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

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.

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.

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