Clinical trial NCT02728843
Conditions: Parkinson's Disease
Keywords: Parkinson's disease Deferiprone
Sponsor: ApoPharma
Start date: 2016-10-12; Completion date: 2019-09-04
Enrollment: 140 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to evaluate the effects of deferiprone, an iron-chelating drug, in patients with Parkinson's disease. Participants will be randomized to receive one of four different dosages of deferiprone or placebo, and will take the assigned study product twice a day for nine months.

Detailed description:
This study will enroll 140 patients who have been diagnosed with Parkinson's disease within the last 3 years and are currently taking antiparkinsonian medication. There are four dosage cohorts, with patients in each cohort receiving either deferiprone tablets or placebo. At the baseline visit, participants will be randomized to a dosage cohort and to either active product or placebo within that cohort, and will take the assigned study product twice-daily for 9 months. They will come back to the study site for assessments at Months 1, 2, 3, 4, 5, 6, and 9, and will need to have their blood count checked weekly, at either the study site or a local laboratory.

Arms: arm 1: One-half of a 600 mg tablet of deferiprone twice a day, for a total daily dosage of 600 mg arm 2: One 600 mg tablet of deferiprone twice a day, for a total daily dosage of 1200 mg arm 3: One and a half 600 mg tablets of deferiprone twice a day, for a total daily dosage of 1800 mg arm 4: Two 600 mg tablets of deferiprone twice a day, for a total daily dosage of 2400 mg arm 5: Depending on dosage cohort, either one half-tablet, one tablet, one and a half tablets, or two tablets of placebo, twice a day
Interventions: intervention 1: Deferiprone intervention 2: Placebo
Intervention descriptions: intervention 1: 600 mg tablets intervention 2: Tablets that match the deferiprone tablets in appearance

Protocol documents:
ICF_002.pdf: 
 
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Informed Consent to Take Part in a Clinical Trial 
Study Title:  A dose-ranging study of the efficacy, safety, and pharmacokinetics  
of deferiprone delayed release tablets in patients with Parkinson’s disease 
Study Code: LA48-0215 
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 Sir or Madam, 
You are invited to take part in a research study. It is important that you fully understand what 
your participation would 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 regular doctor and family members before 
making your decision. 
Taking part in this study is completely up to you. You do not have to say yes, and if you do agree 
to take part, you may later change your mind at any time. 
This study is organized and paid for by the pharmaceutical company ApoPharma Inc. (the 
“Sponsor”).  The Investigator, Dr. [insert name], is being paid by ApoPharma to do this research. 
If there are any conflicts of interest affecting the investigator, identify them here. 
What is the purpose of this study? 
This study is looking at a drug called deferiprone for the treatment of Parkinson’s disease.  While 
the exact cause of Parkinson’s disease is unknown, it is possible that its symptoms are due to a 
build-up of extra iron in certain brain regions. Therefore, getting rid of some of this extra iron 
might lead to improvement in Parkinson’s symptoms.  Deferiprone is an iron chelator, a drug 
that attaches itself to free molecules of iron in the body and causes them to be flushed out or 
redistributed.  There are several different iron chelators available, but deferiprone is better able 
than the others to cross the blood-brain barrier and remove iron from the brain.  Some small pilot 
studies that have looked at the effect of deferiprone in Parkinson’s patients have found evidence 
that it may improve the symptoms of this disease. 


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Deferiprone comes in several forms, including tablets and liquid. Some of the forms are licensed 
to be given to patients with thalassemia, a type of blood disorder, who have too much iron in 
their bodies due to receiving frequent blood transfusions. However, none are licensed for the 
treatment of Parkinson’s disease.  The form of deferiprone that will be given in this study, 
deferiprone delayed release, is not licensed for any type of use, and so far has been tested only 
in healthy people. The Investigator has received permission from [regulatory authority] to give 
deferiprone delayed release tablets to patients with Parkinson’s disease in this research study. 
The purpose of this study is to see what effects, both positive and negative, deferiprone delayed 
release tablets have on patients with Parkinson’s disease, and to find the highest dose that can be 
given without causing severe side effects. 
Where is the study being done, and how many people will take part in it? 
This study is expected to be done at sites in North America and Europe. It is planned that a total 
of 140 patients will take part.  
Who can participate? 
People who are at least 18 years old but less than 80 years old, who have been given a diagnosis 
of Parkinson’s disease within the last three years, and who have been on a stable dose of certain 
types of antiparkinsonian medication for at least the last three months, may be eligible to take part 
in this study. Your doctor will review and discuss the medications with you to confirm eligibility. 
What drugs will be used? 
Patients in this study will continue to take the medication they are already being prescribed for 
the treatment of Parkinson’s disease, and will additionally receive either deferiprone delayed 
release tablets or placebo.  Both these products are provided by ApoPharma Inc., the company 
that is paying for the study. 
 
Each tablet of deferiprone delayed release contains 600 milligrams (mg) of the drug.  Four 
different dosages (strengths) are being tested:  300 mg (one half-tablet), 600 mg (one tablet), 
900 mg (one and a half tablets), and 1200 mg (two tablets).  The medication will be taken 
orally (by mouth) twice a day, for a total daily dosage of 600 mg, 1200 mg, 1800 mg, and 
2400 mg, respectively. 
 
The placebo tablets look exactly the same as the deferiprone tablets but do not contain any 
active ingredient.  The reason for including a placebo group in a drug study is because 
sometimes patients may either start to feel better or develop new symptoms simply because 
they are on a new medication. By comparing people who are getting the active drug to 
those who are getting placebo, we can tell if effects, both positive and negative, are due to 
the drug itself, and not just due to being in a study.  


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Patient’s initials: _____ 
If you enroll in this study, you will be randomized (assigned by chance, like the flip of a coin) 
to receive one of the above treatments.  The chance of being assigned to any of the groups is 
one out of five. Thus, of the 140 patients, a total of 112 will get deferiprone (28 in each of the 
four dosage groups), and 28 will get placebo.  Neither you nor the Investigator or other study 
staff will know which product you received until the study is over. 
What will be done during the study? 
If you decide to take part in this study, you will continue to take your present antiparkinsonian 
medication at exactly the same dose you are on now.  In addition, you will take two doses of the 
assigned study medication (either deferiprone or placebo) every day for 9 months, one in the 
morning and the other in the evening, and will need to come to the treatment center nine times 
over about ten months.  In addition, you will need to have your blood checked once a week for 
safety reasons, but that can be done at a local laboratory.  (In some cases, having this done at 
your home by a visiting nurse may be an option.)  A final telephone call will be made one month 
after your final site visit. 
Before you start the study or undergo any procedures, you must sign and date this informed 
consent form.  The Investigator will then ask you questions and carry out a number of tests to see 
if it would be appropriate for you to take part.  If anything is found that raises concerns about your 
safety or that might make the study findings harder to understand, you will not be enrolled. 
Note the following:  
 
You will need to provide a total of about 60 teaspoons (300 mL) of blood over the ten months 
of the study (plus an additional 0.75 teaspoon/3.5 mL for pregnancy testing if you are a 
woman who is able to get pregnant). This total does not include possible unscheduled visits 
at which you may be asked to provide additional samples, or the possibility that staff may 
need to take extra samples if any are damaged or handled incorrectly. 
 
One of the lab tests at each visit is for fasting glucose.  Therefore, you will need to fast 
(water only) for at least 8 hours before each visit.  All visits will be scheduled in the morning, 
and you will be able to eat as soon as the blood sample has been taken.  At the baseline and 
Month 3 visits, and optionally at the Month 1 visit, there are additional blood tests that 
require a longer fasting period.  On those days, you will need to fast for at least 10 hours 
before coming to the site, and will be allowed to eat about one and a half hours after you 
arrive. 
 
The following samples are optional, and you may still be in the study if you do not wish to 
provide them: 
o At one visit, some extra blood samples (a total of 18 samples taken over 12 hours) 
o At one visit, a single sample of cerebrospinal fluid, collected by doing a spinal tap 


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If you are willing to provide either or both of these types of samples, you will need to read 
and sign a separate consent form. 
 
Because of the possible danger of the study drugs to an unborn child, if you are a woman 
who is able to get pregnant, you must have a negative result on a pregnancy test and must 
agree to do what you can to prevent pregnancy until 30 days after your last dose of study 
medication.  If you are a sexually active heterosexual man, you must agree that you and/or 
your partner will do what you can to prevent pregnancy for this same period of time.  The 
study staff will provide counseling on what types of birth control methods are acceptable. 
 
The details of the study visits are described below. 
Screening Visit (about [xx] hours) 
This visit will take place up to 30 days before the first dose is given. The following will be done: 
 The Investigator or another staff member will explain the study to you, and you will need 
to sign this informed consent form if you wish to continue. 
 You will be asked questions about your health and your medical history, including what 
medications you are now taking. 
 You will provide a blood sample (approximately 12 mL / 2.5 teaspoons) and a urine 
sample for safety lab tests, which includes pregnancy testing if you are a woman who is 
able to get pregnant. 
 You will undergo a physical examination, and your vital signs (heart rate, blood pressure, 
and body temperature), height, and weight will be measured.  
 You will undergo an electrocardiogram (ECG), a test that checks heart function.  This test 
does not hurt. 
 If applicable, the study staff will provide counseling on birth control methods. 
If you are found to be eligible after the results of all tests are in, you will be scheduled to start the 
study soon afterwards. 
Baseline Visit (about [xx] hours) 
 You will be asked questions about any health problems you have experienced and what 
medications you are taking. 
 Your vital signs will be checked. 
 If applicable, a study staff person will provide counseling on birth control methods. 


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 You will undergo a physical examination  
 You will provide baseline (pre-dose) blood samples (approximately 40 mL / 8 teaspoons) 
and a urine sample for the following tests: 
o 
Pharmacokinetics testing, which will look at how long it takes the drug to enter the 
bloodstream, to be metabolized (broken down), and to be excreted (leave the body) 
o 
Biomarkers testing, which will look at the effect of the drug on certain substances 
produced by the body 
o 
Genetic testing, which will look at possible genetic differences in how patients 
respond to deferiprone  
 If you are a female who is able to get pregnant, you will provide both a blood sample and 
a urine sample for pregnancy testing. 
 The Investigator will ask you questions about whether you are having any suicidal thoughts 
or have carried out any self-harming behaviors.  This type of assessment is now a standard 
requirement for many drug trials that are looking at medications that may affect the brain. 
 You will complete two tests that are used to assess the symptoms of Parkinson’s disease:  
the Movement Disorder Society - Unified Parkinson’s Disease Rating Scale and the 
Montreal Cognitive Assessment test.  Your scores on these tests will be your baseline 
results, and will be compared against your scores at later time points in the study.  
 You will be randomized to one of the four dosage groups (one half-tablet, one tablet, one 
and a half tablets, or two tablets), and then further randomized within that group to 
receive either deferiprone tablets or a matching number of placebo tablets.  
 You will take your first dose of study medication. 
 You will provide two more blood samples for pharmacokinetics testing (approximately 5 
mL / 1 teaspoon each): the first one about two hours after you took the dose, and the 
second one about four hours after.  
 You will be given a two-month supply of the assigned study medication (either 
deferiprone or placebo), along with instructions on how to take it.  
 You will be given a diary card in which you must record the amount of study medication 
you take each day for the next month;  the times at which you take it; any other 
medications that you take; and any health problems you experience.  You must bring this 
card, as well as all bottles of study medication, whether empty, partly empty, or 
unopened, back with you at the next visit. 
 You will be given a card with an emergency number to call in case you experience 
certain symptoms.  It is important that you carry this card with you at all times. 


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Later this day, you will take your second dose of study medication.  For the next nine months, 
you will take two doses every day, at least eight hours apart. 
Each remaining visit -- Months 1, 2, 3, 4, 5, 6, and 9 (amount of time per visit will vary) 
At each of these visits, the following will be done: 
 Your vital signs will be checked, blood samples will be taken for lab safety tests and for 
pregnancy testing if applicable, and a staff member will provide birth control counseling if 
applicable. 
 The Investigator or other study staff member will review the information in your diary 
card, and will check your bottles of medication to see how many tablets you have taken and 
how many remain. 
 You will be asked about any suicidal thoughts or behaviors. 
 You will be given a new diary card (except at Month 9). 
In addition, the following procedures will be done at only some visits: 
 Months 2, 4, and 6 only:  Another supply of study medication will be given to you; 
a two-month supply at Months 2 and 4, and a three-month supply at Month 6 
 Months 2, 4, 6, and 9 only:  Physical examination 
 Month 3 only:  Blood for pharmacokinetics testing (three samples over about four hours).  
At this visit, you will need to wait until you arrive at the study site before taking your 
regular morning dose, since the first sample must be taken pre-dose.  In addition, you 
must fast for at least 10 hours before the visit. 
 Month 9 only:  Electrocardiogram and measurement of weight 
 Months 3, 6, and 9 only:  
o Urine sample for safety testing and biomarkers testing 
o Blood samples for biomarkers testing 
o Completion of the Unified Parkinson’s Disease Rating Scale and the Montreal 
Cognitive Assessment test 
In addition, the following procedures will be done on only those patients who volunteer for them: 
 Month 1:  If you agree, you will give extra blood for pharmacokinetics testing (18 blood 
samples over 12 hours, so this visit will last until the evening). 


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 Month 3:  If you agree, a sample of fluid will be taken by spinal tap at one of three 
possible times:  either just before you take your morning dose, about two hours after 
you take it, or about four hours after you take it 
Details of these optional procedures are provided in a separate consent form. 
 
Weekly blood testing (about 15 minutes) 
On each week up to Month 9 that does not have a scheduled site visit, you will need to provide a 
blood sample (about 0.6 teaspoon / 3 mL) for checking your white blood cell count, for safety 
reasons.  This can be done either at the study site or at a local laboratory if that is more 
convenient to you (or in some cases, at your own home by a visiting nurse).  If you show any 
signs of infection (for example, fever, sore throat, or flu-like symptoms) or if your last white 
blood cell count was low, you may need to have this testing done more often than once a week.  
The reason for this is explained under the heading “What are the possible risks of taking part in 
the study?” 
Final telephone call 
About four weeks after your last visit, you will receive a telephone call from a study staff 
member to ask about your health. 
After this call, your participation in the study is complete. 
Are there any medications that are not allowed during the study? 
During the study, you must keep taking the same type and dosage of antiparkinsonian medication 
you were on when you enrolled. If the Investigator decides that you need to change anything about 
your medication, you will be withdrawn from the study. 
In addition, there are some medications that may interact with the study drug. The Investigator 
will let you know which ones are not permitted.  You should check before starting any new 
medications while you are in this study. 
What are the possible benefits of taking part in this study? 
Deferiprone may act to improve your symptoms of Parkinson’s disease. However, there is no 
guarantee that this will happen. 
Your health will be monitored very closely during the study, and you will have many chances to 
speak with the Investigator and other health care workers about any medical concerns that you 
would like to discuss. 
Apart from any direct benefit to you, the information we get from your participation will add to 
our knowledge about Parkinson’s disease, and may help other patients in future. 


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What are the possible risks of taking part in the study? 
Risks of receiving deferiprone 
Like all medications, deferiprone can have side effects, although not everyone gets them.  Most 
of the safety information about deferiprone comes from patients with a blood disorder called 
thalassemia, who must receive life-long treatment with iron chelators to treat iron overload caused 
by frequent blood transfusions.  (In this study, the maximum dosage of deferiprone will be lower 
than what is normally given to thalassemia patients.)  From the information we have so far, the 
safety profile of deferiprone in patients with Parkinson’s disease and other diseases that may be 
caused by extra iron in certain brain regions is similar that that seen in iron-overloaded patients. 
The most serious side effect of deferiprone that has been seen in thalassemia patients is a sudden 
sharp drop in neutrophils, a type of white blood cell that is an important part of the immune system. 
A very low neutrophil count, called severe neutropenia or agranulocytosis, has been seen in 
about 2% percent of people who have taken deferiprone in clinical studies. 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. We cannot predict who 
is at risk for agranulocytosis, and people may not realize that they have it until they develop an 
infection, which is why it is so important to have your white blood cell count checked weekly. If 
you ever develop flu-like symptoms such as fever, sore throat, or any other signs of infection, you 
must stop taking deferiprone immediately and check with the Investigator. Any patient who 
develops agranulocytosis will be immediately withdrawn from the study and given treatment, and 
will come back only for follow-up tests.  
Other side effects that have been seen in thalassemia 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 


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Events of joint pain and swelling (seen in 5% to 12% of patients) have ranged from mild pain in 
one or more joints to severe disability.  In most cases, the pain disappeared after the patients had 
been taking deferiprone for some time. 
Since deferiprone acts to rid the body of iron, patients who do not suffer from general iron 
overload may experience a drop in their blood iron to a level that is too low.  If that happens to 
you, you may be given iron supplements. 
In animal studies, no harmful effects have been seen when deferiprone was given at the doses 
that are permitted for humans, with the exception of birth defects in some species, which is why 
deferiprone is not given to pregnant women. 
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 you ever get any of these symptoms, call an emergency 
service at once, and let Dr. [name of investigator] know as soon as possible, at [telephone 
number].  
With any drug, there is always a chance that an unexpected or serious side effect that has not 
previously been reported may happen. If you experience any side effects not listed here, please 
tell the Investigator. 
Risks of receiving placebo 
If you are assigned to the group that gets placebo, you will not be receiving any active medication 
other than the antiparkinsonian drugs you are presently taking to treat your symptoms. 
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. 
Risks of having a spinal tap 
This procedure is optional.  While it is generally safe, there are some risks associated with it. 
These are described in a separate consent form titled “Informed Consent for Providing 
Additional Samples for Pharmacokinetics Testing”. 
Risks to an unborn child 
Since it is possible that deferiprone could harm a fetus, it is very important to not become 
pregnant or father a child while on this study.  Therefore, patients must abide by the following: 


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Women:  If you are pregnant or nursing, you will not be enrolled. If you are capable of becoming 
pregnant, you will need to have a negative pregnancy test within 24 hours before receiving the first 
dose of study drug. Following enrollment, you must use birth control during the entire study and 
for at least 30 days after it has ended. If you do become pregnant during the study, you must 
immediately stop taking the drug and must inform Dr. [name] at [phone number]. You will be 
monitored until delivery, and your baby will be examined and monitored for any medical problems. 
Men: If you are heterosexual and fertile, you must confirm that you and/or your partner will 
use an effective method of birth control during the entire study and for at least 30 days after it 
has ended. If your partner does become pregnant during this study, you must immediately call 
Dr. [name] at [phone number].  It would be desirable for your partner to agree to be monitored 
until delivery, and for the baby to be examined and monitored for any medical problems. The 
Sponsor may ask to collect confidential information about the health of the baby. 
The following are common methods of contraception (patients must check with the Investigator 
to make sure that the method they are using is acceptable): 
 
Birth control pills and other hormonal devices 
 
Intrauterine device (IUD) in place for at least 3 months before the first dose of study drug 
 
Condom or diaphragm, provided it is used with spermicidal cream 
 
Tubal ligation (women) or vasectomy ( men) 
 
Abstinence 
To be considered to be of non-childbearing potential, a woman must be defined as surgically 
sterile (complete hysterectomy or removal of both ovaries) or must be in a menopausal state 
(being 50 years of age or older and at least 1 year without menses). 
Are there other treatments available? 
A number of other medications are available to treat the symptoms of Parkinson’s disease, and 
all patients in this study must in fact already be receiving such treatment.  However, once the 
study begins, patients will need to stay on the exact same regimen they were on at the start, so 
anyone who is likely to be changing regimens soon will not be enrolled, You should discuss the 
options with the Investigator and/or your regular doctor, to decide which treatment might be the 
most suitable for you.  
What will happen if new information becomes available? 
If any new information is discovered that may affect the risk to you or may affect your willingness 
to 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 to continue in the study. 


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Patient’s initials: _____ 
What will happen if I don’t want to take part? 
Participation in this study is completely voluntary. If you do not wish to enroll, or if you agree to 
enroll but then change your mind, there will be no penalty or loss of benefits to which you are 
entitled. 
If you decide to leave the study after enrolling, we ask that you let us know, and that you return 
to have some final tests so that we can check on your safety and collect more information that will 
help our understanding of the study product. 
If you withdraw, any study information that was collected up to the date you leave will still be used. 
Can I be taken out of the study even if I want to stay in it? 
The Investigator may withdraw you from the study at any time without your consent if you are 
not following instructions or if there are concerns about your safety, including the development 
of other medical problems or of severe side effects from the study medication.  
If the study is cancelled for administrative or other reasons, all patients will be withdrawn. 
What will happen if I am harmed by being in this study? 
If you are 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 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 to me for being in this study? 
There will be no cost to you for any of the study visits, examinations, tests, and drug supplies.  
For each visit that you attend, you will receive [insert amount] to compensate you for 
transportation and parking costs. 
If you agree to provide the extra blood samples at Month 1 and/or the sample of cerebrospinal 
fluid at Month 3, additional compensation will be provided.  Details are provided in a separate 
consent form. 


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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. 
Who will be allowed to see my information? 
Access to your 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 to check that the 
study information is being collected properly. Any information about you 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 name.  Only the Investigator will have access to the 
code numbers that link your study information to your identity. By signing this consent form, you 
agree to this inspection and disclosure. 
If the findings of this study are published or presented, your identity will remain private. 
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, as required 
by U.S. law. This web site will not include information that can identify you. At most, it will 
include a summary of the results. You can search this web site at any time.  Similar study 
information may be posted on other government web sites as required by local law. 
Your information and results will be kept on file by the Investigator and Sponsor for at least [xx] 
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 primary care physician that you are taking part in this study. 
What will happen to my blood samples? 
The blood samples that you provide for safety assessments will be analyzed at a local laboratory 
and destroyed after they have been analyzed.  
The samples that you provide for pharmacokinetic and biomarker analyses will be shipped to one 
of several central laboratories for analysis. Portions of these samples will be stored for possible 
additional analyses, and will be destroyed after the report on this study has been produced, which 
will be a maximum of 1 year after the end of the study. 
The analyses include tests to see if certain genetic differences affect how individual patients 
respond to deferiprone.  We will not look for any genetic information other than this, and we will 
not share any genetic information with your insurance company or anyone else. We would like to 


ApoPharma Model ICF Version 4.0, 07 APR 2017 
Site-Specific ICF Version [x.x], DD MMM YYYY 
 
Study Code:  LA48-0215 
13 of 16 
I have read this page 
 
 
 
Patient’s initials: _____ 
keep these samples stored in case other genes associated with Parkinson’s disease are discovered 
in future and we would want to do some further analyses.  If you do not agree to this, any leftover 
blood will be discarded after the study is completed. If you do agree and then later change your 
mind, your stored sample will be destroyed. 
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 participation in the study, 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 rights as a study subject, you may contact the research ethics 
committee at [phone number of IRB/IEC]. 


ApoPharma Model ICF Version 4.0, 07 APR 2017 
Site-Specific ICF Version [x.x], DD MMM YYYY 
 
Study Code:  LA48-0215 
14 of 16 
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 
 
Patient’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 take part in this study and to follow the instructions I am given.  
_ 
I understand that my participation is voluntary, and that I am free to 
leave the study at any time without my medical care or legal rights being 
affected. 
_ 
I understand that information collected about me during the study may 
be looked at by representatives of the Sponsor, regulatory authorities, or 
the research ethics committee. I give permission for these individuals to 
have access to my records. 
_ 
I will contact the Investigator immediately if I experience any unexpected 
or unusual health problems during the study. 
_ 
I understand that I will receive a photocopy of this informed consent 
form after it is signed and dated. 
_ 
 
 
I agree that the study site may inform my primary care physician of my participation in this study 
(please check one):  
 
Yes  
 
 
No  
 
 
Consent for additional analyses:  
☐ I consent to my blood sample being saved and stored for possible analyses of different genes 
that may be discovered in future 
☐ I do not consent to my blood sample being saved and stored for possible analyses of different 
genes that may be discovered in future 


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Study Code:  LA48-0215 
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Name of patient (please print) 
 
 
 
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:    hr 
Name of patient or legal 
representative (please print) 
 
Signature of patient or legal 
representative 
 
Date: (DD MMM YYYY) 
and time (24-hr clock) 
 
 
If signed by a legal representative, identify the authority to act on the individual’s behalf. 
 
Individual is:  
__ Incompetent 
 
 
__ Disabled 
 
 
Authority: 
 
__ Power of Attorney Healthcare 
   
 
 
__ Authorized Legal Representative  
   
 
 
__ Other (specify): _________________ 
 
 
 
/ 
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Name of impartial witness, 
if required (please print) 
 
Signature of impartial 
witness 
 
Date: (DD MMM YYYY) 
and time (24-hr clock) 
 
 
 
Signature of person authorized to obtain consent: 
I, the undersigned, acknowledge having provided all the necessary information for comprehension 
of this protocol to the individual identified above. 
 
 
         
/      :      hr 
Name (please print) 
 
Signature 
 
Date: (DD MMM YYYY) 
and time (24-hr clock) 
 


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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 to conduct the study according to applicable Good Clinical 
Practice guidelines and regulations. 
 
 
 
         
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Prot_000.pdf: 
 
 
 
CONFIDENTIAL 
Page 1 of 80 
A Dose-Ranging Study of the Efficacy, Safety, and Pharmacokinetics of 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
LA48-0215 
CLINICAL STUDY PROTOCOL 
 
 
 
 
IND Number: 
126655 
EudraCT Number: 
2015-004344-19 
Investigational Product: 
Deferiprone delayed release formulation 
Development Phase: 
Phase 2 
Indication Studied: 
Parkinson’s disease 
Study Design: 
Multi-center, randomized, double-blind, placebo-controlled, 
dose-ranging study in patients with Parkinson’s disease 
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, 20 MAR 2017 
 
The information contained in this document is the property of ApoPharma Inc. and is 
confidential. It may be submitted to a regulatory authority, an ethics committee, or an 
investigator for the purpose of initiation of a clinical study. Reproduction or disclosure of 
this information, in whole or in part, is forbidden without the written consent of ApoPharma Inc. 


