Muscular Dystrophy, Duchenne
Conditions
Keywords
Muscular Dystrophies, Musculoskeletal Diseases, Neuromuscular Diseases, Duchenne muscular dystrophy, DMD, dystrophin, dystrophy, Duchenne
Brief summary
The PolarisDMD study is a Phase 3, global study to evaluate the efficacy and safety of edasalonexent in pediatric patients with a genetically confirmed diagnosis of DMD. Male patients from 4-7 years of age (up to 8th birthday) will be enrolled. Edasalonexent is an orally administered small molecule that inhibits NF-kB, which is the key link between loss of dystrophin and disease pathology and plays a fundamental role in the initiation and progression of skeletal and cardiac muscle disease in DMD.
Detailed description
The study includes a 52-week, randomized, double-blind, placebo-controlled period, followed by a 2-week follow- up. Approximately 125 boys with DMD will be enrolled in this trial, with 2 boys receiving edasalonexent for every 1 boy receiving placebo. Following completion of the treatment period, patients may elect to continue in a separate open-label extension study.
Interventions
DRUGEdasalonexent
100 mg/kg/day
DRUGPlacebo
Placebo
Sponsors
Catabasis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
MALE
Age
4 Years to 7 Years
Healthy volunteers
No
Inclusion criteria
* Written consent/assent by patient and/or legal guardian as per regional and/or Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requirements * Diagnosis of DMD based on a clinical phenotype with increased serum creatine kinase (CK) and documentation of mutation(s) in the dystrophin gene known to be associated with a DMD phenotype * Able to perform stand from supine without assistance in ≤ 10 seconds * Able to perform the 10MWT and 4-stair climb * Followed by a doctor or medical professional who coordinates Duchenne care on a regular basis and willingness to disclose patient's study participation with medical professionals
Exclusion criteria
* Use of corticosteroids within 24 weeks prior to Day 1; use of inhaled, intranasal, and topical corticosteroids is permitted * Use of another investigational drug, idebenone, or dystrophin-focused therapy within 4 weeks. Exception: Patients who have received at least 24 weeks of a stable dose of eteplirsen prior to Day 1, and expected to continue treatment, will be eligible * Use of the following within 4 weeks prior to Day 1: immunosuppressive therapy, warfarin, phenytoin, S mephenytoin, cyclosporine, dihydroergotamine, ergotamine, fentanyl, alfentanil, pimozide, quinidine, sirolimus, tacrolimus, or paclitaxel * Use of human growth hormone within 3 months prior to Day 1 * Other prior or ongoing significant medical conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in North Star Ambulatory Assessment (NSAA) | Baseline (Day 1) to Week 52 | To assess change from baseline in North Star Ambulatory Assessment(NSAA) Total Score at Wk52. NSAA is clinician-reported outcome instrument designed to measure ambulatory function in males with Duchenne muscular dystrophy(DMD). Patients asked to perform 17 different functional activities,including 10MWT,rising from sit to stand,standing on one leg,climbing & descending a step,stand from supine, lifting the head, standing on heels, & jumping. Each function activity will be scored as0=(unable to achieve independently),scored as1=(modified method but achieves goal independent of physical assistance from another),or scored as2=(no obvious modification of activity)or Not Scored. If NSAA test was performed & any of the individual items are scored as not scored(i.e, for reasons unrelated to patients physical capabilities), corresponding total score will be set to missing. Sum of 17 scores will be used to form an ordinal total score(range 0-34).Higher scores imply better functional status |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 10-meter Walk/Run Test | Baseline (Day 1) to Week 52 | To assess the changes from baseline to Week 52 on the 10-meter walk/run test (10MWT). For timed function tests (TFTs), the time will be set to 12 seconds and the speed to 0 if the TFT assessment meets the following TFT grading criteria. Grade of 1 or 2 (from a 6-point scale). 1=Unable to walk independently 2=Unable to walk independently but can walk with knee-ankle foot orthoses or support from a person 3=Highly adapted wide based lordotic gait. Cannot increase walking speed 4=Moderately adapted gait. Can pick up speed but cannot run 5=Able to pick up speed, but runs with a double stance phase, i.e. cannot achieve both feet off the ground 6=Runs and gets both feet off the ground (with no double stance phase) |
| Change From Baseline in Time to Stand From Supine | Baseline (Day 1) to Week 52 | To assess the change from baseline in the stand from supine speed at Week 52. For timed function tests (TFTs) , the time will be set to 12 seconds and the speed to 0 if the TFT assessment meets the following TFT grading criteria. Grade of 1 or 2 (from a 6-point scale). 1 = Unable to stand from supine, even with use of a chair, 2 = Assisted Gowers - requires furniture for assist in arising from supine to full upright posture (no time to be recorded) 3=Rolls over, stands up with both hands climbing up the legs to achieve full upright posture 4=Rolls over, stands up with 1 hand support on leg 5=Rolls to the side and stands up with one or both hands on the floor to start to rise but does not touch legs 6=Stands up without rolling over or using hands on legs or floor |
| Change From Baseline in 4-stair Climb | Baseline (Day 1) to Week 52 | To assess the change from baseline to Week 52 on the 4-Stair Climb. For timed function tests (TFTs) , the time will be set to 12 seconds and the speed to 0 if the TFT assessment meets the following TFT grading criteria. Grade of 1(from a 6-point scale)1=Unable to climb 4 standard stairs(no time recorded) 2=Climbs 4 standard stairs marking time(climbs one foot at a time, with both feet on a step before moving to next step), uses both arms on one or both handrails or uses 1 handrail and the other arm pushes on the leg 3=Climbs 4 standard stairs marking time, using one arm on one handrail or one hand pushing on leg or body 4=Climbs 4 standard stairs marking time, not needing handrail and not using hands to push on leg 5=Climbs 4 standard stairs alternating feet, needs handrail/s for support or uses arms to push on the leg or body 6=Climbs 4 standard stairs alternating feet, not needing handrail support or using arm to push on the leg |
| Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Up to Week 52 | Adverse events that occurred from the time of the administration of the first dose of investigational product (IP) through the end of the safety follow-up were considered treatment-emergent AEs (TEAEs). Serious adverse event (SAE). |
Countries
Australia, Canada, Germany, Ireland, Israel, Sweden, United Kingdom, United States
Participant flow
Recruitment details
This was a multi-center study conducted by 37 principal investigators at 37 study centers in 8 countries (United States, Canada, United Kingdom, Germany, Ireland, Israel, Sweden, and Australia.)
Pre-assignment details
A total of 151 patients were screened of which 20 failed screening. 131 patients who participated in the study included 126 randomized patients and 5 participants who were dosed siblings of previously randomized patients.
Participants by arm
| Arm | Count |
|---|---|
| Dose 1 Edasalonexent 100 mg/kg/day. Capsules taken by mouth three times per day.
Edasalonexent: 100 mg/kg/day | 88 |
| Placebo Matching placebo
Placebo: Placebo | 43 |
| Total | 131 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Non-compliance with study drug | 0 | 1 |
| Overall Study | noncompliance with study procedures | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Progressive disease | 1 | 0 |
| Overall Study | Starting another treatment | 0 | 1 |
| Overall Study | Withdrawal by parent/guardian | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Total | Dose 1 |
|---|---|---|---|
| Age, Continuous | 5.77 years STANDARD_DEVIATION 0.995 | 5.69 years STANDARD_DEVIATION 1.029 | 5.65 years STANDARD_DEVIATION 1.048 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 20 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 104 Participants | 69 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 7 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 38 Participants | 112 Participants | 74 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 43 Participants | 131 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 88 | 0 / 43 |
| other Total, other adverse events | 85 / 88 | 41 / 43 |
| serious Total, serious adverse events | 1 / 88 | 1 / 43 |
Outcome results
Primary
Change From Baseline in North Star Ambulatory Assessment (NSAA)
To assess change from baseline in North Star Ambulatory Assessment(NSAA) Total Score at Wk52. NSAA is clinician-reported outcome instrument designed to measure ambulatory function in males with Duchenne muscular dystrophy(DMD). Patients asked to perform 17 different functional activities,including 10MWT,rising from sit to stand,standing on one leg,climbing & descending a step,stand from supine, lifting the head, standing on heels, & jumping. Each function activity will be scored as0=(unable to achieve independently),scored as1=(modified method but achieves goal independent of physical assistance from another),or scored as2=(no obvious modification of activity)or Not Scored. If NSAA test was performed & any of the individual items are scored as not scored(i.e, for reasons unrelated to patients physical capabilities), corresponding total score will be set to missing. Sum of 17 scores will be used to form an ordinal total score(range 0-34).Higher scores imply better functional status
Time frame: Baseline (Day 1) to Week 52
Population: Full Analysis population: All patients in the Randomized Population who received at least 1 dose of study drug and provided at least 1 valid post Baseline NSAA efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 | Change From Baseline in North Star Ambulatory Assessment (NSAA) | -1.5 score on a scale | Standard Deviation 4.41 |
| Placebo | Change From Baseline in North Star Ambulatory Assessment (NSAA) | -1.8 score on a scale | Standard Deviation 3.81 |
Secondary
Change From Baseline in 10-meter Walk/Run Test
To assess the changes from baseline to Week 52 on the 10-meter walk/run test (10MWT). For timed function tests (TFTs), the time will be set to 12 seconds and the speed to 0 if the TFT assessment meets the following TFT grading criteria. Grade of 1 or 2 (from a 6-point scale). 1=Unable to walk independently 2=Unable to walk independently but can walk with knee-ankle foot orthoses or support from a person 3=Highly adapted wide based lordotic gait. Cannot increase walking speed 4=Moderately adapted gait. Can pick up speed but cannot run 5=Able to pick up speed, but runs with a double stance phase, i.e. cannot achieve both feet off the ground 6=Runs and gets both feet off the ground (with no double stance phase)
