Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year

NCT ID: NCT02496767

Last Updated: 2020-09-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 744 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-03
• Study Completion Date: 2017-09-27

Brief Summary

This study assessed the effect of tirasemtiv versus placebo on respiratory function in patients with ALS.

Detailed Description

CY 4031 was a multi-national, double-blind, randomized, placebo-controlled, stratified, parallel group study of tirasemtiv in patients with ALS. The study had three phases: an open-label phase (2 weeks), a double-blind, placebo-controlled phase (48 weeks), and a double-blind, placebo-controlled tirasemtiv withdrawal phase (4 weeks). Patients who completed 2 weeks of treatment with open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three dose levels of tirasemtiv (250 mg/day, 375 mg/day, or 500 mg/day). Approximately 600 patients were planned to be enrolled into the open-label treatment phase.

Patients taking riluzole at study entry could continue use of riluzole during the study as long as they had been on a stable dose for at least 30 days prior to study screening. In addition, for patients randomized to tirasemtiv, the riluzole dose was reduced to half the approved dose (ie, reduced to 50 mg once daily) because administration of tirasemtiv approximately doubles the exposure to concomitant riluzole. Patients randomized to placebo continued riluzole at 50 mg twice daily. This was accomplished without unmasking the study's blind as follows:

1. All patients on riluzole took their morning 50 mg dose of riluzole from their personal riluzole supply.

2. The sponsor supplied the evening riluzole dose as double-blind study medication, as follows: (a) for patients randomized to placebo, the double-blind, evening riluzole dose was 50 mg of active riluzole; (b) for patients randomized to tirasemtiv, the double-blind, evening riluzole dose was a matching placebo for riluzole.

Conditions

Amyotrophic Lateral Sclerosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Group 1 - Placebo

Day 1 through Week 48: 2 placebo tablets twice daily

Group Type: PLACEBO_COMPARATOR

Placebo tablets

Intervention Type: DRUG

Group 2 - 250 mg tirasemtiv

Day 1 through Week 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM

Group Type: EXPERIMENTAL

Tirasemtiv

Intervention Type: DRUG

Placebo tablets

Intervention Type: DRUG

Group 3 - 375 mg tirasemtiv

Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the PM; Weeks 3 through 48: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM

Group Type: EXPERIMENTAL

Tirasemtiv

Intervention Type: DRUG

Placebo tablets

Intervention Type: DRUG

Group 4 - 500 mg tirasemtiv

Day 1 through Week 2: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in PM; Weeks 3 and 4: 1 tablet of tirasemtiv (125 mg) and 1 tablet of matching placebo in the AM and 2 tablets of tirasemtiv (250 mg) in the PM; Weeks 5 through 48: 2 tablets of tirasemtiv (250 mg) in the AM and 2 tablets of tirasemtiv (250 mg) in the PM

Group Type: EXPERIMENTAL

Tirasemtiv

Intervention Type: DRUG

Placebo tablets

Intervention Type: DRUG

Interventions

Tirasemtiv

Intervention Type: DRUG

Placebo tablets

Intervention Type: DRUG

Other Intervention Names

CK-2017357

Eligibility Criteria

Inclusion Criteria

• 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) ≤ 24 months prior to screening
• Upright SVC ≥ 70 % of predicted for age, height and sex
• Able to swallow tablets without crushing, and in the opinion of the Investigator, is expected to continue to be able to do so during the trial
• A caregiver if one is needed
• Clinical laboratory findings within the normal range or, if outside 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 childbearing potential (i.e., following menarche until post-menopausal if not anatomically and physiologically incapable of becoming pregnant) 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, unless the male patient has had a vasectomy and confirmed sperm count is zero
• 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 effective contraceptive drugs or devices while requiring male partner to use a condom 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 until they complete study drug dosing

Exclusion Criteria

• At the time of screening, any use of non-invasive positive pressure ventilation (NIPPV, e.g. continuous positive airway pressure [CPAP] or bi-level 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
• BMI of 20.0 kg/m2 or lower
• Unwilling or unable to discontinue tizanidine and theophylline-containing medications during study participation
• Serum chloride outside the normal reference range
• Neurological impairment due to a condition other than ALS, including history of transient ischemic attack within the past year
• Presence at screening of any medically significant cardiac, pulmonary, 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, including, but not limited to:

1. Poorly controlled hypertension

2. NYHA Class II or greater congestive heart failure

3. Chronic obstructive pulmonary disease or asthma requiring daily use bronchodilator medications

4. GI disorder that might impair absorption of study drug

5. History of significant liver disease defined by bilirubin > 2 times the upper limit of normal (ULN) or ALT or AST > 3 times the ULN on repeat testing

6. Poorly controlled diabetes mellitus

7. History of vertigo within three months of study entry

8. History of syncope without an explainable or treated cause

9. History of untreated intracranial aneurysm or poorly controlled seizure disorder

10. Amputation of a limb

11. Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient's ability to give informed consent and to understand and/or comply with study procedures

12. Cancer with metastatic potential (other than basal cell carcinoma, carcinoma in situ of the cervix, or squamous cell carcinoma of the skin excised with clean margins) diagnosed and treated within the last two years

13. Any other condition, impairment or social circumstance that, in the opinion of the Investigator, would render the patient not suitable to participate in the study

14. Patient judged to be actively suicidal or a suicide risk by the Investigator

• Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is greater, prior to dosing
• Prior participation in any form of stem cell therapy for the treatment of ALS
• Previously received tirasemtiv in any previous clinical trial

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cytokinetics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

MD

Role: STUDY_DIRECTOR

Cytokinetics

Locations

St. Joseph's Hospital & Medical Center - Barrow Neurology Clinics

Phoenix, Arizona, United States

University of California San Diego

La Jolla, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

University of California, Irvine

Orange, California, United States

University of California Davis Medical Center

Sacramento, California, United States

Forbes Norris MDA/ALS Research Center

San Francisco, California, United States

Stanford Hospital and Clinics

Stanford, California, United States

University of Colorado Hospital Anschutz Outpatient Pavilion

Aurora, Colorado, United States

Hospital for Special Care

New Britain, Connecticut, United States

George Washington University Medical Center

Washington D.C., District of Columbia, United States

Mayo Clinic

Jacksonville, Florida, United States

University of Miami

Miami, Florida, United States

Carol and Frank Morsini Center for Advanced Health Care - University of South Florida

Tampa, Florida, United States

The Emory Clinic

Atlanta, Georgia, United States

Georgia Regents University

Augusta, Georgia, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

Indiana University

Indianapolis, Indiana, United States

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Johns Hopkins University

Baltimore, Maryland, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts, United States

University of Michigan Hospital and Health System

Ann Arbor, Michigan, United States

Henry Ford Health System

Detroit, Michigan, United States

Hennepin County Medical Center

Minneapolis, Minnesota, United States

Saint Louis University

St Louis, Missouri, United States

Barnes-Jewish Hospital

St Louis, Missouri, United States

Neurology Associates

Lincoln, Nebraska, United States

Dartmouth Hitchcock Medical Center Dept of Neurology

Lebanon, New Hampshire, United States

Hospital for Special Surgery

New York, New York, United States

Neurological Institute Columbia University Medical Center

New York, New York, United States

SUNY Upstate Medical University

Syracuse, New York, United States

Neurosciences Institute: Neurology - Charlotte

Charlotte, North Carolina, United States

Duke Neurological Disorders Clinic

Durham, North Carolina, United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

Providence Brain and Spine Institute ALS Center

Portland, Oregon, United States

Oregon Health and Science Center

Portland, Oregon, United States

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania, United States

The Penn Comprehensive Neuroscience Center

Philadelphia, Pennsylvania, United States

Temple University School of Medicine

Philadelphia, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Texas Neurology

