Amyotrophic Lateral Sclerosis
Conditions
Keywords
Amyotrophic Lateral Sclerosis, ALS, CK-2127107, Reldesemtiv
Brief summary
The purpose of this study was to assess the effect of CK-2127107 (hereafter referred to as reldesemtiv) versus placebo on respiratory function and other measures of skeletal muscle function in patients with ALS.
Detailed description
This was a double-blind, randomized, placebo-controlled, dose ranging study of reldesemtiv in patients with ALS. Eligible patients were randomized (1:1:1:1) to receive placebo or one of three doses of reldesemtiv (150, 300, or 450 mg twice daily) for 12 weeks. Randomization was stratified by riluzole concomitant use/non-use and edaravone concomitant use/non-use. Concomitant riluzole and edaravone were allowed as long as the riluzole dose had been stable for at least 30 days prior to screening and edaravone had been taken for 2 cycles prior to screening; these drugs could not be initiated during the study. A total of 7 study visits were planned: screening, Day 1 (first dosing day), Weeks 2, 4, 8, and 12, and follow-up (4 weeks after the last dose of study drug). Study drug (placebo or reldesemtiv) was to be taken twice daily, approximately 12 hours (± 2 hours) apart and within 2 hours following a meal.
Interventions
DRUGReldesemtiv
Oral tablet
DRUGPlacebo
Oral tablet
Sponsors
Astellas Pharma Inc
Cytokinetics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of familial or sporadic ALS ≤ 24 months prior to screening * Upright Slow Vital Capacity (SVC) ≥ 60% of predicted for age, height and sex at screening * Able to swallow tablets * A caregiver (if one is needed) * Able to perform reproducible pulmonary function tests * Pre-study clinical laboratory findings within the normal range or, if outside the normal range, deemed not clinically significant by the Investigator * Male patients who have not had a vasectomy and confirmed zero sperm count must agree after receiving the first dose of study drug until 10 weeks after the last dose to either use acceptable methods of contraception or abstain from sex * Female patients must be post-menopausal or sterilized or must not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the study and use acceptable methods of contraception or abstain from heterosexual intercourse from Screening until 10 weeks after last dose of study drug * Patients must be either on riluzole for at least 30 days prior to screening or have not taken riluzole for at least 30 days prior to screening and not planning to start riluzole during the course of the study. * Patients on edaravone must have completed at least 2 cycles of dosing with edaravone at the time of screening or have not taken edaravone for at least 30 days prior to screening and not planning to start edaravone during the course of the study.
Exclusion criteria
* At the time of screening, any use of non-invasive ventilation (NIV), e.g. continuous positive airway pressure \[CPAP\], noninvasive bi-level positive airway pressure \[NPPV\] or noninvasive volume ventilation \[NVV\] for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation * Neurological impairment due to a condition other than ALS * 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 * Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is longer, prior to dosing * Known to have received CK-2127107 or tirasemtiv in any previous clinical trial * Has received or is considering receiving during the course of the study any form of stem cell therapy for the treatment of ALS * Has received or is considering receiving during the course of the study any form of gene therapy for the treatment of ALS * Has received or is considering obtaining during the course of the study a diaphragmatic pacing system * History of substance abuse within the past 2 years * Use of certain medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC) | Baseline to Week 12 | Slow vital capacity was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, 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 using the Global Lung Initiative equation (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics \[eg, height, age, sex\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score | Baseline to Week 12 | The ALSFRS-R is used to measure the progression and severity of disability in patients with ALS. The ALSFRS-R consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in the following 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. Higher scores reflect more normal function and lower scores reflect more impaired function. |
| Slope of Muscle Strength Mega-score From Baseline to Week 12 | Baseline to Week 12 | A hand-held dynamometer, 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, wrist extension, first dorsal interosseous, hip flexion, knee extension, and ankle dorsiflexion; all muscle groups were evaluated bilaterally. For each postbaseline assessment of muscle strength, the percent change from baseline was calculated for each muscle group and handgrip strength, using the following equation: (\[postbaseline value - baseline value\] / baseline value) × 100. The muscle-strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each of the muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength. |
Countries
Australia, Canada, Ireland, Netherlands, Spain, United States
Participant flow
Recruitment details
Patients with familial or sporadic ALS were enrolled at 65 sites in Australia, Canada, Ireland, Netherlands, Spain, and the United States. The first patient was screened on 16 August 2017 and the last patient completed on 07 March 2019.
Pre-assignment details
Eligible patients were male or female, ≥18 - ≤80 years of age, with familial or sporadic ALS diagnosed for ≤24 months. At screening, patients were to have upright slow vial capacity (SVC) ≥60% of predicted; must have been able to swallow tablets, perform reproducible pulmonary function tests; have normal lab tests; and have a caregiver (if needed).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients in this group received placebo twice daily for 12 weeks | 115 |
| Reldesemtiv 150 mg Twice Daily Patients in this group received 150 mg reldesemtiv twice daily for 12 weeks | 112 |
| Reldesemtiv 300 mg Twice Daily Patients in this group received 300 mg reldesemtiv twice daily for 12 weeks | 113 |
| Reldesemtiv 450 mg Twice Daily Patients in this group received 450 mg reldesemtiv twice daily for 12 weeks | 117 |
| Total | 457 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 8 | 7 | 10 |
| Overall Study | Death | 1 | 0 | 0 | 1 |
| Overall Study | Difficulty Traveling to Clinic Visits | 3 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 2 |
| Overall Study | Other | 2 | 0 | 2 | 2 |
| Overall Study | Physician Decision | 1 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 4 | 1 | 2 | 1 |
| Overall Study | Protocol Violation | 1 | 0 | 2 | 0 |
| Overall Study | Sponsor Discretion | 2 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 3 | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Reldesemtiv 150 mg Twice Daily | Reldesemtiv 300 mg Twice Daily | Reldesemtiv 450 mg Twice Daily | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 10.6 | 57.1 years STANDARD_DEVIATION 10.91 | 57.8 years STANDARD_DEVIATION 10.17 | 60.1 years STANDARD_DEVIATION 11 | 58.7 years STANDARD_DEVIATION 10.72 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 7 Participants | 1 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 6 Participants | 0 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants | 3 Participants | 9 Participants |
| Race (NIH/OMB) White | 107 Participants | 103 Participants | 100 Participants | 113 Participants | 423 Participants |
| Region of Enrollment Australia | 5 participants | 4 participants | 4 participants | 7 participants | 20 participants |
| Region of Enrollment Canada | 24 participants | 22 participants | 27 participants | 27 participants | 100 participants |
| Region of Enrollment Ireland | 2 participants | 2 participants | 0 participants | 0 participants | 4 participants |
| Region of Enrollment Netherlands | 4 participants | 2 participants | 1 participants | 4 participants | 11 participants |
| Region of Enrollment Spain | 8 participants | 9 participants | 10 participants | 11 participants | 38 participants |
| Region of Enrollment United States | 72 participants | 73 participants | 71 participants | 68 participants | 284 participants |
| Sex: Female, Male Female | 47 Participants | 41 Participants | 42 Participants | 50 Participants | 180 Participants |
| Sex: Female, Male Male | 68 Participants | 71 Participants | 71 Participants | 67 Participants | 277 Participants |
| Site of symptom onset Bulbar | 22 Participants | 18 Participants | 17 Participants | 30 Participants | 87 Participants |
| Site of symptom onset Lower limb | 44 Participants | 42 Participants | 40 Participants | 43 Participants | 169 Participants |
| Site of symptom onset Upper limb | 49 Participants | 52 Participants | 56 Participants | 44 Participants | 201 Participants |
| Time since ALS symptom onset | 22.13 months STANDARD_DEVIATION 12.375 | 23.87 months STANDARD_DEVIATION 27.503 | 22.52 months STANDARD_DEVIATION 14.635 | 22.69 months STANDARD_DEVIATION 18.662 | 22.80 months STANDARD_DEVIATION 19.08 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 115 | 0 / 112 | 0 / 113 | 1 / 117 |
| other Total, other adverse events | 95 / 115 | 99 / 112 | 97 / 113 | 107 / 117 |
| serious Total, serious adverse events | 10 / 115 | 8 / 112 | 8 / 113 | 8 / 117 |
Outcome results
Primary
Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC)
Slow vital capacity was measured using a spirometer (in units of liters). Following 3 to 5 breaths at rest, 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 using the Global Lung Initiative equation (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics \[eg, height, age, sex\]).