ApoPhanna Inc. ~
._'v,. 
LA48-021S 
;(. 
SIGNATURE PAGES 
Sponsor 
Deferiprone delayed release tablets 
Clinical Study Proto<:ol, v 4.0 
We, the undersigned, hereby declare that this study will be carried out under our supervision 
in accordance with the methods described herein. 
Study Title: 
A dose-ranging study of the efficacy, safety, and pharmacokinetics of 
deferiprone delayed release tablets in patients with Parkinson's disease 
Study Code: 
LA48-0215 
Version Number: 
4.0 
Version Date: 
20 MAR 2017 
Caroline Fradette, PhD 
Pharmalnc. 
Anna Rozova, MD 
Director of Medical Safety, ApoPharma Inc. 
. ef Scientific Officer, Biopbarmaceutics & 
Biostatistics, Apotex Inc. 
CONFIDENTIAL 
Date (DD MMM YYYY) 
7U((J/'Wl· 
Date (DD MMM YYYY) 
"2 z /1AIl... 
~17 
Date (DD MMM YYYY) 
Page 2 of80 


LA48-0215           
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 3 of 80 
ApoPharma Inc. 
Deferiprone delayed release tablets 
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: 
A dose-ranging study of the efficacy, safety, and 
pharmacokinetics of deferiprone delayed release tablets in 
patients with Parkinson’s disease 
Study Code: 
LA48-0215 
Version Number: 
4.0 
Version Date: 
20 MAR 2017 
Name of Principal Investigator: 
 
Name of Study Site: 
 
Location of Study Site: 
(City, region/province/state, 
country) 
 
 
 
 
 
Signature 
 
Date (DD MMM YYYY) 
 
 


LA48-0215           
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 4 of 80 
ApoPharma Inc. 
Deferiprone delayed release tablets 
SYNOPSIS 
Title of study: 
A dose-ranging study of the efficacy, safety, and pharmacokinetics of deferiprone 
delayed release tablets in patients with Parkinson’s disease 
Study code: 
LA48-0215 
Phase of development: 
Phase 2 
Objectives: 
Primary objective 
 To evaluate the efficacy of four different dosages of deferiprone delayed 
release (deferiprone-DR) tablets in  patients with Parkinson’s disease 
Secondary objectives 
 To evaluate the safety and tolerability of deferiprone-DR tablets in  patients 
with Parkinson’s disease 
 To evaluate the pharmacokinetics of deferiprone-DR tablets in a subset of 
study participants 
 To evaluate the relationship between the pharmacokinetics and 
pharmacodynamics of deferiprone-DR tablets 
Exploratory objectives 
 To determine whether the efficacy responses to deferiprone differ depending 
on the genotype of certain enzymes that are implicated in Parkinson’s disease 
 To determine whether the efficacy responses to deferiprone are correlated 
with ceruloplasmin levels or ceruloplasmin ferroxidase activities 
Study design: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Multi-center, randomized, double-blind, placebo-controlled, dose-ranging study in 
140 patients who have been diagnosed with typical Parkinson’s disease up to  3 
years prior to the screening visit and are currently taking antiparkinsonian 
medication. Screening will be conducted within 30 days prior to the start of dosing. 
At baseline, eligible participants will be randomized to one of four dosage cohorts, 
and within each cohort will be further randomized in a 4:1 ratio to receive either 
active product or placebo. The assigned study product will be taken twice-daily 
(b.i.d.), at least 8 hours apart, for 9 months.  Dosages are as follows: 
 Cohort 1:  300 mg deferiprone-DR tablets (n=28) or placebo (n=7) 
 Cohort 2:  600 mg deferiprone-DR tablets (n=28) or placebo (n=7) 
 Cohort 3:  900 mg deferiprone-DR tablets (n=28) or placebo (n=7) 
 Cohort 4:  1200 mg deferiprone-DR tablets (n=28) or placebo (n=7) 
Patients will return to the site at Months 1, 2, 3, 4, 5, 6, and 9, and will receive a 
follow-up telephone call at Month 10. Safety parameters will be assessed at each 
site visit and at the follow-up call.  For safety reasons, all patients will additionally 
have their absolute neutrophil count monitored weekly after the start of dosing, at 
either the study site or a local laboratory (or possibly at home, by a visiting study 
nurse). Efficacy measures will be assessed at baseline and Months 3, 6, and 9; and 
sparse pharmacokinetics (PK) sampling will be done on all patients at baseline and 
Month 3.  In addition, an optional subset of 16 patients will undergo extensive 


LA48-0215           
 
Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 5 of 80 
ApoPharma Inc. 
Deferiprone delayed release tablets 
 Study design 
(cont’d): 
blood sampling for PK analysis at Month 1, and an optional subset of 18 patients 
will each provide one sample of cerebrospinal fluid (CSF) for drug level assessment 
at Month 3.  
Any patient who withdraws before completing treatment will be requested to return 
for an Early Termination visit, at which time the procedures normally scheduled for 
the Month 9 visit will be conducted. 
Duration of 
participation: 
The duration of participation in the study for each patient, including the screening 
period and the follow-up telephone call, will be approximately 11 months. 
Criteria for 
evaluation: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Criteria 
Primary efficacy criterion: 
Change from baseline to Month 9 in the motor examination subscale (Part III) of 
the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) 
 
Secondary efficacy criteria: 
 
Change from baseline to Month 9 in the following measures: 
o 
Total score on the MDS-UPDRS 
o 
Scores on the individual subscales Part I (non-motor experiences of 
daily living), Part II (motor experiences of daily living), and Part IV 
(motor complications) of the MDS-UPDRS 
o 
Combined scores from Parts II and III of the MDS-UPDRS 
o 
Overall cognitive function, as assessed by the Montreal Cognitive 
Assessment (MoCA) test 
o 
Pharmacodynamics measures of the following oxidative stress 
biomarkers: total antioxidant status, lipid peroxidation 
(malondialdehyde), protein carbonyls, 8-OHdG, glutathione, 
superoxide dismutase 
o 
Pharmacodynamics measures of the following inflammatory factor 
biomarkers: TNF alpha and IL-6 
 
Time elapsed until the need for rescue medication 
Exploratory efficacy criteria: 
Mechanism of action (MOA) biomarkers to evaluate the following: 
 
Whether specific genotypes of the following enzymes which play a role in 
Parkinson’s disease affect the potential disease-modifying action of 
deferiprone: 
o 
D544E polymorphisms of the glycoprotein ceruloplasmin 
o 
V158M polymorphisms of the enzyme catechol O-methyltransferase 
(the only analysis will be determination at baseline of the COMT 
genotype) 
 
Whether the degree of change from baseline in ceruloplasmin levels and 
ceruloplasmin ferroxidase activity is correlated with the efficacy of deferiprone 


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Clinical Study Protocol, v 4.0 
 
 
CONFIDENTIAL 
Page 6 of 80 
ApoPharma Inc. 
Deferiprone delayed release tablets 
Criteria for 
evaluation (cont’d): 
Safety Criteria 
 
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 
 
Laboratory measures (hematology, blood chemistry, and urinalysis) 
 
ECG 
 
Vital signs 
 
Physical examination 
 
Assessment of suicidality (based on the Columbia Suicide Severity Rating 
Scale) 
Pharmacokinetics Criteria 
The following PK parameters will be determined for deferiprone and its 3-O-
glucuronide metabolite in the subset of patients who undergo extensive PK 
sampling: 
 
Cmax 
 
Tmax 
 
AUC0-t 
 
AUC0-∞ 
 
λZ 
 
T½ 
T½ and AUC0-∞ will be determined only in patients in whom the log-linear terminal 
phase can be clearly defined. 
Pharmacokinetics/Pharmacodynamics Criteria 
Possible relationships between pharmacokinetic findings and efficacy biomarkers 
and endpoints will be evaluated.  
Number of patients: 
A planned total of 140 patients will be enrolled:  112 to receive one of the 4 dosages 
of deferiprone, and 28 to receive placebo. 
Diagnosis and main 
criteria for inclusion: 
 
 
 
 
 
 
 
 
Main inclusion criteria 
 
Male or female aged ≥18 to < 80 years 
 
Body weight ≥60 kg but ≤100 kg 
 
Parkinson’s disease diagnosed according to UK Parkinson’s Disease Society 
Brain Bank Clinical Diagnostic Criteria and based on the presence of at least 
two of the three cardinal features of the disease (rest tremor, bradykinesia, 
and rigidity). If rest tremor is not present, patient must have unilateral onset 
of symptoms. 
 
Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1.0 x 109/L for Black 
population) at screening 


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Page 7 of 80 
ApoPharma Inc. 
Deferiprone delayed release tablets 
Diagnosis and main 
criteria for inclusion 
(cont’d) 
 
On a stable dose for at least  3 months prior to the screening visit of any of 
the following treatments at an L-dopa equivalent daily dose of up to 600 mg: 
o Dopaminergic agonist alone  
o L-dopa alone 
o Combination therapy with dopaminergic agonist and L-dopa  
o Rasagiline 
 
At an early stage of the disease, without motor fluctuations and/or L-dopa–
induced dyskinesia 
Main exclusion criteria 
 
Diagnosis of Parkinson’s disease more than 3 years prior to screening visit 
 
Hoehn and Yahr stage ≥ 3 
 
Atypical or secondary Parkinsonism without dopa-sensitivity (e.g., vascular 
parkinsonism, supranuclear palsy, multisystem atrophy) 
 
Progressing Axis I psychiatric disorders (psychosis, hallucinations, compulsive 
disorders, substance addiction, bipolar disorder, severe depression, anxiety) as 
assessed in a semi-structured interview in accordance with the Diagnostic and 
Statistical Manual of Mental Disorders 
 
Not stabilized in terms of the current antiparkinsonian therapeutic regimen: 
already requires dose adaptation and/or is likely to require any change in 
dopamine therapy over the duration of the trial 
 
Current treatment with bromocriptine 
 
Current treatment with any antiparkinsonian drug other than those listed in 
the inclusion criteria 
 
Current treatment with coenzyme Q10 or idebenone.  (Patients who are on 
these medications but stop taking them at least 2 weeks prior to baseline may 
be enrolled.) 
 
Current use of a Deep Brain Stimulation (DBS) system. (Patients who previously 
had a DBS system but have had it removed may be enrolled.) 
Investigational 
product: 
Product: 
Deferiprone delayed release 600 mg bisectable tablets 
Dose: 
300 mg, 600 mg, 900 mg, or 1200 mg b.i.d., for a total daily dosage of 
600 mg, 1200 mg, 1800 mg, or 2400 mg 
Mode of administration:  Oral 
Reference product: 
Product: 
Placebo 
Dose: 
Number of tablets matching that required for a 300, 600, 900, or 1200 mg 
dose of active product 
Mode of administration:  Oral 


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Page 8 of 80 
ApoPharma Inc. 
Deferiprone delayed release tablets 
Schedule of treatment 
and assessments: 
Treatment 
All patients will take the assigned study medication at specified times twice daily, 
at least 8 hours apart, for 9 months. 
Efficacy assessments 
 The MDS-UPDRS and MoCA will be completed at baseline and Months 3, 6, 
and 9 
 Blood samples for the assessment of pharmacodynamics biomarkers and  of 
the MOA biomarkers of total antioxidant status protein carbonyls, glutathione, 
and super-oxide dismutase will be collected at baseline and Months 3, 6, and 9 
 Urine samples for the assessment of the oxidative stress biomarkers 8-OHdG 
and lipid peroxidation (malondialdehyde) will be collected at baseline and 
Months 3, 6, and 9 
Note:  The MDS-UPDRS and MoCA are to be administered early in the morning, 
at approximately the same time (± 1 hour) at each visit, and by the same qualified 
investigator. 
Safety assessments 
 Hematology: Screening and weekly after the start of dosing up to Month 9 
 Blood chemistry:  Screening and  Months 1, 2, 3, 4, 5, 6, and 9 
 Urinalysis:  Screening  and Months 3, 6, and 9 
 ECG:  Screening and Month 9 
 Vital signs:  Each site visit up to Month 9 
 Physical examination:  Screening, baseline, and Months 2, 4, 6, and 9 
 Assessment of suicidality:  Baseline and each visit thereafter up to Month 9 
 Adverse events:  Collected throughout the study, from baseline (post–Dose 1) 
to Month 10 
Pharmacokinetics assessments 
Blood and CSF samples for the assay of deferiprone and its 3-O-glucuronide 
metabolite will be collected at the following time points: 
 
CSF samples (subset 
of 18 patients only) 
Month 3:  A total of 18 samples from 18 patients:  
6 of the samples to be collected pre-dose, 6 to be 
collected at 2 hours post-dose (± 15 minutes), and 
6 to be collected at 4 hours post-dose (± 15 minutes). 
The time of sample collection for each patient will 
be assigned prior to the Month 3 visit. 
 
 


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Page 9 of 80 
ApoPharma Inc. 
Deferiprone delayed release tablets 
Schedule of treatment 
and assessments 
(cont’d): 
 
Sparse collection of 
blood samples (all 
patients) 
Baseline and Month 3:  Three samples collected at 
each visit: 1 collected pre-dose, 1 collected at 
2 hours post-dose (± 45 minutes), and 1 collected 
at 4 hours post-dose (± 45 minutes), with a 
minimum of 1 hour between samples. 
Note:  For the subset of patients who have agreed to 
provide a CSF sample at Month 3, the applicable 
blood sample at Month 3 (either pre-dose, 2 hours 
post-dose, or 4 hours post-dose) is to be taken 
within ± 15 minutes of the CSF sample. 
Extensive collection 
of blood samples 
(subset of 16 patients 
only) 
Month 1:  18 samples from each patient:  Pre-dose 
and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.33, 
2.66, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, and 12.0 
hours post-dose 
 
 
Statistical methods: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data from all patients who were randomized to receive placebo will be combined 
into one group for the statistical analyses. Thus, there will be 5 treatment groups in 
the efficacy and safety analyses:  placebo and 300 mg, 600 mg, 900 mg, and 1200 
mg deferiprone. 
 
Efficacy Analysis 
The data on the change from baseline to each follow-up visit will be summarized, 
by treatment group and overall, using descriptive statistics for each continuous 
efficacy endpoint. Frequency and proportion will be presented for each discrete 
efficacy endpoint. Analysis of variance (ANOVA) will be used to compare means, 
and Fisher’s exact test will be used to compare proportions. 
An analysis of covariance (ANCOVA) approach will be used for assessing the 
deferiprone effect on change from baseline to study end for all efficacy variables 
except time elapsed until rescue medication, with baseline value as a covariate, and 
treatment group and visit as the main factors in the model. Each deferiprone group 
will be compared to the placebo group to assess the treatment effect at each 
deferiprone dose level. Regression analysis will be employed to assess the dose-
response relationship. If a statistically significant relationship exists between 
deferiprone dose and an efficacy outcome, the dose-response relationship will be 
assessed through pairwise comparison of each dose level to the next lower dose 
level: 1200 mg vs. 900 mg, 900 mg vs. 600 mg, and 600 mg vs. 300 mg. A time to 
event analysis will be performed to compare the time elapsed until the need for 
rescue medication among the treatment groups. 
 
Safety Analysis 
The safety data for continuous variables will be summarized using descriptive 
statistics, and the safety data for discrete variables will be tabulated with frequency 
tables. 
 


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Deferiprone delayed release tablets 
Statistical methods 
(cont’d) 
Pharmacokinetic/Pharmacodynamic Analysis 
The pharmacokinetics parameters will be summarized using descriptive statistics. 
The power model will be used for assessing dose proportionality of AUC. 
Relationships will be assessed between the appropriate PK parameters and 
pharmacodynamics biomarkers and efficacy endpoints. 
Version and date of 
protocol: 
Version 4.0, 20 MAR 2017 


LA48-0215           
 
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CONFIDENTIAL 
Page 11 of 80 
ApoPharma Inc. 
Deferiprone delayed release tablets 
 
TABLE OF CONTENTS 
 
SIGNATURE PAGES .............................................................................................................2 
SYNOPSIS ................................................................................................................................4 
LIST OF IN-TEXT TABLES ...............................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................15 
1 
INTRODUCTION......................................................................................................17 
1.1 
Background of the Disease ......................................................................................17 
1.2 
Background of the Investigational Product .............................................................18 
1.3 
Rationale ..................................................................................................................18 
1.4 
Potential Risks and Benefits ....................................................................................19 
2 
STUDY OBJECTIVES ..............................................................................................20 
2.1 
Primary Objective ....................................................................................................20 
2.2 
Secondary Objectives ..............................................................................................20 
2.3 
Exploratory Objectives ............................................................................................20 
3 
STUDY DESIGN ........................................................................................................20 
3.1 
Description of Study Design ...................................................................................20 
3.2 
Rationale for Study Design .....................................................................................21 
3.3 
Rationale for Selection of Doses .............................................................................22 
4 
STUDY POPULATION ............................................................................................23 
4.1 
Number of Patients ..................................................................................................23 
4.2 
Inclusion Criteria .....................................................................................................23 
4.3 
Exclusion Criteria ....................................................................................................24 
4.4 
Enrolment Violations ..............................................................................................25 
4.5 
Patient Withdrawal ..................................................................................................25 
4.5.1 
Follow-up of Patient Withdrawal Due to Pregnancy .......................................26 
4.5.2 
Replacement of Patients Who Withdraw .........................................................27 
4.5.3 
Treatment Interruptions ...................................................................................27 
4.6 
Prior and Concomitant Therapies ............................................................................27 
4.7 
Rescue Medication ..................................................................................................28 
5 
STUDY PROCEDURES ...........................................................................................28 
5.1 
Visit Procedures ......................................................................................................32 
5.2 
Method of Assignment to Treatment .......................................................................43 
5.3 
Blinding Procedures ................................................................................................43 


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Deferiprone delayed release tablets 
5.4 
Allocation of Patient Numbers ................................................................................44 
5.5 
Treatment Compliance ............................................................................................44 
6 
STUDY TREATMENTS ...........................................................................................45 
6.1 
Investigational Product ............................................................................................45 
6.1.1 
Dosage Form and Mode of Administration .....................................................45 
6.1.2 
Precautions for Use ..........................................................................................45 
6.2 
Reference Product ...................................................................................................45 
6.3 
Packaging and Labeling ..........................................................................................45 
6.4 
Shipping and Storage ...............................................................................................46 
6.5 
Dispensing Procedures ............................................................................................46 
6.6 
Product Accountability ............................................................................................46 
6.7 
Replacement Doses .................................................................................................47 
6.8 
Disposition of Unused Product ................................................................................47 
6.9 
Other Study Supplies ...............................................................................................48 
7 
MEASUREMENTS AND EVALUATIONS ...........................................................48 
7.1 
Efficacy Measurements ...........................................................................................48 
7.1.1 
Primary Efficacy Measurements ......................................................................48 
7.1.1.1 
Motor Score on the Unified Parkinson’s Disease Rating Scale ...............48 
7.1.2 
Secondary Efficacy Measurements ..................................................................49 
7.1.2.1 
Total Score on the Unified Parkinson’s Disease Rating Scale .................49 
7.1.2.2 
Other Scores on the Unified Parkinson’s Disease Rating Scale ...............49 
7.1.2.3 
Montreal Cognitive Assessment Test .......................................................49 
7.1.2.4 
Oxidative Stress Biomarkers ....................................................................49 
7.1.2.5 
Inflammatory Factor Biomarkers .............................................................50 
7.1.3 
Exploratory Efficacy Measurements................................................................50 
7.1.3.1 
D544E (AT) Polymorphisms of Ceruloplasmin .......................................50 
7.1.3.2 
Ceruloplasmin Levels and Ceruloplasmin Ferroxidase Activity ..............50 
7.1.3.3 
V158M Polymorphisms of Catechol O-methyltransferase.......................50 
7.2 
Safety Measurements ..............................................................................................51 
7.2.1 
Medical Events, Adverse Events, and Serious Adverse Events ......................51 
7.2.1.1 
Definition of Medical Events and Adverse Events ...................................51 
7.2.1.2 
Monitoring and Documenting of Medical Events and Adverse 
Events .......................................................................................................52 


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7.2.1.3 
Assessment of Causality ...........................................................................53 
7.2.1.4 
Assessment of Intensity ............................................................................54 
7.2.1.5 
Serious Adverse Events ............................................................................54 
7.2.1.6 
Reporting of Serious Adverse Events .......................................................55 
7.2.1.7 
Follow-up and Documentation of SAEs ...................................................55 
7.2.1.8 
Adverse Events of Special Interest ...........................................................56 
7.2.2 
Laboratory Measurements ...............................................................................58 
7.2.3 
Other Safety Measurements .............................................................................59 
7.2.3.1 
Physical Examination ...............................................................................59 
7.2.3.2 
Vital Signs ................................................................................................60 
7.2.3.3 
Electrocardiogram .....................................................................................60 
7.2.3.4 
Columbia Suicide Severity Rating Scale ..................................................60 
7.2.3.5 
Concomitant Medications .........................................................................60 
7.2.4 
Procedures in Case of Pregnancy .....................................................................61 
7.3 
Pharmacokinetics Measurements ............................................................................61 
7.3.1 
Collection of Samples ......................................................................................61 
7.3.2 
Processing of Samples .....................................................................................62 
8 
STUDY COMMITTEES ...........................................................................................62 
9 
STATISTICAL ANALYSIS .....................................................................................62 
9.1 
Endpoints .................................................................................................................62 
9.1.1 
Primary Endpoint .............................................................................................62 
9.1.2 
Secondary Endpoints .......................................................................................63 
9.1.3 
Exploratory Endpoints .....................................................................................63 
9.1.4 
Safety Endpoints ..............................................................................................63 
9.1.5 
Pharmacokinetics Endpoints ............................................................................64 
9.2 
Determination of Sample Size and Study Power ....................................................64 
9.3 
Study Populations ....................................................................................................64 
9.3.1 
Intent-to-Treat Population ................................................................................64 
9.3.2 
Per Protocol Population ...................................................................................65 
9.3.3 
Safety Population .............................................................................................65 
9.3.4 
Pharmacokinetics Population ...........................................................................65 
9.4 
Data Analysis Plan ..................................................................................................65 
9.4.1 
Planned Analyses .............................................................................................65 


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9.4.1.1 
Patient Disposition and Drug Exposure ....................................................65 
9.4.1.2 
Patient Characteristics ..............................................................................66 
9.4.1.3 
Analysis of Efficacy .................................................................................66 
9.4.1.4 
Analysis of Safety .....................................................................................67 
9.4.1.5 
Pharmacokinetics Analyses ......................................................................69 
9.4.2 
Interim Analyses ..............................................................................................69 
9.5 
Criteria for Evaluability of Patient Data ..................................................................69 
10 
DATA MANAGEMENT CONSIDERATIONS......................................................69 
10.1 
Data Management ....................................................................................................69 
10.2 
Case Report Forms ..................................................................................................70 
11 
MONITORING, AUDITS, AND INSPECTIONS ..................................................70 
11.1 
Source Documents ...................................................................................................70 
11.2 
Monitoring ...............................................................................................................71 
11.3 
Audits and Inspections ............................................................................................71 
11.4 
Site Closure .............................................................................................................71 
11.5 
Retention of Records ...............................................................................................72 
12 
ETHICAL CONSIDERATIONS ..............................................................................72 
12.1 
Informed Consent ....................................................................................................72 
12.2 
Institutional Review Board/Independent Ethics Committee ...................................73 
12.3 
Patient Confidentiality .............................................................................................73 
13 
REGULATORY REQUIREMENTS .......................................................................74 
13.1 
Regulatory Obligations ............................................................................................74 
13.2 
Amendments to the Protocol ...................................................................................75 
14 
EARLY STUDY TERMINATION ..........................................................................75 
15 
CONFIDENTIALITY ...............................................................................................75 
16 
OWNERSHIP .............................................................................................................75 
17 
PUBLICATION .........................................................................................................76 
18 
REFERENCES ...........................................................................................................77 
APPENDIX 1:  CLINICAL STUDY ADMINISTRATIVE STRUCTURE .....................80 
 
LIST OF IN-TEXT TABLES  
Table 5.1 
Table of study procedures ..................................................................................29 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
AE 
adverse event 
ANC 
absolute neutrophil count 
ANOVA 
analysis of variance 
ANCOVA 
analysis of covariance 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CS 
clinically significant 
CI 
confidence interval 
CRA 
clinical research associate 
CRO 
contract research organization 
COMT 
catechol O-methyltransferase 
CSF 
cerebrospinal fluid 
DBS 
Deep Brain Stimulation 
DR 
delayed release 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IVRS/IWRS 
interactive voice/web response system 


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Abbreviation 
Definition 
MDS-UPDRS 
Movement Disorder Society-Unified Parkinson’s Disease Rating 
Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MoCA 
Montreal Cognitive Assessment 
MOA 
mechanism of action 
NCS 
not clinically significant 
PD 
Parkinson’s disease 
PK 
pharmacokinetics 
PT 
preferred term 
ROS 
reactive oxygen species 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
WHO 
World Health Organization 


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1 
INTRODUCTION 
1.1 
Background of the Disease 
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects about 1% of 
the over-60 population.  It is characterized by severe motor symptoms including uncontrollable 
tremor, postural imbalance, slowness of movement, rigidity, and psychiatric and cognitive 
disorders,1 as well as by an elevated rate of mortality.2 
The main hallmark of PD is loss of dopaminergic neurons in the substantia nigra; accordingly, 
pharmacological treatments have focused on restoring dopaminergic neurotransmission to 
relieve motor symptoms. However, these treatments have several major limitations. The 
dopaminergic medications that are currently available modulate the several steps involved in 
dopamine transmission, but they do not act directly on the activity of the presynaptic 
dopamine transporter that could directly impact the extracellular dopamine level. Moreover, in 
addition to the dopaminergic system, the noradrenergic, cholinergic, and neurotransmission 
glutamatergic systems are also impacted in PD, and these too may have involvement in a 
variety of motor and non-motor symptoms of PD. All of the treatments currently used in PD 
act on symptoms, not on the disease per se. Thus, there is an urgent need for disease-
modifying treatments that could slow progression and reduce the occurrence of the disabling 
disorders seen in late-stage PD. 
As with several other chronic neurological disorders, PD is associated with brain iron 
accumulation:  specifically, an increase of iron in the substantia nigra is another hallmark of 
the disease.3  While iron is essential for normal physiological function, an excessive amount 
of it or dysregulation of its metabolism is potentially toxic. Excessive “free” iron in tissues is 
believed to lead to generation of reactive oxygen species (ROS), including the extremely 
damaging hydroxyl radical, and to cause localized toxicity and oxidative neuronal destruction.4,5  
Determining the molecular mechanisms that underlie iron dysregulation and the 
neurodegeneration induced by ROS could lead to therapies that would restore brain iron 
homeostasis and reduce neurodegeneration. In PD, the regions of the brain with the highest 
iron accumulation include those that control motor output. Thus, motor impairment is 
thought to be due, at least in part, to the oxidative damage and necrosis that occurs as a result 
of long-term iron-induced damage.6,7,8 
It is possible that if excess labile iron can be sequestered from vulnerable brain regions prior 
to cell death, oxidative neuronal loss may be prevented and thus, disease progression and the 
ensuing clinical symptoms of Parkinson’s disease could be reduced. In conditions of iron 
overload, the accepted therapeutic strategy for the management of iron accumulation is 
administration of iron chelators, which both increases iron excretion and prevents the toxic 


