Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614001281684
Ethics application status
Approved
Date submitted
20/11/2014
Date registered
8/12/2014
Date last updated
1/07/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Study in Healthy Volunteers to Assess the Effects of the Study Drug, Perhexiline, on Measurements of Heart Function.
Scientific title
A Randomized, Double-Blind, Placebo- and Active-Controlled, Parallel Design Study to Evaluate the Effects of Perhexiline on ECG Parameters in Healthy Subjects
Secondary ID [1] 285558 0
HM-PHX-004
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertrophic cardiomyopathy 293377 0
Condition category
Condition code
Cardiovascular 293661 293661 0 0
Normal development and function of the cardiovascular system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a single study with 2 separate phases (as approved by an ethics committee). In the pilot phase of this study, a single cohort of 10 subjects will be dosed with open-label perhexiline oral tablets as follows: Day 1 and 2 - 200 mg every 12 hours, Day 3 and 4 - 200 mg once on each day, Day 5 - 150 to 300 mg (as guided by individual Perhexiline plasma levels) and Day 6 - 400 mg once.
The Thorough QT (TQT) Phase of the study is blinded, randomized, placebo-controlled, parallel-arm design with a nested crossover comparison to moxifloxacin. Up to 100 subjects will participate in this phase, randomized in a 2:1:1 ratio into treatment assignments as listed below:
Day -2 - Placebo Perhexiline (all 3 groups)
Day -1 Placebo Moxifloxacin (Groups 1 and 2a), Moxifloxacin 400 mg (Group 2b)
Days 1 to 6 - Perhexiline (Group 1), Placebo Perhexiline (Groups 2 a and 2b)
Day 7 - Placebo Moxifloxacin (Groups 1 and 2b), Moxifloxacin (Group 2a)
Dosing for Days 1 to 6 is as follows:

Subjects Randomized to Perhexiline:

Days 1 to 2 - 2 x 100 mg Perhexiline in the morning
- 2 x 100 mg Perhexiline in the evening
Days 3 to 4 - 2 x 100 mg Perhexiline in the morning
- No evening dose
Day 5 - Single dose of Perhexiline of between 150 and 300 mg, guided by subject's plasma Perhexiline level
Day 6 - 4 x 100 mg Perhexiline in the morning
- No evening dose

Subjects Randomized to Placebo:

Days 1 to 2 - 2 x 100 mg Placebo in the morning
- 2 x 100 mg Placebo in the evening
Days 3 to 4 - 2 x 100 mg Placebo in the morning
- No evening dose
Day 5 - 3 x 100 mg Placebo and 2 x 25 mg Placebo in the morning
- No evening dose
Day 6 - 4 x 100 mg Placebo in the morning
- No evening dose

On Day 7, all subjects will receive either Moxifloxacin 400 mg or Placebo, orally once.
Subjects enrolled in both the Pilot Phase and the TQT Phase of the study will remain in the unit for the duration of the dosing period, and protocol compliance will be strictly adhered to.
Intervention code [1] 290504 0
Treatment: Drugs
Comparator / control treatment
Moxifloxacin will serve as the positive control in this study.
Perhexiline placebo will also be included in the study dosing.
Perhexiline Maleate matching placebos will be supplied in the identical sizes and colours as the active IR tablets. Placebo Moxifloxacin will also be identical in size and colour to the placebo tablet, both of which will be overencapsulated.
Control group
Active

Outcomes
Primary outcome [1] 293477 0
Following the pilot phase of the study, which will evaluate the targeted perhexiline plasma levels on Days 4 and 6, the primary outcome is to evaluate the baseline-adjusted, placebo-corrected effect on QTcF of Perhexiline on Day 4 (targeting therapeutic plasma levels) and on Day 6 (targeting supratherapeutic plasma levels), or in case of a substantial heart rate effect, the correction formula (QTcF, QTcI and QTcS).
Timepoint [1] 293477 0
Continuous 12-lead ECG extraction will occur at the following timepoints: pre-dose, 0.5 hour, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Days 4 and 6.
Secondary outcome [1] 311320 0
To evaluate the ability of the chosen dosing regimen to achieve targeted perhexiline plasma levels on Day 4 and Day 6 (Pilot Phase)
Timepoint [1] 311320 0
Blood sampling on Days 4 and 6 will occur pre-dose, and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.
Secondary outcome [2] 311325 0
To evaluate the effect of perhexiline on heart rate, PR and QRS intervals and T-wave morphology (TQT Phase)
Timepoint [2] 311325 0
Continuous 12-lead ECG monitoring will occur from approximately 1 hour prior to dosing to approximately 24 hours after dosing on Days -2, -1, 4, 6 and 7.
Secondary outcome [3] 311328 0
To evaluate the relationship between plasma concentration of perhexiline and the effect on the QTcF interval in healthy subjects.
Timepoint [3] 311328 0
Blood sampling will occur pre-dose, and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose. ECG extraction will occur at the same timepoints.
Secondary outcome [4] 311329 0
To evaluate the effect of 400 mg of moxifloxacin on the QTcF interval.
Timepoint [4] 311329 0
Moxifloxacin (or placebo) will be administered on Day -1 and Day 7. Continuous ECG recordings and serial blood samples for pharmacokinetics testing will be performed on these days at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose.
Secondary outcome [5] 311330 0
To evaluate the pharmacokinetics (PK), safety, and tolerability of perhexiline in healthy subjects.
Timepoint [5] 311330 0
For the Pilot Phase, blood sampling for PK assessment will occur at 6 hours after the single dose on Day 3, and on Days 4 and 6 at pre-dose, (single dose) and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose. For the TQT Phase, blood sampling for PK assessment will occur pre-dose, and at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours post-dose on Day -1, Day1, Day 3 to 7, and on Day 8 (24 hour Day 7 sample).
Safety will be assessed by the following:
-Adverse events will be collected from Baseline (Day -2) until study follow-up (16 days plus or minus 2 days).
-Physical examinations will be performed at screening, Day -2/-1, Day 4 and Day 7 (Pilot Phase)/Day 8 (TQT Phase).
-Vital signs (blood pressure, temperature, respiration and pulse) will be performed after the time windows for ECG extraction
- In addition to 12-lead ECGs, safety ECGs will occur 4 hours after morning dose of study drug or single dose (where applicable). This will also be performed on Day 7 for the Pilot Phase, and Day 8 for the TQT Phase.
- Complete blood count, chemistry panel and urinalysis will be performed at screening, baseline, Day 4 and Day 7 (Pilot Phase)/Day 8 (TQT Phase) and follow-up (Day 16 plus or minus 2 days - both study phases).
Secondary outcome [6] 311331 0
In case of a substantial heart rate effect, to evaluate the effect of perhexiline on QTc not chosen as the primary endpoint (QTcF, QTcI and/or QTcS).
Timepoint [6] 311331 0
Continuous 12-lead ECG monitoring will occur from approximately 1 hour prior to dosing to approximately 24 hours after dosing on Days -2, -1, 4, 6 and 7.

Eligibility
Key inclusion criteria
1. Healthy, non-smoking, male or female subjects ages 18 to 55 years inclusive, at the time of informed consent
2. Body mass index (BMI) of 18 to 30 kg/m2 inclusive, at Screening
3. Females must not be lactating or pregnant at Screening or Baseline
4. Provide written informed consent
5. Willing and able to comply with all aspects of the protocol
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. CYP2D6 poor metabolizer, as determined via genotype
2. Clinically significant illness that requires medical treatment within 8 weeks or a clinically significant infection that requires medical treatment within 4 weeks before dosing
3. Evidence of disease that may influence the outcome of the study within 4 weeks before dosing
4. Any history of gastrointestinal surgery that may affect the pharmacokinetic profile of either study drug
5. Any clinically abnormal symptom or organ impairment found by medical history, physical examinations, vital signs, ECG finding, or laboratory test results that requires medical treatment at Screening or Baseline
6. History of any medical condition which, in the opinion of the investigator, may interfere with study procedures or compromise subject safety
7. A prolonged QT/corrected QT interval (QTc) interval (QTc > 450 ms), inverted or flat T waves that may interfere with QT analysis at Screening or Baseline, or any other clinically significant ECG abnormalities at Screening or Baseline
8. History of risk factors for torsade de pointes or the use of concomitant medications that prolong the QT/QTc interval
9. Persistent systolic blood pressure (BP) > 130 mmHg or < 90 mmHg and diastolic BP >85 mmHg or <50 mmHg at Screening or Baseline
10. Heart rate < 50 or > 100 beats/minute at Screening
11. History of prolonged QT/QTc interval
12. History of myocardial infarction or active ischemic heart disease
13. History of clinically significant arrhythmia or uncontrolled arrhythmia
14. Known history of clinically significant drug allergy (including to study drugs or any of their excipients) at Screening or Baseline
15. Known history of food allergies or presently experiencing significant seasonal or perennial allergy at Screening or Baseline
16. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
17. History of drug or alcohol dependency or abuse within the 2 years before Screening, or who have a positive urine drug or alcohol test at Screening or Baseline
18. Use of recreational drugs
19. Intake of caffeinated beverages or food within 72 hours before dosing
20. Intake of nutritional supplements, juice, and herbal preparations or other foods or beverages that may affect the various drug metabolizing enzymes and transporters (eg., alcohol, grapefruit, grapefruit juice, apple or orange juice, vegetables from the mustard green family) within 1 week before dosing
21. Intake of herbal preparations containing St John's Wort within 4 weeks before dosing
22. Use of prescription drugs within 4 weeks before dosing
23. Intake of over-the-counter (OTC) medications within 2 weeks before dosing
24. Smoking or use of tobacco or nicotine-containing products within 4 weeks before dosing
25. Engagement in strenuous exercise within 2 weeks before dosing
26. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days preceding informed consent

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/12/2014
Actual
2/12/2014
Date of last participant enrolment
Anticipated
Actual
10/04/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
110
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 290263 0
Commercial sector/Industry
Name [1] 290263 0
Heart Metabolics, Ltd.
Country [1] 290263 0
Ireland
Primary sponsor type
Commercial sector/Industry
Name
Heart Metabolics, Ltd.
Address
88 Harcourt Street Dublin 2
Country
Ireland
Secondary sponsor category [1] 288969 0
Commercial sector/Industry
Name [1] 288969 0
CPR Pharma Services Pty Ltd
Address [1] 288969 0
28 Dalgleish St
Thebarton SA 5031
Country [1] 288969 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291958 0
Bellberry Limited
Ethics committee address [1] 291958 0
Ethics committee country [1] 291958 0
Australia
Date submitted for ethics approval [1] 291958 0
29/10/2014
Approval date [1] 291958 0
27/11/2014
Ethics approval number [1] 291958 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 52362 0
Dr Jason Lickliter
Address 52362 0
Nucleus Network Limited
Level 5 Burnet Institute,
AMREP Precinct
89 Commercial Road,
Melbourne
Victoria, 3004
Country 52362 0
Australia
Phone 52362 0
+61 3 9076 8960
Fax 52362 0
Email 52362 0
[email protected]
Contact person for public queries
Name 52363 0
Jeffery Wong
Address 52363 0
Nucleus Network Limited
Level 5 Burnet Institute,
AMREP Precinct
89 Commercial Road,
Melbourne
Victoria, 3004
Country 52363 0
Australia
Phone 52363 0
+61 3 9076 8909
Fax 52363 0
Email 52363 0
[email protected]
Contact person for scientific queries
Name 52364 0
Gregory Ayres
Address 52364 0
Heart Metabolics USA, Inc.
1700 Owens Street Suite 595
San Francisco
California 94158
Country 52364 0
United States of America
Phone 52364 0
+1 206-390-6714
Fax 52364 0
Email 52364 0
[email protected]

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No Supporting Document Provided



Results publications and other study-related documents

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