Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year (VITALITY-ALS)

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)

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

Study Overview

• Status: Completed
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: Placebo tablets; Drug: Tirasemtiv

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.

• Study Type: Interventional
• Enrollment (Actual): 744
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Vlaams Brabant
    • Leuven, Vlaams Brabant, Belgium, 3000
      • UZ Leuven - Campus Gasthuisberg
• Canada
  • Quebec, Canada, G1J 1Z4
    • CHU de Quebec - Universite Laval Hopital de l'Enfant-Jesus
  • Alberta
    • Calgary, Alberta, Canada, T3M 1M4
      • University of Calgary
    • Edmonton, Alberta, Canada, T6G 1Z1
      • Edmonton Kaye Clinic
  • New Brunswick
    • Fredericton, New Brunswick, Canada, E3B OC7
      • Stan Cassidy Centre for Rehabilitation
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • QE II Health Sciences Centre, NHI Site
  • Ontario
    • Hamilton, Ontario, Canada, L8N 4K1
      • McMaster University Medical Centre
    • London, Ontario, Canada, N6A 5A5
      • London Health Sciences Centre
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H3A 2B4
      • Montreal Neurological Institute and Hospital
    • Montreal, Quebec, Canada, H2L 4M1
      • Notre-Dame Hospital/CHUM
• France
  • Lille Cedex, France, 59037
    • Hopital R. Salengro, CHRU Lille
  • Limoges cedex, France, 87042
    • Chu Dupuytren
  • Marseille, France, 13005
    • Hopital de la Timone
  • Montpellier, France, 34295
    • Hopital Gui de Chauliac
  • Nice Cedex 1, France, 06001
    • CHU de Nice - Hôpital Pasteur 2
  • Paris, France, 75651
    • Hôpital de la Salpétrière
  • Tours Cedex 9, France, 37044
    • Bretonneau University Hospital
• Germany
  • Berlin, Germany, 13353
    • Charite Campus Virchow-Klinikum, Neurology Department
  • Baden-Wuerttemberg
    • Ulm, Baden-Wuerttemberg, Germany, 89081
      • University of Ulm, Department of Neurology
  • Lower Saxony
    • Hannover, Lower Saxony, Germany, 30625
      • Hannover Medical School, Department of Neurology
• Ireland
  • Dublin, Ireland, Dublin 9
    • Clinical research centre, Beaumont Hospital
• Italy
  • Milan, Italy, 20149
    • IRCCS Istituto Auxologico Italiano - U.O. Neurologia
  • Milan, Italy, 20162
    • Centro Clinico NEMO - Fondazione Serena Onlus, ASST Grande Ospedale Metropolitano Niguarda
  • Torino, Italy, 10126
    • Dipartimento di Neuroscienze "Rita Levi Moltalcini" A.O.U. Citta della Salute e della Scienza di Torino P.O. "Molinette"
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht
• Portugal
  • Lisboa, Portugal, 1649-035
    • Hospital Santa Maria-Centro Hospitalar Lisboa Norte
• Spain
  • Madrid, Spain, 28016
    • Hospital San Rafael
• United Kingdom
  • Liverpool, United Kingdom, L9 7LJ
    • Walton Centre For Neurology and Neurosurgery
  • London, United Kingdom, SE59RS
    • Kings College Hospital
  • London, United Kingdom, E1 2AT
    • Clinical Research Centre, Royal London Hospital
  • Devon
    • Plymouth, Devon, United Kingdom, PL6 8DH
      • Derriford Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital & Medical Center - Barrow Neurology Clinics
  • California
    • La Jolla, California, United States, 92093
      • University of California San Diego
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Orange, California, United States, 92868
      • University of California, Irvine
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Francisco, California, United States, 94115
      • Forbes Norris MDA/ALS Research Center
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital Anschutz Outpatient Pavilion
  • Connecticut
    • New Britain, Connecticut, United States, 06053
      • Hospital for Special Care
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic
    • Miami, Florida, United States, 33136
      • University of Miami
    • Tampa, Florida, United States, 33612
      • Carol and Frank Morsini Center for Advanced Health Care - University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory Clinic
    • Augusta, Georgia, United States, 30912
      • Georgia Regents University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University Feinberg School of Medicine
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Hospital and Health System
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Barnes-jewish Hospital
    • 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 Dept of Neurology
  • New York
    • New York, New York, United States, 10021
      • Hospital for Special Surgery
    • New York, New York, United States, 10032
      • Neurological Institute Columbia University Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Neurosciences Institute: Neurology - Charlotte
    • Durham, North Carolina, United States, 27705
      • Duke Neurological Disorders Clinic
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Columbus, Ohio, United States, 43221
      • The Ohio State University Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Brain and Spine Institute ALS Center
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University School of Medicine
    • Philadelphia, Pennsylvania, United States, 19107
      • The Penn Comprehensive Neuroscience Center
  • 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
      • University of Texas Health Science Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virgina Health System
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Department of Neurology
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Memorial Lutheran Hospital, Department of Neurology

