Amyotrophic Lateral Sclerosis
Conditions
Keywords
Amyotrophic Lateral Sclerosis, ALS, Motor Neurone Disease, Motor Neuron Disease, Lou Gehrig's disease
Brief summary
The purpose of this study is to determine whether dexpramipexole (150 mg twice daily) is safe and effective in the treatment of Amyotrophic Lateral Sclerosis (ALS).
Detailed description
Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive, degenerative disease of motor neurons in the brain and spinal cord that leads to muscle atrophy and spasticity in limb and bulbar muscles resulting in weakness and loss of ambulation, oropharyngeal dysfunction, weight loss, and ultimately respiratory failure. The purpose of this study is to determine whether dexpramipexole (150 mg twice daily) is safe and effective in the treatment of ALS.
Interventions
DRUGDexpramipexole
Oral tablet 150mg twice daily for up to 18 months.
DRUGPlacebo
Oral tablet twice daily for up to 18 months.
Sponsors
Knopp Biosciences
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
* Aged 18 to 80 years old, inclusive, on Day 1. * Diagnosis of sporadic or familial ALS. * Onset of first ALS symptoms within 24 months prior to Day 1. * World Federation of Neurology El Escorial criteria are met for a possible, laboratory-supported probable, probable, or definite ALS diagnosis. * Upright slow vital capacity (SVC) of 65% or more at screening. * Patients taking or not taking Riluzole are eligible for this study: if a patient has never taken Riluzole, he or she is eligible; if a patient is currently taking Riluzole, he or she must have been on a stable dose for at least 60 days; if a patient has discontinued Riluzole, he or she must have stopped taking it for at least 30 days. * Must be able to swallow tablets at the time of study entry.
Exclusion criteria
* Other medically significant illness. * Clinically significant abnormal laboratory values. * Pregnant women or women breastfeeding. * Prior exposure to dexpramipexole. * Currently taking pramipexole or other dopamine agonists. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Assessment of Function and Survival (CAFS) at 12 Months | 12 months | The Composite Assessment of Function and Survival (CAFS) is a between-group comparison of a single ranked clinical outcome based on (1) the change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) score and (2) time to death. Each subject is ranked according to time-to-death (earlier deaths ranked lower than later deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than less worsening or an improvement in ALSFRS-R). The ranked scores range from 001 to 941 (the number of subjects in the Efficacy Population) with larger rank score numbers associated with a better outcome. The ranks were analyzed using an ANCOVA model, which includes treatment as a fixed effect and adjusts for baseline ALSFRS-R score, duration of symptoms, site of onset, and use of riluzole. The least square mean rank score is presented for each treatment group. |
| Death up to 12 Months (CAFs Individual Component) | 12 months | The longest duration of follow-up for this time to the death analysis was 12 months. In the study, subjects were followed for 12-18 months. |
| Change From Baseline in ALSFRS-R at 12 Months (CAFs Individual Component) | 12 months | The ALSFRS-R (ALS functional rating scale with respiratory component) is a validated scale which measures 4 functional domains, comprising respiratory function, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48, with higher scores representing better function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Death or Respiratory Insufficiency (DRI) up to Month 18 | 18 months | Time to Death or Respiratory Insufficiency (DRI) is defined as receipt of a tracheostomy or the use of non-invasive ventilation (NIV) for ≥22 hours per day for at least 10 consecutive days. If NIV is used to meet the criteria for respiratory insufficiency, no measured slow vital capacity (SVC) at any subsequent assessment may be \>50%. Time to DRI is calculated from the date of the first dose to the first date of one of the following events: death, tracheostomy, or the 10th day of consecutive NIV with no measured SVC \>50% at any subsequent assessment. |
