Clinical trial NCT02496767: Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
Official title: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis
Keywords: fast skeletal troponin activator
tirasemtiv
CK-2017357
double-blind
randomized
placebo-controlled
Lead sponsor: Cytokinetics
Sponsor class: INDUSTRY
First posted: 2015-07-14
Enrollment: 744
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: 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.

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

Primary outcomes:
measure: Change From Baseline to Week 24 of the Double-blind, Placebo-controlled Phase in Percent Predicted Slow Vital Capacity (SVC)
timeFrame: 24 weeks
Secondary outcomes:
measure: Change From Baseline in the ALSFRS-R Respiratory Domain Score at the End of 48 Weeks of Double-blind, Placebo-controlled Treatment
timeFrame: 48 weeks
measure: Slope of Mega-score of Muscle Strength During the 48 Weeks of Double-blind, Placebo-controlled Treatment
timeFrame: 48 weeks
measure: 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
timeFrame: 48 weeks
measure: 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
timeFrame: 48 weeks
measure: Change From Baseline in the ALSFRS-R Total Score to the End of 48 Weeks of the Double-blind, Placebo-controlled Treatment
timeFrame: 48 weeks
measure: Time to the First Use of Mechanical Ventilatory Assistance or Death During All 48 Weeks of Double-blind, Placebo-controlled Treatment
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital & Medical Center - Barrow Neurology Clinics
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Orange
country: United States
facility: University of California, Irvine
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: San Francisco
country: United States
facility: Forbes Norris MDA/ALS Research Center
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital Anschutz Outpatient Pavilion
state: Colorado
city: New Britain
country: United States
facility: Hospital for Special Care
state: Connecticut
city: Washington
country: United States
facility: George Washington University Medical Center
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: Carol and Frank Morsini Center for Advanced Health Care - University of South Florida
state: Florida
city: Atlanta
country: United States
facility: The Emory Clinic
state: Georgia
city: Augusta
country: United States
facility: Georgia Regents University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
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 Medical Center
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 Memorial Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Hospital and Health System
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Saint Louis
country: United States
facility: Saint Louis University
state: Missouri
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
city: Lincoln
country: United States
facility: Neurology Associates
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center Dept of Neurology
state: New Hampshire
city: New York
country: United States
facility: Hospital for Special Surgery
state: New York
city: New York
country: United States
facility: Neurological Institute Columbia University Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: Neurosciences Institute: Neurology - Charlotte
state: North Carolina
city: Durham
country: United States
facility: Duke Neurological Disorders Clinic
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Providence Brain and Spine Institute ALS Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science Center
state: Oregon
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: The Penn Comprehensive Neuroscience Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University School of Medicine
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: University of Texas Health Science Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virgina Health System
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Morgantown
country: United States
facility: West Virginia University Department of Neurology
state: West Virginia
city: Milwaukee
country: United States
facility: Froedtert Memorial Lutheran Hospital, Department of Neurology
state: Wisconsin
city: Leuven
country: Belgium
facility: UZ Leuven - Campus Gasthuisberg
state: Vlaams Brabant
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: Edmonton Kaye Clinic
state: Alberta
city: Fredericton
country: Canada
facility: Stan Cassidy Centre for Rehabilitation
state: New Brunswick
city: Halifax
country: Canada
facility: QE II Health Sciences Centre, NHI Site
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster University Medical Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: Notre-Dame Hospital/CHUM
state: Quebec
city: Montreal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Quebec
country: Canada
facility: CHU de Quebec - Universite Laval Hopital de l'Enfant-Jesus
city: Lille Cedex
country: France
facility: Hopital R. Salengro, CHRU Lille
city: Limoges cedex
country: France
facility: CHU Dupuytren
city: Marseille
country: France
facility: Hopital de la Timone
city: Montpellier
country: France
facility: Hopital Gui de Chauliac
city: Nice Cedex 1
country: France
facility: CHU de Nice - Hopital Pasteur 2
city: Paris
country: France
facility: Hopital de la Salpetriere
city: Tours Cedex 9
country: France
facility: Bretonneau University Hospital
city: Ulm
country: Germany
facility: University of Ulm, Department of Neurology
state: Baden-Wuerttemberg
city: Hannover
country: Germany
facility: Hannover Medical School, Department of Neurology
state: Lower Saxony
city: Berlin
country: Germany
facility: Charite Campus Virchow-Klinikum, Neurology Department
city: Dublin
country: Ireland
facility: Clinical Research Centre, Beaumont Hospital
city: Milan
country: Italy
facility: IRCCS Istituto Auxologico Italiano - U.O. Neurologia
city: Milan
country: Italy
facility: Centro Clinico NEMO - Fondazione Serena Onlus, ASST Grande Ospedale Metropolitano Niguarda
city: Torino
country: Italy
facility: Dipartimento di Neuroscienze "Rita Levi Moltalcini" A.O.U. Citta della Salute e della Scienza di Torino P.O. "Molinette"
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Lisboa
country: Portugal
facility: Hospital Santa Maria-Centro Hospitalar Lisboa Norte
city: Madrid
country: Spain
facility: Hospital San Rafael
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
state: Devon
city: Liverpool
country: United Kingdom
facility: Walton Centre for Neurology and Neurosurgery
city: London
country: United Kingdom
facility: Clinical Research Centre, Royal London Hospital
city: London
country: United Kingdom
facility: Kings College Hospital
Study officials:
affiliation: Cytokinetics
name: MD
role: STUDY_DIRECTOR
References:
citation: 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.