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effects of iron excess. Although patients with PD do not have generalized iron overload, 
mismanagement of iron in the brain appears to lead to neurotoxicity and to localized 
deposition of excess iron. These deposits may contribute to or mark an aspect of disease 
pathology, or may reflect the tissues’ attempt to render labile iron less harmful. In either case, 
removal of the excess iron may be a strategy for treating PD. The aim of chelation would be 
to bind excess labile cell iron and transfer it, directly or indirectly, to endogenous acceptors, 
such as transferrin, for transport to other compartments inside or outside the cells for reuse.6 
1.2 
Background of the Investigational Product 
Deferiprone (IUPAC name 3-hydroxy-1,2-dimethylpyridin-4-one) is an iron (III)-chelating 
agent. An immediate-release formulation of deferiprone, Ferriprox®, was first approved in 
1999 by the European Medicines Agency for the treatment of systemic iron overload in 
patients with thalassemia major; and deferiprone is currently approved for that indication in 
over 60 countries. 
Deferiprone appears to fulfill several criteria required of a chelator with clinical applicability 
in localized intracellular iron mismanagement in the brain: 
 It has the ability to gain access to cells,9 effectively bind to labile iron within a cell to 
create an iron-chelator complex,10 and exit the cell in that form, thereby reducing the 
formation of iron-dependent free radicals 11,12,13 
 It spares extracellular transferrin-bound iron and potentially transfers chelated iron to 
transferrin 14,15,16,17 
 It can donate iron for metabolic reutilization 16 
 Because of its low molecular weight and favorable physicochemical properties, it has 
been shown in animal studies to readily cross the blood-brain barrier, 18 and there is 
indirect evidence to suggest that it does so in human as well 14 
Deferiprone has been investigated in several neurological disorders that are associated with 
localized iron accumulation or disturbance of iron homeostasis.  In patients with PD, 
Friedreich’s ataxia, and pantothenate kinase-associated neurodegeneration, deferiprone has 
been shown to reduce the characteristic regionally elevated levels of brain iron, as evidenced 
by MRI scans.19,20,21 
1.3 
Rationale 
Based on reports in the literature that deferiprone can act to reduce iron within the substantia 
nigra as well as slow the progression of motor handicap symptoms associated with PD, 19,21 
ApoPharma Inc. is proceeding with a clinical development plan to investigate the use of 


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deferiprone for this indication.  The trials will use a new formulation of deferiprone that is 
currently under development: an enteric-coated 600 mg delayed release tablet, deferiprone-DR, 
which would support less frequent administration than the licensed immediate-release tablets 
and may be associated with better tolerability. In a Phase 1 study conducted in healthy 
volunteers, single doses of deferiprone-DR were found to be safe and well tolerated, and 
showed a similar extent of drug exposure but a 50% lower peak exposure when compared to 
the immediate-release formulation.22 
The Phase 2 dose-ranging trial described in this protocol seeks to establish the dosages of 
deferiprone-DR in Parkinson’s disease patients that would show clinical efficacy while 
maintaining an acceptable safety profile.  A population of patients with relatively recent 
onset of the disease (<3 years since diagnosis) will be studied, as the goal is to sequester 
excess labile iron from vulnerable brain regions prior to cell death. 
1.4 
Potential Risks and Benefits 
Risks:  The safety profile of deferiprone has been extensively characterized in patients with 
systemic iron overload. The most serious adverse event associated with its use in that 
population 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 mechanism of deferiprone-associated agranulocytosis 
is unknown. Agranulocytosis usually resolves upon discontinuation of deferiprone, but there 
have been post-marketing reports of it leading to death.  Accordingly, deferiprone recipients 
are required to undergo weekly hematology testing to ensure early detection of a drop in ANC.  
The most common non-serious adverse reactions reported during clinical trials have been 
chromaturia (due to iron excretion), nausea, vomiting, abdominal pain, increased alanine 
aminotransferase, arthralgia, and mild or moderate neutropenia (ANC less than 1.5 × 109/L).23  
The safety profile observed so far in patients with local iron overload has been found to be 
similar to that seen in the population with systemic iron overload, with respect to major risks.  
For detailed information on adverse events associated with deferiprone, see the Investigator’s 
Brochure. 24 
Benefits:  The findings of preclinical and clinical research suggest that deferiprone has the 
potential to access pathologically relevant brain iron and to produce clinical benefit in 
patients with Parkinson’s disease. The currently available medications for PD act only on 
symptoms, not on the underlying cause of the disorder. This treatment may possibly act to 
prevent the cell death that gives rise to those symptoms. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To evaluate the efficacy of four different dosages of deferiprone delayed release tablets in 
patients with Parkinson’s disease. 
The endpoints for the primary objective are provided in Section 9.1.1. 
2.2 
Secondary Objectives 
 To evaluate the safety and tolerability of deferiprone delayed release tablets in 
patients with Parkinson’s disease 
 To evaluate the pharmacokinetics of deferiprone delayed release tablets in a subset of 
study participants 
 To evaluate the relationship between the pharmacokinetics and pharmacodynamics of 
deferiprone delayed release tablets 
The endpoints for the secondary objectives are provided in Section 9.1.2. 
2.3 
Exploratory Objectives 
 To determine whether the efficacy responses to deferiprone differ depending on the 
genotype of certain enzymes that are implicated in Parkinson’s disease 
 To determine whether the efficacy responses to deferiprone are correlated with 
ceruloplasmin levels or ceruloplasmin ferroxidase activities 
The endpoints for the exploratory objectives are provided in Section 9.1.3. 
3 
STUDY DESIGN 
3.1 
Description of Study Design 
This is a multi-center, randomized, double-blind, placebo-controlled, dose-ranging study in 
140  patients who have been diagnosed with typical Parkinson’s disease within the last 3 
years and are currently taking antiparkinsonian medication.  Screening will be conducted 
within 30 days prior to the start of dosing. At baseline, eligible participants will be 
randomized to one of four dosage cohorts, and within each cohort will be further randomized 
in a 4:1 ratio to receive either active product or placebo. The assigned study product will be 
taken twice-daily (b.i.d.), at least 8 hours apart, for 9 months.  Dosages are as follows: 


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 Cohort 1:  300 mg deferiprone delayed release tablets (n=28) or placebo (n=7) 
 Cohort 2:  600 mg deferiprone delayed release tablets (n=28) or placebo (n=7) 
 Cohort 3:  900 mg deferiprone delayed release tablets (n=28) or placebo (n=7) 
 Cohort 4:  1200 mg deferiprone delayed release tablets (n=28) or placebo (n=7) 
 
Patients will return to the site at Months 1, 2, 3, 4, 5, 6, and 9, and will receive a follow-up 
telephone call at Month 10. Safety will be assessed at each site visit and at the follow-up call; 
efficacy measures will be assessed at baseline and Months 3, 6, and 9; and sparse 
pharmacokinetics (PK) sampling will be done on all patients at baseline and Month 3.  In 
addition, an optional subset of 16 patients will undergo extensive blood sampling for PK 
analysis at Month 1, and an optional subset of 18 patients will each provide one sample of 
cerebrospinal fluid (CSF) for drug level analysis at Month 3.  (No selection will be done to 
enroll these subsets:  all patients will be asked if they are willing to provide either or both of 
these types of samples, and they will be enrolled as they come until the total number of 
subjects is reached for each subset.)  For safety reasons, all patients will have their absolute 
neutrophil count  monitored weekly after the start of dosing. This procedure may be done 
either at either the study site or a local laboratory, or, with sponsor approval, at the patient’s 
home by a visiting study nurse. 
Any patient who withdraws before completing treatment will be requested to return within 
one month for an Early Termination visit, at which time the procedures normally scheduled 
for the Month 9 visit will be conducted.   
3.2 
Rationale for Study Design 
The study is placebo-controlled since improvement, stabilization, or even a lesser worsening 
of motor symptoms in the active treatment groups compared to the placebo group would 
indicate efficacy. 
The rationale for enrolling patients who are currently on antiparkinsonian medications is 
because the MDS-UPDRS scores of such patients are expected to be higher than those of 
patients who are treatment-naïve and recently diagnosed. Since the primary endpoint of the 
study is the change from baseline in MDS-UPDRS score, and the N is relatively small, the 
presence of higher scores at the start of the study should more easily permit the detection of a 
significant change in score between the deferiprone-treated and the placebo-treated groups.  
Furthermore, this population matches those used in investigator-led studies that showed 
promising results. 19,21   
The selection of study duration is based on findings in the literature.  An investigator-driven 
pilot study found a significant difference between deferiprone and placebo after 6 months, 


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indicating that this duration might be sufficient to assess a symptomatic effect.19 However, in 
order to assess a delay in the progression of the disease, treatment of 9 months would be 
preferable. Indeed, in the only study to have successfully demonstrated such an effect in 
PD,25,26 treatment of 9 months was chosen as being a balance between being sufficiently long to 
observe the best global effect, but sufficiently brief to avoid the need for any change in current 
antiparkinsonian treatment. Hence, the duration of treatment in study LA48-0215 will be 
9 months.  
3.3 
Rationale for Selection of Doses 
The objective of this study is to determine what dose of deferiprone is likely to provide the 
most favorable benefit/risk ratio for the treatment of patients with PD:  i.e., the balance 
between being high enough to have an effect but low enough to avoid clinically important 
toxicity.  Data from two investigator-driven studies suggest that 15 mg/kg b.i.d. is the dose 
most likely to provide the greatest benefit vs. risk, but relatively few patients were enrolled in 
those studies. 19,21  In the case of thalassemia patients with systemic iron overload, dosages of 
Ferriprox are defined in terms of mg per kg of body weight; however, the span of weight in 
that patient population varies 10-fold, as both children and adults are being treated. In the case 
of PD, body weight is likely to vary less than 4-fold for the vast majority of patients, and 
according to key opinion leaders in the PD field, the average body weight in patients with PD 
is about 80 kg.  Using 4 fixed doses of 300, 600, 900, and 1200 mg b.i.d. (i.e., for total daily 
dosages of 600, 1200, 1800, and 2400 mg) and an inclusion criterion of body weight between 
60 and 100 kg, the following doses in terms of mg/kg/day should be obtained: 
 
Actual Dose Received (mg/kg/day) When Prescribed Fixed Doses 
Body weight (kg) 
300 mg b.i.d. 
600 mg b.i.d. 
900 mg b.i.d. 
1200 mg b.i.d. 
60 
10 
20 
30 
40 
70 
9 
17 
26 
34 
80 
8 
15 
23 
30 
90 
6 
13 
20 
27 
100 
6 
12 
18 
24 
 


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4 
STUDY POPULATION 
4.1 
Number of Patients 
A total of 140 patients will be randomized. 
4.2 
Inclusion Criteria 
Individuals will be eligible to enroll in the study if they meet all the following criteria: 
1. Male or female aged ≥18 to < 80 years 
2. Body weight ≥60 kg but ≤100 kg 
3. Diagnosis of Parkinson’s disease according to UK Parkinson’s Disease Society Brain 
Bank Clinical Diagnostic Criteria and based on the presence of at least two of the three 
cardinal features of the disease (rest tremor, bradykinesia, and rigidity).  If rest tremor is 
not present, patient must have unilateral onset of symptoms. 
4. Absolute neutrophil count ≥1.5 x 109/L (≥1.0 x 109/L for Black population) at screening 
5. On a stable dose for at least 3 months prior to the screening visit of any of the following 
treatments at an L-dopa equivalent daily dose of up to 600 mg: 
o 
Dopaminergic agonist alone  
o 
L-dopa alone 
o 
Combination therapy with dopaminergic agonist and L-dopa 
o 
Rasagiline 
6. At an early stage of the disease, without motor fluctuations and/or L-dopa–induced 
dyskinesia 
7. A female patient must meet one of the following criteria: 
 If of childbearing potential, have a negative pregnancy test result at screening.  In 
addition, she must: 
a. Agree to use an effective method of contraception according to local 
requirements, during the study and for 30 days following the last dose of study 
medication, OR 
b. Have undergone a tubal ligation (supporting evidence required), OR 
c. Abstain from heterosexual intercourse, OR 
d. Have a male sexual partner who has been sterilized (supporting evidence 
required) 
 Be of non-childbearing potential, defined as surgically sterile, having undergone 
complete hysterectomy or bilateral oophorectomy (supporting evidence required) or 


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being in a menopausal state (being 50 years of age or older and at least 1 year without 
menses) 
8. Fertile heterosexual males must agree to use an effective method of contraception during 
the study and for 30 days following their last dose of study medication 
9. All patients and/or their authorized legal representatives must provide signed and dated 
written informed consent prior to the first study intervention, and patients must be able to 
adhere to study restrictions, appointments, and evaluation schedules 
4.3 
Exclusion Criteria 
Individuals will be excluded from enrollment if they meet any of the following criteria: 
1. Diagnosis of Parkinson’s disease more than 3 years prior to screening visit 
2. Hoehn and Yahr stage ≥ 3 
3. Atypical or secondary Parkinsonism without dopa-sensitivity (e.g., vascular parkinsonism, 
supranuclear palsy, multisystem atrophy) 
4. Progressing Axis I psychiatric disorders (psychosis, hallucinations, compulsive disorders, 
substance addiction, bipolar disorder, severe depression, anxiety) as assessed in a semi-
structured interview in accordance with the Diagnostic and Statistical Manual of Mental 
Disorders 
5. Not stabilized in terms of the current antiparkinsonian therapeutic regimen:  already 
requires dose adaptation and/or is likely to require any change in dopamine therapy over 
the duration of the trial 
6. Current treatment with bromocriptine 
7. Current treatment with any antiparkinsonian drug other than those listed in inclusion 
criterion #5 
8. Current treatment with coenzyme Q10 or idebenone.  (Patients who are on these 
medications but stop taking them at least 2 weeks prior to baseline may be enrolled.) 
9. Current use of a Deep Brain Stimulation (DBS) system. (Patients who previously had a 
DBS system but have had it removed may be enrolled.) 
10. History of malignancy, with the exception of cancers that have been in remission for 
≥5 years at the time of screening 
11. 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) 
12. A serious, unstable illness, as judged by the investigator, during the past 3 months before 
screening visit, including but not limited to hepatic, renal, gastro-enterologic, respiratory, 
cardiovascular, endocrinologic, or immunologic disease 


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13. Disorders associated with neutropenia (ANC < 1.5 x 109/L; < 1.0 x 109/L in Black 
population) or thrombocytopenia (platelet count < 50 x 109/L) in the 12 months preceding 
the initiation of the study medication. Exception: For 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 is back to a normal level at the 
screening visit. 
14. Clinically significant abnormalities on 12-lead ECG, as judged by the investigator 
15. Myocardial infarction, cardiac arrest, or cardiac failure within 1 year before screening visit 
16. Bowel disease causing malabsorption 
17. History of allergy or sensitivity to deferiprone or to other components of the formulation 
18. Receipt of any investigational products within the past 30 days or 5 half-lives (whichever 
is longer) preceding the first dose of study medication 
19. 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 screening 
until 30 days post-treatment in the current study 
20. History of or current drug or alcohol use or dependence which in the opinion of the 
investigator would interfere with adherence to study requirements 
21. Presence of any medical, psychological, or psychiatric condition which in the opinion of 
the investigator would cause participation in the study to be unwise 
22. Pregnant, breastfeeding, or planning to become pregnant during the study period 
23. Identified as an investigator or other site staff directly affiliated with this study, or an 
immediate family member (spouse, parent, child, or sibling, whether biological or legally 
adopted) of either of the above 
4.4 
Enrolment Violations 
The criteria for enrolment must be followed explicitly.  If there is inadvertent enrolment of a 
patient who does not meet the enrolment criteria, the investigator should consider withdrawing 
that individual from the study. 
4.5 
Patient Withdrawal 
Patients have the right to withdraw from the study at any time and for any reason without 
consequence to future care by the investigator or study site. 
A patient may be withdrawn from the study at any time for any of the following reasons: 


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 
Medical or safety reasons considered significant by the patient and/or the investigator 
 
Requirement for concomitant medication that might interfere with the evaluation of 
study treatment or may be contraindicated 
 
Occurrence of other illnesses that might affect the patient’s further participation in 
the study or evaluation of study treatment 
 
A protocol deviation that might interfere with study assessments, as judged by the 
investigator 
 
Repetitive patient non-compliance with the protocol or with instructions of the 
investigator 
 
Any other situation where, in the opinion of the investigator, continuation of the 
study would not be in the best interest of the patient 
A patient must be withdrawn from the study if any of the following conditions apply: 
 
Pregnant or planning to become pregnant during the study period (see Section 7.2.4, 
Procedures in Case of Pregnancy) 
 
Occurrence of severe neutropenia/agranulocytosis (see Section 7.2.1.8.1, Neutropenia) 
 
Occurrence of any adverse event characterized as life-threatening or disabling that is 
not associated with the patient’s condition 
 
Receipt of a rescue medication (see Section 4.7 for definition) 
 
Termination of the study by the sponsor 
Patients who decide to withdraw from the study should always be contacted, if possible, in 
order to ask about the reason for withdrawal, whether any adverse events (AEs) occurred, 
and use of concomitant medications.  A withdrawn patient should return for an Early 
Termination Visit within one month of withdrawal. All study product and materials should be 
returned.  If any AEs occurred, the investigator must attempt to follow up the outcome for 30 
days post-termination. 
If a patient withdraws or is withdrawn before completing the study, the date and reason for 
the withdrawal must be entered on the source document and on the appropriate page of the 
electronic case report form (eCRF), and all other appropriate eCRF pages must be completed. 
4.5.1 Follow-up of Patient Withdrawal Due to Pregnancy 
All females of childbearing potential must have a negative serum pregnancy test at the 
screening visit and prior to first administration of the study drug, and must agree to use an 
approved method of contraception throughout the course of the trial and up to 1 month 


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following the last dose of study medication.  If a patient does become pregnant, the 
investigator must do the following upon becoming aware of the pregnancy: 
 Ensure that the study medication is stopped immediately 
 Inform the sponsor via the pregnancy report form 
 With the patient’s consent, follow the pregnancy closely, and provide reports to the 
sponsor until delivery or other resolution 
A male patient must inform the investigator if his female partner becomes pregnant during 
the trial or within 1 month following the last dose of study medication. As with the 
pregnancy of a female patient, the site must inform the sponsor and, if the partner consents, 
follow the pregnancy and provide the sponsor with a report on its outcome. 
4.5.2 Replacement of Patients Who Withdraw 
Patients who are withdrawn from the study will not be replaced. 
4.5.3 Treatment Interruptions 
Patients should be advised to immediately report any symptoms indicative of infection such 
as fever (≥38.5°C), sore throat, or flu-like symptoms. If a patient develops fever or any type 
of infection, 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 (<1.0 x 109/L for 
black patients). Therapy with deferiprone can be re-initiated once all symptoms have 
resolved and it is deemed safe by the investigator. 
4.6 
Prior and Concomitant Therapies 
Prior Therapies:  
 Patients must have been on a stable dose for at least the past 3 months of any of the 
following treatments at an L-dopa equivalent daily dose of up to 600 mg: 
o Dopaminergic agonist alone  
o L-dopa alone 
o Combination therapy with dopaminergic agonist and L-dopa 
o Rasagiline 
 If coenzyme Q10 or idebenone is being taken, it must be stopped at least 2 weeks prior 
to baseline 
 If a Deep Brain Stimulation (DBS) system had been in place, it must have been 
removed at least 3 months prior to  baseline 


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Concomitant Therapies:   
 The regimen of antiparkinsonian medication that was in effect at the time of screening 
must remain stable throughout the trial 
 During the trial, patients may not use a DBS system; may not take coenzyme Q10, 
idebenone, bromocriptine, or any antiparkinsonian drug other than those listed in 
inclusion criterion #5; and may not take any other investigational product or any drugs 
that are known to cause neutropenia or agranulocytosis. Other medications that are 
being taken on a stable regimen and that are considered necessary for the patient’s 
welfare may continue to be taken, at the discretion of the investigator. 
All medications (including herbal medications and over-the-counter medications) and 
nutritional supplements taken from 3 months prior to screening up to Month 10 or early 
termination must be reviewed by the investigator and recorded in the source document and 
in the appropriate section of the eCRF. 
4.7 
Rescue Medication 
A patient whose regimen of antiparkinsonian medication is changed, including a change in 
dosage, must be withdrawn from the trial. 
In order for rescue medication to be provided, the patient must a) request it and b) show a 
worsening of condition as evidenced by at least one of the following: 
 An increase of ≥5 points on the MDS-UPDRS Part III score from baseline 
 An increase of ≥8 points on the total MDS-UPDRS score from baseline 
For patients who meet the above criteria, the reason for withdrawal will be defined as need 
for a rescue medication. 
 
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 -30–0 
(Screening) 
Month 0, 
Day 0 
(Baseline) 
Month 1 
± 5 days 
Month 2 
± 5 days 
Month 3 
± 5 days 
Month 4 
± 5 days 
Month 5 
± 5 days 
Month 6 
± 5 days 
Month 9 
± 5 days 
or Early 
Termination 
Month 10 
 +5 days 
Telephone 
Call 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
V 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
MDS-UPDRS 1  
 
X 
 
 
X 
 
 
X 
X 
 
MoCA 1 
 
X 
 
 
X 
 
 
X 
X 
 
C-SSRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 2 
X 3 
Weekly (±3 days) after start of dosing until Month 9 
 
Blood chemistry 4 
X 3 
 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 5 
X 3 
 
 
 
X 
 
 
X 
X 
 
Pregnancy testing 6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination 7 
X 
X 
 
X 
 
X 
 
X 
X 
 
Vital signs (supine and 
standing) and body 
temperature 8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
X 3 
 
 
 
 
 
 
 
X 
 
Contraceptive counseling  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood for PK analysis 
 
X 9 
X 10 
 
X 11 
 
 
 
 
 
Blood for biomarkers 12 
 
X 
 
 
X 
 
 
X 
X 
 
Urine for biomarkers 13 
 
X 
 
 
X 
 
 
X 
X 
 
CSF sampling 14 
 
 
 
 
X 
 
 
 
 
 


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Day -30–0 
(Screening) 
Month 0, 
Day 0 
(Baseline) 
Month 1 
± 5 days 
Month 2 
± 5 days 
Month 3 
± 5 days 
Month 4 
± 5 days 
Month 5 
± 5 days 
Month 6 
± 5 days 
Month 9 
± 5 days 
or Early 
Termination 
Month 10 
 +5 days 
Telephone 
Call 
Dispense study 
medication 15 
 
X 
 
X 
 
X 
 
X 
 
 
Provide diary card 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Dosing 16 
 
Twice daily from baseline until Month 9 
 
Review and collect diary 
card 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Collect used and unused 
study medication 
containers 
 
 
 
X 
 
X 
 
X 
X 
 
Treatment compliance 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Prior & concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical events 
 
X  
 
 
 
 
 
 
 
 
Adverse events 
 
Throughout the study after start of dosing 
 
Abbreviations 
V:  Verify;  ECG:  Electrocardiogram; C-SSRS:  Columbia Suicide Severity Rating Scale; MDS-UPDRS:  Movement Disorder Society - Unified Parkinson’s Disease 
Rating Scale;  MoCA:  Montreal Cognitive Assessment; PK:  Pharmacokinetics;  CSF:  cerebrospinal fluid 
1 
The MDS-UPDRS and the MoCA are to be conducted early in the morning, at approximately the same time (± 1 hour) at each visit, and by the same 
qualified investigator at each visit. 
2 
Hematology:  Hemoglobin, total WBC count, ANC, MCV, and platelet count. 
3 
If performed more than 14 days prior to Week 0 (baseline visit), must be repeated before Day 0. 
4 
Blood chemistry:  Total protein, GGT, lactate dehydrogenase (LDH), sodium, potassium, chloride, fasting glucose, bilirubin (total, direct, and indirect), 
AST, ALT, albumin, blood urea nitrogen, calcium, creatinine, uric acid, alkaline phosphatase, amylase, serum ferritin, blood iron, zinc, and copper. 


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5 
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. 
6 
Pregnancy testing:  Females of childbearing potential only.  Both urine and serum tests will be done at baseline; serum test only at all other time points. 
7 
Physical examination:  Weight (without shoes) will be measured only at screening and Month 9 (or early termination visit).  Height will be measured only 
at screening. 
8 
Vital signs:  Orthostatic vital signs (pulse and blood pressure) will be measured in the supine followed by the standing position. At baseline, three sets of 
orthostatic measurements will be conducted, with 10–30 minute intervals between measurements. At all other time points, a single set of measurements 
will be performed. 
9 
PK at baseline: All patients; pre-dose, at 2 hours post-dose (± 45 minutes), and at 4 hours post-dose (± 45 minutes) with a minimum of 1 hour between samples. 
10 
PK at Month 1:  A subset of 16 patients will provide samples pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.33, 2.66, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 
and 12.0 hours post-dose. 
11 
PK at Month 3:  All patients; pre-dose, at 2 hours post-dose (± 45 minutes), and at 4 hours post-dose (± 45 minutes), with a minimum of 1 hour between 
samples.  Note:  For the subset of patients who have agreed to provide a CSF sample at Month 3, the applicable blood sample (either pre-dose, 2 hours 
post-dose, or 4 hours post-dose) is to be taken within ± 15 minutes of the CSF sample. 
12 
Blood samples:  The following biomarkers will be determined: 
 
Oxidative stress biomarkers: total antioxidant status, protein carbonyls,  glutathione, and super oxide dismutase 
 
Inflammatory factor biomarkers: TNF alpha and IL-6 
 
Mechanism of action biomarkers: Determination of catechol O-methyltransferase and ceruloplasmin genotypes (baseline only) and of ceruloplasmin 
levels and ceruloplasmin ferroxidase activity 
13 
Urine sample:  The oxidative stress biomarkers of 8-OHdG and lipid peroxidation (malondialdehyde) will be assessed. 
14 
CSF:  Subset of 18 patients; 6 to provide a sample pre-dose, 6 to provide one at 2 hours post-dose (± 15 minutes), and 6 to provide one at 4 hours post-dose 
(± 15 minutes). The time of sample collection for each of the 18 subjects will be assigned prior to the Month 3 visit. 
15 
Dispensing: A 2-month supply of study product will be provided at Months 0, 2, and 4, and a 3-month supply will be provided at Month 6 
16  
Dosing:  Deferiprone delayed release 600 mg tablets (assigned dose of 300 mg, 600 mg, 900 mg, or 1200 mg) b.i.d. or matching placebo tablets b.i.d, at 
least 8 hours apart 


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5.1 
Visit Procedures 
Note:  Patients are to be instructed to fast before each site visit, including the screening visit.  
On most days the fast will be for at least 8 hours, and on days when pharmacokinetics testing 
is done, it must be for at least 10 hours. 
Screening Visit (Day -30 to Day 0) 
 Explain the study to the patient, and obtain written informed consent 
 Collect demographic information 
 Collect medical history 
 Administer the Hoehn and Yahr scale to determine the patient’s stage of PD (not 
required if supporting documentation from within the last 6 months is available) 
 Conduct a semi-structured interview in accordance with the Diagnostic and Statistical 
Manual of Mental Disorders to determine the presence of Axis I psychiatric disorders 
(not required if supporting documentation from within the last 6 months is available) 
 Collect information on prior and concomitant medications 
 Perform a physical examination (to be completed by the investigator or a qualified 
delegate), including measurement of weight and height (without shoes) 
 Measure orthostatic vital signs (pulse and blood pressure), first in the supine and then in 
the standing position, and body temperature 
 Collect blood samples for the following assessments: 
o Hematology and blood chemistry (including fasting glucose) 
o Pregnancy testing for females of childbearing potential 
 Collect a urine specimen for urinalysis 
 Perform a 12-lead ECG 
 Conduct contraceptive counseling if applicable 
 Schedule baseline visit if all eligibility criteria are met 
Baseline Visit (Month 0, Day 0) 
Notes: 
- 
Hematology, blood chemistry, urinalysis, and ECG testing must have been done within 
14 days prior to the baseline visit. If more than 14 days have elapsed since the 
screening visit, those tests will need to be repeated prior to the baseline visit. 


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- 
As pharmacokinetics testing will be done at this visit, patients must be told 
beforehand to fast for 10 hours rather than 8. (They will be allowed to eat about 1.5 
hours after dosing.) 
- 
At this visit, it must be kept in mind that at Months 3, 6, and 9, the MDS-UPDRS and 
MoCA will need to be administered at approximately the same time of day as at baseline 
(early in the morning) and must be conducted by the same qualified investigator. 
 Collect information on any medical events 
 Collect information on concomitant medications 
 Measure vital signs: three sets of orthostatic vital signs (pulse and blood pressure), first 
in the supine and then in the standing position, with a 10- to 30-minute interval between 
sets, and a single measurement of body temperature 
 Perform a physical examination (to be completed by the investigator or a qualified delegate) 
 Collect blood samples for the following pre-dose assessments: 
o Pharmacokinetics 
o Pharmacodynamics biomarkers (oxidative stress, inflammatory factors) 
o Mechanism of action biomarkers (determination of genotype for ceruloplasmin and 
COMT, ceruloplasmin levels, ceruloplasmin ferroxidase activity) 
 Collect a urine sample for the pre-dose assessment of oxidative stress biomarkers  
 Collect both a blood sample and a urine sample for pregnancy testing (females of 
childbearing potential only). A negative result on the urine test is required for the start of 
dosing, and a negative result on the serum test is required for study continuation. 
 
Complete the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale 
(MDS-UPDRS) * 
 Complete the Montreal Cognitive Assessment (MoCA) * 
 Complete the Columbia Suicide Severity Rating Scale (C-SSRS) 
 Verify eligibility 
 Contact the Interactive Voice (or Web) Randomization System (IVRS/IWRS) to have 
the patient randomized to one of the four dosage cohorts and to receive either active 
product or placebo within that cohort 
 Dispense a 2-month supply of study medication (see Section 6.5), along with instructions 
on how to take it 
                                                 
* Must be conducted by the qualified investigator, early in the morning 


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 Administer first dose of study medication 
 Collect blood samples for post-dose PK testing at 2 hours post-dose (± 45 minutes) and 
at 4 hours post-dose (± 45 minutes), with a minimum of 1 hour between samples 
 Conduct contraceptive counseling if applicable 
 Provide patient with a diary card and explain how to complete it 
 Provide patient with an emergency card with contact information, and explain that it is to 
be carried at all times 
 Instruct patient to do the following: 
o Undergo a weekly blood draw, at either the study site or a local laboratory, or, with 
sponsor approval, at the patient’s home by a visiting study nurse 
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 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, return to 
the clinic for an Early Termination Visit as soon as possible, and no later than one 
month following the last dose of study medication 
 Schedule next study visit. 
Weekly Blood Draws (every 7 ± 3 days except on weeks that include a study visit) 
Patients must provide a weekly blood sample for hematology testing. The results should be 
reviewed by the investigator as soon as they are received, preferably within 24 hours. 
Note: This procedure may be done either at a local laboratory or at the study site, or, with 
sponsor approval, at the patient’s home by a visiting study nurse. 
Month 1 (± 5 days) 
Note:  Since this visit will include pre-dose blood sampling for PK testing in a subset of 
patients, those individuals must be reminded beforehand to not take their morning dose that 
day before coming to the site, and to have fasted for at least 10 hours rather than 8.  (They 
will be allowed to eat about 1.5 hours after dosing.) In addition, those who agreed to take 
part in the extensive PK testing need to be reminded that this visit will involve an all-day 
stay at the site. 


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 Collect blood samples for the following assessments: 
o Hematology and blood chemistry (including fasting glucose) 
o Pregnancy testing for all females of childbearing potential (a negative result is 
required for study continuation) 
o Subset of patients who have agreed to undergo extensive PK testing:  Pre-dose PK 
sample 
 Administer morning dose of study medication, and note the time at which it was given 
 Subset of patients who have agreed to undergo extensive PK testing:  Collect blood 
samples at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.33, 2.66, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 10.0, 
and 12.0 hours post-dose 
 Complete the C-SSRS 
 Verify treatment compliance through review of patient diary card and tablet count, and 
confirm that the patient has enough medication to last until the next visit 
 Additionally review diary card for information on adverse events and use of concomitant 
medications, and file the diary card with the source documents 
 Measure vital signs, first in the supine and then in the standing position (single measurement 
for each) and body temperature 
 Conduct contraceptive counseling if applicable 
 Give patient a new diary card, along with a reminder if necessary about how to complete it 
 Remind patient to do the following: 
o Undergo a weekly blood draw, at either the study site or a local laboratory, or, with 
sponsor approval, at the patient’s home by a visiting study nurse 
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 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, return to 
the clinic for an Early Termination Visit as soon as possible, and no later than one 
month following the last dose of study medication 
 Schedule next study visit 
Month 2 (± 5 days) 
 Collect all medication containers, whether empty, partly used, or unopened, and account 
for the medication dispensed 
 Calculate treatment compliance through review of diary card and tablet count 


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 Additionally review diary card for information on adverse events and use of concomitant 
medications, and file the diary card with the source documents 
 Measure vital signs, first in the supine and then in the standing position (single 
measurement for each), and body temperature 
 Perform a physical examination (to be completed by the investigator or a qualified delegate) 
 Conduct contraceptive counseling if applicable 
 Collect blood samples for the following assessments: 
o Hematology and blood chemistry  (including fasting glucose) 
o Pregnancy testing for all females of childbearing potential (a negative result is 
required for study continuation) 
 Complete the C-SSRS 
 Dispense a 2-month supply of study medication (see Section 6.5), along with instructions 
if necessary on how to take it 
 Give patient a new diary card, along with a reminder if necessary about how to complete it 
 Remind patient to do the following: 
o Undergo a weekly blood draw, at either the study site or a local laboratory, or, with 
sponsor approval, at the patient’s home by a visiting study nurse 
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 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, return to 
the clinic for an Early Termination Visit as soon as possible, and no later than one 
month following the last dose of study medication 
 Schedule next study visit 
Month 3 (± 5 days) 
Notes:   
- 
Since this visit will include pre-dose blood sampling for PK testing and pre-dose 
CSF sampling in subsets of patients, those individuals must be reminded beforehand 
to not take their morning dose that day before coming to the site, and to fast for at 
least 10 hours beforehand rather than 8. (They will be allowed to eat about 1.5 hours 
after dosing.) 


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- 
The MDS-UPDRS and the MoCA are to be conducted early in the morning, at 
approximately the same time (± 1 hour) that they were done at baseline, and must be 
conducted by the same qualified investigator who completed them at baseline. 
 
 Collect blood samples for the following assessments: 
o Hematology and blood chemistry  (including fasting glucose) 
o Pregnancy testing for all females of childbearing potential (a negative result is 
required for study continuation) 
o Pre-dose PK sample 
Note:  For the subset of 6 patients who will also be contributing a pre-dose CSF 
sample, this blood sample is to be collected within ±15 minutes of the CSF sample. 
 For the subset of 6 patients who agreed to undergo CSF sampling and were assigned the 
pre-dose time point, collect a single CSF sample 
 Administer morning dose of study medication, and note the time at which it was given 
 Complete the MDS-UPDRS * 
 Complete the MoCA * 
 Complete the C-SSRS 
 Collect blood samples for the following, and note the time at which they are collected: 
o 
Pharmacodynamics biomarkers (oxidative stress, inflammatory factors) 
o 
Mechanism of action biomarkers (ceruloplasmin levels, ceruloplasmin ferroxidase 
activity) 
 Collect a urine sample for the following, and note the time at which it is collected: 
o Assessment of oxidative stress biomarkers 
o Urinalysis 
 Collect blood samples for post-dose PK testing at 2 hours post-dose (± 45 minutes), and 
at 4 hours post-dose (± 45 minutes), with a minimum of 1 hour between samples. 
Note:  For the subsets of patients who will be contributing CSF samples at 2 hours or 
4 hours post-dose, the applicable blood sample is to be collected within ±15 minutes of 
the CSF sample. 
                                                 
* Must be conducted by the same qualified investigator as before, early in the morning 


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 For the two subsets of patients (n=6 each) who were assigned to give a post-dose CSF 
sample, collect a single sample at either 2 hours (±15 minutes) or 4 hours (±15 minutes) 
post-dose 
 Verify treatment compliance through review of patient diary card and tablet count, and 
confirm that the patient has enough medication to last until the next visit 
 Additionally review diary card for information on adverse events and use of concomitant 
medications, and file the diary card with the source documents 
 Measure vital signs, first in the supine and then in the standing position (single 
measurement for each), and body temperature 
 Conduct contraceptive counseling if applicable 
 Give patient a new diary card, along with a reminder if necessary about how to complete it 
 Remind patient to do the following: 
o Undergo a weekly blood draw, at either the study site or a local laboratory, or, with 
sponsor approval, at the patient’s home by a visiting study nurse 
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 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, return to 
the clinic for an Early Termination Visit as soon as possible, and no later than one 
month following the last dose of study medication 
 Schedule next study visit 
Month 4 (± 5 days) 
 Collect all medication containers, whether empty, partly used, or unopened, and account 
for the medication dispensed 
 Calculate treatment compliance through review of diary card and tablet count 
 Additionally review diary card for information on adverse events and use of concomitant 
medications, and file the diary card with the source documents 
 Measure vital signs, first in the supine and then in the standing position (single 
measurement for each), and body temperature 
 Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
 Conduct contraceptive counseling if applicable 


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 Collect blood samples for the following assessments: 
o Hematology and blood chemistry  (including fasting glucose) 
o Pregnancy testing for all females of childbearing potential (a negative result is 
required for study continuation) 
 Complete the C-SSRS 
 Dispense a 2-month supply of study medication (see Section 6.5), along with instructions 
if necessary on how to take it 
 Give patient a new diary card, along with a reminder if necessary about how to complete it 
 Remind patient to do the following: 
o Undergo a weekly blood draw, at either the study site or a local laboratory, or, with 
sponsor approval, at the patient’s home by a visiting study nurse 
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 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, return to 
the clinic for an Early Termination Visit as soon as possible, and no later than one 
month following the last dose of study medication 
 Schedule next study visit 
Month 5 (± 5 days) 
 Verify treatment compliance through review of patient diary card and tablet count, and 
confirm that patient has enough medication to last until the next visit 
 Additionally review diary card for information on adverse events and use of concomitant 
medications, and file the diary card with the source documents 
 Measure vital signs, first in the supine and then in the standing position (single 
measurement for each), and body temperature 
 Conduct contraceptive counseling if applicable 
 Collect blood samples for the following assessments: 
o Hematology and blood chemistry  (including fasting glucose) 
o Pregnancy testing for all females of childbearing potential (a negative result is 
required for study continuation) 
 Complete the C-SSRS 


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 Give patient a new diary card, along with a reminder if necessary about how to complete it 
 Remind patient to do the following: 
o Undergo a weekly blood draw, at either the study site or a local laboratory, or, with 
sponsor approval, at the patient’s home by a visiting study nurse 
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 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, return to 
the clinic for an Early Termination Visit as soon as possible, and no later than one 
month following the last dose of study medication 
 Schedule next study visit 
 
Month 6 (± 5 days) 
Notes: 
- 
Patients are to be instructed beforehand that on the day of this visit, they are either to 
not take their morning dose before coming to the site, or if they do take it, to note the 
time and inform the investigator of it when they arrive. 
- 
The MDS-UPDRS and the MoCA are to be conducted early in the morning, at 
approximately the same time (± 1 hour) that they were done at baseline, and must be 
conducted by the same qualified investigator who completed them at baseline. 
 
 Collect all medication containers, whether empty, partly used, or unopened, and account 
for the medication dispensed  
 Collect blood samples for the following assessments: 
o Hematology and blood chemistry  (including fasting glucose) 
o Pregnancy testing for all females of childbearing potential (a negative result is 
required for study continuation) 
 If patient did not yet take the day’s morning dose, administer it at this time.  If patient 
did take the dose before arriving, record the time at which it was taken. 


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 Complete the MDS-UPDRS * 
 Complete the MoCA * 
 Complete the C-SSRS 
 Collect blood samples for the following, and note the time at which they are collected: 
o 
Pharmacodynamics biomarkers (oxidative stress, inflammatory factors) 
o 
Mechanism of action biomarkers (ceruloplasmin levels, ceruloplasmin ferroxidase 
activity) 
 Collect a urine sample for the following, and note the time at which it is collected: 
o Assessment of oxidative stress biomarkers 
o Urinalysis 
 Calculate treatment compliance through review of patient diary card and tablet count 
 Additionally review diary card for information on adverse events and use of concomitant 
medications, and file the diary card with the source documents 
 Measure vital signs, first in the supine and then in the standing position (single 
measurement for each), and body temperature 
 Perform a physical examination (to be completed by the investigator or a qualified 
delegate) 
 Conduct contraceptive counseling if applicable 
 Dispense a 3-month supply of study medication (see Section 6.5), along with instructions 
if necessary on how to take it 
 Give patient a new diary card, along with a reminder if necessary about how to complete it 
 Remind patient to do the following: 
o Undergo a weekly blood draw, at either the study site or a local laboratory, or, with 
sponsor approval, at the patient’s home by a visiting study nurse 
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 visit, bring back the completed diary card plus all medication containers, 
whether empty, partly used, or unopened 
                                                 
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o In the event of a decision to withdraw from the study before completion, return to 
the clinic for an Early Termination Visit as soon as possible, and no later than one 
month following the last dose of study medication 
 Schedule next study visit 
Month 9 (± 5 days) – End-of-study visit/Early termination visit 
Notes:   
- 
Patients are to be instructed beforehand that on the day of this visit, they are either to 
not take their morning dose before coming to the site, or if they do take it, to note the 
time and inform the investigator of it when they arrive. 
- 
The MDS-UPDRS and the MoCA are to be conducted early in the morning, at 
approximately the same time (± 1 hour) that they were done at baseline, and must be 
conducted by the same qualified investigator who completed them at baseline. 
 
 If patient did not yet take the day’s morning dose, administer it at this time.  If patient 
did take the dose before arriving, record the time at which it was taken. 
 Complete the MDS-UPDRS* 
 Complete the MoCA* 
 Collect blood samples for the following, and note the time at which they are collected: 
o 
Hematology and blood chemistry (including fasting glucose) 
o 
Pregnancy testing for all females of childbearing potential 
o 
Pharmacodynamics biomarkers (oxidative stress, inflammatory factors) 
o 
Mechanism of action biomarkers (ceruloplasmin levels, ceruloplasmin ferroxidase 
activity) 
 Collect a urine sample for the following, and note the time at which it is collected: 
o Assessment of oxidative stress biomarkers 
o Urinalysis 
 Complete the C-SSRS 
 Review patient diary card; collect and document information on adverse events, use of 
concomitant medications, and treatment compliance; and file the diary card with the 
source documents 
                                                 
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 Calculate treatment compliance through review of diary card and tablet count. 
 Collect all containers of study medication, whether empty, partly used, or unopened, and 
account for the medication dispensed 
 Measure vital signs, first in the supine and then in the standing position (single 
measurement for each), and body temperature 
 Perform a physical examination,(to be completed by the investigator or a qualified 
delegate) including measurement of weight (without shoes) 
 Perform a 12-lead ECG 
 Conduct contraceptive counseling if applicable 
 Schedule follow-up telephone call 
 Advise patient to immediately report any symptoms indicative of infection such as fever, 
sore throat, and flu-like symptoms during the first week following completion of 
treatment.  If infection is found to be present, the patient’s ANC must be monitored in 
order to check for neutropenia. 
Month 10 Follow-up Telephone Call (+ 5 days) 
Call patient to collect information about any adverse events that may have occurred since the 
last visit and any concomitant medications that were taken.  If this call is made earlier than 
30 days after the last dose of study medication, ask the patient to inform the site if he/she 
experiences a serious adverse event (SAE) in the next couple of days. 
5.2 
Method of Assignment to Treatment 
At baseline, 140 eligible participants will be randomized to one of four dosage cohorts 
(n=35 each), and within each cohort will be further randomized in a 4:1 ratio to receive either 
active product (n=28) or placebo (n=7).  Thus, a total of 112 patients will receive one of the 
four dosages of deferiprone, and a total of 28 will receive placebo. 
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 IVRS/IWRS 
will be used to perform the randomization in this study. 
5.3 
Blinding Procedures 
The placebo tablets will have the same appearance as the deferiprone tablets. Within each cohort, 
all participants will take the same number of tablets at each dose:  1 half-tablet in Cohort 1; 
1 tablet in Cohort 2; 1.5 tablets in Cohort 3; and 2 tablets in Cohort 4. 


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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, each patient will be assigned a unique ID number and 
will be identified in all study data by this number. The ID number will consist of 6 digits, 
where the first digit represents the country code, the next 2 digits represent the site code (01 
for site #1, 02 for site #2, etc.), and the next 3 digits (separated from the first 3 by a hyphen) 
are assigned sequentially for each individual screened at that site. For example, if site #1 
from the country designated as “1” screens 8 patients, the ID numbers will be 101-001 
through 101-008.  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) the patient will use the daily diary card to 
record the number of tablets taken, and 2) at each visit, the investigator or delegate will 
inspect the medication containers whether empty, partly used, or unopened, and will check 
the number of tablets remaining.  Compliance will be calculated by the number of tablets 
taken divided by the number of tablets prescribed as per the dosing frequency and length of 
treatment.  Any discrepancies must be discussed with the patient and documented in the 
source documents.  Reasons for non-compliance with the treatment will be recorded in the 
source document and in the eCRFs. The investigator should discuss treatment compliance with 
the patient at each visit. 
 If the number of returned tablets is less than it should be, but the patient reports having taken 
the correct amount of medication, the site will report compliance as 100% in the eCRF, and 
will provide the reason for the apparent over-compliance (e.g., tablets were accidentally 
spoiled and could not be ingested), along with the actual percentage. Both under-
compliance < 80% and over-compliance >120% will be reported as a protocol deviation, 
unless under-compliance is due to treatment interruption because of infection or neutropenia or 
other extenuating circumstances (see Section 7.2.1.8). 


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6 
STUDY TREATMENTS 
Patients will receive either deferiprone delayed release tablets or placebo tablets. 
6.1 
Investigational Product 
Deferiprone delayed release tablets are manufactured by Apotex Inc., and will be supplied to 
the clinical sites by ApoPharma Inc.  The tablets are biconvex, capsule-shaped, white to off-
white in color, enteric-coated, engraved with “APO 400” on one side, and scored on both sides.  
Each tablet contains 600 mg of deferiprone.  Non-medicinal ingredients are hypromellose 
acetate succinate, magnesium oxide, magnesium stearate, colloidal silicon dioxide, triethyl 
citrate, sucrose, talc 500 mesh, methacrylic acid copolymer dispersion, and titanium dioxide. 
6.1.1 Dosage Form and Mode of Administration 
The tablets are scored in a way that they can be split into two halves that maintain the release 
characteristics of the whole tablets.  Depending on the cohort, study participants will take either 
1 half-tablet (300 mg), 1 tablet (600 mg), 1.5 tablets (900 mg), or 2 tablets (1200 mg) twice a 
day, at least 8 hours apart.  Patients in Cohorts 1 and 3 will be instructed to cut their tablets 
on an as-needed basis, not all at once upon receipt of the medication.  The route of 
administration is oral. 
6.1.2 Precautions for Use 
The tablets are to be stored at 15–30°C in a tightly closed bottle in order to protect them from 
moisture and light, and the bottle kept out of the reach and sight of children. 
The study product can be taken with or without food. 
6.2 
Reference Product 
Placebo tablets are identical in appearance to the deferiprone delayed release tablets.  Within 
each cohort, the number of placebo tablets taken at each dose will match that of the 
corresponding active product :  i.e., 1 half-tablet, 1 tablet, 1.5 tablets, or 2 tablets.  Placebo 
tablets will be taken twice a day, at least 8 hours apart. 
6.3 
Packaging and Labeling 
The study products will be supplied in high-density polyethylene (HDPE) bottles with child-
resistant closure, containing 100 tablets each. Each bottle will contain a desiccant bag. 
The bottles will be provided with a label whose content is in accordance with all applicable 
regulatory requirements. The label will include protocol number, expiry date, lot/batch number, 


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investigational statement, storage temperature, dosage, direction for use, visit number, date 
dispensed, and name and address of the sponsor. 
6.4 
Shipping and Storage 
The study medication at each site will be kept in a secure location  (a locked room or cabinet) 
under adequate storage conditions, as per label requirements, under the control of the 
investigator  and with access to authorized individuals only. Product is to be kept at room 
temperature (15–30 ºC / 59–86 ºF). The room must have a calibrated digital temperature-
monitoring device, and site personnel must use a temperature log to facilitate daily recording 
of the temperature of the storage facility. Temperature deviations must be immediately 
reported to the sponsor for investigation and determination of impact on the study medication. 
Each shipment of investigational product will include shipment documents, which the 
investigator or a designate must complete as per the provided instructions and retain the 
original copies in the Investigator Trial File. 
6.5 
Dispensing Procedures 
Patients will be dispensed a 2-month supply of study medication at baseline, Month 2, and 
Month 4, and a 3-month supply at Month 6. Dispensing of study medication must be done by 
appropriately qualified staff (e.g., physician, pharmacist, or nurse). 
Patients will be dispensed a sufficient amount of study medication, with an allowance for the 
visit windows of ±5 days.  Each bottle of deferiprone-DR or placebo contains 100 tablets.  
Hence, the following quantities will be provided: 
 
Baseline, Month 2, and Month 4 
Month 6 
Cohort 1 
1 bottle 
2 bottles 
Cohort 2 
2 bottles 
3 bottles 
Cohort 3 
3 bottles 
4 bottles 
Cohort 4 
3 bottles 
5 bottles 
 
6.6 
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 


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 Name of investigator 
 Study identifier 
 Date and quantity of investigational product received from sponsor 
 Lot/batch number 
For each patient, the investigator must maintain an updated Patient Investigational Drug 
Dispensing Record. This log will include at a minimum: 
 Patient identification number 
 Date of dispensing and return 
 Dispenser’s initials 
 Quantity dispensed and returned 
At the conclusion of the study, a final inventory must be performed by the investigator (or 
delegate). If any tablets or bottles are missing, this must be indicated on the study drug 
accountability form, together with an explanation of the discrepancy. These forms must be 
available for sponsor clinical monitoring as well as for sponsor audit and regulatory authority 
inspection purposes at any time. 
It is the responsibility of the investigator to ensure that all study drug received at the 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. 
6.7 
Replacement Doses 
Patients who report that their medication has been lost or damaged will need to return to the 
study site to receive replacement tablets. Requests for replacement must be made in writing 
to the sponsor by the qualified staff member, and the study coordinator must contact the 
IVRS/IWRS again to ensure that the patient is provided with the correct product. 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. 
6.8 
Disposition of Unused Product 
All investigational product that has been returned by the patient or that is unused for any 
other reasons will be returned to the sponsor or discarded by the site according to internal 
procedures, if approved, in writing, by the sponsor. The destruction procedures must include 
the issuance of appropriate signed destruction certificates including mode of destruction and 


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complete drug accountability of destroyed materials. The destruction may take place only 
after written approval by the sponsor. 
6.9 
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 using 1) the Movement Disorder Society-Unified Parkinson’s 
Disease Rating Scale (MDS-UPDRS), 2) the Montreal Cognitive Assessment (MoCA) test, 
3) pharmacodynamic biomarkers, and 4) mechanism of action biomarkers. 
7.1.1 Primary Efficacy Measurements 
7.1.1.1 
Motor Score on the Unified Parkinson’s Disease Rating Scale 
The MDS-UPDRS is the most recent version of the major rating scale used to assess the 
severity of symptoms of PD.  It consists of 4 parts: Part I, non-motor experiences of daily 
living; Part II, motor experiences of daily living;  Part III, motor examination; and Part IV, 
motor complications. Part I has two components:  I-A concerns a number of behaviors that 
are assessed by the investigator using all pertinent information from patient and caregiver, 
and I-B is completed by the patient with or without the aid of the caregiver, but independently 
of the investigator. These sections can, however, be reviewed by the rater to ensure that all 
questions are answered clearly, and the rater can help explain any perceived ambiguities. 
Part II is designed to be a self-administered questionnaire, but can be reviewed by the 
investigator to ensure completeness and clarity. Part III has instructions for the rater to give 
or demonstrate to the patient; it is completed by the rater. Part IV has instructions for the 
rater and also instructions to be read to the patient. This part integrates patient-derived 
information with the rater’s clinical observations and judgments, and is completed by the 
rater. Each time the MDS-UPDRS is completed, both individual subscale scores and a total 
score are generated. The MDS-UPDRS is to always be administered by the same qualified 
investigator, at approximately the same time (early in the morning). 
The primary measurement for efficacy in this study is the score on the motor examination 
section (Part III). It will be obtained at baseline and Months 3, 6, and 9. 


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7.1.2 Secondary Efficacy Measurements 
7.1.2.1 
Total Score on the Unified Parkinson’s Disease Rating Scale 
The total score derived from all of the MDS-UPDRS subscale scores will be obtained at 
baseline and Months 3, 6, and 9. 
7.1.2.2 
Other Scores on the Unified Parkinson’s Disease Rating Scale 
The individual scores derived from the MDS-UPDRS Part I (non-motor experiences of daily 
living), Part II (motor experiences of daily living), and Part IV (motor complications) as well 
as the combined score from Parts II and III will be obtained at baseline and Months 3, 6, and 9. 
7.1.2.3 
Montreal Cognitive Assessment Test 
The Montreal Cognitive Assessment (MoCA) test is a rapid screening instrument 
(administration time around 10 minutes) for the detection of mild cognitive dysfunction.  It 
is used to assess the following cognitive domains: short-term memory recall, visuospatial 
abilities, executive functions, attention, concentration, working memory, language, and 
orientation to time and place. The full version of the scale will be used in this study. 
The MoCA will be completed at baseline and Months 3, 6, and 9. It is always to be 
administered by the same qualified investigator, at approximately the same time (early in the 
morning). 
7.1.2.4 
Oxidative Stress Biomarkers 
Free radicals, oxygen-containing molecules with one or more unpaired electrons, are highly 
reactive with other molecules and will appropriate their electrons in order to become stabilized; 
this triggers a chain of reactions as each target molecule in turn seeks to appropriate an electron 
from another, and can result in serious damage to cell components including lipids, proteins, 
and DNA. Antioxidants are molecules within cells that prevent these chain reactions by donating 
an electron to the free radicals without becoming destabilized themselves. When there is an 
imbalance between oxidants and antioxidants, i.e., when the production of free radicals 
surpasses a cell’s ability to counteract or detoxify their harmful effects through neutralization 
by antioxidants, the result is oxidative stress. This condition is seen in various neurodegenerative 
disorders, including Parkinson’s disease.  Hence, measuring biomarkers that are indicators of 
oxidative stress may serve as a measure of progression or improvement of disease. 
The oxidative stress biomarkers of total antioxidant status, protein carbonyls, glutathione, 
and super-oxide dismutase will be measured in a panel of blood/serum tests at baseline and 
Months 3, 6, and 9.  The oxidative stress biomarkers of 8-OHdG and of malondialdehyde, 
which results from lipid peroxidation of polyunsaturated fatty acids, will be assessed in 
urine at these same time points. 


