Amyotrophic Lateral Sclerosis
Conditions
Keywords
Arimoclomol, ALS
Brief summary
A multicenter, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of arimoclomol in amyotropic lateral sclerosis (ALS)
Detailed description
Screening up to 4 weeks Treatment up to 76 weeks
Interventions
DRUGArimoclomol
2 capsules (2 x 124 mg arimoclomol base; equivalent to 2 x 200 mg arimoclomol citrate) taken 3 times daily
DRUGPlacebo
2 matched placebo capsules taken 3 times daily
Sponsors
ZevraDenmark
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind
Intervention model description
Placebo-controlled, parallel group
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject meets revised El Escorial criteria for clinically possible, clinically probable / clinically probable ALS laboratory-supported, clinically definite ALS or clinically definite familial ALS laboratory-supported * 18 months or less since first appearance of weakness (e.g. limb weakness, dysarthria, dysphagia, shortness of breath) * ALS Functional Rating Scale-Revised (ALSFRS-R) equal to or above 35 and erect (seated) Slow Vital Capacity (SVC) % predicted equal to or above 70% at Screening
Exclusion criteria
* Tracheostomy or use of non-invasive ventilation for more than 2 hours during waking hours at the time of Screening and Baseline * Pregnant or breast-feeding * Current or anticipated use of diaphragmatic pacing * Any other relevant medically significant condition which could present risk to the subject or interfere with the assessment of safety or has an increased risk of causing death during the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Combined Assessment of Function and Survival (CAFS) | Over 76 Weeks | Combined Assessment of Function and Survival (CAFS) is a composite endpoint that includes 1) the change from baseline in revised ALS functional rating scale (ALSFRS-R) and 2) the survival endpoint (time to permanent assisted ventilation \[PAV\], tracheostomy or death). On the ALSFRS-R, 12 functions are rated on 5-point ordinal rating scales (from 0 to 4) with a total score range (minimum and maximum score) of 0-48 (sum of all 12 items). The higher the score the better functioning. For the survival endpoint, the longer time to PAV, tracheostomy, or death the better outcome. A patient's CAFS score represents a patient's rank in the study based on comparing the patient's outcome for both the change in ALSFRS-R and the time to event (PAV, tracheostomy, or death) to the outcome for all other patients in the study in a pairwise fashion. A higher rank score (range 0-1) is considered a better outcome. The reported values are the mean rank scores in each group for the composite endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Permanent Assisted Ventilation (PAV) / Tracheostomy / Death | Over 76 weeks | Time from baseline to one of the events (PAV / tracheostomy / death). PAV is defined as the first of 7 consecutive days on which PAV was used for \>22 hours/day |
| Change From Baseline to Week 76 (or End-of-trial) in the Revised ALS Functional Rating Scale (ALSFRS-R) | Week 76 (or end of trial) | The ALSFRS-R score is based on a rating scale where 12 functions are rated on 5-point ordinal rating scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items). The higher the score the better functioning. |
| Change From Baseline to Week 76 (or End-of-trial) in Percent (%) Predicted Slow Vital Capacity (SVC) | Week 76 (or end of trial) | Slow Vital Capacity (SVC) is a measure of breathing function. SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. The percent (%) of predicted SVC is reported. |
Countries
Belgium, Canada, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arimoclomol (up to 76 Weeks) Arimoclomol base 248 mg 3 times daily for up to 76 weeks | 160 |
| Placebo (up to 76 Weeks) Matching placebo 3 times daily for up to 76 weeks | 79 |
| Total | 239 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 1 |
| Overall Study | Lost to Follow-up | 2 | 0 |
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Withdrawal by Subject | 22 | 15 |
Baseline characteristics
| Characteristic | Total | Arimoclomol (up to 76 Weeks) | Placebo (up to 76 Weeks) |
|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 10.85 | 58.0 years STANDARD_DEVIATION 11.26 | 56.6 years STANDARD_DEVIATION 9.97 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 13 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 196 Participants | 132 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 23 Participants | 15 Participants | 8 Participants |