| Death up to 18 Months | 18 months | Estimated time to death up to 18 months. This includes deaths reported greater than 30 days following discontinuation from the study (the time period for reporting all-cause mortality), regardless of subject disposition, up to 18 months from first dose. |
| ≤50% Predicted Upright Slow Vital Capacity (SVC) or Died up to 18 Months | 18 months | The date of reaching ≤50% of predicted upright slow vital capacity (SVC) is defined as the date of the first visit at which a predicted upright SVC is ≤50% and continues to remain ≤50% at the subsequent visit except for the last available observation. The time to reach ≤50% of predicted upright SVC is defined as the duration between the date of reaching ≤50% of predicted upright SVC and the date of the first dose of study medication. If the subject is alive and does not reach ≤50% of predicted upright SVC, the time to reach ≤50% of predicted upright SVC will be censored and equal to the number of days from the first dose of study medication until the visit date when the subject's last available SVC assessment is performed. The earliest time (Reaching ≤50% Predicted Upright SVC or death) is used in analysis. |
Countries
Australia, Belgium, Canada, France, Germany, Ireland, Netherlands, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
There were 942 participants (468 received placebo and 474 received dexpramipexole) recruited from 81 investigational sites in 11 countries worldwide. One additional participant was randomized in error and was not dosed. This subject was assigned to the placebo arm, but was removed from the intent-to-treat population as a result of the unintentional randomization performed in error by the site.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching Placebo: Oral tablet twice daily. | 468 |
| Dexpramipexole Dexpramipexole: Oral tablet 150 mg twice daily. 300 mg/day | 474 |
| Total | 942 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 9 |
| Overall Study | Death | 103 | 91 |
| Overall Study | Lost to Follow-up | 6 | 4 |
| Overall Study | Other | 8 | 12 |
| Overall Study | Physician Decision | 2 | 3 |
| Overall Study | Withdrawal by Subject | 21 | 24 |
Baseline characteristics
| Characteristic | Placebo | Total | Dexpramipexole |
|---|---|---|---|
| Age, Customized Age (yrs) <50 | 114 Participants | 228 Participants | 114 Participants |
| Age, Customized Age (yrs) 50-65 | 233 Participants | 477 Participants | 244 Participants |
| Age, Customized Age (yrs) >65 | 121 Participants | 237 Participants | 116 Participants |
| ALS family history Missing | 0 Participants | 1 Participants | 1 Participants |
| ALS family history No | 442 Participants | 882 Participants | 440 Participants |
| ALS family history Yes | 26 Participants | 59 Participants | 33 Participants |
| Baseline ALSFRS-R total scores | 37.9 units on a scale STANDARD_DEVIATION 5.65 | 38.2 units on a scale STANDARD_DEVIATION 5.45 | 38.4 units on a scale STANDARD_DEVIATION 5.24 |
| Baseline predicted upright slow vital capacity (%) <65% | 27 Participants | 55 Participants | 28 Participants |
| Baseline predicted upright slow vital capacity (%) 65-75% | 84 Participants | 163 Participants | 79 Participants |
| Baseline predicted upright slow vital capacity (%) >75% | 357 Participants | 724 Participants | 367 Participants |
| Baseline predicted upright slow vital capacity (%) | 89.1 % STANDARD_DEVIATION 17.71 | 89.1 % STANDARD_DEVIATION 17.63 | 89.0 % STANDARD_DEVIATION 17.57 |
| Body mass index | 26.15 kg/m^2 STANDARD_DEVIATION 4.33 | 26.08 kg/m^2 STANDARD_DEVIATION 4.283 | 26.00 kg/m^2 STANDARD_DEVIATION 4.239 |
| Concomitant use of riluzole No | 119 Participants | 234 Participants | 115 Participants |
| Concomitant use of riluzole Yes | 349 Participants | 708 Participants | 359 Participants |
| El Escorial Criteria for ALS Definite | 156 Participants | 303 Participants | 147 Participants |
| El Escorial Criteria for ALS Possible | 44 Participants | 88 Participants | 44 Participants |
| El Escorial Criteria for ALS Probable | 174 Participants | 359 Participants | 185 Participants |
| El Escorial Criteria for ALS Probable laboratory supported | 94 Participants | 192 Participants | 98 Participants |
| Height | 172.0 cm STANDARD_DEVIATION 10.22 | 172.0 cm STANDARD_DEVIATION 9.77 | 172.0 cm STANDARD_DEVIATION 9.3 |
