A Study of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)

• ClinicalTrials.gov Identifier: NCT01089010
• Recruitment Status: Completed
• First Posted: March 18, 2010
• Last Update Posted: May 10, 2019
• Sponsor: Cytokinetics
• Information provided by (Responsible Party): Cytokinetics

Tracking Information

• First Submitted Date: March 16, 2010
• First Posted Date: March 18, 2010
• Last Update Posted Date: May 10, 2019
• Study Start Date: March 2010
• Actual Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 3, 2019)

• ALSFRS-R [ Time Frame: 2 days ]
  An instrument for evaluating the functional status of patients with ALS. Minimum score is 0 and maximum score is 40. The higher the score the more function is retained.
• Maximum grip strength [ Time Frame: 2 days ]
  Measured using the DynEx Electronic Hand Dynamometer. Patients asked to squeeze the device with the maximum possible force to establish the maximum voluntary contraction.
• Maximum grip strength fatigability [ Time Frame: 2 days ]
  Handgrip fatigue is measured using the DynEx Electronic Hand Dynamometer. Patient is asked to squeeze the device until they can no longer stay above 60% of target or 120 seconds.
• Shoulder extension fatigue [ Time Frame: 2 days ]
  Patient is asked to hold one arm outstretched in front of them at a 90 degree angle. The time the arm falls below 90 degrees for > 2 seconds will be recorded, up to a total evaluation time of 2 minutes. This is then repeated with the other arm.
• Slow Vital Capacity (SVC) [ Time Frame: 2 days ]
  SVC is measured using the Puritan Bennett Renaissance II Spirometry System and accessories.
• Maximum Voluntary Ventilation (MVV) [ Time Frame: 2 days ]
  MVV is the volume of air that can be exhaled during 12 seconds of rapid deep breathing. The actual volume is extrapolated to one minute. the Puritan Bennett Renaissance II Spirometry System and accessories is used for this measurement.
• Sniff Inspiratory Pressure (SNIP) [ Time Frame: 2 days ]
  SNIP is measured at Functional Residual Capacity, the bottom of the tidal breathing cycle, through one plugged nostril while the other remains open using the Micro Medical MicroRPM Respiratory Pressure Meter
• Maximum Voluntary Muscle Contraction (MVC) [ Time Frame: 2 days ]
  MVC is measured using the MicroFET 2 HHD.
• Repeated Sub-Maximum Grip Strength Fatigability [ Time Frame: 2 days ]
  Sub-Maximum Grip Strength Fatigability is measured using the DynEx Electronic Hand. Dynamometer

Original Primary Outcome Measures (submitted: March 17, 2010)

The primary objective of this study is to demonstrate a pharmacodynamic effect of CK-2017357 on measures of skeletal muscle function or fatigability in patients with ALS. [ Time Frame: 2 days ]

In this hypothesis-generating early Phase II study, multiple assessments of skeletal muscle function will be made without specifying a single primary endpoint, including:

1. ALS Functional Assessment
2. Maximum Grip Strength (bilateral)
3. Maximum Grip Strength Fatigability (bilateral)
4. Shoulder Extension Fatigue (bilateral)
5. Slow Vital Capacity
6. Maximal Voluntary Ventilation
7. Sniff Inspiratory Pressure
8. Maximum Voluntary Muscle Contraction of multiple bilateral muscle groups using Hand Held Dynamometry
9. Repeated Sub-Maximum Grip Strength Fatigability (bilateral)

Current Secondary Outcome Measures (submitted: May 3, 2019)

