsor will discuss this with the 
investigator (including the reasons for taking such action) at that time. The sponsor will 
promptly inform all other investigators conducting the study if the study is suspended or 
terminated for safety reasons, and will also inform the regulatory authorities of the 
suspension or termination of the study and the reason(s) for the action. If required by 
applicable regulations, the investigator must inform the IRB/IEC promptly and provide the 
reason for the suspension or termination. 
If the study is prematurely discontinued, all study data must be returned to the sponsor. In 
addition, the site must conduct final disposition of all unused study medication in accordance 
with the study procedures. 
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 


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11.5 
Retention of Records 
In accordance with applicable regulatory requirements, following closure of the study, the 
investigator will maintain a copy of all site study records in a safe and secure location. The 
sponsor will inform the investigator of the time period for retaining these records to comply 
with all applicable regulatory requirements. 
12 
ETHICAL CONSIDERATIONS 
12.1 
Informed Consent/Assent 
Prior to entering a patient into the study, the investigator or a designate must obtain written 
informed consent from the parent/guardian and/or where applicable a legally authorized 
representative, according to the sponsor’s procedures and as described in the Declaration of 
Helsinki, the Federal Food, Drug and Cosmetic Act, and U.S. applicable Code of Federal 
Regulations Title 21, Part 50.  In the case of patients who are capable of assenting, 
informed assent is to be obtained as well. The investigator will ensure that the 
parent/guardian/patient/legal representative is given full and adequate verbal and written 
information about the nature, purpose, and possible risks and benefits of the study, and is 
given ample opportunity to ask questions and to discuss the study with other family members. 
The investigator must make a conscientious effort to be fully satisfied that this individual has 
truly understood that for which the consent has been given. The parent/guardian/ legal 
representative must be notified that he/she is free to discontinue the patient’s participation in 
the study at any time, and that such withdrawal will not affect present or future care. In the 
case of a child who is capable of forming an opinion and assessing the study information, the 
investigator must ensure that this individual’s decision to not participate or to withdraw from 
the study will be respected even if consent is given by the legal representative. 
The sponsor will provide model versions of the informed consent/assent forms to the sites as 
separate documents. Each site may then revise these versions according to the requirements 
of its individual IRB/IEC. 
The parent/guardian and/or legal representative will sign and date the consent form prior to 
the first study intervention, and will be provided with a copy of the signed and dated ICF. 
Should a protocol amendment be made, the ICF may need to be revised to reflect the changes 
to the protocol. The investigator must then ensure that the revised ICF is signed by the parent/
guardian of all patients currently enrolled as well as those subsequently entered in the study. 
12.2 
Institutional Review Board/Independent Ethics Committee 
It is the investigator’s responsibility to ensure that the protocol is reviewed and approved by 
a properly constituted IRB or IEC (according to ICH GCP guidelines, Section 3.2). The 
IRB/IEC must also review and approve the site’s ICF and any other written information that 


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will be provided to patients, prior to any enrollment and the release of any advertisements for 
patient recruitment. Prior to the start of the study, the investigator or designee must forward 
copies of the IRB/IEC approval and the approved ICF materials to the sponsor. 
If it is necessary to amend either the protocol or the ICF during the study, the investigator 
will be responsible for ensuring that the IRB/IEC reviews these amended documents, and that 
IRB/IEC approval of the amended ICF is obtained before any additional patients are enrolled. 
Copies of the amended ICF and of the IRB/IEC’s approval of it must be forwarded to the 
sponsor as soon as they are available. 
12.3 
Patient Confidentiality 
To ensure that patients’ identities remain unknown to the sponsor, all data will be identified 
by patient ID. 
The investigator must inform the parent/guardian (and patient, if applicable) of the possibility 
that representatives from regulatory authorities and/or the sponsor may require access to 
hospital or clinic records for verification of data pertinent to the study, including their child’s 
medical history. 
The investigator is responsible for keeping a list of all patients entered, including patient 
code, patient ID, full name, and last known address. 
13 
REGULATORY REQUIREMENTS 
13.1 
Regulatory Obligations 
This trial is to be conducted in accordance with the Declaration of Helsinki, the ICH 
Consolidated Guidelines for Good Clinical Practice (GCP), FDA regulations, and any local 
regulatory requirements. The trial will not begin at any given site until the site has provided 
the following documents to the sponsor or its delegate, as per the ICH Consolidated 
Guideline on GCP (Section 8.2): 
1. Signed and dated IRB/IEC approval indicating review and approval of each the following 
documents: 
• Protocol and any amendments 
• Patient Informed Consent Form 
• Any written information to be provided to patients 
• Any advertisements for patient recruitment 
• Any compensation to patients 
2. Membership of the IRB/IEC, to document that the committee is constituted in agreement 
with GCP 


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3. Regulatory authority approval of the protocol 
4. Curriculum vitae of the investigator, sub-investigator(s), study coordinator, and 
pharmacist if applicable (updated within the last 2 years) 
5. For any laboratory evaluations performed at locations other than the study central 
laboratory: 
• Accreditation, certification, established quality control, or external quality assessment 
of the laboratory 
• Normal ranges or values for all laboratory test or procedures conducted during the trial 
6. Financial Disclosure Forms (where applicable) 
7. Regulatory Authority statement of investigator forms (e.g., FDA form 1572 where 
applicable) 
8. Signed Clinical Study Agreement 
13.2 
Amendments to the Protocol 
No amendments to this protocol will be made without consultation with and the agreement of 
the sponsor. Any amendment to the trial that seems indicated as the trial progresses must be 
discussed between the investigator and sponsor concurrently. If agreement is reached 
concerning the need for an amendment, this amendment will be produced in writing by the 
sponsor and will be made a formal part of the protocol. 
The investigator is responsible for ensuring that changes in the approved research project, 
during the period for which IRB/IEC approval has already been given, are not initiated 
without review and approval of the IRB/IEC except where necessary to eliminate apparent 
immediate hazards to the patients. 
14 
EARLY STUDY TERMINATION 
The sponsor reserves the right to discontinue this study at any time; or, an investigator may 
terminate it at his/her respective site following consultation with the sponsor. On 
discontinuance of the study, in its entirety or at a specific site, the investigator(s) will inform 
the study patients, the relevant clinical study staff, and the respective IRB/IEC of the 
discontinuance; provide them with the reasons for the discontinuance; and advise them in 
writing of any potential risks to the health of the study patients. It is the sponsor’s 
responsibility to report discontinuance of the study to regulatory agencies, to provide them 
with the reasons for the discontinuance, and to advise them in writing of any potential risks 
to the health of the study patients. 


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15 
CONFIDENTIALITY 
Each investigator, co-investigator, and institution’s representative must sign a confidentiality 
agreement, in form and content satisfactory to the sponsor, concerning the protection of the 
sponsor’s confidential and proprietary information disclosed to or obtained by the 
investigator during the course of the study. Otherwise, matters of confidentiality will be 
governed by the Clinical Study Agreement.  
16 
DISPUTE RESOLUTION  
Any legal dispute that may arise in respect of the interpretation of this protocol will be settled 
definitively in accordance with the applicable law in accordance with the terms and conditions 
set forth in the Clinical Study Agreement. 
17 
OWNERSHIP 
All data and records provided by the sponsor or its delegate or generated during the study 
(other than a patient’s medical records) and all inventions discovered in the course of 
conducting the study are the exclusive property of the sponsor. Details are provided in the 
Clinical Study Agreement completed by the sponsor and the investigator and/or site. 
18 
PUBLICATION 
Data derived from the study are the exclusive property of the sponsor, and the sponsor will 
be responsible for the primary publication of the data. 
Investigators may publish or otherwise disclose (e.g., present at a conference or use for 
instructional purposes) data from the trial solely in accordance with the terms and conditions 
described in the Clinical Study Agreement. 


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19 
REFERENCES 
1. Cappellini MD, Cohen A, Porter J, Taher A,Viprakasit V, Eds. Thalassaemia 
International Federation. Guidelines for the Management of Transfusion Dependent 
Thalassaemia (TDT)- 3rd edition, 2014. 
2. De Virgiliis S, Congia M, Frau F, Argiolu F, Diana G, Cucca F, Varsi A, Sanna G, Podda 
G, Fodde M, et al. Deferoxamine-induced growth retardation in patients with thalassemia 
major. J Pediatr. 1988 Oct;113(4):661-9. 
3. Berdoukas V, Nord A, Carson S, Puliyel M, Hofstra T, Wood J, Coates TD. Tissue iron 
evaluation in chronically transfused children shows significant levels of iron loading at a 
very young age. Am J Hematol. 2013 Nov;88(11):E283-5. 
4. al-Refaie FN, Wonke B, Wickens DG, Aydinok Y, Fielding A, Hoffbrand AV. Zinc 
concentration in patients with iron overload receiving oral iron chelator 1,2-dimethyl-3-
hydroxypyrid-4-one or desferrioxamine. J Clin Pathol. 1994 Jul;47(7):657-60. 
5. Liu ZD, Hider RC. Design of clinically useful iron(III)-selective chelators. Med Res Rev. 
2002 Jan;22(1):26-64. Review. 
6. Elalfy MS, Sari TT, Lee CL, Tricta F, El-Beshlawy A. The safety, tolerability, and 
efficacy of a liquid formulation of deferiprone in young children with transfusional iron 
overload. J Pediatr Hematol Oncol. 2010 Nov;32(8):601-5. 
7. Devos D, Moreau C, Devedjian JC, Kluza J, Petrault M, Laloux C, Jonneaux A, 
Ryckewaert G, Garçon G, Rouaix N, Duhamel A, Jissendi P, Dujardin K, Auger F, 
Ravasi L, Hopes L, Grolez G, Firdaus W, Sablonnière B, Strubi-Vuillaume I, Zahr N, 
Destée A, Corvol JC, Pöltl D, Leist M, Rose C, Defebvre L, Marchetti P, Cabantchik ZI, 
Bordet R. Targeting chelatable iron as a therapeutic modality in Parkinson's disease. 
Antioxid Redox Signal. 2014 Jul 10;21(2):195-210. 
8. Boddaert N, Le Quan Sang KH, Rötig A, Leroy-Willig A, Gallet S, Brunelle F, Sidi D, 
Thalabard JC, Munnich A, Cabantchik ZI. Selective iron chelation in Friedreich ataxia: 
Biologic and clinical implications. Blood. 2007 Jul 1;110(1):401-8. 
9. Breuer W, Ermers MJ, Pootrakul P, Abramov A, Hershko C, Cabantchik ZI. 
Desferrioxamine-chelatable iron, a component of serum non-transferrin-bound iron, used 
for assessing chelation therapy. Blood. 2001 Feb 1;97(3):792-8. 
10. Evans RW Kong X, Hider RC. Iron mobilization from transferrin by therapeutic iron 
chelating agents. Biochim Biophys Acta. 2012 Mar;1820(3):282-90. 
11. Sohn YS, Breuer W, Munnich A, Cabantchik ZI. Redistribution of accumulated cell iron: 
a modality of chelation with therapeutic implications. Blood. 2008 Feb 1;111(3):1690-9. 


