Clinical trial NCT02644668: A Study of CK-2127107 in Patients With Spinal Muscular Atrophy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Spinal Muscular Atrophy
Keywords: Reldesemtiv
Lead sponsor: Cytokinetics
Sponsor class: INDUSTRY
Collaborators: name: Astellas Pharma Global Development, Inc.
First posted: 2016-01-01
Enrollment: 70
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate 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).

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

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

Eligibility 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

Primary outcomes:
measure: Change From Baseline to Week 8 in Forced Vital Capacity (FVC)
timeFrame: baseline and 8 weeks
measure: Change From Baseline to Week 8 in Maximum Inspiratory Pressure (MIP)
timeFrame: baseline and 8 weeks
measure: Change From Baseline to Week 8 in Maximum Expiratory Pressure (MEP)
timeFrame: baseline and 8 weeks
measure: Muscle Strength Mega-Score at Week 8
timeFrame: baseline and 8 weeks
measure: Change From Baseline to Week 8 in the Hammersmith Functional Motor Scale-Expanded (HFMS-E)
timeFrame: baseline and 8 weeks
measure: Change From Baseline to Week 8 in Revised Upper Limb Module (RULM)
timeFrame: baseline and 8 weeks
measure: Change From Baseline to Week 8 in the TUG Test
timeFrame: baseline and 8 weeks
measure: Change From Baseline to Week 8 in the 6MWT
timeFrame: baseline and 8 weeks
measure: Patient Global Assessment at the End of Week 8
timeFrame: 8 weeks
measure: Investigator Global Assessment at the End of Week 8
timeFrame: 8 weeks
Secondary outcomes:
measure: Reldesemtiv Maximum Observed Plasma Concentration (Cmax)
timeFrame: End of Week 8
measure: Reldesemtiv Area Under the Plasma Concentration-time Curve From 0 to 12 Hours (AUC0-12)
timeFrame: End of Week 8
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA
state: California
city: Orange
country: United States
facility: University of California Irvine
state: California
city: Palo Alto
country: United States
facility: Pediatric Neuromuscular Clinic Stanford University
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Britain
country: United States
facility: Hospital for Special Care
state: Connecticut
city: Orlando
country: United States
facility: Nemours Childrens Hospital
state: Florida
city: Chicago
country: United States
facility: Ann and Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins Hospital Institute for Clinical and Translational Research Pediatric Clinical Research Unit
state: Maryland
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Salt Lake City
country: United States
facility: The University of Utah, Clinical Neurosciences Center
state: Utah
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: Children's and Women's Health Centre of British Columbia
state: British Columbia
city: London
country: Canada
facility: Children's Hospital - LHSC
state: Ontario
city: Montreal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
Study officials:
affiliation: Cytokinetics, Inc.
name: MD, Cytokinetics
role: STUDY_DIRECTOR
References: