Clinical trial NCT02862600
Conditions: Cardiomyopathy, Hypertrophic Cardiomyopathy, Hypertrophic, Familial
Keywords: hypertrophic cardiomyopathy heart failure cardiopulmonary exercise testing 6 minute walk test perhexiline carnitine palmitoyltransferase mixed ion channel effects late sodium current inhibitor calcium channel inhibition
Sponsor: Heart Metabolics Limited
Start date: 2016-08-01; Completion date: 2017-05-22
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the effect of perhexiline on exercise performance (efficacy) and safety in patients with hypertrophic cardiomyopathy and moderate-to-severe heart failure following dosing for 16 weeks.

Detailed description:
Patients with hypertrophic cardiomyopathy and symptoms without severe outflow obstruction will be eligible to participate. Enrollment will be limited to subjects who are unable to attain 75% of their maximum predicted MVO2 at cardiopulmonary exercise testing. Subjects with genetic evidence of CYP2D6 poor metabolizer status will be excluded.

Subjects will undergo functional testing at baseline with CPEX testing and 6 minute walk distance testing. They will begin perhexiline orally, and the dose will be adjusted according to plasma level testing. For the first 8 week period, the target therapeutic range will be 100-300 ng/mL, and for the second 8 week period, the range will be 300-500 ng/mL. Functional testing will be repeated at the end of both periods.

Arms: arm 1: Perhexiline will be administered orally. Dosing will be determined based on plasma level monitoring. For the first 8 week period, the target range will be 100-300 ng/mL, for the second 8 week period, the target range will be 300-500 ng/mL.
Interventions: intervention 1: Perhexiline intervention 2: Use of bioanalytical assay to monitor plasma levels of perhexiline
Intervention descriptions: intervention 1: Period 1 (Weeks 1-8) and Period 2 (Weeks 9-16): dose titrated to two different plasma levels of perhexiline intervention 2: The bioanalytical assay is the device under investigation. It will be used to monitor plasma levels of perhexiline. The data obtained from this analysis will be used to guide dose adjustments of perhexiline.

Protocol documents:
ICF_002.pdf: 
 
Page 1 of 11 
 
Version:4.0 
Date: 13Jul2016 
RESEARCH SUBJECT INFORMATION AND CONSENT FORM 
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3 
TITLE: 
A Phase 2, Multi-Center, Open-Label, Ascending Dose Study on 
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the Efficacy, Safety and Tolerability of Perhexiline in Patients with 
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Hypertrophic Cardiomyopathy and Moderate-to Severe Heart 
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Failure with Preserved Left Ventricular Function 
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8 
PROTOCOL NO.: 
HML-PHX-005 
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WIRB® Protocol # 
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SPONSOR: 
Heart Metabolics, Ltd. 
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13 
INVESTIGATOR: 
Name  
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STUDY-RELATED  
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PHONE NUMBER(S): 
Phone Number(s) (24-hour number required for studies that are 
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more than minimal risk) 
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19 
INTRODUCTION 
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21 
You are being asked to take part in a research study. The purpose of this consent form is to 
22 
help you decide if you want to take part in the research study. 
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24 
You should not join this research study until all of your questions are answered. 
25 
 
26 
Things to know before deciding to take part in a research study:   
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The main goal of a research study is to learn things to help subjects (people who 
28 
voluntarily take part in research studies) in the future. 
29 
• 
The main goal of regular medical care is to help each person. 
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• 
The decision to join or not join the research study will not cause you to lose any medical 
31 
benefits. If you decide not to take part in this study, your doctor will continue to treat you. 
32 
• 
Parts of this study may involve standard medical care. Standard care is the treatment 
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normally given for a certain condition or illness. 
34 
• 
Other parts of this study may involve experimental (investigational) drugs or procedures 
35 
that are being tested for a certain condition or illness. An investigational drug is one that 
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has not been approved by the United States Food & Drug Administration (FDA). 
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• 
After reading the consent form and having a discussion with the research staff, you 
38 
should know which parts of the study are experimental and which are standard medical 
39 
care. 
40 
• 
Your medical records may become part of the research record. If that happens, your 
41 
medical records may be looked at and/or copied by the sponsor of this study and 
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government agencies or other groups associated with the study. 
43 
• 
Your medical insurance may be billed for any standard medical care you receive during 
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the research study. If your insurance company is billed then it may have access to the 
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research records. Insurance companies may not pay for treatment that is part of a 
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research study. Taking part in a research study could affect your current or future 
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insurance coverage. 
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PURPOSE OF THE STUDY 
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2 
You are being asked to take part in this study because you have been diagnosed with 
3 
hypertrophic cardiomyopathy (HCM, which is a thickening of your heart muscles that may make 
4 
it harder for blood to leave the heart) and heart failure (HF, which is when your heart is not able 
5 
to pump blood as well as it should) with preserved left ventricular (LV) function (which is a 
6 
specific part of the heart that appears to have normal muscle function).  
7 
 
8 
The purpose of this study is to test the safety and effectiveness of an investigational drug, 
9 
perhexiline (referred to throughout this form as PEX, the study drug), in subjects with moderate-
10 
to-severe HCM.  Investigational means the drug has not been approved by the United States 
11 
Food and Drug Administration (FDA). 
12 
 
13 
STUDY OVERVIEW 
14 
 
15 
This study will be done at about 10 study centers in the United States. About 33 men and 
16 
women, 18 years of age and older, will be in the study. Each subject will be in the study for 
17 
about 24 weeks.  Those 24 weeks will be broken up as follows: 
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19 
• 
Screening: Up to 4 weeks 
20 
• 
Period 1: 8 Weeks of PEX dosing 
21 
• 
Period 2: 8 Weeks of PEX dosing 
22 
• 
Follow-up: 4 Weeks 
23 
 
24 
PROCEDURES 
25 
 
26 
If you decide you are interested in taking part in the study, you must first read and sign this 
27 
consent form before any study-related tests or procedures can be done.   
28 
 
29 
Screening Visit 
30 
 
31 
The following tests and procedures will be done to see if you are eligible to take part in this 
32 
study: 
33 
 
34 
• 
The study staff will go over the study’s requirements and answer any questions you may 
35 
have.   
36 
• 
The study staff will ask you questions about your health and medical history and 
37 
demographic information (age, sex, race, and ethnic origin). 
38 
• 
The study staff will ask you to list all the medications that you are taking, including all 
39 
medications prescribed by a doctor and those that you bought on your own without a 
40 
doctor’s prescription (herbals and over-the-counter). 
41 
• 
A physical exam will be done, including measurement of your weight and vital signs 
42 
(heart rate, blood pressure, temperature and breathing rate).  This does not include a 
43 
pelvic, breasts or rectal exam. 
44 
• 
You will have three (3) separate electrocardiograms (ECGs).  This is a tracing of your 
45 
heart’s electrical activity. You will lie on your back and electrodes (sticky pads) with wires 
46 
are attached to your chest, wrist and ankles.  It takes about 5 minutes to do all 3 ECGs.   
47 
• 
Blood and urine samples will be collected for: 
48 
o Safety lab tests 
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o A pregnancy test if you are a woman who is able to become pregnant.  The result 
1 
of the pregnancy test must be negative for you to be able to take part in the 
2 
study. 
3 
o Blood test for HbA1c levels. HbA1c represents your blood sugar levels. 
4 
o CYP2D6, to see if your body is able to break down (process) the study drug.  The 
5 
CYP2D6 genetic test is an FDA approved test used to help how you will respond 
6 
to certain medications.   For this study, it will help us determine how rapidly the 
7 
cells in your body can modify the study drug. For this genetic blood test, DNA 
8 
(genetic material) will be removed from your blood sample.  CYP2D6 is deficient 
9 
in some people and they can be identified with this blood test.  If you are deficient 
10 
in this enzyme, you may not be able to participate in this clinical trial. 
11 
• 
A CPEX (Cardio-Pulmonary Exercise) test will be done which uses a stationary bike or 
12 
treadmill to measure your body’s reaction to exercise.  A disease or condition that affects 
13 
your heart, lungs or muscles will limit how much faster and harder you can exercise. A 
14 
CPEX test looks at how well your heart, lungs, and muscles are working separately, and 
15 
also how these systems are working together. You will be closely monitored while doing 
16 
the CPEX test.   
17 
 
18 
Based on these results, if you meet all of the study requirements, you will move on to Period 1. 
19 
 
20 
Period 1: Baseline Visit (Week 1, Day 1) 
21 
 
22 
If you meet all of the study requirements, you will be scheduled to return to the study center no 
23 
more than 28 days after the Screening Visit.  The following tests and procedures will be done: 
24 
 
25 
• 
Your weight and vital signs will be measured. 
26 
• 
You will be asked how you are feeling and about any medications you have taken since 
27 
your last visit. 
28 
• 
Urine sample will be collected for a pregnancy test if you are a woman who is able to 
29 
become pregnant.  The result of the pregnancy test must be negative for you to be able 
30 
to take part in the study 
31 
• 
You will be asked to complete a 6 minute walking test (6MWT).  This test measures how 
32 
far you can walk in 6 minutes.  This is usually done on a measured route or path, like a 
33 
hallway. 
34 
• 
You will have three (3) separate ECGs. 
35 
• 
You will have your second CPEX test. 
36 
 
37 
Study Drug  
38 
 
39 
If you qualify to take part in the study, you will receive a supply of study drug and instructions on 
40 
how to store your study drug.   Study drug will be taken by mouth once a day in the evenings 
41 
(between 8:00p.m. and 11:00p.m.) with a glass of water or other non-alcoholic drink for the next 
42 
112 days.  You will be given a diary to record the number of tablets taken on each day. You will 
43 
also be asked to record the time you take your study drug the evenings before a visit to the 
44 
study center.   
45 
 
46 
You will begin taking a 70 mg a day dose of study drug during Period 1; this is 2 tablets per day.  
47 
You will continue to take 70 mg of study drug each day for 2 weeks.   After two weeks, your 
48 
dose may be adjusted (increased or decreased) based on the results of your blood tests.  Dose 
49 
adjustments may occur every two weeks while you are taking part in the study (or more often, if 
50 
your study doctor decides this is needed). 
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1 
You may receive the following doses during Period 1: 
2 
 
3 
• 
  35 mg; 1 tablet 
4 
• 
  70 mg; 2 tablets 
5 
• 
105 mg; 3 tablets 
6 
• 
140 mg; 4 tablets 
7 
• 
175 mg; 5 tablets 
8 
• 
210 mg; 6 tablets 
9 
 
10 
You may receive the following doses during Period 2: 
11 
 
12 
• 
  35 mg; 1 tablet 
13 
• 
  70 mg; 2 tablets 
14 
• 
105 mg; 3 tablets 
15 
• 
140 mg; 4 tablets 
16 
• 
175 mg; 5 tablets 
17 
• 
210 mg; 6 tablets 
18 
• 
245 mg; 7 tablets 
19 
• 
280 mg; 8 tablets 
20 
 
21 
Period 1: Day 7, 8 or 9 (End of Week 1) 
22 
 
23 
After you have taken the study drug for at least 6 days, the following tests and procedures will 
24 
be done: 
25 
 
26 
• 
You will be asked how you are feeling and about any medications you have taken since 
27 
your last visit. 
28 
• 
A blood sample will be collected for PEX-CIS testing. The PEX-CIS assay (test) is an 
29 
investigational device being used to measure the amount of study drug in your blood at 
30 
each visit once you start taking study drug. The results of this test will be utilized by your 
31 
doctor to assist him/her in changing the dose of study drug that you will receive. This 
32 
device has not been approved by the FDA.  
33 
• 
The study staff will go over study drug storage, dosing and accountability instructions 
34 
with you. 
35 
• 
The study staff will check that you have enough study drug to take every day that will 
36 
last until your next scheduled visit. 
37 
 
38 
Period 1 (Weeks 2, 4, 6 and 8) and Period 2 (Weeks 10, 12 and 14) 
39 
 
40 
The following tests and procedures will be done: 
41 
 
42 
• 
You will be asked how you are feeling and about any medications you have taken since 
43 
your last visit. 
44 
• 
Your vital signs will be measured. 
45 
• 
Your weight will be measured (Week 8 only) 
46 
• 
You will have 3 separate ECGs.   
47 
• 
A blood sample will be collected for: 
48 
o PEX-CIS testing to measure the amount of study drug in your system 
49 
o Safety lab tests (Week 8 only) 
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o HbA1c test (Week 8 only) 
1 
• 
A 6 minute walking test (6MWT)(Week 8 only) 
2 
• 
CPEX testing (Week 8 only) 
3 
• 
The study staff will go over study-drug storage, dosing and accountability instructions 
4 
with you. 
5 
• 
The study staff will check that you have enough study-drug to take every day that will 
6 
last until your next scheduled visit. 
7 
Period 2 (Week 16) 
8 
 
9 
The following tests and procedures will be done: 
10 
 
11 
• 
You will be asked how you are feeling and about any medications you have taken since 
12 
your last visit. 
13 
• 
Your vital signs and weight will be measured. 
14 
• 
You will have 3 separate ECGs.  
15 
• 
A blood sample will be collected for: 
16 
o PEX-CIS testing to measure the amount of study drug in your system 
17 
o Safety lab tests 
18 
o HbA1c test  
19 
• 
A 6 minute walking test (6MWT).  
20 
• 
CPEX testing. 
21 
• 
Study drug will be collected. 
22 
 
23 
Follow-Up Visit 
24 
 
25 
You will return to the study center about 4 weeks after your last dose of study drug. 
26 
The following tests and procedures will be done: 
27 
 
28 
• 
You will be asked how you are feeling and about any medications you have taken since 
29 
your last visit. 
30 
• 
Your weight and vital signs will be measured. 
31 
• 
You will have 3 separate ECGs.   
32 
• 
A blood sample will be collected for: 
33 
o PEX-CIS testing to measure the amount of study drug in your system 
34 
o Safety lab tests 
35 
o Pregnancy test if you are a woman who is able to become pregnant  
36 
o HbA1c test 
37 
 
38 
You may be provided transportation to and from the site. 
39 
 
40 
RISKS AND DISCOMFORTS  
41 
 
42 
The following side effects have occurred while taking PEX: 
43 
Short Term (happens after as little as 24 hours of taking PEX): nausea (feeling sick to 
44 
your stomach), dizziness (usually for a short time), hypoglycemia (low blood sugar in 
45 
people who have diabetes) and torsade de pointes (a rare, abnormal heart rhythm that 
46 
may result in death). 
47 
 
48 
Long Term (usually happens after more than 3 months of taking PEX): peripheral 
49 
neuropathy (nerve damage in your hands and feet), hepatitis/cirrhosis (liver damage, 
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inflammation and scarring), extrapyramidal dysfunction (not being able to easily 
1 
move/movement disorders), muscle weakness and ataxia (loss of control of body 
2 
movement). 
3 
 
4 
In general, when side effects happen, their severity appears to depend upon the amount of the 
5 
drug that has built up in the patient’s body. Because of this you will be asked to give a blood 
6 
sample on a regular basis to allow a lab to check what levels of the study drug are in your body; 
7 
depending on the result your dose of study drug may be increased or decreased. In this way it is 
8 
expected that the risk of adverse events will be greatly reduced. 
9 
 
10 
7 to 8% of all people taking PEX have side effects that are severe enough that they stop taking 
11 
it. Most side effects usually happen in the first weeks of taking it. The side effects may be 
12 
passing and may disappear in two to four weeks. Most of the time, the side effects are not as 
13 
severe when the dose is reduced, but sometimes PEX must be stopped.  
14 
Side effects reported the most often are dizziness (feeling faint) or a "drunken" sensation, gait 
15 
(walking) disorders, unsteadiness, as well as nausea, vomiting, headache, anorexia (loss of 
16 
appetite, don’t feel hungry) and moderate weight loss (4-8 pounds). 
17 
 
18 
Side effects reported often are moderate (and generally, these are passing) increases of 
19 
proteins and markers that can be detected in your blood (AST/SGOT, ALT/SGPT, ALP, LDH 
20 
and bilirubin). Increases in total lipids (cholesterol) and triglycerides, hypoglycemia (low blood 
21 
sugar) and ECG changes (which are changes in your hearts electrical activity). 
22 
 
23 
Side effects reported less often are general weakness, nervousness (feeling anxious), lassitude 
24 
(not having any energy), insomnia (unable to sleep), tremors (shaking), paresthesias (general 
25 
feeling of tingling or pricking) , or changes in libido (sexual desire). 
26 
 
27 
Occasionally, the following more severe side effects happen:  
28 
• 
Peripheral neuropathy:  This involves the partial loss of sensation or strength due to 
29 
PEX’s effect on the nerves of the body.  It may be associated with numbness or tingling, 
30 
particularly in the hands and feet. 
31 
• 
Severe hypoglycemia (low blood sugar)  
32 
• 
Hypertriglyceridemia (high fat levels in the blood, which might raise your risk of heart 
33 
disease). 
34 
• 
Significant weight loss (more than 10% of your weight before taking PEX), which can 
35 
progress to true cachexia (weakness and wasting of the body due to chronic illness). 
36 
Polyradiculoneuritis, hypoglycemia and weight loss usually go away when you stop 
37 
taking PEX.   
38 
• 
Hepatopathology, including some cases of subacute alcoholic type hepatitis 
39 
(inflammation of the liver). Some people have had cirrhosis (scarring of the liver). The 
40 
state of the liver before treatment with PEX, the influence of other therapies or etiological 
41 
factors such as alcohol and viral hepatitis, are not known. In rare cases, hepatic (liver) 
42 
damage or hypoglycemia (low blood sugar) have led to the death of the person. 
43 
 
44 
PEX is known to sometimes change the electrocardiogram (ECG), and this change is referred to 
45 
as “QT prolongation”. With some drugs, QT prolongation has been associated with an increase 
46 
in the risk of suffering a fatal heart arrhythmia. PEX has been prescribed in Australia and New 
47 
Zealand for many years to treat chest pain caused by reduced blood flow to the heart muscle 
48 
(angina) and this arrhythmia has not been associated with the use of PEX in this setting. 
49 
Nevertheless, it remains a possible risk which needs to be considered when you are deciding 
50 
about whether or not to participate in the clinical study.  You will undergo heart monitoring 
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(ECG) during this study to see if QT prolongation occurs, and you may be asked to change 
1 
dosage or stop taking PEX if QT prolongation is seen. 
2 
 
3 
There may be side effects that are not known at this time. 
4 
 
5 
Reproductive Risks 
6 
 
7 
Taking the study drug may involve unknown risks to a pregnant woman, an embryo, fetus 
8 
(unborn baby) or nursing infant.  Therefore, if you are pregnant, planning to become pregnant or 
9 
are breastfeeding a child, you cannot take part in this study. 
10 
 
11 
In order to reduce the risk of pregnancy, you must use an effective method of birth control while 
12 
in this study.  If you are already using a method of birth control, the study staff will discuss with 
13 
you whether your current method of birth control is acceptable. 
14 
 
15 
If, during this study or within 30 days after stopping the study drug, you become pregnant, you 
16 
should notify the study staff as soon as possible.  If you become pregnant during the study, the 
17 
study drug will be stopped and you will no longer be able to be in this study will end.  
18 
Information about your pregnancy and its outcome will be collected and used to learn more 
19 
about the effects of the study drug on pregnancy. 
20 
 
21 
Other Risks 
22 
 
23 
Your condition may not get better or may get worse.  
24 
 
25 
Blood Draws 
26 
 
27 
You may have pain, swelling, or bruising where the needle enters your vein. There may be risk 
28 
of infection. You may feel dizzy or you may faint.  The amount of blood collected during this 
29 
study is about 85-90mL (about 6 tablespoons). 
30 
 
31 
ECG Risks    
32 
 
33 
Skin irritation is rare but could happen from the electrodes or gel that is used. 
34 
 
35 
CPEX Test Risks 
36 
 
37 
This may cause changes in your blood pressure and heart rate.  You may feel short of breath, 
38 
have tightness in your chest, cramping in your legs or fall. Fainting can happen, and in very rare 
39 
cases, heart attack or stroke. 
40 
 
41 
Walking Test Risks 
42 
 
43 
This may cause changes in your blood pressure and heart rate.   You may fall, get short of 
44 
breath, and have pain in your legs. Fainting can happen, and in very rare cases, heart attack or 
45 
stroke. 
46 
 
47 
NEW INFORMATION  
48 
 
49 
You will be told about any new information that might change your decision to be in this study. 
50 
You may be asked to sign a new consent form if this occurs. 
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1 
BENEFITS 
2 
 
3 
Your HCM and HF may improve while you are in this study; however, this cannot be promised. 
4 
The results of this study may help people with HCM and HF in the future. 
5 
COSTS 
6 
 
7 
Heart Metabolics, Ltd. will provide the study drug free of charge during this study. Tests and 
8 
procedures that are done only for the study will not be billed to you or your insurance company.  
9 
 
10 
You or your insurance company may be billed for: 
11 
• 
Any standard medical care given during this research study. 
12 
• 
[list other costs as necessary] 
13 
 
14 
You may want to talk with your insurance company about its payment policy for standard 
15 
medical care given during a research study. If your insurance company does not pay, you may 
16 
be billed for those charges. 
17 
 
18 
You might have unexpected expenses from being in this study. Ask your study doctor to discuss 
19 
the costs that will or will not be covered by the sponsor. This discussion should include who will 
20 
pay the costs of treating possible side effects. 
21 
 
22 
PAYMENT FOR PARTICIPATION   
23 
 
24 
You will not be paid for being in this study. 
25 
 
26 
Transportation to and from the site may be provided or you will be reimbursed for your own 
27 
travel costs. 
28 
 
29 
ALTERNATIVE TREATMENT  
30 
 
31 
If you decide not to take part in this study, there are other choices available. These include:  the 
32 
use of drugs used more commonly in other conditions but which have not been proven to be 
33 
effective in HCM.  Another acceptable course of action would be to do nothing. Ask the study 
34 
doctor to discuss these alternatives with you. You do not need to be in this study to receive 
35 
treatment for your condition. 
36 
 
37 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH PURPOSES  
38 
 
39 
What information may be used and given to others? 
40 
The study staff will get your personal and medical information. For example:  
41 
 
42 
• 
Past and present medical records 
43 
• 
Research records 
44 
• 
Records about phone calls made as part of this research 
45 
• 
Records about your study visits 
46 
 
47 
Who may use and give out information about you? 
48 
The study staff, which includes the study doctor.  
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Who might get this information? 
1 
The sponsor of this research. “Sponsor” means any persons or companies that are: 
2 
 
3 
• 
working for or with the sponsor, or  
4 
• 
owned by the sponsor. 
5 
 
6 
Your information may be given to:  
7 
• 
The U.S. Food and Drug Administration (FDA), 
8 
• 
Department of Health and Human Services (DHHS) agencies, 
9 
• 
Governmental agencies in other countries, 
10 
• 
Governmental agencies to whom certain diseases (reportable diseases) must be reported, 
11 
and 
12 
• 
Western Institutional Review Board® (WIRB®).  
13 
 
14 
Why will this information be used and/or given to others? 
15 
• 
to do the research,  
16 
• 
to study the results, and  
17 
• 
to see if the research was done right.  
18 
 
19 
If the results of this study are made public, information that identifies you will not be used. 
20 
 
21 
What if I decide not to give permission to use and give out my health information? 
22 
Then you will not be able to be in this research study. 
23 
 
24 
May I review or copy my information? 
25 
Yes, but only after the research is over.  
26 
 
27 
May I withdraw or revoke (cancel) my permission? 
28 
Yes, but this permission will not stop automatically. 
29 
[or] 
30 
This permission will be good until [date] [required in CA, DE, IN, IL, WA, and WI]. 
31 
 
32 
You may withdraw or take away your permission to use and disclose your health information at 
33 
any time. You do this by sending written notice to the study doctor. If you withdraw your 
34 
permission, you will not be able to stay in this study. 
35 
 
36 
When you withdraw your permission, no new health information identifying you will be gathered 
37 
after that date. Information that has already been gathered may still be used and given to others.  
38 
 
39 
Is my health information protected after it has been given to others? 
40 
There is a risk that your information will be given to others without your permission. 
41 
 
42 
CONFIDENTIALITY 
43 
 
44 
Information from this study will be given to the sponsor.  “Sponsor” includes any persons or 
45 
companies that are contracted by the sponsor to have access to the research information during 
46 
and after the study. 
47 
 
48 
The information will also be given to the U.S. Food and Drug Administration (FDA).  It may be 
49 
given to governmental agencies in other countries where the study drug may be considered for 
50 
approval.  Medical records which identify you and the consent form signed by you will be looked 
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at and/or copied for research or regulatory purposes by: 
1 
 
2 
• 
the sponsor 
3 
• 
Medpace, an agent for the sponsor; 
4 
 
5 
and may be looked at and/or copied for research or regulatory purposes by: 
6 
 
7 
• 
the FDA 
8 
• 
Department of Health and Human Services (DHHS) agencies 
9 
• 
governmental agencies in other countries, and 
10 
• 
Western Institutional Review Board® (WIRB®). 
11 
 
12 
COMPENSATION FOR INJURY 
13 
 
14 
If you are injured or get sick as a result of being in this study, call the study staff immediately. 
15 
The study staff will provide emergency medical treatment. The sponsor has in place an 
16 
insurance policy in case you get sick from taking the study drug.  If the injury or sickness is not 
17 
related to the study then your insurance will be billed for any treatments received.  
18 
 
19 
No other payment is routinely available from the study staff or sponsor. 
20 
 
21 
VOLUNTARY PARTICIPATION AND WITHDRAWAL 
22 
 
23 
Taking part in this study is voluntary. You may decide not to take part or you may leave the 
24 
study at any time. Your decision will not result in any penalty or loss of benefits to which you are 
25 
entitled. 
26 
 
27 
Your participation in this study may be stopped at any time by the study doctor or the sponsor 
28 
without your consent for any reason, including: 
29 
 
30 
• 
if you have a side effect from the study drug 
31 
• 
if you need a treatment not allowed in this study 
32 
• 
if you do not follow the study procedures as instructed 
33 
• 
if you do not consent to continue in the study after being told of changes in the research 
34 
that may affect you 
35 
• 
if you become pregnant, or 
36 
• 
if the study is canceled by the FDA 
37 
 
38 
If you leave the study before the planned final visit, you may be asked by the study staff to have 
39 
some tests or procedures done so that you leave the study safely. 
40 
 
41 
SOURCE OF FUNDING FOR THE STUDY 
42 
 
43 
The sponsor, Heart Metabolics, Ltd. will pay for this research study. 
44 
 
45 
QUESTIONS 
46 
 
47 
Contact [name] at [number(s)] for any of the following reasons: 
48 
 
49 
• 
if you have any questions about taking part in this study,   
50 


 
Page 11 of 11 
 
Version:4.0 
Date: 13Jul2016 
• 
if you feel you have had a research-related injury or a reaction to the study drug, or 
1 
• 
if you have questions, concerns or complaints about the research. 
2 
If you have questions about your rights as a research subject or if you have questions, concerns or 
3 
complaints about the research, you may contact: 
4 
 
5 
 
Western Institutional Review Board® (WIRB®) 
6 
 
1019 39th Avenue SE Suite 120 
7 
 
Puyallup, Washington 98374-2115 
8 
 
Telephone:  1-800-562-4789 or 360-252-2500 
9 
 
E-mail:  Help@wirb.com 
10 
 
11 
WIRB is a group of people who independently review research. 
12 
 
13 
WIRB will not be able to answer some study-specific questions, such as questions about 
14 
appointment times. However, you may contact WIRB if the research staff cannot be reached or 
15 
if you wish to talk to someone other than the research staff.  
16 
 
17 
Do not sign this consent form unless you have had a chance to ask questions and have gotten 
18 
satisfactory answers. 
19 
 
20 
If you agree to be in this study, you will receive a signed and dated copy of this consent form for 
21 
your records. 
22 
 
23 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
24 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
25 
will include a summary of the results. You can search this Web site at any time. 
26 
 
27 
CONSENT 
28 
 
29 
I have read this consent form (or it has been read to me). All my questions about the study and 
30 
my part in it have been answered. I freely consent to be in this research study. 
31 
 
32 
I authorize the release of my medical and research records for the purpose of this study. 
33 
By signing this consent form, I have not given up any of my legal rights. 
34 
 
35 
__________________________________________ 
36 
Subject Name (printed) 
37 
 
38 
________________________________________ 
__________________ 
39 
Signature of Subject 
Date 
40 
 
41 
________________________________________ 
__________________ 
42 
Printed Name of Person Conducting the 
Position 
43 
Informed Consent Discussion 
44 
 
45 
________________________________________ 
__________________ 
46 
Signature of Person Conducting the  
Date 
47 
Informed Consent Discussion 
48 
 
49 

Prot_000.pdf: 
Protocol No.  HML-PHX-005 
Version 11.0 
 
02 DEC 2016 
Heart Metabolics — Company Confidential 
 
Page 1 of 58 
Title 
A Phase 2, Multi-Center, Open-Label, Ascending Dose Study on 
the Efficacy, Safety and Tolerability of Perhexiline in Patients with 
Hypertrophic Cardiomyopathy and Moderate-to Severe Heart 
Failure with Preserved Left Ventricular Function 
Study Number 
HML-PHX-005 
Indication 
Treatment of Moderate-to-Severe Symptomatic Hypertrophic 
Cardiomyopathy 
Study Phase 
Phase 2 
Sponsor 
Heart Metabolics, Ltd. 
US IND 
118,826 
Study Sites 
Multicenter 
Protocol Physician 
Mark Midei, M.D. 
Study Dates 
Anticipated Initiation:  
Q3 2016 
Anticipated Completion: 
Q1 2017 
Version and Date: 
Version 11.0, 02 December 2016 
 
 
This document contains information that is confidential and proprietary to the Sponsor, Heart 
Metabolics, Ltd.  This information is being provided to you solely for the purpose of evaluating 
and/or conducting a clinical trial for the Sponsor.  You may disclose the contents of this 
document only to study personnel under your supervision, the Institutional Review Board, the 
United States Food and Drug Administration, or duly authorized representatives of regulatory 
agencies for this purpose under the condition that they maintain confidentiality.  The contents 
of this document may not be used in any other clinical trial, disclosed to any other person or 
entity, and/or published without the prior written permission of the Sponsor.  The foregoing shall 
not apply to disclosure required by any regulations; however, you will give prompt notice to the 
Sponsor of any such disclosure. 




Protocol No.  HML-PHX-005 
Version 11.0 
 
02 DEC 2016 
Heart Metabolics — Company Confidential 
 
Page 3 of 58 
Table of Contents 
 
1 
CLINICAL PROTOCOL SYNOPSIS .................................................................... 7 
2 
INTRODUCTION .............................................................................................. 14 
2.1 
Hypertrophic Cardiomyopathy ........................................................................... 14 
2.2 
Unmet Clinical Need in Symptomatic Hypertrophic Cardiomyopathy ................ 14 
2.3 
Perhexiline ........................................................................................................ 14 
2.4 
Mixed Ion Channel Effects of Perhexiline .......................................................... 15 
2.5 
Perhexiline Thorough QT Study ........................................................................ 15 
2.6 
Perhexiline Summary ........................................................................................ 15 
2.7 
PEX-CIS Assay ................................................................................................. 16 
2.7.1 
Description of PEX-CIS Assay .......................................................................... 16 
2.7.2 
Use of the PEX-CIS Assay in This Study .......................................................... 16 
2.8 
Study Rationale ................................................................................................ 16 
2.8.1 
Therapeutic Window Rationale ......................................................................... 17 
2.8.2 
Primary Endpoint Rationale .............................................................................. 17 
2.8.3 
Mitigation of Potential QT Prolongation ............................................................. 17 
2.8.4 
Monitoring of Systemic Levels and Dose Adjustment of Perhexiline ................. 19 
3 
OBJECTIVES ................................................................................................... 19 
3.1 
Primary Objective ............................................................................................. 19 
3.2 
Secondary Objectives ....................................................................................... 19 
4 
INVESTIGATIONAL PLAN ................................................................................ 20 
4.1 
Overall Study Design ........................................................................................ 20 
4.2 
Inclusion Criteria ............................................................................................... 20 
4.2.1 
General Inclusion Criteria.................................................................................. 20 
4.2.2 
Cardiomyopathy-Related Inclusion Criteria ....................................................... 20 
4.3 
Exclusion Criteria .............................................................................................. 21 
4.3.1 
General Exclusion Criteria: ............................................................................... 21 
4.3.2 
QT Interval-Related Exclusion Criteria .............................................................. 22 
4.3.3 
Other Exclusion Criteria .................................................................................... 22 
4.3.4 
Cardiomyopathy-related Exclusion Criteria ....................................................... 22 
4.4 
Study-Drug Dosing and Systemic Drug-Level Monitoring .................................. 22 
4.4.1 
Study-Drug Dosing............................................................................................ 22 
4.4.2 
Monitoring of Systemic Perhexiline and cis- and trans-Hydroxy Perhexiline ...... 23 
4.4.3 
Dose-Adjustment of Study Drug ........................................................................ 23 
4.4.4 
Dose-Adjustment for QTcF/JTcF Prolongation .................................................. 24 
4.5 
Management of Possible PEX Overdosage ...................................................... 25 
4.6 
Patient Withdrawal and Discontinuation ............................................................ 25 
4.7 
Concomitant Medication ................................................................................... 26 


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4.8 
Study Monitoring Team ..................................................................................... 26 
5 
STUDY DRUG SUPPLIES ................................................................................ 27 
5.1 
Perhexiline ........................................................................................................ 27 
5.2 
Study Drug Formulation .................................................................................... 27 
5.3 
Drug Storage .................................................................................................... 27 
5.4 
Study-Drug Dispensing and Dosing Instructions ............................................... 27 
5.5 
Withdrawal of Perhexiline at Study Termination ................................................ 28 
5.6 
Treatment Compliance ...................................................................................... 28 
5.7 
Drug Accountability ........................................................................................... 28 
6 
STUDY SCHEDULE AND ACTIVITIES ............................................................. 28 
6.1 
Scheduling Windows for Study Procedures and Evaluations ............................ 28 
6.2 
Schedule of Assessments ................................................................................. 29 
6.3 
Screening ......................................................................................................... 33 
6.4 
Period 1: Baseline Visit and Commencement of Study-Drug Dosing ................. 33 
6.5 
Period 1; Day 8 (± 1 Day), After Completion of Week 1 .................................... 35 
6.6 
Periods 1 and 2 ................................................................................................. 35 
6.7 
Period 1; Additional Procedures At Completion of Week 8 ................................ 36 
6.8 
Period 2: End of Treatment and After Completion of Week 16 .......................... 36 
6.9 
Follow-up Visit (Four Weeks following the conclusion of dosing)....................... 36 
6.10 
Patient Contact for Dose-Adjustment Instructions ............................................. 37 
6.11 
Subjects Who Withdraw From the Study ........................................................... 37 
7 
SAFETY MONITORING .................................................................................... 37 
7.1 
Adverse Events ................................................................................................. 37 
7.2 
Life-threatening adverse event or life-threatening suspected adverse reaction . 37 
7.3 
Serious Adverse Event or Serious Suspected Adverse Reaction ...................... 38 
7.4 
Suspected Adverse Reaction ............................................................................ 39 
7.5 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction. ....... 39 
7.6 
Assignment of Adverse Event Intensity and Relationship to Perhexiline ........... 39 
7.7 
Collection and Reporting of Adverse Events ..................................................... 39 
7.7.1 
Reporting Serious Adverse Events or Serious Suspected Adverse Reaction .... 40 
7.7.2 
Handling of Expedited Safety Reports .............................................................. 40 
7.7.3 
Non-serious Adverse Events ............................................................................. 41 
7.8 
Laboratory Test Abnormalities .......................................................................... 41 
7.9 
Adverse Device Effects ..................................................................................... 41 
7.9.1 
Definitions ......................................................................................................... 41 
7.9.2 
Reporting of ADEs ............................................................................................ 41 
7.9.3 
Unanticipated Adverse Device Effect (UADE) ................................................... 41 
7.10 
PEX Overdose .................................................................................................. 41 
7.11 
Pregnancy ........................................................................................................ 42 


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7.11.1 
Pregnancy Testing ............................................................................................ 42 
7.11.2 
Reporting of Pregnancy .................................................................................... 42 
7.12 
Other Safety Considerations ............................................................................. 42 
8 
STATISTICAL CONSIDERATIONS .................................................................. 42 
8.1 
Primary and Secondary Endpoints .................................................................... 42 
8.1.1 
Primary Endpoint .............................................................................................. 42 
8.1.2 
Secondary Endpoints ........................................................................................ 42 
8.1.3 
Exploratory Endpoints ....................................................................................... 43 
8.2 
Sample Size Determination ............................................................................... 43 
8.3 
Patient Population for Analysis ......................................................................... 43 
8.4 
Analyses ........................................................................................................... 43 
8.4.1 
Demographics and Baseline Characteristics ..................................................... 43 
8.4.2 
Safety Analyses ................................................................................................ 43 
8.4.3 
Efficacy Analyses .............................................................................................. 44 
8.4.4 
Pharmacokinetic Analyses ................................................................................ 44 
8.4.5 
Pharmacogenetic Analyses ............................................................................... 44 
8.4.6 
Pharmacodynamic Analyses ............................................................................. 44 
8.4.7 
Ongoing Data Review and Analyses ................................................................. 44 
8.5 
Replacement Policy .......................................................................................... 44 
9 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................ 44 
9.1 
Good Clinical Practice ....................................................................................... 44 
9.2 
Institutional Review Board / Independent Ethics Committee ............................. 45 
9.3 
Informed Consent ............................................................................................. 45 
10 
ADMINISTRATIVE CONSIDERATIONS ........................................................... 45 
10.1 
Compliance with the Protocol ............................................................................ 45 
10.2 
Protocol Modifications ....................................................................................... 46 
10.3 
Protocol Termination ......................................................................................... 46 
10.4 
Audits, Monitoring and Inspections ................................................................... 46 
10.5 
Records Retention and Data Protection ............................................................ 46 
10.6 
Publication of Data ............................................................................................ 46 
11 
REFERENCES ................................................................................................. 48 
12 
ABBREVIATIONS ............................................................................................. 51 
Appendix A: 
Concomitant Medication .......................................................................... 53 
Appendix B: 
ACC/AHA HCM Diagnostic Criteria .......................................................... 54 
Appendix C: 
Discontinuation for Persistent Clinical Laboratory Elevations ................... 58 
 
 
List of Tables 
 
Table 1.1 
Dose-adjustments from Week 2, Period 1 and throughout Period 2 ........... 9 


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Table 4.1  
Possible dose-adjustments in Periods 1 and 2 ......................................... 24 
Table 6.1 
Time windows for study procedures and evaluations ............................... 29 
Table 6.2 
Schedule of Time and Events for Protocol Activities ................................ 30 
 
List of Figures 
Figure 1.1 
Study design for Periods 1 and 2 ............................................................... 8 
Figure 2.1 
2-Week simulations of PEX concentrations at 70 mg per day for different 
CYP2D6 metabolizers ............................................................................. 18 
Figure 4.1 
Study design for Periods 1 and 2 ............................................................. 20 
Figure 5.1 
Chemical Structure of PHM (CAS-6724-53-4) .......................................... 27 
 
 
 


Protocol No.  HML-PHX-005 
Version 11.0 
 
02 DEC 2016 
Heart Metabolics — Company Confidential 
 
Page 7 of 58 
1 CLINICAL PROTOCOL SYNOPSIS 
Title 
A Phase 2, Multi-Center, Open-Label, Ascending Dose Study on the Efficacy, 
Safety and Tolerability of Perhexiline in Patients with Hypertrophic Cardiomyopathy 
and Moderate-to Severe Heart Failure with Preserved Left Ventricular Function 
Protocol 
Number 
HML-PHX-005 
Phase 
2 
Sponsor 
Heart Metabolics Ltd. 
Investigational 
Product 
Perhexiline 
Indication 
Treatment of moderate-to-severe symptomatic hypertrophic cardiomyopathy 
(HCM) 
Study 
Centers 
Approximately 10 US sites 
Objectives 
Primary: 
• To evaluate the effect of perhexiline (PEX) on the change from baseline of a 
functional status measure (VO2MAX) in patients with HCM and moderate-to-
severe heart failure with preserved left ventricular (LV) function following repeat 
dosing with PEX for 112 days 
Secondary: 
• To evaluate the ascending dose-response effect on the change from baseline 
of VO2MAX in patients with HCM and moderate-to-severe heart failure with 
preserved LV function following repeat dosing with PEX for 112 days 
• To evaluate the electrocardiographic (ECG) response, tolerability and safety of 
orally administered PEX in patients with HCM and moderate-to-severe heart 
failure with preserved LV function following repeat dosing with PEX for 112 
days 
Endpoints 
Primary: 
• Change from baseline of VO2MAX at the end of Period 2 
Secondary Endpoints: 
• The change from baseline of VO2MAX at the end of study-drug dosing Period 
1 compared to the change from baseline at the end of Period 2. 
• An evaluation of the change in VO2MAX at the end of study-drug dosing Period 
1 compared to baseline will be performed 
• The change from baseline of the QTcF interval at the end of study-drug dosing 
Period 1 compared to the change from baseline at the end of Period 2 
• The change from baseline at the end of study-drug dosing Period 2 in the Six-
Minute Walk Test (6MWT) and change from baseline at the end of study-drug 
dosing Period 1 compared to the change from baseline at the end of Period 2 
• Safety data (adverse events [AE], routine laboratory safety test of blood, ECG 
abnormalities, vital signs, and concomitant medication and patient withdrawals) 
during study-drug dosing Period 1 compared to Period 2 
 


Protocol No.  HML-PHX-005 
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Heart Metabolics — Company Confidential 
 
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Exploratory endpoints: 
• Change from baseline of other ECG variables at the end of study-drug dosing 
Period 1 compared to the change from baseline at the end of study-drug dosing 
Period 2 
• Change from baseline of HbA1c at the end of study-drug dosing Period 1 
compared to the change from baseline at the end of study-drug dosing Period 
2 
Study Design 
This is a Phase 2, open label study that will enroll approximately 33 patients with 
HCM who are unable to exercise more than 75% of their maximum predicted 
capacity during Cardio-Pulmonary Exercise Testing (CPEX) at Screening (Figure 
1.1).  They will then be started on 70 mg PEX daily and dose titrated to a plasma 
level of 100-300 ng/ml over 8 weeks (Period 1).  CPEX will be repeated, and then 
the dose will be titrated up to a plasma level of 300-500 ng/ml PEX for a further 8 
weeks (Period 2).  CPEX will be assessed at the end of Period 2. The patients will 
then complete a 4-week safety observation period before study termination. 
Approximately 30 patients are projected to complete the study. 
Figure 1.1 
Study design for Periods 1 and 2 
 
Number of 
Patients 
Approximately 33; anticipate 30 to complete full 16 weeks of dosing 
Target 
Population 
Patients with HCM and moderate to severe heart failure with preserved LV function 
Length of 
Study 
Approximately 24 weeks as follows: 
• Screening: 4 weeks 
• Period 1: 
8 weeks 
• Period 2: 
8 weeks 
• Follow-up: 4 weeks 
Investiga-
tional Drug 
PEX is available as 35 mg tablets 
Study Drug 
Dosing 
All patients will receive 70 mg daily during weeks one and two in Period 1.  Formal 
dose adjustments will not be done during this time, although the PEX dose may be 
decreased at any time for suspected elevated PEX levels or related AE.  Patients 
should take study drug in the evening, preferably between 8 and 11p.m (with the 
exception of the first dose of study drug, which will be administered under the 
supervision of the study-site staff).   
On the morning of day 8 (±1 Day), a blood sample to determine the levels of PEX 
and cis- and trans-hydroxy-perhexiline (CIS, TRANS) will be obtained. Results for 
PEX and CIS will be reported to the study sites in order to: 
• 
Withdraw phenotypic poor metabolizers (PMs) from the study 
On the morning of day 15 (±1 Day), a blood sample to determine the levels of PEX, 
CIS, and TRANS will be obtained.  Results for PEX and CIS will be reported to the 
study sites to: 


Protocol No.  HML-PHX-005 
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Heart Metabolics — Company Confidential 
 
Page 9 of 58 
• 
Evaluate the CIS:PEX ratio.  Patients with a ratio <0.4 will be further 
evaluated and the patient status will be discussed with the Medical Monitor. 
• 
Determine dose adjustment starting after completion of a minimum of 13 
days of study-drug dosing. 
PEX, CIS, and TRANS Levels will continue to be measured every other week 
(Weeks 4, 6, 8, 10, 12 and 14) in order to guide dose adjustment according to Table 
1.1 (below) and to evaluate the CIS:PEX ratio.  At the conclusion of Period 2 (end 
of Week 16), an additional blood sample will be obtained to determine the levels of 
PEX, CIS, and TRANS. 
A final blood sample will be obtained at the conclusion of the 4-week safety follow-
up period (end of week 20) and plasma levels of PEX, CIS and TRANS determined. 
Dose 
Adjustment 
Guidelines 
and 
Algorithm 
1. All patients will receive 70mg/day for the first 14 days. Formal dose-adjustments 
will start at the end of Week 2 / Start of Week 3 in Period 1. However, the dose 
may be decreased at any time for suspected elevated PEX levels or related AE. 
2. Available dose levels will include: 
a. Period 1: 35, 70, 105, 140, 175, and 210 mg (tablet strength is 35 mg) 
b. Period 2: 35, 70, 105, 140, 175, 210, 245, & 280 mg (tablet strength is 35 mg) 
3. In general, only one dose adjustment should be made per two-week period.  If 
the PI thinks an additional dose adjustment should be made, the PI should 
contact the Medical Monitor. 
4. Upon notification of a dose adjustment the site should contact the patient as soon 
as possible to initiate dose adjustment according to Table 1.1, below. 
5. To achieve the higher target range for PEX in Period 2, the dose will initially be 
adjusted based on the plasma PEX level measured at Week 6 in Period 1. This 
dose adjustment will be performed at the Week 8 visit (start of Period 2) in 
accordance with the Period 2 column in Table 1.1, below.  Important:  Any 
change made at Week 6 will need to be accounted for when adjusting the dose 
at Week 8. 
Table 1.1 
Dose-adjustments from Week 2, Period 1 and throughout Period 2 
Systemic 
Perhexiline 
Level 
(PEX) 
(ng/mL)** 
Period 1 (Weeks 2 – 8) 
Target Range 100-300 ng/mL 
 
Start Dose of 70 mg/day, 2 tablets 
per day 
 
 
(Tablets to be taken orally in the 
evening) 
 
Maximum Dose 210 mg 
(6 tablets) 
Period 2 (Weeks 9 – 16) 
Target Range 300-500 ng/mL 
 
Start dose will be the dose-
adjustment decision based on the 
Period 1, Week 6 level of PEX† 
 
(Tablets to be taken orally in the 
evening) 
 
Maximum Dose 280 mg 
(8 tablets) 
< 50 
+2 tablets per day# 
+2 tablets per day# 
50 to 100 
+1 tablet per day# 
+2 tablets per day# 
101 to 200 
No change 
+1 tablet per day# 
201 – 300 
No change 
+1 tablet per day# 
301 – 400 
-1 tablet per day* 
No change 
401 – 500 
-2 tablets per day* 
No change 
501 – 600 
-3 tablets per day* 
-1 tablet per day* 
601 – 700 
Discontinue for 1 day, and  
-3 tablets per day* 
Discontinue for 1 day, and 
-2 tablets per day* 


Protocol No.  HML-PHX-005 
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Heart Metabolics — Company Confidential 
 
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701 - 900 
Discontinue for 3 days, and 
-4 tablets per day* 
Discontinue for 1 day, and 
-3 tablets per day* 
901 - 1200 
Discontinue for 7 days, and 
-5 tablets per day* 
Discontinue for 3 days, and 
-4 tablets per day* 
> 1200 
Discontinue for 7 days, and 
-5 tablets per day* 
Discontinue for 7 days, and 
-5 tablets per day* 
# Unless the patient has already reached the highest daily dose of six (6) tablets 
or 210 mg in Period 1 and eight (8) tablets or 280 mg in Period 2 
* The lowest daily dose is one (1) tablet per day or 35 mg.  
** Blood sampling for plasma PEX, CIS and TRANS measurement should be 
obtained approximately 12 hours following dosing on the previous day. Results 
for systemic PEX and CIS levels will be reported to the study sites. 
† 
Any change made at Week 6 will need to be accounted for when adjusting the 
dose at Week 8. 
 
6. Dose adjustment for QTcF/JTcF prolongation (regardless of PEX levels 
reported, unless the PEX levels and dose adjustment algorithm result in a dose 
reduction or discontinuation of a greater magnitude) will proceed as follows for 
EITHER: 
a. Patients with a QRS interval ≤ 100 msec WITH; 
• 
A prolonged QTcF > 540 msec OR, 
• 
An increase in QTcF > 75 msec over baseline AND QTcF > 500 msec 
b. Patients with a baseline OR any on-study QRS interval > 100 msec WITH: 
• 
An increase in the JTcF > 75 msec over baseline AND the JTcF > 410 
msec OR 
• 
An on-study JTcF interval > 450 msec 
The dose of study drug will be stopped for 2 days and the daily dose 
subsequently reduced by 35 mg (for patients receiving ≤ 105 mg) or 70 mg (for 
patients receiving ≥ 140 mg) and restarted only if the QTcF/JTcF measurement 
has fallen back into the acceptable range for continued dosing.  If the 
QTcF/JTcF measurement has NOT fallen back into the acceptable range after 
stopping drug for 2 days, the process of holding study drug and rechecking the 
ECG every 2 to 3 days will continue until the QTcF or JTcF limits are not 
exceeded and at which time study drug may be restarted at the reduced dose.  
The dose of study drug will not be increased any further during either Period 1 
or Period 2 if a dose reduction for QTcF or JTcF prolongation is required. 
Safety 
Assessment 
A Study Monitoring Team will be established to review all available data in listings 
approximately every 2 months (until the study is completed) following 25% 
enrollment in the study with an emphasis on observed outcomes related to patient 
safety and tolerance (i.e., AEs, adverse device effects (ADE), vital signs 
measurements, ECGs, laboratory assessments, and concomitant medications). 
These listings will be reviewed by the Study Monitoring Team to determine whether 
the dosing regimen should be altered during the course of the study or whether any 
other protocol modifications should be instituted to ensure the safety of the 
patients.  The Study Monitoring Team will include at a minimum an independent 
cardiologist, the Medical Monitor (Contract Research Organization [CRO]), the 
study biostatistician (CRO), and a Sponsor representative. 


Protocol No.  HML-PHX-005 
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Page 11 of 58 
Inclusion 
Criteria 
1. General Criteria 
a. Adult, at least 18 years of age 
b. Able and willing to give written informed consent 
2. Cardiomyopathy-related Criteria 
a. Hypertrophic cardiomyopathy with moderate-to-severe heart failure 
meeting all of the 2011 American College of Cardiology 
Foundation/American Heart Association Criteria for the Diagnosis of 
Hypertrophic Cardiomyopathy [Gersh et al., 2011].   
b. Left ventricular hypertrophy (LVH) with maximum LV wall thickness ≥ 15 
mm measured within the past 12 months without an alternative explanation. 
c. Left ventricular ejection fraction ≥ 50% 
d. Able to perform exercise testing but unable to exceed 75% of the predicted 
age-adjusted maximum level (as determined by VO2MAX measured during 
Screening CPEX).  VO2MAX will be determined again at Baseline and must 
not exceed ±20% of the Screening VO2MAX. 
e. Normal sinus rhythm at Screening and Baseline (atrial fibrillation pattern 
acceptable for patients with chronic atrial fibrillation and controlled 
ventricular response) 
f. If taking any medications for the treatment of HCM (including beta-blockers, 
calcium channel blockers, diuretics), the medication has been taken at a 
stable dose for at least 60 days prior to screening and will be continued at 
the same dose throughout the study  
Exclusion 
Criteria 
1. General Exclusion Criteria: 
a. Pregnant women, women who intend to become pregnant, or woman who 
are not practicing contraception, either pharmacologically or with a barrier 
method 
b. Lactating women 
c. CYP2D6 Poor Metabolizer (PM) status, based on genotype known prior to 
Screening, or as determined by genotype assessed at Screening. 
CYP2D6 Poor Metabolizer status will be reported by the central laboratory 
in the screening report according to the Clinical Pharmacogenetics 
Implementation Consortium (CPIC) guidelines [Crews et al., 2014]. 
d. Any patient who regularly takes a medication known to be a strong 
inhibitor of CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, or 
ritonavir) 
e. Any concomitant disease, condition, or treatment that could interfere with 
the conduct of the study, or that would, in the opinion of the investigator or 
sponsor, pose an unacceptable risk to patients and/or interfere with the 
interpretation of study data. 
f. History of a known toxic or inflammatory peripheral neuropathy, such as 
mononeuritis multiplex, acute or chronic inflammatory demyelinating 
polyneuropathy, 
axonal 
sensorimotor 
neuropathies, 
drug-related 
neuropathy or neuritis, or diabetic neuropathy (history of a compression 
neuropathy, such as carpal tunnel syndrome, is acceptable) 
g. Poorly controlled diabetes mellitus (e.g., HbA1c > 9.0%) 
h. Clinically severe chronic obstructive pulmonary disease (i.e., Chronic 
Obstructive Pulmonary Disease requiring home oxygen or history of intra-
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i. History of a known chronic liver disease including cirrhosis of any cause, or 
chronic hepatitis B or hepatitis C 
j. History of porphyria 
k. History of recurrent hypoglycemia 
l. Active infection requiring antibiotics 
m. Life expectancy of less than 2 years 
n. Evidence of an active or suspected cancer or systemic treatment within the 
previous 5 years for a malignancy, except for skin squamous cell or basal 
cell carcinomas that did not require systemic therapy and are considered to 
be cured 
o. History of substance abuse, including alcohol or illicit drugs within the past 
12 months 
2. QT Interval-Related Exclusion Criteria: 
a. Personal history of congenital long QT syndrome, Torsade de Pointes 
(TdP), or drug-induced long QT 
b. On the basis of the mean of triplicate ECGs at screening or baseline: 
i. 
QTcF > 500 msec if QRS ≤ 100 msec 
ii. 
JTcF > 410 msec if QRS > 100 msec 
c. Serum potassium < 3.8 mEq/L (may be repeated up to two times during 
screening after attempts at medical management) 
d. Currently taking a medication with known risk of QT prolongation and TdP 
as 
listed 
in 
the 
“Known 
Risk 
of 
TdP” 
Risk 
Category 
on 
www.crediblemeds.org [Woosley and Romero]. 
e. If possessing a pacemaker or Implantable Cardioverter Defibrillator (ICD), 
ventricular pacing > 10% of the time  
 
3. Other Exclusion Criteria: 
a. Abnormal safety studies of clinical significance at Screening such as: 
i. 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), or lactate dehydrogenase (LDH) > 1.5 x 
upper limit of normal 
ii. 
Total Bilirubin > 2.0 x upper limit of normal (unless subject is known to 
have Gilbert’s syndrome) 
b. Known hypersensitivity to perhexiline 
c. Unable or unwilling to comply with the protocol 
d. Enrolled in another therapeutic trial for HCM 
4. Cardiomyopathy-Related Exclusion Criteria 
a. Asymptomatic patients or patients whose symptoms are controlled with 
medications 
b. Resting Left Ventricular Outflow Tract (LVOT) gradient > 50 mmHg or 
exercise-induced LVOT gradient > 80 mmHg 
c. Absence of an operational implantable cardioverter defibrillator device if 
there is a history of non-sustained ventricular tachycardia (> 5 beats), or 
an immediate family history of sudden cardiac death or arrest 
d. Known coronary artery disease (> 50% arterial luminal narrowing of a 
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e. History of cardiac transplantation 
f. Cardiac surgery or septal reduction surgery planned in the next 6 months 
or having occurred within the past 6 months 
g. HCM believed to be caused by infiltrative disorders, glycogen storage 
disorders, and/or hypertensive heart disease (including genotypic or 
phenotypic evidence of Fabry’s Disease) 
Study 
Procedures 
Dosing will be initiated at the Baseline Visit after successful completion of the 
Protocol Activities during this visit.  Study medication will be taken once daily in 
the evening (preferably 8-11p.m., with the exception of the first dose of study 
drug, which will be administered under the supervision of the study-site staff) on 
an outpatient basis for 112 consecutive days.  Patients should take the study 
medication with a glass of water or other non-alcoholic beverage, regardless of 
food intake. 
All patients will be started at an initial dose of 70 mg (2 tablets) per day.  After two 
weeks, dose level adjustment will be made every second week according to 
plasma level measurements for Period 1 according to the Dose Adjustment 
Guidelines and Algorithm (Table 1.1). 
At the end of Period 1 (end of Week 8), all patients will undergo CPEX 
examination. Following the successful completion of Period 1, patients will 
undergo dose adjustment every second week according to the higher target 
therapeutic range for plasma levels defined for Period 2 (Table 1.1). 
At the end of Period 2 (end of Week 16), all patients will undergo CPEX testing. 
Statistical 
Analysis 
A two-sided, one-sample t-test of the change from baseline for the end of Period 2 
is planned for VO2MAX; a power of at least 72% is expected for a sample size of 
30 patients for at least a mean change from baseline of 1.2mL O2/kg/min. 
 
