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A Study of CK-2127107 in Patients With Spinal Muscular Atrophy

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: NCT02644668
Recruitment Status : Completed
First Posted : January 1, 2016
Last Update Posted : May 15, 2020
Sponsor:
Collaborator:
Astellas Pharma Global Development, Inc.
Information provided by (Responsible Party):
Cytokinetics

Brief Summary:
This study evaluated the pharmacodynamic (PD) effect of CK-2127107 (hereafter referred to as reldesemtiv) versus placebo on measures of skeletal muscle function or fatigability in patients with Type II, III, or IV spinal muscular atrophy (SMA).

Condition or disease Intervention/treatment Phase
Spinal Muscular Atrophy Drug: Placebo Drug: Reldesemtiv 150 mg Drug: Reldesemtiv 450 mg Phase 2

Detailed Description:

CY 5021 was a Phase 2, double-blind, randomized, placebo-controlled, multiple dose study of reldesemtiv in 2 sequential ascending dose cohorts of patients with SMA. Patients were randomized 2:1 to receive reldesemtiv or placebo twice daily for 8 weeks. Patients randomized to reldesemtiv in Cohort 1 received a dose of 150 mg twice daily and patients randomized to reldesemtiv in Cohort 2 received 450 mg twice daily. Within each cohort, randomization was stratified by ambulatory status (ambulatory versus non ambulatory).

The primary objective of the study was to determine the PD effects of reldesemtiv on measures of pulmonary function, respiratory function, muscle strength, and motor function. Other PD measures included changes in the timed up and go (TUG) test, a 6-minute walk test (6MWT), and patient and investigator global assessments. Secondary objectives included safety of multiple doses of reldesemtiv and an evaluation of the pharmacokinetics of reldesemtiv.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Multiple Dose Study of CK-2127107 in Two Ascending Dose Cohorts of Patients With Spinal Muscular Atrophy
Actual Study Start Date : January 14, 2016
Actual Primary Completion Date : May 31, 2018
Actual Study Completion Date : May 31, 2018


Arm Intervention/treatment
Placebo Comparator: Placebo
Patients randomized to this treatment arm received a placebo suspension twice daily for 8 weeks.
Drug: Placebo
Granules for oral suspension (placebo)

Experimental: Reldesemtiv 150 mg twice daily
Patient randomized to this treatment arm received reldesemtiv suspension at a dose of 150 mg, twice daily for 8 weeks.
Drug: Reldesemtiv 150 mg
Granules for oral suspension, 18.7% reldesemtiv
Other Name: CK-2127107

Experimental: Reldesemtiv 450 mg twice daily
Patients randomized to this treatment arm received reldesemtiv suspension at a dose of 450 mg, twice daily for 8 weeks.
Drug: Reldesemtiv 450 mg
Granules for oral suspension, 56.0% reldesemtiv
Other Name: CK-2127107




Primary Outcome Measures :
  1. Change from Baseline to Week 8 in Percent Predicted Forced Vital Capacity (FVC) [ Time Frame: 8 weeks ]
    FVC was measured using a calibrated spirometer (in units of liters). 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 percent predicted values (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics [eg, height, age, sex]).

  2. Change from Baseline to Week 8 in Maximum Inspiratory Pressure (MIP) [ Time Frame: 8 weeks ]
    MIP was measured (in units of cm H20) using a calibrated spirometer with an inspiratory pressure valve attached. For the test, patients were asked to inhale as forcefully as possible, to their maximum pressure.

  3. Change from Baseline to Week 8 in Maximum Expiratory Pressure (MEP) [ Time Frame: 8 weeks ]
    MEP was measured (in units of cm H20) using a calibrated spirometer with an exspiratory pressure valve attached. For the test, patients were asked to maximally inhale then perform a forced exhalation with as forcefully as possible.

  4. Change from Baseline to Week 8 in Muscle Strength Mega-Score [ Time Frame: 8 weeks ]

    Muscle strength of 3 muscle groups (elbow flexion, knee extension, and shoulder abduction) were measured bilaterally using a hand-held dynamometer. Muscle strength was measured twice for each body location; if the variability between the 2 measures was > 15%, a third measure was obtained.

    The maximum muscle strength of the 2 measurements was identified and transformed as a percent change from baseline using the equation: ([postbaseline value - baseline value] / baseline value) × 100.

    The mega-score was a composite score that averaged strength across the 3 muscle groups. It was calculated as the mean of the non-missing transformed muscle strength scores among the 3 muscle groups each measure bilaterally (totaling 6 body locations).


  5. Change from Baseline to Week 8 in the Hammersmith Functional Motor Scale-Expanded (HFMS-E) [ Time Frame: 8 weeks ]
    The HFMS-E evaluated the level of independent mobility and motor skills through assessment of 33 test-items, each scored from 0 (worse) to 2 (better). The total score was calculated as the sum of the scores among the 33 test items, and has a range from 0 to 66.

  6. Change from Baseline to Week 8 in Revised Upper Limb Module (RULM) [ Time Frame: 8 weeks ]
    The RULM assessed motor function in the upper limbs (specifically shoulder, elbow, wrist, and hand function) that related to activities of everyday life. The RULM consisted of 20 items, 1 of which was scored on a 7-point scale (from 0 to 6) and the remaining 19 were scored on a 3-point scale (from 0 to 2); the higher the total score, the better the function.

  7. Change from Baseline to Week 8 in the TUG Test [ Time Frame: 8 weeks ]
    The TUG test measured the time (in seconds) it took for a patient to rise from a chair, walk 3 meters, turn around, walk back to the chair and sit down.

