Duchenne Muscular Dystrophy
Conditions
Keywords
Clinical trial, Gene therapy, Duchenne muscular dystrophy, fordadistrogene movaparvovec
Brief summary
The study will evaluate the safety and efficacy of gene therapy in boys with DMD. It is a randomized, double-blind, placebo-controlled study with two thirds of participants assigned to gene therapy. The one third of participants who are randomized to the placebo arm will have an opportunity for treatment with gene therapy at the beginning of the second year.
Detailed description
The study will assess the efficacy of PF-06939926 gene therapy on ambulatory function while also monitoring its safety. Approximately 99 boys with DMD will be enrolled and randomly assigned to one of two groups: approximately two thirds will be in Cohort 1 and receive gene therapy at the start of the study; approximately one third will be in Cohort 2 and receive placebo at the start of the study and receive gene therapy after one year, as long as it remains safe to do so. The treatment (PF-06939926 gene therapy or placebo) will be given as an intravenous infusion lasting up to 2 hours. The study includes boys who are at least 4 years old and less than 8 years old (including 7 year olds up until their 8th birthday). All boys will need to be on a daily dose of glucocorticoids (prednisone, prednisolone, or deflazacort) for at least 3 months prior to enrolling and to stay on daily glucocorticoids for the first 2 years of the study. All boys will need to be negative for neutralizing antibodies against AAV9, as measured by the test done for the study as part of screening. The primary outcome of the study will be assessed at 52 weeks. All participants will be followed in the study for 15 years after treatment with gene therapy. Participants who received fordadistrogene movaparvovec in Pfizer studies C3391001 and C3391008 or are currently enrolled in Pfizer study C3391011 will be allowed to roll over into the long-term safety follow-up period of this study and will be considered Cohort 3. The study medication, all medical tests associated with the study, and the visits to the study sites are free of charge. Participants will also be supported for travel costs associated with study visits.
Interventions
GENETICPF-06939926
PF-06939926 will be administered as a single IV infusion at Year 1 for Cohort 1.
OTHERPlacebo
Placebo will be administered as a single IV infusion at Year 1 for Cohort 2.
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The study will be quadruple blind.
Intervention model description
Parallel up to the measurement of the primary outcome at Week 52. At the beginning of study Year 2 participants who were originally assigned to placebo will have the opportunity to receive PF-06939926. All participants will be followed for 5 years following treatment with PF-06939926.
Eligibility
Sex/Gender
MALE
Age
4 Years to 7 Years
Healthy volunteers
No
Inclusion criteria
Key inclusion criteria: 1. Confirmed diagnosis of Duchenne muscular dystrophy by prior genetic testing 2. Receiving a stable daily dose (at least 0.5 mg/kg/day prednisone or prednisolone, or at least 0.75 mg/kg/day deflazacort) for at least 3 months prior to Screening 3. Ambulatory, as assessed by protocol-specified criteria Key
Exclusion criteria
1. Positive test performed by Pfizer for neutralizing antibodies to AAV9 2. Any treatment designed to increase dystrophin expression within 6 months prior to screening (e.g., Translarna™, EXONDYS 51™, VYONDYS 53™) 3. Any prior treatment with gene therapy 4. Any non-healed injury that may impact functional testing (eg NSAA) 5. Abnormality in specified laboratory tests, including blood counts, liver and kidney function 6. Any of the following genetic abnormalities in the dystrophin gene: 1. Any mutation (exon deletion, exon duplication, insertion, or point mutation) affecting any exon between exon 9 and exon 13, inclusive; OR 2. A deletion that affects both exon 29 and exon 30;OR 3. A deletion that affects any exons between 56-71, inclusive.
