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

Amyotrophic Lateral Sclerosis Clinical Trial

— VITALITY-ALS  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02496767
• Other study ID #: CY 4031
• Secondary ID: 2014-005413-23
• Status: Completed
• Phase: Phase 3
• Start date: September 3, 2015
• Est. completion date: September 27, 2017

Study information

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

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 744
• Est. completion date: September 27, 2017
• Est. primary completion date: March 9, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Amyotrophic Lateral Sclerosis
• Motor Neuron Disease
• Sclerosis

Intervention

Drug:
• Tirasemtiv

• Placebo tablets

Locations

Country	Name	City	State
Belgium	UZ Leuven - Campus Gasthuisberg	Leuven	Vlaams Brabant
Canada	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	Montreal Neurological Institute and Hospital	Montreal	Quebec
Canada	Notre-Dame Hospital/CHUM	Montreal	Quebec
Canada	CHU de Quebec - Universite Laval Hopital de l'Enfant-Jesus	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
France	Hopital R. Salengro, CHRU Lille	Lille Cedex
France	CHU Dupuytren	Limoges cedex
France	Hopital de la Timone	Marseille
France	Hopital Gui de Chauliac	Montpellier
France	CHU de Nice - Hopital Pasteur 2	Nice Cedex 1
France	Hopital de la Salpetriere	Paris
France	Bretonneau University Hospital	Tours Cedex 9
Germany	Charite Campus Virchow-Klinikum, Neurology Department	Berlin
Germany	Hannover Medical School, Department of Neurology	Hannover	Lower Saxony
Germany	University of Ulm, Department of Neurology	Ulm	Baden-Wuerttemberg
Ireland	Clinical Research Centre, Beaumont Hospital	Dublin
Italy	Centro Clinico NEMO - Fondazione Serena Onlus, ASST Grande Ospedale Metropolitano Niguarda	Milan
Italy	IRCCS Istituto Auxologico Italiano - U.O. Neurologia	Milan
Italy	Dipartimento di Neuroscienze "Rita Levi Moltalcini" A.O.U. Citta della Salute e della Scienza di Torino P.O. "Molinette"	Torino
Netherlands	University Medical Center Utrecht	Utrecht
Portugal	Hospital Santa Maria-Centro Hospitalar Lisboa Norte	Lisboa
Spain	Hospital San Rafael	Madrid
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	Derriford Hospital	Plymouth	Devon
United States	University of Michigan Hospital and Health System	Ann Arbor	Michigan
United States	The Emory Clinic	Atlanta	Georgia
United States	Georgia Regents University	Augusta	Georgia
United States	University of Colorado Hospital Anschutz Outpatient Pavilion	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Neurosciences Institute: Neurology - Charlotte	Charlotte	North Carolina
United States	University of Virgina Health System	Charlottesville	Virginia
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Texas Neurology	Dallas	Texas
United States	Henry Ford Health System	Detroit	Michigan
United States	Duke Neurological Disorders Clinic	Durham	North Carolina
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Mayo Clinic	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of California San Diego	La Jolla	California
United States	Dartmouth Hitchcock Medical Center Dept of Neurology	Lebanon	New Hampshire
United States	Neurology Associates	Lincoln	Nebraska
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of Miami	Miami	Florida
United States	Froedtert Memorial Lutheran Hospital, Department of Neurology	Milwaukee	Wisconsin
United States	Hennepin County Medical Center	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	Neurological Institute Columbia University Medical Center	New York	New York
United States	University of California, Irvine	Orange	California
United States	Temple University School of Medicine	Philadelphia	Pennsylvania
United States	The Penn Comprehensive Neuroscience Center	Philadelphia	Pennsylvania
United States	St. Joseph's Hospital & Medical Center - Barrow Neurology Clinics	Phoenix	Arizona
United States	Oregon Health and Science Center	Portland	Oregon
United States	Providence Brain and Spine Institute ALS Center	Portland	Oregon
United States	University of California Davis Medical Center	Sacramento	California
United States	Barnes-Jewish Hospital	Saint Louis	Missouri
United States	Saint Louis University	Saint Louis	Missouri
United States	University of Texas Health Science Center	San Antonio	Texas
United States	Forbes Norris MDA/ALS Research Center	San Francisco	California
United States	University of Washington Medical Center	Seattle	Washington
United States	Stanford Hospital and Clinics	Stanford	California
United States	SUNY Upstate Medical University	Syracuse	New York
United States	Carol and Frank Morsini Center for Advanced Health Care - University of South Florida	Tampa	Florida
United States	George Washington University Medical Center	Washington	District of Columbia
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Cytokinetics

Countries where clinical trial is conducted

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

Outcome

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