Amyotrophic Lateral Sclerosis
Conditions
Keywords
ALS, Placebo-Controlled, Double-Blind, Regimen Specific Appendix, Lou Gehrig's Disease, Pridopidine, Prilenia Therapeutics
Brief summary
The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS. Regimen D will evaluate the safety and efficacy of a single study drug, pridopidine, in participants with ALS.
Detailed description
The HEALEY ALS Platform Trial is a perpetual multi-center, multi-regimen clinical trial evaluating the safety and efficacy of investigational products for the treatment of ALS. This trial is designed as a perpetual platform trial. This means that there is a single Master Protocol dictating the conduct of the trial. The HEALEY ALS Platform Trial Master Protocol is registered as NCT04297683. Once a participant enrolls into the Master Protocol and meets all eligibility criteria, the participant will be eligible to be randomized into any currently enrolling regimen. All participants will have an equal chance of being randomized to any currently enrolling regimen. If a participant is randomized to Regimen D Pridopidine, the participant will complete a screening visit to assess additional Regimen D eligibility criteria. Once Regimen D eligibility criteria are confirmed, participants will complete a baseline assessment and be randomized in a 3:1 ratio to either active pridopidine or matching placebo. Regimen D will enroll by invitation, as participants may not choose to enroll in Regimen D. Participants must first enroll into the Master Protocol and be eligible to participate in the Master Protocol before being able to be randomly assigned to Regimen D. For a list of enrolling sites, please see the HEALEY ALS Platform Trial Master Protocol under NCT04297683.
Interventions
DRUGPridopidine
Administration: Oral Dose: 45mg twice daily
DRUGMatching Placebo
Administration: Oral Dose: one capsule twice daily
Sponsors
Prilenia
Merit E. Cudkowicz, MD
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 No maximum
Healthy volunteers
No
Inclusion criteria
* No additional inclusion criteria beyond the inclusion criteria specified in the Master Protocol (NCT NCT04297683).
Exclusion criteria
* The following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Progression as Assessed by the ALSFRS-R Total Score | Baseline to 24 Weeks | Change in disease severity over time as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Each type of function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. Patients with higher scores have more physical function. |
| Mortality Event Rate | Baseline to 24 Weeks | Mortality is defined as death or death equivalent. A participant is determined to meet the criteria of death equivalent if permanent assisted ventilation (PAV) is used for more than 22 hours per day for more than seven days in a row. The rate of mortality was estimated from a Bayesian shared-parametric model that assumed exponentially distributed survival times. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Respiratory Function | Baseline to 24 Weeks | Change in respiratory function over time as measured by Slow Vital Capacity (SVC). |
| Bulbar Function in Participants With Rapid Pre-baseline Progression | Baseline to 24 Weeks | Change in bulbar function over time in participants with rapid pre-baseline progression as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function. Participants were classified with rapid pre-baseline progression if their change in ALSFRS-R total score between Master Protocol Screening and Regimen Baseline was greater than or equal or 0.75 points per month. |
| Change in Bulbar Function in Participants With Bulbar Dysfunction at Baseline | Baseline to 24 Weeks | Change in bulbar function over time in participants with bulbar dysfunction at baseline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function. Participants were classified as having bulbar dysfunction at baseline if their score on the ALSFRS-R bulbar domain (Q1-Q3) score was less than 12. |
| Muscle Strength | Baseline to 24 Weeks | Change in muscle strength over time as measured isometrically using hand-held dynamometry (HHD). |
| Number of Participants That Experienced Death or Death Equivalent | Baseline to 24 Weeks | The number of participants who died or met the criterion for a death equivalent from the date of their baseline visit to the end of the Week 24visit window (generally 175 days after baseline). The death equivalent criterion is use of permanent assisted ventilation (PAV) for more than 22 hours per day for more than 7 days in a row. |
| Time to Bulbar Decline | Baseline to 24 Weeks | Time to first decline of 1-point or greater post baseline in the ALSFRS-R bulbar domain score among all participants. Analysis performed using interval-censored survival analysis. Results presented as median interval (upper & lower bounded) time to event. |
| Bulbar Function in All Randomized Participants | Baseline to 24 Weeks | Change in bulbar function over time in all randomized participants as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pridopidine Pridopidine is administered orally twice daily for 24 weeks.
Pridopidine: Administration: Oral
Dose: 45mg twice daily | 120 |
| Matching Placebo Matching placebo is administered orally twice daily for 24 weeks.
