Amyotrophic Lateral Sclerosis
Conditions
Keywords
ALS, Placebo-Controlled, Double-Blind, Regimen Specific Appendix, Lou Gehrig's Disease, DNL343, Denali 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 G will evaluate the safety and efficacy of a single study drug, DNL343, 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 G DNL343, the participant will complete a screening visit to assess additional Regimen G eligibility criteria. Once Regimen G eligibility criteria are confirmed, participants will complete a baseline assessment and be randomized in a 3:1 ratio to either active DNL343 or matching placebo. Regimen G will enroll by invitation, as participants may not choose to enroll in Regimen G. 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 G. For a list of enrolling sites, please see the HEALEY ALS Platform Trial Master Protocol under NCT04297683.
Interventions
DRUGDNL343
DNL343 is administered orally once daily per day for 24 weeks.
DRUGMatching Placebo
Matching placebo is administered orally once daily per day for 24 weeks.
Sponsors
Merit E. Cudkowicz, MD
Denali Therapeutics Inc.
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 100 Years
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-Slope | Baseline to 24 Weeks | Change in disease severity as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) total score using a Bayesian repeated measures model that accounts for loss to follow-up due to mortality. Each of 12 questions assessing distinct functional ability is scored from 4(normal) to 0 (no ability), with a maximum total score of 48 and a minimum total score of 0. Participants with higher scores have more physical function. Note that only participants who survived to their Week 24 visit contribute to the estimate. |
| Mortality Event Rate | Baseline to 24 weeks | The Mortality Rate, presented as mean deaths per month, was estimated from a Bayesian shared-parametric model that assumed exponentially distributed survival times. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ALSFRS-R Total Score | Baseline to 24 Weeks | Change in ALSFRS-R total score over time. 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. Participants with higher scores have more physical function. |
| Combined Assessment of Function and Survival (CAFS) | Baseline to 24 Weeks | Combined assessment of function and survival (CAFS) ranks participants' clinical outcomes based on survival time and change in the functional score. Each participant's outcome is compared to every other participant's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS rank score indicates a better group outcome. The survival outcome is death or death-equivalent, where 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 functional outcome is the ALS Functional Rating Scale-Revised (ALSFRS-R) score with a maximum total score of 48 and a minimum total score of 0. Participants with higher scores have more physical function. |
| Respiratory Function | Baseline to 24 Weeks | Change in respiratory function over time as assessed by slow vital capacity (SVC) |
| Upper Limb Muscle Strength | 24 weeks | Change in upper limb muscle strength over time as measured isometrically using hand-held dynamometry and grip strength, calculated as the average percent change from baseline of the following muscles/maneuvers: shoulder flexion, elbow flexion, elbow extension, wrist extension, abductor pollicis brevis contraction, abductor digiti minimi contraction, first dorsal interosseous contraction, and grip strength. Note that only those with measurable strength at baseline were included. |
| Number of Participants With Death or Permanent Assisted Ventilation (PAV) | 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 24 visit 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. |
| Number of Participants Who Experience Death | Baseline to 24 weeks | The number of participants who died from the date of their baseline visit to the end of the Week 24 visit window (generally 175 days after baseline). |
| Disease Progression Biomarker | Baseline to 24 weeks | Change in log-transformed serum neurofilament light protein (NfL) concentration from baseline to Week 24 |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMerit Cudkowicz, MD
Massachusetts General Hospital
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 57.3 Years STANDARD_DEVIATION 11.92 |
| ALS Diagnosis from R El Escorial Criteria Clinically Definite ALS | 22 Participants |
| ALS Diagnosis from R El Escorial Criteria Clinically Possible ALS | 25 Participants |
| ALS Diagnosis from R El Escorial Criteria Clinically Probable ALS | 26 Participants |
| ALS Diagnosis from R El Escorial Criteria Clinically Probable ALS - Laboratory Supported | 10 Participants |
| ALSFRS-R Total Score | 36.0 Points STANDARD_DEVIATION 6.31 |
| ALS Onset Location Axial | 1 Participants |
| ALS Onset Location Bulbar | 6 Participants |
| ALS Onset Location Generalized | 0 Participants |
| ALS Onset Location Limb | 155 Participants |
| ALS Onset Location Multiple | 1 Participants |
| ALS Onset Location Respiratory | 0 Participants |
| Baseline Edaravone Use No | 23 Participants |
| Baseline Edaravone Use Yes | 155 Participants |
| Baseline Relyvrio Use No | 84 Participants |
| Baseline Relyvrio Use Yes | 102 Participants |
| Baseline Riluzole Use No | 34 Participants |
| Baseline Riluzole Use Yes | 161 Participants |
| Body Mass Index | 26.3 kg/m^2 STANDARD_DEVIATION 4.54 |
| Delay in ALS Symptom Onset and Diagnosis | 10.8 Months STANDARD_DEVIATION 5.68 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 226 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| King Stage 1 Region with Neuromuscular Dysfunction | 35 Participants |
| King Stage 2 Region with Neuromuscular Dysfunction | 56 Participants |
| King Stage 3 Region with Neuromuscular Dysfunction | 18 Participants |
| King Stage 4a/b Nutritional/Respiratory Failure | 74 Participants |
| Pre-Baseline Decline in ALSFRS-R | 0.70 Points per Month STANDARD_DEVIATION 0.609 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 236 Participants |
| Serum Creatinine Concentration | 0.7 mg/dL STANDARD_DEVIATION 0.16 |
| Serum NfL Concentration | 61.8 ng/L |
| Sex: Female, Male Female | 95 Participants |
| Sex: Female, Male Male | 104 Participants |
| SVC | 83.6 Percent Predicted STANDARD_DEVIATION 15.05 |
| Time Since Symptom Onset at Baseline | 19.7 Months STANDARD_DEVIATION 8.05 |
| Weight | 79.5 Kg STANDARD_DEVIATION 16.06 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 186 | 3 / 63 |
| other Total, other adverse events | 149 / 186 | 43 / 63 |
| serious Total, serious adverse events | 28 / 186 | 10 / 63 |
Outcome results
None listed