Duchenne Muscular Dystrophy
Conditions
Keywords
Duchenne Muscular Dystrophy, DMD, Muscular Dystrophies, Muscular Dystrophy, Duchenne, Muscular Disorders, Atrophic, Muscular Diseases, Musculoskeletal Diseases, Neuromuscular Diseases, Nervous System Diseases, Genetic Diseases, Inborn, Genetic Diseases, X-Linked
Brief summary
To evaluate the efficacy and safety of pamrevlumab versus placebo in combination with systemic corticosteroids administered every 2 weeks in ambulatory participants with Duchenne muscular dystrophy (DMD) (age 6 to \<12 years).
Detailed description
This is a global, randomized, double-blind, trial of pamrevlumab or placebo in combination with systemic corticosteroids in participants with DMD, aged 6 to \<12 years (ambulatory participants only). Approximately 70 participants will be randomized at a 1:1 ratio to Arm A (pamrevlumab + systemic deflazacort or equivalent potency of corticosteroids administered orally) or Arm B (placebo+ systemic deflazacort or equivalent potency of corticosteroids administered orally), respectively. Randomization will be stratified by exon 44 deletion for analysis. Stratification has no impact upon treatment assignment nor dosage. Participants must be fully informed of the potential benefits of approved products and make an informed decision when participating in a clinical trial in which they could be randomized to placebo. The main study has 3 study periods: * Screening period: Up to 4 weeks * Treatment period: 52 weeks * Safety Follow-up period/final assessment: A visit 28 days (+/- 3 Days) and a final safety follow-up phone call 60 days (+ 3 Days) after the last dose Each participant will receive pamrevlumab or placebo at 35 mg/kg every 2 weeks for up to 52 weeks. Participants who complete 52 weeks of treatment may be eligible for an open-label extension (OLE), offering extended treatment with pamrevlumab. Participants who discontinue study treatment for any reason should be encouraged to return to the investigative site to complete final safety and efficacy assessments.
Interventions
DRUGPamrevlumab
Pamrevlumab will be administered per dose and schedule specified in the arm description.
DRUGPlacebo
Placebo will be administered per schedule specified in the arm description.
DRUGCorticosteroids
Systemic deflazacort or equivalent potency of corticosteroids administered orally
Sponsors
Kyntra Bio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
6 Years to 11 Years
Healthy volunteers
No
Inclusion criteria
Age, and consent: 1. Males at least 6 to \<12 years of age at screening initiation 2. Written consent by participant and/or legal guardian as per regional/ country and/or Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requirements DMD diagnosis: 3. Medical history includes diagnosis of DMD and confirmed Duchenne mutation, including status of exon 44 using a validated genetic test. Pulmonary criteria: 4. Average (of screening and Day 0) percent predicted forced vital capacity (FVC) above 45% 5. On a stable dose of systemic corticosteroids for a minimum of 6 months, with no substantial change in dosage for a minimum of 3 months (except for adjustments for changes in body weight) prior to screening. Corticosteroid dosage should be in compliance with the DMD Care Considerations Working Group recommendations (for example, prednisone or prednisolone 0.75 mg/kg per day or deflazacort 0.9 mg/kg per day) or stable dose. A reasonable expectation is that dosage and dosing regimen would not change significantly for the duration of the study. Performance criteria: 6. Able to complete 6-minute walking distance (6MWD) test with a distance of at least 270 meters but no more than 450 meters on two occasions within 3 months prior to randomization with ≤10% variation between these two tests. 7. Able to rise (TTSTAND) from floor in \<10 seconds (without aids/orthoses) at screening visit. 8. Able to undergo magnetic resonance imaging (MRI) test for the lower extremities vastus lateralis muscle. Vaccination: 9. Agreement to receive annual influenza vaccinations during the conduct of the study. Laboratory criteria: 10. Adequate renal function: cystatin C ≤1.4 mg/liter (L) 11. Adequate hematology and electrolytes parameters: 1. Platelets \>100,000/microliter (μL) 2. Hemoglobin \>12 grams (g)/deciliter (dL) 3. Absolute neutrophil count \>1500/μL 4. Serum calcium (Ca), potassium (K), sodium (Na), magnesium (Mg) and phosphorus (P) levels are within a clinically accepted range for DMD participants 12. Adequate hepatic function: 1. No history or evidence of liver disease 2. Gamma glutamyl transferase (GGT) ≤3x upper limit of normal (ULN) 3. Total bilirubin ≤1.5xULN
Exclusion criteria
General Criteria: 1. Concurrent illness other than DMD that can cause muscle weakness and/or impairment of motor function 2. Severe intellectual impairment (for example, severe autism, severe cognitive impairment, severe behavioral disturbances) preventing the ability to perform study assessments in the Investigator's judgment 3. Previous exposure to pamrevlumab 4. Body mass index (BMI) ≥40 kg/square meter (m\^2) or weight \>117 kg 5. History of 1. allergic or anaphylactic reaction to human, humanized, chimeric or murine monoclonal antibodies 2. hypersensitivity to study drug or any component of study drug 6. Exposure to any investigational drug (for DMD or not), in the 30 days prior to screening initiation or use of approved DMD therapies (for example, eteplirsen, ataluren, golodirsen, casimersen) within 5 half-lives of screening, whichever is longer with the exception of the systemic corticosteroids, including deflazacort Pulmonary and Cardiac criteria: 7. Requires ≥16 hours continuous ventilation 8. Poorly controlled asthma or underlying lung disease such as bronchitis, bronchiectasis, emphysema, recurrent pneumonia that in the opinion of the investigator might impact respiratory function 9. Hospitalization due to respiratory failure within the 8 weeks prior to screening 10. Severe uncontrolled heart failure (New York Heart Association \[NYHA\] Classes III-IV) or renal dysfunction, including any of the following: 1. Need for intravenous diuretics or inotropic support within 8 weeks prior to screening 2. Hospitalization for a heart failure exacerbation or arrhythmia within 8 weeks prior to screening 3. Participants with glomerular filtration rate (GFR) of less than 30 mL/minute (min)/1.73 m\^2 or with other evidence of acute kidney injury as determined by investigator 11. Arrhythmia requiring anti-arrhythmic therapy 12. Any other evidence of clinically significant structural or functional heart abnormality Clinical judgment: 13. The Investigator judges that the participant will be unable to fully participate in the study and complete it for any reason, including inability to comply with study procedures and treatment, or any other relevant medical, surgical or psychiatric conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score at Week 52 | Baseline, Week 52 | The NSAA consisted of 17 activities, each scored as 0 (activity could not be performed), 1 (modified method but achieved goal without physical assistance from another), or 2 (normal, achieved goal without assistance). The sum of these 17 scores was used to form a total score ranging from 0 (worst) to 34 (fully independent function). If fewer than 15 of the 17 activities were performed, the total score was considered missing. If 15 to 16 activities were performed, the total score was calculated by multiplying the sum of the scores in the x activities that were performed by 17/x. If an activity could not be performed due to disease progression/loss of ambulation, a score of 0 was assigned. Higher scores indicated better functioning. Least square (LS) mean and standard error (SE) were analyzed using a mixed model for repeated measure (MMRM). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 4-Stair Climb Velocity (4SCV) Assessment at Week 52 | Baseline, Week 52 | The 4SCV (centimeters \[cm\]/second \[sec\]) was calculated as the ratio of the total height (cm) of stairs climbed divided by the number of seconds taken to complete the 4-stair climb. |
| Change From Baseline in the 10-Meter Walk/Run Test at Week 52 | Baseline, Week 52 | The time (in sec) required for a participant to run or walk a distance of 10 meters as quickly as possible was calculated as velocity (meters/sec). |
| Change From Baseline in Time to Stand (TTSTAND) at Week 52 | Baseline, Week 52 | The time (in sec) required for a participant to stand from supine position has been reported. A longer time taken reflected a worse outcome. |
| Time to Loss of Ambulation (LoA) From Baseline to Week 52 | Baseline to Week 52 | Time (days) to LoA was defined as the number of days from randomization to the date of LoA, or all-cause death based on observed data, whichever occurred earlier during the on-study period. Median time (days) to LoA was calculated using Kaplan Meier Survival Estimates. |
Countries
Australia, Austria, Belgium, Canada, China, France, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
The study included 2 periods: a Double-blind (DB) period and an Open-label extension (OLE) period.
