Back to resultsA Study of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)
Primary Purpose
Amyotrophic Lateral Sclerosis
Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Placebo
250 mg CK-2017357
500 mg CK-2017357
Sponsored by
About this trial
This is an interventional treatment trial for Amyotrophic Lateral Sclerosis
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)
- 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)
- Males or females 18 years of age or older
- Body Mass Index (BMI) of 18.0 to 30.0 kg/m2, inclusive
- Maximum voluntary grip strength in at least one hand between 10 and 40 pounds (females) or 10 and 60 pounds (males)
- Able to swallow capsules with water
- Upright Slow Vital Capacity (SVC) > 40% of predicted for age, height, and sex [See Appendix 16.6.1]
- Able to perform pulmonary function tests
- 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
- 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:
- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN)
- Life expectancy < 3 months
- Participation in any trial in which receipt of investigational study drug occurred within 30 days prior to dosing
- Any prior treatment with CK-2017357
- In the opinion of the Investigator, the patient is not suitable to participate in the study
Sites / Locations
- Phoenix Neurological Associates, Ltd.
- University Neurology Associates
- California Pacific Medical Center
- Mayo Clinic Florida
- University of Kentucky
- Johns Hopkins Hospital
- Massachusetts General Hospital
- Washington University
- SUNY Upstate Medical Center
- Duke University
- Providence ALS Center
- Drexel University College of Medicine, Dept of Neurology
- Penn State
- The University of Texas Health Science Center at San Antonio
- University of Vermont
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Treatment Sequence 1
Treatment Sequence 2
Treatment Sequence 3
Treatment Sequence 4
Treatment Sequence 5
Treatment Sequence 6
Arm Description
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.
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.
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.
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.
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.
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.
Outcomes
Primary Outcome Measures
ALSFRS-R
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
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
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
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)
SVC is measured using the Puritan Bennett Renaissance II Spirometry System and accessories.
Maximum Voluntary Ventilation (MVV)
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)
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)
MVC is measured using the MicroFET 2 HHD.
Repeated Sub-Maximum Grip Strength Fatigability
Sub-Maximum Grip Strength Fatigability is measured using the DynEx Electronic Hand. Dynamometer
Secondary Outcome Measures
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and ALSFRS-R.
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
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
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
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
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
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
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
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
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
Effect of CK-2017357 on patient determined global functional assessment
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
Investigator will assess whether they the patient appears the same, better or worse as compared to the patient's status at pre-dose
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01089010
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)
Study Type
Interventional
2. Study Status
Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
March 2010 (undefined)
Primary Completion Date
November 2010 (Actual)
Study Completion Date
November 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Cytokinetics
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
67 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Treatment Sequence 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Treatment Sequence 2
Arm Type
Experimental
Arm Description
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.
Arm Title
Treatment Sequence 3
Arm Type
Experimental
Arm Description
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.
Arm Title
Treatment Sequence 4
Arm Type
Experimental
Arm Description
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.
Arm Title
Treatment Sequence 5
Arm Type
Experimental
Arm Description
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.
Arm Title
Treatment Sequence 6
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Matching placebo in capsules administered as a single oral dose.
Intervention Type
Drug
Intervention Name(s)
250 mg CK-2017357
Other Intervention Name(s)
tirasemtiv
Intervention Description
250 mg CK-2017357 in capsules administered as a single oral dose.
Intervention Type
Drug
Intervention Name(s)
500 mg CK-2017357
Other Intervention Name(s)
tirasemtiv
Intervention Description
500 mg CK-2017357 in capsules administered as a single oral dose.
Primary Outcome Measure Information:
Title
ALSFRS-R
Description
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.
Time Frame
2 days
Title
Maximum grip strength
Description
Measured using the DynEx Electronic Hand Dynamometer. Patients asked to squeeze the device with the maximum possible force to establish the maximum voluntary contraction.
Time Frame
2 days
Title
Maximum grip strength fatigability
Description
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.