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12. Sohn YS, Mitterstiller AM, Breuer W, Weiss G, Cabantchik ZI. Rescuing iron-
overloaded macrophages by conservative relocation of the accumulated metal. Br J 
Pharmacol. 2011 Sep;164(2b):406-18. 
13. Elalfy MS, Adly A, Hazza N, Awed H, Salam MT, Helal B, Berdoukas V, Tricta F.  A 
randomized trial on the safety and efficacy of early start of iron chelation therapy with 
deferiprone in newly diagnosed children with transfusion dependent thalassemia. Poster 
presentation at the 58th Annual Meeting & Exposition for the American Society of 
Hematology, November 2016, San Diego. 
14. Coates TD. Unchanneling cardiac iron in humans. Blood. 2016 Sep 22;128(12):1538-40. 
15. ApoPharma Inc. Ferriprox® (Deferiprone) - Summary of Product Characteristics (EU). 
2012. 
16. ApoPharma Inc. Ferriprox® (Deferiprone)  - United States Prescribing Information 
(USPI): https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021825lbl.pdf 
17. Agarwal MB, Gupte SS, Viswanathan C, Vasandani D, Ramanathan J, Desai N, Puniyani 
RR, Chhablani AT. Long-term assessment of efficacy and safety of L1, an oral iron 
chelator, in transfusion dependent thalassaemia: Indian trial. Br J Haematol. 1992 
Oct;82(2):460-6. 
18. Galanello R. Deferiprone in the treatment of transfusion-dependent thalassemia: a review 
and perspective. Ther Clin Risk Manag. 2007 Oct;3(5):795-805. 
 

SAP_001.pdf: 
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Statistical Analysis Plan: Protocol LA55-0417 
 
 
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STATISTICAL ANALYSIS PLAN 
 
 
LA55-0417 
 
 
Safety and efficacy of early-start deferiprone treatment in infants and young 
children newly diagnosed with transfusion-dependent beta thalassemia 
 
 
 
Final Version 1 
 
24 SEP 2020 
 
 
 
 
 
 




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Table of Contents 
 
 
Title page.......................................................................................................................1 
 
Approvals ......................................................................................................................2 
 
List of Abbreviations ...................................................................................................5 
1. Introduction ..................................................................................................................8 
2. Study Objectives...........................................................................................................8 
2.1 
Primary Objective ..............................................................................................8 
2.2 
Secondary Objective ..........................................................................................8 
3. Study Design .................................................................................................................8 
3.1 
Description of Study Design ..............................................................................8 
3.2 
Number of Patients .............................................................................................9 
3.3 
Study Procedures ................................................................................................9 
4. Measurements and Evaluations ................................................................................15 
4.1 
Efficacy Measurements ....................................................................................15 
4.1.1 
Serum Ferritin (μg/L) ...........................................................................15 
4.1.2 
Transferrin Saturation (%) ...................................................................15 
4.1.3 
Labile Plasma Iron (µM) ......................................................................15 
4.2 
Safety Measurements .......................................................................................16 
4.2.1 
Medical Events, Adverse Events, and Serious Adverse Events ..........16 
4.2.2 
Laboratory Measurements ...................................................................16 
4.2.3 
Physical Examinations .........................................................................17 
4.2.4 
Vital Signs ............................................................................................17 
4.2.5 
Concomitant Medications ....................................................................17 
5. Statistical Analysis .....................................................................................................18 
5.1 
Study Populations .............................................................................................18 
5.1.1 
Intent-to-Treat Population ....................................................................18 
5.1.2 
Per Protocol Population .......................................................................18 
5.1.3 
Safety Population .................................................................................18 
5.2 
Efficacy Endpoints ...........................................................................................18 
5.2.1 
Primary Efficacy Endpoint ..................................................................18 
5.2.2 
Secondary Efficacy Endpoints .............................................................19 


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5.3 
Safety Endpoints ...............................................................................................19 
5.4 
Patient Disposition and Drug Exposure .........................................................19 
5.5 
Patient Characteristics .....................................................................................19 
5.6 
Analysis of Efficacy ..........................................................................................20 
5.7 
Analysis of Safety .............................................................................................22 
5.7.1 
AEs and SAEs ......................................................................................22 
5.7.2 
Number of discontinuations due to AEs ..............................................23 
5.7.3 
Hematology and biochemistry .............................................................23 
5.7.4 
Urinalysis .............................................................................................23 
5.7.5 
Vital signs ............................................................................................23 
5.7.6 
Prior and concomitant medications ......................................................24 
5.7.7 
Time to withdrawal ..............................................................................24 
5.7.8 
Height and weight ................................................................................24 
SUMMARY TABLES AND FIGURES .........................................................................25 
14.1 
Patient disposition, demographics, and baseline data ..................................25 
14.2 
Efficacy analyses ...............................................................................................25 
14.2.1 
 Serum ferritin (µg/L) ........................................................................25 
14.2.2 
 Labile plasma iron (µM)...................................................................25 
14.2.3 
 Transferrin saturation (%) ..............................................................26 
14.3 
Safety analyses ..................................................................................................26 
14.3.1 
 Adverse events ...................................................................................26 
14.3.2 
 Vital signs ...........................................................................................27 
14.3.3 
 Height .................................................................................................27 
14.3.4 
 Weight ................................................................................................27 
14.3.5 
 Concomitant medications .................................................................28 
14.3.6 
 Laboratory data ................................................................................28 
14.3.6.1 Hematology ..........................................................................................28 
14.3.6.2 Biochemistry ........................................................................................28 
14.3.7 
 Prolactin .............................................................................................28 
14.4 
Other analyses ..................................................................................................28 
14.2 
Efficacy ..............................................................................................................29 
14.3 
Safety .................................................................................................................29 


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14.3.1 
 Hematology ........................................................................................29 
14.3.2 
 Biochemistry ......................................................................................29 
DATA LISTINGS ............................................................................................................30 
TABLE SHELLS .............................................................................................................32 
14.1 
Patient disposition, demographics, and baseline data ..................................33 
14.2 
Efficacy Analyses ..............................................................................................39 
14.2.1 
 Serum Ferritin (µg/L) .......................................................................39 
14.2.2 
 Labile Plasma Iron (µM) ..................................................................43 
14.2.3 
 Transferrin Saturation (%) .............................................................47 
14.3 
Safety analyses ..................................................................................................51 
14.3.1 
 Adverse events ...................................................................................51 
14.3.2 
 Vital signs ...........................................................................................54 
14.3.3 
 Height .................................................................................................56 
14.3.4 
 Weight ................................................................................................59 
14.3.5 
 Concomitant medications .................................................................62 
14.3.6 
 Laboratory data ................................................................................63 
14.3.6.1 Hematology ..........................................................................................63 
14.3.6.2 Biochemistry ........................................................................................66 
14.3.7 
 Prolactin .............................................................................................70 
14.4 
Other analyses ..................................................................................................71 


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List of Abbreviations 
 
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
ANCOVA 
analysis of covariance 
AST 
aspartate transaminase 
CS 
clinically significant 
CI 
confidence interval 
CRA 
clinical research associate 
CRF 
case report form 
CRO 
contract research organization 
CRP 
C-reactive protein 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
US Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
HIV 
human immunodeficiency virus 
HPLC 
high performance liquid chromatography 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
LPI 
labile plasma iron 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
not clinically significant 
NTBI 
non-transferrin-bound iron 
PP 
per protocol 
PT 
preferred term 
RBC 
red blood cell 
SADR 
serious adverse drug reaction 


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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SF 
serum ferritin 
SOC 
system organ class 
t.i.d 
three times a day 
TSAT 
transferrin saturation 
ULN 
upper limit normal 
WBC 
white blood cell 
WHO 
World Health Organization 
 
 
 


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1. Introduction 
This document outlines the statistical analysis plan (SAP) for clinical study LA55-0417, 
titled “Safety and efficacy of early-start deferiprone treatment in infants and young children 
newly diagnosed with transfusion-dependent beta thalassemia”. 
The SAP details the statistical methods to be used in analyzing the data from the study, and 
presents the mock-up tables that will be included in the clinical study report. When the SAP 
and the clinical study protocol are different with respect to the planned analyses, the SAP is to 
supersede the clinical study protocol. 
The standards used to compile the clinical data will be based on the Study Data Tabulation 
Model v1.4, SDTM implementation guide v 3.2 as well as controlled terminology v 2017-06-
30 from the Clinical Data Interchange Standards Consortium (CDISC). Tables, listings and 
figures will be programmed using data from the SDTM datasets. 
2. Study Objectives 
2.1 
Primary Objective  
To evaluate the effect of early treatment with deferiprone on lessening progressive iron 
overload in infants and young children with transfusion-dependent β-thalassemia. 
2.2 
Secondary Objective 
To evaluate the safety and tolerability of early treatment with deferiprone in infants and 
young children with transfusion-dependent β-thalassemia.  
3. Study Design 
3.1 
Description of Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled study in infants and 
young children newly diagnosed with transfusion-dependent β-thalassemia.  Patients start on a 
red blood cell (RBC) transfusion regimen designed to maintain a hemoglobin level > 9 g/dL, 
but still have a serum ferritin level well below the threshold that current treatment guidelines 
state should be reached before iron chelation therapy can begin. 
Screening is conducted within 14 days prior to the start of dosing. At baseline, eligible 
participants are randomized in a 1:1 ratio to receive either deferiprone oral solution 
80 mg/mL or matching placebo.  Visits are scheduled approximately monthly (every 
30 ±10 days) for the determination of levels of serum ferritin (SF), labile plasma iron (LPI), 
and transferrin saturation (TSAT), and for assessments of safety that include determination of 
liver enzymes (ALT and AST) and growth measurements. 
Dosage begins at 25 mg/kg/day, divided into 3 doses (t.i.d.), and is increased to 
50 mg/kg/day (divided t.i.d.) after 2 weeks. After that, it is increased to 75 mg/kg/day 
(divided t.i.d.) for patients who meet either of the following criteria: 


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• An SF value ≥ 800 μg/L (but still below 1000 μg/L) and/or an LPI value ≥ 0.6 µM 
and/or a TSAT value ≥ 60% at 2 consecutive visits, or 
• An increasing trend in any of the above 3 measures (SF, LPI, and/or TSAT) at 
3 consecutive visits, regardless of value 
If a single occurrence of any of the following is detected at any time, treatment is interrupted: 
• SF value below the lower reference range for the child’s age  
• Mild neutropenia, defined as an absolute neutrophil count (ANC) < 1.5 x 109/L but 
≥ 1.0 x 109/L  
• Fever or other signs of infection, prior to confirmation that ANC is ≥ 1.5 x 109/L 
As these parameters are known to fluctuate, the assessment is repeated as soon as possible to 
verify that treatment interruption is necessary.  Treatment is re-initiated after the abnormally 
low SF or ANC level is recovered, or when the fever or infection resolves or is determined 
to not be indicative of neutropenia.  
If moderate neutropenia (ANC < 1.0 x 109/L) is confirmed, the patient is withdrawn from 
the study. 
Patients remain in the study for 12 months or until their SF level is found to be ≥ 1000 μg/L at 2 
consecutive visits, whichever comes first. Since SF level may be impacted by the presence of 
infection, it must additionally be verified that the child has had no signs of infection in the 
previous 7 days, including the day of the visit, and that the level of C-reactive protein (CRP) 
is no greater than 20% higher than the normal range for the patient’s age. If there are signs of 
infection and/or the CRP level is above this threshold, the SF level must be checked again a 
minimum of one week later. (Note:  If an investigator  has valid reason to believe that an SF 
level ≥ 1000 μg/L may be attributable to infection even if this is not indicated by the CRP 
result, SF may be rechecked once more a minimum of one week later.) 
3.2 
Number of Patients 
A planned total of 64 patients are to be enrolled in the study, 32 in each arm.  
3.3 
Study Procedures 
The procedures and assessments to be conducted at each study visit are shown in Table 1. 
Remote patient visits due to the COVID-19 
Due to the COVID-19 pandemic, some patients were unable to attend the site due to 
transportation disruptions, site restrictions/availability and to maintain social distancing. In 
cases where patients are unable to attend the site due to COVID-19 restrictions, remote 
patient visits have been performed as follows: 