Matching Placebo: Administration: Oral
Dose: one capsule twice daily | 42 |
| Total | 162 |
Baseline characteristics
| Characteristic | Matching Placebo | Total | Pridopidine |
|---|---|---|---|
| Age, Continuous | 57.1 years STANDARD_DEVIATION 9.86 | 57.7 years STANDARD_DEVIATION 10.01 | 57.9 years STANDARD_DEVIATION 10.1 |
| ALSFRS-R Total Score | 35.0 points STANDARD_DEVIATION 7.07 | 34.5 points STANDARD_DEVIATION 6.79 | 34.3 points STANDARD_DEVIATION 6.71 |
| ALS Onset Location Axial | 2 Participants | 3 Participants | 1 Participants |
| ALS Onset Location Bulbar | 10 Participants | 33 Participants | 23 Participants |
| ALS Onset Location Generalized | 0 Participants | 2 Participants | 2 Participants |
| ALS Onset Location Limb | 30 Participants | 123 Participants | 93 Participants |
| ALS Onset Location Multiple | 0 Participants | 1 Participants | 1 Participants |
| Baseline Decline in ALSFRS-R | 0.71 points per month STANDARD_DEVIATION 0.455 | 0.75 points per month STANDARD_DEVIATION 0.488 | 0.77 points per month STANDARD_DEVIATION 0.5 |
| Baseline Edaravone Use Flag No | 32 Participants | 124 Participants | 92 Participants |
| Baseline Edaravone Use Flag Yes | 10 Participants | 38 Participants | 28 Participants |
| Baseline Riluzole Use Flag No | 9 Participants | 39 Participants | 30 Participants |
| Baseline Riluzole Use Flag Yes | 33 Participants | 123 Participants | 90 Participants |
| Body Mass Index | 25.9 kg/m^2 STANDARD_DEVIATION 4.07 | 26.1 kg/m^2 STANDARD_DEVIATION 4.48 | 26.1 kg/m^2 STANDARD_DEVIATION 4.63 |
| Delay in ALS Symptom Onset and Diagnosis | 10.4 months STANDARD_DEVIATION 6.5 | 10.5 months STANDARD_DEVIATION 6.36 | 10.5 months STANDARD_DEVIATION 6.34 |
| El Escorial Diagnosis Clinically Definite ALS | 18 Participants | 68 Participants | 50 Participants |
| El Escorial Diagnosis Clinically Possible ALS | 7 Participants | 15 Participants | 8 Participants |
| El Escorial Diagnosis Clinically Probable ALS | 12 Participants | 52 Participants | 40 Participants |
| El Escorial Diagnosis Clinically Probable ALS - Laboratory Supported | 5 Participants | 27 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 12 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 148 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Kings Stage 1 Region with Neuromuscular Dysfunction | 7 Participants | 28 Participants | 21 Participants |
| Kings Stage 2 Regions with Neuromuscular Dysfunction | 7 Participants | 43 Participants | 36 Participants |
| Kings Stage 3 Regions with Neuromuscular Dysfunction | 18 Participants | 49 Participants | 31 Participants |
| Kings Stage 4a/4b Nutritional/Respiratory Failure | 10 Participants | 42 Participants | 32 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 9 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 39 Participants | 144 Participants | 105 Participants |
| Serum Cereatinine Concentration | 0.8 mg/dL STANDARD_DEVIATION 0.18 | 0.7 mg/dL STANDARD_DEVIATION 0.19 | 0.7 mg/dL STANDARD_DEVIATION 0.19 |
| Serum NfL Concentration | 114.6 ng/L STANDARD_DEVIATION 73.25 | 98.2 ng/L STANDARD_DEVIATION 64.93 | 92.7 ng/L STANDARD_DEVIATION 61.24 |
| Sex: Female, Male Female | 9 Participants | 57 Participants | 48 Participants |
| Sex: Female, Male Male | 33 Participants | 105 Participants | 72 Participants |
| SVC | 77.5 percent predicted STANDARD_DEVIATION 16.72 | 78.1 percent predicted STANDARD_DEVIATION 17.13 | 78.3 percent predicted STANDARD_DEVIATION 17.35 |
| Time Since Symptom Onsent at Baseline (Months since ALS symptom onset) | 21.6 months STANDARD_DEVIATION 10 | 20.8 months STANDARD_DEVIATION 8.65 | 20.6 months STANDARD_DEVIATION 8.16 |
| Weight | 79.3 kg STANDARD_DEVIATION 15.63 | 77.3 kg STANDARD_DEVIATION 15.84 | 76.6 kg STANDARD_DEVIATION 15.92 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 120 | 0 / 42 |
| other Total, other adverse events | 106 / 121 | 37 / 41 |
| serious Total, serious adverse events | 16 / 121 | 3 / 41 |
Outcome results
Primary
Disease Progression as Assessed by the ALSFRS-R Total Score
Change in disease severity over time as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). Each type of function is scored from 4 (normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. Patients with higher scores have more physical function.
Time frame: Baseline to 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pridopidine | Disease Progression as Assessed by the ALSFRS-R Total Score | -0.99 points per month | Standard Deviation 0.077 |
| Matching Placebo | Disease Progression as Assessed by the ALSFRS-R Total Score | -1.00 points per month | Standard Deviation 0.07 |
95% CI: [0.801, 1.207]Bayesian shared-parameter model
Primary
Mortality Event Rate
Mortality is defined as death or death equivalent. A participant is determined to meet the criteria of death equivalent if permanent assisted ventilation (PAV) is used for more than 22 hours per day for more than seven days in a row. The rate of mortality was estimated from a Bayesian shared-parametric model that assumed exponentially distributed survival times.
Time frame: Baseline to 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pridopidine | Mortality Event Rate | 0.012 events per month | Standard Deviation 0.0029 |
| Matching Placebo | Mortality Event Rate | 0.012 events per month | Standard Deviation 0.0029 |
Secondary
Bulbar Function in All Randomized Participants
Change in bulbar function over time in all randomized participants as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function.
Time frame: Baseline to 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pridopidine | Bulbar Function in All Randomized Participants | -1.16 point change from baseline | Standard Error 0.169 |
| Matching Placebo | Bulbar Function in All Randomized Participants | -1.25 point change from baseline | Standard Error 0.141 |
p-value: 0.659495% CI: [-0.33, 0.52]Mixed Models Analysis
Secondary
Bulbar Function in Participants With Rapid Pre-baseline Progression
Change in bulbar function over time in participants with rapid pre-baseline progression as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function. Participants were classified with rapid pre-baseline progression if their change in ALSFRS-R total score between Master Protocol Screening and Regimen Baseline was greater than or equal or 0.75 points per month.
Time frame: Baseline to 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pridopidine | Bulbar Function in Participants With Rapid Pre-baseline Progression | -1.54 points change from baseline | Standard Error 0.297 |
| Matching Placebo | Bulbar Function in Participants With Rapid Pre-baseline Progression | -1.54 points change from baseline | Standard Error 0.302 |
p-value: 0.990395% CI: [-0.83, 0.84]Mixed Models Analysis
Secondary
Change in Bulbar Function in Participants With Bulbar Dysfunction at Baseline
Change in bulbar function over time in participants with bulbar dysfunction at baseline as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) bulbar subdomain. Each question is scored from 4 (normal) to 0 (no ability), with a maximum total score of 12 and a minimum total score of 0 for the bulbar subdomain. Patients with higher scores have more bulbar function. Participants were classified as having bulbar dysfunction at baseline if their score on the ALSFRS-R bulbar domain (Q1-Q3) score was less than 12.
Time frame: Baseline to 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pridopidine | Change in Bulbar Function in Participants With Bulbar Dysfunction at Baseline | -1.78 point change from baseline | Standard Error 0.261 |
| Matching Placebo | Change in Bulbar Function in Participants With Bulbar Dysfunction at Baseline | -1.69 point change from baseline | Standard Error 0.21 |
p-value: 0.7895% CI: [-0.75, 0.57]Mixed Models Analysis
Secondary
Muscle Strength
Change in muscle strength over time as measured isometrically using hand-held dynamometry (HHD).
Time frame: Baseline to 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pridopidine | Muscle Strength | -26.74 percent change | Standard Error 2.556 |
| Matching Placebo | Muscle Strength | -24.97 percent change | Standard Error 2.123 |
p-value: 0.588895% CI: [-8.23, 4.67]Mixed Models Analysis
Secondary
Number of Participants That Experienced Death or Death Equivalent
The number of participants who died or met the criterion for a death equivalent from the date of their baseline visit to the end of the Week 24visit window (generally 175 days after baseline). The death equivalent criterion is use of permanent assisted ventilation (PAV) for more than 22 hours per day for more than 7 days in a row.
Time frame: Baseline to 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pridopidine | Number of Participants That Experienced Death or Death Equivalent | 5 Participants |
| Matching Placebo | Number of Participants That Experienced Death or Death Equivalent | 6 Participants |
p-value: 0.969Log Rank
Secondary
Respiratory Function
Change in respiratory function over time as measured by Slow Vital Capacity (SVC).
Time frame: Baseline to 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pridopidine | Respiratory Function | -8.81 percent change | Standard Error 1.351 |
| Matching Placebo | Respiratory Function | -8.35 percent change | Standard Error 1.132 |
p-value: 0.791895% CI: [-3.89, 2.96]Mixed Models Analysis
Secondary
Time to Bulbar Decline
Time to first decline of 1-point or greater post baseline in the ALSFRS-R bulbar domain score among all participants. Analysis performed using interval-censored survival analysis. Results presented as median interval (upper & lower bounded) time to event.
Time frame: Baseline to 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set, which included shared placebo from other regimens, as pre-specified in the Regimen Statistical Analysis Plan. Regimen A (NCT04436497), Regimen B (NCT04436510) and Regimen C (NCT04414345) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pridopidine | Time to Bulbar Decline | Lower Bound of Interval | 84 days |
| Pridopidine | Time to Bulbar Decline | Upper Bound of Interval | 86 days |
| Matching Placebo | Time to Bulbar Decline | Lower Bound of Interval | 66 days |
| Matching Placebo | Time to Bulbar Decline | Upper Bound of Interval | 77 days |
95% CI: [0.69, 1.27]Regression, Cox