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7.1.2.5 
Inflammatory Factor Biomarkers 
Numerous studies have indicated the presence of an inflammatory process in PD. Hence, 
biomarkers of such processes may serve as a measure of worsening or improvement of 
disease. 
The inflammatory factor biomarkers of TNF alpha and IL-6 will be measured in a panel of 
blood tests at baseline and Months 3, 6, and 9. 
7.1.3 Exploratory Efficacy Measurements 
Mechanism of Action (MOA) biomarkers will be examined to evaluate whether specific 
genotypes of enzymes that play a role in Parkinson’s disease affect the potential disease-
modifying action of deferiprone. 
7.1.3.1 
D544E (AT) Polymorphisms of Ceruloplasmin 
Ceruloplasmin is a glycoprotein that plays a role in the oxidation of iron, oxidizing toxic 
ferrous iron (Fe2+) into ferric iron (Fe3+) and enabling iron transportation between blood 
and cells. The genotypes AT and AA determine whether an individual is a low or a high 
metabolizer of ceruloplasmin, respectively.  Individuals with the AT genotype, who are low 
metabolizers, have lower ceruloplasmin ferroxidase activity, which may result in increased 
brain iron overload. 
A blood sample for the determination of ceruloplasmin genotype will be taken at baseline. 
7.1.3.2 
Ceruloplasmin Levels and Ceruloplasmin Ferroxidase Activity 
Blood samples for the measurement of ceruloplasmin levels and ceruloplasmin ferroxidase 
activity will be collected at baseline and Months 3, 6, and 9. 
7.1.3.3 
V158M Polymorphisms of Catechol O-methyltransferase 
Catechol O-methyltransferase (COMT) is a metabolic enzyme that participates in the 
inactivation of dopamine and other neurotransmitters. The Val158Met (V158M) polymorphism 
of COMT is associated with Parkinson’s disease. 
A blood sample for the determination of the COMT genotype will be taken at baseline. 


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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. 
AEs include: 
 Exacerbation of a pre-existing illness, including acute episodes/crisis of a chronic 
underlying condition 
 An increase in frequency or intensity of a pre-existing episodic event or condition 
 A condition detected or diagnosed after study treatment administration, even though it 
may have been present prior to the start of the study 
 A continuous persistent disease or symptom present at baseline that worsens following 
the start of the study 
 Accidents (e.g., involving a motor vehicle) 
 Reasons for changes in concomitant medication (type of drug and/or dose) 
 Medical, nursing, or pharmacy consultation 
 Admission to hospital and surgical operations 
 Abnormalities in laboratory findings (e.g., clinical chemistry, hematology, urinalysis), 
ECG, or other assessments (e.g., vital signs) that are not part of a larger medical 
condition already recorded as an AE and which are judged by the investigator to be 
clinically significant. The investigator should exercise medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant. 
 


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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;  non-serious AEs will be collected from the first dose until the final day 
of dosing;  AEs that are still ongoing at the time of study termination will be followed until 
resolution or stabilization of the event or its sequelae;  and serious AEs will be collected from 
the first dose until 30 days after the last dose of study medication. 
AEs and SAEs that are related to the underlying medical condition for which the patient 
enrolled in the clinical trial will be recorded separately from others. 
Patients will be instructed to report any MEs/AEs to the investigator or a delegate.  In 
addition, the investigator will solicit information about the occurrence of MEs/AEs through 
open-ended, non-leading verbal questions such as: 
 How are you feeling? 
 Have you had any medical problems since the last visit? 
 Have you taken any new medications, other than those provided in this study, since 
the last visit? 
Based on the patient’s response to these questions, the investigator or delegate should ask 
additional questions relevant to the specific complaint, such as: 
 How severe is/was the symptom? 
 How often did the symptom occur? 
 How long did the symptom last? 
The patient should also be questioned about any previously reported AEs that have not resolved. 


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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. 
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. 


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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 eCRF as mild, moderate, or severe, according 
to the definitions provided below.  In addition, to maximize consistency in assessment, it is 
recommended that the National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) scale be used. 
 
Intensity 
Corresponding 
NCI CTCAE Grade 
Mild: awareness of a sign or symptom but easily tolerated 
1 
Moderate: discomfort sufficient to cause interference with normal daily 
activities 
2 
Severe: resulting in inability to do work or perform normal daily activities 
3–5 
7.2.1.5 
Serious Adverse Events 
An SAE is an adverse event occurring at any dose that results in any of the following 
outcomes: 
 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. 


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 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 the last dose of study medication must be 
reported to the sponsor, regardless of whether they are suspected of having a causal 
relationship with the study drug. Any SAEs for which the investigator does suspect a causal 
relationship must be reported to the sponsor regardless of the time elapsed since the last dose 
of the study drug. 
Patients will be instructed to report SAEs to the investigator within 24 hours, by telephone. 
In turn, the investigator must report all SAEs to the sponsor within 24 hours of occurrence 
or notification by the patient, using the sponsor’s SAE form. The sponsor will provide 
contact information for reporting SAEs. An assessment of causality must be provided at the 
time of the initial report. 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 per local policy, 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. 


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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 a new SAE report form, indicated as 
follow-up, and signed and dated by the investigator. 
The clinical research associate (CRA) will verify the original SAE report form against the 
source documents at the next monitoring visit. 
7.2.1.8 
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: 
 
Category 
Black Population 
All Other Races 
Mild 
A confirmed ANC < 1.0 x 109/L 
but ≥ 0.65 x 109/L 
A confirmed ANC < 1.5 x 109/L 
but ≥1.0 x 109/L  
Moderate 
A confirmed ANC < 0.65 x 109/L 
but ≥ 0.5 x 109/L 
A confirmed ANC < 1.0 x 109/L 
but ≥ 0.5 x 109/L 
Severe/agranulocytosis 
A confirmed ANC < 0.5 x 109/L 
For a case of neutropenia to be confirmed, there must be 2 consecutive counts, a maximum 
of 3 days apart, that are both less than the specified value. If the 2 counts are not in the same 
severity category, a third count will be required to determine the severity. If a patient has just 
a single ANC value less than 1.5 x 109/L (< 1.0 x 109/L for a black patient), 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, patients will be advised to immediately report any 
symptoms indicative of infection such as fever (≥ 38.5°C), sore throat, and flu-like symptoms 
at any time during treatment or during the first week following treatment. They will be 


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provided with an emergency services card with contact information, and advised to carry it 
with them at all times. 
Depending of the severity of neutropenia, patients will either remain in or be withdrawn 
from the study. The management of different severities of neutropenia is described below. 
Mild and moderate neutropenia: 
A patient who develops either mild or moderate neutropenia is to interrupt treatment as soon 
as the neutropenia is confirmed, and ANC is to be monitored every 2 days until resolution. 
The patient should re-initiate treatment once the event is resolved, defined as 2 consecutive 
ANC ≥ 1.5 x 109/L (ANC ≥ 1.0 x 109/L for a black patient). If ANC is still < 1.5 x 109/L after 
14 days, the investigator is to do the following: 
 Withdraw patient from the study and monitor him/her until resolution of the event 
 Advise patient regarding protective isolation 
 Examine patient the same day (if possible), including drug history and physical 
examination 
 Notify ApoPharma Inc. using the SAE form 
Severe neutropenia/agranulocytosis: 
A patient in whom a single ANC measurement < 0.5 x 109/L is detected is to immediately 
stop treatment, without waiting for confirmation of the count, and a second measurement is 
to be done the following day. If the second ANC is still < 0.5 x 109/L, the patient is to be 
permanently withdrawn from the study, and ANC is to be monitored daily until resolution. 
The following procedures should be done by the investigator or the treating physician, as 
appropriate: 
 Provide protective isolation; if clinically indicated, admit patient to hospital and 
obtain vital signs every 4 hours 
 Examine the patient the same day, if possible, including drug history and physical 
examination 
 With the patient’s consent, 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: 


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 If possible, consider obtaining bone marrow aspirate for: 
o Histology 
o Progenitor culture 
o Frozen storage (1 mL sample) 
 If possible, consider obtaining bone marrow biopsy (minimum length 3 mm) 
 Perform septic work-up including chest X-ray, blood, urine, and throat cultures 
 Obtain q4h temperatures from patient (monitored by family at home if patient is not 
in the hospital) 
 If warranted, administer granulocyte stimulating factors, such as G-CSF 10 μg/kg, on 
an in-patient basis if possible, beginning the same day that the ANC is confirmed as 
< 0.5 x 109/L; administer daily until ANC is > 1.5 x 109/L on 2 consecutive days 
 If ANC < 0.5 x 109/L for 7 days, repeat bone marrow biopsy and aspirate weekly 
during the period of agranulocytosis, if warranted 
7.2.1.8.2 
Infections 
If a patient develops fever (≥ 38.5°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 (ANC < 1.0 x 109/L for a black patient).  
Therapy with deferiprone can be re-initiated once all symptoms have been resolved and it is 
deemed safe by the investigator. 
7.2.1.8.3 
Decreased Serum Ferritin 
As deferiprone is an iron chelator, treatment might decrease the levels of serum ferritin to a 
level that could fall below normal limits.  The levels of serum ferritin will therefore be 
monitored during this study.  A patient who is found to have low serum ferritin may be 
prescribed iron supplements, based on investigator judgment. 
7.2.2 Laboratory Measurements 
Analyses will be performed at a central laboratory, with the exception of the weekly 
hematology assessments which may be performed at a local laboratory or, with sponsor 
approval, at the patient’s home by a visiting study nurse.  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 


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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. 
The following laboratory tests will be performed: 
Hematology:  hemoglobin, total WBC count, ANC, 
MCV, and platelet count 
Screening and weekly after start of 
dosing until Month 9 
Blood chemistry:  Total protein, GGT, lactate 
dehydrogenase (LDH), sodium, potassium, chloride, 
fasting glucose, bilirubin (total, direct, and indirect), 
AST, ALT, albumin, blood urea nitrogen, calcium, 
creatinine, uric acid, alkaline phosphatase, amylase, 
serum ferritin, blood iron, zinc, and copper 
Screening and each visit after start of 
dosing until Month 9 
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 Months 3, 6, and 9 
Pregnancy testing (women of childbearing 
potential only):  Both urine and serum tests at 
baseline; only serum test at each other time point 
Each visit 
7.2.3 Other Safety Measurements 
7.2.3.1 
Physical Examination 
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. 
Examinations will be performed at screening, baseline, and Months 2, 4, 6, and 9. 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. 
Body weight (without shoes) will be measured at screening and Month 9. Height will be 
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7.2.3.2 
Vital Signs 
Supine and standing heart rate, supine and then standing blood pressure, and body 
temperature will be taken.  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. At the Day 0 visit (baseline), 
3 sets of orthostatic vital signs (pulse and blood pressure), first in the supine and then in the 
standing position, are to be conducted prior to start of treatment, with 10- to 30-minute 
intervals between measurements. A single set of measurements is to be performed at all other 
time points. 
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 
Electrocardiogram 
A standard 12-lead ECG will be performed at screening and Month 9.  At a minimum, the 
following parameters will be assessed:  HR, PR, QRS, QT, QTcF, and QTcB. The results will 
be interpreted by the investigator, and the overall interpretation will be documented. 
7.2.3.4 
Columbia Suicide Severity Rating Scale 
Current guidelines for clinical trials of investigational neurological drugs call for the 
prospective assessment of suicidal ideation and behavior, whereby the physician actively 
queries the patient rather than relying on the patient to report any occurrences spontaneously. 
The Columbia Suicide Severity Rating Scale (C-SSRS) is designed to track suicidal adverse 
events across a treatment trial. The scale assesses a range of ideation and behavior, as well as 
intensity of ideation. The Baseline/Screening version of the scale will be used at baseline, 
and the Since Last Visit version will be used at post-baseline visits. 
The C-SSRS will be completed at each visit from baseline to Month 9 by the qualified 
investigator or delegate. 
7.2.3.5 
Concomitant Medications 
The following information about prior and concomitant medications is to be recorded: 
 All medications used within the 3 months prior to screening 
 Any medications that the patient continues to take during the study 
 Any medications that the patient starts to take during the study 


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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 eCRFs, as well as whether or not 
the medication was used to treat an AE. 
Information on concurrent medications will be obtained at every site visit and at the follow-
up telephone call. 
7.2.4 Procedures in Case of Pregnancy 
If a patient becomes pregnant during the course of the study, she will be immediately 
withdrawn. The pregnancy is to be immediately reported to the sponsor, and information 
about the pregnancy is to be recorded on the appropriate form and in the patient’s eCRF. The 
patient will be followed to determine the outcome, and any premature termination of the 
pregnancy will be reported.  Upon delivery, the child will be examined for any adverse 
symptoms or congenital anomalies. Follow-up information on the status of the mother and 
child will be forwarded to the sponsor no later than 8 weeks following the delivery. 
If the partner of a male patient becomes pregnant during the course of the study, or if the 
fetus may have been exposed to the patient’s study products either through maternal 
exposure or through transmission via semen following paternal exposure, the pregnancy must 
be reported to the sponsor, and information about the pregnancy must be recorded on the 
appropriate form and in the patient’s eCRF.  If the partner provides consent for follow-up of 
the pregnancy, she will be followed until the delivery of the child, and information on the 
delivery status of the mother and child will be forwarded to the sponsor no later than 8 weeks 
following the delivery date. 
Any SAE occurring as a result of a post-study pregnancy that the investigator believes may 
have been caused by the study product or by a protocol procedure will be reported to the 
sponsor as described in Section 7.2.1.6. 
7.3 
Pharmacokinetics Measurements 
7.3.1 
Collection of Samples 
Blood (5 mL at each time point) and cerebrospinal fluid (0.5–1.0 mL) for analyses of 
deferiprone and deferiprone 3-O-glucuronide will be collected. Details on sample collection 
will be provided in a separate laboratory manual. 
 
All patients: At baseline and Month 3, a total of 3 blood samples will be collected: pre-dose, 
at 2 hours post-dose (± 45 minutes), and at 4 hours post-dose (± 45 minutes), with a minimum 
of 1 hour between samples. 
Note:  For the subset of 18 patients who have agreed to undergo CSF sampling, the post-dose 
blood samples at Month 3 will be taken at 2 hours (± 15 minutes) and 4 hours (± 15 minutes) 
post-dose, to be aligned with the timing of the CSF samples. 


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Subset of 16 patients:  At Month 1, a total of 18 blood samples per patient will be collected:  
pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.33, 1.66, 2.0, 2.33, 2.66, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 
10.0, and 12.0 hours post-dose. 
 
Subset of 18 patients:  At Month 3, patients who agree to undergo a spinal tap will contribute 
one sample of CSF. Six of the 18 patients will provide this sample pre-dose, 6 will provide it at 
2 hours post-dose (± 15 minutes), and 6 will provide it at 4 hours post-dose (± 15 minutes).  
The time of sample collection will be assigned prior to the Month 3 visit. 
7.3.2 
Processing of Samples 
Details on the processing of blood and CSF samples will be provided in the laboratory manual. 
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. 
9 
STATISTICAL ANALYSIS 
9.1 
Endpoints 
9.1.1 Primary Endpoint 
The primary endpoint is the change from baseline to Month 9 in the motor examination 
subscale (Part III) of the Movement Disorder Society-Unified Parkinson’s Disease Rating 
Scale (MDS-UPDRS). 


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9.1.2 Secondary Endpoints 
 Change from baseline to Month 9 in the following measures: 
o 
Total score on the MDS-UPDRS 
o 
Scores on the individual subscales Part I (non-motor experiences of daily living), 
Part II (motor experiences of daily living), and Part IV (motor complications) of the 
MDS-UPDRS 
o 
Combined scores from Parts II and III of the MDS-UPDRS 
o 
Overall cognitive function, as assessed by the Montreal Cognitive Assessment 
(MoCA) test 
o 
Pharmacodynamics measures of the following oxidative stress biomarkers: total 
antioxidant status, lipid peroxidation (malondialdehyde), protein carbonyls, 8-
OHdG, glutathione, superoxide dismutase 
o 
Pharmacodynamics measures of the following inflammatory factor biomarkers:  
TNF alpha and IL-6 
 Time elapsed until the need for rescue medication 
9.1.3 Exploratory Endpoints 
The following Mechanism of Action (MOA) biomarkers will be examined to evaluate 
whether specific genotypes of enzymes that play a role in Parkinson’s disease affect the 
potential disease-modifying action of deferiprone: 
 
D544E polymorphisms of the glycoprotein ceruloplasmin 
 
V158M polymorphisms of the enzyme catechol O-methyltransferase 
 
Ceruloplasmin levels (to be analyzed depending on the outcomes of the primary and/or 
secondary efficacy endpoints) 
 
Ceruloplasmin ferroxidase activity (to be analyzed depending on the outcomes of the 
primary and/or secondary efficacy endpoints) 
9.1.4 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 
 
Laboratory measures (hematology, blood chemistry, and urinalysis) 


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 
ECG 
 
Change from baseline in vital signs (the average of the three sets of vital signs 
collected at the baseline visit will be considered the baseline value) 
 
Physical examination 
 
Assessment of suicidality (as per the Columbia Suicide Severity Rating Scale) 
9.1.5 Pharmacokinetics Endpoints 
The following PK parameters will be determined for deferiprone and its 3-O-glucuronide 
metabolite in the subset of patients who undergo extensive PK sampling: 
 
Cmax 
 
Tmax 
 
AUC0-t 
 
AUC0-∞ 
 
λZ 
 
T½ 
The parameters of λZ, T½, and AUC0-∞ will be determined only in patients in whom the log-
linear terminal phase can clearly be defined. In addition, Cltot/F and VD/F will also be 
determined for deferiprone. 
9.2 
Determination of Sample Size and Study Power 
There is no formal sample size and power calculation. Based on preliminary data from other 
investigators, it is estimated that 28 subjects per dosage will be sufficient to provide 
meaningful assessment of each dosage for the study objectives. 
9.3 
Study Populations 
Four study populations for analysis will be defined:  Intent-to-Treat (ITT), Per-Protocol (PP), 
Safety, and Pharmacokinetics. All efficacy endpoints will be analyzed for the ITT population, 
which represents the primary analysis population. The primary efficacy endpoint will also be 
analyzed for the PP population, which represents the secondary analysis population. 
9.3.1 Intent-to-Treat Population 
The ITT population is defined as all randomized patients who received at least one dose of 
study drug and have a baseline and at least one post-baseline efficacy assessment. All 
efficacy endpoints will be analyzed for the ITT population. 


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9.3.2 Per Protocol Population 
The PP population is defined as all randomized patients who complete the study, have no 
major protocol violations, and have an efficacy assessment at the end of the study. Prior to 
database lock, protocol violations will be reviewed for their seriousness, and patients with 
major violations will be excluded from the PP population. Only the primary efficacy 
endpoint will be analyzed for the PP population. 
9.3.3 Safety Population 
The Safety population will include all randomized patients who received at least one dose of 
study drug. 
9.3.4 Pharmacokinetics Population 
The Pharmacokinetics population will include all patients who have sufficient PK data to 
derive at least one PK parameter. 
9.4 
Data Analysis Plan 
Separate statistical analysis plans (SAPs) will be prepared, one for the efficacy and safety 
analyses, and either one or two others for the pharmacokinetics and the pharmacokinetics/
pharmacodynamics analyses.  The SAPs will detail the specifications given below, and will 
be approved prior to database lock. Any changes in the planned statistical methods will be 
documented in the final study report. 
9.4.1 Planned Analyses 
Data from all patients who were randomized to receive placebo will be combined into one 
group for the statistical analyses. Thus, there will be 5 treatment groups in the efficacy and 
safety analyses:  placebo and 300 mg, 600 mg, 900 mg, and 1200 mg deferiprone. 
9.4.1.1 
Patient Disposition and Drug Exposure 
Patient disposition, based on the ITT population, will be summarized descriptively. Data will 
include the number and percentages of patients who were screened, enrolled, completed the 
study, and withdrawn (including reasons for withdrawals). 
For each patient, the number of doses taken will be computed from the study drug dispensing 
and accountability eCRFs obtained at each visit. The extent of exposure to the study 
medication as well as compliance during the study will be summarized with descriptive 
statistics. 


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9.4.1.2 
Patient Characteristics 
Baseline characteristics will be summarized by descriptive statistics: mean, standard 
deviation, minimum, median and maximum values (by ITT and PP populations). Medical 
history and prior medications will be summarized descriptively using number of patients and 
percentage. 
9.4.1.3 
Analysis of Efficacy 
The data on the change from baseline to each follow-up visit will be summarized by 
treatment group and overall, using descriptive statistics for each continuous efficacy 
endpoint. Frequency and proportion will be presented for each discrete efficacy endpoint. 
Analysis of variance (ANOVA) will be used to compare means, and Fisher’s exact test will 
be used to compare proportions.  
An analysis of covariance (ANCOVA) approach will be used for assessing the deferiprone 
effect on change from baseline to study end for all efficacy variables except time elapsed 
until rescue medication, with baseline value as a covariate, and treatment group and visit as 
the main factors in the model. Each deferiprone group will be compared to the placebo group 
to assess the treatment effect at each deferiprone dose level. Regression analysis will be 
employed to assess the dose-response relationship. If a statistically significant relationship 
exists between deferiprone dose and an efficacy outcome, the dose-response relationship will 
be assessed through pairwise comparison of each dose level to the next lower dose level: 
1200 mg vs. 900 mg, 900 mg vs. 600 mg, and 600 mg vs. 300 mg. 
For all efficacy data except time elapsed until rescue medication, missing data will be 
assumed to be missing at random (MAR), and a Mixed-Effect Model Repeated Measure 
(MMRM) model will be used as the primary analysis method to analyze the observed data. 
An appropriate sensitivity analysis will be performed to evaluate the robustness of the 
analysis results. Details will be provided in the SAP. 
A time to event analysis will be performed to compare the time elapsed until the need for 
rescue medication among the treatment groups. 
If efficacy is evidenced, exploratory analyses will be performed to study the role of MOA 
biomarkers on the efficacy endpoints. The appropriate analyses will be detailed in the SAP. 
If the blinded review of the efficacy data performed before the breaking of the treatment 
codes indicates a severe non-normality of the data, an appropriate transformation (e.g., log 
transformation) will be applied to the data, or nonparametric statistical methods based on 
ranks will be employed, if warranted. 


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9.4.1.4 
Analysis of Safety 
All safety data collected will be presented in listings and summary tables to give an overview 
of the safety findings. For safety data analyses, no imputation of missing data will be 
performed; analyses will be based on observed cases. 
Adverse Events 
A summary table of adverse events (AEs) by treatment group will include the following 
information: 
 Number of patients exposed to study treatment 
 Number of patients experiencing at least one AE 
 Number of patients experiencing at least one severe AE 
 Number of patients experiencing at least one serious AE 
 Number of patients experiencing at least one drug-related AE 
 Number of deaths 
 Number of patients withdrawn 
 Number of withdrawals due to AEs 
Untoward medical occurrences, whether new events or worsening of severity or frequency 
of pre-existing conditions, will be coded using MedDRA (Medical Dictionary for Regulatory 
Activities), and will be summarized by treatment and by MedDRA system organ class (SOC) 
and preferred term (PT).  An event will be considered an AE if 1) its start date is on or after 
the date of the first dose of study medication, 2) the start date is missing and the stop date is 
on or after the date of the first dose of study medication, or 3) both the start and the stop dates 
are missing.  SAEs that begin within 30 days after the last dose of study medication, and both 
SAEs and non-serious AEs that are still ongoing for up to 30 days after the last dose, will be 
included in the database. 
Adverse events will be summarized using the total number of events, the total number and 
percent of patients who experience an AE, and the number and percent of patients who 
experienced an AE within each SOC (and PT within an SOC). AEs will also be presented by 
intensity (mild, moderate, severe), by seriousness (serious, non-serious) and by relationship 
to study medication (at least possibly related, not related). The number of patients withdrawn 
and the reasons for withdrawal will also be presented. 
To count the number of patients who experienced each AE, patients who experienced the 
same AE multiple times will only be counted once for the corresponding preferred term. 
Similarly, if a patient experiences multiple AEs within the same SOC, that patient will be 
counted only once for that SOC. AEs will be tabulated by presenting the SOCs alphabetically, 


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and within each SOC, the preferred term will be presented in decreasing order of the total 
number of patients who experienced each AE. In summaries presenting the incidence of AEs 
by severity, seriousness, and relation to study medication, a patient with multiple events 
coded to a given 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. 
Listing of SAEs and listing of withdrawals due to AEs will be presented. Patient deaths will 
be listed separately, and will be described in narratives. 
Vital Signs and Weight 
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will be 
presented at each visit for supine and standing heart rate, supine and standing blood pressure, 
body temperature, and weight. Data will also be presented graphically for examination of 
possible trends. Change from baseline in vital signs (at baseline, the values for orthostatic 
vital signs will be the average of the three sets collected) and weight will be assessed. 
Electrocardiogram 
The number and percentage of patients with normal and abnormal ECG results will be 
provided. Descriptive statistics will be presented for HR, PR, QRS, QT, QTcF, and QTcB. 
Biochemistry, Hematology and Urinalysis 
Descriptive statistics for each clinical laboratory test will be presented for each scheduled 
visit. According to the laboratory normal ranges, laboratory test results will be categorized as 
low (< lower normal limit), normal (within normal range), and high (> upper normal limit). 
Shift tables comparing the distributions of these three categories at baseline versus end of 
treatment will be presented. Continuous data will also be presented graphically for 
examination of possible trends. 
Clinically significant laboratory values will be reported in the adverse event analysis. 
Concomitant Medications 
Medications will be coded using the WHO Drug Dictionary.  Medications taken during the 
course of the trial (on or after the first study drug dose and before or on the study termination 
date) will be considered as concomitant medications. Medications started after the study 
termination date will not be reported in tables, but will be presented in listings. Concomitant 
medications that were used to treat adverse events will be differentiated from others. 
Concomitant medications will be summarized according to the preferred terms only. To count 
the number of patients who took a certain medication, a patient taking the same medication 
multiple times will only be counted once for that medication. Medications will be tabulated 


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in decreasing order of the total number of patients who took each medication. In addition, the 
total number of patients to ever take any concomitant medications will be presented. 
Concomitant medications will be presented based on the Safety population. 
Suicidality 
Descriptive statistics will be presented for C-SSRS at each visit. Data will also be presented 
graphically for examination of possible trends. 
9.4.1.5 
Pharmacokinetics Analyses 
The pharmacokinetics parameters will be summarized using descriptive statistics (arithmetic 
mean, SD, CV, median, minimum and maximum values). The power model will be used for 
assessing dose proportionality of AUC. Actual sampling times will be used for 
pharmacokinetic evaluations.  Relationships will be assessed between the appropriate PK 
parameters and pharmacodynamics biomarkers through correlation analysis. 
Additional pharmacokinetics analyses may be performed if deemed appropriate. 
Detailed analyses on PK assessments and pharmacokinetics/pharmacodynamics assessments 
will be included in separate statistical analysis plans. 
9.4.2 Interim Analyses 
No interim analysis is planned. 
9.5 
Criteria for Evaluability of Patient Data 
Statistical analysis will be based on the study populations defined in Section 9.3. 
10 
DATA MANAGEMENT CONSIDERATIONS 
10.1 
Data Management 
The sponsor’s Clinical Data Management group will be responsible for the processing, 
coding, and validating/cleaning of clinical study data. Patient data will be entered by the 
investigator or designee using the electronic Case Report Forms (eCRFs) provided by the 
sponsor. Clinical data will be entered and stored into a validated database. The eCRFs will be 
provided in the Electronic Data Capture (EDC) system hosted by the sponsor. Trained users 
will access the system via a secured gateway. Users will be only authorized to access data for 
their study site. Data will be entered directly into the system from the source documents in 
lieu of the paper CRFs. On-line and off-line edit checks will be used to prompt the user to 
provide clean and accurate data. Clinical Data Management will code and monitor the data 


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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 
patient data are ready for analysis. 
Integrity of the database will be assured by limiting access through username/password 
combination and account control. Authorized access to the database will be provided to those 
individuals with an inspection/auditing function (Regulatory Authorities/Quality Assurance); 
“read only” access will be provided to avoid unintentional corruption of the database. 
The database will be backed up daily. 
10.2 
Case Report Forms 
Electronic CRFs may be generated and/or printed at any time using the sponsor’s EDC 
system.  These eCRFs may be used for electronic submission data archiving or data review. 
A copy of the final patient-specific eCRFs will be sent to the clinical study sites after 
database freeze. 
11 
MONITORING, AUDITS, AND INSPECTIONS 
11.1 
Source Documents 
The investigator or delegate will maintain adequately detailed source documents supporting 
significant source data for each patient. Source data are defined as all information in original 
records and/or certified copies of original records of clinical findings, observations, or other 
activities in a clinical study that are necessary for the reconstruction and evaluation of the 
study: e.g., medical history, physical examination, laboratory results, and x-ray or ultrasound 
results. The investigator will also retain all printouts/reports of tests or procedures performed 
as a requirement of the study. All source data that is printed on thermal paper, including 
laboratory printouts and ECGs scans, must be photocopied, initialed, and dated as authentic 
equivalents to the thermal paper documents to enable extended retention time. 
The source documents must be available at the time of an audit; a site visit from the sponsor, 
sponsor representatives, or IRB/IEC; and a regulatory authority inspection. 


