Duchenne Muscular Dystrophy
Conditions
Brief summary
The purpose of this study is to determine if ACE-031 is safe and well-tolerated in boys with Duchenne Muscular Dystrophy (DMD) and to select the optimal doses of ACE-031 in terms of safety and pharmacodynamic (PD) activity for designing future studies. \[Note: This study was terminated based on safety data\]
Detailed description
ACE-031, a soluble form of the human activin receptor type IIB, was administered once every 2 to 4 weeks by subcutaneous (SC) injection to boys with DMD. Dose levels and regimens for this multiple-dose study were based on data from the initial clinical studies in healthy subjects in which doses of 0.02 to 3 mg/kg SC were evaluated. A total of 24 subjects were enrolled into the study; 18 received ACE-031 and 6 placebo. All subjects were treated for a period of 12 weeks.The pharmacodynamic effects of ACE-031 treatment were assessed by a battery of motor function test that included the 6-Minute Walk Test, the 10-Minute Walk/Run Test, the 4-Stair Climb Test and the Gower Maneuver (GW). Muscle strength was assessed by hand-held myometry and fixed system testing. Body composition (i.e., spine BMD, lean mass, and fat mass) was assessed by whole body and lumbar spine DXA scans. Pulmonary function was assessed by forced vital capacity (FVC), maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). ACE-031 safety was evaluated through observation of the incidence and severity of adverse events.
Interventions
BIOLOGICALACE-031 0.5 mg/kg q4wk
ACE-031 0.5 mg/kg subcutaneously once every 4 weeks for 12 weeks.
BIOLOGICALACE-031 1.0 mg/kg q2wk
ACE-031 1.0 mg/kg subcutaneously once every 2 weeks for 12 weeks.
OTHERPlacebo
Matching volume placebo subcutaneously every 2 or 4 weeks for 12 weeks.
Sponsors
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of DMD confirmed * Ambulant * Corticosteroid therapy for at least one year prior to study day 1 and on a stable dose and schedule for at least 6 months prior to study day 1 * Evidence of muscle weakness by clinical assessment
Exclusion criteria
* Any previous treatment with another investigational product within 6 months prior to study day 1 * Any clinically significant cardiac, endocrine, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease that is not related to DMD * Inability to perform a whole body dual x-ray absorptiometry (DXA) scan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Adverse Reactions. | From treatment initiation to End-of-Study Visit, approximately 24 weeks later | Number of subjects in each cohort with a treatment-emergent adverse event considered at least possibly related to study drug |
| Number of Subjects With Clinical Laboratory Adverse Reactions. | Baseline to End-of-Study Visit, approximately 24 weeks later. | Number of subjects in each cohort with treatment-emergent adverse laboratory values judged to be at least possibly related to study drug |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Lumbar Spine Bone Mineral Density by DXA Scan. | Baseline to End-of-Study Visit, approximately 24 weeks later. | — |
| Percent Change in Muscle Strength Score by Hand-held Myometry. | Baseline to End-of-Study Visit, approximately 24 weeks later. | Manual Muscle Testing (MMT) is a procedure to measure the function and strength of individual muscles and muscle groups. Hand-held myometry, using a device known as a dynamometer, is one method used for MMT. The dynamometer is held against the patient's limb by the examiner and the patient is asked to resist the force applied by the examiner. The dynamometer measures the force applied by the patient, providing a quantitative and objective assessment of strength of the particular muscle or muscle group. The effectiveness of a therapeutic intervention on muscle strength, as measured by hand-held myometry, can be assessed by comparing post-treatment to pre-treatment (baseline) measurements. |
| Change in Distance Traveled in 6 Minutes (Standardized 6-Minute-Walk Test). | Baseline to End-of-Study Visit, approximately 24 weeks later. | Change in distance traveled in 6 minutes (standardized 6-Minute-Walk Test); stratified by baseline age (\<10 years vs. \>=10 years) |
