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Trial record 2 of 9 for:    tirasemtiv OR ck-2127107 AND ALS

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02496767
Recruitment Status : Completed
First Posted : July 14, 2015
Results First Posted : June 19, 2020
Last Update Posted : September 9, 2020
Sponsor:
Information provided by (Responsible Party):
Cytokinetics

Tracking Information
First Submitted Date  ICMJE July 10, 2015
First Posted Date  ICMJE July 14, 2015
Results First Submitted Date  ICMJE May 6, 2020
Results First Posted Date  ICMJE June 19, 2020
Last Update Posted Date September 9, 2020
Actual Study Start Date  ICMJE September 3, 2015
Actual Primary Completion Date March 9, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 17, 2020)
Change From Baseline to Week 24 of the Double-blind, Placebo-controlled Phase in Percent Predicted Slow Vital Capacity (SVC) [ Time Frame: 24 weeks ]
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).
Original Primary Outcome Measures  ICMJE
 (submitted: July 10, 2015)
Change From Baseline to Week 24 of the Double-blind, Placebo-controlled Phase in Percent Predicted Slow Vital Capacity (SVC) [ Time Frame: 24 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 17, 2020)
  • Change From Baseline in the ALSFRS-R Respiratory Domain Score at the End of 48 Weeks of Double-blind, Placebo-controlled Treatment [ Time Frame: 48 weeks ]
    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.
  • Slope of Mega-score of Muscle Strength During the 48 Weeks of Double-blind, Placebo-controlled Treatment [ Time Frame: 48 weeks ]
    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.
  • 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 [ Time Frame: 48 weeks ]
    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.
  • 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 [ Time Frame: 48 weeks ]
    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.
  • Change From Baseline in the ALSFRS-R Total Score to the End of 48 Weeks of the Double-blind, Placebo-controlled Treatment [ Time Frame: 48 weeks ]
    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.
  • Time to the First Use of Mechanical Ventilatory Assistance or Death During All 48 Weeks of Double-blind, Placebo-controlled Treatment [ Time Frame: 48 weeks ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: July 10, 2015)
  • Time to the first occurrence of a decline in the respiratory components of the ALS functional rating scale- revised (ALSFRS-R) (i.e., items 10, 11, and 12) or death during double-blind, placebo-controlled treatment [ Time Frame: 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 during double-blind, placebo-controlled treatment [ Time Frame: 48 weeks ]
  • Time to the first occurrence of any use of assisted ventilation or death during double-blind, placebo-controlled treatment [ Time Frame: 48 weeks ]
  • Time to the first occurrence of a decline in SVC to ≤ 50% predicted or the onset of respiratory insufficiency or death during double-blind, placebo-controlled treatment [ Time Frame: 48 weeks ]
  • Slope in muscle strength mega-score change from baseline during the randomized, double-blind, placebo-controlled phase [ Time Frame: 24 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
Official Title  ICMJE 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)
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Amyotrophic Lateral Sclerosis
Intervention  ICMJE
  • Drug: Tirasemtiv
    Other Name: CK-2017357
  • Drug: Placebo tablets
Study Arms  ICMJE
  • Placebo Comparator: Group 1 - Placebo
    Day 1 through Week 48: 2 placebo tablets twice daily
    Intervention: 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
    Interventions:
    • Drug: Tirasemtiv
    • Drug: Placebo tablets
  • 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
    Interventions:
    • Drug: Tirasemtiv
    • Drug: Placebo tablets
  • 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
    Interventions:
    • Drug: Tirasemtiv
    • Drug: Placebo tablets
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 17, 2020)
744
Original Estimated Enrollment  ICMJE
 (submitted: July 10, 2015)
445
Actual Study Completion Date  ICMJE September 27, 2017
Actual Primary Completion Date March 9, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   France,   Germany,   Ireland,   Italy,   Netherlands,   Portugal,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02496767
Other Study ID Numbers  ICMJE CY 4031
2014-005413-23 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Cytokinetics
Study Sponsor  ICMJE Cytokinetics
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: MD Cytokinetics
PRS Account Cytokinetics
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP