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

Amyotrophic Lateral Sclerosis Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01709149
• Other study ID #: CY 4026
• Status: Completed
• Phase: Phase 2
• Start date: October 2012
• Est. completion date: March 2014

Study information

• Verified date: March 2020
• Source: Cytokinetics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 711
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

Drug:
• CK-2017357
CK-2017357 125 mg tablets twice daily

Other:
• Placebo tablets
Tablets

Drug:
• Riluzole
Tablets

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Cytokinetics

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Ireland,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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