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• Patients were contacted and verbally consented to having their visits performed 
remotely, including having lab samples collected from Al Mokhtabar /Prodia 
phlebotomists at their home (if Al Mokhtabar /Prodia cannot continue at home visits, 
the patients will have to attend the closest local branch), and IP delivered, and 
completed patient diary cards and used/unused IP from the last visit collected by the 
courier. This discussion occurred before any aspect of remote visits occurred and was 
documented in the source. 
• The patient was called by the PI/delegated site staff for their remote visit. These calls 
must be documented in the source.  
• Recommendation that the site try to use the later dates within the visit windows to 
have visits. 
• Sample collection: weekly, bi-weekly and monthly samples (CBCs, biochemistry, 
LPI, serum ferritin, C-reactive protein, transferrin saturation and CRP if applicable) 
were collected by AM/Prodia phlebotomists at the patients’ homes and/or local 
branch. 
It is noted that:  
• The morning dose should be taken AFTER these samples are collected. Therefore, the 
samples should have been collected in the morning.  
• Review of the results within 24 hours of receipt is still in effect. 
• If a transfusion was scheduled on the day of the visit, the blood samples for serum 
ferritin, LPI, and TSAT must have been collected before the transfusion was 
performed. 
• Dose escalations and withdrawal criteria remained unchanged. 
• LPI samples were collected in both Indonesia and Egypt as per protocol, however, 
shipments were suspended due to Covid-19 and the third-party analysis laboratory, 
Radbound, had closed until 28 APR 2020. 
• PI/site staff reviewed and followed up on: Transfusion history, AE/SAEs and 
concomitant medication, exposure and dosing. 
• All study reminders were communicated to the patients. 
• If possible M12 and/or Early Termination Visits (within 30 days of the last dose) 
were conducted on-site. These have more time sensitive collections for prolactin. 
• If possible, patients were asked to perform the following assessments and share the 
information over the phone during the visit: Patient’s body temperature taken with the 
thermometers provided at study start; Measurement height/length: using string and/or 
tape measure. 
 


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IP and patient diary card: 
• IP was called from IVRS by the site staff using the weight from the last on-site visit. 
• Only a 1-month supply was provided to the patient as per protocol. 
• IP accountability was maintained via the logs as per usual. 
• IP and blank patient diary card were collected by courier arranged by EPx/Sydna and 
transported to the patients’ home: 
• The patients: verbally consented to allowing IP to be delivered, understanding that 
their address will be shared with the courier; and that they must sign for the IP upon 
receipt. 
• The courier used temperature monitoring devices (TMD), which were stopped when 
IP is delivered.  
• The patients did not begin the new medication until the TMD readings were 
downloaded and verified by Chiesi Canada Corp.  
• The site printed off the IVRS report for IP dispensation and wrote the TMD used for 
each shipment. This is to be filed in the patient binder.  
• Used and unused IP and the patient diary card from the previous visit were returned 
to the site via courier. The site reviewed the compliance and patient diary card for 
AEs/SAEs, concomitant medications and exposure and contacted the patient if 
needed to clarify any information recorded. 
The sites must clearly document which patients were participating in remote visits, and 
which assessments were not collected as per protocol. Potential protocol deviations following 
the above process must be documented and can include heart rate and blood pressure not 
collected, physical exam not performed, visits out of window due to Covid-19 and weight 
(weight from the previous on-site visit to be used for dispensation/dosing if  unable to be 
collected during remote visit). 
Once Covid-19 restrictions are lifted, on-site study visits are to resume. 
 


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Table 1 
Table of study procedures 
 
Day -14 
to 0 
(Screenin
g) 
Month 
0,  
Day 0 
(Baselin
e) 
Month 
1 1 
Month 
2 
Month 
3 
Month 
4 
Mont
h 5 
Month 
6 
Month 
7 
Month 
8 
Month 
9 
Month 
10 
Month 
11 
Month 
12 or 
End 
of 
Study 
2 
Informed consent/ 
assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
V 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 3 
X 
X 
Weekly (±3 days) after start of dosing up to Month 6 
Biweekly (±3 days) until termination from the study 
Blood chemistry 4,5 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
DNA testing (if 
applicable) 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 5,7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serology 8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 5 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Labile plasma iron 
11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Chiesi Canada Corp.                                                                         
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Day -14 
to 0 
(Screenin
g) 
Month 
0,  
Day 0 
(Baselin
e) 
Month 
1 1 
Month 
2 
Month 
3 
Month 
4 
Mont
h 5 
Month 
6 
Month 
7 
Month 
8 
Month 
9 
Month 
10 
Month 
11 
Month 
12 or 
End 
of 
Study 
2 
Transferrin 
saturation 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum ferritin 11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prolactin 12 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Dispense study 
medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Provide diary card 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing 13 
 
Three times daily from baseline until termination from the study 
Review and 
collect diary card 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect study 
medication 
containers 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess treatment 
compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior & 
concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical events 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
Throughout the study after start of dosing 
Transfusion 
history 
Throughout the study 


Chiesi Canada Corp.                                                                         
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V: 
Verify 
  
1 
Visits are scheduled every 30 days (± 10 days). 
2 
Patients terminate from the study at Month 12 or when they have been found to have a serum ferritin level ≥ 1000 μg/L at 2 consecutive visits, whichever 
comes first. 
3 
Hematology:  Hemoglobin, total WBC count, ANC, MCV, and platelet count. 
4 
Blood chemistry:  Total protein, GGT, glucose, bilirubin (total, direct, and indirect), AST, ALT, albumin, blood urea nitrogen, calcium, creatinine, total 
iron binding capacity, serum iron, zinc. and CRP. 
5 
The results obtained at screening for blood chemistry, physical examination, and urinalysis are considered to be the baseline results.  These tests are not 
repeated at Day 0. 
6 
A blood sample for DNA testing is to be taken only if DNA confirmation of a diagnosis of beta-thalassemia is not available at the time of screening.  
7 
Urinalysis:  pH, specific gravity, glucose, protein, ketones, blood, and (if indicated by the dipstick results), sediment microscopy.  If there is blood in the 
urine or three or more “plus signs” for protein, samples must be sent for microscopy. 
8  
Hepatitis B, hepatitis C, and HIV. 
9  
Heart rate, blood pressure, and body temperature.  At the time of these measurements, the child must be calm and not crying. 
10 
For infants not yet able to stand upright, stature is measured as recumbent length. 
11 
For TSAT and SF, the values obtained at the screening visit (not those obtained at baseline) are used for the eligibility criteria. 
12 
Blood samples for the assessment of prolactin are taken pre-dose and at + 1.5 h +/- 5 minutes post-dose. The second set of samples are taken only from 
patients who are still in the study at Month 12; they are not taken from patients who are terminated before that time. 
13 
Dosing:  Deferiprone oral solution 80 mg/mL or matching placebo solution. 
 
 


Chiesi Canada Corp.                                                                         
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4. Measurements and Evaluations 
4.1 
Efficacy Measurements 
Efficacy is measured by monitoring levels of serum ferritin, transferrin saturation, and labile 
plasma iron. 
4.1.1 
Serum Ferritin (μg/L) 
Ferritin is a protein that stores iron in a non-toxic form, transports it to areas where it is required, and 
releases it in a controlled manner, thereby acting as a buffer against iron deficiency and iron 
overload. It is mainly found in tissues, but small amounts are measured in the serum, where it can 
serve as an indirect but easily measurable marker of the total amount of iron stored in the body.  
(Drawbacks of using it as a marker include lack of specificity, as disorders other than iron overload 
can cause large amounts of ferritin to be released into the circulation, and inter-patient variability.)  
Levels of serum ferritin above 1000 ng/mL are often considered to be associated with iron toxicity.  
In young children who have only recently begun an RBC transfusion regimen, it takes some time for 
this level to be reached, but in the absence of chelation it inevitably is reached. 
Serum ferritin is measured at each visit, and the time to reach a level ≥ 1000 μg/L will be compared 
between the treatment arms. Patient is to be withdrawn from the study when they attain a serum 
ferritin level ≥ 1000 μg/L at 2 consecutive visits provided that the child has had no signs of infection 
in the previous 7 days and that CRP level is not greater than 20% higher than the normal range for 
the patient’s age. 
4.1.2 
Transferrin Saturation (%)  
Transferrin is a protein that combines with iron and transports it to where iron is required.  When its 
capacity to bind incoming iron is exceeded, excess iron circulates as free non-transferrin-bound iron 
(NTBI) and is taken up by tissues where it can cause cell and organ damage. Transferrin saturation, 
defined as the percentage of the iron-binding sites of transferrin that are already occupied, is easily 
measured and hence serves as a marker for NTBI.  High levels of transferrin saturation are associated 
with iron toxicity.  As this measure is highly variable, the blood samples for its assessment are to be 
collected at approximately the same time of day and at approximately the same amount of time after 
the last dose of study medication, in an attempt to decrease variability as much as possible. 
Transferrin saturation is measured at each visit, and the time to reach a level ≥ 60% will be compared 
between the treatment arms. 
4.1.3 
Labile Plasma Iron (µM) 
Labile plasma iron is a component of NTBI, and is considered the most toxic form of iron since it 
acts as a catalyst in the formation of harmful free hydroxyl radicals which can damage cellular DNA, 


Chiesi Canada Corp.                                                                         
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proteins, and membrane lipids. High levels of this form of iron may be found in individuals with 
conditions of iron overload.  As this measure is highly variable, the blood samples for its assessment 
are to be collected at approximately the same time of day and at approximately the same amount of 
time after the last dose of study medication, in an attempt to decrease variability as much as possible. 
Labile plasma iron is measured at each visit, and the time to reach a level ≥ 0.6 µM will be compared 
between the treatment arms. 
4.2 
Safety Measurements 
4.2.1 
Medical Events, Adverse Events, and Serious Adverse Events 
Refer to section 7.2.1 of the LA55-0417 study protocol for the definitions of medical events, adverse 
events, and serious adverse events.  
4.2.2 
Laboratory Measurements 
Analyses are performed at a central laboratory, with the exception of the weekly or biweekly 
hematology assessments which may be performed at a local laboratory.  Investigators interpret each 
report promptly (preferably within 24 hours) and document their review by signing or initialing and 
dating it. Any laboratory values that fall outside a clinically accepted range, or that differ 
significantly from previous values, are assessed for clinical significance, and are marked by the 
investigator as either “CS” (clinically significant) or “NCS” (not clinically significant).  Any 
clinically significant abnormalities or changes that are not part of a larger medical condition that is 
already recorded are further explained on the laboratory report and documented as an adverse event 
in the eCRF. 
Samples for laboratory safety assessments are taken at the time points indicated below.  If a patient 
withdraws from the study, the End of Study procedures are to be performed at an early termination 
visit. 
Hematology:  Hemoglobin, total WBC count, 
ANC, MCV, and platelet count 
Screening and weekly after start of dosing up 
to Month 6 visit, then biweekly until Month 12 
or early termination from the study 
Blood chemistry:  Total protein, GGT, fasting 
glucose, bilirubin (total, direct, and indirect), 
AST, ALT, albumin, blood urea nitrogen, 
calcium, creatinine, total iron binding capacity, 
serum iron, zinc, and C-reactive protein (CRP) 
Screening and Months 1, 3, 6, 9, and 12 (or 
end of study)  