 


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2 INTRODUCTION 
2.1 HYPERTROPHIC CARDIOMYOPATHY 
Hypertrophic Cardiomyopathy (HCM) is an inherited disease in which defective production of 
contractile proteins in the cardiac sarcomere leads to excessive growth of heart muscle tissue. 
Only a small percentage of patients with the genetic propensity for the disease develop any 
signs or symptoms for which medical treatment is necessary. Response to medical therapy is 
often incomplete, and typically temporary. Once a patient has recognizable symptoms, the 
patient’s condition may become rapidly and progressively worse, and the risk that the patient 
experiences sudden death is increased [Krikler et al., 1980, McKenna and Camm 1989]. 
Symptoms in HCM are ultimately due to LV dysfunction consequent to associated cellular 
energy deficit and ischemia. Patients with heart failure with preserved LV systolic function 
have reduced myocardial energy reserve which leads to a dynamic impairment in active 
relaxation during exercise [Phan et al., 2009a] especially in HCM, where the energy demands 
may be greater than most any other cardiac condition [Jung et al., 1998]. Impaired cardiac 
energetics have been demonstrated in patients with HCM, and are associated with abnormal 
cardiac muscle cell function [Crilley et al., 2003, Morimoto 2008, Phan et al., 2009a].  
2.2 UNMET CLINICAL NEED IN SYMPTOMATIC HYPERTROPHIC CARDIOMYOPATHY 
There are no drugs approved in the United States for the treatment of HCM. Off-label use of 
drugs for other, more common, forms of cardiomyopathy is unpredictable and occasionally 
dangerous because of the different underlying pathology and pathophysiology of HCM [Gersh 
et al., 2011]. None of the drugs the US Food and Drug Administration has approved for the 
treatment of either systolic heart failure or angina have been tested in clinical trials of HCM 
patients. Current HCM therapy consists of negatively inotropic agents that reduce myocardial 
oxygen demand by reducing heart muscle contractility but variable patient response and their 
limited anti-ischemic potential in HCM results in unpredictable benefit. 
Recognition of HCM as a disease of disordered metabolism by an NHLBI Working Group 
highlighted this as an opportunity for further study of potential therapies [Force et al., 2010].  
2.3 PERHEXILINE 
Perhexiline (PEX) was developed as an anti-ischemic drug for treatment of angina pectoris 
but interest in its use was tempered by its poorly understood side effects, most notably liver 
and nerve toxicity in a small proportion of patients. Understanding of PEX’s metabolism has 
allowed its continued safe usage in tandem with accurate and vigilant monitoring of blood 
levels and dose adjustment. It has been in continuous use in Australia and New Zealand for 
more than 30 years with over 100,000 patient-years of exposure.  More recently, PEX has 
been used in randomized controlled trials and in open label studies in the United Kingdom 
[Phan et al., 2009b]. 
PEX is an inhibitor of carnitine palmitoyltransferase (CPT), the enzyme responsible for 
mitochondrial uptake of long-chain fatty acids. This results in a greater cellular dependence 
on carbohydrate utilization for energy production which is inherently more efficient that fatty 
acid oxidation. The shift in cardiac metabolism to carbohydrates in the presence of PEX 
explains its potent beneficial effects on coronary ischemia and symptoms of angina [Ashrafian 
et al., 2007, Essop and Opie 2004, Lee et al., 2004]. By inhibiting CPT in HCM patients, PEX 
may improve the balance of myocardial oxygen demand by shifting metabolic utilization from 
free fatty acids to carbohydrates thereby improving efficiency of cardiac energy production. 
PEX is known to correct the energy deficit seen in HCM [Horowitz and Chirkov 2010, Ashrafian 
et al., 2011] leading to significant improvements in multiple metabolic and clinical parameters 
in HCM.  
In 46 patients with HCM and symptomatic exercise limitation, PEX increased maximal oxygen 
output (VO2MAX) on CPEX, improved diastolic filling, restored depleted myocardial energy 


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stores more quickly and improved New York Heart Association class of heart failure symptoms 
versus placebo [Abozguia et al., 2010].  
2.4 MIXED ION CHANNEL EFFECTS OF PERHEXILINE 
PEX is known to alter myocellular electrical activity through blockade of voltage gated L-type 
calcium [Barry et al., 1985] and sodium channels [Grima et al., 1988]. PEX is also known to 
block the voltage-dependent Kv1.5 potassium channel in human embryonic kidney cells (IC50 
= 1.5 μM) and also inhibits the ultra-rapidly activating K+ channel (IKur), encoded by Kv1.5, in 
human atrial myocytes [Rampe et al., 1995]. At the ventricular level PEX causes voltage-
dependent block of the human ether-a-go-go-related gene (hERG) channel (IC50 7.8 μM) 
[Walker et al., 1999]. 
PEX inhibits major cardiac ion channels with IC50 in the low micromolar range. Ventricular 
therapeutic concentrations of PEX in humans are in the range of 17.45 to 76.8µM [Drury et 
al., 2014, Drury et al., 2013] and therefore the cardiac ion channel blocking properties of PEX 
are likely to play a role in the cardiac effects of the drug.  This is especially true for hERG, 
calcium channel and late sodium current inhibition. 
The effects of PEX on late sodium current (late hNav1.5 or INaL) and the L-type calcium 
current (hCav1.2) may reduce the potential pro-arrhythmic effects associated with IKr block 
(as measured by the hERG current). Most drugs that have been shown to prolong the QTcF 
interval in humans and induce Torsade de Pointes (TdP) inhibit the rapid component of the 
delayed rectifier potassium current (IKr) in cardiac cells, as does PEX.  However, the reverse 
is not true, i.e., drugs that decrease IKr do not necessarily cause TdP.  Examples include 
verapamil (L-type calcium channel block), ranolazine and amiodarone (late INa inhibition).  It 
is recognized that a balanced multiple ion-channel effect (MICE), especially inhibition of 
Cav1.2 and late INa, can result in no or a reduced pro-arrhythmic potential [Eichenbaum et 
al., 2012, Shantsilla et al., 2007; Sager et al., 2014].  
2.5 PERHEXILINE THOROUGH QT STUDY 
PEX has MICE which might also predict a potential QT prolongation effect. Nevertheless, pro-
arrhythmic effects have not been seen to any significant extent in its > 30 year clinical 
experience.  The Australian Therapeutic Goods Administration label notes that the drug may 
be associated with QT prolongation and has been associated with a single report of TdP. 
A thorough QT (TQT) study was done to establish the frequency and degree of PEX effects 
on the QT/QTcF interval. In that study PEX caused QT prolongation (∆∆ QTcF of 15.3 and 
22.8 msec at mean Cmax of 278.6 and 677.9 ng/mL, respectively) within the plasma 
concentration ranges tested in this study. Most of the QTcF prolongation was the result of the 
∆∆Tpeak-Tendc at all timepoints up to and including 8 hours post-dosing.  Subsequently the 
QTcF prolongation was the product of similar, combined effects of the ∆∆Tpeak-Tendc and 
∆∆J-Tpeakc.  This suggests that PEX has mixed ion channel effects at relevant plasma levels, 
reducing the effect of hERG inhibition. PEX also had a mild effect on heart rate and AV nodal 
conduction indicating possible late sodium channel effect. PEX was well tolerated with few 
AEs and no serious adverse events (SAE); there were no pro-arrhythmic events seen during 
the study. In view of the QTcF prolongation, enhanced cardiac screening and monitoring for 
QT prolongation and arrhythmias will be included in this clinical study. 
2.6 PERHEXILINE SUMMARY 
The mechanism of action of PEX in HCM is likely two-fold, one metabolic, the other through 
its inhibitory MICE, especially Calcium and INaL: 
• 
By inhibiting CPT, PEX improves oxygen consumption and therefore decreases the 
levels of oxygen free radicals that contribute to the development of INaL and 
intracellular calcium overload. 


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• 
By its MICE, especially by inhibiting Ca and INaL, PEX protects and perhaps reverses 
the development of intracellular calcium overload, thereby improving the 
electromechanical properties of the left ventricle. Furthermore, its Ca channel 
properties (hCav1.2 IC50 = 0.068 µM) may further protect cardiac myocytes from 
calcium overload and cell death as well as counteract the IKr inhibition and its 
attendant cardiac arrhythmias. 
2.7 PEX-CIS ASSAY 
2.7.1 Description of PEX-CIS Assay 
The PEX-CIS assay is a straightforward protein precipitation assay.  It extracts perhexiline 
(PEX), cis-hydroxy perhexiline (CIS) and two internal standards (referred to as IS-PEX and 
IS-CIS) from human plasma.  The internal standards were designed specifically to enhance 
the performance of the PEX-CIS assay.  The analytes are separated by HPLC on a XBP-C8(L) 
column, and the eluates are monitored by an API4000 MS/MS detector in positive MRM mode.  
The extract is then assayed against a calibration curve.  The data are acquired by the data 
acquisition system Analyst® (Sciex) and processed in Watson LIMS.  The method range is 
from 10.0 to 1500 ng/ml for PEX and CIS, and requires 50 µL aliquot of human plasma.  The 
method has a run time of approximately 4.5 minutes per sample. 
The test has been validated using an independent laboratory following principles of Good 
Laboratory Practice (GLP), International Organization for Standardization and the 
International Electrotechnical Commission 17025 as well as FDA’s Guidance documents for 
Bioanalytical method validation.  The test method selectivity, accuracy, precision, recovery, 
linearity, sensitivity, dilution and stability during processing were investigated and 
consideration was given to batch sizes during sample analysis. 
2.7.2 Use of the PEX-CIS Assay in This Study 
The test is not required for enrollment in this study.  However, there is a 1% incidence of what 
is known as phenotypic poor metabolizers (PMs) that the test will be used to identify around 
day 8, based on a metabolic ratio of CIS to parent PEX, which are determined from the assay. 
In addition to identifying phenotypic PMs, the assay will also be used for dose adjustments 
throughout the study. 
2.8 STUDY RATIONALE 
This is an open-label, phase II study to confirm the optimal dosing regimen of PEX for use in 
a future phase III study in patients with HCM. The previous study [Abozguia, 2010] in HCM 
patients demonstrated that a safe and effective plasma concentration for PEX was 150-600 
ng/mL.  However, a more refined dosing study to evaluate safety and efficacy at low (100-300 
ng/mL) and high (300-500 ng/mL) plasma PEX levels has not yet been performed.  Potentially, 
equal efficacy with improved safety could be achieved at lower concentrations of PEX. 
A population pharmacokinetic (PK) evaluation of the PK data from the PEX-TQT study was 
done to identify and characterize patient factors influencing PEX PK and the magnitude of 
unexplained PK variability [Mould, 2016].  Application of this newly developed model 
compared to a previously published model [Hussein et al., 2001] showed the new model better 
describes PEX PK, particularly in extensive metabolizer (EM) and intermediate metabolizer 
(IM) groups. 
The 2-compartment PK model developed from this exercise was used to predict drug 
exposures after single and multiple doses of PEX 70, 140, and 280 mg in all CYP2D6 
genotypes [Mould, 2016]. Simulations of multiple dose administrations demonstrated that 
therapeutic levels of PEX in the range of 150-600 ng/mL for all the CYP2D6 genotypes eligible 
could be achieved in this study with doses of 70 to 280 mg daily. Figure 2.1 shows the initial 
response to 70 mg daily in IM, EM, and PM subjects, and clearly shows that all subjects, 
including phenotypic PM subjects can be safely dosed through two weeks without reaching 


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excessive PEX levels.  However, conservatively, a blood sample to measure PEX and CIS 
levels will be obtained at day 8 to withdraw phenotypic PMs from the study.  Then starting on 
day 15, PEX levels will continue to be measured every other week (Weeks 2, 4, 6, 8, 10, 12 
and 14) in order to guide dose adjustment and to achieve the desired plasma concentrations.  
The following doses are expected to produce therapeutic concentrations in the majority of 
patients (PMs are being excluded from the study): 
• 
Intermediate Metabolizers (IM): 
70 to 140 mg daily 
• 
Extensive Metabolizers (EM):  
140 to 210 mg daily 
• 
Ultra-rapid Metabolizers (UM): 
May require maximum doses of 210 (Period 1) or 
280 (Period 2) mg daily.  These subjects may not reach the target therapeutic level. 
2.8.1 Therapeutic Window Rationale 
The therapeutic window of PEX has been established as a range from 150ng/mL to 600ng/mL 
[Pexsig Product Information, 2000]. Regular monitoring of systemic levels of PEX is 
recommended to inform dose-adjustment decisions to maintain systemic levels within the 
therapeutic window. 
2.8.2 Primary Endpoint Rationale 
HCM patients suffer from significant exercise limitation [Abozguia, 2010]. CPEX testing 
provides a noninvasive method for assessing the cardiovascular, pulmonary, and skeletal 
muscle components of exercise performance [Balady et al., 2012]. Patients with HCM routinely 
undergo CPEX testing where V̇ O2MAX is used as the primary measure of exercise 
performance. CPEX testing provides prognostic information in patients with hypertrophic 
cardiomyopathy where sub-maximal exercise parameters predict death from heart failure 
[Coats et al., 2014]. 
2.8.3 Mitigation of Potential QT Prolongation 
In order to ensure that risk of QT prolongation is minimized in this study, patients with a 
screening or baseline QTcF >500msec if QRS is ≤100msec or a JTcF >410msec if QRS 
>100msec will be excluded; these limits were chosen in light of the QT prolongation observed 
in the TQT study. In addition, dose adjustment for QTcF/JTcF prolongation will be done after 
either: 
a. Patients with a QRS interval ≤ 100 msec WITH; 
• 
A prolonged QTcF > 540 msec OR, 
• 
An increase in QTcF > 75 msec over baseline AND QTcF > 500 msec 
b. Patients with a baseline OR any on-study QRS interval > 100 msec WITH: 
• 
An increase in the JTcF > 75 msec over baseline AND the JTcF > 410 msec OR 
• 
An on-study JTcF interval > 450 msec 


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Figure 2.1 
2-Week simulations of PEX concentrations at 70 mg per day for different 
CYP2D6 metabolizers 
A) Intermediate metabolizer 
 
B) Extensive metabolizer 
 
 
 
 


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C) Poor metabolizer 
 
2.8.4 Monitoring of Systemic Levels and Dose Adjustment of Perhexiline 
Because of the potential safety risk from study-drug accumulation, a dose-adjustment 
algorithm will be used (see section 4.4.3) based on the systemic plasma levels of PEX 
determined from regular blood sampling throughout the dosing regimens in Periods 1 and 2.  
The objective of the dose adjustment decisions will be to achieve steady-state systemic 
plasma levels of PEX within the recommended target therapeutic range of either 100-300 
ng/mL in Period 1 or 300-500 ng/ml in Period 2. 
Considering the intra-day Cmin-Cmax range of plasma concentrations projected by PK 
simulations (section 2.8) it is proposed that the blood sampling timepoints will be scheduled 
approximately 12h following study drug dosing on the previous day in order to coincide with 
the approximate intra-day mean systemic plasma level of PEX. 
3 OBJECTIVES 
3.1 PRIMARY OBJECTIVE 
The primary objective of the study is to evaluate the effect of PEX on the change from baseline 
of VO2MAX in patients with HCM and moderate-to-severe heart failure with preserved LV 
function following repeat dosing with PEX for 112 days. 
3.2 SECONDARY OBJECTIVES 
The secondary objectives of the study are to evaluate: 
• 
The ascending dose-response effect on the change from baseline of VO2MAX in 
patients with HCM and moderate-to-severe heart failure with preserved LV function 
following repeat dosing with PEX for 112 days 
• 
The electrocardiographic (ECG) response, tolerability and safety of orally administered 
PEX in patients with HCM and moderate-to-severe heart failure with preserved LV 
function following repeat dosing with PEX for 112 days 
Poor Metabolizer 
70 mg Daily 


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4 INVESTIGATIONAL PLAN 
4.1 OVERALL STUDY DESIGN 
This is a Phase 2, open label study that will enroll approximately 33 patients with HCM at 
approximately 7-10 study sites in the US; recruitment will be competititve across sites. Eligible 
patients will be unable to exercise more than 75% of their maximum predicted VO2MAX 
capacity during CPEX at screening (Figure 4.1). 
Figure 4.1 
Study design for Periods 1 and 2 
 
Following screening, this study will include two sequential, 8-week study-drug dosing periods 
for each patient. The patients will be started on 70 mg PEX daily with subsequent dose titration 
to a plasma level of 100-300 ng/ml over 8 weeks (Period 1).  During the second 8-week period 
(period 2), the dose will be titrated further to a plasma level of 300-500 ng/ml.  CPEX will be 
completed at baseline (before the start of study-drug dosing on Day 1, Week 1, Period 1), and 
again at the end of Periods 1 and 2. After completion of study-drug dosing (end of Period 2) 
there will be a follow-up safety observation period before patients reach end-of-study. 
Approximately 30 patients are projected to reach and complete the end-of-study procedures 
and evaluations. 
4.2 INCLUSION CRITERIA 
4.2.1 General Inclusion Criteria 
a. Adult, at least 18 years of age 
b. Able and willing to give written informed consent 
4.2.2 Cardiomyopathy-Related Inclusion Criteria 
a. Hypertrophic cardiomyopathy with moderate-to-severe heart failure meeting 
all of the 2011 American College of Cardiology Foundation/American Heart 
Association Criteria for the Diagnosis of Hypertrophic Cardiomyopathy [Gersh 
et al. 2011, Appendix B]. 
b. Left ventricular hypertrophy (LVH) with maximum LV wall thickness ≥ 15 mm 
measured within the past 12 months without an alternative explanation. 
c. Left ventricular ejection fraction ≥ 50% 
d. Able to perform exercise testing but unable to exceed 75% of the predicted 
age-adjusted maximum level (as determined by VO2MAX measured during 
Screening CPEX). VO2MAX will be determined again at Baseline and must not 
exceed ±20% of the Screening VO2MAX. 


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e. Normal sinus rhythm at Screening and Baseline (atrial fibrillation pattern 
acceptable for patients with chronic atrial fibrillation and controlled ventricular 
response) 
f. If taking any medications for the treatment of HCM (including beta-blockers, 
calcium channel blockers, diuretics), the medication has been taken a stable 
dose for at least 60 days prior to screening and will be continued at the same 
dose throughout the study 
4.3 EXCLUSION CRITERIA 
4.3.1 General Exclusion Criteria: 
a. Pregnant women, women who intend to become pregnant, or woman who are 
not practicing contraception, either pharmacologically or with a barrier method 
b. Lactating women 
c. CYP2D6 Poor Metabolizer (PM) status, based on genotype known prior to 
Screening, or as determined by genotype assessed at Screening.   
CYP2D6 Poor Metabolizer status will be reported by the central laboratory in 
the screening report according to CPIC guidelines [Crews et al., 2014]. 
d. Any patient who regularly takes a medication known to be a strong inhibitor of 
CYP2D6 (bupropion, fluoxetine, paroxetine, quinidine, or ritonavir) 
e. Any concomitant disease, condition, or treatment that could interfere with the 
conduct of the study, or that would, in the opinion of the investigator or 
sponsor, pose an unacceptable risk to patients and/or interfere with the 
interpretation of study data. 
f. History of a known toxic or inflammatory peripheral neuropathy, such as 
mononeuritis multiplex, acute or chronic inflammatory demyelinating 
polyneuropathy, axonal sensorimotor neuropathies, drug-related neuropathy 
or neuritis, or diabetic neuropathy (history of a compression neuropathy, such 
as carpal tunnel syndrome, is acceptable) 
g. Poorly controlled diabetes mellitus (e.g., HbA1c > 9.0%) 
h. Clinically severe chronic obstructive pulmonary disease (i.e., Chronic 
Obstructive Pulmonary Disease requiring home oxygen or history of intra-
venous or oral steroid use) 
i. History of a known chronic liver disease including cirrhosis of any cause, or 
chronic hepatitis B or hepatitis C 
j. History of porphyria 
k. History of recurrent hypoglycemia 
l. Active infection requiring antibiotics 
m. Life expectancy of less than 2 years 
n. Evidence of an active or suspected cancer or systemic treatment within the 
previous 5 years for a malignancy, except for skin squamous cell or basal cell 
carcinomas that did not require systemic therapy and are considered to be 
cured 
o. History of substance abuse, including alcohol or illicit drugs within the past 12 
months 
 


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4.3.2 QT Interval-Related Exclusion Criteria 
a. Personal history of congenital long QT syndrome, TdP, or drug-induced long 
QT 
b. On the basis of the mean of triplicate ECGs at screening or baseline: 
i. QTcF > 500 msec if QRS ≤ 100 msec 
ii. JTcF > 410 msec if QRS > 100 msec 
c. Serum potassium < 3.8 mEq/L (may be repeated up to two times during 
screening after attempts at medical management) 
d. Currently taking a medication with known risk of QT prolongation and TdP as 
listed in the “Known Risk of TdP” Risk Category on www.crediblemeds.org 
[Woosley and Romero]. 
e. If possessing a pacemaker or Implantable Cardioverter Defibrillator (ICD), 
ventricular pacing > 10% of the time 
4.3.3 Other Exclusion Criteria 
a. Abnormal safety studies of clinical significance at Screening such as: 
i. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), or lactate dehydrogenase (LDH) > 1.5x upper 
limit of normal 
ii Total Bilirubin > 2x upper limit of normal (unless subject is known to have 
Gilbert’s syndrome) 
b. Known hypersensitivity to perhexiline 
c. Unable or unwilling to comply with the protocol 
d. Enrolled in another therapeutic trial for HCM 
4.3.4 Cardiomyopathy-related Exclusion Criteria 
a. Asymptomatic patients or patients whose symptoms are controlled with 
medications 
b. Resting Left Ventricular Outflow Tract (LVOT) gradient > 50 mmHg or 
exercise-induced LVOT gradient > 80 mmHg 
c. Absence of an operational implantable cardioverter defibrillator if there is a 
history of non-sustained ventricular tachycardia (> 5 beats), or an immediate 
family history of sudden cardiac death or arrest 
d. Known coronary artery disease (> 50% arterial luminal narrowing of a major 
epicardial vessel 
e. History of cardiac transplantation 
f. Cardiac surgery or septal reduction surgery planned in the next 6 months or 
having occurred within past 6 months 
g. HCM believed to be caused by infiltrative disorders, glycogen storage 
disorders, and hypertensive heart disease (including genotypic or phenotypic 
evidence of Fabry’s Disease) 
4.4 STUDY-DRUG DOSING AND SYSTEMIC DRUG-LEVEL MONITORING 
4.4.1 Study-Drug Dosing 
Patients who meet inclusion and exclusion criteria will be admitted to the study on the morning 
of Day 1, Week 1 when they will start their open-label, study-drug dosing regimen with PEX 
and the first dose of study drug will be administered under the supervision of the study-site 
staff. Subsequent daily dosing throughout the dosing period of 112 days will be done in the 
evening (preferably between 8-11p.m.). Patients should take the study medication with a glass 


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of water or other non-alcoholic oral beverage, regardless of food intake. All patients will initially 
receive 70mg daily during weeks one and two in Period 1.  Formal dose adjustments will not 
be done during this time, although the PEX dose may be decreased at any time for suspected 
elevated PEX levels or related AE. 
4.4.2 Monitoring of Systemic Perhexiline and cis- and trans-Hydroxy Perhexiline 
All determinations of systemic blood levels of PEX, CIS, and TRANS will be measured using 
the PEX-CIS assay. 
On the morning of day 8 (± 1 day) (after completion of a minimum of 6 days of dosing) patients 
will provide a blood sample for the measurement of PEX, CIS and TRANS; the sampling 
timepoint will be scheduled at approximately 12h after dosing on the previous study day. The 
analytical results will be available within 3-5 calendar days of the blood sampling and results 
for PEX and CIS will be reported to the study sites. These will be used to determine the 
following: 
• 
Patients deemed to be phenotypic PMs based on these results will be immediately 
withdrawn from study-drug dosing. A phenotypic PM is defined as a patient whose 
CIS:PEX ratio is <0.4. 
On the morning of day 15 (± 1 day) (after completion of a minimum of 13 days of dosing) 
patients will provide a blood sample for the measurement of PEX, CIS and TRANS; the 
sampling timepoint will be scheduled at approximately 12h after dosing on the previous study 
day. The analytical results will be available within 3-5 calendar days of the blood sampling and 
results for PEX and CIS will be reported to the study sites. These will be used to determine 
the following: 
• 
The CIS:PEX ratio will be evaluated and patients with a ratio <0.4 will be further 
evaluated and the patient status will be discussed with the Medical Monitor. 
• 
Dose adjustment will be decided according to the dose-adjustment algorithm 
presented in section 4.4.3 and Table 4.1 below. 
Subsequent blood samples will be obtained and plasma levels of PEX, CIS and TRANS 
determined at the end (±3 days) of every second week (weeks 4, 6, and 8 in Period 1, and 
weeks 10, 12 and 14 in Period 2); the sampling timepoint will be scheduled at approximately 
12h after dosing on the previous study day. The analytical results will be available within 3-5 
calendar days of the blood sampling and results for PEX and CIS will be reported to the study 
sites. These will be used to guide dose adjustment according to Table 4.1 below and to 
evaluate the CIS:PEX ratio.  At the conclusion (± 3 days) of Period 2 (end of Week 16), an 
additional blood sample will be obtained at approximately 12h after dosing on the previous 
study day and plasma levels of PEX, CIS and TRANS determined.  A final blood sample will 
be obtained at the conclusion of the 4-week safety follow-up period (end of week 20) and 
plasma levels of PEX, CIS and TRANS determined. 
4.4.3 Dose-Adjustment of Study Drug 
Throughout the dosing period the following will apply: 
1) 
PEX dose may be decreased at any time for suspected elevated PEX levels or 
related AE. 
2) 
Possible PEX dose levels will be: 
a. Period 1: 35, 70, 105, 140, 175, and 210 mg (tablet strength of 35 mg). 
b. Period 2: 35, 70, 105, 140, 175, 210, 245, and 280 mg (tablet strength of 35 
mg). 
3) 
In general, only one dose adjustment should be made per two-week period starting 
at the end of week 2 in Period 1.  If the PI thinks an additional dose adjustment 
should be made, the PI should contact the Medical Monitor. 
4) 
Upon notification of a dose adjustment the site should contact patient as soon as 
possible to initiate dose adjustment. 


