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

Cytokinetics67 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

Conditions

Amyotrophic Lateral Sclerosis

Interventions

PlaceboDRUG

Matching placebo in capsules administered as a single oral dose.

250 mg CK-2017357DRUG

250 mg CK-2017357 in capsules administered as a single oral dose.

500 mg CK-2017357DRUG

500 mg CK-2017357 in capsules administered as a single oral dose.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (15)

Phoenix Neurological Associates, Ltd.

Phoenix, Arizona, United States

University Neurology Associates

Fresno, California, United States

Outcomes

Primary Outcomes

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.

Time frame: 2 days

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.

Time frame: 2 days

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.

Time frame: 2 days

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.

Time frame: 2 days

Slow Vital Capacity (SVC)

SVC is measured using the Puritan Bennett Renaissance II Spirometry System and accessories.

Time frame: 2 days

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.

Time frame: 2 days

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

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

Time frame: 2 days

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.

Time frame: 2 days

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.

Time frame: 2 days

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.

Time frame: 2 days

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.

Time frame: 2 days

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.

Time frame: 2 days

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.

Time frame: 2 days

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.

Time frame: 2 days

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.

Time frame: 2 days

Number of patients with adverse events

Time frame: 4 weeks

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

Time frame: 2 days

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

Time frame: 2 days