| Change in Pulmonary Function Test (MIP) | Baseline to End-of-Study Visit. approximately 24 weeks | Maximum Inspiratory Pressure (MIP); 2 of 3 separate tests employed to assess pulmonary function in this study |
| Change in Pulmonary Function Tests (FVC) | Baseline to End-of-Study Visit, approximately 24 weeks later. | Forced Vital Capacity (FVC); 1 of 3 separate tests employed to assess pulmonary function in this study |
| Change in Pulmonary Function Test (MEP) | Baseline to End-of-Stuidy Visit, approximately 24 weeks | Maximum Expiratory Pressure (MEP); 3 of 3 separate tests employed to assess pulmonary function in this study |
| Change From Baseline in Time to Travel 10 Meters (Standardized 10-Meter-Walk/Run Test). | Baseline to End-of-Study Visit, approximately 24 weeks later. | — |
| Percent Change in Total Lean Body Mass by DXA Scan. | Baseline to End-of-Study Visit, approximately 24 weeks later. | — |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ACE-031 0.5 mg/kg q4wk ACE-031 0.5 mg/kg q4wk: ACE-031 0.5 mg/kg subcutaneously once every 4 weeks for 12 weeks. | 9 |
| ACE-031 1.0 mg/kg q2wk ACE-031 1.0 mg/kg q2wk: ACE-031 1.0 mg/kg subcutaneously once every 2 weeks for 12 weeks. | 9 |
| ACE-031 ACE-03 2.5 mg/kg q4wk ACE-031 2.5 mg/kg q4wk: ACE-031 2.5 mg/kg subcutaneously once every 4 weeks for 12 weeks. | 0 |
| Placebo Placebo: Matching volume placebo subcutaneously every 2 or 4 weeks for 12 weeks. | 6 |
| Total | 24 |
Baseline characteristics
| Characteristic | ACE-031 0.5 mg/kg q4wk | Total | Placebo | ACE-031 1.0 mg/kg q2wk |
|---|---|---|---|---|
| Able to ambulate 10 meters in < 12 seconds | 9 participants | 24 participants | 6 participants | 9 participants |
| Age, Categorical <=18 years | 9 Participants | 24 Participants | 6 Participants | 9 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 24 Participants | 6 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Canada | 9 participants | 24 participants | 6 participants | 9 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 9 Participants | 24 Participants | 6 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 9 | 6 / 9 | 0 / 0 | 3 / 6 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 0 | 0 / 6 |
Outcome results
Primary
Number of Subjects With Adverse Reactions.
Number of subjects in each cohort with a treatment-emergent adverse event considered at least possibly related to study drug
Time frame: From treatment initiation to End-of-Study Visit, approximately 24 weeks later
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Number of Subjects With Adverse Reactions. | 1 Number of subjects |
| ACE-031 1.0 mg/kg q2wk | Number of Subjects With Adverse Reactions. | 6 Number of subjects |
| Placebo | Number of Subjects With Adverse Reactions. | 0 Number of subjects |
Primary
Number of Subjects With Clinical Laboratory Adverse Reactions.
Number of subjects in each cohort with treatment-emergent adverse laboratory values judged to be at least possibly related to study drug
Time frame: Baseline to End-of-Study Visit, approximately 24 weeks later.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Number of Subjects With Clinical Laboratory Adverse Reactions. | 0 Number of subjects |
| ACE-031 1.0 mg/kg q2wk | Number of Subjects With Clinical Laboratory Adverse Reactions. | 0 Number of subjects |
| Placebo | Number of Subjects With Clinical Laboratory Adverse Reactions. | 0 Number of subjects |
Secondary
Change From Baseline in Time to Travel 10 Meters (Standardized 10-Meter-Walk/Run Test).
Time frame: Baseline to End-of-Study Visit, approximately 24 weeks later.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Change From Baseline in Time to Travel 10 Meters (Standardized 10-Meter-Walk/Run Test). | 0.7 Change (sec) in 10MWT from baseline | Standard Deviation 0.9 |
| ACE-031 1.0 mg/kg q2wk | Change From Baseline in Time to Travel 10 Meters (Standardized 10-Meter-Walk/Run Test). | 0.7 Change (sec) in 10MWT from baseline | Standard Deviation 0.9 |
| Placebo | Change From Baseline in Time to Travel 10 Meters (Standardized 10-Meter-Walk/Run Test). | 1.0 Change (sec) in 10MWT from baseline | Standard Deviation 0.8 |
Secondary
Change in Distance Traveled in 6 Minutes (Standardized 6-Minute-Walk Test).