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5) 
To achieve the higher target range for PEX in Period 2, the dose will initially be 
adjusted based on the plasma PEX level measured at Week 6 in Period 1. This 
dose adjustment will be performed at the end of the Week 8 visit (start of Period 2) 
in accordance with the Period 2 column in Table 4.1.  Important:  Any change 
made at Week 6 will need to be accounted for when adjusting the dose at Week 8. 
6) 
Dose adjustments will proceed based on the following criteria (see Table 4.1): 
Table 4.1  
Possible dose-adjustments in Periods 1 and 2 
Systemic 
Perhexiline 
Levels 
(PEX) 
(ng/mL)** 
Period 1 (Weeks 2 – 8) 
Target Range 100-300 ng/mL 
 
Start Dose of 70 mg/day, 2 tablets/day 
 
 
 
(tablets to be taken orally in the evening) 
 
Maximum Dose 210 mg 
(6 tablets) 
Period 2 (Weeks 9 – 16) 
Target Range 300-500 ng/mL 
 
Start dose will be the dose-adjustment 
decision based on the Period 1, Week 6 
level of PEX† 
 
(tablets to be taken orally in the evening) 
 
Maximum Dose 280 mg 
(8 tablets) 
< 50 
+2 tablets per day# 
+2 tablets per day# 
50 to 100 
+1 tablet per day# 
+2 tablets per day# 
101 to 200 
No change 
+1 tablet per day# 
201 – 300 
No change 
+1 tablet per day# 
301 – 400 
-1 tablet per day* 
No change 
401 – 500 
-2 tablets per day* 
No change 
501 – 600 
-3 tablets per day* 
-1 tablet per day* 
601 – 700 
Discontinue for 1 day, and  
-3 tablets per day* 
Discontinue for 1 day, and 
-2 tablets per day* 
701 - 900 
Discontinue for 3 days, and 
-4 tablets per day* 
Discontinue for 1 day, and 
-3 tablets per day* 
901 - 1200 
Discontinue for 7 days, and 
-5 tablets per day* 
Discontinue for 3 days, and 
-4 tablets per day* 
> 1200 
Discontinue for 7 days, and 
-5 tablets per day* 
Discontinue for 7 days, and 
-5 tablets per day* 
# Unless the patient has already reached the highest daily dose permitted of six (6) 
tablets or 210 mg in Period 1 and eight (8) tablets or 280 mg in Period 2 
* The lowest daily dose is one (1) tablet per day or 35 mg.  
** Blood sampling for plasma PEX, CIS and TRANS measurement should be obtained 
approximately 12 hours following dosing on the previous day. 
† Any change made at Week 6 will need to be accounted for when adjusting the dose at 
Week 8. 
 
4.4.4 Dose-Adjustment for QTcF/JTcF Prolongation 
Any dose adjustment instructions due to QTcF/JTcF prolongation will be at the direction of the 
ECG Core laboratory.  Decisions to hold dosing until ECG Core Laboratory analysis is 
complete may be made at the site. 


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Dose adjustment for QTcF/JTcF prolongation (regardless of systemic PEX levels, unless the 
PEX levels and dose adjustment algorithm result in a dose reduction or discontinuation of a 
greater magnitude) will be done as described below for: 
a. Patients with a QRS interval ≤ 100 msec WITH; 
• 
A prolonged QTcF > 540 msec OR, 
• 
An increase in QTcF > 75 msec over baseline AND QTcF > 500 msec 
b. Whenever either the baseline or a subsequent ECG has a prolonged QRS > 100 msec, 
changes in the JTcF will be used for all further dose-adjustment decisions throughout 
the remainder of the study for those patients.  In a patient with a baseline or an on-
study ECG showing a QRS interval >100 msec, the dose will be adjusted as described 
below IF; 
• 
The change from baseline in JTcF is > 75 msec over baseline AND the JTcF 
interval is > 410 msec OR, 
• 
An on-study JTcF interval is > 450 msec 
The dose of study drug for such patients will be stopped for 2 days and the daily dose 
subsequently reduced by 35 mg (for patients receiving ≤ 105 mg) or 70 mg (for patients 
receiving ≥ 140 mg) and restarted only if the QTcF/JTcF measurement has fallen back into 
the acceptable range for continued dosing.  If the QTcF/JTcF measurement has NOT fallen 
back into the acceptable range after stopping drug for 2 days, the process of holding study 
drug and rechecking the ECG every 2 to 3 days will continue until the QTcF or JTcF limits are 
not exceeded and at which time study drug may be restarted at the reduced dose.  The dose 
of study drug will not be increased any further during the remainder of the study (neither Period 
1 or Period 2) if a dose reduction for QTcF or JTcF prolongation is required. 
4.5 MANAGEMENT OF POSSIBLE PEX OVERDOSAGE 
For the purpose of this study an overdose is defined when there is a systemic level of PEX 
>1,200 ng/ml at any timepoint. Suspected overdose associated with lower PEX systemic 
levels should also be reported as an AE or SAE if warranted by the clinical history and/or 
laboratory findings. Alternative explanations, such as a change in medications that may alter 
the patient’s CYP2D6 metabolism, should be considered. 
Reported symptoms following overdosage are nausea and vomiting. Other symptoms that 
have not been reported but would be anticipated are ataxia and headache. Hepatic damage 
and cardiac arrhythmias may possibly occur [Pexsig Product Information 2000].  
Treatment should be symptomatic and supportive. PEX overdose should result in careful 
monitoring of drug levels, continuous cardiac monitoring and serial blood glucose recordings 
in diabetic patients. In patients who are not fully conscious or have impaired gag reflex, 
consideration should be given to administering activated charcoal via a nasogastric tube, once 
the airway is protected. Adequate urinary output should also be maintained.  
Dialysis is not indicated because of the high degree of protein and tissue binding. 
4.6 PATIENT WITHDRAWAL AND DISCONTINUATION 
Patients have the right to withdraw from the study at any time without needing to give any 
reason. Should a patient withdraw, all efforts should be made to complete and report 
observations prior to withdrawal as thoroughly as possible. Patients who choose to discontinue 
from the study will not be replaced. 
The Investigator may withdraw patients in the event of intercurrent illness, AEs, protocol 
violations, administrative or other reasons.  The Investigator is strongly encouraged to contact 
the Medical Monitor prior to discontinuation of study drug or withdrawal of patient from the 
study. 
Discontinuation of PEX or discontinuation from the study is mandatory for: 


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• 
Patients whose baseline VO2MAX is more than ±20% of their screening VO2MAX, i.e.; 
(𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑉𝑉𝑉𝑉2𝑀𝑀𝑀𝑀𝑀𝑀−𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑉𝑉𝑉𝑉2𝑀𝑀𝑀𝑀𝑀𝑀)/ 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑉𝑉𝑉𝑉2𝑀𝑀𝑀𝑀𝑀𝑀 > ±20% 
• 
Patients who are unable or unwilling to return to the study site to repeat a CPEX test 
that did not meet the prospectively defined acceptance criteria as determined by the 
centralized CPEX assessor 
• 
Patients identified as PMs of PEX at the week 1 (day 8) study visit. Despite the 
screening genotyping, which is 95-97% effective at identifying PMs, there may a limited 
number of phenotypic PMs.  Phenotypic PM subjects will be identified by determination 
of the PEX metabolic ratio (MR).  This MR is the ratio of CIS to the parent compound, 
PEX.  If the CIS:PEX is <0.4, the patient will be deemed a phenotypic PM regardless 
of genotype.  These patients are at risk for clinically significant elevated plasma PEX 
levels.  Such elevated plasma levels could decrease tolerability or increase the risk of 
short, self-limited toxicity; if unchecked longer term toxicities could result.  Hence, as 
with the genotypic PMs, these phenotypic PM subjects will be withdrawn from the 
study.  (Patients with a CIS:PEX ratio <0.4 after the week 1 visit will not automatically 
be withdrawn from the study.  These patients should be further evaluated and the 
patient status will be discussed with the Medical Monitor.) 
• 
Patients with persistent elevations in ALT or AST; see Appendix C for the definition of 
“persistent” 
• 
Female study participants discovered to be pregnant during the treatment period 
Discontinuation of PEX should be considered in the following situations [Phan et al., 2009a] 
following discussion with the Medical Monitor: 
• 
Appearance of new onset or exacerbation of peripheral neuropathy. However, 
discontinuation for peripheral neuropathy should only be done after consultation with 
the Medical Monitor. 
• 
Persistent or marked hypoglycemia that is unresponsive to therapeutic modification 
(such as reduction of dose of insulin or oral hypoglycemic agent) 
• 
Excessive weight loss 
• 
Hospitalization for newly diagnosed ventricular tachycardia, or ventricular fibrillation 
4.7 CONCOMITANT MEDICATION 
Some medications or drug classes are known to have potential for adverse interactions with 
PEX. They may be used in the protocol, but they should be considered with caution. A list of 
these agents is included in the Appendix A: Concomitant Medication. 
4.8 STUDY MONITORING TEAM 
A Study Monitoring Team will be established to review and discuss the available study data 
as patients are enrolled.  The team will evaluate all available data listings approximately 
every two months (until the study is completed) following 25% enrollment in the study.  The 
review will include observed outcomes related to patient safety and tolerance (i.e., AEs, 
adverse device effects [ADEs], vital signs measurements, ECGs, laboratory assessments, 
and concomitant medications). These listings will be reviewed by the Study Monitoring Team 
to determine whether the dosing regimen should be altered during the course of the study or 
whether any other protocol modifications should be instituted to ensure the safety of the 
patients.  The Study Monitoring Team will include at a minimum an independent cardiologist, 
the Medical Monitor (CRO), the study biostatistician (CRO), and a Sponsor representative.   


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5 STUDY DRUG SUPPLIES 
5.1 PERHEXILINE 
The pharmaceutical formulation contains PEX as its maleate salt (PHM); 2-(2,2-
Dicyclohexylethyl) piperidine maleate and its chemical structure is shown in Figure 5.1. The 
molecular formula of PHM is C19H35N,C4H4O4 
Figure 5.1 
Chemical Structure of PHM (CAS-6724-53-4) 
 
 
5.2 STUDY DRUG FORMULATION 
PEX investigational tablets will be supplied in a dose strength of 35 mg. The study-drug tablets 
will be packaged and supplied in induction-sealed HDPE bottles with child-resistant closures. 
The investigational drug products are immediate release tablets containing 35 mg of PEX for 
every 50 mg of PHM.  Excipients include mannitol, microcrystalline cellulose, starch, 
croscarmelose sodium, talc and magnesium stearate. The tablets are coated with an aqueous, 
yellow film coat. 
5.3 DRUG STORAGE  
All study drug required for completion of this study will be provided by the Sponsor or its 
designee. Upon receipt of clinical trial materials, the study-site recipient will acknowledge 
receipt of the drug indicating shipment content and condition. Damaged supplies will be 
replaced. The Investigator or designee will inventory supplies and return appropriate copies 
of the shipment receipt form to the Sponsor and/or the drug supply vendor. The Investigator 
will maintain study drug in a pharmacy or locked and secure storage facility with a temperature 
control monitoring system, accessible only to those individuals authorized by the Investigator 
to dispense the study drug. The study drug should be stored at controlled room temperature 
from 15°C to 25°C with an allowed range up to 30°C for short time periods. 
5.4 STUDY-DRUG DISPENSING AND DOSING INSTRUCTIONS 
It is the responsibility of the Investigator to ensure that investigational product is only 
dispensed to study patients. The investigational product must be dispensed only from official 
study sites by authorized personnel according to local regulations. All material not dispensed 
to patients must be accounted for and retained at the study site until the conclusion of the trial 
when the sponsor authorizes the destruction or return of material. The names and signatures 
of site personnel authorized by the Investigator to dispense study drug must be documented 
on the site personnel log, or other appropriate form. 
Patients will be given instructions on the number of tablets to take in each dose and on the 
timing of dosing.  All study-drug dosing must be completed in the evening (preferably 8-
11p.m.) on every day of dosing (with the exception of the first dose of study drug, which will 


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be administered under the supervision of the study-site staff). Patients will record daily dosing 
(number of tablets taken) on each day in a patient diary designed for that purpose. In addition, 
the patients will record the time of dosing on the day prior to study-site visits to facilitate the 
calculation of the time of blood sampling (approximately 12h after dosing) for the determination 
of systemic study-drug levels. It is the Investigator’s responsibility to ensure, at each study 
visit, that patients understand these dosing requirements.  
Patients will be instructed to store their dispensed study-drug supplies at ambient room 
temperature and to take precautions to ensure that those supplies do not experience extremes 
of temperature (e.g., not to store in a refrigerator, not to leave the study drug in their car or 
near a window where it may be exposed to direct sunlight and or heat for a prolonged period 
of time). 
5.5 WITHDRAWAL OF PERHEXILINE AT STUDY TERMINATION 
At completion of study-drug dosing or premature withdrawal, diabetic subjects who require 
hypoglycemic agents should be cautioned that the need for an increase in dosage of the 
hypoglycemic medications may be required when PEX is discontinued. 
5.6 TREATMENT COMPLIANCE 
Patients will record their study-drug dosing details in a diary which will be reviewed by study-
site staff in addition to a study-drug tablet count at each study visit. 
5.7 DRUG ACCOUNTABILITY 
An accurate accounting of study medication received and dispensed must be recorded by the 
study pharmacist or designated study personnel on the Drug Accountability Forms. 
Investigational drug shipment requests, site records of drug receipt, dispensing records, and 
all inventory forms will be examined and reconciled for each subject enrolled in the study. Both 
used and unused drug must be accounted for on a drug disposition and accountability form. 
Instructions for return or destruction of unused drug will be reviewed at the end of the study. 
Copies of all drug accountability forms must be retained in the pharmacy and/or Investigator 
file on site and be available for inspection by the monitor or regulatory agency. Upon receipt 
of clinical trial materials, the Investigator or designee will inventory supplies and return 
appropriate copies of the shipment receipt form to the Sponsor or the drug supply vendor. The 
Investigator or designee will maintain adequate drug accountability records, including 
shipment and receipt forms, drug disposition with dates, quantity, dispensation, and use by 
subjects, and return forms. 
The study drug must not be used outside the context of this protocol. Under no circumstances 
should the investigator or site personnel supply study drug to other clinical sites, investigators 
or subjects, or allow the study drug to be used other than as directed by this protocol without 
prior authorization from the Sponsor or its designee. 
Periodically during the study, the Sponsor or designee will conduct a drug supply inventory 
and verify disposition on the drug accountability log. 
6 STUDY SCHEDULE AND ACTIVITIES 
6.1 SCHEDULING WINDOWS FOR STUDY PROCEDURES AND EVALUATIONS 
The scheduling windows for the various timepoints for study procedures and evaluations are 
summarized in Table 6.1, below. Study procedures and evaluations should be scheduled to 
commence in the morning of each study site visit. 


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Table 6.1 
Time windows for study procedures and evaluations 
Timepoint 
Permitted Time Window 
Screening 
In the 28 days before the Baseline visit 
Baseline Visit (Day 1) 
This is time zero for the study and all other visit dates 
will be estimated in reference to this visit 
Day 8 (±1 Day), End Week 1 / 
Start Week 2, Period 1 
Day 7, 8, or 9; following at least the first 6 days of 
study-drug dosing 
Day 15 (±1 Day), End Week 2 / 
Start Week 3, Period 1 
Day 14, 15 or 16; following at least the first 13 days of 
study-drug dosing 
All other timepoints 
±3 Days. Subject should be taking study-drug until the 
day prior to the End of Treatment visit. 
6.2 SCHEDULE OF ASSESSMENTS 
The flowchart of procedures, measurements and other assessments is shown in table 6.2. 


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Table 6.2 
Schedule of Time and Events for Protocol Activities 
Complete Schedule of 
Protocol Activities 
Screening [A] 
Baseline 
Week 1 (Day 1) 
[A] 
After Completion 
of Week 1 
(Day 8) 
After Completion of Weeks 2, 4, 
6, 8, 10, 12 & 14 
(Days 15, 29, 43, 57, 71, 85 & 99) 
End of Treatment 
After Completion of 
Week 16 
(Day 113) 
Final Visit 
Week 20 
(Day 140) 
Time window permitted 
-28 days 
n.a. 
±1 Day 
±1 Day for Week 2 
±3 Days for other timepoints  
±3 Days 
±3 Days 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X [B] 
 
 
 
 
Demographics, Medical History, Physical 
Exam 
X 
 
 
 
 
 
12-lead ECG [C, D] 
X 
X [E] 
 
X 
X 
X 
CPEX Testing [D, F] 
X 
X [G] 
 
After End of Week 8 
X [H] 
 
Weight 
X 
X 
 
After End of Week 8 
X 
X 
Vital Signs [I] 
X 
X 
 
X 
X 
X 
Laboratory Procedures [J] 
 
 
 
 
 
 
Serum Pregnancy Test [K] 
X 
 
 
 
 
X 
Urine Pregnancy Test [J, K] 
 
X 
 
 
 
 
Serum Chemistry [L] 
X 
 
 
After End of Week 8 
X 
X 
Complete Blood Count [M] 
X 
 
 
 
X 
X 
Coagulation Tests [N] 
X 
 
 
 
 
 
CYP2D6 Screening [O] 
X 
 
 
 
 
 
Plasma PEX, CIS & TRANS [P] 
 
 
X 
X 
X 
X 
Biomarkers (Hemoglobin A1c) 
X 
 
 
After End of Week 8 
X 
X 
Study Dosing & Dose Adjustment as per 
Guidelines & Algorithm [Q] 
 
Start at 70 mg 
[R] 
X 
X 
 
 
Review of Dosing Instructions and 
Adherence to Dosing 
 
X 
X 
X 
X 
 
Adverse Event Assessment [S] 
X 
X 
X 
X 
X 
X 
Adverse Device Effect Assessment [T] 
 
 
X 
X 
X 
X 
Concomitant Medication Review [U] 
X 
X 
X 
X 
X 
X 
6 Minute Walk Test (6MWT) [D] 
 
X 
 
After End of Week 8 
X 
 


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Footnotes: 
A. The Screening visit must be performed within 28 days prior to dosing. 
B. Entry criteria to be evaluated: Baseline CPEX compared to Screening CPEX, and ECG exclusion criteria 
C. ECGs should be done in triplicate prior to blood draws when possible and obtained after the patient has been resting comfortably in a supine position 
for approximately 10 minutes.   
D. ECGs will be done first, the CPEX test will be second, and the 6MWT will be the last procedure completed during any visit by the patient to the study 
site in order to facilitate the patient’s ability to adequately complete a CPEX and a 6MWT in a single day 
E. The baseline ECG must not meet any of the exclusion criteria detailed in section 4.3.2; this must be confirmed by the central ECG reader before study-
drug can be dispensed to the patient 
F. i.    All CPEX test results will be reviewed by the centralized CPEX assessor for compliance with prospectively defined CPEX test acceptance criteria 
ii. The Screening CPEX will be performed to show that patient is able to perform exercise testing but unable to exceed 75% of the predicted age-
adjusted maximum level (as determined by VO2MAX).  
G. i. 
A valid Screening CPEX must be confirmed by the centralized CPEX assessor before the Baseline CPEX is done 
 ii. 
The Baseline VO2MAX must not vary from the screening VO2MAX by more than ±20% (with the screening test being the reference); this will be 
calculated by study-site staff in order to allow a decision on patient inclusion in the study during the Baseline site-visit 
H. If the centralized CPEX assessor deems the EOT CPEX test to be invalid, the subject may be required to return for a repeat test. 
I. 
Heart rate and blood pressure assessed in the seated position after 5 minutes of rest. 
J. Samples for laboratory assays will be sent to the central lab for analysis (with the exception of the urine pregnancy test at Baseline which will be 
performed locally). 
K. Females of child bearing potential.  (Eligible patients will be advised to use an adequate contraceptive method.) 
L. Serum Chemistry:  sodium, potassium, bicarbonate, chloride, calcium, phosphorus, glucose, creatinine, BUN, CPK, uric acid, albumin, total protein, total 
bilirubin, alkaline phosphatase, ALT (SGPT), AST (SGOT), LDH, total cholesterol 
M. CBC:  hemoglobin, hematocrit, RBC, MCV, MCH, MCHC, RDW, WBC count with differential (neutrophils, bands, lymphocytes, monocytes, eosinophils, 
basophils), platelets. 
N. Coagulation tests:  prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). 
O. CYP2D6 Poor Metabolizer status is defined by the CPIC guidelines. 
P. All determinations of systemic blood levels of PEX, CIS, and TRANS will be measured using the PEX-CIS assay.  Blood sampling for determination of 
PEX, CIS and TRANS will be scheduled approximately 12h after dosing on the previous study day. Results for PEX and CIS will be reported to the study 
sites for confirmation of a patient’s phenotypic status for PEX metabolism and for dose-adjustment decisions. 
Q. Patients will be provided with up to 4 weeks’ worth of study medication at the Baseline, Week 2, 4, 6, 8, 10, 12 and 14 study visits. 
 
 


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R. Study-drug will be dispensed once the ECG Corelab confirms that the Baseline ECG meets the entry criteria. The first study-drug dose will be 
administered under the supervision of the study-site staff once the study-site staff confirm that the Baseline VO2MAX is within ±20% of the Screening 
CPEX. 
Note: 
• 
If for any reason the ECG Corelab is not able to immediately confirm the ECG outcome, the patient will return home without receiving any 
dispensed study-drug. In such cases, once the ECG Corelab confirmation becomes available the patient will return to the site to collect the study-
drug supply. The patient will then commence study-drug dosing (defined as Day 1). 
• 
All Baseline ECG confirmations will be received by study sites from the ECG Corelab within a maximum of 48h. 
• 
Before dosing has commenced; if the centralized CPEX assessor confirms the Baseline VO2MAX is not within ±20% of the Screening CPEX then 
the patient will not enter the study 
• 
Before dosing has commenced; if the centralized CPEX assessor confirms an invalid Baseline VO2MAX the patient will be invited to repeat the 
Baseline CPEX test within the 28-day period allowed between Screening and the start of study-drug dosing 
• 
After dosing has commenced; if the centralized CPEX assessor deems the Baseline CPEX test to have been invalid or not within ±20% of the 
Screening CPEX then the patient will remain in the study and the patient’s Screening CPEX result will be taken as the valid Baseline result 
• 
All Baseline CPEX confirmations will be received by study sites from the centralized CPEX assessor within a maximum of 48h. 
S. AEs should be documented and recorded at each visit.  All AEs (serious and non-serious, and related and non-related) will be documented and recorded 
through the Follow-Up visit.  Patients must be followed for AEs until the final required protocol visit or until all drug-related toxicities and SAEs have 
resolved (or are considered chronic/stable). 
T. If an AE is determined to have been the result of a PEX-CIS Assay abnormality (e.g., false positive, false negative, measurement error), it will be deemed 
an ADE for the purpose of device reporting. 
U. Concomitant Medications should be collected and recorded at each visit.  All concomitant medications received up to and including 30 days prior to the 
start of study medication through the Follow-Up visit will be recorded. 
 
