Amyotrophic Lateral Sclerosis
Conditions
Keywords
ALS, Placebo-Controlled, Double-Blind, Regimen-Specific Appendix, Lou Gehrig's Disease, CNM-Au8, Clene Nanomedicine
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 C will evaluate the safety and efficacy of a single study drug, CNM-Au8, 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 C - CNM-Au8, the participant will complete a screening visit to assess additional Regimen C eligibility criteria. Once Regimen C eligibility criteria are confirmed, participants will complete a baseline assessment and be randomized in a 3:1 ratio to either active CNM-Au8 or matching placebo. Regimen C will enroll by invitation, as participants may not choose to enroll in Regimen C. 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 C. For a list of enrolling sites, please see the HEALEY ALS Platform Trial Master Protocol under NCT04297683.
Interventions
DRUGCNM-Au8
Drug: CNM-Au8 Administration: Oral Dosage: 30 mg or 60 mg daily
DRUGMatching Placebo
Drug: Matching Placebo Administration: Oral Dosage: 2 bottles daily
Sponsors
Clene Nanomedicine
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 exclusion criterion is in addition to the
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 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 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 as assessed by slow vital capacity (SVC). |
| Muscle Strength | Baseline to 24 Weeks | Change in muscle strength as measured isometrically using hand-held dynamometry (HHD). |
| Number of Participants That Experienced Death or Death Equivalent | 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 22hours per day for more than 7 days in a row. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| CNM-Au8 Drug: CNM-Au8
Administration: Oral
Dosage: 30 mg or 60 mg daily
CNM-Au8: Drug: CNM-Au8
Administration: Oral
Dosage: 30 mg or 60 mg daily | 120 |
| Matching Placebo Administration: Oral
Dosage: 2 bottles daily
Matching Placebo: Drug: Matching Placebo
Administration: Oral
Dosage: 2 bottles daily | 41 |
| Total | 161 |
Baseline characteristics
| Characteristic | Matching Placebo | CNM-Au8 | Total |
|---|---|---|---|
| Age, Continuous | 57.0 years STANDARD_DEVIATION 11.72 | 58.2 years STANDARD_DEVIATION 9.99 | 57.9 years STANDARD_DEVIATION 10.43 |
| ALSFRS-R Total Score | 36.1 scores on a scale STANDARD_DEVIATION 5.91 | 34.3 scores on a scale STANDARD_DEVIATION 6.56 | 34.7 scores on a scale STANDARD_DEVIATION 6.43 |
| ALS Onset Location Bulbar | 6 Participants | 18 Participants | 24 Participants |
| ALS Onset Location Limb | 35 Participants | 102 Participants | 137 Participants |
| Baseline Edaravone Use No | 31 Participants | 92 Participants | 123 Participants |
| Baseline Edaravone Use Yes | 10 Participants | 28 Participants | 38 Participants |
| Baseline Riluzole Use No | 9 Participants | 26 Participants | 35 Participants |
| Baseline Riluzole Use Yes | 32 Participants | 94 Participants | 126 Participants |
| Body Mass Index | 28.4 kg/m^2 STANDARD_DEVIATION 5.47 | 27.0 kg/m^2 STANDARD_DEVIATION 5.07 | 27.4 kg/m^2 STANDARD_DEVIATION 5.2 |
| Change in ALSFRS-R prior to Baseline | 0.60 points per month STANDARD_DEVIATION 0.353 | 0.72 points per month STANDARD_DEVIATION 0.535 | 0.69 points per month STANDARD_DEVIATION 0.497 |
| Delay in ALS Symptom Onset and Diagnosis | 10.0 months STANDARD_DEVIATION 5.64 | 10.5 months STANDARD_DEVIATION 5.92 | 10.3 months STANDARD_DEVIATION 5.84 |
| El Escorial Diagnosis Clinically Definite ALS | 14 Participants | 58 Participants | 72 Participants |
| El Escorial Diagnosis Clinically Possible ALS | 1 Participants | 3 Participants | 4 Participants |
| El Escorial Diagnosis Clinically Probable ALS | 10 Participants | 43 Participants | 53 Participants |
| El Escorial Diagnosis Clinically Probable ALS - Laboratory Supported | 16 Participants | 16 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants | 116 Participants | 154 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Kings Stage 1 Region with Neuromuscular Dysfunction | 9 Participants | 13 Participants | 22 Participants |
| Kings Stage 2 Regions with Neuromuscular Dysfunction | 11 Participants | 36 Participants | 47 Participants |
| Kings Stage 3 Regions with Neuromuscular Dysfunction | 7 Participants | 41 Participants | 48 Participants |
| Kings Stage 4a/b Nutritional/Respiratory Failure | 0 Participants | 1 Participants | 1 Participants |
| Kings Stage 4b Respiratory Failure | 14 Participants | 29 Participants | 43 Participants |
| Neurofilament Light (NfL) Protein in Serum | 85.3 ng/L STANDARD_DEVIATION 71.63 | 91.6 ng/L STANDARD_DEVIATION 58.04 | 90.0 ng/L STANDARD_DEVIATION 61.53 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 38 Participants | 120 Participants | 158 Participants |
| Serum Creatinine Concentration | 0.7 mg/dL STANDARD_DEVIATION 0.2 | 0.7 mg/dL STANDARD_DEVIATION 0.17 | 0.7 mg/dL STANDARD_DEVIATION 0.18 |
| Sex: Female, Male Female | 12 Participants | 49 Participants | 61 Participants |
| Sex: Female, Male Male | 29 Participants | 71 Participants | 100 Participants |
| SVC | 76.1 percent predicted STANDARD_DEVIATION 16.79 | 75.2 percent predicted STANDARD_DEVIATION 16.08 | 75.4 percent predicted STANDARD_DEVIATION 16.22 |
| Time Since Symptom onset at Baseline | 21.9 months STANDARD_DEVIATION 8.49 | 22.7 months STANDARD_DEVIATION 8.64 | 22.5 months STANDARD_DEVIATION 8.58 |
| Weight | 87.1 kg STANDARD_DEVIATION 20.38 | 79.6 kg STANDARD_DEVIATION 16.74 | 81.5 kg STANDARD_DEVIATION 17.97 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 120 | 1 / 41 |
| other Total, other adverse events | 110 / 120 | 38 / 41 |
| serious Total, serious adverse events | 16 / 120 | 7 / 41 |
Outcome results
Primary
Disease Progression as Assessed by the ALSFRS-R Total Score
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 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 Zilucoplan (NCT04436497), Regimen B Verdiperstat (NCT04436510), and Regimen D Pridopidine (NCT04615923) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CNM-Au8 | Disease Progression as Assessed by the ALSFRS-R Total Score | -1.01 ALSFRS-R total score points per month | Standard Deviation 0.075 |
| Matching Placebo | Disease Progression as Assessed by the ALSFRS-R Total Score | -1.03 ALSFRS-R total score points per month | Standard Deviation 0.072 |
95% CI: [0.797, 1.188]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 Zilucoplan (NCT04436497), Regimen B Verdiperstat (NCT04436510), and Regimen D Pridopidine (NCT04615923) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CNM-Au8 | Mortality Event Rate | 0.006 events per month | Standard Deviation 0.002 |
| Matching Placebo | Mortality Event Rate | 0.007 events per month | Standard Deviation 0.002 |
Secondary
Muscle Strength
Change in muscle strength 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 Zilucoplan (NCT04436497), Regimen B Verdiperstat (NCT04436510), and Regimen D Pridopidine (NCT04615923) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CNM-Au8 | Muscle Strength | -27.54 percent change | Standard Error 2.647 |
| Matching Placebo | Muscle Strength | -24.44 percent change | Standard Error 2.26 |
p-value: 0.362195% CI: [-9.78, 3.58]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 22hours per day for more than 7 days in a row.
Time frame: 24 Weeks
Population: Outcome measure data was analyzed using the Full Analysis Set (FAS), which includes shared placebo from other regimens.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CNM-Au8 | Number of Participants That Experienced Death or Death Equivalent | 3 Participants |
| Matching Placebo | Number of Participants That Experienced Death or Death Equivalent | 5 Participants |
p-value: 0.7398Log Rank
Secondary
Respiratory Function
Change in respiratory function as assessed 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 Zilucoplan (NCT04436497), Regimen B Verdiperstat (NCT04436510), and Regimen D Pridopidine (NCT04615923) contributed placebo participants into the shared placebo cohort used for analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| CNM-Au8 | Respiratory Function | -9.32 percent change | Standard Error 1.362 |
| Matching Placebo | Respiratory Function | -8.53 percent change | Standard Error 1.146 |
p-value: 0.65795% CI: [-4.25, 2.68]Mixed Models Analysis