Chiesi Canada Corp.                                                                         
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Urinalysis:  pH, specific gravity, glucose, protein, 
ketones, blood, and (if indicated by the dipstick 
results), sediment microscopy.  If there is blood in 
the urine or three or more “plus signs” for protein, 
samples must be sent for microscopy. 
Screening and Month 12 (or end of study) 
Serology: Hepatitis B, hepatitis C, HIV 
Screening 
Other: Prolactin 
Baseline and Month 12 
 
4.2.3 
Physical Examinations 
Physical examination consists of an examination of head, ears, eyes, nose, throat and neck, 
respiratory system, cardiovascular system, gastrointestinal system, musculoskeletal system, 
neurological systems (central and peripheral), and skin, nails, hair, and scalp. It is to be performed at 
screening and at Months 1, 3, 6, 9, and 12 (or end of study). Any clinically significant abnormalities 
noted prior to the screening visit are recorded as medical history, any noted between screening and 
the first dose of study medication is recorded as medical events, and any that are noted post–Dose 1 
are recorded as AEs. 
The growth parameters of body weight and height (or length, in infants not yet able to stand upright) 
which are separate safety endpoints, are measured at each post-screening visit. 
4.2.4 
Vital Signs 
Resting heart rate, resting blood pressure, and body temperature are taken.  (“Resting” implies that 
the child must be calm and not crying.) Blood pressure should always be measured after a minimum 
3-minute resting period, and using the same arm each time if possible. Systolic and diastolic blood 
pressures are to be recorded from one measurement. 
Vital signs are measured at each site visit. Clinically significant out-of-range values for vital signs are 
reported as AEs. 
4.2.5 
Concomitant Medications 
The following information about prior and concomitant medications are recorded: 
• All medications used within the 3 months prior to baseline 
• Any medications that the patient continues to take during the study 
• Any medications that the patient starts to take during the study 


Chiesi Canada Corp.                                                                         
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The name, dose, route, frequency, indication, and stop and start dates of all medications used during 
the study must be noted in the source documents and CRFs, as well as whether or not the medication 
was used to treat an AE. 
Information on concurrent medications are obtained at every site visit. 
5. Statistical Analysis 
A two-sided p-value of 0.05 will be used as the significance level for the determination of statistical 
significance in all statistical tests. 
All statistical analyses of efficacy and safety data will be performed using SAS (version 9.4 or 
higher) on the Windows operating system.  
5.1 
Study Populations 
5.1.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will be composed of patients who were randomized, have received at 
least one dose of study medication, and have had at least one post-baseline measurement on the efficacy 
variables.  All efficacy endpoints will be analyzed for the ITT population, which represents the 
primary analysis population. 
5.1.2 
Per Protocol Population 
The per protocol (PP) population will represent the secondary analysis population, and will be 
composed of the same patients as in the intent-to-treat (ITT) population without major protocol 
deviations. Patients with major protocol deviation(s) will be determined before the database is 
locked. The efficacy endpoints will be analyzed for this population as well. 
5.1.3 
Safety Population 
The safety population will be composed of patients who have received at least one dose of study 
medication.  
5.2 
Efficacy Endpoints 
5.2.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percentage of patients who still have a serum ferritin level < 1000 μg/L 
at Month 12. 


Chiesi Canada Corp.                                                                         
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5.2.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• The percentage of patients whose serum ferritin level is still less than 1000 μg/L at each visit 
• The percentage of patients whose LPI value is still less than 0.6 µM at each visit 
• The percentage of patients whose TSAT value is still less than 60% at each visit 
• Time to reach a serum ferritin level ≥ 1000 μg/L (Note: a patient is to be withdrawn from the 
study only if the repeated serum ferritin level is ≥ 1000 μg/L.)  
• Time to reach an LPI value ≥ 0.6 µM 
• Time to reach a TSAT value ≥ 60% 
5.3 
Safety Endpoints 
The safety endpoints are: 
• Adverse events (AEs):  Frequency, intensity, time to onset, duration, and relatedness to study 
drug 
• Serious adverse events (SAEs):  Frequency, intensity, time to onset, duration, and relatedness to 
study drug 
• Number of discontinuations due to AEs 
• Growth parameters:  Weight, height, and height velocity, as classified using the Z-score system 
• Change in prolactin level from baseline to Month 12 
5.4 
Patient Disposition and Drug Exposure 
The numbers of patients who were screened, randomized, exposed to the study medication, who 
completed the study, and who withdrew from the study (along with reasons for withdrawals) will be 
presented. 
5.5 
Patient Characteristics 
Patient characteristics at baseline, including demographics, will be summarized with descriptive 
statistics for continuous variables and with frequency tables for categorical variables. Medical history 
will be summarized using the Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 
or higher. 


Chiesi Canada Corp.                                                                         
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5.6 
Analysis of Efficacy 
The percentage of patients who have not reached levels of LPI ≥ 0.6 µM, TSAT ≥ 60%, or SF ≥ 1000 
μg/L will be compared between the two treatment groups at each monthly time point as well as at the 
end of study, using the Fisher’s exact test. (Note: the repeated SF value will be used to determine this 
for those patients whose SF is ≥ 1000 μg/L.)  
The effect of baseline value on each of the 3 efficacy endpoints will be examined in a covariate 
analysis. As an example for serum ferritin, the following SAS code of MIXED procedure will be 
used to produce the differences in Least Squares (LS) Mean of change in serum ferritin at Months 1, 
2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 between deferiprone and placebo groups and the corresponding 
95% confidence intervals.  
 
proc mixed data=sf; 
  class patient base_sf treat month; 
  model sf_change = base_sf treat month treat*month / 
  noint solution ddfm=kr; 
  repeated month / Patient=patient(treat) type=ar(1); 
  lsmeans treat*month; 
estimate 'Deferiprone - Placebo at Month 1'   
          treat 1 -1  
          treat*month  1 0 0 0 0 0 0 0 0 0 0 0 
                      -1 0 0 0 0 0 0 0 0 0 0 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 2'   
          treat 1 -1   
          treat*month  0  1 0 0 0 0 0 0 0 0 0 0 
                       0 -1 0 0 0 0 0 0 0 0 0 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 3'   
          treat 1 -1  
          treat*month  0 0  1 0 0 0 0 0 0 0 0 0 
                       0 0 -1 0 0 0 0 0 0 0 0 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 4'   
          treat 1 -1   
          treat*month  0 0 0  1 0 0 0 0 0 0 0 0 
                       0 0 0 -1 0 0 0 0 0 0 0 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 5'   
          treat 1 -1  
          treat*month  0 0 0 0  1 0 0 0 0 0 0 0  
                       0 0 0 0 -1 0 0 0 0 0 0 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 6'   
          treat 1 -1  
          treat*month  0 0 0 0 0  1 0 0 0 0 0 0 
                       0 0 0 0 0 -1 0 0 0 0 0 0/ cl alpha=0.05; 
 
 


Chiesi Canada Corp.                                                                         
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estimate 'Deferiprone - Placebo at Month 7'   
          treat 1 -1  
          treat*month  0 0 0 0 0 0  1 0 0 0 0 0 
                       0 0 0 0 0 0 -1 0 0 0 0 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 8'   
          treat 1 -1  
          treat*month  0 0 0 0 0 0 0  1 0 0 0 0 
                       0 0 0 0 0 0 0 -1 0 0 0 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 9'   
          treat 1 -1  
          treat*month  0 0 0 0 0 0 0 0  1 0 0 0 
                       0 0 0 0 0 0 0 0 -1 0 0 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 10'   
          treat 1 -1  
          treat*month  0 0 0 0 0 0 0 0 0  1 0 0 
                       0 0 0 0 0 0 0 0 0 -1 0 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 11’   
          treat 1 -1  
          treat*month  0 0 0 0 0 0 0 0 0 0  1 0 
                       0 0 0 0 0 0 0 0 0 0 -1 0/ cl alpha=0.05; 
estimate 'Deferiprone - Placebo at Month 12'   
          treat 1 -1  
          treat*month  0 0 0 0 0 0 0 0 0 0 0  1 
                       0 0 0 0 0 0 0 0 0 0 0 -1/ cl alpha=0.05; 
run; 
 
A Kaplan-Meier survival curve for the time to reach a serum ferritin level ≥ 1000 μg/L, an LPI value 
≥ 0.6 µM, or a TSAT value ≥ 60% will be generated for the two treatment groups. Log-rank test will 
be used for comparing the two survival curves for each of the 3 efficacy endpoints.  
As an example, for serum ferritin, the following SAS code of LIFETEST procedure will be used to 
compare the two survival curves. A variable status is the censoring indicator. A status of 1 indicates 
an event time when a serum ferritin level reaches ≥ 1000 μg/L and a status of 0 indicates the event of 
serum ferritin level ≥ 1000 μg/L has not occurred by the end of the study. 
proc lifetest data=sf method=km plot=(s) graphics; 
   time month*status(0); 
   strata treat; 
run; 
Trend analysis over time for LPI, TSAT, and SF measures will be performed to compare the rate of 
change per month in these measures between the two treatment groups. As an example, for serum 
ferritin, the following SAS code of MIXED procedure will be used to compare the two slopes 
between the two treatment groups:  
 


Chiesi Canada Corp.                                                                         
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proc mixed data=sf; 
  class treat patient; 
  model sf = treat month treat*month / noint solution; 
  repeated / type=ar(1) Patient=patient(treat); 
  estimate 'Slope for deferiprone' month 1 treat*month 1 0; 
  estimate 'Slope for placebo’     month 1 treat*month 0 1; 
  estimate 'Slope for deferiprone minus placebo' treat*month 1 -1;  
run; 
 
5.7 
Analysis of Safety 
Descriptive statistics (mean, standard deviation, minimum, and maximum) will be produced for 
continuous variables, and frequency tables will be produced for discrete variables by treatment group. 
Summaries of adverse events and serious adverse events will be produced by treatment group. Shift 
tables will be generated for comparing the screening/baseline values and end of study values of the 
relevant measures. 
The following safety data will be summarized by treatment group: 
• Adverse events (AEs), adverse drug reactions (ADRs), serious adverse events (SAEs), and 
serious adverse drug reactions (SADRs)  
• Number of discontinuations due to AEs 
• Hematology assessments 
• Biochemistry assessments 
• Urinalysis 
• Vital signs 
• Prior and concomitant medications 
Prolactin is measured at baseline and Month 12. The change in prolactin level from baseline to 
Month 12 will be compared between the two treatment groups using an ANCOVA model with 
baseline value as a covariate and treatment as the main factor. 
5.7.1 
AEs and SAEs 
Adverse events (AEs) are coded using MedDRA version 23.0 or higher. In counting the number of 
patients who experienced each AE, any patients who experienced the same AE multiple times will be 
counted only once for the corresponding preferred term (PT). Similarly, any patients who experienced 
multiple AEs within the same system organ class (SOC) will be counted only once for that SOC. AEs 
will be tabulated alphabetically by SOC; and within each SOC, the PTs will be presented 
alphabetically. In tables that present the incidence of AEs by severity, seriousness, and relation to study 


