Duchenne Muscular Dystrophy
Conditions
Keywords
Duchenne Muscular Dystrophy, DMD
Brief summary
To evaluate the efficacy and safety of pamrevlumab versus placebo in combination with systemic corticosteroids in participants with non-ambulatory Duchenne muscular dystrophy (age 12 years and older).
Detailed description
This is a global, Phase 3, randomized, double-blind trial of pamrevlumab or placebo in combination with systemic corticosteroids in participants with non-ambulatory Duchenne muscular dystrophy, aged 12 years and older. Approximately 90 male participants will be randomized at a 1:1 ratio to Arm A (pamrevlumab + systemic corticosteroid) or Arm B (placebo+ systemic corticosteroid), respectively. Participants must be fully informed of the potential benefits of approved products and make an informed decision that they prefer to participate in a clinical trial in which they could be randomized to placebo. This trial has 3 study periods: * Screening period: Up to 4 weeks * Treatment period: 52 weeks * Safety Follow-up period/End of Study (EOS): A visit 28 days (+/- 3 Days) and a final safety follow-up phone call 60 days (+ 3 Days) after the last dose In the screening period, participants will be evaluated per the protocol inclusion/exclusion criteria to determine eligibility for participation in this trial. During the treatment period, each participant will receive pamrevlumab or placebo at 35 mg/kg every 2 weeks for up to 52 weeks. Participants who complete the 52-week study (either arm) may be eligible for rollover into an open-label extension treatment (OLE) with pamrevlumab + systemic corticosteroids. 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 per dose and schedule specified in the arm description
DRUGPlacebo
Matching placebo per schedule specified in the arm description
DRUGCorticosteroids
Systemic deflazacort or equivalent potency of corticosteroids administered orally
Sponsors
FibroGen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males at least 12 years of age, non-ambulatory 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 3. Male participants with partners of childbearing potential must use contraception during the conduct of the study, and for 12 weeks after the last dose of study drug. 4. Medical history includes diagnosis of DMD and confirmed Duchenne mutation using a validated genetic test 5. Brooke Score for Arms and Shoulders ≤5 6. Able to undergo MRI test for the upper arm extremities (Biceps Brachii muscle) and cardiac muscle 7. Able to perform spirometry 8. Average (of Screening and Day 0) percent predicted forced vital capacity (FVC) between 45 and 85, inclusive 9. Left ventricular ejection fraction ≥50% as determined by local cardiac MRI read at screening or within 3 months prior to randomization (Day 0) 10. If participants have a history of cardiomyopathy, then participant must be on a stable dose of cardiomyopathy/ heart failure medications (for example, angiotensin converting enzyme inhibitors, aldosterone receptors blockers, angiotensin-receptor blockers, and betablockers) for at least 1 month prior to screening. If participants have no diagnosis of cardiomyopathy, then no dose of cardiomyopathy/heart failure medication is required for eligibility. 11. 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. 12. Agreement to receive annual influenza vaccinations during the course of the study. 13. Adequate renal function: cystatin C ≤1.4 mg/liter (L) 14. 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. 15. 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
1. Previous exposure to pamrevlumab 2. BMI ≥40 kg/square meter (m\^2) or weight \>117 kg 3. 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 3. hypersensitivity reaction to Gadolinium-based Contrast Agents (GBCA) required for MRI acquisition 4. 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 \[exondys 51\], ataluren, golodirsen \[vyondys 53\], casimersen \[amondys 45\]) within 5 half-lives of screening, whichever is longer, with the exception of the systemic corticosteroids, including deflazacort 5. Severe uncontrolled heart failure (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 6. Arrhythmia requiring anti-arrhythmic therapy 7. Requires ≥16 hours continuous ventilation 8. Hospitalization due to respiratory failure within the 8 weeks prior to screening 9. 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 10. 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 or psychiatric conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Total Score of Performance of Upper Limb (PUL) 2.0 Version at Week 52 | Baseline, Week 52 | The PUL module is an observer-administered performance battery of upper extremity mobility tasks for the shoulder (upper, 6 items, 12 points), elbow (middle, 9 items, 17 points) and wrist/hand (distal, 7 items, 13 points). Higher scores indicate higher level of function. Total score ranges from 0-42 points and is the sum of the scores for the 3 subscales. Analysis was done using a random coefficient model (RCM), which included fixed effects of time (as a continuous variable), treatment, and treatment-by-time interaction, with baseline ordinal PUL entry score as covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percent Predicted Forced Vital Capacity (ppFVC) at Week 52, Assessed by Spirometry | Baseline, Week 52 | FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted FVC is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (observed value)/(predicted value) \* 100%. Analysis was done using an RCM, which included fixed effects of time (as a continuous variable), treatment, and treatment-by-time interaction, with baseline value as covariate. |
| Change From Baseline in the Grip Strength of the Hands at Week 52, Assessed by Hand Held Myometry (HHM) | Baseline, Week 52 | The HHM was used to measure distal upper arm strength (grip strength). Data has been presented by dominant and non-dominant hand. Grip Strength was analyzed using a MMRM with fixed effects for treatment, visit (as a factor), treatment-by-visit interaction, and covariates (baseline values). |
| Change From Baseline in Left Ventricular Ejection Fraction Percentage (LVEF %) at Week 52, Assessed by Magnetic Resonance Imaging (MRI) | Baseline, Week 52 | LVEF% is an important measure of cardiac function. LVEF is a fraction of blood (in percent) pumped out of the left ventricle of the heart (the main pumping chamber). The LVEF% was analyzed using an analysis of covariance (ANCOVA) model with treatment and baseline value. |
| Change From Baseline in Percent Predicted Peak Expiratory Flow (ppPEF) at Week 52, Assessed by Spirometry | Baseline, Week 52 | The ppPEF is a measure of the maximal or peak flow produced during an exhalation with maximal effort and, as such, is the most effort-dependent measure of lung function. The ppFEV1 was analyzed using an RCM including fixed effects of time, treatment, and treatment-by-time interaction, with baseline as covariate. |
Countries
Australia, Austria, Belgium, Canada, China, Czechia, France, Israel, Italy, Netherlands, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
The study included 2 periods: Double-blind (DB) Treatment Period and Open-label Extension (OLE) Period.
Participants by arm
| Arm | Count |
|---|---|
| Pamrevlumab Participants received pamrevlumab IV every 2 weeks for up to 52 weeks in the DB treatment period. After completing Week 52 of the DB treatment period, participants in the OLE period then moved to Week 2 of the OLE period and received pamrevlumab IV every 2 weeks. | 49 |
| Placebo Participants received placebo matched to pamrevlumab IV every 2 weeks for up to 52 weeks in the DB treatment period. After completing Week 52 of the DB treatment period, participants in the OLE period then moved to Week 2 of the OLE period and received pamrevlumab IV every 2 weeks. | 49 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| DB Treatment Period (52 Weeks) | Adverse Event | 3 | 1 |
| DB Treatment Period (52 Weeks) | Other than specified | 1 | 0 |
| DB Treatment Period (52 Weeks) | Participant/Legal Guardian Decision | 1 | 2 |
| OLE (Maximum Exposure: 93.4 Weeks) | Other than specified | 1 | 0 |
| OLE (Maximum Exposure: 93.4 Weeks) | Participant/Legal Guardian Decision | 2 | 2 |
| OLE (Maximum Exposure: 93.4 Weeks) | Sponsor Decision to Terminate Study | 40 | 41 |
Baseline characteristics
| Characteristic | Placebo | Total | Pamrevlumab |
|---|---|---|---|
| Age, Continuous | 15.5 years STANDARD_DEVIATION 2.42 | 15.5 years STANDARD_DEVIATION 2.57 | 15.6 years STANDARD_DEVIATION 2.74 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 6 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 41 Participants | 85 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 15 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 4 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 | 35 Participants | 77 Participants | 42 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 49 Participants | 98 Participants | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 48 | 0 / 49 | 0 / 86 |
| other Total, other adverse events | 42 / 48 | 44 / 49 | 53 / 86 |
| serious Total, serious adverse events | 8 / 48 | 6 / 49 | 5 / 86 |
Outcome results
Primary
Change From Baseline in the Total Score of Performance of Upper Limb (PUL) 2.0 Version at Week 52
The PUL module is an observer-administered performance battery of upper extremity mobility tasks for the shoulder (upper, 6 items, 12 points), elbow (middle, 9 items, 17 points) and wrist/hand (distal, 7 items, 13 points). Higher scores indicate higher level of function. Total score ranges from 0-42 points and is the sum of the scores for the 3 subscales. Analysis was done using a random coefficient model (RCM), which included fixed effects of time (as a continuous variable), treatment, and treatment-by-time interaction, with baseline ordinal PUL entry score as covariate.
Time frame: Baseline, Week 52
Population: The modified intent-to-treat (mITT) population included all randomized participants with a PUL Entry score ≥2 (excluding PUL entry scores of 1) at baseline. Here, 'Overall number of participants analyzed' = participants evaluable for specified outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pamrevlumab | Change From Baseline in the Total Score of Performance of Upper Limb (PUL) 2.0 Version at Week 52 | -2.036 units on a scale | Standard Error 0.4471 |
| Placebo | Change From Baseline in the Total Score of Performance of Upper Limb (PUL) 2.0 Version at Week 52 | -2.119 units on a scale | Standard Error 0.3367 |
p-value: 0.880295% CI: [-1.01, 1.176]Random coefficient model
Secondary
Change From Baseline in Left Ventricular Ejection Fraction Percentage (LVEF %) at Week 52, Assessed by Magnetic Resonance Imaging (MRI)
LVEF% is an important measure of cardiac function. LVEF is a fraction of blood (in percent) pumped out of the left ventricle of the heart (the main pumping chamber). The LVEF% was analyzed using an analysis of covariance (ANCOVA) model with treatment and baseline value.