Time frame: Baseline to Week 12
Population: The outcome measure was analyzed for the Full Analysis Set, which consisted of all randomized patients who received any amount of study drug and had a baseline and at least 1 postbaseline efficacy assessment during double-blind treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC) | -6.46 percent predicted | Standard Error 0.964 |
| Reldesemtiv 150 mg Twice Daily | Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC) | -4.97 percent predicted | Standard Error 0.952 |
| Reldesemtiv 300 mg Twice Daily | Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC) | -4.62 percent predicted | Standard Error 0.963 |
| Reldesemtiv 450 mg Twice Daily | Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC) | -4.58 percent predicted | Standard Error 0.927 |
| Reldesemtiv 300 mg & 450 mg | Change From Baseline to Week 12 in the Percent Predicted Slow Vital Capacity (SVC) | -4.60 percent predicted | Standard Error 0.701 |
Comparison: The statistical null hypothesis was as follows: there was no assumed dose-response relationship in percent predicted SVC change from baseline to Week 12 among all three active doses and placebo, expressed as:~H0: -5 x µ placebo - 1 x µ 150 mg twice daily + 3 x µ 300 mg twice daily + 3 x µ 450 mg twice daily = 0 where µ was the mean of the efficacy endpoint for the designated group.p-value: 0.109595% CI: [-0.36, 3.58]Mixed Models Analysis
p-value: 0.250195% CI: [-1.05, 4.03]Mixed Models Analysis
p-value: 0.154995% CI: [-0.7, 4.38]Mixed Models Analysis
p-value: 0.141795% CI: [-0.63, 4.38]Mixed Models Analysis
p-value: 0.096495% CI: [-0.33, 4.05]Mixed Models Analysis
Secondary
Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score
The ALSFRS-R is used to measure the progression and severity of disability in patients with ALS. The ALSFRS-R consists of 12 questions, assessing a patient's capability and independence in functional activities relevant to ALS, categorized in the following 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. Higher scores reflect more normal function and lower scores reflect more impaired function.
Time frame: Baseline to Week 12
Population: The outcome measure was analyzed for the Full Analysis Set, which consisted of all randomized patients who received any amount of study drug and had a baseline and at least 1 postbaseline efficacy assessment during double-blind treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score | -3.53 change in score | Standard Error 0.313 |
| Reldesemtiv 150 mg Twice Daily | Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score | -2.40 change in score | Standard Error 0.311 |
| Reldesemtiv 300 mg Twice Daily | Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score | -2.62 change in score | Standard Error 0.317 |
| Reldesemtiv 450 mg Twice Daily | Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score | -2.94 change in score | Standard Error 0.307 |
| Reldesemtiv 300 mg & 450 mg | Change From Baseline to Week 12 in the ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score | -2.78 change in score | Standard Error 0.228 |
p-value: 0.09395% CI: [-0.09, 1.22]Mixed Models Analysis
p-value: 0.008795% CI: [0.29, 1.97]Mixed Models Analysis
p-value: 0.035195% CI: [0.06, 1.75]Mixed Models Analysis
p-value: 0.164295% CI: [-0.24, 1.43]Mixed Models Analysis
p-value: 0.043595% CI: [0.02, 1.48]Mixed Models Analysis
Secondary
Slope of Muscle Strength Mega-score From Baseline to Week 12
A hand-held dynamometer, 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, wrist extension, first dorsal interosseous, hip flexion, knee extension, and ankle dorsiflexion; all muscle groups were evaluated bilaterally. For each postbaseline assessment of muscle strength, the percent change from baseline was calculated for each muscle group and handgrip strength, using the following equation: (\[postbaseline value - baseline value\] / baseline value) × 100. The muscle-strength mega-score was calculated as the average of the changes (ie, percent change from baseline) observed for each of the muscle groups as well as handgrip strength. For this endpoint, negative values indicate a decline in muscle strength.
Time frame: Baseline to Week 12
Population: The outcome measure was analyzed for the Full Analysis Set, which consisted of all randomized patients who received any amount of study drug and had a baseline and at least 1 postbaseline efficacy assessment during double-blind treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Slope of Muscle Strength Mega-score From Baseline to Week 12 | -0.1444 change in mega-score per day | Standard Error 0.02492 |
| Reldesemtiv 150 mg Twice Daily | Slope of Muscle Strength Mega-score From Baseline to Week 12 | -0.1198 change in mega-score per day | Standard Error 0.02463 |
| Reldesemtiv 300 mg Twice Daily | Slope of Muscle Strength Mega-score From Baseline to Week 12 | -0.1299 change in mega-score per day | Standard Error 0.02474 |
| Reldesemtiv 450 mg Twice Daily | Slope of Muscle Strength Mega-score From Baseline to Week 12 | -0.0956 change in mega-score per day | Standard Error 0.02421 |
| Reldesemtiv 300 mg & 450 mg | Slope of Muscle Strength Mega-score From Baseline to Week 12 | -0.1127 change in mega-score per day | Standard Error 0.01731 |
p-value: 0.313495% CI: [-0.0261, 0.0813]Mixed Models Analysis
p-value: 0.482495% CI: [-0.0442, 0.0935]Mixed Models Analysis
p-value: 0.678795% CI: [-0.0544, 0.0835]Mixed Models Analysis
p-value: 0.160495% CI: [-0.0194, 0.1171]Mixed Models Analysis
p-value: 0.296695% CI: [-0.0279, 0.0913]Mixed Models Analysis