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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, the study 
site may be inspected by regulatory authorities and/or audited by ApoPharma Quality 
Assurance (QA) or their designates. The investigator and relevant clinical support staff will 
be required to be actively involved in audits and inspections, including staff interviews, and 
to make all necessary documentation and data available upon request. 
During the course of the study and/or after it has been completed, one or more investigator 
site audits may be undertaken by auditors from ApoPharma QA or delegates. The purpose of 
these audits is to determine whether or not the study is being/has been conducted and monitored 
in compliance with recognized ICH E6 Guideline for Good Clinical Practice, protocol and 
approved amendment requirements, applicable local SOPs, and local laws and regulations. It 
is the responsibility of the investigator and site staff to promptly address, by coordinating 
with ApoPharma Clinical Research, any deficiencies stemming out of regulatory inspections 
and ApoPharma QA or delegate audits, and to ensure that agreed-upon corrective and 
preventive actions are implemented as soon as possible. 
An inspection by any regulatory authority may occur at any time during or after completion 
of the study. If an investigator is contacted by a regulatory authority for the purpose of 
conducting an inspection or to discuss any compliance issues, he/she is required to contact 
ApoPharma Clinical Research immediately. 
11.4 
Site Closure 
Upon completion of the study, the investigator must conduct the following activities, when 
applicable: 


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 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. 
11.5 
Retention of Records 
Following closure of the study, the investigator will maintain a copy of all site study records 
in a safe and secure location for at least 25 years or as specified in the Clinical Trial 
Agreement. The sponsor will inform the investigator of the time period for retaining these 
records to comply with all applicable regulatory requirements. 
12 
ETHICAL CONSIDERATIONS 
12.1 
Informed Consent 
Prior to entering a patient into the study, the investigator or a designate must obtain written 
informed consent from the patient and/or where applicable the patient’s legally authorized 
representative, according to the sponsor’s procedures and as described in the Declaration of 
Helsinki, the Federal Food, Drug and Cosmetic Act, and U.S. applicable Code of Federal 
Regulations Title 21, Part 50 and other regulatory authority codes as applicable.  The 
investigator will ensure that the patient and/or legal representative is given full and adequate 
verbal and written information about the nature, purpose, and possible risks and benefits of the 
study, and is given ample opportunity to ask questions and to discuss the study with family 


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members. The investigator must make a conscientious effort to be fully satisfied that the 
patient and/or legal representative has truly understood that for which the consent has been 
given. The patient and/or the legal representative must be notified that he/she is free to 
discontinue participation in the study at any time, and that such withdrawal will not affect 
present or future care. In the case of an incapacitated adult who is capable of forming an 
opinion and assessing the study information, the investigator must ensure that this individual’s 
decision to not participate or to withdraw from the study will be respected even if consent is 
given by the legal representative. 
The sponsor will provide a model version of the informed consent form to the sites as a 
separate document. Each site may then revise this version according to the requirements of 
its individual IRB/IEC. 
The patient and/or legal representative will sign and date the consent form prior to the first 
study intervention, and will be provided with a copy of the signed and dated ICF. Should a 
protocol amendment be made, the ICF may need to be revised to reflect the changes to the 
protocol. The investigator must then ensure that the revised ICF is signed by all patients 
currently enrolled as well as those subsequently entered in the study. 
12.2 
Institutional Review Board/Independent Ethics Committee 
It is the investigator’s responsibility to ensure that the protocol is reviewed and approved by 
a properly constituted IRB or IEC (according to ICH GCP guidelines, Section 3.2). The 
IRB/IEC must also review and approve the site’s ICF and any other written information that 
will be provided to patients, prior to any enrollment and the release of any advertisements for 
patient recruitment. Prior to the start of the study, the investigator or designee must forward 
copies of the IRB/IEC approval and the approved ICF materials to the sponsor. 
If it is necessary to amend either the protocol or the ICF during the study, the investigator 
will be responsible for ensuring that the IRB/IEC reviews these amended documents, and that 
IRB/IEC approval of the amended ICF is obtained before any additional patients are enrolled. 
Copies of the amended ICF and of the IRB/IEC’s approval of it must be forwarded to the 
sponsor as soon as they are available. 
12.3 
Patient Confidentiality 
To ensure that patients’ identities remain unknown to the sponsor, all data will be identified 
by patient ID. 
The investigator must inform patients of the possibility that representatives from regulatory 
authorities and/or the sponsor may require access to hospital or clinic records for verification 
of data pertinent to the study, including medical history. 
The investigator is responsible for keeping a list of all patients entered, including patient 
code, patient ID, full name, and last known address. 


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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 
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, if available: 
 Accreditation, certification, established quality control, or external quality assessment 
of the laboratory 
 Normal ranges or values for all laboratory test or procedures conducted during the 
trial  
6. Financial Disclosure Forms (where applicable) 
7. Regulatory Authority statement of investigator forms (e.g., FDA form 1572 where 
applicable) 
8. Signed Clinical Trial Agreement 


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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. 
15 
CONFIDENTIALITY 
Each investigator must sign a confidentiality agreement, in form and content satisfactory to 
the sponsor, concerning the protection of the sponsor’s confidential and proprietary 
information disclosed to or obtained by the investigator during the course of the study. Other 
than for study recruitment purposes and progress reports required by the regulatory agencies, 
the information contained in this document and all future information relating to this study is 
privileged, confidential, and proprietary, and may not be used or disclosed without the 
expressed written consent of the sponsor or unless otherwise required by law (in which case 
the requirement to make such disclosure shall be communicated to the sponsor in advance 
and in writing). All information provided to the investigator by the sponsor is to be 
considered strictly confidential unless otherwise specified. 
16 
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 


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conducting the study are the exclusive property of the sponsor. Details are provided in the 
Clinical Trial Agreement completed by the sponsor and the investigator and/or site. 
17 
PUBLICATION 
Data derived from the study are the exclusive property of the sponsor, and the sponsor will 
be responsible for the primary publication of the data. 
Investigators may publish or otherwise disclose (e.g., present at a conference or use for 
instructional purposes) data from the trial solely in accordance with the terms and conditions 
described in the Clinical Trial Agreement. 


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18 
REFERENCES 
1. Devos D, Moreau C, Dujardin K, Cabantchik I, Defebvre L, Bordet R. New 
pharmacological options for treating advanced Parkinson's disease. Clin Ther. 2013 
Oct;35(10):1640-52. 
2. Pinter B, Diem-Zangerl A, Wenning GK, Scherfler C, Oberaigner W, Seppi K, Poewe 
W. Mortality in Parkinson’s Disease: A 38-year follow-up study. Movement 
Disorders, Vol. 30 (2), 2015: 266-269. 
3. Weinreb O, Mandel S, Youdim MB, Amit T. Targeting dysregulation of brain iron 
homeostasis in Parkinson's disease by iron chelators. Free Radic Biol Med. 2013 
Sep;62:52-64. 
4. Singh KK. Mitochondria damage checkpoint, aging, and cancer. Ann N Y Acad Sci. 
2006;1067:182-90. 
5. Poulsen HE. Oxidative DNA modifications. Exp Toxicol Pathol. 2005;57 Suppl 
1:161-9. 
6. Kakhlon O, Breuer W, Munnich A, Cabantchik ZI. Iron redistribution as a therapeutic 
strategy for treating diseases of localized iron accumulation. Can J Physiol 
Pharmacol. 2010;88(3):187-96. 
7. Levy M, Turtzo C, Llinas RH. Superficial siderosis: a case report and review of the 
literature. Nat Clin Pract Neurol. 2007;3(1):54-8. 
8. Lotharius J, Brundin P. Pathogenesis of Parkinson's disease: dopamine, vesicles and 
alpha-synuclein. Nat Rev Neurosci. 2002;3(12):932-42 
9. Shanzer A, Libman J, Lytton SD, Glickstein H, Cabantchik ZI. Reversed siderophores 
act as antimalarial agents. Proc Natl Acad Sci U S A. 1991;88(15):6585-9. 
10. Zanninelli G, Choudury R, Loreal O, Guyader D, Lescoat G, Arnaud J, et al. Novel 
orally active iron chelators (3-hydroxypyridin-4-ones) enhance the biliary excretion 
of plasma non-transferrin-bound iron in rats. J Hepatol. 1997;27(1):176-84. 
11. Glickstein H, El RB, Link G, Breuer W, Konijn AM, Hershko C, et al. Action of 
chelators in iron-loaded cardiac cells: Accessibility to intracellular labile iron and 
functional consequences. Blood. 2006;108(9):3195-203. 
12. Molina-Holgado F, Hider RC, Gaeta A, Williams R, Francis P. Metals ions and 
neurodegeneration. Biometals. 2007;20(3-4):639-54. 
13. Glickstein H, Ben El R, Shvartsman M, Cabantchik ZI. Intracellular labile iron pools 
as direct targets of iron chelators. A fluorescence study of chelator action in living 
cells. Blood. 2005;106(9):3242-50. 


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14. Boddaert N, Quan Sang KH, Rotig A, Leroy-Willig A, Gallet S, Brunelle F, et al. 
Selective iron chelation in Friedreich ataxia. Biological and clinical implications. 
Blood. 2007;110(1):401-8. 
15. 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;97(3):792-8. 
16. Sohn YS, Breuer W, Munnich A, Cabantchik ZI. Redistribution of accumulated cell 
iron. A modality of chelation with therapeutic implications. Blood. 2008;111:1690-9. 
17. Evans RW, Sharma M, Ogwang W, Patel KJ, Bartlett AN, Kontoghiorghes GJ. The 
effect of alpha-ketohydroxypyridine chelators on transferrin saturation in vitro and in 
vivo. Drugs of Today. 1992;28(Suppl. A):19-23. 
18. Waldmeier PC, Buchle AM, Steulet AF. Inhibition of catechol-O-methyltransferase 
(COMT) as well as tyrosine and tryptophan hydroxylase by the orally active iron 
chelator, 1,2-dimethyl-3-hydroxypyridin-4-one (L1, CP20), in rat brain in vivo. 
Biochem Pharmacol. 1993;45(12):2417-24. 
19. Devos D, Moreau C, Devedjian JC, Kluza J, Petrault M, Laloux C, et al. Targeting 
chelatable iron as a therapeutic modality in Parkinson's disease. Antioxid Redox 
Signal. 2014 Jul 10;21(2):195-210. 
20. Cossu G, Abbruzzese G, Matta G, Murgia D, Melis M, Ricchi V, et al. Efficacy and 
safety of deferiprone for the treatment of pantothenate kinase-associated 
neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation 
(NBIA): Results from a four years follow-up. Parkinsonism Relat Disord. 2014; 
21. Dexter DT, Martin-Bastida A, Kabba C, Piccini P, Sharp D, Ward R, et al. A pilot 6 
months efficacy and safety study utilising the iron chelator deferiprone in early stage 
Parkinson's disease. Movement Disorders; 2014. 
22. ApoPharma Inc. Study LA46-0114: Single Dose Crossover Comparative 
Bioavailability Study of Deferiprone 600 Mg Delayed Release Tablets Versus 
Deferiprone Solution in Healthy Male and Female Volunteers Following a 1200 mg 
Dose – Fasting and Fed Conditions, 2015. 
23. ApoPharma Inc. Ferriprox® (deferiprone) - Summary of Product Characteristics (EU). 
2012. 
24. ApoPharma Inc. Investigator’s Brochure for Parkinson’s Disease, 2015. 
25. Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, Langston W, 
Melamed E, Poewe W, Stocchi F, Tolosa E; ADAGIO Study Investigators. A double-
blind, delayed-start trial of rasagiline in Parkinson's disease. N Engl J Med. 2009 Sep 
24;361(13):1268-78. 


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26. Rascol O, Fitzer-Attas CJ, Hauser R, Jankovic J, Lang A, Langston JW, Melamed E, 
Poewe W, Stocchi F, Tolosa E, Eyal E, Weiss YM, Olanow CW. A double-blind, 
delayed-start trial of rasagiline in Parkinson’s disease (the ADAGIO study): 
prespecified and post-hoc analyses of the need for additional therapies, changes in 
UPDRS scores, and non-motor outcomes. Lancet Neurol. 2011 May;10(5):415-23.  


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APPENDIX 1:  CLINICAL STUDY ADMINISTRATIVE STRUCTURE 
 
Function 
Name of Organization 
Address and Contact 
Information 
Safety Analysis Laboratories 
Eurofins Central Laboratory, 
LLC.  
2430 New Holland Pike  
Building D, Suite 100 
Lancaster PA 17601, USA 
Tel: +1 717 556 7350 
Fax: +1 717 556 3888 
Eurofins Central Laboratory 
Breda 
Eurofins Central Laboratory 
B.V.  
Bergschot 71 
4817 PA Breda 
The Netherlands 
Tel: +31 76 57 37 373 
Fax: +31 76 57 37 778 
Pharmacokinetics and 
Biomarkers Analysis 
Laboratory 
Algorithme Pharma Inc. 
575, boul. Armand-Frappier 
Laval, Quebec 
Canada H7V 4B3 
Tel: 1-450-973-6077 
Fax: 1-450-973-2801 
Genotyping Laboratory 
PGXL Technologies 
201 E. Jefferson St., Suite 309 
Louisville, KY 40202, USA 
Tel: 1-502-569-1584 
Toll-free: 1-877-564-2199 
Email: info@pgxlab.com 
Interactive Voice/Web 
Response System 
ICON Clinical Research Ltd. 
South County Business Park 
Leopardstown 
Dublin 18, Ireland 
Tel: +353 (1) 291 2000 
Fax: +353 (1) 291 2700 
 

SAP_001.pdf: 




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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
CONFIDENTIAL INFORMATION 
3
 
Table of Contents 
 
 
Title page.......................................................................................................................1 
 
Approvals ......................................................................................................................2 
 
Table of Contents .........................................................................................................3 
 
List of Abbreviations ...................................................................................................5 
1 Introduction ..................................................................................................................6 
2 Study Objectives...........................................................................................................6 
2.1 
Primary Objective ..............................................................................................6 
2.2 
Secondary Objectives .........................................................................................6 
2.3 
Exploratory Objectives ......................................................................................6 
3 Methods .........................................................................................................................6 
3.1 
Study Design and Randomization .....................................................................6 
3.2 
Determination of Sample Size and Study Power .............................................7 
3.3 
Analysis Populations ..........................................................................................7 
3.4 
Interim Analysis .................................................................................................8 
3.5 
Missing Data Handling and Derivation Rules .................................................8 
3.6 
Statistical Software and Level of Significance ...............................................10 
4 Statistical Analyses.....................................................................................................10 
4.1 
Patient Disposition and Drug Exposure .........................................................11 
4.2 
Patient Characteristics .....................................................................................12 
4.2.1 
Demographics ......................................................................................12 
4.2.2 
Medical History ...................................................................................12 
4.2.3 
Prior Medications .................................................................................12 
4.3 
Efficacy Analyses ..............................................................................................12 
4.3.1 
Primary Efficacy Endpoint ..................................................................12 
4.3.2 
Secondary Efficacy Endpoints .............................................................13 
4.3.3 
Exploratory Efficacy Endpoints ...........................................................14 
4.3.4 
Exploratory Analyses/Sensitivity Analysis..........................................15 
4.4 
Safety Analyses .................................................................................................15 
4.4.1 
Adverse Events ....................................................................................16 
4.4.2 
Vital Signs and Weight ........................................................................18 
4.4.3 
12-Lead ECG .......................................................................................18 
4.4.4 
Biochemistry, Hematology and Urinalysis ..........................................18 
4.4.5 
Concomitant Medications ....................................................................18 
4.4.6 
Suicidality ............................................................................................19 
4.4.7 
Treatment Compliance .........................................................................19 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
CONFIDENTIAL INFORMATION 
4
5 Listing of Tables and Figures....................................................................................20 
6 Data Listings ...............................................................................................................25 
7 Table Shells .................................................................................................................27 


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Statistical Analysis Plan: Protocol LA48-0215 
 
CONFIDENTIAL INFORMATION 
5
List of Abbreviations 
 
 
ADR  
Adverse Drug Reaction 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
AUCss 
Area under the concentration-time curve at steady state 
CI 
Confidence Interval 
Cmax 
Maximum Concentration 
COMT 
Catechol O-methyltransferase 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DDFM 
Denominator Degrees of Freedom Method 
DFP 
Deferiprone 
DR 
Delayed Release 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
ITT 
Intent-to-treat 
KR 
Kenward and Roger’s method 
LOCF 
Last Observation Carried Forward 
LSM 
Least Square Mean 
MDS-UPDRS 
Movement Disorder Society-Unified Parkinson’s Disease Rating 
Scale 
MedDRA  
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MMRM 
Mixed-Effect Model Repeated Measure 
MOA 
Mechanism of Action 
MoCA 
Montreal Cognitive Assessment 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PP 
Per protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOC 
System Organ Class 


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Statistical Analysis Plan: Protocol LA48-0215 
 
CONFIDENTIAL INFORMATION 
6
1 Introduction 
This document outlines the statistical analysis plan for the efficacy and safety analysis for 
the clinical trial LA48-0215 sponsored by ApoPharma Inc. 
2 Study Objectives 
2.1 
Primary Objective 
• To evaluate the efficacy of four different dosages of deferiprone delayed release 
(deferiprone-DR) tablets in  patients with Parkinson’s disease 
2.2 
Secondary Objectives 
• To evaluate the safety and tolerability of deferiprone-DR tablets in  patients with 
Parkinson’s disease 
• To evaluate the pharmacokinetics of deferiprone-DR tablets in a subset of study 
participants 
• To evaluate the relationship between the pharmacokinetics and pharmacodynamics 
of deferiprone-DR tablets 
2.3 
Exploratory Objectives 
• To determine whether the efficacy responses to deferiprone differ depending on 
the genotype of certain enzymes that are implicated in Parkinson’s disease 
• To determine whether the efficacy responses to deferiprone are correlated with 
ceruloplasmin levels or ceruloplasmin ferroxidase activities 
3 Methods 
3.1 
Study Design and Randomization 
This is a multi-center, randomized, double-blind, placebo-controlled, dose-ranging study 
in 140  patients who had been diagnosed with typical Parkinson’s disease within the last 
3 years and were taking antiparkinsonian medication at enrollment.  Screening was 
conducted within 30 days prior to the start of dosing. At baseline, eligible participants 
were randomized to one of four dosage cohorts, and within each cohort were further 


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randomized in a 4:1 ratio to receive either active product (n=28) or placebo (n=7).  
Thus, a total of 112 patients received one of the four dosages of deferiprone, and a total 
of 28 received placebo. The assigned study product was taken twice-daily (b.i.d.), at least 
8 hours apart, for 9 months.  Dosages were as follows: 
• Cohort 1:  300 mg deferiprone delayed release tablets (n=28) or placebo (n=7) 
• Cohort 2:  600 mg deferiprone delayed release tablets (n=28) or placebo (n=7) 
• Cohort 3:  900 mg deferiprone delayed release tablets (n=28) or placebo (n=7) 
• Cohort 4:  1200 mg deferiprone delayed release tablets (n=28) or placebo (n=7) 
Patients returned to the site at Months 1, 2, 3, 4, 5, 6, and 9, and received a follow-up 
telephone call at Month 10. Safety was assessed at each site visit and at the follow-up 
call; efficacy measures were assessed at baseline and Months 3, 6, and 9; and sparse 
pharmacokinetics (PK) sampling was done on all patients at baseline and Month 3.  In 
addition, an optional subset of 16 patients underwent extensive blood sampling for PK 
analysis at Month 1, and an optional subset of 18 patients each provided one sample of 
cerebrospinal fluid (CSF) for drug level analysis at Month 3.  (No selection was done to 
enroll these subsets:  all patients were asked if they were willing to provide either or both 
of these types of samples, and they were enrolled as they came until the total number of 
subjects was reached for each subset.)  For safety reasons, all patients had their absolute 
neutrophil count  monitored weekly after the start of dosing, at either the study site or a 
local laboratory. Any patient whose regimen of antiparkinsonian medication was 
changed, including a change in dosage, would be withdrawn from the trial. 
Any patient who withdrew before completing treatment was requested to return within 
one month for an Early Termination visit, at which time the procedures normally 
scheduled for the Month 9 visit were conducted. 
3.2 
Determination of Sample Size and Study Power 
There was no formal sample size and power calculation for this Phase II dose-finding 
study.  
3.3 
Analysis Populations 
Four study populations for analysis  are defined: Intent-to-Treat (ITT), Per-Protocol (PP), 
Safety, and Pharmacokinetics/Pharmacodynamics (PK/PD). For efficacy, all endpoints 
will be analyzed for the ITT population, which represents the primary analysis 
population, and the primary efficacy endpoint will additionally be analyzed for the PP 
population, which represents the secondary analysis population. 
ITT Population  


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The ITT population is defined as all randomized patients who received at least one dose 
of study drug and havea baseline and at least one post-baseline efficacy assessment for 
the primary endpoint. All efficacy endpoints will be analyzed for the ITT population. 
PP Population  
The PP population is defined as all randomized patients who completed the study, have 
no major protocol violations, and have an efficacy assessment for the primary endpoint at 
the end of the study. Prior to database lock, protocol violations will be reviewed for their 
seriousness, and patients with major violations will be excluded from the PP population. 
The only endpoint that will be analyzed for the PP population is the the primary efficacy 
endpoint. 
Safety Population 
The Safety population will include all randomized patients who received at least one dose 
of study drug.  
PK/PD Population 
The Pharmacokinetics/Pharmacodynamics (PK/PD) population will include all patients 
who provided sufficient PK data to derive at least one PK parameter. Detailed analyses 
on PK assessments will be included in separate statistical analysis plan. 
3.4 
Interim Analysis 
No interim analysis is planned or conducted.   
3.5 
Missing Data Handling and Derivation Rules 
For safety data and PD data, all analyses will be based on observed cases (OC).  No 
imputation will be performed on missing data. 
For all efficacy measures but one (time elapsed until rescue medication), when there are 
missing total scores, missing data will be assumed to be missing at random (MAR). A 
Mixed-Effect Model Repeated Measure (MMRM) model will be used as the primary 
analysis method, and the analyses will be based on observed cases.  A sensitivity analysis 
will be conducted for the primary efficacy endpoint, with missing data being imputed as 
follows. In cases where early termination was due to either worsening of disease 
conditions or inadequate efficacy of the drug (as documented in the case report form), the 
“worst score” method will be used to fill in missing data. With this method, for the 
placebo group, the average change score of the placebo group at a particular visit will be 
used to impute any missing data at that visit, while for the active group, the worst change 
score of all patients at that visit will be used.  In cases where early termination was due to 
some other reason, such as a missed visit, the last observation carried forward (LOCF) 


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method will be used to fill in the missing data.  For Movement Disorder Society-Unified 
Parkinson’s Disease Rating Scale (MDS-UPDRS) score, a score will be obtained for each 
part and a total score will be calculated by adding the score of each part.  For each part, 
one would simply add the score obtained for all questions. If there is a missing answer, 
the score for this part will be handled as below: 
o (A x B) / C = D 
o Where: 
▪ A = sum of all item score recorded in a specific part 
▪ B = number of total items in a specific part  
▪ C = number of item with actual score in specific part 
▪ D = final calculated valid Part score 
For example, if a part has 13 items and only 12 items have been rated, one will get the 
sum of these 12 items, multiply it by 13 and dividing this by 12. 
However, for an imputed score to be valid for a specific part, the below maximum of item 
missed per part cannot be exceeded: 
▪ Part I: max of 2 missing items 
▪ Part II: max of 3 missing items 
▪ Part III: max of 9 missing items 
▪ Part IV: max of 1 missing items 
If there are more than the maximum number of item missed in a part, the total score for 
that part will not be imputed and will be left as missing. 
For Montreal Cognitive Assessment (MoCA) test score, the missing component score 
will be assigned a score of zero by the rater so it is expected the number of missing 
component score will be minimal. If there is a missing component score, it will be 
imputed by the LOCF method before the total score is calculated. 
Date of exposure will be defined as Day 1 for all duration calculations. For example, age 
at entry will be calculated as the integer value of the expression:  
Floor(date of exposure – date of birth) / 365.25 
Time in months will be derived by dividing the time in days by 30.4. 


