Amyotrophic Lateral Sclerosis (ALS)
Conditions
Keywords
Amyotrophic Lateral Sclerosis, ALS, tirasemtiv
Brief summary
The purpose of this study is to assess the long-term safety and tolerability of tirasemtiv in patients with ALS who had completed the double-blind placebo-controlled study of tirasemtiv in ALS (CY 4031).
Detailed description
Enrolled participants will begin dosing of tirasemtiv 125 mg twice daily (250 mg/day) for a period of 4 weeks and will titrate to their tolerated dose, the maximum dose being 250 mg twice daily (500 mg/day). This study will also compare the clinical course of patients who completed treatment with tirasemtiv in CY 4031 with those who completed treatment with placebo in CY 4031 during continued treatment of both groups with tirasemtiv during CY 4033, compare the clinical course of patients who completed treatment with tirasemtiv in CY 4031 during that study with their clinical course during continued treatment with tirasemtiv during CY 4033, and compare the clinical course of patients who completed treatment with placebo in CY 4031 during that study with their clinical course during treatment with tirasemtiv during CY 4033.
Interventions
DRUGtirasemtiv
Oral
Sponsors
Cytokinetics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Able to comprehend and willing to sign an Informed Consent Form (ICF). If verbal consent is given, a Legal Designee of the patient must sign the ICF form * Completed participation on study drug and the Follow-Up Visit in the CY 4031 study * Male patients, who have not had a vasectomy AND confirmed zero sperm count, must agree for the duration of their participation in the study to either: * Use a condom during sexual intercourse with female partners who are of childbearing potential AND to have female partners use a highly effective means of contraception OR * Abstain from sexual intercourse during participation in the study * Female patients who are not post-menopausal (≥ 1 year) or sterilized, must: * Not be breastfeeding * Have a negative pregnancy test * Have no intention to become pregnant during participation in the study AND * Practice sexual abstinence, defined as refraining from intercourse during the duration of the study OR if male partners are not vasectomized with a confirmed zero sperm count, require use of a condom AND use of a highly effective contraceptive measure
Exclusion criteria
* Has a diaphragm pacing system (DPS) at study entry or anticipate DPS placement during the course of the study * Has taken an investigational study drug (other than tirasemtiv) prior to dosing, within 30 days or five half-lives of the prior agent, whichever is greater * Use of tizanidine and theophylline-containing medications during study participation * Participation or planning to participate in any form of stem cell therapy for the treatment of ALS or another investigational drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From the first dose of tirasemtiv through 28 days after the last dose | The number of participants with adverse events was used as the measure for the long-term safety and tolerability of tirasemtiv. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 24 in CY 4033 | baseline and 24 weeks | Slow vital capacity (SVC) 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 (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics \[eg, height, age, sex\]). |
| Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 48 in CY 4033 | baseline and 48 weeks | 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 (ie, the test result as a percent of predicted values for patients of similar demographic and baseline characteristics \[eg, height, age, sex\]). |
| Change From CY 4031 Baseline in ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score at Week 24 | baseline and 24 weeks | 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, with higher scores reflecting more normal function and lower scores reflecting more impaired function. Comparing postbaseline to baseline assessments, a negative value indicates a worsening in function. |
| Change From CY 4031 Baseline in ALSFRS-R Total Score at Week 48 | baseline and 48 weeks | 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, with higher scores reflecting more normal function and lower scores reflecting more impaired function. Comparing postbaseline to baseline assessments, a negative value indicates a worsening in function. |
Countries
Belgium, Canada, France, Germany, Ireland, Italy, Netherlands, Portugal, Spain, United Kingdom, United States
Participant flow
Recruitment details
Patients with ALS were enrolled at 69 sites in Belgium, Canada, France, Germany, Ireland, Italy, Netherlands, Portugal, Spain, the United Kingdom, and the United States. The study was conducted from 17 October 2016 (date first patient enrolled) through 26 October 2018 (date of last patient contact).
Pre-assignment details
Eligible patients completed participation in Study CY 4031 on study drug and had completed the scheduled follow-up visit for that study.