Dallas, Texas, United States

Baylor College of Medicine

Houston, Texas, United States

University of Texas Health Science Center

San Antonio, Texas, United States

University of Virgina Health System

Charlottesville, Virginia, United States

University of Washington Medical Center

Seattle, Washington, United States

West Virginia University Department of Neurology

Morgantown, West Virginia, United States

Froedtert Memorial Lutheran Hospital, Department of Neurology

Milwaukee, Wisconsin, United States

UZ Leuven - Campus Gasthuisberg

Leuven, Vlaams Brabant, Belgium

University of Calgary

Calgary, Alberta, Canada

Edmonton Kaye Clinic

Edmonton, Alberta, Canada

Stan Cassidy Centre for Rehabilitation

Fredericton, New Brunswick, Canada

QE II Health Sciences Centre, NHI Site

Halifax, Nova Scotia, Canada

McMaster University Medical Centre

Hamilton, Ontario, Canada

London Health Sciences Centre

London, Ontario, Canada

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Notre-Dame Hospital/CHUM

Montreal, Quebec, Canada

Montreal Neurological Institute and Hospital

Montreal, Quebec, Canada

CHU de Quebec - Universite Laval Hopital de l'Enfant-Jesus

Québec, , Canada

Hopital R. Salengro, CHRU Lille

Lille, , France

CHU Dupuytren

Limoges, , France

Hopital de la Timone

Marseille, , France

Hopital Gui de Chauliac

Montpellier, , France

CHU de Nice - Hopital Pasteur 2

Nice, , France

Hopital de la Salpetriere

Paris, , France

Bretonneau University Hospital

Tours, , France

University of Ulm, Department of Neurology

Ulm, Baden-Wurttemberg, Germany

Hannover Medical School, Department of Neurology

Hanover, Lower Saxony, Germany

Charite Campus Virchow-Klinikum, Neurology Department

Berlin, , Germany

Clinical Research Centre, Beaumont Hospital

Dublin, , Ireland

IRCCS Istituto Auxologico Italiano - U.O. Neurologia

Milan, , Italy

Centro Clinico NEMO - Fondazione Serena Onlus, ASST Grande Ospedale Metropolitano Niguarda

Milan, , Italy

Dipartimento di Neuroscienze "Rita Levi Moltalcini" A.O.U. Citta della Salute e della Scienza di Torino P.O. "Molinette"

Torino, , Italy

University Medical Center Utrecht

Utrecht, , Netherlands

Hospital Santa Maria-Centro Hospitalar Lisboa Norte

Lisbon, , Portugal

Hospital San Rafael

Madrid, , Spain

Derriford Hospital

Plymouth, Devon, United Kingdom

Walton Centre for Neurology and Neurosurgery

Liverpool, , United Kingdom

Clinical Research Centre, Royal London Hospital

London, , United Kingdom

Kings College Hospital

London, , United Kingdom

Countries

United States; Belgium; Canada; France; Germany; Ireland; Italy; Netherlands; Portugal; Spain; United Kingdom

References

Simkins TJ, Kupfer S, Malik FI, Meng L, Rudnicki SA, Wei J, Shefner JM, Bowser R. Plasma neurofilament analysis in VITALITY-ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2025 Feb;26(1-2):103-112. doi: 10.1080/21678421.2024.2423707. Epub 2024 Nov 8.

Reference Type: DERIVED

PMID: 39513379 (View on PubMed)

Andrews JA, Cudkowicz ME, Hardiman O, Meng L, Bian A, Lee J, Wolff AA, Malik FI, Shefner JM. VITALITY-ALS, a phase III trial of tirasemtiv, a selective fast skeletal muscle troponin activator, as a potential treatment for patients with amyotrophic lateral sclerosis: study design and baseline characteristics. Amyotroph Lateral Scler Frontotemporal Degener. 2018 May;19(3-4):259-266. doi: 10.1080/21678421.2018.1426770. Epub 2018 Feb 6.

Reference Type: DERIVED

PMID: 29402141 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2014-005413-23

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CY 4031

Identifier Type: -

Identifier Source: org_study_id