Intermittent Claudication, Peripheral Artery Disease
Conditions
Brief summary
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
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.
Interventions
DRUGPlacebo
Matching placebo in capsules administered as a single oral dose.
DRUG375 mg CK-2017357
375 mg CK-2017357 in capsules administered as a single oral dose.
500 mg CK-2017357 in capsules administered as a single oral dose.
Sponsors
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of single dose of CK-2017357 on number of contractions, time and work to onset of claudication during bilateral heel raises | 1 day | 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 |
| Effect of single dose of CK-2017357 on number of contractions, time and work to intolerable claudication pain or maximal calf muscle fatigue | 1 day | 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 |
| Effect of single dose of CK-2017357 on Six-Minute Walk Test | 1 day | Patient's self-paced walking distance over 6 minutes |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 1 day | 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 |
| Number of patients with adverse events | 4 weeks | — |
| 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 | 1 day | 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 |
| Characterize the relationship, if any, between the plasma concentrations of CK-2017357 and Six-Minute Walk Test | 1 day | 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 |
Countries
United States
Outcome results
None listed