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

Amyotrophic Lateral Sclerosis Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01089010
• Other study ID #: CY 4021
• Status: Completed
• Phase: Phase 2
• Start date: March 2010
• Est. completion date: November 2010

Study information

• Verified date: May 2019
• Source: Cytokinetics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 67
• Est. completion date: November 2010
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

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

Locations

Country	Name	City	State
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	University of Vermont	Burlington	Vermont
United States	Duke University	Durham	North Carolina
United States	University Neurology Associates	Fresno	California
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	University of Kentucky	Lexington	Kentucky
United States	Drexel University College of Medicine, Dept of Neurology	Philadelphia	Pennsylvania
United States	Phoenix Neurological Associates, Ltd.	Phoenix	Arizona
United States	Providence ALS Center	Portland	Oregon
United States	Washington University	Saint Louis	Missouri
United States	The University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	California Pacific Medical Center	San Francisco	California
United States	SUNY Upstate Medical Center	Syracuse	New York
United States	Penn State	University Park	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Cytokinetics

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 act — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	2 days
Primary	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.	2 days
Primary	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.	2 days
Primary	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.	2 days
Primary	Slow Vital Capacity (SVC)	SVC is measured using the Puritan Bennett Renaissance II Spirometry System and accessories.	2 days
Primary	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.	2 days
Primary	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	2 days
Primary	Maximum Voluntary Muscle Contraction (MVC)	MVC is measured using the MicroFET 2 HHD.	2 days
Primary	Repeated Sub-Maximum Grip Strength Fatigability	Sub-Maximum Grip Strength Fatigability is measured using the DynEx Electronic Hand. Dynamometer	2 days
Secondary	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.	2 days
Secondary	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.	2 days
Secondary	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.	2 days
Secondary	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.	2 days
Secondary	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.	2 days
Secondary	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.	2 days
Secondary	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.	2 days
Secondary	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.	2 days
Secondary	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.	2 days
Secondary	Number of patients with adverse events		4 weeks
Secondary	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	2 days
Secondary	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	2 days

External Links

•   Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis.