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
Phase: PHASE2
Conditions: Cardiomyopathy, Hypertrophic, Cardiomyopathy, Hypertrophic, Familial
Sponsor: Heart Metabolics Limited

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 
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Heart Metabolics — Company Confidential 
 
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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 
 
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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 
 

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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: 

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• 
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* 

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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. 

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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-
venous or oral steroid use) 

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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 
major epicardial vessel) 

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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 
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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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perhexiline corrects energy deficiency and improves exercise capacity in symptomatic 
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2007;25:76-97.  
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 
coronary artery surgery: a two-centre randomized double-blind placebo-controlled trial. 
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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10. Eichenbaum G, Pugsley MK, Gallacher DJ, Towart R, McIntyre G, Shukla U, 
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 
ME, Boineau R, Byrne BJ, Cappola TP, Kalluri R, LeWinter MM, Maron MS, Molkentin 
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. 
13. Grima M, VeHy J, Decker N, Marconiak G, Schwartz J. Inhibitory effects of some 
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. 
2001;23(6):636-643. 
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 
Metabolics Ltd. 
20. Morimoto S. Sarcomeric proteins and inherited cardiomyopathies. Cardiovasc Res. 
2008 Mar 1;77(4):659-66. 
21. National Cancer Institute Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs (Effective 
September 16, 2013). 
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 
 

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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 

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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.