 


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6.3 SCREENING 
In the 28 days before the start of study-drug dosing, patients will attend the investigational site 
where they will be screened for eligibility to enter the study. Once a patient has given written 
informed consent to participate in the study the following procedures and measurements will 
be completed and recorded for each patient: 
• 
Inclusion and exclusion criteria will be reviewed  
• 
Demographic data, including age, will be recorded  
• 
Medical history will be recorded 
• 
A physical examination including vital signs and body weight, will be measured; heart 
rate and blood pressure will be measured in the seated position after 5 minutes of rest 
• 
A 12-lead ECG will be recorded in triplicate; ECGs should be taken prior to CPEX 
testing or blood draws and obtained after the patient has been resting comfortably in 
a supine position for approximately 10 minutes 
• 
CPEX Testing to establish VO2MAX will be done; the screening CPEX test results must 
confirm that the patient is able to perform exercise testing but unable to exceed 75% 
of the predicted age-adjusted maximum level 
o A valid Screening CPEX must be confirmed by the centralized CPEX assessor 
before the Baseline CPEX is done 
• 
Blood samples will be taken for routine laboratory testing at a central laboratory 
including; 
o Serum pregnancy test for female patients of child bearing potential; eligible 
patients will be advised to use an adequate contraceptive method 
o Serum Chemistry; sodium, potassium, bicarbonate, chloride, calcium, 
phosphorus, glucose, creatinine, blood urea nitrogen, creatine phosphokinase, 
uric acid, albumin, total protein, total bilirubin, alkaline phosphatase, ALT, AST, 
lactate dehydrogenase, total cholesterol 
o Complete blood count; hemoglobin, hematocrit, red blood cells, mean 
corpuscular volume, mean corpuscular hemoglobin, mean corpuscular 
hemoglobin concentration, red cell distribution, white blood cells with 
differential (neutrophils, bands, lymphocytes, monocytes, eosinophils, 
basophils), platelets 
o CYP2D6 Metabolizer status 
o Coagulation tests:  prothrombin time, partial thromboplastin time, and 
international normalized ratio. 
o Biomarker; Hemoglobin A1c 
• 
AEs that occur after the signing of the informed consent form  
• 
Prior and concomitant medication will be recorded; prior medications received up to 
and including 30 days prior to the start of study medication will be recorded 
6.4 PERIOD 1: BASELINE VISIT AND COMMENCEMENT OF STUDY-DRUG DOSING 
Once a patient has met the entry criteria for the study and completed all of the screening 
procedures they will then visit the study site for the baseline visit and commencement of study-
drug dosing in Period 1. At this visit the following will be completed: 
• 
A 12-lead ECG will be recorded in triplicate 
o ECGs should be taken prior to CPEX testing or blood draws and obtained after 
the patient has been resting comfortably in a supine position for approximately 
10 minutes 


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o The baseline ECG must not meet any of the exclusion criteria detailed in 
section 4.3.2; this must be confirmed by the central ECG reader before study-
drug can be dispensed to the patient 
• 
CPEX testing will follow ECG recording 
o The Baseline VO2MAX must not exceed ±20% of the Screening VO2MAX with 
the screening test being the reference (i.e., (𝐵𝐵𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴𝐴 𝑉𝑉𝑉𝑉2𝑀𝑀𝑀𝑀𝑀𝑀−
𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑉𝑉𝑉𝑉2𝑀𝑀𝑀𝑀𝑀𝑀)/ 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑉𝑉𝑉𝑉2𝑀𝑀𝑀𝑀𝑀𝑀 ≤±20%); this will be calculated by 
study-site staff in order to allow a decision on patient inclusion in the study 
during the Baseline site-visit 
o All Baseline CPEX test validation reports will be received by study sites from 
the centralized CPEX assessor within a maximum of 48h; the timing of the 
availability of the centralized CPEX assessor report will define the following 
status for the patients: 
 
CPEX Report BEFORE study-drug dosing has started shows VO2MAX 
is not within ±20% of the Screening CPEX; the patient will not enter the 
study 
 
CPEX Report BEFORE study-drug dosing has started shows an invalid 
test;  the patient will be invited to repeat the Baseline CPEX test within 
the 28-day period allowed between Screening and the start of study-
drug dosing 
 
CPEX Report AFTER study-drug dosing has started shows an invalid 
test or shows VO2MAX is not within ±20% of the Screening CPEX; the 
patient will remain in the study and the patient’s Screening CPEX result 
will be taken as the valid Baseline result 
• 
Vital signs and body weight, will be measured; heart rate and blood pressure will be 
measured in the seated position after 5 minutes of rest  
• 
Urine sampling for an on-site urine pregnancy test for female patients of child bearing 
potential 
• 
Study-drug storage, dosing and accountability instructions will be reviewed with the 
patient 
• 
Study-drug sufficient for daily dosing until the next scheduled patient visit to the study 
site will be dispensed to the patient 
o Study-drug will be dispensed once the ECG Corelab confirms that the Baseline 
ECG meets the entry criteria 
o If for any reason the ECG Corelab is not able to immediately confirm the ECG 
outcome, the patient will return home without receiving any dispensed study-
drug. In such cases, once the ECG Corelab confirmation becomes available 
the patient will return to the site to collect the study-drug supply. The patient 
will then commence study-drug dosing (defined as Day 1). 
o All Baseline ECG confirmations will be received by study sites from the ECG 
Corelab within a maximum of 48h. 
• 
If, during the Baseline visit, the ECG Corelab confirms that the Baseline ECG meets 
the entry criteria, the first dose of study-drug will then be administered to the patient 
under the supervision of the study-site staff.  If for any reason the ECG Corelab is not 
able to immediately confirm the ECG outcome, the patient will return home without 
receiving any dispensed study-drug. In such cases, once the ECG Corelab 
confirmation becomes available the patient will return to the site to collect the study-
drug supply. The patient will then commence study-drug dosing.  
o The day study-drug dosing commences will be Day 1 of Week 1 in Period 1 


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• 
AEs since the patient’s previous site visit will be recorded.  (As part of the investigation 
and reporting of all SAEs, every attempt will be made to obtain a blood sample for 
analysis of PEX, CIS and TRANS as soon as possible after awareness of an SAE.) 
• 
Concomitant medication used since the patient’s previous visit will be recorded 
• 
A 6MWT will be done as the last procedure of the Baseline visit 
6.5 PERIOD 1; DAY 8 (± 1 DAY), AFTER COMPLETION OF WEEK 1 (AFTER COMPLETION OF 
AT LEAST SIX DAYS OF DOSING) 
After a minimum of 6 days of study-drug dosing the following will be completed: 
• 
A blood sample will be obtained for analysis of PEX, CIS and TRANS approximately 
12h after dosing on the previous study day 
o CIS:PEX ratio will be evaluated for phenotypic PM status (Section 4.4.2) 
• 
Study-drug storage, dosing and accountability instructions will be reviewed with the 
patient 
• 
Study-drug sufficient for daily dosing until the next scheduled patient visit to the study 
site will be dispensed to the patient 
• 
AEs since the patient’s previous site visit will be recorded.  (As part of the investigation 
and reporting of all SAEs, every attempt will be made to obtain a blood sample for 
analysis of PEX, CIS and TRANS as soon as possible after awareness of an SAE.) 
• 
ADEs will be assessed for and recorded 
• 
Concomitant medication used since the patient’s previous visit will be recorded 
6.6 PERIODS 1 AND 2; AFTER COMPLETION OF WEEK 2 (DAY 15 ±1 DAY) AND WEEKS 4, 
6, 8, 10, 12 & 14 (DAYS 29, 43, 57, 71, 85 & 99 ±3 DAYS) 
At these timepoints the following will be completed: 
• 
Vital signs will be measured; heart rate and blood pressure will be measured in the 
seated position after 5 minutes of rest  
• 
A 12-lead ECG will be recorded in triplicate; ECGs should be taken prior to CPEX 
testing (Week 8 only) or blood draws and obtained after the patient has been resting 
comfortably in a supine position for approximately 10 minutes 
• 
A blood sample will be obtained for analysis of PEX, CIS and TRANS approximately 
12h after dosing on the previous study day (blood sampling after 2 weeks must be 
done within ±1 day of study Day 15, and after the completion of at least 13 days of 
dosing; at all other study visits the blood sample will be obtained within ±3 days of the 
calculated calendar date for the visit). 
o Evaluate CIS:PEX ratio (see Section 4.4.2) 
o Evaluate for dose adjustment (see Section 4.4.3) 
• 
Study-drug storage, dosing and accountability instructions will be reviewed with the 
patient 
• 
Study-drug sufficient for daily dosing until the next scheduled patient visit to the study 
site will be dispensed to the patient 
• 
AEs since the patient’s previous site visit will be recorded.  (As part of the investigation 
and reporting of all SAEs, every attempt will be made to obtain a blood sample for 
analysis of PEX, CIS and TRANS as soon as possible after awareness of an SAE.) 
• 
ADEs will be assessed for and recorded 
• 
Concomitant medication used since the patient’s previous visit will be recorded 


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6.7 PERIOD 1; ADDITIONAL PROCEDURES AT COMPLETION OF WEEK 8 (DAY 57) VISIT 
In addition to the procedures described above in section 6.6, the following procedures will be 
completed during the Period 1, Week 8 (Day 57) study visit: 
• 
CPEX testing will be done following completion of the ECG recordings 
• 
Body weight will be measured 
• 
Blood samples will be obtained for routine serum chemistry safety tests and for 
biomarker levels of hemoglobin A1c 
• 
The 6MWT will be done as the last procedure of the Week 8 visit 
6.8 PERIOD 2: END OF TREATMENT AND AFTER COMPLETION OF WEEK 16 (DAY 113 ±3 
DAYS) 
Dosing should continue through the day prior to this visit.  At this visit the following will be 
completed: 
• 
A 12-lead ECG will be recorded in triplicate; ECGs should be taken prior to CPEX 
testing or blood draws and obtained after the patient has been resting comfortably in 
a supine position for approximately 10 minutes 
• 
CPEX testing will be done following completion of the ECG recordings 
o 
If the centralized CPEX assessor deems the EOT CPEX test to be invalid, the subject 
may be required to return for a repeat test 
• 
Vital signs and body weight, will be measured; heart rate and blood pressure will be 
measured in the seated position after 5 minutes of rest  
• 
A blood sample will be obtained for analysis of PEX, CIS and TRANS approximately 
12h after dosing on the previous study day 
• 
Blood samples will be obtained for a complete blood cell count, routine serum 
chemistry safety tests and for biomarker levels of hemoglobin A1c 
• 
Study-drug accountability will be reviewed with the patient.  All remaining study-drug 
will be collected. 
• 
AEs since the patient’s previous site visit will be recorded.  (As part of the investigation 
and reporting of all SAEs, every attempt will be made to obtain a blood sample for 
analysis of PEX, CIS and TRANS as soon as possible after awareness of an SAE.) 
• 
ADEs will be assessed for and recorded 
• 
Concomitant medication used since the patient’s previous visit will be recorded 
• 
A 6MWT will be done as the last procedure of the week 16 visit 
6.9 FOLLOW-UP VISIT (FOUR WEEKS FOLLOWING THE CONCLUSION OF DOSING) 
At this visit the following will be completed: 
• 
Vital signs and body weight, will be measured; heart rate and blood pressure will be 
measured in the seated position after 5 minutes of rest  
• 
A 12-lead ECG will be recorded in triplicate; ECGs should be taken prior to blood draws 
and obtained after the patient has been resting comfortably in a supine position for 
approximately 10 minutes 
• 
A blood sample will be obtained for analysis of PEX, CIS and TRANS 
• 
Blood samples will be obtained for a complete blood cell count, routine serum 
chemistry safety tests, a pregnancy test and for biomarker levels of hemoglobin A1c 
• 
AEs since the patient’s previous site visit will be recorded.  (As part of the investigation 
and reporting of all SAEs, every attempt will be made to obtain a blood sample for 
analysis of PEX, CIS and TRANS as soon as possible after awareness of an SAE.) 


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• 
ADEs will be assessed for and recorded 
• 
Concomitant medication used since the patient’s previous visit will be recorded 
6.10 PATIENT CONTACT FOR DOSE-ADJUSTMENT INSTRUCTIONS 
When the laboratory result for the levels of PEX and CIS are available the Investigators will 
decide if a dose adjustment is required according to the dose adjustment guidelines presented 
in section 4.4.  Patients who require dose adjustment will be contacted immediately by study-
site personnel who will ensure that the dose-adjustment required is fully understood by the 
patient who will initiate the required dose adjustment at their next scheduled study drug dosing. 
6.11 SUBJECTS WHO WITHDRAW FROM THE STUDY 
If a patient chooses to withdraw from the study during the study-drug dosing phase in Period 
1 and 2, the study-site will attempt to get the following information before the patient is lost to 
follow-up: 
• 
Vital signs  
• 
Blood sample for PEX, CIS and TRANS 
• 
Blood sampling for a full blood cell count, routine safety serum chemistry tests, serum 
pregnancy test and serum levels of hemoglobin A1c 
• 
12-Lead ECG 
• 
CPEX Testing 
• 
6MWT 
• 
Treatment Compliance 
• 
Concomitant Medications 
• 
AEs 
• 
Study-drug accountability 
7 SAFETY MONITORING 
The Study Monitoring Team will review all available data in listings approximately every 2 
months (until the study is completed) following 25% enrollment in the study with an emphasis 
on observed outcomes related to patient safety and tolerance (i.e., AEs, ADEs, vital signs 
measurements, ECGs, laboratory assessments, and concomitant medications). These listing 
will be reviewed by the Study Monitoring Team to determine whether the dosing regimen 
should be altered during the course of the study or whether any other protocol modifications 
should be instituted to ensure the safety of the patients. 
7.1 ADVERSE EVENTS 
 
An AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered 
related to the investigational product. 
7.2 LIFE-THREATENING ADVERSE EVENT OR LIFE-THREATENING SUSPECTED ADVERSE 
REACTION 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 


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7.3 SERIOUS ADVERSE EVENT OR SERIOUS SUSPECTED ADVERSE REACTION  
A Serious Adverse Event (SAE) or serious suspected adverse reaction is considered “serious” 
if, in the view of either the investigator or sponsor the event: 
• 
Results in death 
• 
Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is an important medical event, defined as a medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based on appropriate medical 
and scientific judgment, may jeopardize the subject or may require intervention (e.g., 
medical, surgical) to prevent one of the other serious outcomes listed above. Examples 
of such events include but are not limited to intensive treatment in an emergency 
department or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization. 
All pregnancies, regardless of outcome, should be reported to the Sponsor, including 
pregnancies that occur in the female partner of a male study subject. All pregnancies should 
be followed to outcome.  
Although overdose (PEX >1,200 ng/ml) is not always serious by regulatory definition, this 
event should be reported as an SAE in this study. Suspected overdose associated with lower 
PEX systemic levels should also be reported as an AE or SAE if warranted by the clinical 
history and/or laboratory findings. Alternative explanations, such as a change in medications 
that may alter the patient’s CYP2D6 metabolism, should be considered. 
Cancer, also, is not always serious by regulatory definition; this event (excluding basal-cell or 
squamous-cell carcinomas of the skin) should be reported to the Sponsor at the earliest 
possible moment. 
NOTE: The following hospitalizations are not considered SAEs in the Sponsor’s clinical 
studies: 
• 
A visit to the emergency room or other hospital department lasting less than 24 hours 
that does not result in admission (unless considered an “important medical event” or a 
life threatening event) 
• 
Elective surgery planned before signing consent 
• 
Admissions as per protocol for a planned medical/surgical procedure 
• 
Routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 
• 
Medical/surgical admission for purpose other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these cases. 
• 
Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative). 


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7.4 SUSPECTED ADVERSE REACTION 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of IND safety reporting, “reasonable possibility” means 
there is evidence to suggest a causal relationship between the drug and the AE. Suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any AE caused by a drug. 
7.5 UNEXPECTED ADVERSE EVENT OR UNEXPECTED SUSPECTED ADVERSE REACTION. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if 
an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as 
amended. For example, under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the investigator brochure referred only to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected 
(by virtue of greater specificity) if the investigator brochure listed only cerebral vascular 
accidents. “Unexpected,” as used in this definition, also refers to AEs or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
7.6 ASSIGNMENT OF ADVERSE EVENT INTENSITY AND RELATIONSHIP TO PERHEXILINE 
All AEs, including those that are serious, will be graded by the investigator as follows [NCI 
Guidelines, 2013]: 
• 
Mild (Grade 1): asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• 
Moderate (Grade 2); minimal, local, or non-invasive intervention (e.g., packing, 
cautery) indicated; limiting age-appropriate instrumental activities of daily living. 
• 
Severe (Grade 3): medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL. 
The following categories and definitions of causal relationship to investigational product as 
determined by a physician should be used [NCI Guidelines, 2013]: 
• 
Unrelated: The AE is clearly not related to the intervention 
• 
Possibly related: The AE may be related to the intervention 
• 
Probably Related: The AE is likely related to the intervention. 
• 
Definitely Related: The AE is clearly related to the intervention. 
7.7 COLLECTION AND REPORTING OF ADVERSE EVENTS 
AEs can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a subject. To prevent reporting bias, subjects should not be questioned 
regarding the specific occurrence of one or more AEs. 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: 
• 
Onset, 


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• 
Duration, 
• 
Intensity, 
• 
Seriousness, 
• 
Relationship to investigational product, 
• 
Action taken, 
• 
Treatment, if required. 
If treatment for the event was administered, it should be recorded in the medical record. The 
investigator must supply the Sponsor and the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) with any additional information requested, notably for reported deaths 
of subjects. 
Completion of supplemental case report forms (CRFs) may be requested for AEs and/or 
laboratory abnormalities that are reported/identified during the course of the study. 
7.7.1 Reporting Serious Adverse Events or Serious Suspected Adverse Reaction 
Following the subject’s written consent to participate in the study, all SAEs must be collected, 
including those thought to be associated with protocol-specified procedures. Collection of all 
SAEs should continue for 30 days after the last administration of PEX. If applicable, SAEs 
must be collected that relate to any later protocol-specified procedure. The investigator should 
notify the Sponsor of any SAE occurring after this time period that is believed to be related to 
the investigational product or protocol specified procedure. 
If the investigator believes that an SAE is not related to the investigational product but is 
potentially related to the conditions of the study (such as withdrawal of previous therapy, or a 
complication of a study procedure), the potential relationship should be specified in the 
narrative section of the SAE report. 
As part of the investigation and reporting of all SAEs, every attempt will be made to obtain a 
blood sample for analysis of PEX, CIS and TRANS as soon as possible after awareness of 
the event. 
7.7.2 Handling of Expedited Safety Reports 
 
In accordance with local regulations, the Sponsor will notify investigators and appropriate 
regulatory authorities of all unexpected SAEs having a “reasonable possibility” that the drug 
caused the event (i.e. there is evidence to suggest a causal relationship between the drug and 
the AE) /serious unexpected suspected adverse reactions (SUSARs). 
Other important findings that the Sponsor may report as Expedited Safety Reports (ESR) 
include increased frequency of a clinically significant expected SAE, an SAE considered 
associated with study procedures that could modify the conduct of the study, lack of efficacy 
that poses significant hazard to study subjects, clinically significant safety findings from a 
nonclinical (e.g., animal) study, important safety recommendations from a study data 
monitoring committee, or the decision by the Sponsor to end or temporarily halt a clinical study 
for safety reasons. 
Upon receiving an ESR from the Sponsor, the investigator must review and retain the ESR 
with the Investigator Brochure. Where required by local regulations or when there is a central 
IRB/IEC for the study, the Sponsor will submit the ESR to the appropriate IRB/IEC. The 
investigator and IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting any other safety 
information. 


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In addition, the Sponsor will report suspected serious adverse reactions (whether expected or 
unexpected) to the relevant health authorities in all concerned countries according to local 
regulations (either as expedited and/or in aggregate reports). 
7.7.3 Non-serious Adverse Events 
 
Following the subject’s written consent to participate in the study, the investigator will begin 
collecting non-serious AE (NSAE) information. All identified NSAEs must be recorded and 
described on the AE case report form. If an ongoing NSAE worsens in its intensity, or if its 
relationship to the investigational product changes, a new NSAE entry for the event should be 
completed. NSAEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious. Follow up is also required for drug-related NSAEs that cause interruption 
or discontinuation of investigational product, or those that are present at the end of study 
participation. Subjects with drug-related NSAEs at study completion should receive post-
treatment follow up as appropriate. 
7.8 LABORATORY TEST ABNORMALITIES 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. When reporting a test result that constitutes an AE, the clinical term 
should be used; for example, the event should be reported as “anemia” not “low hemoglobin.” 
Test results that constitute SAEs should be documented and reported as such. 
7.9 ADVERSE DEVICE EFFECTS 
If an AE or SAE is determined to have been the result of a PEX-CIS assay abnormality (e.g., 
false positive, false negative, measurement error), it will be deemed an ADE or a Serious ADE 
(SADE) for the purpose of device reporting and statistical analysis. 
7.9.1 Definitions 
Adverse device effect (ADE):  AE related to the use of an investigational medical device (PEX-
CIS assay in the study). 
Serious adverse device effect (SADE):  ADE that has resulted in any of the consequences 
characteristic of a serious AE. 
7.9.2 Reporting of ADEs 
When assessing, recording, and reporting ADEs or SADEs, the same intensity grading system 
(Section 7.6) and reporting period (Sections 7.7.1 and 7.7.3) will be used for collecting and 
reporting of AEs. 
ADEs will be reported on a separate ADE report form.  
7.9.3 Unanticipated Adverse Device Effect (UADE) 
An ADE or SADE is considered “unanticipated” if it was not previously identified in nature, 
severity, or degree of incidence in the investigational plan or application, or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of subjects. 
The sponsor will immediately conduct an evaluation of any UADE. 
7.10 PEX OVERDOSE 
 
A PEX overdose is defined as the accidental or intentional ingestion or infusion of any dose of 
a product that results in a systemic level of PEX >1,200 ng/mL. All occurrences of overdose 
with a systemic PEX level > 1,200 ng/mL must be reported as an SAE.  Suspected overdose 
associated with lower PEX systemic levels should also be reported as an AE or SAE if 
warranted by the clinical history and/or laboratory findings. Alternative explanations, such as 


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a change in medications that may alter the patient’s CYP2D6 metabolism, should be 
considered. 
7.11 PREGNANCY 
 
Before study enrollment, women of child-bearing potential should be adequately advised on 
the potential risks versus benefits of PEX by the Investigator, including the potential risks to a 
human fetus. 
7.11.1 Pregnancy Testing 
Pregnancy testing will be performed as outlined in Section 6.  If the pregnancy of a female 
study participant is discovered during the treatment period, the study medication should be 
discontinued. 
7.11.2 Reporting of Pregnancy 
If, while taking PEX, it is discovered that a study subject is pregnant or may have been 
pregnant at the time of investigational product exposure, including during at least 6 half-lives 
after administration, the investigator will notify the Sponsor of this event and record the 
pregnancy on the Pregnancy Surveillance Form (not on an SAE form). Initial information on a 
pregnancy must be reported to the Sponsor, and information on the outcome provided once it 
is available. Completed Pregnancy Surveillance Forms must be forwarded to the Sponsor 
according to SAE reporting procedures.  
Note: Any pregnancy that occurs in a female partner of a male study subject must also be 
reported to the Sponsor using the Pregnancy Surveillance Form. 
Protocol-required procedures for study discontinuation and follow up must be performed for 
the subject unless contraindicated. Other appropriate pregnancy follow up procedures should 
be considered if indicated. Information regarding the course of the pregnancy, including 
perinatal and neonatal outcome, must be reported to the Sponsor on the Pregnancy 
Surveillance Form. Infants should be followed for a minimum of 8 weeks.  
7.12 OTHER SAFETY CONSIDERATIONS 
Any significant worsening noted in electrocardiograms, x-rays, and any other potential safety 
or physical assessments, whether or not these procedures are required by the protocol, should 
also be recorded in the medical record. 
8 STATISTICAL CONSIDERATIONS 
8.1 PRIMARY AND SECONDARY ENDPOINTS 
8.1.1 Primary Endpoint 
The primary endpoint of the study is the change from baseline of VO2MAX at the end of Period 
2 of the study. 
8.1.2 Secondary Endpoints 
The secondary endpoints of the study are: 
• 
The change from baseline of VO2MAX at the end of study-drug dosing Period 1 
compared to the change from baseline at the end of study-drug dosing Period 2. 
• 
An evaluation of the change in VO2MAX at the end of study-drug dosing Period 1 
compared to baseline will be performed. 
• 
The change from baseline of the QTcF interval at the end of study-drug dosing Period 
1 compared to the change from baseline at the end of study-drug dosing Period 2 


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• 
The change from baseline at the end of study-drug dosing Period 2 in the Six-Minute 
Walk Test (6MWT) and change from baseline at the end of study-drug dosing Period 
1 compared to the change from baseline at the end of study-drug dosing Period 2 
• 
Safety data (AEs, ECG abnormalities, routine laboratory safety test of blood, vital 
signs, and concomitant medication and patient withdrawals) during study-drug dosing 
Period 1 compared to study-drug dosing Period 2 
8.1.3 Exploratory Endpoints 
Exploratory endpoints are: 
• 
Change from baseline of other ECG variables at the end of study-drug dosing Period 
1 compared to the change from baseline at the end of study-drug dosing Period 2 
• 
Change from baseline of HbA1c at the end of study-drug dosing Period 1 compared to 
the change from baseline at the end of study-drug dosing Period 2 
8.2 SAMPLE SIZE DETERMINATION 
A two-sided, one-sample t-test of the change from baseline for the end of Period 2 is planned 
with the following assumptions: 
• 
Mean change from baseline for Period 1 is 1.2mL O2/kg/min  
• 
Mean change from baseline for Period 2 is 2.0mL O2/kg/min 
• 
Standard deviation of change from baseline is 2.5mL O2/kg/min for both periods 
• 
Significance level (alpha) of 0.05 
With these assumptions, a power of > 95% is anticipated for the primary outcome, and 72% 
for the first secondary outcome is expected for a sample size of 30 patients. 
8.3 PATIENT POPULATION FOR ANALYSIS 
The population for analysis for the primary, secondary and exploratory endpoints will be the 
Completer Population which will include all patients who complete all study procedures at 
Baseline, end of Period 1 and end of Period 2. 
The population for safety analysis will be the Safety Population which will include all patients 
who start study-drug dosing following their baseline visit to the study site. The efficacy analysis 
will be repeated on the safety population 
8.4 ANALYSES 
8.4.1 Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be presented as data listings and summary 
statistics. 
8.4.2 Safety Analyses 
8.4.2.1 Adverse Events 
The original terms recorded on the subject’s CRF by the Investigator for AEs will be 
standardized by assigning preferred terms from the Medical Dictionary for Regulatory 
Activities (MedDRA). The Investigator, however, should ensure that the original terms 
recorded accurately reflect their intended description. All AEs will be described by individual 
subject listings and summarized in frequency tables broken down by body system, preferred 
term and dose group. 
8.4.2.2 Vital Signs 
Vital signs data will be presented in individual listings. In addition, tabular summaries will be 
used, as appropriate. 


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8.4.2.3 Clinical Laboratory Test Results 
All clinical laboratory data will be presented as patient listings and summary statistics at each 
assessment time. Values outside the reference ranges will be flagged.  As appropriate, 
summaries may also include change from Baseline and shift tables. 
8.4.2.4 Concomitant Medications 
The original terms recorded on the patient’s eCRF for concomitant medications will be 
standardized by using the World Health Organization Drug (WHO Drug) coding dictionary.  
Concomitant medications will be listed by patient. 
8.4.3 Efficacy Analyses 
All CPEX tests will be assessed by the centralized CPEX assessor for compliance with 
prospectively defined CPEX test-protocol criteria. 
A two-sided, one-sample t-test is planned for the comparison of VO2MAX at the end of Period 
2 compared to baseline. The secondary and exploratory efficacy endpoints of the study will 
be examined by appropriate statistical methods as described in the statistical analysis plan. 
8.4.4 Pharmacokinetic Analyses 
Pharmacokinetic data (PEX, CIS and TRANS) will be listed by patient, and summarized for 
each sampling timepoint. 
8.4.5 Pharmacogenetic Analyses 
Pharmacogenetic data (CYP2D6 genotyping at screening) will be listed by patient, and 
incidences of polymorphisms will be summarized. 
8.4.6 Pharmacodynamic Analyses 
Hemoglobin A1c data will be presented as patient listings and summary statistics at each 
assessment time. Values outside the reference ranges will be flagged.  As appropriate, 
summaries may also include change from Baseline and shift tables. 
8.4.7 Ongoing Data Review and Analyses 
8.4.7.1 Study Monitoring Team 
All available data will be presented in listings approximately every 2 months (until the study is 
completed) following 25% enrollment in the study with an emphasis on observed outcomes 
related to patient safety and tolerance (i.e., AEs, ADEs, vital signs measurements, ECGs, 
laboratory assessments, and concomitant medications). These listings will be reviewed by the 
Study Monitoring Team to determine whether the dosing regimen should be altered during the 
course of the study or whether any other protocol modifications or actions should be instituted 
to ensure the safety of the patients. 
8.4.7.2 CPEX Analysis Following Completion of Period 1 
A snapshot of the database will be taken for the CPEX data (listings and summary statistics) 
when all patients have completed Week 8. A two-sided, one-sample t-test will be performed 
for the comparison of VO2MAX at the end of Period 1 compared to baseline.  
8.5 REPLACEMENT POLICY 
Patients who withdraw from the study or are discontinued for any reason will not be replaced. 
9 ETHICAL AND REGULATORY CONSIDERATIONS 
9.1 GOOD CLINICAL PRACTICE  
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by 
the International Conference on Harmonization (ICH) and in accordance with the ethical 


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principles underlying European Union Directive 2001/20/EC and the United States Code of 
Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any amendments, 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion before initiation of the study. The protocol, 
amendments, and ICF will also be submitted to regulatory authorities prior to commencing the 
trial as required. 
All potential serious breaches must be reported to the Sponsor immediately. A serious breach 
is a breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. This study will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct 
or fraud (e.g., loss of medical licensure; debarment). Systems with procedures that ensure the 
quality of every aspect of the study will be implemented. 
9.2 INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE 
Before study initiation, the investigator will have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials/process (e.g., 
advertisements), and any other written information to be provided to subjects. The investigator 
will also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling, 
information to be provided to subjects, and any updates. The investigator will provide the 
IRB/IEC with reports, updates, and other information (e.g., expedited safety reports, 
amendments, and administrative letters) according to regulatory requirements or institution 
procedures. 
9.3 INFORMED CONSENT 
Investigators must ensure that subjects (or, in those situations where consent cannot be given 
by subjects, the legally acceptable representative) are clearly and fully informed about the 
purpose, potential risks, and other critical issues regarding clinical studies in which they 
volunteer to participate. Freely given written informed consent must be obtained from every 
subject (or, in those situations where consent cannot be given by subjects, the legally 
acceptable representative) before clinical study participation, including informed consent for 
any screening procedures conducted to establish subject eligibility for the study. 
Subjects unable to give their written consent may be enrolled in the study only with the consent 
of a legally acceptable representative. The subject must also be informed about the nature of 
the study to the extent compatible with the subjects’ understanding, and should they become 
capable, they must personally sign and date the consent form as soon as possible. The explicit 
wish of a subject unable to give his or her written consent, who is capable of forming an opinion 
and assessing this information to refuse participation in, or to be withdrawn from, the clinical 
study at any time, should be considered by the investigator. 
10 ADMINISTRATIVE CONSIDERATIONS 
10.1 COMPLIANCE WITH THE PROTOCOL 
The study must be conducted as described in the final IRB/IEC-approved protocol. 
Documentation of approval, signed by the IRB/IEC chairperson or designee, will be sent to 
the Sponsor. 