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:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Group 1 - Placebo; Day 1 through Week 48: 2 placebo tablets twice daily	Drug: Placebo tablets
EXPERIMENTAL: 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	Drug: Placebo tablets; Drug: Tirasemtiv; Other Names: CK-2017357
EXPERIMENTAL: 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	Drug: Placebo tablets; Drug: Tirasemtiv; Other Names: CK-2017357
EXPERIMENTAL: 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	Drug: Placebo tablets; Drug: Tirasemtiv; Other Names: CK-2017357

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 24 of the Double-blind, Placebo-controlled Phase in Percent Predicted Slow Vital Capacity (SVC)	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 patients of similar demographic and baseline characteristics [eg, height, age, sex], based on Knudson 83 normative values).	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the ALSFRS-R Respiratory Domain Score at the End of 48 Weeks of Double-blind, Placebo-controlled 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: bulbar functions, fine motor tasks, gross motor tasks, and respiratory function. Respiratory function consists of 3 of the 12 questions, which assess dyspnea, orthopnea, and respiratory insufficiency. Each question is scored from 0 (indicating incapable or dependent) to 4 (normal). The sum of the response to these 3 questions represents the respiratory domain score. The respiratory domain score ranges from 0 to 12, with higher scores reflecting more normal function and lower scores reflecting more impaired function.	48 weeks
Slope of Mega-score of Muscle Strength During the 48 Weeks of Double-blind, Placebo-controlled Treatment	A hand-held dynomometer, 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). The muscle strength mega-score was calculated as the average of responses to all tested muscles as well as handgrip strength. The slope of muscle strength mega-score was the change over time (48 weeks) and analyzed using a mixed model that assumed a random slope effect. For this endpoint, negative values indicate a decline in muscle strength over time.	48 weeks
Time to the First Occurrence of a Decline From Baseline in Percent Predicted SVC ≥ 20 Percentage Points or the Onset of Respiratory Insufficiency or Death All 48 Weeks of Double-blind, Placebo-controlled Treatment	This endpoint evaluated the time to occurrence of a decline in percent predicted SVC (as measured by spirometry) of ≥ 20 percentage points, or the onset of respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for ≥ 22 hours per day for ≥10 consecutive days), or death, whichever was first, during the 48-week double-blind, placebo-controlled treatment phase. Note: The median time to a ≥ 20% decline in percent predicted SVC, onset of respiratory insufficiency, or death was 302 days for the placebo group and 359, 334, and 337 days for the 250 mg, 375 mg, and 500 mg tirasemtiv groups, respectively. The data presented for this endpoint are the number and percent of patients who met the endpoint.	48 weeks
Time to the First Occurrence of a Decline in SVC to ≤ 50% Predicted, or the Onset of Respiratory Insufficiency, or Death During the 48 Weeks of Double-blind, Placebo-controlled Treatment	This endpoint evaluated the time to occurrence of a decline in SVC (as measured by spirometry) to ≤ 50% predicted, or the onset of respiratory insufficiency (defined as tracheostomy or the use of non-invasive ventilation for ≥ 22 hours per day for ≥10 consecutive days), or death, whichever was first, during the 48-week double-blind, placebo-controlled treatment phase. Note: The median time to a decline in SVC to ≤ 50% predicted, onset of respiratory insufficiency, or death was not estimable for the placebo group or the 375 mg tirasemtiv group. The median time was estimated as 363 and 351 days for the 250 mg and 500 mg tirasemtiv groups, respectively. The data presented for this endpoint are the number and percent of patients who met the endpoint.	48 weeks
Change From Baseline in the ALSFRS-R Total Score to the End of 48 Weeks of the Double-blind, Placebo-controlled 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.	48 weeks
Time to the First Use of Mechanical Ventilatory Assistance or Death During All 48 Weeks of Double-blind, Placebo-controlled Treatment	This endpoint evaluated the time to occurrence of mechanical ventilatory assistance (defined as invasive or non-invasive ventilation for at least 2 hours over a 24-hour period for at least 5 consecutive days) or death, whichever was first, during the 48-week double-blind, placebo-controlled treatment phase. Note: The median time to first use of mechanical ventilatory assistance or death was not estimable for all but the 375 mg tirasemtiv group (with a value of 367 days). As such the number and percent of patients who met the endpoint (ie, had mechanical ventilatory assistance or died) are presented.	48 weeks

Collaborators and Investigators

• Sponsor: Cytokinetics
• Investigators: Study Director: MD, Cytokinetics

Publications and helpful links

General Publications

• 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. Erratum In: Amyotroph Lateral Scler Frontotemporal Degener. 2018 May;19(3-4):321.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 3, 2015
• Primary Completion (ACTUAL): March 9, 2017
• Study Completion (ACTUAL): September 27, 2017

Study Registration Dates

• First Submitted: July 10, 2015
• First Submitted That Met QC Criteria: July 10, 2015
• First Posted (ESTIMATE): July 14, 2015

Study Record Updates

• Last Update Posted (ACTUAL): September 9, 2020
• Last Update Submitted That Met QC Criteria: August 21, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: randomized; placebo-controlled; double-blind; tirasemtiv; fast skeletal troponin activator; CK-2017357
• 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
• Other Study ID Numbers: CY 4031; 2014-005413-23 (EUDRACT_NUMBER)