Time Frame
2 days
Title
Shoulder extension fatigue
Description
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.
Time Frame
2 days
Title
Slow Vital Capacity (SVC)
Description
SVC is measured using the Puritan Bennett Renaissance II Spirometry System and accessories.
Time Frame
2 days
Title
Maximum Voluntary Ventilation (MVV)
Description
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.
Time Frame
2 days
Title
Sniff Inspiratory Pressure (SNIP)
Description
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
Time Frame
2 days
Title
Maximum Voluntary Muscle Contraction (MVC)
Description
MVC is measured using the MicroFET 2 HHD.
Time Frame
2 days
Title
Repeated Sub-Maximum Grip Strength Fatigability
Description
Sub-Maximum Grip Strength Fatigability is measured using the DynEx Electronic Hand. Dynamometer
Time Frame
2 days
Secondary Outcome Measure Information:
Title
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and ALSFRS-R.
Description
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.
Time Frame
2 days
Title
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum grip strength
Description
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.
Time Frame
2 days
Title
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum grip strength fatigability
Description
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.
Time Frame
2 days
Title
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and shoulder extension fatigue
Description
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.
Time Frame
2 days
Title
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and slow vital capacity
Description
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.
Time Frame
2 days
Title
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum voluntary ventilation
Description
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.
Time Frame
2 days
Title
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and sniff inspiratory pressure
Description
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.
Time Frame
2 days
Title
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum voluntary muscle contraction
Description
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.
Time Frame
2 days
Title
Characterize the relationship, if any, between the plasma concentration of CK-2017357 and repeated sub-maximum grip strength fatigability
Description
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.
Time Frame
2 days
Title
Number of patients with adverse events
Time Frame
4 weeks
Title
Effect of CK-2017357 on patient determined global functional assessment
Description
Patients will be asked to assess whether they feel the same, better or worse as compared to how they felt pre-dose
Time Frame
2 days
Title
Effect of CK-2017357 on investigator determined global functional assessment
Description
Investigator will assess whether they the patient appears the same, better or worse as compared to the patient's status at pre-dose
Time Frame
2 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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)
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)
Males or females 18 years of age or older
Body Mass Index (BMI) of 18.0 to 30.0 kg/m2, inclusive
Maximum voluntary grip strength in at least one hand between 10 and 40 pounds (females) or 10 and 60 pounds (males)
Able to swallow capsules with water
Upright Slow Vital Capacity (SVC) > 40% of predicted for age, height, and sex [See Appendix 16.6.1]
Able to perform pulmonary function tests
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
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:
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN)
Life expectancy < 3 months
Participation in any trial in which receipt of investigational study drug occurred within 30 days prior to dosing
Any prior treatment with CK-2017357
In the opinion of the Investigator, the patient is not suitable to participate in the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeremy M Shefner, MD, PhD
Organizational Affiliation
State University of New York - Upstate Medical University
Official's Role
Study Chair
Facility Information:
Facility Name
Phoenix Neurological Associates, Ltd.
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85018
Country
United States
Facility Name
University Neurology Associates
City
Fresno
State/Province
California
ZIP/Postal Code
93701
Country
United States
Facility Name
California Pacific Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94115
Country
United States
Facility Name
Mayo Clinic Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
University of Kentucky
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
SUNY Upstate Medical Center
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27705
Country
United States
Facility Name
Providence ALS Center
City
Portland
State/Province
Oregon
ZIP/Postal Code
97213
Country
United States
Facility Name
Drexel University College of Medicine, Dept of Neurology
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19102
Country
United States
Facility Name
Penn State
City
University Park
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Facility Name
The University of Texas Health Science Center at San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
University of Vermont
City
Burlington
State/Province
Vermont
ZIP/Postal Code
05401
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
22591195
Citation
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.
Results Reference
result
Links:
URL
http://www.ncbi.nlm.nih.gov/pubmed/22591195
Description
Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis.
Learn more about this trial
A Study of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS)
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