Change in distance traveled in 6 minutes (standardized 6-Minute-Walk Test); stratified by baseline age (\<10 years vs. \>=10 years)
Time frame: Baseline to End-of-Study Visit, approximately 24 weeks later.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Change in Distance Traveled in 6 Minutes (Standardized 6-Minute-Walk Test). | <10 years of age at baseline | 43.8 change (m) in 6MWT from baseline | Standard Deviation 61.5 |
| ACE-031 0.5 mg/kg q4wk | Change in Distance Traveled in 6 Minutes (Standardized 6-Minute-Walk Test). | >=10 years of age at baseline | 4.5 change (m) in 6MWT from baseline | Standard Deviation 37.6 |
| ACE-031 1.0 mg/kg q2wk | Change in Distance Traveled in 6 Minutes (Standardized 6-Minute-Walk Test). | >=10 years of age at baseline | -3.2 change (m) in 6MWT from baseline | Standard Deviation 35.5 |
| ACE-031 1.0 mg/kg q2wk | Change in Distance Traveled in 6 Minutes (Standardized 6-Minute-Walk Test). | <10 years of age at baseline | 2.5 change (m) in 6MWT from baseline | Standard Deviation 35.6 |
| Placebo | Change in Distance Traveled in 6 Minutes (Standardized 6-Minute-Walk Test). | <10 years of age at baseline | 5.2 change (m) in 6MWT from baseline | Standard Deviation 23.6 |
| Placebo | Change in Distance Traveled in 6 Minutes (Standardized 6-Minute-Walk Test). | >=10 years of age at baseline | -47.6 change (m) in 6MWT from baseline | Standard Deviation 34.5 |
Secondary
Change in Pulmonary Function Test (MEP)
Maximum Expiratory Pressure (MEP); 3 of 3 separate tests employed to assess pulmonary function in this study
Time frame: Baseline to End-of-Stuidy Visit, approximately 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Change in Pulmonary Function Test (MEP) | 11.9 cm H2O | Standard Deviation 12.5 |
| ACE-031 1.0 mg/kg q2wk | Change in Pulmonary Function Test (MEP) | 0.8 cm H2O | Standard Deviation 3.9 |
| Placebo | Change in Pulmonary Function Test (MEP) | 5.8 cm H2O | Standard Deviation 12.1 |
Secondary
Change in Pulmonary Function Test (MIP)
Maximum Inspiratory Pressure (MIP); 2 of 3 separate tests employed to assess pulmonary function in this study
Time frame: Baseline to End-of-Study Visit. approximately 24 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Change in Pulmonary Function Test (MIP) | 17.2 cm H2O | Standard Deviation 17.2 |
| ACE-031 1.0 mg/kg q2wk | Change in Pulmonary Function Test (MIP) | 8.7 cm H2O | Standard Deviation 7.6 |
| Placebo | Change in Pulmonary Function Test (MIP) | 8.8 cm H2O | Standard Deviation 22.1 |
Secondary
Change in Pulmonary Function Tests (FVC)
Forced Vital Capacity (FVC); 1 of 3 separate tests employed to assess pulmonary function in this study
Time frame: Baseline to End-of-Study Visit, approximately 24 weeks later.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Change in Pulmonary Function Tests (FVC) | 0.1 Liters | Standard Deviation 0.2 |
| ACE-031 1.0 mg/kg q2wk | Change in Pulmonary Function Tests (FVC) | 0.1 Liters | Standard Deviation 0.1 |
| Placebo | Change in Pulmonary Function Tests (FVC) | 0.1 Liters | Standard Deviation 0.2 |
Secondary
Percent Change in Lumbar Spine Bone Mineral Density by DXA Scan.
Time frame: Baseline to End-of-Study Visit, approximately 24 weeks later.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Percent Change in Lumbar Spine Bone Mineral Density by DXA Scan. | 1.6 percentage change from baseline | Standard Error 1.8 |
| ACE-031 1.0 mg/kg q2wk | Percent Change in Lumbar Spine Bone Mineral Density by DXA Scan. | 4.4 percentage change from baseline | Standard Error 1.5 |
| Placebo | Percent Change in Lumbar Spine Bone Mineral Density by DXA Scan. | 0.3 percentage change from baseline | Standard Error 4.4 |
p-value: 0.039ANCOVA
Secondary
Percent Change in Muscle Strength Score by Hand-held Myometry.