Participants by arm
| Arm | Count |
|---|---|
| Pamrevlumab Participants received pamrevlumab 35 mg/kg by IV infusion every 2 weeks + systemic deflazacort or equivalent potency of corticosteroids administered orally for up to 52 weeks in the DB period and continued to receive the same dose of pamrevlumab for up to 52 weeks in the OLE period or until pamrevlumab was commercially available, or the sponsor decided to end the study, whichever occurred first. | 37 |
| Placebo Participants received placebo matched to pamrevlumab by IV infusion every 2 weeks + systemic deflazacort or equivalent potency of corticosteroids administered orally for up to 52 weeks in the DB period. Participants received pamrevlumab 35 mg/kg by IV infusion every 2 weeks + systemic deflazacort or equivalent potency of corticosteroids administered orally for up to 52 weeks in the OLE period or until pamrevlumab was commercially available, or the sponsor decided to end the study, whichever occurred first. | 36 |
| Total | 73 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| DB Period (52 Weeks) | Participant/Legal Guardian Decision | 2 | 0 |
| OLE Period (52 Weeks) | Adverse Event | 1 | 0 |
| OLE Period (52 Weeks) | Entered into OLE but not treated | 0 | 1 |
| OLE Period (52 Weeks) | Lost to Follow-up | 0 | 1 |
| OLE Period (52 Weeks) | Other than specified | 0 | 1 |
| OLE Period (52 Weeks) | Participant/Legal Guardian Decision | 11 | 13 |
| OLE Period (52 Weeks) | Physician Decision | 1 | 0 |
| OLE Period (52 Weeks) | Sponsor Decision to Terminate Study | 21 | 19 |
Baseline characteristics
| Characteristic | Placebo | Total | Pamrevlumab |
|---|---|---|---|
| Age, Continuous | 9.0 years STANDARD_DEVIATION 1.56 | 9.0 years STANDARD_DEVIATION 1.5 | 9.1 years STANDARD_DEVIATION 1.46 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 6 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 62 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 19 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 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 | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) White | 22 Participants | 45 Participants | 23 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 36 Participants | 73 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 37 | 0 / 36 | 0 / 69 |
| other Total, other adverse events | 35 / 36 | 33 / 36 | 45 / 68 |
| serious Total, serious adverse events | 3 / 36 | 1 / 36 | 0 / 68 |
Outcome results
Primary
Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score at Week 52
The NSAA consisted of 17 activities, each scored as 0 (activity could not be performed), 1 (modified method but achieved goal without physical assistance from another), or 2 (normal, achieved goal without assistance). The sum of these 17 scores was used to form a total score ranging from 0 (worst) to 34 (fully independent function). If fewer than 15 of the 17 activities were performed, the total score was considered missing. If 15 to 16 activities were performed, the total score was calculated by multiplying the sum of the scores in the x activities that were performed by 17/x. If an activity could not be performed due to disease progression/loss of ambulation, a score of 0 was assigned. Higher scores indicated better functioning. Least square (LS) mean and standard error (SE) were analyzed using a mixed model for repeated measure (MMRM).
Time frame: Baseline, Week 52
Population: The ITT set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pamrevlumab | Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score at Week 52 | -3.022 units on a scale | Standard Error 0.5505 |
| Placebo | Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score at Week 52 | -2.494 units on a scale | Standard Error 0.6962 |
p-value: 0.555395% CI: [-2.308, 1.251]Mixed Models Analysis
Secondary
Change From Baseline in 4-Stair Climb Velocity (4SCV) Assessment at Week 52
The 4SCV (centimeters \[cm\]/second \[sec\]) was calculated as the ratio of the total height (cm) of stairs climbed divided by the number of seconds taken to complete the 4-stair climb.
Time frame: Baseline, Week 52
Population: The ITT set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pamrevlumab | Change From Baseline in 4-Stair Climb Velocity (4SCV) Assessment at Week 52 | -1.858 cm/sec | Standard Deviation 4.5459 |
| Placebo | Change From Baseline in 4-Stair Climb Velocity (4SCV) Assessment at Week 52 | -3.797 cm/sec | Standard Deviation 5.1899 |
Secondary
Change From Baseline in the 10-Meter Walk/Run Test at Week 52
The time (in sec) required for a participant to run or walk a distance of 10 meters as quickly as possible was calculated as velocity (meters/sec).
Time frame: Baseline, Week 52
Population: The ITT set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pamrevlumab | Change From Baseline in the 10-Meter Walk/Run Test at Week 52 | -0.176 meters/sec | Standard Deviation 0.2193 |
| Placebo | Change From Baseline in the 10-Meter Walk/Run Test at Week 52 | -0.196 meters/sec | Standard Deviation 0.3552 |
Secondary
Change From Baseline in Time to Stand (TTSTAND) at Week 52
The time (in sec) required for a participant to stand from supine position has been reported. A longer time taken reflected a worse outcome.
Time frame: Baseline, Week 52
Population: The ITT set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pamrevlumab | Change From Baseline in Time to Stand (TTSTAND) at Week 52 | 2.24 sec | Standard Deviation 3.353 |
| Placebo | Change From Baseline in Time to Stand (TTSTAND) at Week 52 | 1.94 sec | Standard Deviation 3.688 |
Secondary
Time to Loss of Ambulation (LoA) From Baseline to Week 52
Time (days) to LoA was defined as the number of days from randomization to the date of LoA, or all-cause death based on observed data, whichever occurred earlier during the on-study period. Median time (days) to LoA was calculated using Kaplan Meier Survival Estimates.
Time frame: Baseline to Week 52
Population: The ITT set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pamrevlumab | Time to Loss of Ambulation (LoA) From Baseline to Week 52 | NA days |
| Placebo | Time to Loss of Ambulation (LoA) From Baseline to Week 52 | NA days |