A Study of CK-2017357 in Patients With Peripheral Artery Disease and Symptomatic Claudication

The primary objective of this early-stage clinical study is to demonstrate an effect of single doses of CK-2017357 on measures of skeletal muscle function and fatigability in patients with peripheral artery disease and symptomatic claudication.

This study is a Phase II, double-blind, randomized, placebo-controlled, three-way crossover design of two single doses of CK-2017357 in patients with peripheral artery disease and symptomatic claudication. 36 to 72 patients will be randomized at approximately 15 study centers to one of six different treatment sequences. Each treatment sequence consists of three dosing periods in which patients receive single oral doses of placebo, 375 mg and 500 mg of CK-2017357. All six treatment sequences will enroll approximately the same number of patients. A wash out period of at least 6 days (to a maximum of 10 days) will be employed between the individual doses for each patient. This study is designed to assess the effects of CK-2017357 on measures of endurance/fatigue, work output, and walking capacity. The PK and PD relationship of CK-2017357 after two single doses will be assessed versus placebo, and the CK-2017357 concentration versus time data obtained in this study may be used to develop a population PK model to estimate intra- and inter-patient variability of PK parameters in patients with claudication.

Eligibility Criteria:
Inclusion Criteria:

1. Ability to comprehend and willing to sign an Informed Consent Form (ICF)
2. Ability to understand written and oral English language
3. Peripheral arterial disease defined as an ankle-brachial index (ABI) at rest ≤ 0.90 in at least one leg in which the patient experiences claudication
4. Stable claudication symptoms over past 6 months (Fontaine Stage II) in at least one calf muscle due to documented peripheral artery disease
5. Females (of non-childbearing potential) or males who are 40 years of age or older
6. Body mass index (BMI) of 18.0 to 30.0 kg/m2, inclusive
7. Ability to perform the bilateral heel raise familiarization sufficient to induce typical claudication at a contraction frequency of once every other second
8. Ability to complete a six-minute walking test
9. Pre-study clinical laboratory findings (including troponin I \[TnI\] and creatine phosphokinase \[CPK\]) within the normal range, or if outside of the normal range, deemed not clinically significant by the Investigator and Sponsor's Medical Monitor
10. For female patients only: Non-childbearing potential (e.g., documented post-menopausal ≥ 1 year, sterilized, status-post hysterectomy) For male patients only: Agreement either

    * To use a condom during sexual intercourse with female partners who are of reproductive potential and to have female partners use an additional effective means of contraception (e.g., diaphragm plus spermicide, or oral contraceptives) for the duration of the study and 10 weeks after the end of the study or
    * To abstain from sexual intercourse for the duration of the study and 10 weeks after the end of the study

Exclusion Criteria:

1. Asymptomatic peripheral artery disease classified as Fontaine Stage I
2. Critical leg ischemia classified as Fontaine Stage III-IV (rest pain, tissue necrosis or gangrene)
3. Non-atherosclerotic causes of arterial occlusive disease
4. "Atypical leg pain," defined as significant residual leg discomfort at rest
5. Leg, hip, or knee surgery within 6 months prior to randomization
6. Any revascularization procedure (coronary or peripheral) within 3 months prior to randomization
7. Life-threatening ventricular arrhythmias, unstable angina, stroke, and/or myocardial infarction within 3 months prior to randomization
8. Moderate/severe symptomatic heart failure defined as NYHA Class III or IV; in patients with NYHA Class I or II heart failure, the screening heel raise familiarization must elicit claudication symptoms and not cardiac symptoms
9. Severe COPD or other respiratory impairment defined as receiving supplemental oxygen therapy at home or by clinical assessment of the Investigator
10. Poorly controlled hypertension (defined as supine resting BP \>180 mmHg systolic or \> 100 mmHg diastolic, or both)
11. Hypotension (defined as supine resting BP \< 95 mmHg systolic or \< 55 mmHg diastolic, or both, or symptomatic hypotension \[standing, supine, or orthostatic\])
12. Exercise tolerance (including ability to perform heel raise and six-minute walk test) that, in the opinion of the Investigator, is significantly limited by other co-morbid conditions or diseases other than claudication
13. Type 1 diabetes (juvenile onset, insulin-dependent), or poorly controlled Type 2 diabetes (defined as HbA1c \> 9.0% in the past 3 months)
14. Hepatic insufficiency (defined as ALT or AST \> 3x ULN, or total bilirubin \> 3 mg/dL)
15. Renal insufficiency (defined as serum creatinine \> 2.5 mg/dL or receiving dialysis)
16. Anemia (defined as hemoglobin \< 12.0 g/dL)
17. Participation in any other investigational study drug or device trial in which receipt of an investigational study drug or device occurred within 30 days prior to dosing
18. Previous treatment with gene therapy or other vascular endothelial growth factor (VEGF)-related therapy
19. Any prior treatment with CK-2017357
20. Recent history of alcoholism or drug abuse, or significant behavioral or psychiatric problems, or other conditions which in the Investigator's opinion may impair ability to adequately comply with the requirements of the study