Chiesi Canada Corp.                                                                         
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medication, any patients with multiple events coded to a given  PT or SOC will be counted only once 
for that PT or SOC according to the most severe event, the most serious event, or the event with the 
closest relationship to study medication. 
AEs will be summarized for the total number of AEs, the total number and percent of patients who 
experienced at least one AE, and the total number and percent of patients who experienced an AE 
within each SOC (and each PT within an SOC). A p-value comparing the percentages of each AE 
among treatment groups will be calculated by using Fisher’s exact test.  
The incidences of AEs, SAEs, adverse drug reactions (ADRs), and serious ADRs (SADRs) will be 
tabulated by treatment group.  The relationship to study medication for AEs will be tabulated by 
treatment group.   
A listing of SAEs and a listing of withdrawals due to AEs with time to withdrawal will be produced. 
Any deaths will be listed separately and discussed in narratives. 
5.7.2 
Number of discontinuations due to AEs 
The percent of patients who have been withdrawn for the study due to AEs will be compared between 
the two treatment groups using Fisher’s exact test. 
5.7.3 
Hematology and biochemistry 
Hematology and biochemistry data will be summarized by using descriptive statistics at each 
assessment by treatment group. Change from baseline to each follow-up assessment will also be 
summarized by using descriptive statistics by treatment group. The data listings of patients who have 
abnormal values as well as patients who have clinically significant values will be produced for each 
parameter. The number (%) of patients who have ALT > 2 x ULN, 3 x ULN, and 5 x ULN during the 
study will be compared between the two treatment groups. 
5.7.4 
Urinalysis 
Urinalysis assessments consist of pH, specific gravity, glucose, protein, ketones, blood, and (if 
indicated by the dipstick results), sediment microscopy.  If there is blood in the urine or three or more 
“plus signs” for protein, samples must be sent for microscopy. Clinically significant laboratory values 
for urinalysis are reported as AEs.  
5.7.5 
Vital signs 
Temperature, resting heart rate, and diastolic and systolic blood pressures 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.   


Chiesi Canada Corp.                                                                         
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5.7.6 
Prior and concomitant medications 
Prior and concomitant medications are summarized using the WHO Drug Dictionary (WHO-DD) 
version B2 (March 2018). 
5.7.7 
Time to withdrawal  
 
A Kaplan-Meier survival curve for the time to be withdrawn from the study will be generated for the 
two treatment groups. The Log-rank test will be used for comparing the two survival curves.  
5.7.8 
Height and weight  
For height (cm) and weight (kg), the change from baseline to last assessment will be compared 
between the two treatment groups using an ANCOVA model with baseline value as a covariate and 
treatment as the main factor. The rate of change in height will be assessed using regression analysis. 
Child growth standards for 2007 are available at the WHO website 
https://www.who.int/childgrowth/standards/en/.. This site provides mean and standard deviation for 
height and weight from 0 to 5 years old by day for males and females. It has mean and standard 
deviation for height from 5 to 19 years old by month for male and female and for weight from 5 to 10 
years old by month for males and females. 
Z scores will be calculated by matching sex and age in days until 5 years old and by matching sex 
and age in months from 5 to 10 years old as follows: 
(Observed data from LA55 – Mean from WHO data) / (Standard deviation from WHO data) 
The change from baseline to last assessment in Z score will be compared between the two treatment 
groups using an ANCOVA model with baseline value as a covariate and treatment as the main factor. 
 
Impact of COVID-19 on the primary efficacy endpoints 
Sensitivity analyses may be performed, if warranted, by excluding data that might have been 
impacted by COVID-19.  
 


Chiesi Canada Corp.                                                                         
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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 
Patient disposition, demographics, and baseline data 
Table 14.1.1 Patient disposition 
Table 14.1.2 Number of patients by study site  
Table 14.1.3 Number of patients in safety, ITT, and PP populations  
Table 14.1.4 Reasons for not completing the study 
Table 14.1.5 Demographics data  
Table 14.1.6 Medical history  
Table 14.1.7 Serum ferritin, LPI, and TSAT at baseline 
14.2 
Efficacy analyses 
14.2.1  
Serum ferritin (µg/L)  
Table 14.2.1.1 Serum ferritin (µg/L) at each assessment – ITT population 
Table 14.2.1.1a Serum ferritin (µg/L) at each assessment – PP population 
Table 14.2.1.2 Change in serum ferritin (µg/L) from baseline at each follow-up assessment – ITT population 
Table 14.2.1.2a Change in serum ferritin (µg/L) from baseline at each follow-up assessment – PP population 
Table 14.2.1.3 LS Means for change in serum ferritin (µg/L) from ANCOVA model at each follow-up 
assessment – ITT population  
Table 14.2.1.3a LS Means for change in serum ferritin (µg/L) from ANCOVA model at each follow-up 
assessment – ITT population  
Table 14.2.1.4 Trend analysis for serum ferritin (µg/L) over time – ITT population 
Table 14.2.1.4a Trend analysis for serum ferritin (µg/L) over time – PP population 
Table 14.2.1.5 Percent of patients who had serum ferritin < 1000 µg/L at each assessment – ITT population 
Table 14.2.1.5a Percent of patients who had serum ferritin < 1000 µg/L at each assessment – PP population 
14.2.2  
Labile plasma iron (µM) 
Table 14.2.2.1 LPI (µM) at each assessment – ITT population 


Chiesi Canada Corp.                                                                         
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Table 14.2.2.1a LPI (µM) at each assessment – PP population 
Table 14.2.2.2 Change in LPI (µM) from baseline at each follow-up assessment – ITT population 
Table 14.2.2.2a Change in LPI (µM) from baseline at each follow-up assessment – PP population 
Table 14.2.2.3 LS Means for change in LPI (µM) from ANCOVA model at each follow-up assessment – ITT 
population  
Table 14.2.2.3a LS Means for change in LPI (µM) from ANCOVA model at each follow-up assessment – PP 
population  
Table 14.2.2.4 Trend analysis for LPI (µM) over time – ITT population 
Table 14.2.2.4a Trend analysis for LPI (µM) over time – PP population 
Table 14.2.2.5 Percent of patients who had LPI < 0.6 µM  at each assessment – ITT population 
Table 14.2.2.5a Percent of patients who had LPI < 0.6 µM  at each assessment – PP population 
 
14.2.3  
Transferrin saturation (%)  
Table 14.2.3.1 TSAT (%) at each assessment – ITT population 
Table 14.2.3.1a TSAT (%) at each assessment – PP population 
Table 14.2.3.2 Change in TSAT (%) from baseline at each follow-up assessment – ITT population 
Table 14.2.3.2a Change in TSAT (%) from baseline at each follow-up assessment – PP population 
Table 14.2.3.3 LS Means for change in TSAT (%) from ANCOVA model at each follow-up assessment – ITT 
population  
Table 14.2.3.3a LS Means for change in TSAT (%) from ANCOVA model at each follow-up assessment – PP 
population  
Table 14.2.3.4 Trend analysis for TSAT (%) over time – ITT population 
Table 14.2.3.4a Trend analysis for TSAT (%) over time – PP population 
Table 14.2.3.5 Percent of patients who had TSAT < 60% at each assessment – ITT population 
Table 14.2.3.5a Percent of patients who had TSAT < 60% at each assessment – PP population 
 
14.3 
Safety analyses 
14.3.1  
Adverse events 
Table 14.3.1.1 Overall summary of adverse events 
Table 14.3.1.2 Adverse events 


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Table 14.3.1.3 Most common Adverse Events >= 5 percent 
Table 14.3.1.4 Adverse events with the maximum severity/intensity 
Table 14.3.1.5 Adverse drug reactions  
Table 14.3.1.6 Most common Adverse drug reactions >= 5 percent 
Table 14.3.1.7 Adverse drug reaction with the maximum severity/intensity 
Table 14.3.1.8 Serious adverse events  
Table 14.3.1.9 Serious adverse events with the maximum severity/intensity 
Table 14.3.1.10 Serious adverse drug reactions  
Table 14.3.1.11 Serious adverse drug reactions with the maximum severity/intensity 
Table 14.3.1.12 Adverse events by relatedness to study medication 
Table 14.3.1.13 Adverse events – event count and rate 
14.3.2  
Vital signs 
Table 14.3.2.1 Temperature (C) Heart rate at each assessment  
Table 14.3.2.2 Change in temperature (C) from baseline at each follow-up assessment  
Table 14.3.2.3 Heart rate (bpm) at each assessment  
Table 14.3.2.4 Change in heart rate (bpm) from baseline to each follow-up assessment  
Table 14.3.2.5 Diastolic blood pressure (mmHg) at each assessment  
Table 14.3.2.6 Change in diastolic blood pressure (mmHg) from baseline at each follow-up assessment   
Table 14.3.2.7 Systolic blood pressure (mmHg) at each assessment  
Table 14.3.2.8 Change in systolic blood pressure (mmHg) from baseline at each follow-up assessment  
14.3.3  
Height  
Table 14.3.3.1 Height (cm) at each assessment  
Table 14.3.3.2 Change in height (cm) from baseline to at each follow-up assessment  
Table 14.3.3.3 LS Means for change in height (cm) from ANCOVA model at Month 12  
Table 14.3.3.4 Trend analysis for height (cm) over time  
Table 14.3.3.5 Z score analysis for height (cm)  
14.3.4  
Weight 
Table 14.3.4.1 Weight (kg) at each assessment  
Table 14.3.4.2 Change in weight (kg) from baseline to at each follow-up assessment 
Table 14.3.4.3 LS Means for change in weight (kg) from ANCOVA model at Month 12   


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Table 14.3.4.4 Trend analysis for weight (kg) over time  
Table 14.3.4.5 Z score analysis for weight (kg)  
14.3.5  
Concomitant medications 
Table 14.3.4.1 Concomitant medications 
14.3.6  
Laboratory data 
14.3.6.1 Hematology 
Table 14.3.6.1.1 Hematology data at each assessment 
Table 14.3.6.1.2 Change in hematology data from baseline to each follow-up assessment 
Table 14.3.6.1.3 Shift table for hematology data: deferiprone group  
Table 14.3.6.1.4 Shift table for hematology data: placebo group  
 
14.3.6.2 Biochemistry 
Table 14.3.6.2.1 Biochemistry data at each assessment  
Table 14.3.6.2.2 Change in biochemistry data from baseline to at each follow-up assessment  
Table 14.3.6.2.3 Shift table for biochemistry data: deferiprone group  
Table 14.3.6.2.4 Shift table for biochemistry data: placebo group  
Table 14.2.6.2.5 Percent of patients who had ALT > 2 x ULN, 3 x ULN, or 5 x ULN during the study 
Table 14.2.6.2.6 Percent of patients who had AST > 2 x ULN, 3 x ULN, or 5 x ULN during the study 
14.3.7  
Prolactin 
Table 14.3.7.1 Prolactin at each assessment 
Table 14.3.7.2 Change in prolactin from pre-dose to Month 12 
Table 14.3.7.3 LS Means of change in prolactin from pre-dose to Month 12 from the ANCOVA model 
14.4 
Other analyses 
Table 14.4.1 Compliance (%) at each assessment 
Table 14.4.2 Overall mean of transfusional iron input (mg/kg/day) during the study 
Table 14.4.3 Overall mean of total daily dose (mg/kg/day) during the study 
Table 14.1.4 Patient exposure to study medication 
Table 14.1.5 Duration of study drug exposure 


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FIGURES 
14.2 
Efficacy 
Figure 14.2.1 Mean line graph for serum ferritin over time 
Figure 14.2.2 Mean line graph for LPI over time 
Figure 14.2.3 Mean line graph for TSAT over time 
Figure 14.2.4 Mean line graph for change from baseline in serum ferritin over time 
Figure 14.2.5 Mean line graph for change from baseline in LPI over time 
Figure 14.2.6 Mean line graph for change from baseline in TSAT over time 
Figure 14.2.7 Kaplan-Meier survival curve for the time to reach serum ferritin level ≥ 1000 μg/L 
Figure 14.2.8 Kaplan-Meier survival curve for the time to reach LPI value ≥ 0.6 µM 
Figure 14.2.9 Kaplan-Meier survival curve for the time to reach TSAT value ≥ 60%  
14.3 
Safety 
14.3.1  
Hematology 
Figure 14.3.1.1 Mean line graph for the hematology data over visit  
Figure 14.3.1.2 Proportion of patients with abnormal hematology data at each assessment  
Figure 14.3.1.3 ANC graphs for patients with neutropenia 
Figure 14.3.1.4 ANC graphs for patients with agranulocytosis   
14.3.2  
Biochemistry 
Figure 14.3.2.1 Mean line graph for the biochemistry data over visit 
Figure 14.3.2.2 Proportion of patients with abnormal biochemistry data at each assessment  
 
16.1.9 Documents of Statistical Methods 
SAS output 16.1.9.1 Kaplan-Meier survival analysis for the time to reach serum ferritin level ≥ 1000 μg/L 
SAS output 16.1.9.2 Kaplan-Meier survival analysis for the time to reach LPI value ≥ 0.6 µM 
SAS output 16.1.9.3 Kaplan-Meier survival analysis for the time to reach TSAT value ≥ 60%  
 SAS output 16.1.9.4 Kaplan-Meier survival analysis for the time to be withdrawn from the study 
 


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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. 
 