Participants by arm
| Arm | Count |
|---|---|
| Delayed Start Treatment The Delayed Start Treatment group consisted of patients who received placebo in CY 4031 and tirasemtiv in CY 4033. | 111 |
| Early Start Treatment The Early Start Treatment group consisted of patients who received tirasemtiv in both CY 4031 and CY 4033. | 162 |
| Total | 273 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 43 | 25 |
| Overall Study | Death | 9 | 15 |
| Overall Study | Lack of effect/Entry into other study | 31 | 65 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Physician Decision | 2 | 9 |
| Overall Study | Progressive Disease | 10 | 18 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Sponsor Discretion | 10 | 16 |
| Overall Study | Withdrawal by Subject | 8 | 15 |
Baseline characteristics
| Characteristic | Delayed Start Treatment | Total | Early Start Treatment |
|---|---|---|---|
| Age, Continuous | 55.7 years STANDARD_DEVIATION 10.07 | 56.9 years STANDARD_DEVIATION 9.56 | 57.7 years STANDARD_DEVIATION 9.13 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 105 Participants | 263 Participants | 158 Participants |
| Sex: Female, Male Female | 35 Participants | 81 Participants | 46 Participants |
| Sex: Female, Male Male | 76 Participants | 192 Participants | 116 Participants |
| Time since ALS symptom onset at screening in parent study | 23.60 months STANDARD_DEVIATION 17.078 | 20.96 months STANDARD_DEVIATION 13.961 | 19.15 months STANDARD_DEVIATION 11.041 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 21 / 115 | 28 / 165 |
| other Total, other adverse events | 111 / 115 | 155 / 165 |
| serious Total, serious adverse events | 32 / 115 | 53 / 165 |
Outcome results
Primary
Number of Participants With Adverse Events
The number of participants with adverse events was used as the measure for the long-term safety and tolerability of tirasemtiv.
Time frame: From the first dose of tirasemtiv through 28 days after the last dose
Population: The data are presented for the Safety Analysis Set, which consisted of all patients who enrolled and received at least 1 dose of tirasemtiv in Study CY 4033.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Delayed Start Treatment | Number of Participants With Adverse Events | 112 Participants |
| Early Start Treatment | Number of Participants With Adverse Events | 157 Participants |
Secondary
Change From CY 4031 Baseline in ALSFRS-R Total Score at Week 48
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, with higher scores reflecting more normal function and lower scores reflecting more impaired function. Comparing postbaseline to baseline assessments, a negative value indicates a worsening in function.
Time frame: baseline and 48 weeks
Population: The analysis population includes patients who received at least 1 dose of tirasemtiv and had an ALSFRS-R total score at Week 48.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Delayed Start Treatment | Change From CY 4031 Baseline in ALSFRS-R Total Score at Week 48 | -17.61 scores on a scale | Standard Error 1.171 |
| Early Start Treatment | Change From CY 4031 Baseline in ALSFRS-R Total Score at Week 48 | -17.82 scores on a scale | Standard Error 0.956 |
p-value: 0.888795% CI: [-3.186, 2.763]Mixed Models Analysis
Secondary
Change From CY 4031 Baseline in ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score at Week 24
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, with higher scores reflecting more normal function and lower scores reflecting more impaired function. Comparing postbaseline to baseline assessments, a negative value indicates a worsening in function.
Time frame: baseline and 24 weeks
Population: The analysis population includes patients who received at least 1 dose of tirasemtiv and had an ALSFRS-R total score at Week 24.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Delayed Start Treatment | Change From CY 4031 Baseline in ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score at Week 24 | -13.78 scores on a scale | Standard Error 0.934 |
| Early Start Treatment | Change From CY 4031 Baseline in ALS Functional Rating Scale - Revised (ALSFRS-R) Total Score at Week 24 | -14.35 scores on a scale | Standard Error 0.767 |
p-value: 0.635495% CI: [-2.946, 1.801]Mixed Models Analysis
Secondary
Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 24 in CY 4033
Slow vital capacity (SVC) 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 (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 and 24 weeks
Population: The analysis population includes patients who received at least 1 dose of tirasemtiv and had slow vital capacity results at Week 24.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Delayed Start Treatment | Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 24 in CY 4033 | -28.79 change in % predicted SVC | Standard Error 2.845 |
| Early Start Treatment | Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 24 in CY 4033 | -32.69 change in % predicted SVC | Standard Error 2.285 |
p-value: 0.282195% CI: [-11.035, 3.23]Mixed Models Analysis
Secondary
Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 48 in CY 4033
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 (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 and 48 weeks
Population: The analysis population includes patients who received at least 1 dose of tirasemtiv and had slow vital capacity results at Week 48.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Delayed Start Treatment | Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 48 in CY 4033 | -35.55 percent predicted slow vital capacity | Standard Error 3.332 |
| Early Start Treatment | Change From CY 4031 Baseline in Percent Predicted Slow Vital Capacity to Week 48 in CY 4033 | -40.87 percent predicted slow vital capacity | Standard Error 2.667 |
p-value: 0.211895% CI: [-13.711, 3.067]Mixed Models Analysis