Clinical trial NCT01709149: Study of Safety, Tolerability & Efficacy of CK-2017357 in Amyotrophic Lateral Sclerosis (ALS)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Lead sponsor: Cytokinetics
Sponsor class: INDUSTRY
First posted: 2012-10-18
Enrollment: 711
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Baseline, 8 weeks, 12 weeks
Secondary outcomes:
measure: 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
timeFrame: Baseline, 8 weeks, 12 weeks
measure: 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
timeFrame: Baseline, 8 weeks, 12 weeks
measure: 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
timeFrame: Baseline, 8 weeks, 12 weeks
measure: 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
timeFrame: Baseline, 8 weeks, 12 weeks
measure: 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
timeFrame: Baseline, 8 weeks, 12 weeks
measure: 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
timeFrame: Baseline, 8 weeks, 12 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurology
state: Arizona
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Orange
country: United States
facility: UC Irvine ALS & Neuromuscular Center
state: California
city: San Diego
country: United States
facility: Coordinated Clinical Research
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center Forbes Norris MDA/ALS Research Center
state: California
city: New Britain
country: United States
facility: Hospital for Special Care
state: Connecticut
city: Washington
country: United States
facility: The George Washington University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic Florida Department of Neurology
state: Florida
city: Atlanta
country: United States
facility: Emory University, School of Medicine
state: Georgia
city: Augusta
country: United States
facility: Georgia Health Sciences University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University Department of Neurology
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Medical School
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Grand Rapids
country: United States
facility: St Mary's Healthcare
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center - Berman Center for Research
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Lincoln
country: United States
facility: Neurology Associates
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center
state: New Hampshire
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center Department of Neurology
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University, School of Medicine
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Department of Neurology
state: Ohio
city: Portland
country: United States
facility: Providence ALS Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Neuroscience Clinics
state: Pennsylvania
city: Philadelphia
country: United States
facility: Drexel Neurology
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: Texas Neurology
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: UTHSCSA Department of Neurology
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Morgantown
country: United States
facility: West Virginia University Department of Neurology
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Calgary
country: Canada
facility: Heritage Medical Research
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta Hospital
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Fredericton
country: Canada
facility: Stan Cassidy Centre for Rehabilitation
state: New Brunswick
city: Halifax
country: Canada
facility: QE II Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster University Medical Centre
state: Ontario
city: Kingston
country: Canada
facility: Queen's University : Kingston General
state: Ontario
city: London
country: Canada
facility: London Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: Univ. of Toronto - Sunnybrook Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: Hôpital Notre Dame (CHUM) Centre Hospitalier de l'Universite de Montreal
state: Quebec
city: Montreal
country: Canada
facility: Montreal Neurological Institute
state: Quebec
city: Quebec
country: Canada
facility: CHU de Quebec: Hopital l'Enfant-Jesus
city: Lille
country: France
facility: CHRU de Lille - Hôpital Roger Salengro
city: Limoges
country: France
facility: CHU de Limoges - Hôpital Dupuytren
city: Marseille
country: France
facility: Hôpital La Timone Adulte
city: Montpellier
country: France
facility: CHU Montepellier
city: Nice
country: France
facility: Hôpital Archet 1
city: Paris
country: France
facility: Hôpital de la Salpêtrière
city: Tours
country: France
facility: Hôpital Bretonneau
city: Berlin
country: Germany
facility: Charite Universitätsmedizin
city: Hannover
country: Germany
facility: Hannover Medical School
city: Ulm
country: Germany
facility: University of Ulm
city: Dublin
country: Ireland
facility: Trinity College, Beaumont Hospital
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Madrid
country: Spain
facility: Hospital Carlos III
city: Whitechapel
country: United Kingdom
facility: Barts and the London MND & the Centre Royal London Hospital
state: London
city: Liverpool
country: United Kingdom
facility: Walton Centre for Neurology and Neurosurgery
city: London
country: United Kingdom
facility: Kings College Hospital NHS Foundation Trust
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
city: Plymouth
country: United Kingdom
facility: Plymouth Hospitals NHS Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Institute for Translational Neuroscience
Study officials:
affiliation: Cytokinetics, Inc.
name: Jinsy Andrews, MD
role: STUDY_DIRECTOR
affiliation: State University of New York - Upstate Medical University
name: Jeremy Shefner, MD, PhD
role: STUDY_CHAIR
affiliation: State University of New York - Upstate Medical University
name: Jeremy Shefner, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: