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

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)

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).

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: CK-2017357; Drug: Riluzole; Other: Placebo tablets

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 711
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1J 1Z4
    • CHU de Quebec: Hopital l'Enfant-Jesus
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • Heritage Medical Research
    • Edmonton, Alberta, Canada, B3H 3A7
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 2G9
      • University of British Columbia
  • New Brunswick
    • Fredericton, New Brunswick, Canada, E3B 0C7
      • Stan Cassidy Centre for Rehabilitation
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • QE II Health Sciences Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8S 4K1
      • McMaster University Medical Centre
    • Kingston, Ontario, Canada, K7L 2V7
      • Queen's University : Kingston General
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences
    • Toronto, Ontario, Canada, M4N 3M5
      • Univ. of Toronto - Sunnybrook Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute
    • Montreal, Quebec, Canada, H2L4M1
      • Hôpital Notre Dame (CHUM) Centre Hospitalier de l'Universite de Montreal
• France
  • Lille, France, F-59037 LILLE cedex
    • CHRU de Lille - Hôpital Roger Salengro
  • Limoges, France, 87042 LIMOGES CEDEX
    • Chu de Limoges - Hopital Dupuytren
  • Marseille, France, 13005
    • Hopital la Timone Adulte
  • Montpellier, France, 34295 Montpellier Cedex 5
    • CHU Montepellier
  • Nice, France, 06602
    • Hôpital Archet 1
  • Paris, France, Cedex 13
    • Hôpital de la Salpêtrière
  • Tours, France, 37000
    • Hopital Bretonneau
• Germany
  • Berlin, Germany, 13353
    • Charite Universitatsmedizin
  • Hannover, Germany, 30625
    • Hannover Medical School
  • Ulm, Germany, 89081
    • University of Ulm
• Ireland
  • Dublin, Ireland, 9
    • Trinity College, Beaumont Hospital
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
• Spain
  • Madrid, Spain, 28029
    • Hospital Carlos III
• United Kingdom
  • Liverpool, United Kingdom, L9 7LJ
    • Walton Centre For Neurology And Neurosurgery
  • London, United Kingdom, SE5 8AF
    • Kings College Hospital NHS Foundation Trust
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
  • Plymouth, United Kingdom, PL6 8DH
    • Plymouth Hospitals NHS Trust
  • Sheffield, United Kingdom, S10 2HQ
    • Sheffield Institute for Translational Neuroscience
  • London
    • Whitechapel, London, United Kingdom
      • Barts and the London MND & the Centre Royal London Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurology
  • California
    • La Jolla, California, United States, 92093
      • University of California, San Diego
    • Orange, California, United States, 92868
      • UC Irvine ALS & Neuromuscular Center
    • San Diego, California, United States, 92103
      • Coordinated Clinical Research
    • San Francisco, California, United States, 94115
      • California Pacific Medical Center Forbes Norris MDA/ALS Research Center
  • Connecticut
    • New Britain, Connecticut, United States, 06053
      • Hospital for Special Care
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • The George Washington University
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida Department of Neurology
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University, School of Medicine
    • Augusta, Georgia, United States, 30912
      • Georgia Health Sciences University
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Department of Neurology
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Grand Rapids, Michigan, United States, 49503
      • St Mary's Healthcare
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center - Berman Center for Research
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University
    • Saint Louis, Missouri, United States, 63104
      • Saint Louis University
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Neurology Associates
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New York
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
    • Rochester, New York, United States, 14642
      • University of Rochester
    • Syracuse, New York, United States, 13120
      • SUNY Upstate Medical University
  • North Carolina
    • Charlotte, North Carolina, United States, 27406
      • Carolinas Medical Center Department of Neurology
    • Durham, North Carolina, United States, 27705
      • Duke University
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University, School of Medicine
  • Ohio
    • Columbus, Ohio, United States, 43221
      • Ohio State University Department of Neurology
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University
    • Portland, Oregon, United States, 97213
      • Providence ALS Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Neuroscience Clinics
    • Philadelphia, Pennsylvania, United States, 19107
      • University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Drexel Neurology
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75214
      • Texas Neurology
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78229
      • UTHSCSA Department of Neurology
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Department of Neurology
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Able to comprehend and willing to sign an Informed Consent Form (ICF)
2. Male or female 18 years of age or older
3. 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)
4. Upright Slow Vital Capacity (SVC) >50 % of predicted for age, height and sex
5. At least 4 of the 12 ALSFRS-R questions must be scored 2 or 3
6. 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)
7. Able to swallow tablets without crushing
8. A caregiver (if one is needed) who can and will observe and report the patient's status
9. Pre-study clinical laboratory findings within normal range or, if outside of the normal range, deemed not clinically significant by the Investigator
10. 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
11. 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
12. 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:

1. 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
2. Patients with a diaphragm pacing system (DPS) at study entry or who anticipate DPS placement during the course of the study
3. Body Mass Index (BMI) of 19.0 kg/m2 or lower
4. Unwilling to discontinue tizanidine and theophylline-containing medications during study participation
5. Serum chloride < 100 mmol/L
6. Neurological impairment due to a condition other than ALS, including history of transient ischemic attack (TIA) within the past year
7. 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
8. Has taken any investigational study drug within 30 days or 5 half-lives of the prior agent, whichever is greater, prior to dosing
9. Previously received CK-2017357 in any previous clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo tablets	Drug: Riluzole; Tablets; Other Names: Rilutek; Other: Placebo tablets; Tablets
Experimental: CK-2017357; 125 mg tablets	Drug: CK-2017357; CK-2017357 125 mg tablets twice daily; Other Names: tirasemtiv; Drug: Riluzole; Tablets; Other Names: Rilutek

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Cytokinetics
• Investigators: Principal Investigator: Jeremy Shefner, MD, PhD, State University of New York - Upstate Medical University; Study Director: Jinsy Andrews, MD, Cytokinetics, Inc.

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: October 16, 2012
• First Submitted That Met QC Criteria: October 17, 2012
• First Posted (Estimate): October 18, 2012

Study Record Updates

• Last Update Posted (Actual): March 31, 2020
• Last Update Submitted That Met QC Criteria: March 30, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neuroprotective Agents; Protective Agents; Anticonvulsants; Riluzole
• Other Study ID Numbers: CY 4026