A Phase 3, Multi-National, Double-Blind, Randomized, Placebo-Controlled, Stratified, Parallel Group, Study to Evaluate the Safety, Tolerability and Efficacy of Tirasemtiv in Patients With Amyotrophic Lateral Sclerosis (ALS)

Study Purpose:

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

Study Status:

Not recruiting


Amyotrophic Lateral Sclerosis

Study Type:


Type of Intervention:


Intervention Name:

Tirasemtiv, Placebo tablets



Phase 3

Study Chair(s)/Principal Investigator(s):

MD, Cytokinetics

Clinicaltrials.gov ID:


Neals Affiliated?


Coordinating Center Contact Information

MD Cytokinetics

United States

Full Study Summary:

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.

Study Sponsor:


Estimated Enrollment:


Estimated Study Start Date:

09 / 03 / 2015

Estimated Study Completion Date:

09 / 27 / 2017

Posting Last Modified Date:

09 / 09 / 2020

Date Study Added to neals.org:

07 / 14 / 2015

Minimum Age:

18 Years

Maximum Age:


Can participants use Riluzole?


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

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

Phoenix, Arizona 85013
United States

University of California San Diego

La Jolla, California 92093
United States

Cedars-Sinai Medical Center

Los Angeles, California 90048
United States

University of California, Irvine

Orange, California 92868
United States

University of California Davis Medical Center

Sacramento, California 95817
United States

Forbes Norris MDA/ALS Research Center

San Francisco, California 94115
United States

Stanford Hospital and Clinics

Stanford, California 94305
United States

University of Colorado Hospital Anschutz Outpatient Pavilion

Aurora, Colorado 80045
United States

Hospital for Special Care

New Britain, Connecticut 06053
United States

George Washington University Medical Center

Washington, District of Columbia 20037
United States

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

Tampa, Florida 33612
United States

University of Miami

Miami, Florida 33136
United States

Mayo Clinic

Jacksonville, Florida 32224
United States

The Emory Clinic

Atlanta, Georgia 30322
United States

Georgia Regents University

Augusta, Georgia 30912
United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois 60611
United States

Indiana University

Indianapolis, Indiana 46202
United States

University of Iowa Hospitals and Clinics

Iowa City, Iowa 52242
United States

University of Kansas Medical Center

Kansas City, Kansas 66160
United States

Johns Hopkins University

Baltimore, Maryland 21287
United States

Massachusetts General Hospital

Boston, Massachusetts 02114
United States

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts 01655
United States

University of Michigan Hospital and Health System

Ann Arbor, Michigan 48109
United States

Henry Ford Health System

Detroit, Michigan 48202
United States

Hennepin County Medical Center

Minneapolis, Minnesota 55415
United States

Saint Louis University

Saint Louis, Missouri 63104
United States

Barnes-Jewish Hospital

Saint Louis, Missouri 63110
United States

Neurology Associates

Lincoln, Nebraska 68506
United States

Dartmouth Hitchcock Medical Center Dept of Neurology

Lebanon, New Hampshire 03756
United States

Hospital for Special Surgery

New York, New York 10021
United States

Neurological Institute Columbia University Medical Center

New York, New York 10032
United States

SUNY Upstate Medical University

Syracuse, New York 13210
United States

Neurosciences Institute: Neurology - Charlotte

Charlotte, North Carolina 28207
United States

Duke Neurological Disorders Clinic

Durham, North Carolina 27705
United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina 27157
United States

The Ohio State University Wexner Medical Center

Columbus, Ohio 43221
United States

Oregon Health and Science Center

Portland, Oregon 97239
United States

Providence Brain and Spine Institute ALS Center

Portland, Oregon 97213
United States

Penn State Milton S. Hershey Medical Center

Hershey, Pennsylvania 17033
United States

The Penn Comprehensive Neuroscience Center

Philadelphia, Pennsylvania 19107
United States

Temple University School of Medicine

Philadelphia, Pennsylvania 19140
United States

Vanderbilt University Medical Center

Nashville, Tennessee 37232
United States

Texas Neurology

Dallas, Texas 75214
United States

Baylor College of Medicine

Houston, Texas 77030
United States

University of Texas Health Science Center

San Antonio, Texas 78229
United States

University of Virgina Health System

Charlottesville, Virginia 22908
United States

University of Washington Medical Center

Seattle, Washington 98195
United States

West Virginia University Department of Neurology

Morgantown, West Virginia 26506
United States

Froedtert Memorial Lutheran Hospital, Department of Neurology

Milwaukee, Wisconsin 53226
United States

UZ Leuven - Campus Gasthuisberg

Leuven, Vlaams Brabant 3000

Edmonton Kaye Clinic

Edmonton, Alberta T6G 1Z1

Stan Cassidy Centre for Rehabilitation

Fredericton, New Brunswick E3B OC7

QE II Health Sciences Centre, NHI Site

Halifax, Nova Scotia B3H 1V7

McMaster University Medical Centre

Hamilton, Ontario L8N 4K1

London Health Sciences Centre

London, Ontario N6A 5A5

Sunnybrook Health Sciences Centre

Toronto, Ontario M4N 3M5

Notre-Dame Hospital/CHUM

Montreal, Quebec H2L 4M1

Montreal Neurological Institute and Hospital

Montreal, Quebec H3A 2B4

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

Quebec G1J 1Z4

University of Calgary

Calgary, Alberta T3M 1M4

CHU de Nice - Hopital Pasteur 2

Nice Cedex 1 06001

Bretonneau University Hospital

Tours Cedex 9 37044

Hopital de la Salpetriere

Paris 75651

Hopital Gui de Chauliac

Montpellier 34295

Hopital de la Timone

Marseille 13005

CHU Dupuytren

Limoges cedex 87042

Hopital R. Salengro, CHRU Lille

Lille Cedex 59037

University of Ulm, Department of Neurology

Ulm, Baden-Wuerttemberg 89081

Hannover Medical School, Department of Neurology

Hannover, Lower Saxony 30625

Charite Campus Virchow-Klinikum, Neurology Department

Berlin 13353

Clinical Research Centre, Beaumont Hospital

Dublin Dublin 9

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

Torino 10126

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

Milan 20162

IRCCS Istituto Auxologico Italiano - U.O. Neurologia

Milan 20149

University Medical Center Utrecht

Utrecht 3584 CX

Hospital Santa Maria-Centro Hospitalar Lisboa Norte

Lisboa 1649-035

Hospital San Rafael

Madrid 28016

Derriford Hospital

Plymouth, Devon PL6 8DH
United Kingdom

Walton Centre for Neurology and Neurosurgery

Liverpool L9 7LJ
United Kingdom

Clinical Research Centre, Royal London Hospital

London E1 2AT
United Kingdom

Kings College Hospital

London SE59RS
United Kingdom