| Percent (%) Predicted Slow Vital Capacity (SVC) | 96.5 percent (%) predicted SVC STANDARD_DEVIATION 15.6 | 95.8 percent (%) predicted SVC STANDARD_DEVIATION 15.98 | 98.1 percent (%) predicted SVC STANDARD_DEVIATION 14.78 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 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 | 34 Participants | 23 Participants | 11 Participants |
| Race (NIH/OMB) White | 202 Participants | 136 Participants | 66 Participants |
| Revised ALS Functional Rating Scale (ALSFRS-R) | 40.5 units on a scale STANDARD_DEVIATION 3.83 | 40.6 units on a scale STANDARD_DEVIATION 3.93 | 40.2 units on a scale STANDARD_DEVIATION 3.65 |
| Sex: Female, Male Female | 88 Participants | 54 Participants | 34 Participants |
| Sex: Female, Male Male | 151 Participants | 106 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 29 / 160 | 18 / 79 |
| other Total, other adverse events | 149 / 160 | 71 / 79 |
| serious Total, serious adverse events | 36 / 160 | 20 / 79 |
Outcome results
Primary
Combined Assessment of Function and Survival (CAFS)
Combined Assessment of Function and Survival (CAFS) is a composite endpoint that includes 1) the change from baseline in revised ALS functional rating scale (ALSFRS-R) and 2) the survival endpoint (time to permanent assisted ventilation \[PAV\], tracheostomy or death). On the ALSFRS-R, 12 functions are rated on 5-point ordinal rating scales (from 0 to 4) with a total score range (minimum and maximum score) of 0-48 (sum of all 12 items). The higher the score the better functioning. For the survival endpoint, the longer time to PAV, tracheostomy, or death the better outcome. A patient's CAFS score represents a patient's rank in the study based on comparing the patient's outcome for both the change in ALSFRS-R and the time to event (PAV, tracheostomy, or death) to the outcome for all other patients in the study in a pairwise fashion. A higher rank score (range 0-1) is considered a better outcome. The reported values are the mean rank scores in each group for the composite endpoint.
Time frame: Over 76 Weeks
Population: modified intention-to-treat (mITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arimoclomol (up to 76 Weeks) | Combined Assessment of Function and Survival (CAFS) | 0.51 score on a scale | Standard Deviation 0.291 |
| Placebo (up to 76 Weeks) | Combined Assessment of Function and Survival (CAFS) | 0.49 score on a scale | Standard Deviation 0.283 |
p-value: 0.6208Gehan's extended Wilcoxon's test
Secondary
Change From Baseline to Week 76 (or End-of-trial) in Percent (%) Predicted Slow Vital Capacity (SVC)
Slow Vital Capacity (SVC) is a measure of breathing function. SVC measures the volume that can be exhaled from a full inhalation after exhaling to a maximum as slowly as possible. The percent (%) of predicted SVC is reported.
Time frame: Week 76 (or end of trial)
Population: modified intention-to-treat (mITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arimoclomol (up to 76 Weeks) | Change From Baseline to Week 76 (or End-of-trial) in Percent (%) Predicted Slow Vital Capacity (SVC) | -30.65 percent (%) predicted SVC | Standard Deviation 26.346 |
| Placebo (up to 76 Weeks) | Change From Baseline to Week 76 (or End-of-trial) in Percent (%) Predicted Slow Vital Capacity (SVC) | -30.38 percent (%) predicted SVC | Standard Deviation 23.839 |
Secondary
Change From Baseline to Week 76 (or End-of-trial) in the Revised ALS Functional Rating Scale (ALSFRS-R)
The ALSFRS-R score is based on a rating scale where 12 functions are rated on 5-point ordinal rating scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items). The higher the score the better functioning.
Time frame: Week 76 (or end of trial)
Population: modified intention-to-treat (mITT)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arimoclomol (up to 76 Weeks) | Change From Baseline to Week 76 (or End-of-trial) in the Revised ALS Functional Rating Scale (ALSFRS-R) | -15.4 units on a scale | Standard Deviation 8.71 |
| Placebo (up to 76 Weeks) | Change From Baseline to Week 76 (or End-of-trial) in the Revised ALS Functional Rating Scale (ALSFRS-R) | -15.0 units on a scale | Standard Deviation 9.1 |
Secondary
Time to Permanent Assisted Ventilation (PAV) / Tracheostomy / Death
Time from baseline to one of the events (PAV / tracheostomy / death). PAV is defined as the first of 7 consecutive days on which PAV was used for \>22 hours/day
Time frame: Over 76 weeks
Population: modified intention-to-treat (mITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arimoclomol (up to 76 Weeks) | Time to Permanent Assisted Ventilation (PAV) / Tracheostomy / Death | NA days |
| Placebo (up to 76 Weeks) | Time to Permanent Assisted Ventilation (PAV) / Tracheostomy / Death | NA days |