Clinical trial NCT01089010: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Lead sponsor: Cytokinetics
Sponsor class: INDUSTRY
First posted: 2010-03-18
Enrollment: 67
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: ALSFRS-R
timeFrame: 2 days
measure: Maximum grip strength
timeFrame: 2 days
measure: Maximum grip strength fatigability
timeFrame: 2 days
measure: Shoulder extension fatigue
timeFrame: 2 days
measure: Slow Vital Capacity (SVC)
timeFrame: 2 days
measure: Maximum Voluntary Ventilation (MVV)
timeFrame: 2 days
measure: Sniff Inspiratory Pressure (SNIP)
timeFrame: 2 days
measure: Maximum Voluntary Muscle Contraction (MVC)
timeFrame: 2 days
measure: Repeated Sub-Maximum Grip Strength Fatigability
timeFrame: 2 days
Secondary outcomes:
measure: Characterize the relationship, if any, between the plasma concentration of CK-2017357 and ALSFRS-R.
timeFrame: 2 days
measure: Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum grip strength
timeFrame: 2 days
measure: Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum grip strength fatigability
timeFrame: 2 days
measure: Characterize the relationship, if any, between the plasma concentration of CK-2017357 and shoulder extension fatigue
timeFrame: 2 days
measure: Characterize the relationship, if any, between the plasma concentration of CK-2017357 and slow vital capacity
timeFrame: 2 days
measure: Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum voluntary ventilation
timeFrame: 2 days
measure: Characterize the relationship, if any, between the plasma concentration of CK-2017357 and sniff inspiratory pressure
timeFrame: 2 days
measure: Characterize the relationship, if any, between the plasma concentration of CK-2017357 and maximum voluntary muscle contraction
timeFrame: 2 days
measure: Characterize the relationship, if any, between the plasma concentration of CK-2017357 and repeated sub-maximum grip strength fatigability
timeFrame: 2 days
measure: Number of patients with adverse events
timeFrame: 4 weeks
measure: Effect of CK-2017357 on patient determined global functional assessment
timeFrame: 2 days
measure: Effect of CK-2017357 on investigator determined global functional assessment
timeFrame: 2 days
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Neurological Associates, Ltd.
state: Arizona
city: Fresno
country: United States
facility: University Neurology Associates
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Syracuse
country: United States
facility: SUNY Upstate Medical Center
state: New York
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Portland
country: United States
facility: Providence ALS Center
state: Oregon
city: Philadelphia
country: United States
facility: Drexel University College of Medicine, Dept of Neurology
state: Pennsylvania
city: University Park
country: United States
facility: Penn State
state: Pennsylvania
city: San Antonio
country: United States
facility: The University of Texas Health Science Center at San Antonio
state: Texas
city: Burlington
country: United States
facility: University of Vermont
state: Vermont
Study officials:
affiliation: State University of New York - Upstate Medical University
name: Jeremy M Shefner, MD, PhD
role: STUDY_CHAIR
References:
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.