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10.2 PROTOCOL MODIFICATIONS 
Protocol modifications to ongoing studies must be made only after consultation between an 
appropriate representative of the Sponsor and the coordinating investigator. Protocol 
modifications must be prepared, reviewed and approved by the Sponsor and by the relevant 
IRBs/IECs. 
All protocol amendments and revisions to the informed consent will be submitted to the 
Sponsor and to the IRB/IEC. No protocol amendments will be implemented until written 
approval has been given by the IRB/IEC, except when necessary to eliminate an immediate 
hazard to study subjects. Administrative letters should also be sent to the Sponsor and 
IRB/IEC; however, they do not require approval. The protocol, amendments, and ICF will also 
be submitted to regulatory authorities prior to commencing the trial as required. 
If a protocol amendment mandates a revision to the informed consent, the revised consent 
must be used to obtain consent from subjects currently enrolled in the study if it affects them 
(e.g., if it contains new information regarding safety), and the revised consent must be used 
to obtain consent from new subjects before enrollment. 
10.3 PROTOCOL TERMINATION 
Both the Sponsor and the investigator reserve the right to terminate the study at any time. 
Should this be necessary, both parties will arrange the procedures on an individual study basis 
after review and consultation. In terminating the study, the Sponsor and the investigator will 
assure that adequate consideration is given to the protection of the patient’s interests. 
10.4 AUDITS, MONITORING AND INSPECTIONS 
This study will be monitored by the Sponsor regularly to verify informed consent, source 
documentation, etc., are collected and stored according to the regulations and the data is 
entered into the electronic case report forms accurately. 
10.5 RECORDS RETENTION AND DATA PROTECTION 
The investigator will retain, in a confidential manner, all data pertinent to the study for all 
treated subjects as well as those entered as control subjects, if applicable. The investigator 
will retain source documents and accurate case histories that record all observations and other 
data pertinent to the investigation (e.g., the medical record) for the maximum period required 
by applicable regulations and guidelines or following institutional procedures. If the 
investigator withdraws from the study (e.g., relocation or retirement), the records will be 
transferred to a mutually agreed upon designee, such as another investigator or an IRB. 
Written documentation of such transfer will be provided to the Sponsor. 
The patient's personal data and Investigator's personal data which may be included in the 
Sponsor database shall be treated in compliance with all applicable laws and regulations. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
10.6 PUBLICATION OF DATA 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor prior 
to submission. This allows the sponsor to protect proprietary information and to provide 
comments based on information from other studies that may not yet be available to the 
investigator. 
In accord with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter trials only in their entirety and not as individual center data. In this 
case, a coordinating investigator will be designated by mutual agreement. 


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Any formal publication of the study in which input of the Sponsor personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor’s personnel. Authorship will be determined by mutual agreement. 
 
 


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3. Ashrafian H, McKenna WJ, Watkins H. Disease pathways and novel therapeutic 
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7. Crews, KR, Gaedigk A, Dunnenberger HM, Leeder JS, Klein TE, Caudle KE, Haidar 
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8. Drury NE, Howell NJ, Weber RJM, Calvert MJ, Lewis ME, Viant MR, Freemantle N, 
Frenneaux MP, Pagano D. Effect of perhexiline on myocardial protection during 
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Lancet. 2013;381:S36. 
9. Drury NE, Licari G, Chong C-R,Howell NJ, Frenneaux MP, Horowitz JD, Pagano D, 
Sallustio BC. Relationship between plasma, atrial and ventricular perhexiline 
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Davenport JM, Lu HR, Rohrbacher J, Hillsamer V. Role of mixed ion channel effects 
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11. Force T, Bonow RO, Houser SR, Solaro RJ, Hershberger RE, Adhikari B, Anderson 
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JD, Ommen SR, Regnier M, Tang WH, Tian R, Konstam MA, Maron BJ, Seidman CE. 
Research priorities in hypertrophic cardiomyopathy: report of a Working Group of the 
National Heart, Lung, and Blood Institute. Circulation. 2010;122(11):1130-3. 
12. Gersh BJ, Maron BJ, Bonow RO, Dearani JA, Fifer MA, et al. 2011 ACCF/AHA 
Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy. A Report 
of the American College of Cardiology Foundation/American Heart Association Task 
Force on Practice Guidelines Developed in Collaboration With the American 
Association for Thoracic Surgery, American Society of Echocardiography, American 
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Society, Society for Cardiovascular Angiography and Interventions, and Society of 
Thoracic Surgeons. J Am Coll Cardiol. 2011;58:(25):212-260. 
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cyclohexylaralkylamines related to perhexiline on sodium binding, influx of 
[3H]batrachotoxinin A 20-α-benzoate and [3H] nitrendipine on guinea pig left atria 
contractions. Euro J Pharmacol. 1988;147:173-185. 
14. Horowitz JD, Chirkov YY. Perhexiline and hypertrophic cardiomyopathy: a new horizon 
for metabolic modulation. Circulation. 2010;122(16):1547-9. 
15. Hülsman R, Berger R, Storm B, Bojic A, Woloszczuk W, Bergler-Klein, Pacher R. 
Prediction of outcome by neurohumoral activation, the six minute walk test and the 
Minnesota Living with Heart Failure Questionnaire in an outpatient cohort with 
congestive heart failure. Eur Heart J. 2002;23:886-91. 
16. Hussein, R, Charles BG, Morris, RG, Rasiah, RL. Population pharmacokinetics of 
perhexiline from very sparse, routine monitoring data. Therapeutic Drug Monitoring. 
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17. Krikler DM, Davies MJ, Rowland E, Goodwin JF, Evans RC, Shaw DB. Sudden death 
in hypertrophic cardiomyopathy: associated accessory atrioventricular pathways. Br 
Heart J. 1980;43(3):245-51. 
18. McKenna WJ, Camm AJ. Sudden death in hypertrophic cardiomyopathy. Assessment 
of patients at high risk. Circulation. 1989;80(5):1489-92. 
19. Mould D. Population Pharmacokinetic Analysis of Heart Metabolics Perhexiline, 
Protocol HM-PHX-004. Projections research Inc. 2016; Study Report for Heart 
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20. Morimoto S. Sarcomeric proteins and inherited cardiomyopathies. Cardiovasc Res. 
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21. National Cancer Institute Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs (Effective 
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http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm 
22. Pexsig Product Information. Aspen Pharma Pty Ltd. 2000. 
23. Phan TT, Abozguia K, Shivu GN, Mahadevan G, Ahmed I, Williams L, Dwivedi G, Patel 
K, Steendijk P, Ashrafian H, Henning A, Frenneaux, M. Heart failure with preserved 
ejection fraction is characterized by dynamic impairment of active relaxation and 
contraction of the left ventricle on exercise and associated with myocardial energy 
deficiency. Journal of the American College of Cardiology. 2009a;54(5):402-9. 
24. Phan TT, Shivu GN, Choudhury A, Abozguia K, Davies C, Naidoo U, Ahmed I, Yousef 
Z, Horowitz J, Frenneaux M. Multi-centre experience on the use of perhexiline in 
chronic heart failure and refractory angina: old drug, new hope. Eur J Heart Fail. 
2009b;11:881-6. 
25. Rampe D, Wang Z, Fermini B, Wible B, Dage RC, Nattel S. Voltage- and Time-
Dependent Block by Perhexiline of K+ Currents in Human Atrium and in Cells 
Expressing a Kv1.5-Type Cloned Channel.  J Pharmacol Exp Ther. 1995;274:444-449. 
26. Sager PT, Gintant G, Turner JR, et al. Rechanneling the cardiac proarrhythmia safety 
paradigm: a meeting report from the Cardiac Safety Research Consortium. Am Heart 
J 2014;167:292-300. 
27. Shantsila E, Watson T, Lip GYH. Drug-induced QT-interval prolongation and 
proarrhythmic risk in the treatment of atrial arrhythmias. Eur Soc Cardiol. 2007;Suppl 
4:iv37-44. 
28. Walker BD, Valenzuela SM, Singleton CB, Tie H, Bursill JA, Wyse KR, Qiu MR, Breit 
SN, Campbell TJ. Inhibition of HERG channels stably expressed in a mammalian cell 
line by the antianginal agent perhexiline maleate. Brit J Pharmacol. 1999;127:243-251. 


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29. Woosley, RL and Romero, KA,  www.crediblemeds.org,  QT Drugs List, Accession 
Date October 1, 2016, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ  85755. 
 
 


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12 ABBREVIATIONS 
Abbreviation 
Definition 
6MWT 
Six minute walk test 
ADE 
Adverse device effect 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CAD 
Coronary Artery Disease 
CIS 
cis-Hydroxy-Perhexiline 
CMR 
Cardiovascular Magnetic Resonance 
CPEX 
Cardiopulmonary Exercise 
CPIC 
Clinical Pharmacogenetics Implementation Consortium 
CPK 
Creatine Phosphokinase 
CPT 
Carnitine palmitoyltransferase 
CRO 
Contract Research Organization 
CYP2D6 
Cytochrome P450 2D6 
CRF 
Case Report Form(s) 
ECG 
Electrocardiogram or electrocardiographic 
EM 
Extensive Metabolizer 
ESR 
Expedited safety report 
GCP 
Good clinical practice 
GLP 
Good laboratory practice 
HbA1c 
Hemoglobin A1c or glycosylated hemoglobin 
HCM 
Hypertrophic Cardiomyopathy 
ICD 
Implantable cardiac defibrillator 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IM 
Intermediate metabolizer 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
LDH 
Lactate dehydrogenase 
LGE 
Late Gadolinium Enhancement 
LV 
Left ventricular 
LVH 
Left ventricular hypertrophy 
LVOT 
Left ventricular outflow tract 
MedDRA 
Medical Dictionary for Regulatory Activities 
MICE 
Multiple Ion Channel Effect 
MPI 
Myocardial Perfusion Imaging 
NHLBI 
National Heart, Lung, and Blood Institute 
NSAE 
Non-serious adverse event 


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Abbreviation 
Definition 
PET 
Positron Emission Tomography 
PEX 
Perhexiline 
PHM 
Perhexiline Maleate, when referring to the pharmaceutical formulation 
PK 
Pharmacokinetic 
PM 
Poor metabolizer 
QTc 
Corrected QT interval 
QTcF 
QT corrected according to Fridericia’s formula 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SCD 
Sudden Cardiac Death 
SPECT 
Single Photon Emission Computed Tomography 
SUSAR 
Suspected unexpected serious adverse reaction 
TdP 
Torsade de Pointes 
TEE 
Trans-Esophageal Echocardiogram 
TQT 
Thorough QT 
TRANS 
trans-Hydroxy-Perhexiline 
TTE 
Trans-Thoracic Echocardiogram 
UADE 
Unanticipated Adverse Device Effect 
ULN 
Upper limit of normal 
UM 
Ultra-rapid metabolizer 
VO2MAX 
Maximal oxygen consumption 
VT 
Ventricular Tachycardia 
 
 
 


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APPENDIX A: 
CONCOMITANT MEDICATION 
The following agents (and drug classes) may have interactions with the effects or metabolism 
of PEX and should be used with caution: 
• 
Insulin and antidiabetic agents 
• 
Adriamycin 
• 
Anticoagulants, e.g. warfarin and phenindione 
• 
Cytochrome P450 2D6 inhibitors or substrates, such as  
o Β-Blockers (metoprolol, timolol, alprenolol, carvedilol, bufuralol, nebivolol, 
propranolol 
o Selective serotonin (5HT) uptake inhibitors, e.g. fluoxetine* and paroxetine* 
o Tricyclic and tetracyclic antidepressants, e.g. clomipramine hydrochloride and 
mirtazapine 
o Antiviral agents, e.g. ritonavir* and delavirdine 
o Antimalarials, e.g. proguanil and lumefantrine 
o Antinauseants, antiemetics, e.g. dolasetron and metoclopramide 
o Narcotic analgesics: e.g. codeine, morphine, oxycodone, pethidine and 
tramadol 
o Neuroleptics: e.g. risperidone 
o Cytotoxic drugs: e.g. tamoxifen, vinblastine, vincristine, vinorelbine, gefitinib 
and imatinib 
o Chlorpheniramine, dextromethorphan, ethosuximide, galantamine, tolterodine, 
celecoxib, cimetidine, terbinafine, bupropion* and moclobemide (RIMA). 
 
*  Bupropion, fluoxetine, paroxetine, and ritonavir known to be strong inhibitors of 
CYP2D6.  Any patient who regularly takes one of these medications cannot be enrolled 
in this study per the protocol-defined inclusion and exclusion criteria.  Any subject who 
is being considered for initiation of therapy with one of these medications during the 
study should be discussed with the medical monitor prior to initiating the medication. 
 
 
 


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APPENDIX B: 
ACC/AHA HCM DIAGNOSTIC CRITERIA 
GENETIC TESTING STRATEGIES/FAMILY SCREENING — RECOMMENDATIONS 
CLASS I 
1. Evaluation of familial inheritance and genetic counselling is recommended as part of 
the assessment of patients with HCM 
2. Patients who undergo genetic testing should also undergo counseling by someone 
knowledgeable in the genetics of cardiovascular disease so that results and their 
clinical significance can be appropriately reviewed with the patient 
3. Screening (clinical, with or without genetic testing) is recommended in first-degree 
relatives of patients with HCM 
4. Genetic testing for HCM and other genetic causes of unexplained cardiac hypertrophy 
is recommended in patients with an atypical clinical presentation of HCM or when 
another genetic condition is suspected to be the cause 
CLASS IIa 
1. Genetic testing is reasonable in the index patient to facilitate the identification of first-
degree family members at risk for developing HCM 
CLASS IIb 
1. The usefulness of genetic testing in the assessment of risk of Sudden Cardiac Death 
(SCD) in HCM is uncertain  
CLASS III: NO BENEFIT 
1. Genetic testing is not indicated in relatives when the index patient does not have a 
definitive pathogenic mutation 
2. Ongoing clinical screening is not indicated in genotype negative relatives in families 
with HCM 
GENOTYPE-POSITIVE/PHENOTYPE-NEGATIVE PATIENTS — RECOMMENDATION 
CLASS I 
1. In individuals with pathogenic mutations who do not express the HCM phenotype, it is 
recommended to perform serial ECG, Transthoracic Echocardiogram (TTE), and 
clinical assessment at periodic intervals (12 to 18 months in children and adolescents 
and about every 5 years in adults), based on the patient’s age and change in clinical 
status 
ELECTROCARDIOGRAPHY — RECOMMENDATIONS 
CLASS I 
1. A 12-lead ECG is recommended in the initial evaluation of patients with HCM 
2. Twenty-four–hour 
ambulatory 
(Holter) 
electrocardiographic 
monitoring 
is 
recommended in the initial evaluation of patients with HCM to detect ventricular 
tachycardia (VT) and identify patients who may be candidates for ICD therapy 
3. Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring or event 
recording is recommended in patients with HCM who develop palpitations or light-
headedness 
4. A repeat ECG is recommended for patients with HCM when there is worsening of 
symptoms. 


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5. A 12-lead ECG is recommended every 12 to 18 months as a component of the 
screening algorithm for adolescent first degree relatives of patients with HCM who 
have no evidence of hypertrophy on echocardiography 
6. A 12-lead ECG is recommended as a component of the screening algorithm for first-
degree relatives of patients with HCM 
CLASS IIa 
1. Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring, repeated every 
1 to 2 years, is reasonable in patients with HCM who have no previous evidence of VT 
to identify patients who may be candidates for ICD therapy 
2. Annual 12-lead ECGs are reasonable in patients with known HCM who are clinically 
stable to evaluate for asymptomatic changes in conduction or rhythm (i.e., AF). 
CLASS IIb 
1. Twenty-four–hour ambulatory (Holter) electrocardiographic monitoring might be 
considered in adults with HCM to assess for asymptomatic paroxysmal atrial 
fibrillation/atrial flutter.  
IMAGING 
Echocardiography — Recommendations 
CLASS I 
1. A TTE is recommended in the initial evaluation of all patients with suspected HCM 
2. A TTE is recommended as a component of the screening algorithm for family members 
of patients with HCM unless the family member is genotype negative in a family with 
known definitive mutations 
3. Periodic (12 to 18 months) TTE screening is recommended for children of patients with 
HCM, starting by age 12 years or earlier if a growth spurt or signs of puberty are evident 
and/or when there are plans for engaging in intense competitive sports or there is a 
family history of SCD 
4. Repeat TTE is recommended for the evaluation of patients with HCM with a change in 
clinical status or new cardiovascular event 
5. A trans-esophageal echocardiogram (TEE) is recommended for the intraoperative 
guidance of surgical myectomy 
6. TTE or TEE with intracoronary contrast injection of the candidate’s septal perforator(s) 
is recommended for the intra-procedural guidance of alcohol septal ablation 
7. TTE should be used to evaluate the effects of surgical myectomy or alcohol septal 
ablation for obstructive HCM 
CLASS IIa 
1. TTE studies performed every 1 to 2 years can be useful in the serial evaluation of 
symptomatically stable patients with HCM to assess the degree of myocardial 
hypertrophy, dynamic obstruction, and myocardial function 
2. Exercise TTE can be useful in the detection and quantification of dynamic LVOT 
obstruction in the absence of resting outflow tract obstruction in patients with HCM 
3. TEE can be useful if TTE is inconclusive for clinical decision making about medical 
therapy and in situations such as planning for myectomy, exclusion of subaortic 
membrane or mitral regurgitation secondary to structural abnormalities of the mitral 
valve apparatus, or in assessment for the feasibility of alcohol septal ablation 
4. TTE combined with the injection of an intravenous contrast agent is reasonable if the 
diagnosis of apical HCM or apical infarction or severity of hypertrophy is in doubt, 


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particularly when other imaging modalities such as Cardiovascular Magnetic 
Resonance (CMR) are not readily available, not diagnostic, or are contraindicated 
5. Serial TTE studies are reasonable for clinically unaffected patients who have a first-
degree relative with HCM when genetic status is unknown. Such follow-up may be 
considered every 12 to 18 months for children or adolescents from high-risk families 
and every 5 years for adult family members 
CLASS III: NO BENEFIT 
1. TTE studies should not be performed more frequently than every 12 months in patients 
with HCM when it is unlikely that any changes have occurred that would have an impact 
on clinical decision making 
2. Routine TEE and/or contrast echocardiography is not recommended when TTE 
images are diagnostic of HCM and/or there is no suspicion of fixed obstruction or 
intrinsic mitral valve pathology 
 
STRESS TESTING — RECOMMENDATIONS 
CLASS IIa 
1. Treadmill exercise testing is reasonable to determine functional capacity and response 
to therapy in patients with HCM 
2. Treadmill testing with monitoring of an ECG and blood pressure is reasonable for SCD 
risk stratification in patients with HCM 
3. In patients with HCM who do not have a resting peak instantaneous gradient of greater 
than or equal to 50 mm Hg, exercise echocardiography is reasonable for the detection 
and quantification of exercise-induced dynamic LVOT obstruction 
 
CARDIAC MAGNETIC RESONANCE — RECOMMENDATIONS 
CLASS I 
1. CMR Imaging is indicated in patients with suspected HCM when echocardiography is 
inconclusive for diagnosis 
2. CMR Imaging is indicated in patients with known HCM when additional information that 
may have an impact on management or decision making regarding invasive 
management, such as magnitude and distribution of hypertrophy or anatomy of the 
mitral valve apparatus or papillary muscles, is not adequately defined with 
echocardiography 
CLASS IIa 
1. CMR Imaging is reasonable in patients with HCM to define apical hypertrophy and/or 
aneurysm if echocardiography is inconclusive 
CLASS IIb 
1. In selected patients with known HCM, when SCD risk stratification is inconclusive after 
documentation of the conventional risk factors, CMR imaging with assessment of late 
gadolinium enhancement (LGE) may be considered in resolving clinical decision 
making 
2. CMR Imaging may be considered in patients with LV hypertrophy and the suspicion of 
alternative diagnoses to HCM, including cardiac amyloidosis, Fabry disease, and 
genetic phenocopies such as LAMP2 cardiomyopathy 
 


Protocol No.  HML-PHX-005 
Version 11.0 
 
02 DEC 2016 
Heart Metabolics — Company Confidential 
 
Page 57 of 58 
DETECTION OF CONCOMITANT CORONARY DISEASE — RECOMMENDATIONS 
CLASS I 
1. Coronary arteriography (invasive or computed tomographic imaging) is indicated in 
patients with HCM with chest discomfort who have an intermediate to high likelihood 
of Coronary Artery Disease (CAD) when the identification of concomitant CAD will 
change management strategies 
CLASS IIa 
1. Assessment of coronary anatomy with computed tomographic angiography is 
reasonable for patients with HCM with chest discomfort and a low likelihood of CAD to 
assess for possible concomitant CAD 
2. Assessment of ischemia or perfusion abnormalities suggestive of CAD with single 
photon emission computed tomography (SPECT) or positron emission tomography 
(PET) myocardial perfusion imaging (MPI; because of excellent negative predictive 
value) is reasonable in patients with HCM with chest discomfort and a low likelihood of 
CAD to rule out possible concomitant CAD 
CLASS III: NO BENEFIT 
1. Routine SPECT MPI or stress echocardiography is not indicated for detection of “silent” 
CAD-related ischemia in patients with HCM who are asymptomatic 
2. Assessment for the presence of blunted flow reserve (microvascular ischemia) using 
quantitative myocardial blood flow measurements by PET is not indicated for the 
assessment of prognosis in patients with HCM 


Protocol No.  HML-PHX-005 
Version 11.0 
 
02 DEC 2016 
Heart Metabolics — Company Confidential 
 
Page 58 of 58 
APPENDIX C: 
DISCONTINUATION FOR PERSISTENT CLINICAL 
LABORATORY ELEVATIONS 
A patient will be discontinued from the study if persistent elevations in ALT or AST, occur 
according to the following criteria: 
• 
If a patient develops an elevation in ALT or AST >5 × ULN, the test will be repeated 
within 7 days. 
o If, upon re-test, ALT or AST remains >5 × ULN, study drug should be stopped 
and the patient discontinued from the study. 
o If, upon re-test, ALT or AST is ≤5 × ULN, the patient may continue in the study 
and follow-up will be performed at regular study visits with unscheduled visits 
as needed at the discretion of the Investigator. 
• 
The patient will be followed as clinically indicated/necessary until the abnormality 
reverts to normal or to patient’s baseline level or until the abnormalities stabilize. 
If at any time during the study a patient develops elevations in ALT or AST >5 x ULN, the study 
site will be alerted by the central laboratory. 
 

SAP_001.pdf: 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
A Phase 2, Multi-Center, Open-Label, Ascending Dose Study on the 
Efficacy, Safety and Tolerability of Perhexiline in Patients with 
Hypertrophic Cardiomyopathy and Moderate-to Severe Heart 
Failure with Preserved Left Ventricular Function 
 
 
Investigational Product: Perhexiline 
Protocol Number: HML-PHX-005 (Version 11.0, 02 December 2016) 
 
 
 
Sponsor: 
Heart Metabolics, Ltd 
20B Beckett Way 
Dublin, Ireland 
 
 
SAP Version Number: V1.0 
Date: 01 June 2017 
 
 
 
 
 
CONFIDENTIAL 
This document contains information that is confidential and proprietary to the Sponsor, Heart Metabolics, 
Ltd.  The contents of this document may not be used in any other clinical study, disclosed to any other 
person or entity, and/or published without the prior written permission of the Sponsor. The foregoing shall 
not apply to disclosure required by any regulations; however, you will give prompt notice to the Sponsor 
of any such disclosure 


 
Statistical Analysis Plan 
 
Protocol Number:  HML-PHX-005 
SAP Version Number:  1.0 
Page 2 of 31 
SAP Version Date:  01 June 2017 
 
SIGNATURE PAGE 
 
A Phase 2, Multi-Center, Open-Label, Ascending Dose Study on the Efficacy, Safety and 
Tolerability of Perhexiline in Patients with Hypertrophic Cardiomyopathy and Moderate-to 
Severe Heart Failure with Preserved Left Ventricular Function 
HML-PHX-005 (Version 10.0, 12 October 2016) 
 
We, the undersigned, have reviewed and approve this Statistical Analysis Plan. 
 
Signature 
Date 
 
 
 
______________________________________________ 
Suzanne Lloyd, MSc 
Project Statistician 
Medpace Inc. 
 
 
 
___________________________ 
 
 
______________________________________________ 
Rong Zhou, PhD 
Therapeutic Lead Statistician 
Medpace Inc. 
___________________________ 
 
 
______________________________________________ 
Pirouz Shamszad, MD, FACC, FAAP 
Medical Monitor 
Medpace Inc. 
___________________________ 
 
 
______________________________________________ 
Mark Midei, MD,  
Executive Director,  
Head of Cardiology 
Heart Metabolics Ltd 
___________________________ 
 
 
______________________________________________ 
Charlotte Hartman, PharmD,  
VP, Clinical Development 
Heart Metabolics Ltd 
___________________________ 
 
 


 
Statistical Analysis Plan 
 
Protocol Number:  HML-PHX-005 
SAP Version Number:  1.0 
Page 3 of 31 
SAP Version Date:  01 June 2017 
 
 
VERSION HIST ORY 
 
Version  
Date 
Description 
V1.0 
01 June 2017 
Final version for approval 
 
 
 


 
Statistical Analysis Plan 
 
Protocol Number:  HML-PHX-005 
SAP Version Number:  1.0 
Page 4 of 31 
SAP Version Date:  01 June 2017 
 
 
TABLE OF CONTENTS 
 
1 
Introduction ............................................................................................................................. 8 
2 
Overview ................................................................................................................................. 8 
2.1 Objectives ......................................................................................................................... 8 
2.1.1 Primary Objective ................................................................................................... 8 
2.1.2 Secondary Objectives ............................................................................................. 8 
2.2 Study Design .................................................................................................................... 8 
3 
Analysis Variables ................................................................................................................. 13 
3.1 Efficacy Variables .......................................................................................................... 13 
3.1.1 Primary efficacy variable ..................................................................................... 13 
3.1.2 Secondary efficacy variables ................................................................................ 13 
3.2 Safety Variables ............................................................................................................. 14 
3.2.1 Adverse Events ..................................................................................................... 14 
3.2.2 Safety Laboratory Evaluations ............................................................................. 15 
3.2.3 Pregnancy Testing ................................................................................................ 17 
3.2.4 Vital Signs ............................................................................................................ 18 
3.2.5 12-Lead ECG ........................................................................................................ 18 
3.2.6 Physical Examination ........................................................................................... 20 
3.3 Pharmacokinetic Variables ............................................................................................. 20 
3.3.1 Concentration Data ............................................................................................... 20 
3.4 Baseline Variables .......................................................................................................... 20 
3.4.1 Prior and Concomitant Medication ...................................................................... 20 
3.4.2 Demographic Data ................................................................................................ 21 
3.4.3 Medical History .................................................................................................... 21 
3.4.4 Coagulation Profile ............................................................................................... 21 
3.4.5 CYP2D6 Screening .............................................................................................. 21 
3.5 Study Medication ........................................................................................................... 21 
3.5.1 Compliance and Exposure .................................................................................... 21 
3.5.2 Dose Titration ....................................................................................................... 22 
4 
Analysis Populations ............................................................................................................. 23 
4.1.1 Safety Population ................................................................................................. 23 
4.1.2 Modified Intention to Treat Population ................................................................ 23 
4.1.3 Completer Population ........................................................................................... 23 
4.1.4 Pharmacokinetic Population ................................................................................. 23 
5 
General Considerations for Data Analysis ............................................................................ 23 
5.1 Evaluation of Center Effect ............................................................................................ 24 
5.2 Assessment Windows ..................................................................................................... 24 


 
Statistical Analysis Plan 
 
Protocol Number:  HML-PHX-005 
SAP Version Number:  1.0 
Page 5 of 31 
SAP Version Date:  01 June 2017 
 
5.3 Handling of Dropouts and Missing Data........................................................................ 24 
5.4 Other Data Handling Approaches .................................................................................. 24 
6 
Analysis of Disposition and Patient Characteristics .............................................................. 25 
6.1 Disposition and Analysis Populations ............................................................................ 25 
6.2 Eligibility Criteria and Protocol Deviations ................................................................... 25 
6.3 Demographics and Baseline Characteristics .................................................................. 25 
6.4 Concomitant Medications .............................................................................................. 26 
6.5 Study Medication ........................................................................................................... 26 
7 
Analysis of Efficacy .............................................................................................................. 26 
7.1 Primary Efficacy Analysis ............................................................................................. 26 
7.2 Secondary Efficacy Analyses ......................................................................................... 27 
7.2.1 Difference between Period 2 and Period 1 Change from Baseline in VO2MAX ... 27 
7.2.2 Change from Baseline in VO2MAX at the end of Period 1 .................................... 27 
7.2.3 Change from Baseline in 6MWT at the end of Period 2 ...................................... 27 
7.2.4 Difference between Period 2 and Period 1 Change from Baseline in 6MWT ..... 27 
7.2.5 Change from Baseline in 6MWT at the end of Period 1 ...................................... 28 
8 
Analysis of Safety .................................................................................................................. 28 
8.1 Extent of Exposure ......................................................................................................... 28 
8.2 Adverse Events ............................................................................................................... 28 
8.3 Safety Laboratory Parameters ........................................................................................ 29 
8.4 HbA1c ............................................................................................................................ 29 
8.5 Vital Signs ...................................................................................................................... 29 
8.6 ECG Parameters ............................................................................................................. 30 
8.7 Physical Examinations ................................................................................................... 30 
8.8 Pharmacokinetic Analysis .............................................................................................. 30 
9 
Data Safety Monitoring Board .............................................................................................. 30 
9.1 Study Monitoring Team ................................................................................................. 30 
10 Interim Snapshot Analysis ..................................................................................................... 31 
11 Sample Size and Power Considerations ................................................................................ 31 
12 Changes from Protocol-Specified Statistical Analyses ......................................................... 31 
 
 
 


 
Statistical Analysis Plan 
 
Protocol Number:  HML-PHX-005 
SAP Version Number:  1.0 
Page 6 of 31 
SAP Version Date:  01 June 2017 
 
LIST OF ABBREVIATIONS 
 
6MWT 
Six minute walk test 
ADE 
Adverse device effect 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate aminotransferase 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CIS 
cis-Hydroxy-Perhexiline 
CPEX 
Cardiopulmonary Exercise 
CPIC 
Clinical Pharmacogenetics Implementation Consortium 
CPK 
Creatine Phosphokinase 
CRO 
Contract Research Organization 
CYP2D6 
Cytochrome P450 2D6 
CRF 
Case Report Form(s) 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram or electrocardiographic 
EM 
Extensive Metabolizer 
HbA1c 
Hemoglobin A1c or glycosylated hemoglobin 
HCM 
Hypertrophic Cardiomyopathy 
IM 
Intermediate metabolizer 
INR 
International Normalized Ratio 
LDH 
Lactate dehydrogenase 
LV 
Left ventricular 
LVH 
Left ventricular hypertrophy 
LVOT 
Left ventricular outflow tract 
MedDRA 
Medical Dictionary for Regulatory Activities 
MITT 
Modified Intention to Treat 
msec 
milliseconds 
PEX 
Perhexiline 
PM 
Poor metabolizer 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QTc 
Corrected QT interval 
QTcF 
QT corrected according to Fridericia’s formula 
RBC 
Red Blood Cells 


 
Statistical Analysis Plan 
 
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SAP Version Number:  1.0 
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SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
TE 
Treatment-Emergent 
TEAE 
Treatment-Emergent Adverse Event 
TRANS 
trans-Hydroxy-Perhexiline 
ULN 
Upper limit of normal 
UM 
Ultra-rapid metabolizer 
VO2MAX 
Maximal oxygen consumption 
 
 
 


 
Statistical Analysis Plan 
 
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SAP Version Number:  1.0 
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1 
INTRODUC TION 
The purpose of this document is to provide a description of the statistical methods and procedures 
to be implemented for the analysis of data from Heart Metabolics, HML-PHX-005.  This document 
is based on protocol version 11, 02 December 2016.  If circumstances arise during the study such 
that more appropriate analytic procedures become available, this statistical analysis plan (SAP) 
may be revised.  Any revisions to the SAP (both alternative and additional methods) will be made 
prior to database lock and reasons for such revisions will be described in the final Clinical Study 
Report (CSR). 
2 
OVERVIEW 
2.1 
Objectives 
2.1.1 Primary Objective 
The primary objective of the study is to evaluate the effect of PEX on the change from Baseline 
of maximal oxygen consumption (VO2MAX) in patients with hypertrophic cardiomyopathy (HCM) 
and moderate-to-severe heart failure with preserved left ventricular (LV) function following repeat 
dosing with PEX for 112 days. 
2.1.2 Secondary Objectives 
The secondary objectives of the study are to evaluate: 
• The ascending dose-response effect on the change from Baseline of VO2MAX in patients 
with HCM and moderate-to-severe heart failure with preserved LV function following 
repeat dosing with PEX for 112 days. 
• The electrocardiographic (ECG) response, tolerability and safety of orally administered 
PEX in patients with HCM and moderate-to-severe heart failure with preserved LV 
function following repeat dosing with PEX for 112 days. 
2.2 
Study Design 
This Phase 2, open-label, single arm study aims to confirm the optimal dosing regimen of PEX for 
use in a future phase 3 study.  The study had planned to enroll approximately 33 patients with 
HCM from approximately 7-10 study sites in the US. 
In the 28 days before the planned start of study dosing, each patient was to be screened for 
eligibility.  A complete list of all eligibility criteria is available in section 4.2 and 4.3 of the study 
protocol. 
Following screening, a patient’s suitability to enter the study was to be confirmed at the Baseline 
assessment.  Confirmation would include an evaluation of the patient’s Baseline 12-lead ECG by 
a central assessor from ECG Corelab.  Study medication was only to be dispensed after 
confirmation of the patient’s suitability to enter the study.  Any delays in the central assessment of 


 
Statistical Analysis Plan 
 
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SAP Version Number:  1.0 
Page 9 of 31 
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the Baseline ECG could result in the patient having to return to the site for study drug dispensing 
and having a Baseline assessment split over more than one day.  The day that study drug dosing 
commenced was to be regarded as Day 1. 
Patients who met the study inclusion and exclusion criteria were to be admitted to the study on the 
morning of Day 1 when they were to start their open-label, study-drug dosing regimen with PEX.  
The first dose of study drug was to be administered under the supervision of the study-site staff.  
Subsequent daily dosing throughout the dosing period of 112 days was to be done in the evening 
(preferably between 8-11p.m.). 
CPEX was to be completed at Baseline (before the start of study-drug dosing on Day 1), and again 
at the end of Periods 1 and 2.  After completion of study drug dosing (end of Period 2) there was 
to be a follow-up safety observation period before patients completed the study. 
Figure 1 Outline Study Design 
Screening 
 
Treatment 
 
Follow-up 
 
Epoch 
 
Epoch 
 
Epoch 
 
 
33 HCM Patients with 
V02MAX < 75% predicted 
during CPEX 
 
Period 1 
8 Weeks 
Starting dose 70 mg qd 
 
Period 2 
8 Weeks 
 
Follow-up 
4 Weeks 
 
 
 
 
 
 
 
 
 
Dose adjust to  
plasma level  
100-300 ng/mL 
 
Dose adjust to 
plasma level  
300-500 ng/mL 
 
Off Drug 
 
 
CPEX 
 
CPEX 
 
CPEX 
 
If a patient chose to withdraw from the study during the dosing phase, the site was to attempt to 
complete the following assessments: 
• CPEX Testing and 6-Minute Walk Test 
• vital signs and 12-Lead ECG 
• Blood sample for PEX, CIS and TRANS, full blood cell count, routine safety serum 
chemistry tests, serum pregnancy test and serum levels of hemoglobin A1c 
• Concomitant Medications and AEs 
• Study drug accountability and treatment compliance 
The total study duration for safety and efficacy follow-up was to be 24 weeks. 


 
Statistical Analysis Plan 
 
Protocol Number:  HML-PHX-005 
SAP Version Number:  1.0 
Page 10 of 31 
SAP Version Date:  01 June 2017 
 
 
Complete Schedule of 
Protocol Activities 
 
 
Screening [A] 
 
Baseline Week 1 
(Day 1) [A] 
 
After 
Completion of 
Week 1 
(Day 8) 
 
After Completion of Weeks 2, 4, 
6, 8, 10, 12 & 14 
(Days 15, 29, 43, 57, 71, 85 & 99) 
End of Treatment 
After Completion 
of Week 16 
(Day 113) 
 
Final 
Visit 
Week 20 
(Day 140) 
Time window permitted 
-28 days 
n.a. 
±1 Day 
±1 Day for Week 2 
±3 Days for other timepoints 
±3 Days 
±3 Days 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X [B] 
 
 
 
 
Demographics, Medical Hist, Physical Exam 
X 
 
 
 
 
 
12-lead ECG [C, D] 
X 
X [E] 
 
X 
X 
X 
CPEX Testing [D, F] 
X 
X [G] 
 
After End of Week 8 
X [H] 
 
Weight 
X 
X 
 
After End of Week 8 
X 
X 
Vital Signs [I] 
X 
X 
 
X 
X 
X 
Laboratory Procedures [J] 
 
 
 
 
 
 
      Serum Pregnancy Test [K] 
X 
 
 
 
 
X 
      Urine Pregnancy Test [J, K] 
 
X 
 
 
 
 
      Serum Chemistry [L] 
X 
 
 
After End of Week 8 
X 
X 
      Complete Blood Count [M] 
X 
 
 
 
X 
X 
      Coagulation Tests [N] 
X 
 
 
 
 
 
      CYP2D6 Screening [O] 
X 
 
 
 
 
 
      Plasma PEX, CIS & TRANS [P] 
 
 
X 
X 
X 
X 
      Biomarkers (Hemoglobin A1c) 
X 
 
 
After End of Week 8 
X 
X 
Study Dosing & Dose Adjustment as per 
Guidelines & Algorithm [Q] 
 
Start at 70 mg 
[R] 
X 
X 
 
 
Review of Dosing Instructions and 
Adherence to Dosing 
 
X 
X 
X 
X 
 
Adverse Event Assessment [S] 
X 
X 
X 
X 
X 
X 
Adverse Device Effect Assessment [T] 
 
 
X 
X 
X 
X 
Concomitant Medication Review [U] 
X 
X 
X 
X 
X 
X 
6 Minute Walk Test (6MWT) [D] 
 
X 
 
After End of Week 8 
X 
 
 
 


 
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SAP Version Number:  1.0 
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Footnotes: 
A. The Screening visit was to be performed within 28 days prior to dosing. 
B. Entry criteria was to be evaluated: Baseline CPEX compared to Screening CPEX, and ECG exclusion criteria 
C. ECGs were to be done in triplicate prior to blood draws when possible and obtained after the patient had been resting comfortably in a supine position 
for approximately 10 minutes. 
D. ECGs were to be performed first, the CPEX second, and the 6MWT last during any visit. 
E. The Baseline ECG were not to meet any of the exclusion criteria detailed in section 4.3.2; this was to be confirmed by the central ECG reader before 
study drug could be dispensed to the patient 
F. i   All CPEX test results were to be reviewed by the centralized CPEX assessor for compliance with prospectively defined CPEX test acceptance criteria 
ii  The Screening CPEX was to be performed to show that patient was able to perform exercise testing but unable to exceed 75% of the predicted age-
adjusted maximum level (as determined by VO2MAX). 
G. i   A valid Screening CPEX was to be confirmed by the centralized CPEX assessor before the Baseline CPEX was done 
ii  The Baseline VO2MAX was not to vary from the screening VO2MAX by more than ±20% (with the screening test being the reference); this was to be 
calculated by study-site staff in order to allow a decision on patient inclusion in the study during the Baseline site-visit 
H. If the centralized CPEX assessor deemed the EOT CPEX test to be invalid, the patient may be required to return for a repeat test. 
I. 
Heart rate and blood pressure assessed in the seated position after 5 minutes of rest. 
J. 
Samples for laboratory assays were to be sent to the central lab for analysis (with the exception of the urine pregnancy test at Baseline which were to be 
performed locally). 
K. Females of child bearing potential. (Eligible patients were to be advised to use an adequate contraceptive method.) 
L. Serum Chemistry: sodium, potassium, bicarbonate, chloride, calcium, phosphorus, glucose, creatinine, BUN, CPK, uric acid, albumin, total protein, 
total bilirubin, alkaline phosphatase, ALT (SGPT), AST (SGOT), LDH, total cholesterol 
M. CBC: hemoglobin, hematocrit, RBC, MCV, MCH, MCHC, RDW, WBC count with differential (neutrophils, bands, lymphocytes, monocytes, 
eosinophils, basophils), platelets. 
N. Coagulation tests: prothrombin time (PT), partial thromboplastin time (PTT), and international normalized ratio (INR). 
O. CYP2D6 Poor Metabolizer status as defined by the CPIC guidelines. 
P. All determinations of systemic blood levels of PEX, CIS, and TRANS were to be measured using the PEX-CIS assay.  Blood sampling for 
determination of PEX, CIS and AS was to be scheduled approximately 12h after dosing on the previous study day. Results for PEX and CIS were to be 
reported to the study sites for confirmation of a patient’s phenotypic status for PEX metabolism and for dose-adjustment decisions. 
Q. Patients were to be provided with up to 4 weeks’ worth of study medication at the Baseline, Week 2, 4, 6, 8, 10, 12 and 14 study visits 
R. Study-drug was to be dispensed once the ECG Corelab confirmed that the Baseline ECG met the entry criteria. The first study-drug dose was to be 
administered under the supervision of the study-site staff once the study-site staff confirmed that the Baseline VO2MAX was within ±20% of the 
Screening CPEX. 
 
 


 
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SAP Version Number:  1.0 
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SAP Version Date:  01 June 2017 
 
Note: 
i. 
If for any reason the ECG Corelab was not able to immediately confirm the ECG outcome, the patient was to return home without receiving any 
dispensed study-drug. In such cases, once the ECG Corelab confirmation became available the patient was to return to the site to collect the study 
drug supply. The patient was then to commence study-drug dosing (defined as Day 1). 
ii. 
All Baseline ECG confirmations were to be received by study sites from the ECG Corelab within a maximum of 48h. 
iii. 
Before dosing commenced; if the centralized CPEX assessor confirmed the Baseline VO2MAX was not within ±20% of the Screening CPEX then 
the patient was not to enter the study 
iv. 
Before dosing commenced; if the centralized CPEX assessor confirms an invalid Baseline VO2MAX the patient was to be invited to repeat the 
Baseline CPEX test within the 28-day period allowed between Screening and the start of study-drug dosing 
v. 
After dosing commenced; if the centralized CPEX assessor deems the Baseline CPEX test to have been invalid or not within ±20% of the 
Screening CPEX then the patient was to remain in the study and the patient’s Baseline CPEX result will be taken as the valid Baseline result 
vi. 
All Baseline CPEX confirmations were to be received by study sites from the centralized CPEX assessor within a maximum of 48h. 
 
S. AEs were to be documented and recorded at each visit. All AEs (serious and non-serious, and related and non-related) were to be documented and 
recorded through the Follow-Up visit.  Patients were to be followed for AEs until the final required protocol visit or until all drug-related toxicities and 
SAEs have resolved (or are considered chronic/stable). 
T. If an AE was determined to have been the result of a PEX-CIS Assay abnormality (e.g., false positive, false negative, measurement error), it will be 
deemed an ADE for the purpose of device reporting. 
U. Concomitant Medications was to be collected and recorded at each visit. All concomitant medications received up to and including 30 days prior to the 
start of study medication through the Follow-Up visit were to be recorded 
 


 
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SAP Version Number:  1.0 
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3 
ANALYSIS VARIABLES 
3.1 
Efficacy Variables 
3.1.1 Primary efficacy variable 
The primary endpoint of the study is the change from Baseline of VO2MAX at the end of Period 2. 
Cardio-Pulmonary Exercise Testing (CPEX) was to be performed at Screening and repeated at 
Baseline (Day 1), at the end of Period 1 (Week 8) and the end of Period 2 (Week 16).  Details of 
the exercise test performed and the resultant VO2MAX evaluations were to be reported in the CRF.  
For entry into the study, the patient’s VO2MAX at Screening could not exceed 75% of the predicted 
age-adjusted value and the VO2MAX.at Baseline (Day 1) could not be outside ± 20% of the 
Screening VO2MAX value (if the centralized CPEX assessor deems the Baseline CPEX test is not 
within ±20% of the Screening CPEX after dosing with study medication has already commenced, 
the subject will remain in the study and the subject’s Baseline CPEX result will be taken as the 
valid Baseline result, unless it is deemed invalid or if the CPEX test was administered after the 
start of study medication). 
CPEX reports were to be validated by a centralized CPEX assessor. 
The VO2MAX at the Day 1 assessment will be regarded as Baseline unless the CPEX was reported 
to have been assessed after the start of study medication.  If this situation arises, the VO2MAX from 
Screening will be regarded as Baseline.  Changes and percent changes from Baseline to the end of 
Period 2 VO2MAX value will be derived: 
Change at Period 2 = Period 2 VO2MAX– Baseline VO2MAX 
Percent Change at Period 2 = (Period 2 VO2MAX– Baseline VO2MAX)/Baseline VO2MAX 
If the patient withdraws from the study early, but provides an unscheduled or early end-of-Period 2 
VO2MAX assessment then this VO2MAX assessment will be used in the derivation of efficacy 
endpoints.  Only if the unscheduled or early end-of-Period 2 VO2MAX assessment is within ±7 days 
of the intended target assessment (Period 2 target = Day 113), relative to Day 1, will the derived 
change in VO2MAX be used in the primary analysis using the Completer Population (see section 7.1, 
below). 
3.1.2 Secondary efficacy variables 
Change from Baseline in VO2MAX to end of Period 1 compared to Period 2 and Change from 
Baseline in VO2MAX to end of Period 1 
The change and percent change from Baseline in VO2MAX to the end of study-drug dosing Period 1 
and Period 2 will be derived: 


 
Statistical Analysis Plan 
 
Protocol Number:  HML-PHX-005 
SAP Version Number:  1.0 
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Change at Period 1 = Period 1 VO2MAX – Baseline VO2MAX 
Percent Change at Period 1 = (Period 1 VO2MAX – Baseline VO2MAX)/Baseline VO2MAX 
Change at Period 2 = Period 2 VO2MAX – Baseline VO2MAX 
Percent Change at Period 2 = (Period 2 VO2MAX – Baseline VO2MAX)/Baseline VO2MAX 
As in the primary endpoint, the VO2MAX.at the Day 1 assessment will be regarded as Baseline. 
In the same way as for the primary endpoint, if the patient withdraws from the study early, but 
provides an unscheduled or early end-of-Period 1 or end-of-Period 2 VO2MAX assessment then this 
VO2MAX assessment will be used in the derivation of efficacy endpoints.  Only if the unscheduled 
or early end-of-Period 1 or end-of-Period 2 VO2MAX assessment is within ±7 days of the intended 
target assessment (Period 1 target = Day 57; Period 2 target = Day 113), relative to Day 1, will the 
derived change in VO2MAX values be used in the principal analysis of this endpoint using the 
Completer Population (see sections 7.2.1 and 7.2.2). 
6 Minute Walk Test 
A 6-minute walk test (6MWT) was to be performed at the Baseline (Day 1) assessment and 
repeated at the end of Period 1 (Week 8) and the end of Period 2 (Week 16). 
The change and percent change from Baseline at the end of study-drug dosing Period 2 and the 
change and percent change from Baseline at the end of study-drug dosing Period 1 will be derived, 
taking the Day 1 assessment as Baseline. 
If a patient withdraws from the study early, but provides an end-of-Period 1 or end-of Period 2 
assessment then this assessment will be used in the derivation of the efficacy endpoints.  As in the 
analysis of the primary endpoint, only if the unscheduled or early end-of-Period 1 or end-of-
Period 2 6MWT assessment is within ±7 days of the intended target assessment (Period 1 target = 
Day 57; Period 2 target = Day 113), relative to Day 1, will the derived change in 6MWT values be 
used in the principal analysis of this endpoint using the Completer Population (see section7.2.3 
and 7.2.4). 
3.2 
Safety Variables 
3.2.1 Adverse Events 
Adverse events (AEs) were to be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a patient.  The protocol (section 7.1) defines an AE as 
any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. 
The following information was to be captured for all AEs: 
• Start date 


 
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• End date (or ongoing status, if ongoing at the end of study) 
• Outcome (Recovered/Resolved; Recovered/Resolved with Sequelae; 
Recovering/Resolving; Not Recovered/Not Resolved; Fatal; Unknown) 
• Relationship to study treatment (Definitely Related; Probably Related; Possibly Related; 
Unrelated) 
• Action taken with study treatment (Drug Withdrawn; Drug Interrupted; Dose Reduced; 
Dose Not Changed; Dose Increased; Other; Not Applicable) 
• Any other action taken (No; Yes) 
• Caused study discontinuation (No; Yes) 
• Severity (Mild; Moderate; Severe) 
• Seriousness (No; Yes) 
• Adverse Device Effects (No; Yes) 
• Is the event an overdose (No; Yes) 
• Is the event a cancer event (No; Yes) 
If the investigator deemed the AE to be serious, the reason(s) for being considered serious would 
be recorded in the eCRF. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
A treatment-emergent adverse event (TEAE) is defined as any AE with a recorded start date on or 
after the date of the first dose of study medication.  Treatment emergent (TE) status of AEs with a 
partial start date will be determined using available incomplete date information.  For example, if 
the AE has a missing day field but the non-missing month and year fields place the start of the AE 
after the start of study medication, then the AE will be designated TE.  For AEs where the available 
partial date information is inconclusive (for example, missing day but available month and year 
are equal to the month and year of start of study medication) then the AE will be classified as TE.  
In particular, AEs with a completely missing start date will be assumed to be TE (unless the AE 
stop date places the AE prior to starting treatment). 
TEAEs will be split further according to whether the AE start date occurred during Period 1 or 
Period 2 of the Treatment Epoch, or during the Follow-up Epoch. 
3.2.2 Safety Laboratory Evaluations 
Serum Chemistry 
Blood samples were to be obtained for routine serum chemistry safety tests at Screening, and 
repeated at the end of Period 1 (Week 8), at the end of Period 2 (Week 16) and at Follow-up 
(planned for Week 20) visit.  The following safety chemistry parameters levels were to be assessed 
by a central laboratory: 


 
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• Sodium [mmol/L] 
• Potassium [mmol/L] 
• Bicarbonate [mmol/L] 
• Chloride [mmol/L] 
• Calcium [mmol/L] 
• Phosphorus [mmol/L] 
• Glucose [mmol/L] 
• Creatinine [umol/L] 
• BUN [mmol/L] 
• Creatine Kinase [U/L] 
• Uric acid [umol/L] 
• Albumin [g/L] 
• Total protein [g/L] 
• AST (SGOT) [U/L] 
• ALT (SGPT) [U/L] 
• Alkaline phosphatase [U/L] 
• Total bilirubin [umol/L] 
• Lactate dehydrogenase (LDH) [U/L] 
• Total cholesterol [mmol/L] 
The Baseline value for each parameter will be identified as the last assessment value taken prior 
to the start of study medication.  For most parameters and most patients, this will be taken as the 
Screening assessment, however, if any patients have an unscheduled assessment after their 
Screening assessment and before starting study medication, this will be used. 
The change and percentage change from Baseline to the end of Period 1 (Week 8), end of Period 2 
(Week 16) and Follow-up (Week 20) assessment will also be derived. 
For transaminases, any assessments that are outside the following upper limit of normal (ULN) 
threshold multiples will be identified electronically in the analysis dataset: 
AST (SGOT) [U/L] 
> 3 x ULN 
ALT (SGPT) [U/L] 
> 3 x ULN 
Alkaline phosphatase [U/L] 
> 2.5 x ULN 
Total bilirubin [mg/dL] 
> 2 x ULN 
Complete Blood Count 
Blood samples were to be obtained for complete blood count at Screening, and repeated at the end 
of the study, Period 2 (Week 16), and Follow-up (Week 20) assessment.  The following parameters 
levels were to be assessed by a central laboratory: 


 
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• Hemoglobin [g/L] 
• Hematocrit [%] 
• Red blood cells (RBC) [10^12/L] 
• MCV [fL] 
• MCH [pg] 
• MCHC [g/L] 
• White blood cells [10^9/L] 
• Neutrophils [10^9/L and %] 
• Lymphocytes [10^9/L and %] 
• Monocytes [10^9/L and %] 
• Eosinophils [10^9/L and %] 
• Basophils [10^9/L and %] 
• Platelets [10^9/L] 
The Baseline value for each parameter will be identified as the last assessment value taken prior 
to the start of study medication.  For most parameters and most patients, this will be taken as the 
Screening assessment, however, if any patients have an unscheduled assessment after their 
Screening assessment and before starting study medication, this will be used.  The change and 
percentage change from Baseline to the end of Period 1 (Week 8), end of Period 2 (Week 16), and 
Follow-up (Week 20) assessment will also be derived. 
Biomarker Hemoglobin A1c Testing 
Sampling for biomarker levels of hemoglobin A1c was to be performed at Screening, and repeated 
at the end of the Period 1 (Week 8), at the end of Period 2 (Week 16), and at the Follow-up 
(Week 20) assessment. 
• Hemoglobin A1c (HbA1c) [%] 
The Baseline HbA1c value will be identified as the last assessment value taken prior to the start of 
study medication.  For most patients, this will be taken as the Screening assessment, however, if 
any patients have an unscheduled assessment after their Screening assessment and before starting 
study medication, this will be used.  The change and percentage change from Baseline to the end 
of Period 1 (Week 8), end of Period 2 (Week 16) and Follow-up (Week 20) assessment will also 
be derived. 
3.2.3 Pregnancy Testing 
A serum pregnancy test was to be performed at Screening and Week 20, and a urine pregnancy 
test was to be performed at Baseline (Day 1). 
 


 
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3.2.4 Vital Signs 
Vital signs were to be recorded at Screening and repeated at Baseline (Day 1), and at the study 
visit at Week 2, 4, 6, and 8 during Period 1 and at Week 10, 12, 14, and16 during Period 2 and at 
the Follow-up (Week 20) assessment.  Vital signs assessments would include: height (at Screening 
only), weight (at Screening, Week 8, 16, and 20 only), systolic and diastolic blood pressure, heart 
rate and temperature (all assessments). 
The screening weight value will be taken as Baseline.  The Baseline value for each of the remaining 
recurring vital signs parameters will be identified as the last assessment value taken prior to the 
start of study medication.  For most parameters and most patients, this will be taken as the Baseline 
(Day 1) assessment, however, if any patients have an unscheduled assessment after their Day 1 
assessment and before starting study medication, this will be used; or if a patient has a missing 
Day 1 value, then their Screening value will be used.  The change and percentage change from 
Baseline to each post-Baseline assessment will be derived for each vital signs parameter. 
Values from each assessment or changes from Baseline that are outside the thresholds presented 
below will be identified in an analysis dataset by electronic programming for reporting purposes. 
 
Threshold 
Systolic BP (mmHg) 
≥ 160 
Diastolic BP (mmHg) 
≥ 100 
Heart Rate (bpm) 
≤ 50 
Heart Rate (bpm) 
≥ 120 
 
 
Change in Systolic BP (mmHg) 
≥ 30 
Change in Diastolic BP (mmHg) 
≥ 30 
Change in Heart Rate (bpm) 
≥ 30 
 
3.2.5 12-Lead ECG 
A 12-lead ECG was to be performed at Screening, and repeated at Baseline (Day 1), and at the 
scheduled visits at Week 2, 4, 6, and 8 during Period 1 and at Week 10, 12, 14, and 16 during 
Period 2, and the Follow-up (Week 20) assessment. 


 
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At each ECG assessment, three traces were to be performed, each containing three complexes (of 
a single beat).  From each complex, the following ECG parameters were to be reported by the ECG 
Corelab: 
• RR [ms] 
• PR [ms] 
• QRS [ms] 
• QT [ms] 
• T-Peak (TP) [ms] 
• T-wave amplitude (Tamp) [mV] 
• J-Tpeak 
• Tpeak-Tend 
From the exported parameters listed above, the following additional parameters will be derived by 
statistical programming for each available complex: 
QTcF = QT/ 3√RR 
JTcF = QTcF - QRS 
For each ECG parameter (RR, PR, QRS, QT, TP, T-wave, QTcF, JTcF) within each trace, a mean 
of the three complexes was to be derived.  A mean of the three traces was then to be derived from 
the mean of the three complexes.  This mean (of traces) of the mean (of complexes) will be 
presented in the ECG listings and used in the ECG descriptive statistics and analyses.  Individual 
complexes will be available in the SDTM and ADaM datasets only and will not be presented in 
study listings. 
ECG Corelab will also provide a Global RR value for the whole ECG trace.  From this Global RR, 
statistical programming will derive ECG heart rate: 
HR = 60/[Global RR/1000] 
In addition to the above measurements, ECG Corelab was to provide an overall interpretation of 
the ECG.  ECG traces were also to be made available to the study site Investigator, who would 
provide their overall interpretation and an indication of the clinical significance of any findings. 
Changes in each of the ECG parameters from Baseline to each post-Baseline will be derived.  The 
last ECG assessment prior to starting study medication will be regarded as Baseline (this will 
usually be the Day 1 assessment). 
Assessment values or changes from Baseline that are outside the thresholds presented below will 
be identified in an analysis dataset by electronic programming for reporting purposes. 


 
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Thresholds 
QT (msec) 
>450 
>480 
>500 
Changes in QT (msec) 
>30 
>60 
QTcF (msec) 
>450 
>480 
>500 
Changes in QTcF (msec) 
>30 
>60 
 
3.2.6 Physical Examination 
A physical examination was to be performed at Screening. 
3.3 
Pharmacokinetic Variables 
3.3.1 Concentration Data 
A plasma sample for analysis of PEX, CIS and TRANS was to be obtained approximately 12 hours 
after dosing on the previous study day at scheduled visits at Week 1, 2, 4, 6, 8 from Period 1 and 
at Week 10, 12, 14, 16 from Period 2 and at Week 20, Final visit. 
On the morning of Week 1 (after completion of a minimum of 6 days of dosing), patients were to 
provide a blood sample for the measurement of PEX, CIS and TRANS.  These will be used to 
identify phenotypic Poor Metabolizer (PM), ie a patient whose CIS:PEX ratio is <0.4.  Based on 
these results, PM patients will be immediately withdrawn from study-drug dosing. 
On the morning of Week 2 (after completion of a minimum of 13 days of dosing), patients were 
to provide a blood sample for PEX, CIS and TRANS evaluation.  Patients with a CIS:PEX ratio 
<0.4 will be discussed with the Medical Monitor. 
At all assessments from Week 2 onwards, dose adjustment will be considered based on 
determination of plasma PEX levels. 
3.4 
Baseline Variables 
3.4.1 Prior and Concomitant Medication 
Prior medications, received up to and including 30 days prior to the start of study medication, and 
concomitant medications received at any point during the study were to be recorded in the CRF. 
Some medications or drug classes are known to have potential for adverse interactions with PEX. 
Although, their use was permitted in the protocol, they were to be considered with caution.  A list 
of these agents is included in Appendix A of the protocol. 


 
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The original terms recorded on the patient’s eCRF for concomitant medications will be 
standardized by assigning preferred terms from the International Non-Proprietary Name drug 
terms and procedures dictionary for treatments and surgical and medical procedures. 
Medication start and stop dates, recorded on the eCRF, will be used to determine programmatically 
whether the medications were (i) started and stopped prior to the study period or (ii) used during 
the study period.  To implement this, any medication with a reported stop date that is before the 
first dose of any study medication will be regarded as a (i) Prior medication.  Medications that start 
before the first dose of any study medication and are continued into the study or start on or after 
the first dose of any study medication or will be regarded as (ii) Concomitant medication. 
3.4.2 Demographic Data 
Demographic data, including date of birth, age, sex, race, ethnicity and child bearing potential, 
were to be recorded at Screening. 
3.4.3 Medical History 
Medical history, including event or diagnosis description, start and stop dates or ongoing status 
were to be recorded at Screening.  All terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
3.4.4 Coagulation Profile 
A coagulation profile was to be performed at Screening only: 
• prothrombin time (PT) [Sec] 
• partial thromboplastin time (PTT) [Sec] 
• international normalized ratio (INR) [None] 
3.4.5 CYP2D6 Screening 
CYP2D6 was to be assessed at Screening to identify Poor Metabolizer (PM) status, which was to 
be defined according to the CPIC guidelines. 
Any incidences of polymorphisms will be identified and reported under the header CYP2D6 
Genotype. 
3.5 
Study Medication 
3.5.1 Compliance and Exposure 
Patients were to complete two sequential, 8-week study drug-dosing periods.  At the start of 
Period 1, patients were to commence treatment on 70 mg PEX daily with subsequent dose titration 
to a plasma level of 100-300 ng/ml (or ug/L) over 8 weeks.  During the 8-weeks of Period 2, the 
dose was to be titrated further to a plasma level of 300-500 ng/ml. 


 
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For each of the following study medication accounting periods, the number of tablets dispensed 
and returned was to be recorded on the CRF and used to derive the number of tablets taken: 
Period 1: Day 1 to Week 1 
Period 1: Week 1 to Week 2 
Period 1: Week 2 to Week 4 
Period 1: Week 4 to Week 6 
Period 1: Week 6 to Week 8 
Period 2: Week 8 to Week 10 
Period 2: Week 10 to Week 12 
Period 2: Week 12 to Week 14 
Period 2: Week 14 to Week 16 
For each study medication accounting period an estimate of the total dose and daily dose will be 
derived from the number of tablets taken.  Due to the potential for dose titrations, study medication 
compliance will not be derived by comparing the number of tablets taken with the intended dose. 
Study medication exposure will be derived as the number of days that the patient remained on 
study medication.  Exposure in days will be classified into one of the following categories: 
1-  8 days (Week 1) 
9- 29 days (Week 4) 
30- 43 days (Week 6) 
44- 57 days (Week 8) 
58- 71 days (Week 10) 
72- 85 days (Week 12) 
86- 99 days (Week 14) 
100-113 days (Week 16) 
>113 days 
3.5.2 Dose Titration 
The dose titration algorithm was to be based on the systemic plasma levels of PEX throughout the 
dosing regimens in Periods 1 and 2.  On the morning of Day 8 (± 1 day) (after completion of a 
minimum of 6 days of dosing) patients were to provide a blood sample for the measurement of 
PEX, CIS and TRANS. The analytical results were to be available within 3-5 days of the blood 
sampling and results for PEX and CIS reported to the study sites and used to determine the 
following: 
• Patients deemed to be phenotypic PMs based on these results were to be immediately 
withdrawn from study-drug dosing.  A phenotypic PM is defined as a patient whose 
CIS:PEX ratio is <0.4 
On the morning of Day 15 (± 1 day) (after completion of a minimum of 13 days of dosing) patients 
were to provide a blood sample for the measurement of PEX, CIS and TRANS. The analytical 
results were to be available within 3-5 days of the blood sampling and results for PEX and CIS 
reported to the study sites and used to determine the following: 


 
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• The CIS:PEX ratio will be evaluated and patients with a ratio <0.4 will be further evaluated 
and the patient status will be discussed with the Medical Monitor. 
• Dose  adjustment  will  be  decided  according  to  the  dose-adjustment  algorithm presented 
in section 4.4.3 and Table 4.1 below. 
Subsequent blood samples were to be obtained and plasma levels of PEX, CIS and TRANS 
determined at the end of Week 4, 6, and 8 in Period 1, and Week 10, 12 and 14 in Period 2. 
The following doses were expected to produce therapeutic concentrations in the majority of 
patients included in the study. 
Intermediate Metabolizers (IM) 
70 to 140 mg daily 
Extensive Metabolizers (EM) 
140 to 210 mg daily 
Ultra-rapid Metabolizers (UM) 
May require maximum doses of: 
210 (Period 1) or 280 (Period 2) mg daily. 
 
4 
ANALYSIS POPULATI ONS 
4.1.1 Safety Population 
The Safety Population will include all patients who receive study drug. 
4.1.2 Modified Intention to Treat Population 
The Modified Intention to Treat Population (MITT) will include all patients who receive study 
drug and have at least one post-Baseline efficacy assessment. 
4.1.3 Completer Population 
The Completer Population will include all patients who receive study drug and complete all study 
procedures at Baseline, end of Period 1 and end of Period 2 and have their Period 2 CPEX 
assessment within 7 days of the target day of 113. 
4.1.4 Pharmacokinetic Population 
The Pharmacokinetic Population will include all patients who receive study drug and had at least 
one plasma sample collected. 
5 
GENERAL CONSI DERATIONS FOR DATA ANALYSIS 
Statistical analyses will be performed using SAS® (Cary, NC) version 9.3 or above. 
All available data will be presented in patient data listings, which will be sorted by site number, 
unique patient identifier and where appropriate, visit number and visit/assessment date. 


 
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5.1 
Evaluation of Center Effect 
This is a single arm open-label study that will be reported using descriptive stats and a one-sample 
t-test.  Therefore, no adjustments for center effects will be implemented. 
5.2 
Assessment Windows 
No visit windowing required. 
5.3 
Handling of Dropouts and Missing Data 
If the patient withdraws from the study early, but provides an unscheduled or early end-of-Period 1 
or end-of-Period 2 VO2MAX assessment then this VO2MAX assessment will be used in the 
derivation of efficacy endpoints.  Only if the unscheduled or early VO2MAX assessment is within 
±7 days of the intended target assessment relative to Day 1, will the derived change in VO2MAX be 
used in the primary analysis using the Completer Population (see section 7.1, below), but will be 
used in the supportive analysis, based on the MITT. 
Dates will be printed in ISO 8601 date format (YYYY-MM-DD). If only year and month are 
available, date will be displayed as YYYY-MM. If only year, then just YYYY. Dates that are 
missing because they are not applicable for the patients are output as “NA”, unless otherwise 
specified. 
Adverse events with missing start dates will be considered as treatment-emergent unless the partial 
date excludes that possibility, e.g. the adverse event month is prior to the treatment month. 
5.4 
Other Data Handling Approaches 
The programming specification, including the mock-up analysis tables, figures, and data listings, 
as well as the derived database specification, will be prepared in stand-alone documents.  The 
programming specification document will be finalized prior to the database lock. 
Descriptive statistics (n, mean, standard deviation, median, maximum, and minimum) will be used 
to summarize the continuous data.  Unless otherwise stated, descriptive statistics showing the mean 
or median will be displayed to one more decimal place than the original data; the standard deviation 
will be displayed to two decimal places more than the original data; minimum and maximum will 
be displayed to the same number of decimal places as the original data. 
Discrete measures will be summarized using counts and percentages.  Percentages will be 
displayed with 1 decimal place and percentages for zero counts will be omitted from the presented 
results. 
P-values will be presented to 4 decimals. When a p-value is less than 0.0001, ‘<0.0001’ will be 
displayed. 


 
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6 
ANALYSIS OF DISPOSITION AND PATIE NT CHAR ACTERIST ICS 
6.1 
Disposition and Analysis Populations 
The reason given for each screen failure (did not satisfy all inclusion/exclusion criteria, withdrawal 
by patient, physician decision, adverse event, lost to follow-up, other) will be listed and 
summarized. 
A data listing will be presented to indicate which patients satisfied the criteria for inclusion in the 
Safety, Modified Intention to Treat, Completer and Pharmacokinetic Populations.  The number of 
patients included in each population will be summarized using counts and percentages, with 
percentages based on Safety Population as denominator. 
Patient disposition will be presented for all patients in the Safety Population.  The number and 
percentage of patients in each of the following disposition categories will be presented, with 
percentages based on Safety Population as denominator: 
• Patients who completed screening (number of patients only) 
• Patients who started study treatment 
• Patients who completed Period 1 treatment 
• Patients who completed Period 2 treatment 
• Patients who completed the study as planned to the follow up visit 
For patients in the Safety Population who withdraw early from the study treatment or withdrew 
from the study before the follow up visit, the primary reason for the early withdrawal will be listed 
and summarized. 
6.2 
Eligibility Criteria and Protocol Deviations 
A list of any inclusion or exclusion criteria failures will be presented in data listings and 
summarized to show the number and percent of patients failing each criterion for the Safety 
Population. 
Any additional CSR-reportable deviations, drawn from the monitoring reports, will be listed for 
the Safety Population. 
6.3 
Demographics and Baseline Characteristics 
Demographics characteristics will be presented as data listings and summary statistics using the 
Safety Population. 
Medical history findings reported at Screening will be presented in data listings and summarized 
to show the number and percent of patients within each Preferred Term within each System Organ 
Class term for the Safety Population. 


 
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6.4 
Concomitant Medications 
Prior and concomitant medications will be listed by patient for the Safety Population, with an 
indication of whether the medication was regarded as Prior or Concomitant (see section 3.4.1).  
Concomitant medications will be summarized by Therapeutic Class and Preferred Term, showing 
the number and percentage of patients from the Safety Population taking each medication. 
6.5 
Study Medication 
Study medication, in terms of number of tablets dispensed, returned and assumed taken during 
each study medication accounting period (see section 3.5.1) will be listed for the Safety Population 
along with the derived estimated total and daily dose. 
7 
ANALYSIS OF EFFICACY 
7.1 
Primary Efficacy Analysis 
The primary endpoint is the change from Baseline of VO2MAX at the end of Period 2.  This will be 
analyzed using an Analysis of Covariance (ANCOVA) with covariates of baseline VO2MAX and 
the mean plasma PEX level, with the mean taken from all available Period 2 assessments (> 
Week 8 to Week 16).  The primary analysis population will be the Completer Population and will 
include an efficacy endpoint from all patients with an assessment within ±7 days of the planned 
assessment.  The estimated mean change in VO2MAX from Baseline to Period 2 will be presented 
along with a 95% confidence interval of the change and the p-value.  This analysis will be repeated 
for the percent change from Baseline of VO2MAX at the end of Period 2, including the same 
covariates. 
Descriptive statistics of the Baseline value, VO2MAX at the end of Period 2 and the change and 
percent change from Baseline to end of Period 2 will be presented for the Completer Population. 
The primary analysis and descriptive statistics table will be repeated for the MITT, and will include 
any imputed change in VO2MAX values for patients who did not complete the study to the end of 
Period 2 but provided an end of Period 2 VO2MAX assessment (see section 3.1.1). 
Example SAS code is shown below: 
proc mixed data=dataP2; 
    class Period; 
    model CHG=BASE PEXALL Period/ solution cl; 
    lsmeans Period/ cl; 
run; 


 
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7.2 
Secondary Efficacy Analyses 
7.2.1 Difference between Period 2 and Period 1 Change from Baseline in VO2MAX 
The first secondary efficacy endpoint is the change from Baseline of VO2MAX at the end of Period 1 
compared to the change from Baseline at the end of Period 2.  This will be analyzed using an 
ANCOVA with covariates of baseline VO2MAX and the Period-mean plasma PEX level for the 
Completer Population.  The estimated mean change in VO2MAX from Baseline to Period 1 and to 
Period 2 and the difference between Period 1 and Period 2 will be presented along with a 95% 
confidence interval and the p-value.  This analysis will be repeated for the MITT, and will include 
any imputed change in VO2MAX as in the primary analysis. 
Example SAS code is shown below: 
proc mixed data=dataP1P2; 
    class Period; 
    model CHG=BASE PEXP1P2 Period/ solution cl; 
    lsmeans Period/ cl diffs; 
    estimate "Period 2 vs. Period 1" Period -1 1/ cl; 
run; 
7.2.2 Change from Baseline in VO2MAX at the end of Period 1 
The second secondary efficacy endpoint is the change from Baseline of VO2MAX at the end of 
Period 1.  Similar to the primary efficacy endpoint, this will be analyzed using an ANCOVA with 
covariates of baseline VO2MAX and the Period 1 mean plasma PEX level for the Completer 
Population.  This will be repeated for the MITT, including any imputed change in VO2MAX values 
for patients who did not complete the study to the end of Period 1.  Descriptive statistics of the 
Baseline value, VO2MAX at the end of Period 1 and the change from Baseline to end of Period 1 
will be presented for the Completer Population and the MITT Population. 
7.2.3 Change from Baseline in 6MWT at the end of Period 2 
The change from Baseline in the 6MWT at the end of Period 2 will be analyzed using an ANCOVA 
with covariates of baseline VO2MAX and the Period 2 mean plasma PEX level.  This will be 
presented for the Completer Population and repeated for the MITT including any imputed change 
from Baseline values for patients who did not complete the study to the end of Period 2. 
7.2.4 Difference between Period 2 and Period 1 Change from Baseline in 6MWT 
The change from Baseline in the 6MWT at the end of Period 1 compared to the change from 
Baseline at the end of Period 2 will be analyzed using an ANCOVA with covariates of baseline 
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7.2.5 Change from Baseline in 6MWT at the end of Period 1 
The change from Baseline in the 6MWT at the end of Period 1 will be analyzed using an ANCOVA 
with covariates of baseline VO2MAX and the Period 1 mean plasma PEX level.  This will be 
presented for the Completer Population and repeated for the MITT including any imputed change 
from Baseline values for patients who did not complete the study to the end of Period 1. 
8 
ANALYSIS OF SAFETY 
8.1 
Extent of Exposure 
The number of days of exposure to study medication will be listed and summarized using 
descriptive statistics and using counts and percentages of the number of patients in each exposure 
category listed in section 3.5.1. 
8.2 
Adverse Events 
Treatment-emergent AEs (TEAEs) occurring in patients from the Safety Population will be 
presented in data listings with an indication of whether the AE start date occurred during Period 1, 
Period 2, or the Follow-up Period.  Any AEs that were recorded in the CRF from patients who 
were not included in the Safety Population will be listed separately and will not be included in any 
subsequent listings or tables. 
A summary overview of TEAEs will be provided, which will present the number and percentage 
of patients satisfying each of the following categories.  This table will be presented for Period 1 
and Period 2 (see 3.2.1 for derivation) separately and for Period 1 and Period 2 combined and for 
the Follow-up Period, using the Safety Population. 
• Any TEAEs 
• Maximum severity of TEAEs 
• Study drug-related TEAEs 
• All TE SAEs 
• All TE study drug-related TE SAEs 
• TEAEs leading to death 
• TEAEs leading to withdrawal of study medication 
The number and percentage of patients with TEAEs will be summarized by their MedDRA 
preferred term within system organ class.  This will be presented for Period 1 and Period 2 
separately and for Period 1 and Period 2 combined and for the Follow-up Period, using the Safety 
Population.  In this summary, any patients reporting multiple episodes of the same TEAE (i.e. 
same preferred term) within a single period, will be counted once.  It is acknowledged that any 
conclusions that arise from a comparison of AEs reported during Period 1 and Period 2 may be 
limited due to the consecutive nature of the periods.  A similar summary will be provided for study 
drug-related TEAEs. 


 
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The number and percentage of patients with TEAEs will be summarized by reported severity 
(Severity = ‘Mild’, ‘Moderate’, ‘Severe’) within each MedDRA preferred term within system 
organ class.  This will be presented for Period 1 and Period 2 separately and for Period 1 and 
Period 2 combined and for the Follow-up Period, using the Safety Population.  In this summary, 
any patients reporting multiple episodes of the same TEAE (i.e. same preferred term) within a 
single period, will be counted once against the most severely reported category. 
8.3 
Safety Laboratory Parameters 
Laboratory chemistry and hematology data will be listed for each subject in the Safety Population 
with values outside the normal reference ranges flagged as low or high. 
Descriptive statistics of each chemistry and hematology parameter will be presented for the Safety 
Population, showing the observed visit and change from Baseline to each visit value. 
The number of patients with reported transaminases (AST, ALT, Alkaline phosphatase, total 
bilirubin) that are outside the defined ULN threshold multiples (see section 3.2.2) will be 
summarized showing the counts and percentages for Period 1 and Period 2 separately and for 
Period 1 and Period 2 combined, using the Safety Population. 
Pharmacogenetic data (CYP2D6 genotyping at screening) will be listed for each subject in the 
Safety Population.  Any incidences of polymorphisms (see section 3.4.5) will be summarized for 
the Safety Population. 
A cross-tabulation will be displayed to show the agreement between the CYP2D6 genotyping 
status (PM, IM, EM, UM) and the phenotype status defined from the ratio of the CIS:PEX ratio 
(<0.4, ≥0.4) from the Week 1 plasma levels (see section 3.3.1). 
8.4 
HbA1c 
HbA1c data will be listed for each subject in the Safety Population with values outside the normal 
reference ranges flagged as low or high. 
The change from Baseline to the end of Period 2 will be analyzed using an ANCOVA with a 
covariate of baseline HbA1c for the Completer Population. 
The difference between the change from Baseline at the end of Period 1 compared to the change 
from Baseline at the end of Period 2 will be analyzed using an ANCOVA with a covariate of 
baseline HbA1c for the Completer Population. 
The change from Baseline to the end of Period 1 will be analyzed using an ANCOVA with a 
covariate of baseline HbA1c for the Completer Population. 
8.5 
Vital Signs 
Vital signs data from patients in the Safety Population will be presented in a data listing.  The 
listing will identify the Baseline value, and present the visit value and change from Baseline to 


 
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each visit value, for each parameter.  Values outside the thresholds indicated in section 3.2.4 will 
be identified on the listing. 
Descriptive statistics of each vital signs parameter will be presented for the Safety Population, 
showing the observed visit and change from Baseline to each visit value.  The number of patients 
who report a vital signs parameter outside the thresholds at any visit during Period 1, or Period 2 
will be summarized using counts and percentages for the Safety Population. 
Shift tables will be used to indicate the number of patients with systolic or diastolic blood pressure 
or heart rate values that changed status relative to the thresholds identified above (section 3.2.4) 
between Baseline and any vital signs assessment during each period. 
8.6 
ECG Parameters 
All ECG data from patients in the Safety Population will be presented in a data listing.  The listing 
will identify the Baseline value, and present the visit value and change from Baseline to each visit 
value, for each parameter.  Each ECG parameter will be summarized using descriptive statistics 
for each assessment visit using the Safety Population. 
The number of patients experiencing visit values or changes from Baseline within the ranges 
specified in section 3.2.5 will be summarized by counts and percentages for patients in the Safety 
Population. 
Shift tables will be used to indicate the number of patients with QT or QTcF values or changes 
from Baseline values that changed status relative to the thresholds identified above (section 3.2.5) 
between Baseline and any ECG during each period. 
The change from Baseline of the QTcF interval at the end of study-drug dosing Period 1 compared 
to the change from Baseline at the end of study-drug dosing Period 2 will be analyzed using an 
ANCOVA for the Safety Population. 
8.7 
Physical Examinations 
Physical examination information will be listed for the Safety Population. 
8.8 
Pharmacokinetic Analysis 
Pharmacokinetic data for PEX, CIS and TRANS, will be listed by patient and summarized for 
each sampling time point. 
9 
DATA SAFETY MONITORIN G BOARD 
9.1 
Study Monitoring Team 
A Study Monitoring Team will be established to review and discuss the available study data as 
patients are enrolled.  The Study Monitoring Team will include at a minimum an independent 


 
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cardiologist, the Medical Monitor (CRO), the study biostatistician (CRO), and the Sponsor Chief 
Medical Officer or Chief Operating Officer and a Sponsor Representative. 
The team will evaluate all available data listings every two months (until the study is completed) 
following 25% enrollment in the study.  The review will include observed outcomes related to 
patient safety and tolerance (i.e., AEs, adverse device effects [ADEs], vital signs measurements, 
ECGs, laboratory assessments, and concomitant medications).  These listings will be reviewed by 
the Study Monitoring Team to determine whether the dosing regimen should be altered during the 
course of the study or whether any other protocol modifications should be instituted to ensure the 
safety of the patients. 
10 INTE RIM  SNAPSHOT ANALYSIS 
An interim analysis (referred to as a snapshot in the protocol) will be performed on the CPEX data 
(listings and summary statistics) from Period 1 when all patients have completed Week 8.  A two-
sided, one-sample t-test will be performed for the comparison of VO2MAX at the end of Period 1 
compared to Baseline. 
11 SAMPLE SIZE AND POWE R CONSIDERAT IONS 
The sample size was based on a two-sided, one-sample t-test of the change from Baseline for the 
end of Period 2 with the following assumptions: 
• Mean change from Baseline for Period 1 is 1.2mL O2/kg/min 
• Mean change from Baseline for Period 2 is 2.0mL O2/kg/min 
• Standard deviation of change from Baseline is 2.5mL O2/kg/min for both periods 
• Significance level (alpha) of 0.05 
With these assumptions, a power of > 95% is anticipated for the primary outcome, and 72% for 
the first secondary outcome is expected for a sample size of 30 patients. 
12 CHANGES FROM  PROTOCO L-SPECIF IED STATISTICAL ANALYSES 
1. Added Modified Intention to Treat Population as a sensitivity analysis population for 
efficacy analyses. 
2. Added inclusion of early withdrawal efficacy assessments in efficacy analyses that use 
the MITT Population. 
3. The protocol specified that each analysis would be performed using a t-test.  During 
preparation of the statistical analysis plan, it was decided to change this to analysis of 
covariance (ANCOVA).  The intention was to allow covariate adjustment for a Baseline 
value, to adjust for baseline severity, and in some analyses the plasma PEX level, to 
adjust for some measure of study medication intake level.