| Race/Ethnicity, Customized Race Asian | 7 Participants | 11 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Black or African American | 10 Participants | 13 Participants | 3 Participants |
| Race/Ethnicity, Customized Race Not reported | 7 Participants | 16 Participants | 9 Participants |
| Race/Ethnicity, Customized Race Other | 5 Participants | 13 Participants | 8 Participants |
| Race/Ethnicity, Customized Race White | 439 Participants | 889 Participants | 450 Participants |
| Sex: Female, Male Female | 170 Participants | 337 Participants | 167 Participants |
| Sex: Female, Male Male | 298 Participants | 605 Participants | 307 Participants |
| Site of onset Bulbar | 112 Participants | 219 Participants | 107 Participants |
| Site of onset Other | 356 Participants | 723 Participants | 367 Participants |
| Time since ALS diagnosis | 7.62 months STANDARD_DEVIATION 5.015 | 7.42 months STANDARD_DEVIATION 4.869 | 7.22 months STANDARD_DEVIATION 4.718 |
| Time since ALS symptom onset | 15.53 months STANDARD_DEVIATION 5.411 | 15.22 months STANDARD_DEVIATION 5.337 | 14.92 months STANDARD_DEVIATION 5.251 |
| Weight | 77.76 kg STANDARD_DEVIATION 16.008 | 77.48 kg STANDARD_DEVIATION 15.516 | 77.21 kg STANDARD_DEVIATION 15.027 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 108 / 468 | 97 / 474 |
| other Total, other adverse events | 447 / 468 | 459 / 474 |
| serious Total, serious adverse events | 233 / 468 | 225 / 474 |
Outcome results
Primary
Change From Baseline in ALSFRS-R at 12 Months (CAFs Individual Component)
The ALSFRS-R (ALS functional rating scale with respiratory component) is a validated scale which measures 4 functional domains, comprising respiratory function, bulbar function, gross motor skills, and fine motor skills. There are a total of 12 questions, each scored from 0 to 4 for a total possible score of 48, with higher scores representing better function.
Time frame: 12 months
Population: The efficacy population is defined as subjects who were randomized and received at least 1 dose of study treatment and who either had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects will be analyzed in the treatment group to which they are randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in ALSFRS-R at 12 Months (CAFs Individual Component) | -13.415 units on a scale |
| Dexpramipexole | Change From Baseline in ALSFRS-R at 12 Months (CAFs Individual Component) | -13.339 units on a scale |
p-value: 0.901995% CI: [-1.128, 1.28]mixed-effects repeated-measures model
Primary
Composite Assessment of Function and Survival (CAFS) at 12 Months
The Composite Assessment of Function and Survival (CAFS) is a between-group comparison of a single ranked clinical outcome based on (1) the change from baseline in ALS Functional Rating Scale-Revised (ALSFRS-R) score and (2) time to death. Each subject is ranked according to time-to-death (earlier deaths ranked lower than later deaths). Subjects who survive are ranked more favorably than subjects who died. Among the survivors, subjects are ranked according to change in ALSFRS-R (greater worsening of ALSFRS-R is ranked lower than less worsening or an improvement in ALSFRS-R). The ranked scores range from 001 to 941 (the number of subjects in the Efficacy Population) with larger rank score numbers associated with a better outcome. The ranks were analyzed using an ANCOVA model, which includes treatment as a fixed effect and adjusts for baseline ALSFRS-R score, duration of symptoms, site of onset, and use of riluzole. The least square mean rank score is presented for each treatment group.
Time frame: 12 months
Population: The efficacy population is defined as subjects who were randomized and received at least 1 dose of study treatment and who either had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects were analyzed in the treatment group to which they are randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Composite Assessment of Function and Survival (CAFS) at 12 Months | 438.84 units on a scale |
| Dexpramipexole | Composite Assessment of Function and Survival (CAFS) at 12 Months | 441.76 units on a scale |
p-value: 0.856895% CI: [-28.751, 34.576]ANCOVA
Primary
Death up to 12 Months (CAFs Individual Component)
The longest duration of follow-up for this time to the death analysis was 12 months. In the study, subjects were followed for 12-18 months.