• Characterize the relationship, if any, between the plasma concentration of CK-2017357 and ALSFRS-R. [ Time Frame: 2 days ]
  ALSFRS-R assessments will be paired with PK concentrations obtained at or near the same time as the ALSFRS-R assessments and analyzed for concentration related effects.
• Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum grip strength [ Time Frame: 2 days ]
  Maximum grip strength assessments will be paired with PK concentrations obtained at or near the same time as the maximum grip strength assessments and analyzed for concentration related effects.
• Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum grip strength fatigability [ Time Frame: 2 days ]
  Maximum grip strength fatigability assessments will be paired with PK concentrations obtained at or near the same time as the maximum grip strength fatigability assessments and analyzed for concentration related effects.
• Characterize the relationship, if any, between the plasma concentration of CK-2017357 and shoulder extension fatigue [ Time Frame: 2 days ]
  Shoulder extension fatigue assessments will be paired with PK concentrations obtained at or near the same time as the shoulder extension fatigue assessments and analyzed for concentration related effects.
• Characterize the relationship, if any, between the plasma concentration of CK-2017357 and slow vital capacity [ Time Frame: 2 days ]
  Slow vital capacity assessments will be paired with PK concentrations obtained at or near the same time as the slow vital capacity assessments and analyzed for concentration related effects.
• Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum voluntary ventilation [ Time Frame: 2 days ]
  Maximum voluntary ventilation assessments will be paired with PK concentrations obtained at or near the same time as the maximum voluntary ventilation assessments and analyzed for concentration related effects.
• Characterize the relationship, if any, between the plasma concentration of CK-2017357 and sniff inspiratory pressure [ Time Frame: 2 days ]
  Sniff inspiratory pressure assessments will be paired with PK concentrations obtained at or near the same time as the sniff inspiratory pressure assessments and analyzed for concentration related effects.
• Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum voluntary muscle contraction [ Time Frame: 2 days ]
  Maximum voluntary muscle contraction assessments will be paired with PK concentrations obtained at or near the same time as the maximum voluntary muscle contraction assessments and analyzed for concentration related effects.
• Characterize the relationship, if any, between the plasma concentration of CK-2017357 and repeated sub-maximum grip strength fatigability [ Time Frame: 2 days ]
  Repeated sub-maximum grip strength fatigability assessments will be paired with PK concentrations obtained at or near the same time as the repeated sub-maximum grip strength fatigability assessments and analyzed for concentration related effects.
• Number of patients with adverse events [ Time Frame: 4 weeks ]
• Effect of CK-2017357 on patient determined global functional assessment [ Time Frame: 2 days ]
  Patients will be asked to assess whether they feel the same, better or worse as compared to how they felt pre-dose
• Effect of CK-2017357 on investigator determined global functional assessment [ Time Frame: 2 days ]
  Investigator will assess whether they the patient appears the same, better or worse as compared to the patient's status at pre-dose

Original Secondary Outcome Measures (submitted: March 17, 2010)

• To evaluate and characterize the relationship, if any, between the plasma concentration of CK-2017357 and its pharmacodynamic effects (PK/PD relationship) [ Time Frame: 2 day ]
• To evaluate the safety and tolerability of 2 doses of CK-2017357 given as single doses administered orally to patients with ALS [ Time Frame: 4 weeks ]
• To evaluate the effect of CK-2017357 on patient and investigator determined global functional assessment [ Time Frame: 2 days ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)
• Official Title: A Phase II, Double-Blind, Randomized, Placebo-Controlled, Three-Way Crossover, Pharmacokinetic and Pharmacodynamic Study of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)
• Brief Summary: The primary objective of this study is to demonstrate a pharmacodynamic effect of CK 2017357 on measures of skeletal muscle function or fatigability in patients with ALS.
• Detailed Description: This study is a Phase II, double-blind, randomized, placebo-controlled, three-way crossover study of CK-2017357 in patients with ALS. 36 to 72 patients will be randomized to one of six different treatment sequences. Each treatment sequence consists of three dosing periods; in each dosing period¸ patients receive a single oral dose of placebo, 250 mg of CK-2017357, or 500 mg of CK-2017357. All six treatment sequences will enroll approximately the same number of patients. A washout period of at least 6 days (to a maximum of 10 days) will be employed between the doses for each patient. This study is designed to assess the effect of CK-2017357 on maximal voluntary muscle strength, on the development of fatigue at maximal and sub-maximal voluntary muscle contraction, and on selected pulmonary function parameters. The plasma concentration of CK-2017357 will be measured at selected time points after each of two single doses of CK-2017357 in men and women. The plasma concentration versus time data obtained in this study may be used to develop a population PK model and estimate inter-subject variability of PK parameters in this target patient population, in particular between male and female study patients.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Amyotrophic Lateral Sclerosis

Intervention

• Drug: Placebo
  Matching placebo in capsules administered as a single oral dose.
• Drug: 250 mg CK-2017357
  250 mg CK-2017357 in capsules administered as a single oral dose.
  Other Name: tirasemtiv
• Drug: 500 mg CK-2017357
  500 mg CK-2017357 in capsules administered as a single oral dose.
  Other Name: tirasemtiv

Study Arms

• Experimental: Treatment Sequence 1
  Treatment sequence 1 consisted of three dosing periods in which patients received single oral doses of placebo, 250 mg, and 500 mg of CK-2017357, in that order, with approximately one week between each dose. Each patient acted as their own control, as all doses were represented in each treatment sequence.
  Interventions:

  • Drug: Placebo
  • Drug: 250 mg CK-2017357
  • Drug: 500 mg CK-2017357
• Experimental: Treatment Sequence 2
  Treatment sequence 2 consisted of three dosing periods in which patients received single oral doses of placebo, 500 mg, and 250 mg of CK-2017357, in that order, with approximately one week between each dose. Each patient acted as their own control, as all doses were represented in each treatment sequence.
  Interventions:

