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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase II, Double-Blind, Randomized, Placebo-Controlled, Three-Way Crossover, Pharmacokinetic and Pharmacodynamic Study of CK-2017357 in Patients With Claudication

Conditions
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Intermittent Claudication, Peripheral Artery Disease

Intervention / Treatment
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* Drug: Placebo
* Drug: 375 mg CK-2017357
* Drug: 500 mg CK-2017357


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to comprehend and willing to sign an Informed Consent Form (ICF) Ability to understand written and oral English language 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 Stable claudication symptoms over past 6 months (Fontaine Stage II) in at least one calf muscle due to documented peripheral artery disease Females (of non-childbearing potential) or males who are 40 years of age or older Body mass index (BMI) of 18.0 to 30.0 kg/m2, inclusive Ability to perform the bilateral heel raise familiarization sufficient to induce typical claudication at a contraction frequency of once every other second Ability to complete a six-minute walking test 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 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: Asymptomatic peripheral artery disease classified as Fontaine Stage I Critical leg ischemia classified as Fontaine Stage III-IV (rest pain, tissue necrosis or gangrene) Non-atherosclerotic causes of arterial occlusive disease Atypical leg pain, defined as significant residual leg discomfort at rest Leg, hip, or knee surgery within 6 months prior to randomization Any revascularization procedure (coronary or peripheral) within 3 months prior to randomization Life-threatening ventricular arrhythmias, unstable angina, stroke, and/or myocardial infarction within 3 months prior to randomization 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 Severe COPD or other respiratory impairment defined as receiving supplemental oxygen therapy at home or by clinical assessment of the Investigator Poorly controlled hypertension (defined as supine resting BP >180 mmHg systolic or > 100 mmHg diastolic, or both) Hypotension (defined as supine resting BP < 95 mmHg systolic or < 55 mmHg diastolic, or both, or symptomatic hypotension [standing, supine, or orthostatic]) 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 Type 1 diabetes (juvenile onset, insulin-dependent), or poorly controlled Type 2 diabetes (defined as HbA1c > 9.0% in the past 3 months) Hepatic insufficiency (defined as ALT or AST > 3x ULN, or total bilirubin > 3 mg/dL) Renal insufficiency (defined as serum creatinine > 2.5 mg/dL or receiving dialysis) Anemia (defined as hemoglobin < 12.0 g/dL) 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 Previous treatment with gene therapy or other vascular endothelial growth factor (VEGF)-related therapy Any prior treatment with CK-2017357 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

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence 1<br>Dosing Period 1 - Placebo; Dosing Period 2 - 375 mg CK-2017357; Dosing Period 3 - 500 mg CK-2017357 | Drug: Placebo<br>* Matching placebo in capsules administered as a single oral dose.<br>Drug: 375 mg CK-2017357<br>* 375 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;Drug: 500 mg CK-2017357<br>* 500 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;|
| Experimental: Treatment Sequence 2<br>Dosing Period 1 - Placebo; Dosing Period 2 - 500 mg CK-2017357; Dosing Period 3 - 375 mg CK-2017357 | Drug: Placebo<br>* Matching placebo in capsules administered as a single oral dose.<br>Drug: 375 mg CK-2017357<br>* 375 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;Drug: 500 mg CK-2017357<br>* 500 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;|
| Experimental: Treatment Sequence 3<br>Dosing Period 1 - 375 mg CK-2017357; Dosing Period 2 - Placebo; Dosing Period 3 - 500 mg CK-2017357 | Drug: Placebo<br>* Matching placebo in capsules administered as a single oral dose.<br>Drug: 375 mg CK-2017357<br>* 375 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;Drug: 500 mg CK-2017357<br>* 500 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;|
| Experimental: Treatment Sequence 4<br>Dosing Period 1 - 375 mg CK-2017357; Dosing Period 2 - 500 mg CK-2017357; Dosing Period 3 - Placebo | Drug: Placebo<br>* Matching placebo in capsules administered as a single oral dose.<br>Drug: 375 mg CK-2017357<br>* 375 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;Drug: 500 mg CK-2017357<br>* 500 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;|
| Experimental: Treatment Sequence 5<br>Dosing Period 1 - 500 mg CK-2017357; Dosing Period 2 - Placebo; Dosing Period 3 - 375 mg CK-2017357 | Drug: Placebo<br>* Matching placebo in capsules administered as a single oral dose.<br>Drug: 375 mg CK-2017357<br>* 375 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;Drug: 500 mg CK-2017357<br>* 500 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;|
| Experimental: Treatment Sequence 6<br>Dosing Period 1 - 500 mg CK-2017357; Dosing Period 2 - 375 mg CK-2017357; Dosing Period 3 - Placebo | Drug: Placebo<br>* Matching placebo in capsules administered as a single oral dose.<br>Drug: 375 mg CK-2017357<br>* 375 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;Drug: 500 mg CK-2017357<br>* 500 mg CK-2017357 in capsules administered as a single oral dose.<br>* Other names: tirasemtiv;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of single dose of CK-2017357 on number of contractions, time and work to onset of claudication during bilateral heel raises | Heel raises will be monitored by an electrogoniometer placed on the index leg and performed once every other second until onset of claudication pain or fatigue as determined by electrogoniometry | 1 day | 
| Effect of single dose of CK-2017357 on number of contractions, time and work to intolerable claudication pain or maximal calf muscle fatigue | Heel raises will be monitored by an electrogoniometer placed on the index leg and performed once every other second until limited by intolerable claudication pain or fatigue as determined by electrogoniometry | 1 day | 
| Effect of single dose of CK-2017357 on Six-Minute Walk Test | Patient's self-paced walking distance over 6 minutes | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize the relationship, if any, between the plasma concentrations of CK-2017357 and number of contractions, time and work to onset of claudication during bilateral heel raises | Bilateral heel raise assessments will be paired with PK concentrations obtained at or near the same time as the bilateral heel raises assessments and analyzed for concentration related effects | 1 day | 
| Characterize the relationship, if any, between the plasma concentrations of CK-2017357 and number of contractions, time and work to intolerable claudication pain or maximal calf muscle fatigue during bilateral heel raises | Bilateral heel raise assessments will be paired with PK concentrations obtained at or near the same time as the bilateral heel raises assessments and analyzed for concentration related effects | 1 day | 
| Characterize the relationship, if any, between the plasma concentrations of CK-2017357 and Six-Minute Walk Test | Six-Minute Walk Test will be paired with PK concentrations obtained at or near the same time Six Minute Walk Test and analyzed for concentration related effects | 1 day | 
| Number of patients with adverse events |  | 4 weeks |