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

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

Study Overview

• Status: Completed
• Conditions: Intermittent Claudication; Peripheral Artery Disease
• Intervention / Treatment: Drug: Placebo; Drug: 500 mg CK-2017357; Drug: 375 mg CK-2017357

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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85032
      • Tatum Ridge Internal Medicine
  • California
    • Santa Ana, California, United States, 92705
      • Apex Research Institute
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Colorado
    • Denver, Colorado, United States, 80204
      • Denver Health Medical Center
  • Florida
    • Clearwater, Florida, United States, 33761
      • Tampa Bay Medical Research
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research
    • Pinellas Park, Florida, United States, 33782
      • DMI Research, Inc
  • Maine
    • Auburn, Maine, United States, 04210
      • Maine Research Associates
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78229
      • Clinical Trials of Texas, Inc.
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • National Clinical Research - Norfolk, Inc.
    • Richmond, Virginia, United States, 23294
      • National Clinical Research - Richmond, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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
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 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

Collaborators and Investigators

• Sponsor: Cytokinetics
• Investigators: Study Director: William Hiatt, MD, Colorado Prevention Center; Principal Investigator: Alan Hirsch, MD, University of Minnesota

Publications and helpful links

General Publications

• Hiatt WR, Hirsch AT, Bauer TA, Malik F, Lee J, Lin Y, Han FX, Chen MM, Jones D, Cedarbaum JM, Wolff AA. Efficacy and Tolerability of the Novel Fast Skeletal Muscle Troponin Activator, CK-2017357, in Patients with Claudication. 22nd Annual Sessions of the Society for Vascular Medicine. Boston, MA, June 2011
• Bauer TA, Wolff AA, Hirsch AT, Meng LL, Rogers K, Malik FI, Hiatt WR. Effect of tirasemtiv, a selective activator of the fast skeletal muscle troponin complex, in patients with peripheral artery disease. Vasc Med. 2014 Aug;19(4):297-306. doi: 10.1177/1358863X14534516. Epub 2014 May 28.

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion (ACTUAL): March 1, 2011
• Study Completion (ACTUAL): March 1, 2011

Study Registration Dates

• First Submitted: May 25, 2010
• First Submitted That Met QC Criteria: May 25, 2010
• First Posted (ESTIMATE): May 26, 2010

Study Record Updates

• Last Update Posted (ACTUAL): May 14, 2019
• Last Update Submitted That Met QC Criteria: May 9, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Vascular Diseases; Peripheral Arterial Disease; Intermittent Claudication
• Other Study ID Numbers: CY 4022