16.2.1 Discontinued patients 
             16.2.1.1 Listing of disposition 
16.2.1.2 Listing of withdrawals due to AEs 
 16.2.2 Protocol deviation 
16.2.2.1 Listing of assessed protocol deviations 
16.2.2.2 Listing of protocol deviations - monitoring plan (Appendix C) 
 16.2.3 Patients excluded from efficacy  
16.2.3.1 Listing of assignment of patients to analysis sets 
16.2.4 Demographic data 
            16.2.4.1 Listing of demographics 
 16.2.5 Compliance_Drug concentration data 
16.2.5.1 Listing of compliance 
 16.2.6 Individual efficacy response data 
16.2.6.1 Listing of labile plasma iron (LPI) 
16.2.6.2 Listing of serum ferritin (SF) 
16.2.6.3 Listing of transferrin saturation (TSAT) 
 16.2.7 Adverse events 
16.2.7.1 Listing of medical events 
16.2.7.2 Listing of adverse events 
16.2.7.3 Listing of serious adverse events 
 16.2.8 Individual lab measurements by patient 
16.2.8.1 Listing of hematology 
16.2.8.1a Listing of patients who have had abnormal values in hematology 
16.2.8.1b Listing of patients who have had clinically significant values in hematology 
16.2.8.2 Listing of urinalysis 
16.2.8.3 Listing of serology 
16.2.8.4 Listing of biochemistry 
16.2.8.4a Listing of patients who have had abnormal values in biochemistry 


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16.2.8.4b Listing of patients who have had clinically significant values in biochemistry 
16.2.8.5 Listing of prolactin 
  
16.2.9 Other measurements 
16.2.9.1 Listing of informed consent / Assent form 
16.2.9.2 Listing of primary diagnosis 
16.2.9.3 Listing of medical history 
16.2.9.4 Listing of randomization 
16.2.9.5 Listing of vital signs 
16.2.9.6 Listing of physical examination 
16.2.9.7 Listing of transfusion 
16.2.9.8 Listing of exposure 
16.2.9.9 Listing of concomitant medications 


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TABLE SHELLS 
The following table shells provide a framework for the display of data from this study. These tables may not 
be designed exactly as shown in the shells, but are intended to reflect the general layout of the data that will be 
included in the clinical study report. 
Note that ‘c’ in the table shells indicates an alphanumeric character and ‘x’ indicates a number from 0 to 9.  


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14.1 
Patient disposition, demographics, and baseline data 
Table 14.1.1 Patient disposition 
 
Deferiprone 
Placebo 
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: 16.2.1.1 Listing of disposition 
 
  
Table 14.1.2 Number of patients by study site 
Country 
Site 
Deferiprone 
Placebo 
Total 
Egypt 
003 
xx 
xx 
xx 
 
004 
xx 
xx 
xx 
 
005 
xx 
xx 
xx 
Indonesia 
006 
xx 
xx 
xx 
 
Total 
xx 
xx 
xx 
Data source: 16.2.4.1 Listing of demographics 
 
 


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Table 14.1.3 Number of patients in safety, ITT, and PP populations 
 
 
Deferiprone 
Placebo 
Safety population 
 
xx 
xx 
 
ITT population 
Serum ferritin 
xx 
xx 
LPI  
xx 
xx 
TSAT 
xx 
xx 
 
PP population 
Serum ferritin 
xx 
xx 
LPI 
xx 
xx 
TSAT 
xx 
xx 
Data source: 16.2.3.1 Listing of assignment of patients to analysis sets 
 
 


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Table 14.1.4 Reasons for not completing the study  
 
 
Deferiprone 
Placebo 
Total 
n (%) 
n (%) 
n (%) 
N 
 
xx (100) 
xx (100) 
xx (100) 
Reason: 
Detail 
 
 
 
    Adverse event 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
   Withdrawal by 
parent/guardian 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
   Lost to follow-up 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
   Physician decision 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
   Protocol deviation 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Lack of efficacy 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
   Other 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Ccccc 
xx (xx) 
xx (xx) 
xx (xx) 
Total 
 
xx (xx) 
xx (xx) 
xx (xx) 
Data source:  16.2.1.1 Listing of disposition


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Table 14.1.5 Demographics data   
 
Deferiprone 
Placebo 
Total 
 
N 
xx 
xx 
xx 
p-value§ 
Age (years): 
  Mean  
  SD 
  Minimum 
  Maximum 
 
xx.x  
xx.x 
 xx.x 
 xx.x 
 
xx.x  
xx.x 
 xx.x 
 xx.x 
 
xx.x  
xx.x 
 xx.x 
 xx.x 
0.xxxx 
Sex: n (%)  
   Female 
   Male 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
0.xxxx 
Ethnic Origin: n (%) 
   Hispanic/Latino  
   Not Hispanic/Latino 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
 
xx (xx) 
xx (xx) 
0.xxxx 
Racial Origin: n (%) 
 Asian 
American Indian or Alaska Native 
Black or African American 
Native Hawaiian or Other Pacific Islander 
White 
Other   
 
 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx(xx) 
 
 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx(xx) 
 
 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx(xx) 
0.xxxx 
 
 
 
 
 
 
§T-test for age;  Fisher’s exact test for sex, ethnic origin, and racial origin      
Data source: 16.2.4.1 Listing of demographics 
 
 
 


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Table 14.1.6 Medical history  
 
Deferiprone 
Placebo 
Total 
N 
xx 
xx 
xx 
Illness/Event by 
MedDRA Primary 
System Organ Class and 
Preferred Term 
Resolved 
    n (%) 
ongoing   
    n (%) 
resolved   
    n (%) 
ongoing 
    n (%) 
resolved   
    n (%) 
ongoing 
   n (%) 
Cccccc 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 Cccccc 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 Cccccc 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
 Cccccc 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
xx (xx) 
Data source: 16.2.9.3 Listing of medical history 
 
 
 


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Table 14.1.7 Serum ferritin, LPI, and TSAT at baseline 
 
Deferiprone 
Placebo 
 
N 
xx 
xx 
 
 
Mean ± SD 
(Min, Max) 
Mean ± SD 
(Min, Max) 
P-value (t-test) 
Serum Ferritin 
(µg/L) 
xxxx ± xxxx 
(xxxx, xxxx) 
xxxx ± xxxx 
(xxxx, xxxx) 
0.xxxx 
LPI (µM) 
x.xx ± x.xx 
(x.xx, x.xx) 
x.xx ± x.xx 
(x.xx, x.xx) 
0.xxxx 
TSAT (%) 
xx ± xx 
(xx, xx) 
xx ± xx 
(xx, xx) 
0.xxxx 
Data source: 16.2.6.2 Listing of serum ferritin (SF) 
                     16.2.6.1 Listing of labile plasma iron (LPI) 
                     16.2.6.3 Listing of transferrin saturation (TSAT) 
 
 
 
Table 14.1.8 Serology data at baseline  
Positive result 
Deferiprone 
Placebo 
P-value 
(Fisher's exact test) 
Hepatitis B 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Hepatitis C 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
HIV 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Data source: 16.2.8.3 Listing of serology 
 


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14.2 
Efficacy Analyses 
14.2.1  
Serum Ferritin (µg/L)  
Table 14.2.1.1 Serum ferritin (µg/L) at each assessment – ITT population 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 1  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 2  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 3  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 4  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 5  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 6  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 7  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 8  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 9  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 10  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 11  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 12  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Data source: 16.2.6.2 Listing of serum ferritin (SF) 
Note: Similar Table 14.2.1.1a will be made for PP population  


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Table 14.2.1.2 Change in serum ferritin (µg/L) from baseline to each follow-up assessment – ITT 
population 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Month 1  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 2  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 3  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 4  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 5  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 6  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 7  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 8  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 9  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 10  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 11  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Month 12  
xx 
xxxx ± xxxx (xxxx,xxxx) 
xx 
xxxx ± xxxx 
(xxxx,xxxx) 
0.xxxx 
Data source: 16.2.6.2 Listing of serum ferritin (SF) 
Note: Similar Table 14.2.1.2a will be made for PP population  
 
 


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Table 14.2.1.3 LS Means for change in serum ferritin (µg/L) from ANCOVA model at each follow-
up assessment – ITT population  
 
Deferiprone 
Placebo 
Deferiprone  
Minus Placebo 
95% C.I. 
N 
xx 
xx 
xx 
 
 
LS Mean ± SE 
LS Mean ± SE 
LS Mean ± SE 
 
Month 1 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 2 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 3 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 4 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 5 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 6 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 7 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 8 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 9 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 10 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 11 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Month 12 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Data source: 16.2.6.2 Listing of serum ferritin (SF) 
Note: Similar Table 14.2.1.3a will be made for PP population  
 
 
 


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Table 14.2.1.4 Trend analysis for serum ferritin (µg/L) over time – ITT population 
 
 
 
 
 
Rate of change per 
month 
Deferiprone 
Placebo 
      Deferiprone             
minus Placebo 
       P-value 
     Mean ± SE 
xxxx ± xxxx 
xxxx ± xxxx 
xxxx ± xxxx  
         0.xxxx 
Data source: 16.2.6.2 Listing of serum ferritin (SF) 
Note: Similar Table 14.2.1.4a will be made for PP population  
 
 
Table 14.2.1.5 Percent of patients who had serum ferritin < 1000 µg/L at each assessment – ITT 
population 
 
Deferiprone 
Placebo 
P-value 
(Fisher's exact test) 
Baseline 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 1 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 2 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 3 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 4 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 5 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 6 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 7 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 8 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 9 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 10 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 11 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 12 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Data source: 16.2.6.2 Listing of serum ferritin (SF) 
Note: Similar Table 14.2.1.5a will be made for PP population  
 
 
 


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14.2.2  
Labile Plasma Iron (µM) 
Table 14.2.2.1 LPI (µM) each assessment – ITT population 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 1  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 2  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 3  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 4  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 5  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 6  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 7  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 8  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 9  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 10  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 11  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 12  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Data source: 16.2.6.1 Listing of labile plasma iron (LPI) 
Note: Similar Table 14.2.2.1a will be made for PP population  
 
 


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Table 14.2.2.2 Change in LPI (µM) from baseline to each follow-up assessment – ITT population 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Month 1  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 2  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 3  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 4  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 5  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 6  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 7  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 8  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 9  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 10  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 11  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Month 12  
xx 
x.xx ± x.xx (x.xx, x.xx) 
xx 
x.xx ± x.xx (x.xx, x.xx) 
0.xxxx 
Data source: 16.2.6.1 Listing of labile plasma iron (LPI) 
Note: Similar Table 14.2.2.1a will be made for PP population  
 
 
 
 


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Table 14.2.2.3 LS Means for change in LPI (µM) from ANCOVA model at each follow-up 
assessment – ITT population  
 
Deferiprone 
Placebo 
Deferiprone  
Minus Placebo 
95% C.I. 
N 
xx 
xx 
xx 
 
 
LS Mean ± SE 
LS Mean ± SE 
LS Mean ± SE 
 
Month 1 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 2 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 3 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 4 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 5 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 6 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 7 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 8 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 9 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 10 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 11 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Month 12 
x.xx ± x.xx  
x.xx ± x,xx 
x.xx ± x.xx 
(x.xx, x.xx) 
Data source: 16.2.6.1 Listing of labile plasma iron (LPI) 
Note: Similar Table 14.2.2.3a will be made for PP population  
 
 
 


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Table 14.2.2.4 Trend analysis for LPI (µM) over time – ITT population 
 
 
 
 
 
Rate of change per 
month 
Deferiprone 
Placebo 
      Deferiprone             
minus Placebo 
       P-value 
      Mean ± SE 
x.xx ± x.xx 
x.xx ± x.xx 
x.xx ± x.xx  
         0.xxxx 
Data source: 16.2.6.1 Listing of labile plasma iron (LPI) 
Note: Similar Table 14.2.2.4a will be made for PP population  
 
 
Table 14.2.2.5 Percent of patients who had LPI < 0.6 µM at each assessment – ITT population 
 
Deferiprone 
Placebo 
P-value 
(Fisher's exact test) 
Baseline 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 1 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 2 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 3 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 4 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 5 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 6 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 7 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 8 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 9 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 10 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 11 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 12 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Data source: 16.2.6.1 Listing of labile plasma iron (LPI) 
Note: Similar Table 14.2.2.5a will be made for PP population  
 
 
 


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14.2.3  
Transferrin Saturation (%)  
Table 14.2.3.1 TSAT (%) each assessment – ITT population 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 1  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 2  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 3  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 4  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 5  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 6  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 7  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 8  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 9  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 10  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 11  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 12  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Data source: 16.2.6.3 Listing of transferrin saturation (TSAT) 
Note: Similar Table 14.2.3.1a will be made for PP population  
 
 


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Table 14.2.3.2 Change in TSAT (%) from baseline to each follow-up assessment – ITT population 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Month 1  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 2  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 3  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 4  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 5  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 6  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 7  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 8  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 9  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 10  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 11  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Month 12  
xx 
xx.x ± xx.x (xx.x, xx.x) 
xx 
xx.x ± xx.x (xx.x, x.xx) 
0.xxxx 
Data source: 16.2.6.3 Listing of transferrin saturation (TSAT) 
Note: Similar Table 14.2.3.2a will be made for PP population  
 
 


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Table 14.2.3.3 LS Means for change in TSAT (%) from ANCOVA model at each follow-up 
assessment – ITT population  
 
Deferiprone 
Placebo 
Deferiprone  
Minus Placebo 
95% C.I. 
N 
xx 
xx 
xx 
 
 
LS Mean ± SE 
LS Mean ± SE 
LS Mean ± SE 
 
Month 1 
xx.x ± xx.x  
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Month 2 
xx.x ± xx.x  
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Month 3 
xx.x ± xx.x  
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Month 4 
xx.x ± xx.x  
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Month 5 
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 7 
xx.x ± xx.x  
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Month 8 
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 10 
xx.x ± xx.x  
xx.x ± xx.x 
xx.x ± xx.x 
(xx.x, xx.x) 
Month 11 
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: 16.2.6.3 Listing of transferrin saturation (TSAT) 
Note: Similar Table 14.2.3.3a will be made for PP population  
 
 
 


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Table 14.2.3.4 Trend analysis for TSAT (%) over time – ITT population 
 
 
 
 
 
Rate of change per 
month 
Deferiprone 
Placebo 
      Deferiprone             
minus Placebo 
       P-value 
      Mean ± SE 
xx.x ± xx.x 
xx.x ± xx.x 
xx.x ± xx.x  
         0.xxxx 
Data source: 16.2.6.3 Listing of transferrin saturation (TSAT) 
Note: Similar Table 14.2.3.4a will be made for PP population  
 
Table 14.2.3.5 Percent of patients who had TSAT < 60% at each assessment – ITT population 
 
Deferiprone 
Placebo 
P-value 
(Fisher's exact test) 
Baseline 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 1 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 2 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 3 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 4 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 5 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 6 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 7 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 8 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 9 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 10 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 11 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Month 12 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
Data source: 16.2.6.3 Listing of transferrin saturation (TSAT) 
Note: Similar Table 14.2.3.5a will be made for PP population  
 
 
 
 


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14.3 
Safety analyses 
14.3.1  
Adverse events 
Table 14.3.1.1 Overall summary of adverse events  
 
Deferiprone 
Placebo 
 
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: 16.2.7.2 Listing of adverse events  
 
 


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Table14.3.1.2 Adverse events  
  
  
  
  
Deferiprone  
(N=xx) 
Placebo 
(N=xx) 
  
Fisher’s  
exact test 
 
 
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 
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 
……... 
……... 
……... 
……... 
Data source: 16.2.7.2 Listing of adverse events  
Note: Similar Table 14.3.1.2 to Table 14.3.1.11 will be produced.       
 


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Table 14.3.1.12 Adverse events by causality 
Deferiprone 
(N=xx) 
Placebo 
(N=xx) 
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: 16.2.7.2 Listing of adverse events  
 
Table 14.3.1.13 Adverse events – event count and rate 
 
  
  
  
Deferiprone  
(N=xx) 
Placebo 
(N=xx) 
Exposure (Patient-years):x.xx 
Exposure (Patient-years):x.xx 
Total Events (Rate/100 patient- years): 
xx (x.xx) 
Total Events (Rate/100 patient- years): 
xx (x.xx) 
System Organ Class 
  Preferred Term 
xx (x.xx) 
(x.xx) 
CCCCCC 
xx (x.xx) 
xx (x.xx) 
  Cccccc 
xx (x.xx) 
xx (x.xx) 
  Cccccc 
xx (x.xx) 
xx (x.xx) 
  Cccccc 
xx (x.xx) 
xx (x.xx) 
……... 
……... 
……... 
Data source: 16.2.7.2 Listing of adverse events  
 
 
 


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14.3.2  
Vital signs 
Table 14.3.2.1 Temperature (C) at each assessment  
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 1  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 2  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 3  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 4  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 5  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 6  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 7  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 8  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 9  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 10  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 11  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 12  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Data source: 16.2.9.5 Listing of vital signs 
Note: Similar Tables 14.3.2.3, 14.3.2.5, and 14.3.2.7 for heart rate, diastolic blood pressure, and 
systolic blood pressure will be produced, respectively. 
 
 
 
 


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Table 14.3.2.2 Change in temperature (C) from baseline to at each follow-up assessment  
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Month 1  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 2  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 3  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 4  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 5  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 6  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 7  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 8  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 9  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 10  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 11  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 12  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Data source: 16.2.9.5 Listing of vital signs  
Note: Similar Tables 14.3.2.4, 14.3.2.6, 14.3.2.8 for heart rate, diastolic, and systolic blood pressure 
will be produced, respectively. 
 
 
 


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14.3.3  
Height 
Table 14.3.3.1 Height (cm) at each assessment 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 1  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 2  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 3  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 4  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 5  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 6  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 7  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 8  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 9  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 10  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 11  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 12  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Data source: 16.2.9.5 Listing of vital signs  
 
 


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Table 14.3.3.2 Change in height (cm) from baseline to at each follow-up assessment 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Month 1  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 2  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 3  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 4  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 5  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 6  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 7  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 8  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 9  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 10  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 11  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 12  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Data source: 16.2.9.5 Listing of vital signs  
 


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Table 14.3.3.3 LS Means for change in height (cm) from ANCOVA model at Month 12  
 
Deferiprone 
Placebo 
Deferiprone  
Minus Placebo 
95% C.I. 
N 
xx 
Xx 
xx 
 
 
LS Mean ± SE 
LS Mean ± SE 
LS Mean ± SE 
 
Month 12 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Data source: 16.2.9.5 Listing of vital signs  
 
 
Table 14.3.3.4 Trend analysis for height (cm) over time  
 
 
 
 
 
Rate of change per 
month 
Deferiprone 
Placebo 
      Deferiprone             
minus Placebo 
       P-value 
      Mean ± SE 
xxxx ± xxxx 
xxxx ± xxxx 
xxxx ± xxxx  
         0.xxxx 
Data source: 16.2.9.5 Listing of vital signs  
 
Table 14.3.3.5 Z score analysis for height (cm) 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
x.x ± x.x (x.x, x.x) 
xx 
x.x ± x.x (x.x, x.x) 
0.xxxx 
Month 12 
xx 
x.x ± x.x (x.x, x.x) 
xx 
x.x ± x.x (x.x, x.x) 
0.xxxx 
Change 
xx 
x.x ± x.x (x.x, x.x) 
xx 
x.x ± x.x (x.x, x.x) 
0.xxxx 
Data source: 16.2.9.5 Listing of vital signs  
 
 


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14.3.4  
Weight 
Table 14.3.4.1 Weight (kg) at each assessment 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 1  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 2  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 3  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 4  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 5  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 6  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 7  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 8  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 9  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 10  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 11  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 12  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Data source: 16.2.9.5 Listing of vital signs  
 
 


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Table 14.3.4.2 Change in weight (kg) from baseline to at each follow-up assessment 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Month 1  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 2  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 3  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 4  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 5  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 6  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 7  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 8  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 9  
xx 
xxx ± xxx (xxx, xxx) 
xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 10  
xx 
xxx ± xxx (xxx, xxx) 
Xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 11  
xx 
xxx ± xxx (xxx, xxx) 
Xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Month 12  
xx 
xxx ± xxx (xxx, xxx) 
Xx 
xxx ± xxx (xxx, xxx) 
0.xxxx 
Data source: 16.2.9.5 Listing of vital signs 
 
 


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Table 14.3.4.3 LS Means for change in weight (kg) from ANCOVA model at Month 12   
 
Deferiprone 
Placebo 
Deferiprone  
Minus Placebo 
95% C.I. 
N 
xx 
xx 
xx 
 
 
LS Mean ± SE 
LS Mean ± SE 
LS Mean ± SE 
 
Month 12 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Data source: 16.2.9.5 Listing of vital signs 
 
 
Table 14.3.4.4 Trend analysis for weight (kg) over time  
 
 
 
 
 
Rate of change per 
month 
Deferiprone 
Placebo 
      Deferiprone             
minus Placebo 
       P-value 
      Mean ± SE 
xxxx ± xxxx 
xxxx ± xxxx 
xxxx ± xxxx  
         0.xxxx 
Data source: 16.2.9.5 Listing of vital signs 
 
Table 14.3.4.5 Z score analysis for weight (kg) 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
x.x ± x.x (x.x, x.x) 
Xx 
x.x ± x.x (x.x, x.x) 
0.xxxx 
Month 12 
xx 
x.x ± x.x (x.x, x.x) 
Xx 
x.x ± x.x (x.x, x.x) 
0.xxxx 
Change 
xx 
x.x ± x.x (x.x, x.x) 
Xx 
x.x ± x.x (x.x, x.x) 
0.xxxx 
Data source: 16.2.9.5 Listing of vital signs 
 
 


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14.3.5  
Concomitant medications 
Table 14.3.5.1 Concomitant medications  
  
  
  
Deferiprone 
(N) 
Placebo 
(N) 
Total 
(N) 
Exposure  
(Patient-years):  
x.xx 
Exposure 
(Patient-
years): 
 x.xx 
Exposure 
(Patient-
years): 
x.xx 
Total Patients  
Reporting: xx 
Total Patients 
 Reporting: xx 
Total Patients 
Reporting: xx 
Preferred Name 
n Patients (%)  
n Patients (%) n Patients (%) 
  cccccc 
x (x.x) 
x (x.x) 
x (x.x) 
  cccccc 
x (x.x) 
x (x.x) 
x (x.x) 
  cccccc 
x (x.x) 
x (x.x) 
x (x.x) 
……... 
……... 
……... 
……... 
Data source: 16.2.9.9 Listing of concomitant medications 
 
 


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14.3.6  
Laboratory data 
14.3.6.1 Hematology 
Table 14.3.6.1.1 Hemoglobin at each assessment  
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 1  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 2  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 3 
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 4  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Weekly up to 6 months 
Week 28 
xx 
xx.x ± xx.x (xx.x,xx.x) 
Xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 30 
xx 
xx.x ± xx.x (xx.x,xx.x) 
Xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 32 
xx 
xx.x ± xx.x (xx.x,xx.x) 
Xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 36 
xx 
xx.x ± xx.x (xx.x,xx.x) 
Xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Biweekly until termination from the study 
Data source: 16.2.8.1 Listing of hematology 
Note: Similar tables will be produced for total WBC count, ANC, MCV, and platelet count. 
 
 


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Table 14.3.6.1.2 Change in hemoglobin from baseline to at each follow-up assessment   
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Week 1  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 2  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 3 
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 4  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Weekly up to 6 months 
Week 28 
xx 
xx.x ± xx.x (xx.x,xx.x) 
Xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 30 
xx 
xx.x ± xx.x (xx.x,xx.x) 
Xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 32 
xx 
xx.x ± xx.x (xx.x,xx.x) 
Xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Week 36 
xx 
xx.x ± xx.x (xx.x,xx.x) 
Xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Biweekly until termination from the study 
Data source: 16.2.8.1 Listing of hematology 
Note: Similar tables will be produced for total WBC count, ANC, MCV, and platelet count. 
 
 


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Table 14.3.6.1.3 Shift table for hemoglobin at baseline vs last assessment: deferiprone group 
 
 
Baseline 
 
 
N (%) 
Low 
Normal 
High 
P-value (McNemar-Bowker’s test) 
Last assessment 
Low 
xx (xx) 
xx (xx) 
xx (xx) 
 
0.xxxx 
Normal 
xx (xx) 
xx (xx) 
xx (xx) 
High 
xx (xx) 
xx (xx) 
xx (xx) 
Data source: 16.2.8.1 Listing of hematology 
Note: Similar tables will be produced for total white blood cell (WBC), absolute neutrophil count 
(ANC), and platelets. 
 
Table 14.3.6.1.4 Shift table for hemoglobin at baseline vs last assessment: placebo group  
 
 
Baseline 
 
 
N (%) 
Low 
Normal 
High 
P-value (McNemar-Bowker’s test) 
Last assessment 
Low 
xx (xx) 
xx (xx) 
xx (xx) 
 
0.xxxx 
Normal 
xx (xx) 
xx (xx) 
xx (xx) 
High 
xx (xx) 
xx (xx) 
xx (xx) 
Data source: 16.2.8.1 Listing of hematology 
Note: Similar tables will be produced for total white blood cell (WBC), absolute neutrophil count 
(ANC), and platelets. 
 
 
 


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14.3.6.2 Biochemistry 
Table 14.3.6.2.1 Albumin at each assessment  
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Baseline  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 1  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 3  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 6  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 9  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 12  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Data source: 16.2.8.4 Listing of biochemistry 
Note: Similar tables will be produced for total protein, GGT, glucose, bilirubin (total, direct, and 
indirect), AST, ALT, blood urea nitrogen, calcium, creatinine, total iron binding capacity, serum 
iron, and zinc. 
 
 


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Table 14.3.6.2.2 Change in albumin from baseline to at each follow-up assessment 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (T-
test) 
Month 1  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 3  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 6  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 9  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 12  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Data source: 16.2.8.4 Listing of biochemistry 
Note: Similar tables will be produced for total protein, GGT, glucose, bilirubin (total, direct, and 
indirect), AST, ALT, blood urea nitrogen, calcium, creatinine, total iron binding capacity, serum 
iron, and zinc. 
 
 


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Table 14.3.6.2.3 Shift table for albumin at baseline vs last assessment: deferiprone group  
 
 
Baseline 
 
 
N (%) 
Low 
Normal 
High 
P-value (McNemar-Bowker’s test) 
Last assessment 
Low 
xx (xx) 
xx (xx) 
xx (xx) 
 
0.xxxx 
Normal 
xx (xx) 
xx (xx) 
xx (xx) 
High 
xx (xx) 
xx (xx) 
xx (xx) 
Data source: 16.2.8.4 Listing of biochemistry 
Note: Similar tables will be produced for total protein, GGT, glucose, bilirubin (total, direct, and 
indirect), AST, ALT, blood urea nitrogen, calcium, creatinine, total iron binding capacity, serum 
iron, and zinc. 
 
 
Table 14.3.6.2.4 Shift table for albumin at baseline vs last assessment: placebo group  
 
 
Baseline 
 
 
N (%) 
Low 
Normal 
High 
P-value (McNemar-Bowker’s test) 
Last assessment 
Low 
xx (xx) 
xx (xx) 
xx (xx) 
 
0.xxxx 
Normal 
xx (xx) 
xx (xx) 
xx (xx) 
High 
xx (xx) 
xx (xx) 
xx (xx) 
Data source: 16.2.8.4 Listing of biochemistry  
Note: Similar tables will be produced for total protein, GGT, glucose, bilirubin (total, direct, and 
indirect), AST, ALT, blood urea nitrogen, calcium, creatinine, total iron binding capacity, serum 
iron, and zinc. 
 
 


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Table 14.2.6.2.5 Percent of patients who had ALT > 2 x ULN, 3 x ULN, or 5 x ULN during the 
study 
 
Deferiprone 
Placebo 
P-value 
(Fisher's exact test) 
ALT > 2 x ULN 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
ALT > 3 x ULN 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
ALT > 5 x ULN 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
 
Table 14.2.6.2.6 Percent of patients who had AST > 2 x ULN, 3 x ULN, or 5 x ULN during the 
study 
 
Deferiprone 
Placebo 
P-value 
(Fisher's exact test) 
AST > 2 x ULN 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
AST > 3 x ULN 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
AST > 5 x ULN 
 xx% (xx / xx) 
xx% (xx / xx) 
0.xxxx 
 
 
 


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14.3.7  
Prolactin 
Table 14.3.7.1 Prolactin at each assessment  
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Pre-dose  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Post-dose  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Month 12  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Data source: 16.2.8.5 Listing of prolactin 
 
Table 14.3.7.2 Change in prolactin from pre-dose to Month 12 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Month 12  
xx 
xx.x ± xx.x (xx.x,xx.x) 
xx 
xx.x ± xx.x (xx.x,xx.x) 
0.xxxx 
Data source: 16.2.8.5 Listing of prolactin  
 
Table 14.3.7.3 LS Means for change in prolactin from pre-dose to Month 12 from ANCOVA model   
 
Deferiprone 
Placebo 
Deferiprone  
Minus Placebo 
95% C.I. 
N 
xx 
xx 
xx 
 
 
LS Mean ± SE 
LS Mean ± SE 
LS Mean ± SE 
 
Month 12 
xxxx ± xxxx  
xxxx ± xxxx 
xxxx ± xxxx 
(xxxx, xxxx) 
Data source: 16.2.8.5 Listing of prolactin  
 
 
 


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14.4 
Other analyses 
Table 14.4.1 Compliance (%) at each assessment 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD (Min, Max) 
N 
Mean ± SD (Min, Max) 
P-value (t-test) 
Month 1  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 2  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 3  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 4  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 5  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 6  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 7  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 8  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 9  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 10  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 11  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Month 12  
xx 
xx ± xx (xx, xx) 
xx 
xx ± xx (xx, xx) 
0.xxxx 
Data source: 16.2.5.1 Listing of compliance 
 
 


Chiesi Canada Corp. 
 
              Statistical Analysis Plan: Protocol LA55-0417 
 
 
CONFIDENTIAL 
Page 72 of 73 
 
Table 14.4.2 Overall mean of transfusional iron input (mg/kg/day) during the study 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
P-value (t-test) 
Overall mean of transfusional iron 
input (mg/kg/day) during the study 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Data source: 16.2.9.7 Listing of transfusion 
 
 
Table 14.4.3 Overall mean of total daily dose (mg/kg/day) during the study 
 
Deferiprone 
Placebo 
 
 
N 
Mean ± SD 
(Min, Max) 
N 
Mean ± SD 
(Min, Max) 
P-value (t-test) 
Overall mean of total daily dose 
(mg/kg/day) during the study 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
xx 
xx.x ± xx.x 
(xx.x, xx.x) 
0.xxxx 
Data source: 16.2.9.8 Listing of exposure 
 
Table 14.4.4 Patient exposure to study medication 
 
Data source: 16.2.9.8 Listing of exposure 
 
 
 
Deferiprone 
Placebo 
Total Patients Exposed [N]   
xx 
xx 
Total Patient-Years Exposure 
xxx 
xxx 
Length of Exposure (years)   
 
 
    Mean                     
  xx.x 
  xx.x 
    SD                       
  xx.x 
  xx.x 
    Median                   
  xx.x 
  xx.x 
    Min, Max                 
xx.x, xx.x 
xx.x, xx.x 


Chiesi Canada Corp. 
 
              Statistical Analysis Plan: Protocol LA55-0417 
 
 
CONFIDENTIAL 
Page 73 of 73 
 
Table 14.4.5 Duration of study drug exposure 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data source: 16.2.9.8 Listing of exposure 
 
 
 
 
Deferiprone 
Placebo 
Duration of Exposure [n(%)]  
 
 
    Any Exposure             
xx (xx.x) 
xx (xx.x) 
    >= 1 Month               
xx (xx.x) 
xx (xx.x) 
    >= 2 Months              
xx (xx.x) 
xx (xx.x) 
    >= 3 Months              
xx (xx.x) 
xx (xx.x) 
    >= 4 Months              
xx (xx.x) 
xx (xx.x) 
    >= 5 Months              
xx (xx.x) 
xx (xx.x) 
    >= 6 Months              
xx (xx.x) 
xx (xx.x) 
    >= 9 Months              
xx (xx.x) 
xx (xx.x) 
    >= 12 Months             
xx (xx.x) 
xx (xx.x)