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3.6 
Statistical Software and Level of Significance 
All statistical analyses will be performed using SAS (version 9.3 or higher) on the 
Windows operating system. The null hypotheses tested are that there is no difference in 
true parameter between comparison groups, unless otherwise stated. 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.   
4 Statistical Analyses 
Data from all patients who were randomized to receive placebo will be combined into 
one group for the efficacy and safety analyses. Thus, there will be a total of 5 treatment 
groups:  the placebo group and the 300 mg, 600 mg, 900 mg, and 1200 mg deferiprone 
groups. Descriptive statistics will be used to summarize continuous variables, while 
frequency and percentage will be presented for each discrete variable. Where applicable, 
analysis of variance (ANOVA) will be used to compare means, and Fisher’s exact test 
will be used to compare proportions.  
As patients may not attend each study visit within the specified time window, efficacy 
data will be classified into scheduled visits according to the time elapsed from the first 
dose of medication (date of exposure) to the date of assessment, as follows: 
 
Month 3 visit: 0 to < 4.5 months 
 
Month 6 visit: 4.5 to < 7.5 months 
 
Month 9 visit: 7.5 to < 10.5 months 
The calculation of time elapsed from the date of exposure to the date of assessment is 
done as follows:  
Time elapsed = (date of sample assessment) – (date of exposure) +1 
The resulting time elapsed will be expressed in months. If this results in overlap in visits, 
the average value of the same visits will be used in the analysis.  
For all continuous efficacy outcomes except for time elapsed until rescue medication 
(addressed below),  a Mixed-Effect Model Repeated Measure (MMRM) model will be 
used as the primary analysis method to assess the effect of deferiprone on change from 
baseline to Month 9. The MMRM model will include the baseline value of the outcome 
as a covariate and treatment group and visit as the main factors. Baseline value is the 
value collected the closest prior to baseline visit.  
The MIXED procedure in SAS will be used for the MMRM model analysis. Data from 
each patient at different visits will be considered repeated measures. A first-order 


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autoregressive (AR) covariance structure will be used to model the correlation between 
repeated measures within the same patient, and Kenward and Roger’s method will be 
used to estimate the denominator degrees of freedom (DDFM). The Least Square Mean 
(LSM) and 95% confidence interval (CI) of the LSM difference will be calculated by the 
LSMEANS statement.  
A sample SAS code for the MMRM model is shown in the box below: 
proc mixed; 
  class TREAT USUBJID VISIT; 
  model CHG=TREAT VISIT TREAT*VISIT BASE/solution ddfm=kr; 
  repeated VISIT/ subject=USUBJID type=ar(1); 
  lsmeans TREAT*VISIT / diff cl; 
run; 
 
where TREAT is the discrete variable for treatment group, USUBJID represents the 
patient ID, VISIT is the discrete variable representing the scheduled study visit after the 
baseline visit, CHG is the change in value of efficacy outcome from baseline to the 
scheduled visit, and BASE is the baseline value of efficacy outcome. 
If the treatment effect is found to be statistically significant, each deferiprone group will 
be compared to the placebo group to assess the treatment effect at each deferiprone dose 
level using the SAS code for MMRM model as presented above. Linear regression 
analysis will be employed to assess the dose-response relationship through a linear 
regression model, with the change at the study end as the dependent variable and the 
treatment dose as the continuous variable.  If a statistically significant relationship exists 
between deferiprone dose and an efficacy outcome, the dose-response relationship will be 
further assessed and reported through pairwise comparison of each dose level to the next 
lower dose level: 1200 mg vs. 900 mg, 900 mg vs. 600 mg, and 600 mg vs. 300 mg, 
using the MMRM model SAS code as presented above. 
For the analysis of time elapsed until the need for rescue medication, a time to event 
analysis using the Kaplan-Meier survival curve will be performed and the log-rank test 
will be used to compare the treatment groups. The LIFETEST procedure in SAS will be 
used to perform this analysis. 
4.1 
Patient Disposition and Drug Exposure 
Patient disposition, based on the Safety population, will be summarized descriptively. 
Data will include the numbers and percentages of patients who were screened, enrolled, 
completed the study, and withdrawn (including reasons for withdrawals).  


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For each patient, the number of doses taken will be computed from the study drug 
dispensing and accountability eCRFs obtained at each visit. The extent of exposure to 
study medication, as well as compliance during the study, will be summarized with 
descriptive statistics. 
The number of exposed patients at each study site will be presented by treatment group, 
and the number of subjects included in each population will be tabulated by treatment 
group. 
4.2 
Patient Characteristics 
Baseline characteristics will be summarized by mean, standard deviation (SD), median, 
and minimum and maximum values, for  the ITT, PP and the Safety populations. Medical 
history and prior medications will be summarized descriptively as number of patients and 
percentage. 
4.2.1 Demographics 
Demographic data (age, sex, ethnicity, and race) will be summarized by treatment group. 
4.2.2 Medical History 
Medical history on current and historical diagnoses and co-morbidities will be coded 
using the preferred terms (PTs) of the Medical Dictionary for Regulatory Activities 
(MedDRA), and will be summarized by treatment group. 
4.2.3 Prior Medications 
Prior medication use will be summarized by treatment group.  
4.3 
Efficacy Analyses 
4.3.1 Primary Efficacy Endpoint 
The primary endpoint is the change from baseline to Month 9 in score on the motor 
examination subscale (Part III) of the MDS-UPDRS.  For a detailed definition, see 
Section 7.1.1 of the study protocol. 
The primary efficacy endpoint will be analyzed based on the ITT population. The 
analysis will be repeated for the PP population as a sensitivity analysis. 


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The data on the change in Part III score of the MDS-UPDRS from baseline to Month 9 
will be summarized by treatment group. The MMRM model will be used to compare the 
change in score among treatment groups.  
4.3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are listed below.  For detailed definitions, see Section 
7.1.2 of the study protocol. 
• Change from baseline to Month 9 in total score on the MDS-UPDRS 
• Change from baseline to Month 9 in scores on the individual subscales of the 
MDS-UPDRS:  Part I (non-motor experiences of daily living), Part II (motor 
experiences of daily living), and Part IV (motor complications) 
• Change from baseline to Month 9 in the combined scores from Parts II and III of 
the MDS-UPDRS 
• Change from baseline to Month 9 in overall cognitive function, as assessed by the 
Montreal Cognitive Assessment (MoCA) test 
• Change from baseline to Month 9 in pharmacodynamics measures of the following 
oxidative stress biomarkers: total antioxidant status, lipid peroxidation 
(malondialdehyde), protein carbonyls, 8-OHdG, glutathione, superoxide dismutase 
• Change from baseline to Month 9 in pharmacodynamics measures of the following 
inflammatory factor biomarkers:  TNF alpha and IL-6 
• Time elapsed until the need for rescue medication 
The secondary efficacy endpoints will be analyzed based on the ITT population only. 
The data on the changes from baseline to Month 9 in the MDS-UPDRS total score, the 
Parts I, II, and IV subscale scores, the combined Part II and Part III score, and the MoCA 
score will be summarized by treatment group. The MMRM model will be used to 
compare the change in each score between treatment groups. 
The data on the changes from baseline to Month 9 in oxidative stress biomarkers and 
inflammatory factor biomarkers will be summarized by treatment group. 
The time elapsed until the need for rescue medication will be presented using the Kaplan-
Meier survival curve, and will be compared among the treatment groups using the log-
rank test.  


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4.3.3 Exploratory Efficacy Endpoints 
The exploratory objectives of this study are to evaluate whether the potential disease-
modifying action of deferiprone is correlated with 1) specific genotypes of enzymes that 
play a role in Parkinson’s disease, and 2) the degree of change from baseline in 
ceruloplasmin levels and ceruloplasmin ferroxidase activity. The Mechanism of Action 
(MOA) biomarkers that will be examined are listed below.  For detailed definitions, see 
Section 7.1.3 of the study protocol.  
The biomarkers are: 
• 
D544E polymorphisms of the glycoprotein ceruloplasmin 
• 
V158M polymorphisms of the enzyme catechol O-methyltransferase (COMT) 
• 
Ceruloplasmin levels (to be analyzed depending on the outcomes of the primary 
and/or secondary efficacy endpoints) 
• 
Ceruloplasmin ferroxidase activity (to be analyzed depending on the outcomes of 
the primary and/or secondary efficacy endpoints) 
To evaluate the impact of the D544E and V158M genotypes on the treatment effect of 
deferiprone in Parkinson’s disease, subgroup analyses of the data from the two genotypes 
will be done based on the MMRM analysis performed on the primary endpoint (change 
from baseline to Month 9 on the Part III score of the MDS-UPDRS), using the ITT 
population. If there is a treatment effect on the score from other parts of MDS-UPDRS, 
this analysis will be repeated for those outcomes as well.  For details, see Section 4.3.4. 
If there is evidence of efficacy based on the primary and/or secondary efficacy endpoints, 
the data on the change from baseline to Month 9 in ceruloplasmin level and 
ceruloplasmin ferroxidase activity will be summarized by treatment group.  The MMRM 
model will be used to compare the change in these two biomarkers between treatment 
groups. Correlation analysis between the change and the primary efficacy endpoint will 
be performed for each biomarker.  These two variables will also be included in the main 
MMRM model for the primary endpoint, in order to study the relationship between these 
two MOA biomarkers and the effect of deferiprone.  
Correlation analysis of the PD endpoints (change from baseline to Month 9 for 
biomarkers of interest) and the PK parameters (AUC0-∞ and Cmax) will be performed if 
efficacy is evidenced. This analysis will be performed for the PK/PD population.  


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4.3.4 Exploratory Analyses/Sensitivity Analysis 
If there are unevenly distributed baseline factors among the treatment groups, the effects 
of those factors on the efficacy measurements will be examined by including them in the 
MMRM model. 
Subgroup analyses will be performed for the ITT population on the following factors: 
D544E genotype (Aspartate/Aspartate vs. Aspartate/Glutamate) and V158M genotype 
(Methionine/Methionine vs. Valine/Methionine vs. Valine/Valine). For D544E genotype, 
Aspartate/Aspartate corresponds to the high metabolizer phenotype (AA) and 
Aspartate/Glutamate to the low metabolizer phenotype (AT). For the V158M genotypes, 
the corresponding phenotypes are High COMT Activity, Intermediate COMT Activity, 
and Low COMT Activity. The analysis results will be presented by the phenotypes for 
each factor. 
Besides analysis for the ITT population, the primary efficacy endpoint will also be 
analyzed for the PP population as sensitivity analyses. 
As a sensitivity analysis, the efficacy data will be re-analyzed with the missing data being 
imputed as described in section 3.5.  The sensitivity analysis will be performed only on 
the primary efficacy endpoint using the ITT population. 
If the blinded review of the efficacy data performed before the breaking of the treatment 
codes indicates a severe non-normality of the data, an appropriate transformation (for 
example, log transformation) will be applied to the data, or nonparametric statistical 
methods based on ranks will be employed, if warranted.  
Other exploratory analyses may be performed after examining the planned analyses if 
they are considered interesting and necessary. 
4.4 
Safety Analyses 
The safety endpoints are listed below.  For detailed definitions, see Section 7.2 of the 
study protocol.Adverse events (AEs) 
• Serious adverse events (SAEs) 
• Number of discontinuations due to AEs 
• Laboratory measures (hematology, blood chemistry, and urinalysis) 
• ECG 
• Change from baseline in vital signs 


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• Physical examination 
• Assessment of suicidality (as per the Columbia Suicide Severity Rating Scale, 
C-SSRS) 
All safety data collected will be presented in listings and summary tables or graphs to 
give an overview of the findings. All safety endpoints will be analyzed based on the 
Safety population. 
For laboratory findings, since patients may not attend each study visit within the 
scheduled time window or may withdraw early, data will be classified into visits 
according to the time elapsed from the first dose of study medication (date of exposure) 
to the date of assessment.  For biochemistry, the following time windows will be 
employed: 
Month 1 visit: 0 to <1.5 months 
 
Month 2 visit: 1.5 to <2.5 months 
 
Month 3 visit: 2.5 to <3.5 months 
 
Month 4 visit: 3.5 to <4.5 months 
Month 5 visit: 4.5 to <5.5 months 
 
Month 6 visit: 5.5 to <7.5 months 
 
Month 9 visit: 7.5 to <10 months 
For the weekly hematology visits, data will be classified using half-weeks: 
Week 1 visit: 0 to <1.5 weeks 
 
Week 2 visit: 1.5 to <2.5 weeks 
 
…. 
For other measurements that fall on the same scheduled visits as the efficacy outcomes, 
such as urinalysis, the rule defined for efficacy outcomes in the beginning of Section 4 
will apply. 
4.4.1 Adverse Events 
A summary table of adverse events by treatment group will include the following 
information: 


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• Number of patients exposed to study treatment 
• Number of patients experiencing at least one AE 
• Number of patients experiencing at least one severe AE 
• Number of patients experiencing at least one serious AE 
• Number of patients experiencing at least one drug-related AE 
• Number of deaths 
• Total number of patients withdrawn 
• Number of withdrawals due to AEs 
Untoward medical occurrences, whether new events or the worsening of severity or 
frequency of pre-existing conditions, will be coded using MedDRA , and summarized by 
treatment and by system organ class (SOC) and preferred term (PT).  An event will be 
considered an AE if 1) its start date is on or after the date of the first dose of study 
medication, 2) the start date is missing and the stop date is on or after the date of the first 
dose of study medication, or 3) both the start and the stop dates are missing.  SAEs that 
begin within 30 days after the last dose of study medication, and both SAEs and non-
serious AEs that are still ongoing for up to 30 days after the last dose, will be included in 
the database. 
Adverse events will be summarized using the total number of events, the total number 
and percent of patients who experience an AE, and the number and percent of patients 
who experienced an AE within each SOC (and each PT within an SOC). AEs will also be 
presented by intensity (mild, moderate, severe), by seriousness (serious, non-serious) and 
by relationship to study medication (at least possibly related, not related). The number of 
patients withdrawn and the reasons for withdrawal will also be presented. 
To count the number of patients who experienced each AE, a patient who experienced the 
same AE multiple times will be counted only once for the corresponding preferred term. 
Similarly, a patient who experienced multiple AEs within the same SOC will be counted 
only once for that SOC. AEs will be tabulated by presenting the SOCs alphabetically, and 
within each SOC, the preferred terms will be presented in decreasing order of the total 
number of patients who experienced each one. In summaries presenting the incidence of 
AEs by severity, seriousness, and relation to study medication, 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. 
Listing of SAEs and listing of withdrawals due to AEs will be presented. Patient deaths 
will be listed separately and will be described in narratives. 


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4.4.2 Vital Signs and Weight 
Descriptive statistics (mean, median, standard deviation, minimum and maximum) will 
be presented at each visit for supine and standing heart rate, supine and standing blood 
pressure, and weight. Data will also be presented graphically, for examination of possible 
trends.  Change from baseline in these measures (for orthostatic vital signs, the baseline 
values will be the average of the three sets collected) will be assessed. 
4.4.3 12-Lead ECG 
The number and percentage of patients with normal and abnormal ECG results will be 
provided. Descriptive statistics will be presented for HR, PR, QRS, QT, QTcF, and 
QTcB. 
4.4.4 Biochemistry, Hematology and Urinalysis 
Descriptive statistics for each clinical laboratory test will be presented for each scheduled 
visit. For each test, if multiple measurements are taken on the same visit for a patient, the 
average value will be used. Using the laboratory’s normal ranges, the results will be 
categorized as low (< lower normal limit), normal (within normal range), or high (> 
upper normal limit). Shift tables comparing the distributions of these three categories at 
baseline versus end of treatment will be presented.  
Continuous data will also be presented graphically, for examination of possible trends. 
Clinically significant abnormalities in laboratory values will be included in the analyses 
of adverse events. 
4.4.5 Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. Medications taken during the course of the trial (on or after the first study 
drug dose and before or on the date of study termination will be considered to be 
concomitant medications. Medications started after the study termination date will not be 
reported in tables, but will be presented in patient data listings. Concomitant medications 
that were used to treat adverse events will be differentiated from others. 
Concomitant medications will be summarized according to preferred names only. To 
count the number of patients who took each type of medication, a patient who took the 
same medication multiple times will be counted only once for that medication. 
Medications will be tabulated in decreasing order of the total number of patients who 
took each one. In addition, the total number of patients to ever take any concomitant 
medications will be presented. 
Concomitant medications will be presented based on the Safety population. 


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4.4.6 Suicidality 
The Columbia Suicide Severity Rating Scale (C-SSRS) is an instrument used to measure 
suicidal ideation and behavior.  For each treatment group, descriptive statistics 
(frequency and percentage) will be presented for any suicidal ideation and behavior 
reported by patients at each visit.  
4.4.7 Treatment Compliance 
Compliance will be determined as follows: 1) patients will use the daily diary card to 
record the number of tablets taken, and 2) at each visit, the investigator or a delegate will 
inspect the medication containers, whether empty, partly used, or unopened, and will 
check the number of tablets remaining.  Compliance will be calculated by the number of 
tablets taken divided by the number prescribed, as per the dosing frequency and length of 
treatment. Compliance at each follow-up visit will be summarized descriptively by 
treatment group in a table.  


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5 Listing of Tables and Figures 
The summary tables and figures that will be produced based on the statistical analyses 
detailed in this document are listed bleow. All tables and figures will be presented by 
treatment group. Tables and figures are numbered following ICH structure, but the final 
numberings that appear in the clinical study report may be changed if more tables and/or 
figures are added. 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. 
 
Tables Listing: 
 
14.1 
Disposition, Demographics and Baseline Data 
 
Table 14.1.1 
Number of patients in different populations 
Table 14.1.2 
Subject disposition – Safety population 
Table 14.1.3 
Subject exposure to study medication – Safety population 
Table 14.1.4 
Number of patients enrolled by study site – Safety population 
Table 14.1.5 
Summary of the reasons for not completing the study – Safety 
population 
Table 14.1.6 
Summary of demographics data at baseline – ITT population 
Table 14.1.6a 
Summary of demographics data at baseline – PP population 
Table 14.1.6b 
Summary of demographics data at baseline – Safety population 
Table 14.1.7 
Summary of baseline characteristics – ITT population 
Table 14.1.7a 
Summary of baseline characteristics – PP population 
Table 14.1.8 
Medical History – Safety population 
Table 14.1.9 
Prior Medication – Safety population 
 
14.2 
Efficacy Analyses 
 
14.2.1 Primary Efficacy Endpoint 
 
Table 14.2.1.1 
Change in MDS-UPDRS Part III score at each follow-up visit – ITT 
population 
Table 14.2.1.1a 
Change in MDS-UPDRS Part III score at each follow-up visit – PP 
population 
Table 14.2.1.2 
Primary outcome least square mean (LSM) change from baseline to 
month 9 from MMRM model – ITT population 
Table 14.2.1.2a 
Primary outcome least square mean (LSM) change from baseline to 
month 9 from MMRM model – PP population 
Table 14.2.1.2s 
Primary outcome least square mean (LSM) change from baseline to 
month 9 from MMRM model – Sensitivity Analysis population 


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Table 14.2.1.2.1 Primary outcome least square mean (LSM) change from baseline to 
month 9 from MMRM model – ITT population and D544E 
polymorphisms = AA 
Table 14.2.1.2.2 Primary outcome least square mean (LSM) change from baseline to 
month 9 from MMRM model – ITT population and D544E 
polymorphisms = AT 
Table 14.2.1.2.3 Primary outcome least square mean (LSM) change from baseline to 
month 9 from MMRM model – ITT population and V158M 
polymorphisms = High COMT Activity 
Table 14.2.1.2.4 Primary outcome least square mean (LSM) change from baseline to 
month 9 from MMRM model – ITT population and V158M 
polymorphisms = Intermediate COMT Activity 
Table 14.2.1.2.5 Primary outcome least square mean (LSM) change from baseline to 
month 9 from MMRM model – ITT population and V158M 
polymorphisms = Low COMT Activity 
Table 14.2.1.3 
Dose-response assessment for all efficacy outcomes by linear 
regression model – ITT population 
Table 14.2.1.4 
Primary outcome least square mean (LSM) change from baseline to 
month 9 from MMRM model 2 – ITT population 
 
14.2.2 Secondary Efficacy Endpoints 
 
Table 14.2.2.1 
Change in other MDS-UPDRS scores and MoCA at each follow-up 
visit – ITT population 
Table 14.2.2.2 
Change in oxidative stress biomarkers at each follow-up visit – ITT 
population 
Table 14.2.2.3 
Change in inflammatory factor biomarkers at each follow-up visit – 
ITT population 
Table 14.2.2.4 
Secondary outcomes least square mean (LSM) change from baseline to 
month 9 from MMRM model – ITT population 
Table 14.2.2.5 
Secondary outcomes least square mean (LSM) change from baseline to 
month 9 from MMRM model 2 – ITT population 
 
14.2.3 Exploratory Efficacy Endpoints (only produced if efficacy is evidenced) 
 
Table 14.2.3.1 
Change in MOA biomarkers at each follow-up visit – ITT population 
Table 14.2.3.2 
MOA biomarkers least square mean (LSM) change from baseline to 
month 9 from MMRM model – ITT population 
Table 14.2.3.3 
MOA biomarkers least square mean (LSM) change from baseline to 
month 9 from MMRM model 2 – ITT population 
 
14.3 
Safety Analyses 
 
14.3.1 Adverse Events 
 


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Table 14.3.1.1 Overall summary of adverse events – safety population 
Table 14.3.1.2 Summary of adverse events – safety population 
Table 14.3.1.3 All adverse events by severity – safety population 
Table 14.3.1.4 All adverse events by seriousness – safety population 
Table 14.3.1.5 All adverse events by relatedness to study medication – safety 
population 
Table 14.3.1.6 Summary of most common (>5%) adverse drug reactions – safety 
population 
 
 14.3.2 Hematology and Biochemistry and Urinalysis 
 
Table 14.3.2.1.1 Hematology at each follow-up visit – safety population 
Table 14.3.2.1.2 Shift table comparing three laboratory value categories at baseline and 
end of study - Hematology – safety population 
Table 14.3.2.2.1 Blood biochemistry at each follow-up visit – safety population 
Table 14.3.2.2.2 Shift table comparing three laboratory value categories at baseline and 
end of study - Blood biochemistry – safety population 
Table 14.3.2.3.1 Proportions of abnormal urinalysis results in each visit – safety 
population 
 
14.3.3 Vital Signs and Weight 
 
Table 14.3.3.1 
Summary of vital signs at each follow-up visit – safety population 
Table 14.3.3.2 
Change of vital signs from baseline at each follow-up visit – safety 
population 
Table 14.3.3.3 
Summary of weight at each follow-up visit – safety population 
Table 14.3.3.4 
Change of weight from baseline at each follow-up visit – safety 
population 
 
14.3.4 12-Lead ECG 
 
Table 14.3.4.1 
Summary of 12-lead ECG parameters at each follow-up visit – safety 
population 
Table 14.3.4.2 
Proportions of normal and abnormal ECG results in each visit – safety 
population 
 
14.3.5 Treatment Compliance 
 
Table 14.3.5.1 
Treatment compliance (%) by visit – safety population 
 
14.3.6 Concomitant Medications 
 
Table 14.3.6.1 
Concomitant Medications – safety population 
Table 14.3.6.2 
Concomitant PD Medications – safety population 
 


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14.3.7 C-SSRS 
 
Table 14.3.7.1 
Summary of  C-SSRS in each visit – safety population 
 
Figures Listing: 
 
14.2 
Efficacy 
 
Figure 14.2.1.1 
Mean line graph for MDS-UPDRS Part III over visit – ITT population 
Figure 14.2.1.2 
Mean line graph for MDS-UPDRS Total Score over visit – ITT 
population 
Figure 14.2.1.3 
Mean line graph for MDS-UPDRS Part I over visit – ITT population 
Figure 14.2.1.4 
Mean line graph for MDS-UPDRS Part II over visit – ITT population 
Figure 14.2.1.5 
Mean line graph for MDS-UPDRS Part IV over visit – ITT population 
Figure 14.2.1.6 
Mean line graph for MDS-UPDRS Part II/Part III over visit – ITT 
population 
Figure 14.2.1.7 
Mean line graph for MoCA over visit – ITT population 
Figure 14.2.1.8 
Mean line graph for Total Antioxidant Status over visit – ITT 
population 
Figure 14.2.1.9 
Mean line graph for Lipid Peroxidation over visit – ITT population 
Figure 14.2.1.10 Mean line graph for Protein Carbonyls over visit – ITT population 
Figure 14.2.1.11 Mean line graph for 8-OHdG over visit – ITT population 
Figure 14.2.1.12 Mean line graph for Glutathione over visit – ITT population 
Figure 14.2.1.13 Mean line graph for Superoxide Dismutase over visit – ITT population 
Figure 14.2.1.14 Mean line graph for TNF Alpha over visit – ITT population 
Figure 14.2.1.15 Mean line graph for IL-6 over visit – ITT population 
Figure 14.2.2.1 
Kaplan-Meier survival curve for the time to the need for rescue 
medication 
 
14.3 
Safety 
 
14.3.1 Hematology 
 
Figure 14.3.1.1 
Mean line graph for hemoglobin over visit – safety population 
Figure 14.3.1.2 
Mean line graph for total white blood cell (WBC) count over visit – 
safety population 
Figure 14.3.1.3 
Mean line graph for absolute neutrophil count (ANC) over visit – 
safety population 
Figure 14.3.1.4 
Mean line graph for platelets over visit – safety population 
Figure 14.3.1.5 
Mean line graph for mean corpuscular volume (MCV) over visit – 
safety population 
 
14.3.2 Biochemistry 
 
Figure 14.3.2.1 
Mean line graph for serum ferritin over visit – safety population 


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Figure 14.3.2.2 
Mean line graph for total protein over visit – safety population 
Figure 14.3.2.3 
Mean line graph for gamma-glutamyl transferase (GGT) over visit – 
safety population 
Figure 14.3.2.4 
Mean line graph for lactate dehydrogenase (LDH) over visit – safety 
population 
Figure 14.3.2.5 
Mean line graph for sodium over visit – safety population 
Figure 14.3.2.6 
Mean line graph for potassium over visit – safety population 
Figure 14.3.2.7 
Mean line graph for chloride over visit – safety population 
Figure 14.3.2.8 
Mean line graph for glucose over visit – safety population 
Figure 14.3.2.9 
Mean line graph for total bilirubin over visit – safety population 
Figure 14.3.2.10 Mean line graph for direct bilirubin over visit – safety population 
Figure 14.3.2.11 Mean line graph for indirect bilirubin over visit – safety population 
Figure 14.3.2.12 Mean line graph for aspartate aminotransferase (AST) over visit – 
safety population 
Figure 14.3.2.13 Mean line graph for alanine transaminase (ALT) over visit – safety 
population 
Figure 14.3.2.14 Mean line graph for albumin over visit – safety population 
Figure 14.3.2.15 Mean line graph for blood urea nitrogen (BUN) over visit – safety 
population 
Figure 14.3.2.16 Mean line graph for calcium over visit – safety population 
Figure 14.3.2.17 Mean line graph for creatinine over visit – safety population 
Figure 14.3.2.18 Mean line graph for uric acid over visit – safety population 
Figure 14.3.2.19 Mean line graph for alkaline phosphatase (ALP) over visit – safety 
population 
Figure 14.3.2.20 Mean line graph for amylase over visit – safety population 
Figure 14.3.2.21 Mean line graph for blood iron over visit – safety population 
Figure 14.3.2.22 Mean line graph for zinc over visit – safety population 
Figure 14.3.2.23 Mean line graph for copper over visit – safety population 
 
14.3.3 Vital Signs and Weight 
 
Figure 14.3.3.1 
Mean line graph for supine heart rate over visit – safety population 
Figure 14.3.3.2 
Mean line graph for standing heart rate over visit – safety population 
Figure 14.3.3.3 
Mean line graph for supine systolic blood pressure over visit – safety 
population 
Figure 14.3.3.4 
Mean line graph for standing systolic blood pressure over visit – safety 
population 
Figure 14.3.3.5 
Mean line graph for supine diastolic blood pressure over visit – safety 
population 
Figure 14.3.3.6 
Mean line graph for standing diastolic blood pressure over visit – 
safety population 
Figure 14.3.3.7 
Mean line graph for weight over visit – safety population 
 


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6 Data Listings 
Data listings are numbered following ICH structure. The final numberings for subject data 
listings in the clinical study report can be changed if more subject data listings are made in 
the addition to those in the SAP. Collected data have been mapped to SDTM compliant 
terminology. Randomized subjects who received at least one dose of study drug are included 
in the listings. 
 