Time frame: 12 months
Population: The efficacy population is defined as subjects who were randomized and received at least 1 dose of study treatment and who either had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects were analyzed in the treatment group to which they are randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Death up to 12 Months (CAFs Individual Component) | 17.2 percentage of participants |
| Dexpramipexole | Death up to 12 Months (CAFs Individual Component) | 16.0 percentage of participants |
p-value: 0.837595% CI: [0.75, 1.427]Cox Proportional Hazards model
Secondary
≤50% Predicted Upright Slow Vital Capacity (SVC) or Died up to 18 Months
The date of reaching ≤50% of predicted upright slow vital capacity (SVC) is defined as the date of the first visit at which a predicted upright SVC is ≤50% and continues to remain ≤50% at the subsequent visit except for the last available observation. The time to reach ≤50% of predicted upright SVC is defined as the duration between the date of reaching ≤50% of predicted upright SVC and the date of the first dose of study medication. If the subject is alive and does not reach ≤50% of predicted upright SVC, the time to reach ≤50% of predicted upright SVC will be censored and equal to the number of days from the first dose of study medication until the visit date when the subject's last available SVC assessment is performed. The earliest time (Reaching ≤50% Predicted Upright SVC or death) is used in analysis.
Time frame: 18 months
Population: The intent-to-treat (ITT) population is defined as subjects who were randomized and received at least 1 dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | ≤50% Predicted Upright Slow Vital Capacity (SVC) or Died up to 18 Months | 41.9 percentage of participants |
| Dexpramipexole | ≤50% Predicted Upright Slow Vital Capacity (SVC) or Died up to 18 Months | 36.5 percentage of participants |
p-value: 0.77295% CI: [0.789, 1.192]Cox Proportional Hazards model
Secondary
Death or Respiratory Insufficiency (DRI) up to Month 18
Time to Death or Respiratory Insufficiency (DRI) is defined as receipt of a tracheostomy or the use of non-invasive ventilation (NIV) for ≥22 hours per day for at least 10 consecutive days. If NIV is used to meet the criteria for respiratory insufficiency, no measured slow vital capacity (SVC) at any subsequent assessment may be \>50%. Time to DRI is calculated from the date of the first dose to the first date of one of the following events: death, tracheostomy, or the 10th day of consecutive NIV with no measured SVC \>50% at any subsequent assessment.
Time frame: 18 months
Population: The efficacy population is defined as subjects who were randomized and received at least 1 dose of study treatment and who either had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects were analyzed in the treatment group to which they are randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Death or Respiratory Insufficiency (DRI) up to Month 18 | 27.2 percentage of participants |
| Dexpramipexole | Death or Respiratory Insufficiency (DRI) up to Month 18 | 22.3 percentage of participants |
p-value: 0.771595% CI: [0.801, 1.348]Cox Proportional Hazards model
Secondary
Death up to 18 Months
Estimated time to death up to 18 months. This includes deaths reported greater than 30 days following discontinuation from the study (the time period for reporting all-cause mortality), regardless of subject disposition, up to 18 months from first dose.
Time frame: 18 months
Population: Subjects who were randomized, received at least 1 dose of study treatment, had at least 1 available post-dosing efficacy evaluation (ALSFRS-R) or died during the study period. Subjects were analyzed in the treatment group to which they are randomized. An attempt was made to collect living status for each subject 18 months after randomization, regardless of the subject's disposition in the study (active or discontinued) or primary reasons for discontinuation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Death up to 18 Months | 23.1 percentage of participants |
| Dexpramipexole | Death up to 18 Months | 20.5 percentage of participants |
p-value: 0.903395% CI: [0.745, 1.298]Cox Proportional Hazards model