  • Drug: Placebo
  • Drug: 250 mg CK-2017357
  • Drug: 500 mg CK-2017357
• Experimental: Treatment Sequence 3
  Treatment sequence 3 consisted of three dosing periods in which patients received single oral doses of 250 mg, placebo and 500 mg of CK-2017357, in that order, with approximately one week between each dose. Each patient acted as their own control, as all doses were represented in each treatment sequence.
  Interventions:

  • Drug: Placebo
  • Drug: 250 mg CK-2017357
  • Drug: 500 mg CK-2017357
• Experimental: Treatment Sequence 4
  Treatment sequence 4 consisted of three dosing periods in which patients received single oral doses of 250 mg, 500 mg and placebo of CK-2017357, in that order, with approximately one week between each dose. Each patient acted as their own control, as all doses were represented in each treatment sequence.
  Interventions:

  • Drug: Placebo
  • Drug: 250 mg CK-2017357
  • Drug: 500 mg CK-2017357
• Experimental: Treatment Sequence 5
  Treatment sequence 5 consisted of three dosing periods in which patients received single oral doses of 500 mg, placebo, and 250 mg of CK-2017357, in that order, with approximately one week between each dose. Each patient acted as their own control, as all doses were represented in each treatment sequence.
  Interventions:

  • Drug: Placebo
  • Drug: 250 mg CK-2017357
  • Drug: 500 mg CK-2017357
• Experimental: Treatment Sequence 6
  Treatment sequence6 consisted of three dosing periods in which patients received single oral doses of 500 mg, 250 mg, and placebo of CK-2017357, in that order, with approximately one week between each dose. Each patient acted as their own control, as all doses were represented in each treatment sequence.
  Interventions:

  • Drug: Placebo
  • Drug: 250 mg CK-2017357
  • Drug: 500 mg CK-2017357

• Publications *: Shefner J, Cedarbaum JM, Cudkowicz ME, Maragakis N, Lee J, Jones D, Watson ML, Mahoney K, Chen M, Saikali K, Mao J, Russell AJ, Hansen RL, Malik F, Wolff AA; Neals/Cytokinetics Study Team. Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012 Sep;13(5):430-8. doi: 10.3109/17482968.2012.684214. Epub 2012 May 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 11, 2011): 67
• Original Estimated Enrollment (submitted: March 17, 2010): 36
• Actual Study Completion Date: November 2010
• Actual Primary Completion Date: November 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

For enrollment, patients were required to satisfy all of the following criteria at baseline:

1. Able to comprehend and willing to sign an Informed Consent Form (ICF)

1. A diagnosis of familial or sporadic ALS (defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology El Escorial criteria) (Brooks, Miller et al. 2000)
2. Males or females 18 years of age or older
3. Body Mass Index (BMI) of 18.0 to 30.0 kg/m2, inclusive
4. Maximum voluntary grip strength in at least one hand between 10 and 40 pounds (females) or 10 and 60 pounds (males)
5. Able to swallow capsules with water
6. Upright Slow Vital Capacity (SVC) > 40% of predicted for age, height, and sex [See Appendix 16.6.1]
7. Able to perform pulmonary function tests
8. Pre-study clinical laboratory findings (including troponin I [TnI] and creatine phosphokinase [CPK]) within normal range, or, if outside of the normal range, deemed not clinically significant by the Investigator
9. For female patients only: The patient is post-menopausal (≥ 1 year) or sterilized, or if she is of childbearing potential, she is not breastfeeding, her pregnancy test is negative, she has no intention to become pregnant during the course of the study, and she is using contraceptive drugs or devices for the duration of the study and for 10 weeks after the end of the study.

For male patients only: Male patients agree for the duration of the study and 10 weeks after the end of the study 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) or the male patient must agree to abstain from sexual intercourse for 10 weeks after the end of the study.

Exclusion Criteria

Patients satisfying any of the following criteria at baseline were excluded from enrollment:

1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN)
2. Life expectancy < 3 months
3. Participation in any trial in which receipt of investigational study drug occurred within 30 days prior to dosing
4. Any prior treatment with CK-2017357
5. In the opinion of the Investigator, the patient is not suitable to participate in the study

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01089010
• Other Study ID Numbers: CY 4021
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Cytokinetics
• Original Responsible Party: Andrew Wolff, MD, FACC, Chief Medical Officer, Cytokinetics, Inc.
• Current Study Sponsor: Cytokinetics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Jeremy M Shefner, MD, PhD; State University of New York - Upstate Medical University

• PRS Account: Cytokinetics
• Verification Date: May 2019