  8. Change from Baseline to Week 8 in the 6MWT [ Time Frame: 8 weeks ]
    The 6MWT measured the distance (in meters) a patient walked in 6 minutes.

  9. Patient Global Assessment: Proportion of Patients with an Improvement [ Time Frame: 8 weeks ]
    The patient assessed whether they felt the same, better, or worse than prior to dosing on Day 1.

  10. Investigator Global Assessment: Proportion of Patients with an Improvement [ Time Frame: 8 weeks ]
    The Investigator assessed whether patient appeared the same, better, or worse than prior to dosing on Day 1.


Secondary Outcome Measures :
  1. Reldesemtiv maximum observed plasma concentration (Cmax) [ Time Frame: End of Week 8 ]
    Determined by evaluation of reldesemtiv plasma concentrations from blood samples collected prior to dosing and at 1, 3, and 6 hours following dosing

  2. Reldesemtiv area under the plasma concentration-time curve from 0 to 12 hours (AUC0-12) [ Time Frame: End of Week 8 ]
    Determined by evaluation of reldesemtiv plasma concentrations from blood samples collected prior to dosing and at 1, 3, and 6 hours following dosing



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Able to comprehend and willing to sign an Informed Consent Form (ICF) for patients 18 years of age and older. For patients less than 18 years of age, parent(s)/legal guardian(s) of patients must provide written informed consent prior to participation in the study and informed assent will be obtained from minors at least 12 years of age when required by regulation.
  • Males or females with genetically confirmed diagnosis of SMA who are Type II, III or IV and at least 12 years of age
  • Ambulatory patients, once having achieved a standing position independently, must be able to complete at least one lap in the 6-minute walk test (at least 50 meters) within 6 minutes without assistance.
  • Non-ambulatory patients (defined as individuals who are effectively requiring a wheelchair for all mobility needs; they may be able to stand or walk short distances, but unable to walk 50 meters without assistance in 6 minutes). Non-ambulatory patients must be able to tolerate an upright sitting position, with support, continuously for 3 hours
  • Hammersmith (HFMS-E) score ≥ 10 and ≤ 54
  • Contracture of the elbow flexion and knee flexion ≤ 90 degrees
  • Pre-study clinical laboratory findings within the normal range or, if outside the normal range, deemed not clinically significant by the Investigator
  • Able to swallow an oral suspension and in the opinion of the Investigator, is expected to continue to be able to do so for the duration of the trial. Administration via a feeding tube is not allowed.
  • Forced vital capacity (FVC) > 20% predicted
  • Male patients who have reached puberty must agree to do either of the following from Screening until 10 weeks after the last dose of the investigational product unless they have had a vasectomy and confirmed sperm count is zero:

    • Abstain from sexual intercourse, OR
    • If having heterosexual intercourse, must use a condom and their female partners who are of childbearing potential must use a highly effective contraception method*
  • Female patients who have had their first period will be considered of childbearing potential unless they are anatomically and physiologically incapable of becoming pregnant. If of childbearing potential, the female patients must:

    • Have a negative urine/serum pregnancy test at Screening AND
    • Abstain from heterosexual intercourse from Screening until 10 weeks after the last dose of investigational product OR
    • If having heterosexual intercourse, must use a highly effective contraception method* and require the male partners to use a condom from Screening until 10 weeks after the last dose of investigational product

      *Highly effective contraception methods include:

    • Established use of oral, injected or implanted hormonal methods of contraception
    • Placement of an intrauterine device (IUD) or intrauterine system (IUS)
  • Male patients must agree to refrain from sperm donation from Screening until 10 weeks after the final study drug administration

Exclusion Criteria:

  • History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator
  • Hospitalization within 2 months of Screening
  • History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (appendectomy, hernia repair, and/or cholecystectomy will be allowed)
  • A clinically significant illness within 4 weeks of Screening
  • History of alcoholism or drug addiction within 2 years prior to Screening
  • History of smoking more than 10 cigarettes (or equivalent amount of tobacco) per day within 3 months prior to Screening
  • Patient has used a strong CYP3A4 inhibitor within 7 days prior to first dose of study drug or a strong CYP3A4 inducer within 14 days prior to first dose of study drug
  • Any other medical condition that would interfere with performance of testing including (but not limited to) significant joint pain or arthritis limiting mobility, and chronic neuromuscular pain sufficient to require ongoing analgesic medication
  • Participation by two people at the same time that are living in the same household
  • Participation in any other investigational study drug trial in which receipt of an investigational study drug occurred within 30 days or five half-lives of the other investigational study drug, whichever is greater, prior to Screening
  • An ALT or AST greater than 2-fold the upper limit of normal (ULN) or has total bilirubin greater than the ULN at screening. These assessments may be repeated once at the investigator's discretion (within the screening window)
  • Currently taking nusinersen, or has taken it in the past, or plans to take it during the course the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02644668


Locations
Show Show 19 study locations
Sponsors and Collaborators
Cytokinetics
Astellas Pharma Global Development, Inc.
Investigators
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Study Director: MD, Cytokinetics Cytokinetics, Inc.
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Responsible Party: Cytokinetics
ClinicalTrials.gov Identifier: NCT02644668    
Other Study ID Numbers: CY 5021
First Posted: January 1, 2016    Key Record Dates
Last Update Posted: May 15, 2020
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Cytokinetics:
Reldesemtiv
Additional relevant MeSH terms:
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Muscular Atrophy
Muscular Atrophy, Spinal
Atrophy
Pathological Conditions, Anatomical
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Spinal Cord Diseases
Central Nervous System Diseases
Motor Neuron Disease
Neurodegenerative Diseases
Neuromuscular Diseases