Time frame: Baseline (Day 1) to Week 52
Population: Full Analysis population: All patients in the Randomized Population who received at least 1 dose of study drug and provided at least 1 valid post Baseline NSAA efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 | Change From Baseline in 10-meter Walk/Run Test | -0.0058 score on a scale | Standard Deviation 0.0301 |
| Placebo | Change From Baseline in 10-meter Walk/Run Test | -0.0093 score on a scale | Standard Deviation 0.02538 |
Secondary
Change From Baseline in 4-stair Climb
To assess the change from baseline to Week 52 on the 4-Stair Climb. For timed function tests (TFTs) , the time will be set to 12 seconds and the speed to 0 if the TFT assessment meets the following TFT grading criteria. Grade of 1(from a 6-point scale)1=Unable to climb 4 standard stairs(no time recorded) 2=Climbs 4 standard stairs marking time(climbs one foot at a time, with both feet on a step before moving to next step), uses both arms on one or both handrails or uses 1 handrail and the other arm pushes on the leg 3=Climbs 4 standard stairs marking time, using one arm on one handrail or one hand pushing on leg or body 4=Climbs 4 standard stairs marking time, not needing handrail and not using hands to push on leg 5=Climbs 4 standard stairs alternating feet, needs handrail/s for support or uses arms to push on the leg or body 6=Climbs 4 standard stairs alternating feet, not needing handrail support or using arm to push on the leg
Time frame: Baseline (Day 1) to Week 52
Population: Full Analysis Population: All patients in the Randomized Population who received at least 1 dose of study drug and provided at least 1 valid post Baseline NSAA efficacy assessment).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 | Change From Baseline in 4-stair Climb | -0.0220 score on a scale | Standard Deviation 0.0892 |
| Placebo | Change From Baseline in 4-stair Climb | -0.0392 score on a scale | Standard Deviation 0.07352 |
Secondary
Change From Baseline in Time to Stand From Supine
To assess the change from baseline in the stand from supine speed at Week 52. For timed function tests (TFTs) , the time will be set to 12 seconds and the speed to 0 if the TFT assessment meets the following TFT grading criteria. Grade of 1 or 2 (from a 6-point scale). 1 = Unable to stand from supine, even with use of a chair, 2 = Assisted Gowers - requires furniture for assist in arising from supine to full upright posture (no time to be recorded) 3=Rolls over, stands up with both hands climbing up the legs to achieve full upright posture 4=Rolls over, stands up with 1 hand support on leg 5=Rolls to the side and stands up with one or both hands on the floor to start to rise but does not touch legs 6=Stands up without rolling over or using hands on legs or floor
Time frame: Baseline (Day 1) to Week 52
Population: Full Analysis population: All patients in the Randomized Population who received at least 1 dose of study drug and provided at least 1 valid post Baseline NSAA efficacy assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose 1 | Change From Baseline in Time to Stand From Supine | -0.0389 score on a scale | Standard Deviation 0.06728 |
| Placebo | Change From Baseline in Time to Stand From Supine | -0.0459 score on a scale | Standard Deviation 0.06171 |
Secondary
Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Adverse events that occurred from the time of the administration of the first dose of investigational product (IP) through the end of the safety follow-up were considered treatment-emergent AEs (TEAEs). Serious adverse event (SAE).
Time frame: Up to Week 52
Population: Safety population: All patients who received at least 1 dose of study drug, with patients analyzed based on the actual study treatment received. This included the set of patients who were assigned the same treatment as their randomized sibling.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose 1 | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Treatment Emergent Adverse Event (TEAEs) | 85 participants |
| Dose 1 | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Related Treatment Emergent Adverse Event (TEAEs) | 61 participants |
| Dose 1 | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Serious TEAE | 1 participants |
| Dose 1 | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Serious Related TEAEs | 0 participants |
| Dose 1 | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs Leading to Study Discontinuation | 1 participants |
| Dose 1 | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Treatment-Related TEAEs Leading to Study Discontinuation | 1 participants |
| Placebo | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs Leading to Study Discontinuation | 0 participants |
| Placebo | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Treatment Emergent Adverse Event (TEAEs) | 41 participants |
| Placebo | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Serious Related TEAEs | 0 participants |
| Placebo | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Related Treatment Emergent Adverse Event (TEAEs) | 14 participants |
| Placebo | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Treatment-Related TEAEs Leading to Study Discontinuation | 0 participants |
| Placebo | Safety and Tolerability Measured by Number of Treatment- Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Serious TEAE | 1 participants |