Study of Safety, Tolerability & Efficacy of CK-2017357 in Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate the safety and effectiveness of CK-2017357 when taken with or without riluzole (also called Rilutek®) in patients with Amyotrophic Lateral Sclerosis (ALS).

Detailed Description
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The length of the study, including screening, dosing, and follow-up, is approximately 20 weeks. After a one-week open-label phase during which all patients will receive CK-2017357 125 milligrams (mg) twice daily, patients who tolerate the open-label 125 mg of CK-2017357 will be randomized one to one (fifty-fifty) to receive double-blind CK-2017357 or matching placebo. The CK-2017357/placebo dose will be increased no faster than weekly to each patient's highest tolerated daily dose, with a maximum of 250 mg twice daily. The dose may be decreased based on tolerability. Patients will continue treatment at the highest tolerated dose to complete a total of 12 weeks of double-blind treatment. Patients may be on riluzole or not on riluzole at study entry. Patients not on riluzole must stay off riluzole. Patients on riluzole who are getting double-blind CK-2017357 will be given riluzole at half the labeled dosage (50 mg once a day instead of 50 mg twice a day). Blood tests for safety will be performed. Information about any side effects that may occur will also be collected.

Official Title
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A Phase IIb, Multi-National, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Efficacy of CK-2017357 in Patients With Amyotrophic Lateral Sclerosis (ALS) (BENEFIT-ALS)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: CK-2017357
* Other: Placebo tablets
* Drug: Riluzole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to comprehend and willing to sign an Informed Consent Form (ICF) Male or female 18 years of age or older 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) Upright Slow Vital Capacity (SVC) >50 % of predicted for age, height and sex At least 4 of the 12 ALSFRS-R questions must be scored 2 or 3 Diminished but measurable maximum voluntary grip strength in at least one hand; i.e., between 10 and 50 pounds (females) and 10 and 70 pounds (males) Able to swallow tablets without crushing A caregiver (if one is needed) who can and will observe and report the patient's status Pre-study clinical laboratory findings within normal range or, if outside of the normal range, deemed not clinically significant by the Investigator Male patients must 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 during and for 10 weeks after the end of the study Female patients must be post-menopausal (≥ 1 year) or sterilized, or, if of childbearing potential, not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the course of the study, and use contraceptive drugs or devices as detailed in item 10 for the duration of the study and for 10 weeks after the end of the study Patients must be either on a stable dose of riluzole 50 mg twice daily for at least 30 days prior to screening or have not taken riluzole for at least 30 days prior to screening and are willing not to begin riluzole use during the conduct of this study. Exclusion Criteria: Any use of non-invasive positive pressure ventilation (NIPPV, e.g. continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP]) for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation Patients with a diaphragm pacing system (DPS) at study entry or who anticipate DPS placement during the course of the study Body Mass Index (BMI) of 19.0 kg/m2 or lower Unwilling to discontinue tizanidine and theophylline-containing medications during study participation Serum chloride < 100 mmol/L Neurological impairment due to a condition other than ALS, including history of transient ischemic attack (TIA) within the past year Presence at screening of any medically significant cardiac, pulmonary, gastrointestinal (GI), musculoskeletal, or psychiatric illness that might interfere with the patient's ability to comply with study procedures or that might confound the interpretation of clinical safety or efficacy data Has taken any investigational study drug within 30 days or 5 half-lives of the prior agent, whichever is greater, prior to dosing Previously received CK-2017357 in any previous clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CK-2017357<br>125 mg tablets | Drug: CK-2017357<br>* CK-2017357 125 mg tablets twice daily<br>* Other names: tirasemtiv;Drug: Riluzole<br>* Tablets<br>* Other names: Rilutek;|
| Placebo Comparator: Placebo<br>Placebo tablets | Other: Placebo tablets<br>* Tablets<br>Drug: Riluzole<br>* Tablets<br>* Other names: Rilutek;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change From Baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) Total Score to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment | The ALSFRS-R is used to measure the progression and severity of disease; it consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in 4 domains: gross motor tasks, fine motor tasks, bulbar functions, and respiratory function. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The total score ranges from 0 to 48, with higher scores reflecting more normal function and lower scores reflecting more impaired function. | Baseline, 8 weeks, 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Maximum Voluntary Ventilation (MVV) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment | MVV was measured as the volume (in liters) of air that could be exhaled during 12 seconds of rapid deep breathing; for analysis purposes, the measured volume was extrapolated to 1 minute (to give units of L/min). | Baseline, 8 weeks, 12 weeks | 
| Change From Baseline in Sniff Nasal Inspiratory Pressure (SNIP) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment | SNIP was measured at functional residual capacity, the bottom of the tidal breathing cycle, through 1 plugged nostril while the other remained open. Inspiratory pressure is a negative number where a larger negative number represents . . . A forceful, maximal inspiratory sniff was performed and a peak pressure value reported. The best result (ie, the highest number) from 5 tests was recorded as the SNIP. | Baseline, 8 weeks, 12 weeks | 
| Change From Baseline in Slow Vital Capacity (SVC) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment | SVC was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, the patients were instructed to take as deep an inspiration as possible followed by a maximum exhalation (blowing out all the air in their lungs). Values obtained were converted to % predicted values (ie, the test result as a percent of predicted values for the patients of similar demographic and baseline characteristics [eg, height, age, sex]). | Baseline, 8 weeks, 12 weeks | 
| Change From Baseline in Maximum Handgrip Strength in the Weaker Hand to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment | Maximum handgrip strength was measured using an electronic hand dynamometer; patients were asked to squeeze the device with the maximum possible force. | Baseline, 8 weeks, 12 weeks | 
| Change From Baseline in Handgrip Fatigability (at 60% of Target in the Weaker Hand) to the Average of Values Obtained at the End of Weeks 8 and 12 of Double-blind Treatment | Handgrip fatigability was measured immediately following determination of maximum handgrip strength (via an electronic hand dynamometer). Once maximum handgrip strength was achieved, the force of the grip was timed for 2 minutes or until the grip strength had dropped to 60% of the maximum, whichever came first. | Baseline, 8 weeks, 12 weeks | 
| Change From Baseline in Muscle Strength Mega-Score Based on Percent Change in Muscle Strength Measurements to the Average at the End of Weeks 8 and 12 of Double-blind Treatment | A hand-held dynamometer (HHD), with a scale of 0 to 300 pounds, was used to measure muscle strength and handgrip strength (bilateral); the muscle groups tested were: elbow flexion (bilateral), wrist extension (bilateral), knee extension (bilateral), and ankle dorsiflexion (bilateral). For each assessment time point, the percent change from baseline was calculated for each muscle group and handgrip strength. The muscle strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength. | Baseline, 8 weeks, 12 weeks |