Manual Muscle Testing (MMT) is a procedure to measure the function and strength of individual muscles and muscle groups. Hand-held myometry, using a device known as a dynamometer, is one method used for MMT. The dynamometer is held against the patient's limb by the examiner and the patient is asked to resist the force applied by the examiner. The dynamometer measures the force applied by the patient, providing a quantitative and objective assessment of strength of the particular muscle or muscle group. The effectiveness of a therapeutic intervention on muscle strength, as measured by hand-held myometry, can be assessed by comparing post-treatment to pre-treatment (baseline) measurements.
Time frame: Baseline to End-of-Study Visit, approximately 24 weeks later.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Percent Change in Muscle Strength Score by Hand-held Myometry. | Elbow extension (kg) | 0.3 percentage change from baseline | Standard Deviation 3.2 |
| ACE-031 0.5 mg/kg q4wk | Percent Change in Muscle Strength Score by Hand-held Myometry. | Elbow flexion (kg) | -0.4 percentage change from baseline | Standard Deviation 3.4 |
| ACE-031 0.5 mg/kg q4wk | Percent Change in Muscle Strength Score by Hand-held Myometry. | Knee extension (kg) | -3.6 percentage change from baseline | Standard Deviation 4.4 |
| ACE-031 0.5 mg/kg q4wk | Percent Change in Muscle Strength Score by Hand-held Myometry. | Knee flexion (kg) | -2.2 percentage change from baseline | Standard Deviation 3.1 |
| ACE-031 1.0 mg/kg q2wk | Percent Change in Muscle Strength Score by Hand-held Myometry. | Knee flexion (kg) | -1.9 percentage change from baseline | Standard Deviation 4.1 |
| ACE-031 1.0 mg/kg q2wk | Percent Change in Muscle Strength Score by Hand-held Myometry. | Elbow extension (kg) | 0.1 percentage change from baseline | Standard Deviation 2.3 |
| ACE-031 1.0 mg/kg q2wk | Percent Change in Muscle Strength Score by Hand-held Myometry. | Knee extension (kg) | -3.3 percentage change from baseline | Standard Deviation 4.4 |
| ACE-031 1.0 mg/kg q2wk | Percent Change in Muscle Strength Score by Hand-held Myometry. | Elbow flexion (kg) | -0.7 percentage change from baseline | Standard Deviation 2.6 |
| Placebo | Percent Change in Muscle Strength Score by Hand-held Myometry. | Knee flexion (kg) | -1.2 percentage change from baseline | Standard Deviation 3.9 |
| Placebo | Percent Change in Muscle Strength Score by Hand-held Myometry. | Elbow flexion (kg) | 0.3 percentage change from baseline | Standard Deviation 3.1 |
| Placebo | Percent Change in Muscle Strength Score by Hand-held Myometry. | Knee extension (kg) | -3.7 percentage change from baseline | Standard Deviation 5 |
| Placebo | Percent Change in Muscle Strength Score by Hand-held Myometry. | Elbow extension (kg) | -0.1 percentage change from baseline | Standard Deviation 2.1 |
Secondary
Percent Change in Total Lean Body Mass by DXA Scan.
Time frame: Baseline to End-of-Study Visit, approximately 24 weeks later.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ACE-031 0.5 mg/kg q4wk | Percent Change in Total Lean Body Mass by DXA Scan. | 3.6 percentage change in lean body mass | Standard Error 1.3 |
| ACE-031 1.0 mg/kg q2wk | Percent Change in Total Lean Body Mass by DXA Scan. | 4.1 percentage change in lean body mass | Standard Error 1.5 |
| Placebo | Percent Change in Total Lean Body Mass by DXA Scan. | 2.6 percentage change in lean body mass | Standard Error 1.8 |
p-value: 0.023ANCOVA
p-value: 0.012ANCOVA
p-value: 0.435ANCOVA