16.2 
Subject Data Listings 
 
16.2.1 Subject Disposition 
 
16.2.1.1 
Listing of Screening Failures 
16.2.1.2 
Listing of Disposition 
 
16.2.2 Protocol Deviations 
 
16.2.2.1 
Listing of Protocol Deviations 
 
16.2.3 Subjects Excluded from the Efficacy Analysis 
 
16.2.3.1 
Listing of Randomization 
16.2.3.2 
Assignment of Subjects to Analysis Sets 
 
16.2.4 Demographic Data and Medical History 
 
16.2.4.1 
Listing of Informed Consent Form 
16.2.4.2 
Listing of Demographics 
16.2.4.3 
Listing of Parkinson’s Disease Diagnosis 
16.2.4.4 
Listing of Physical Exam 
16.2.4.5 
Listing of Medical History 
 
16.2.5 Compliance and/or Drug Concentration Data 
 
16.2.5.1 
Listing of Compliance 
16.2.5.2 
Listing of Exposure 
16.2.5.3 
Listing of Changes to Exposure 
 
16.2.6 Efficacy Data 
 
16.2.6.1 
Listing of  Movement Disorder Society-Unified Parkinson's Disease 
Rating Scale (MDS-UPDRS) scores 
16.2.6.2 
Listing of Montreal-Cognitive Assessment (MoCA) 


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16.2.7 Adverse Events Listing 
 
16.2.7.1 
Listing of Medical Events 
16.2.7.2 
Listing of Adverse Events 
16.2.7.3 
Listing of Adverse Drug Reactions 
16.2.7.4 
Listing of Serious Adverse Events 
16.2.7.5 
Listing of Serious Adverse Drug Reactions 
16.2.7.6 
Listing of Withdrawals due to AEs 
 
 16.2.8 Listing of Individual Laboratory Measurements by Subjects 
 
16.2.8.1 
Listing of Hematology 
16.2.8.2 
Listing of Biochemistry 
16.2.8.3 
Listing of Urinalysis 
16.2.8.4 
Listing of Pregnancy Test 
16.2.8.5 
Listing of Oxidative Stress Biomarkers 
16.2.8.6 
Listing of Inflammatory Factor Biomarkers 
 
 
16.2.9 Other Listings 
 
16.2.9.1 
Listing of Vital Signs 
16.2.9.2 
Listing of Height and Weight 
16.2.9.3 
Listing of Concomitant Medications 
16.2.9.4 
Listing of Concomitant Medications to treat adverse events 
16.2.9.5 
Listing of Medications started after the study termination date 
16.2.9.6 
Listing of Columbia Suicide Severity Rating Scale (C-SSRS) 
16.2.9.7 
Listing of Telephone Contacts 
16.2.9.8 
Listing of Bottle Numbers 
16.2.9.9 
Listing of PK Assessment - Informed Consent Form 
16.2.9.10 
Listing of PK Assessment 
16.2.9.11 
Listing of 12-Lead ECGs 
 
 


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7 Table Shells 
The table shells shown below provide a framework for the display of data in this study. The 
final tables may not be designed exactly as shown here, but the shells are intended to reflect 
the general layout of the data that will be included in the clinical study report.  
• For descriptive statistics except observation number n, one more decimal place than 
in the raw data will be presented, and all percentages will be presented with one 
decimal point unless presented  differently in the actual table.  
• Note that ‘c’ in the table shells indicates an alphanumeric character, while ‘x’ 
indicates a number from 0 to 9.  
• The analysis population is indicated at the end of the table title.  
• For tables that are repeated for different populations, those for the PP population will 
have an ‘a’ added to the table number, those for the Safety population will have a ‘b’ 
added, and those repeated as a sensitivity analysis will have an ‘s’ added:  i.e., Table 
14.x.x for the ITT population, Table 14.x.xa for the PP population, Table 14.x.xb for 
the Safety population, and Table 14.x.xs for the sensitivity analysis.  
 
 
Disposition tables 
 
Table 14.1.1 Number of patients in different populations  
Population 
Placebo 
300 mg 
600 mg 
900 mg 
1200 mg 
Overall 
ITT 
xx 
xx 
xx 
xx 
xx 
xx 
PP 
xx 
xx 
xx 
xx 
xx 
xx 
Safety 
xx 
xx 
xx 
xx 
xx 
xx 
PK/PD 
xx 
xx 
xx 
xx 
xx 
xx 
 


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Table 14.1.2 Subject disposition – Safety population 
 
Screened= xx 
n (%) 
Placebo 
300 mg 
600 mg 
900 mg 
1200 mg 
Overall 
Randomized 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Exposed 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Completed 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Withdrawn 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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Table 14.1.3 Subject exposure to study medication – Safety population 
 
Group 
 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
Overall 
(N=xx) 
Subjects Exposed 
xx 
xx 
xx 
xx 
xx 
xx 
Total Exposure 
(person-years) 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
xxx.x 
Length of Exposure 
(years) 
Mean (SD) 
Median 
(Min, Max) 
 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 


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Table 14.1.4 Number of patients enrolled by study site – Safety population 
Country 
Site 
Group 
Placebo 
300 mg 
600 mg 
900 mg 
1200 mg 
Overall 
Xxx 
000x 
xx 
xx 
xx 
xx 
xx 
xx 
… 
… 
xx 
xx 
xx 
xx 
xx 
xx 
Total 
x 
xx 
xx 
xx 
xx 
xx 
xx 
 
 


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 Table 14.1.5 Summary of the reasons for not completing the study – Safety population 
 
 
Group 
Placebo 
(N=xx) 
 
300 mg  
(N=xx) 
600 mg  
(N=xx) 
900 mg  
(N=xx) 
1200 mg  
(N=xx) 
Reason 
Detail 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Adverse event 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Voluntary withdrawal 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Lost to follow up 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Investigator decision 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Protocol deviation  
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Rescue medication 
used 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Lack of efficacy/ 
worsening of the 
disease 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Other 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Total 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 


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Demographics and baseline characteristics tables 
 
Table 14.1.6 Summary of demographics data at baseline – ITT population 
 
Group 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
Overall 
(N=xx) 
p-value§ 
Age (years) 
(Mean ± SD) 
(Minimum, Median, Maximum) 
 
xx.x ± xx.x 
(xx, xx, xx) 
 
xx.x ± xx.x 
 (xx, xx, xx) 
 
xx.x ± xx.x 
 (xx, xx, xx) 
 
xx.x ± xx.x 
(xx, xx, xx) 
 
xx.x ± xx.x 
 (xx, xx, xx) 
 
xx.x ± xx.x 
 (xx, xx, xx) 
0.xxxx 
Sex: n (%)  
   Female 
   Male 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
0.xxxx 
Racial Origin: n (%) 
   White 
   Black 
   Asian 
   Native American 
   Native Hawaiian or Other Pacific Islander 
   Multi-Racial 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
0.xxxx 
Ethnic Origin: n (%) 
   Hispanic/Latino 
   Other 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
 
xx (xx.x) 
xx (xx.x) 
0.xxxx 
§ ANOVA for means and Fisher’s exact test for percentages  
Similar Table 14.1.6a will be based on PP population  
Similar Table 14.1.6b will be based on Safety population  
 
 


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Table 14.1.7 Summary of baseline characteristics – ITT population 
 
 
 
 
 
 
Group 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg  
(N=xx) 
900 mg  
(N=xx) 
1200 mg 
(N=xx) 
Overall 
(N=xx) 
p-value§ 
MDS-UPDRS Part III 
n 
(Mean ± SD) 
Median 
(Minimum,  Maximum) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
0.xxxx 
MDS-UPDRS Total Score 
n 
(Mean ± SD) 
Median 
(Minimum,  Maximum) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
0.xxxx 
MDS-UPDRS Part I 
n 
(Mean ± SD) 
Median 
(Minimum,  Maximum) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
0.xxxx 
MDS-UPDRS Part II 
n 
(Mean ± SD) 
Median 
(Minimum,  Maximum) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
0.xxxx 
MDS-UPDRS Part IV 
n 
(Mean ± SD) 
Median 
(Minimum,  Maximum) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
0.xxxx 


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MDS-UPDRS Part II/Part III 
n 
(Mean ± SD) 
Median 
(Minimum,  Maximum) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
0.xxxx 
MoCA 
n 
(Mean ± SD) 
Median 
(Minimum,  Maximum) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
 
xx 
xx.x ± xx.x 
xx.x 
(xx.x, xx.x) 
0.xxxx 
§ ANOVA 
Similar Table 14.1.7a will be based on PP population  


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Table 14.1.8 Medical History – Safety population 
 
 
Group 
 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
 600 mg 
(N=xx) 
900 mg 
(N=xx) 
 1200 mg 
(N=xx) 
 Overall 
(N=xx) 
Illness/Event by 
MedDRA Primary 
System Organ Class and Preferred Term 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Cccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 Cccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 cccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 cccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 


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Table 14.1.9 Prior Medication – Safety population 
 
 
Group 
 
 
 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
Overall 
(N=xx) 
Drug Name 
N Subjects (%) N Subjects (%) N Subjects (%) N Subjects (%) N Subjects (%) N Subjects (%) 
Preferred Name xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
  Cccccc 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
… 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


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Efficacy outcomes tables 
 
Table 14.2.1.1 Change in MDS-UPDRS Part III score at each follow-up visit – ITT population 
 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
MDS-UPDRS 
Part III score 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 3 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 6 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 9 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Similar Table 14.2.1.1a will be based on PP population  


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Table 14.2.1.2 Primary outcome least square mean (LSM) change from baseline to month 9 from MMRM model – ITT population 
Outcome 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
300 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
600 mg 
(N=xx) 
600 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
900 mg 
(N=xx) 
900 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
1200 mg 
(N=xx) 
1200 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
MDS-
UPDRS 
Part III 
score  
 
LSM 
(SE) 
xx.x 
(xx.x) 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
 
Similar Table 14.2.1.2a will be based on PP population 
Similar Table 14.2.1.2s will be based on sensitivity analysis population (ITT with missing data imputation) 
 
Similar Tables 14.2.1.2.1 and 14.2.1.2.2 will be based on ITT population and D544E polymorphisms (AA vs. AT) 
Similar Tables 14.2.1.2.3, 14.2.1.2.4 and 14.2.1.2.5  will be based on ITT population and V158M polymorphisms (High vs. 
Intermediate vs. Low COMT Activity) 


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Table 14.2.1.3 Dose-response assessment for all efficacy outcomes by linear regression model – ITT population 
 
Dependent variable 
Regression Slope 
P - value 
MDS-UPDRS Part III score  
x.xx 
0.xxxxx 
Repeat for other secondary and 
exploratory efficacy endpoints 
…. 
…. 
 


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Table 14.2.1.4 Primary outcome least square mean (LSM) change from baseline to month 9 from MMRM model 2 – ITT 
population 
Outcome 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
600 mg – 
300 mg 
LSM 
(95% CI) 
p-value 
900 mg 
(N=xx) 
900 mg – 
600 mg 
LSM 
(95% CI) 
p-value 
1200 mg 
(N=xx) 
1200 mg – 
900 mg 
LSM 
(95% CI) 
p-value 
MDS-
UPDRS Part 
III score  
 
LSM 
(SE) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
 
Note: only produced when there is a significant dose-response relationship in treatment effect 
 


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Table 14.2.2.1 Change in other MDS-UPDRS scores and MoCA at each follow-up visit – ITT population 
 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
MDS-UPDRS 
Total score 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 3 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 6 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 9 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for 
MDS-UPDRS 
Part I, II, IV 
and sum of Part 
II/III score and 
MoCA 
… 
… 
… 
… 
… 
… 


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Table 14.2.2.2 Change in oxidative stress biomarkers at each follow-up visit – ITT population 
 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
Total 
Antioxidant 
Status 
 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 3 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 6 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 9 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for 
Lipid 
Peroxidation, 
Protein 
Carbonyls, 8-
OHdG, 
Glutathione, 
and Superoxide 
Dismutase 
… 
… 
… 
… 
… 
… 


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Table 14.2.2.3 Change in inflammatory factor biomarkers at each follow-up visit – ITT population 
 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
TNF Alpha 
 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 3 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 6 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 9 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for  IL-6 … 
… 
… 
… 
… 
… 


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Table 14.2.2.4 Secondary outcomes least square mean (LSM) change from baseline to month 9 from MMRM model – ITT 
population 
Outcome 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
300 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
600 mg 
(N=xx) 
600 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
900 mg 
(N=xx) 
900 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
1200 mg 
(N=xx) 
1200 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
MDS-
UPDRS 
Total 
score  
 
LSM 
(SE) 
xx.x 
(xx.x) 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
Repeat for 
MDS-
UPDRS 
Part I, II, 
IV and 
sum of 
Part II/III 
score and 
MoCA 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 


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Table 14.2.2.5 Secondary outcomes least square mean (LSM) change from baseline to month 9 from MMRM model 2 – ITT 
population 
Outcome 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
600 mg – 
300 mg 
LSM 
(95% CI) 
p-value 
900 mg 
(N=xx) 
900 mg – 
600 mg 
LSM 
(95% CI) 
p-value 
1200 mg 
(N=xx) 
1200 mg – 
900 mg 
LSM 
(95% CI) 
p-value 
MDS-
UPDRS 
Total score  
 
LSM 
(SE) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Repeat for 
MDS-
UPDRS 
Part I, II, IV 
and sum of 
Part II/III 
score and 
MoCA 
… 
… 
… 
… 
… 
… 
… 
… 
 
Note: only produced when there is a significant dose-response relationship in treatment effect 
 


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 Table 14.2.3.1 Change in MOA biomarkers at each follow-up visit – ITT population 
 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
Ceruloplasmin 
 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 3 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 6 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Change at 
Month 9 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for  
Ceruloplasmin 
ferroxidase 
activity 
… 
… 
… 
… 
… 
… 
 
Note: only produced if efficacy is evidenced 


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Table 14.2.3.2 MOA biomarkers least square mean (LSM) change from baseline to month 9 from MMRM model – ITT population 
Outcome 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
300 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
600 mg 
(N=xx) 
600 mg 
- 
Placebo 
LSM 
(95% 
CI) 
p-value 
900 mg 
(N=xx) 
900 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
1200 mg 
(N=xx) 
1200 mg - 
Placebo 
LSM 
(95% CI) 
p-value 
Ceruloplasmin 
LSM 
(SE) 
xx.x 
(xx.x) 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x 
(xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x 
(xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Repeat for 
Ceruloplasmin 
ferroxidase 
activity 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
Note: only produced if efficacy is evidenced


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Table 14.2.3.3 MOA biomarkers least square mean (LSM) change from baseline to month 9 from MMRM model 2 – ITT 
population 
Outcome 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
600 mg – 
300 mg 
LSM 
(95% CI) 
p-value 
900 mg 
(N=xx) 
900 mg – 
600 mg 
LSM 
(95% CI) 
p-value 
1200 mg 
(N=xx) 
1200 mg – 
900 mg 
LSM 
(95% CI) 
p-value 
Ceruloplasmin 
LSM 
(SE) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x (xx.x) 
xx.x 
(xx.x, 
xx.x) 
0.xxxx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Repeat for 
Ceruloplasmin 
ferroxidase 
activity 
… 
… 
… 
… 
… 
… 
… 
… 
 
Note: only produced if efficacy is evidenced and when there is a significant dose-response relationship in treatment effect 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Safety outcomes tables 
Table 14.3.1.1 Overall summary of adverse events – safety population 
 
Treatment Group 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
Number of subjects with at least one AE 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Number of subjects with at least one SAE 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Number of subjects with at least one severe AE 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Number of subjects with at least one ADR 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Number of deaths 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Number of subject withdrawn 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Number of subject withdrawals due to AE 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.1.2 Summary of adverse events – safety population 
  
  
  
  
Placebo 
300 mg 
Repeat for 600 mg, 900 mg, and 
1200 mg 
Exposure (subject-years): x.xx 
Exposure (subject-years): x.xx 
Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Events: xxx 
Total Events: xxx 
Total Events: xxx 
Total Subjects Reporting: xx (xx%) Total Subjects Reporting: xx (xx%) Total Subjects Reporting: xx (xx%) 
System 
Organ Class 
  Preferred Term 
N Subjects (%)  
N Events 
(Rate/100 patient 
years) 
N Subjects (%)  
N Events 
(Rate/100 patient 
years) 
N Subjects (%)  
N Events 
(Rate/100 patient 
years) 
CCCCCC 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
  Cccccc 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
……... 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
x (x.x) 
x (x.xx) 
 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.1.3 All adverse events by severity – safety population 
 
Placebo 
(N = xx) 
300 mg 
(N = xx) 
Repeat for 600 mg, 900 mg, and 
1200 mg 
 
Mild 
Moderate 
Mild 
Moderate 
Severe 
Severe 
Mild 
Moderate 
Severe 
Any Adverse Event 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Preferred Term 1 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
 
 
 
Continue for all SOC 
and PTs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
SOCs and Preferred 
terms sorted 
alphabetically 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
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Table 14.3.1.4 All adverse events by seriousness – safety population 
 
Placebo  
(N = xx) 
300 mg 
(N = xx) 
Repeat for 600 mg, 900 mg, 
and 1200 mg 
 
Non-serious 
Serious 
Non-serious 
Serious 
Non-serious 
Serious 
Any Adverse Event 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
System Organ Class 1 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Preferred Term 1 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
Continue for all SOC and 
PTs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
SOCs and Preferred terms 
sorted alphabetically 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.1.5 All adverse events by relatedness to study medication – safety population 
 
Placebo  
(N = xx) 
300 mg 
(N = xx) 
Repeat for 600 mg, 900 mg, 
and 1200 mg  
(N = xx) 
 
Related 
Unrelated 
Related 
Unrelated 
Related 
Unrelated 
Any Adverse Event 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
System Organ Class 1 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
Preferred Term 1 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
 
Continue for all SOC and 
PTs 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
SOCs and Preferred terms 
sorted alphabetically 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
xx (xx%) 
 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
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Table 14.3.1.6 Summary of most common (>5%) adverse drug reactions – safety population 
 
Placebo 
(N = xx) 
300 mg 
(N = xx) 
Repeat for 600 mg, 900 mg, and 1200 mg  
 (N = xx) 
 
n (%) 
Time to onset 
(Days) 
Mean (SD) 
Median 
(Min, Max) 
Duration 
(Days) 
 Mean (SD) 
Median 
(Min, Max) 
n (%) 
Time to onset 
(Days) 
Mean (SD) 
Median 
(Min, Max) 
Duration 
(Days) 
 Mean (SD) 
Median 
(Min, Max) 
n (%) 
Time to onset 
(Days) 
Mean (SD) 
Median 
(Min, Max) 
Duration 
(Days) 
 Mean (SD) 
Median 
(Min, Max) 
Any Adverse Event 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
Preferred Term 1 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
 
Continue for all SOC and PTs 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
SOCs and Preferred terms 
sorted alphabetically 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
(xx%) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
xx.xx (xx.x) 
xx.x 
(xx.x, xx.x) 
 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.2.1.1 Hematology at each follow-up visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
Hemoglobin (g/L)  
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 1 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 2 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for 
Month 3, 4, 5, 
6 and 9 visits 
… 
… 
… 
… 
… 
Repeat for other 
hematology parameters 
… 
… 
… 
… 
… 
… 
  


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.2.1.2 Shift table comparing three laboratory value categories at baseline and end of study: Hematology – safety 
population 
Laboratory Test 
Treatment 
Baseline 
End of study 
Total 
Low 
Normal 
High 
Hemoglobin 
 
Placebo 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
300 mg 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
600 mg 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
900 mg 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
1200 mg 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
Repeat for other 
tests of interest 
 
 
 
 
 
 
 
 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.2.2.1 Blood biochemistry at each follow-up visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
Zinc (g/L)   
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 1 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 2 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for 
Month 3, 4, 5, 
6 and 9 visits 
… 
… 
… 
… 
… 
Repeat for other 
biochemistry parameters 
… 
… 
… 
… 
… 
… 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
CONFIDENTIAL INFORMATION 
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 Table 14.3.2.2.2 Shift table comparing three laboratory value categories at baseline and end of study: Blood biochemistry – safety 
population 
Laboratory Test 
Treatment 
Baseline 
End of study 
Total 
Low 
Normal 
High 
Zinc 
 
Placebo 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
300 mg 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
600 mg 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
900 mg 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
1200 mg 
Low 
xx  
xx  
xx  
xx  
Normal 
xx  
xx  
xx  
xx 
High 
xx  
xx  
xx  
xx 
Total 
xx  
xx  
xx  
xx 
Repeat for other 
tests of interest 
 
 
 
 
 
 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
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Table 14.3.2.3.1 Proportions of abnormal urinalysis results in each visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
Abnormal Urinalysis 
n 
Abnormal (n (%)) 
 
Baseline 
xx 
xx (xx.x) 
 
xx 
xx (xx.x) 
 
xx 
xx (xx.x) 
 
xx 
xx (xx.x) 
 
xx 
xx (xx.x) 
 
Month 3 
xx 
xx (xx.x) 
 
xx 
xx (xx.x) 
 
xx 
xx (xx.x) 
 
xx 
xx (xx.x) 
 
xx 
xx (xx.x) 
 
Repeat for Month 6 
and 9 visits 
… 
… 
… 
… 
… 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
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Table 14.3.3.1 Summary of vital signs at each follow-up visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
Supine Heart Rate 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 1 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 2 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for 
Month 3, 4, 5, 
6 and 9 visits 
… 
… 
… 
… 
… 
Repeat for standing 
heart rate, supine and 
standing blood pressure 
… 
… 
… 
… 
… 
… 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.3.2 Change of vital signs from baseline at each follow-up visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
Change in Supine Heart 
Rate 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 1 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Month 2 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
Repeat for 
Month 3, 4, 5, 
6 and 9 visits 
… 
… 
… 
… 
… 
Repeat for standing 
heart rate, supine and 
standing blood pressure 
… 
… 
… 
… 
… 
… 
 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
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Table 14.3.3.3 Summary of weight at each follow-up visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
Weight 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 9 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
CONFIDENTIAL INFORMATION 
63
Table 14.3.3.4 Change of weight from baseline at each follow-up visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
Change in weight 
n 
Mean (SD) 
Median 
(Min, Max) 
p-value 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 9 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
0.xxxx 
 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.4.1 Summary of 12-lead ECG parameters at each follow-up visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
Heart Rate (bpm)  
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 9 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for PR Interval, 
QRS Interval, QT 
Interval, QTcB 
Interval,and QTcF 
Interval 
… 
… 
… 
… 
… 
… 
 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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 Table 14.3.4.2 Proportions of normal and abnormal ECG results in each visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
ECG 
n 
Abnormal (n (%)) 
Normal (n (%)) 
Baseline 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
Month 9 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.5.1 Treatment compliance (%) by visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
Compliance (%) 
n 
Mean (SD) 
Median 
(Min, Max) 
Baseline 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 1 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Month 2 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
xx 
xx.x (xx.x) 
xx.x 
(xx.x, xx.x) 
Repeat for 
Month 3, 4, 5, 
6 and 9 visits 
… 
… 
… 
… 
… 
 


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Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.6.1 Concomitant Medications – safety population 
  
  
  
Placebo 
300 mg 
600 mg 
900 mg 
1200 mg 
Exposure (subject-years): x.xx Exposure (subject-years): x.xx Exposure (subject-years): x.xx Exposure (subject-years): x.xx Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Reporting: xx Total Subjects Reporting: xx Total Subjects Reporting: xx Total Subjects Reporting: xx 
Total Subjects Reporting: xx 
Drug Name 
 
 
Preferred Name 
N Subjects (%) 
N Subjects (%) 
N Subjects (%) 
N Subjects (%) 
N Subjects (%) 
  Cccccc 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
  Cccccc 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
……... 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.6.2 Concomitant PD Medications – safety population 
  
  
  
Placebo 
300 mg 
600 mg 
900 mg 
1200 mg 
Exposure (subject-years): x.xx Exposure (subject-years): x.xx Exposure (subject-years): x.xx Exposure (subject-years): x.xx Exposure (subject-years): x.xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Exposed: xx 
Total Subjects Reporting: xx Total Subjects Reporting: xx Total Subjects Reporting: xx Total Subjects Reporting: xx 
Total Subjects Reporting: xx 
Drug Name 
 
 
Preferred Name 
N Subjects (%) 
N Subjects (%) 
N Subjects (%) 
N Subjects (%) 
N Subjects (%) 
  Cccccc 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
  Cccccc 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
……... 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
x (x.x) 
 


ApoPharma Inc. 
Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease 
Statistical Analysis Plan: Protocol LA48-0215 
 
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Table 14.3.7.1 Summary of  C-SSRS in each visit – safety population 
Test 
Visit 
Placebo 
(N=xx) 
300 mg 
(N=xx) 
600 mg 
(N=xx) 
900 mg 
(N=xx) 
1200 mg 
(N=xx) 
 
C-SSRS 
n 
Any Suicidal Ideation (n (%)) 
Any Suicidal Behavior (n (%)) 
Baseline 
(Lifetime) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
Baseline (past 
9 months) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
Month 1 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
xx 
xx (xx.x) 
xx (xx.x) 
Repeat for 
Month 2, 3, 4, 
5, 6 and 9 
visits 
… 
… 
… 
… 
…