Time frame: Baseline, Week 52
Population: The mITT population included all randomized participants with a PUL Entry score ≥2 (excluding PUL entry scores of 1) at baseline. Here, 'Overall number of participants analyzed' = participants evaluable for specified outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pamrevlumab | Change From Baseline in Left Ventricular Ejection Fraction Percentage (LVEF %) at Week 52, Assessed by Magnetic Resonance Imaging (MRI) | -0.499 percentage of LVEF | Standard Error 0.975 |
| Placebo | Change From Baseline in Left Ventricular Ejection Fraction Percentage (LVEF %) at Week 52, Assessed by Magnetic Resonance Imaging (MRI) | -1.114 percentage of LVEF | Standard Error 0.9204 |
Secondary
Change From Baseline in Percent Predicted Forced Vital Capacity (ppFVC) at Week 52, Assessed by Spirometry
FVC is a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted FVC is based on a formula using sex, age and height of a person, and is an estimate of healthy lung capacity. Percent of predicted FVC = (observed value)/(predicted value) \* 100%. Analysis was done using an RCM, which included fixed effects of time (as a continuous variable), treatment, and treatment-by-time interaction, with baseline value as covariate.
Time frame: Baseline, Week 52
Population: The mITT population included all randomized participants with a PUL Entry score ≥2 (excluding PUL entry scores of 1) at baseline. Here, 'Overall number of participants analyzed' = participants evaluable for specified outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pamrevlumab | Change From Baseline in Percent Predicted Forced Vital Capacity (ppFVC) at Week 52, Assessed by Spirometry | -8.349 percentage of predicted FVC | Standard Error 1.576 |
| Placebo | Change From Baseline in Percent Predicted Forced Vital Capacity (ppFVC) at Week 52, Assessed by Spirometry | -5.989 percentage of predicted FVC | Standard Error 1.2233 |
Secondary
Change From Baseline in Percent Predicted Peak Expiratory Flow (ppPEF) at Week 52, Assessed by Spirometry
The ppPEF is a measure of the maximal or peak flow produced during an exhalation with maximal effort and, as such, is the most effort-dependent measure of lung function. The ppFEV1 was analyzed using an RCM including fixed effects of time, treatment, and treatment-by-time interaction, with baseline as covariate.
Time frame: Baseline, Week 52
Population: The ITT set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for specified outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Pamrevlumab | Change From Baseline in Percent Predicted Peak Expiratory Flow (ppPEF) at Week 52, Assessed by Spirometry | -4.921 percentage of predicted PEF | Standard Error 2.3086 |
| Placebo | Change From Baseline in Percent Predicted Peak Expiratory Flow (ppPEF) at Week 52, Assessed by Spirometry | -4.516 percentage of predicted PEF | Standard Error 1.7663 |
Secondary
Change From Baseline in the Grip Strength of the Hands at Week 52, Assessed by Hand Held Myometry (HHM)
The HHM was used to measure distal upper arm strength (grip strength). Data has been presented by dominant and non-dominant hand. Grip Strength was analyzed using a MMRM with fixed effects for treatment, visit (as a factor), treatment-by-visit interaction, and covariates (baseline values).
Time frame: Baseline, Week 52
Population: The mITT population included all randomized participants with a PUL Entry score ≥2 (excluding PUL entry scores of 1) at baseline. Here, 'Overall number of participants analyzed' = participants evaluable for specified outcome measure. 'Number analyzed' = participants evaluable for specified category.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pamrevlumab | Change From Baseline in the Grip Strength of the Hands at Week 52, Assessed by Hand Held Myometry (HHM) | Grip Strength by Dominant Hand | -7.570 newton | Standard Error 2.0989 |
| Pamrevlumab | Change From Baseline in the Grip Strength of the Hands at Week 52, Assessed by Hand Held Myometry (HHM) | Grip Strength by Nondominant Hand | -7.627 newton | Standard Error 1.8893 |
| Placebo | Change From Baseline in the Grip Strength of the Hands at Week 52, Assessed by Hand Held Myometry (HHM) | Grip Strength by Dominant Hand | -0.072 newton | Standard Error 2.2065 |
| Placebo | Change From Baseline in the Grip Strength of the Hands at Week 52, Assessed by Hand Held Myometry (HHM) | Grip Strength by Nondominant Hand | -0.012 newton | Standard Error 1.8546 |