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

May 7, 2019 updated by: Cytokinetics

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)

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.

Study Overview

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

Enrollment (Actual)

67

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Arizona
      • Phoenix, Arizona, United States, 85018
        • Phoenix Neurological Associates, Ltd.
    • California
      • Fresno, California, United States, 93701
        • University Neurology Associates
      • San Francisco, California, United States, 94115
        • California Pacific Medical Center
    • Florida
      • Jacksonville, Florida, United States, 32224
        • Mayo Clinic Florida
    • Kentucky
      • Lexington, Kentucky, United States, 40536
        • University of Kentucky
    • Maryland
      • Baltimore, Maryland, United States, 21287
        • Johns Hopkins Hospital
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts General Hospital
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University
    • New York
      • Syracuse, New York, United States, 13210
        • SUNY Upstate Medical Center
    • North Carolina
      • Durham, North Carolina, United States, 27705
        • Duke University
    • Oregon
      • Portland, Oregon, United States, 97213
        • Providence ALS Center
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19102
        • Drexel University College of Medicine, Dept of Neurology
      • University Park, Pennsylvania, United States, 17033
        • Penn State
    • Texas
      • San Antonio, Texas, United States, 78229
        • The University of Texas Health Science Center at San Antonio
    • Vermont
      • Burlington, Vermont, United States, 05401
        • University of Vermont

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Matching placebo in capsules administered as a single oral dose.
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
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.
Matching placebo in capsules administered as a single oral dose.
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
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.
Matching placebo in capsules administered as a single oral dose.
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
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.
Matching placebo in capsules administered as a single oral dose.
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
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.
Matching placebo in capsules administered as a single oral dose.
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
500 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
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.
Matching placebo in capsules administered as a single oral dose.
250 mg CK-2017357 in capsules administered as a single oral dose.
Other Names:
  • tirasemtiv
500 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
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.
2 days
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.
2 days
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.
2 days
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.
2 days
Slow Vital Capacity (SVC)
Time Frame: 2 days
SVC is measured using the Puritan Bennett Renaissance II Spirometry System and accessories.
2 days
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.
2 days
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
2 days
Maximum Voluntary Muscle Contraction (MVC)
Time Frame: 2 days
MVC is measured using the MicroFET 2 HHD.
2 days
Repeated Sub-Maximum Grip Strength Fatigability
Time Frame: 2 days
Sub-Maximum Grip Strength Fatigability is measured using the DynEx Electronic Hand. Dynamometer
2 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with adverse events
Time Frame: 4 weeks
4 weeks
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.
2 days
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.
2 days
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.
2 days
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.
2 days
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.
2 days
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.
2 days
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.
2 days
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.
2 days
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.
2 days
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
2 days
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
2 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2010

Primary Completion (Actual)

November 1, 2010

Study Completion (Actual)

November 1, 2010

Study Registration Dates

First Submitted

March 16, 2010

First Submitted That Met QC Criteria

March 17, 2010

First Posted (Estimate)

March 18, 2010

Study Record Updates

Last Update Posted (Actual)

May 10, 2019

Last Update Submitted That Met QC Criteria

May 7, 2019

Last Verified

May 1, 2019

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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