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 was a 17-item test that graded performance of various functional skills using the following scale: 0 (unable to achieve independently), 1 (modified method but achieves goal independent of physical assistance from another), and 2 ("normal"- no obvious modification of activity). Total score was calculated as the sum of all 17 individual item responses and ranged from 0 (worst) to 34 (fully independent function) with higher scores indicating better function. Baseline NSAA total score is defined as the last non-missing NSAA total score collected prior to Year 1 drug administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Percent Normal Dystrophin Expression Level in Muscle Biopsies by Liquid Chromatography Mass Spectrometry (LC-MS) Based on LLQV Peptide at Week 52 | Baseline, Week 52 | The LC-MS assay measured the LLQVAVEDR (LLQV) peptide that detected full-length endogenous dystrophin as well as the mini-dystrophin transgene protein. |
| Change From Baseline in Percent of Muscle Fibers Expressing Mini-Dystrophin in Muscle Biopsies by Immunofluorescence at Week 52 | Baseline, Week 52 | Muscle fibers expressing mini-dystrophin transgene protein were evaluated by immunofluorescent staining using the mini-dystrophin specific antibody which only recognized the mini-dystrophin transgene protein. |
| Change From Baseline in Serum Creatine Kinase (CK) Concentration at Week 52 | Baseline, Week 52 | The CK results were analyzed by the central laboratory. |
| Least Square Mean of Proportion of Skills Gained Based on the Individual Items of the NSAA at Week 52 | Baseline, Week 52 | Proportion of skills gained at Week 52 were expressed as a proportion of the number of skills at Baseline that could be gained (numerator was number of items on NSAA gained at Week 52, with response 1 or 2 and denominator was number of items on NSAA with score 0 at baseline). The NSAA was a 17-item test that graded performance of various functional skills using the following scale: 0 (unable to achieve independently), 1 (modified method but achieves goal independent of physical assistance from another), and 2 ("normal"- no obvious modification of activity). Total score was calculated as the sum of all 17 individual item responses and ranged from 0 (worst) to 34 (fully independent function) with higher scores indicating better function. |
| Least Square Mean of Proportion of Skills Either Improved or Maintained Based on the Individual Items of the NSAA at Week 52 | Baseline, Week 52 | Proportion of skills either improved or maintained at Week 52 was expressed as a proportion of the number of items at Baseline that could be improved or maintained (numerator was the number of items on NSAA improved or maintained at Week 52 and denominator is number of items on NSAA which is 17). The NSAA was a 17-item test that graded performance of various functional skills using the following scale: 0 (unable to achieve independently), 1 (modified method but achieves goal independent of physical assistance from another), and 2 ("normal"- no obvious modification of activity). Total score was calculated as the sum of all 17 individual item responses and ranged from 0 (worst) to 34 (fully independent function) with higher scores indicating better function. |
| Change From Baseline in 10 Meter Run/Walk Velocity at Week 52 | Baseline, Week 52 | Velocity was calculated based on the time it took to complete the 10-meter run/walk test. |
| Change From Baseline in Rise From Floor Velocity at Week 52 | Baseline, Week 52 | Velocity was calculated based on the time it took to rise from floor. |
| Change From Baseline in Modified Pediatric Outcome Data Collection Instrument (PODCI)- Transfer and Basic Mobility Core Scale at Week 52 | Baseline, Week 52 | Modified PODCI- transfer and basic mobility core scale (parent of pediatric participant) consisted of 11 items that assessed how caregivers of participants evaluated a participant's ability to walk, stand, and perform activities of daily living. The scale produced an independent, standardized score ranging from 0-100, with lower scores representing lower levels of function. |
| Change From Baseline in Modified PODCI- Sports and Physical Functioning Core Scale at Week 52 | Baseline, Week 52 | Modified PODCI- sports and physical functioning core scale (parent of pediatric participant) consisted of 21 items that assessed how caregivers of participants evaluated a participant's ability to perform recreational activities. The scale produced an independent, standardized score ranging from 0-100, with lower scores representing lower levels of function. |
Countries
Australia, Belgium, Canada, France, Germany, Israel, Italy, Japan, Russia, South Korea, Spain, Switzerland, Taiwan, United Kingdom, United States
Contacts
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Participant flow
Recruitment details
A total of 114 participants were enrolled and received at least one dose of study treatment. Results are reported based on primary completion date of Week 52.
Pre-assignment details
Primary Completion Date (PCD) defined as the time point when at least 90 randomized participants received investigational product and completed the one-year follow-up/week 52 visit.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Participants were randomized to receive a single dose of fordadistrogene Movaparvovec 2E14 vg/kg on Day 1 (Year 1 Day 1) and a single dose of matching placebo on Day 390 (Year 2 Day 1). | 79 |
| Cohort 2 Participants were randomized to receive a single dose of matching placebo on Day 1 (Year 1 Day 1) and a single dose of fordadistrogene Movaparvovec 2E14 vg/kg on Day 390 (Year 2 Day 1). | 35 |
| Total | 114 |
Baseline characteristics
| Characteristic | Cohort 2 | Total | Cohort 1 |
|---|---|---|---|
| Age, Continuous | 6.6 Years STANDARD_DEVIATION 1.2 | 6.4 Years STANDARD_DEVIATION 1.2 | 6.4 Years STANDARD_DEVIATION 1.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 19 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 93 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 33 Participants | 24 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 2 Participants | 8 Participants | 6 Participants |
| Race (NIH/OMB) White | 24 Participants | 73 Participants | 49 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 35 Participants | 114 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 79 | 0 / 35 |
| other Total, other adverse events | 77 / 79 | 20 / 35 |
| serious Total, serious adverse events | 25 / 79 | 5 / 35 |
Outcome results
Primary
Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score at Week 52
The NSAA was a 17-item test that graded performance of various functional skills using the following scale: 0 (unable to achieve independently), 1 (modified method but achieves goal independent of physical assistance from another), and 2 (normal- no obvious modification of activity). Total score was calculated as the sum of all 17 individual item responses and ranged from 0 (worst) to 34 (fully independent function) with higher scores indicating better function. Baseline NSAA total score is defined as the last non-missing NSAA total score collected prior to Year 1 drug administration.
Time frame: Baseline, Week 52
Population: Full analysis set (FAS) through Week 52 included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score at Week 52 | 1.46 Score on a scale |
| Cohort 2 | Change From Baseline in North Star Ambulatory Assessment (NSAA) Total Score at Week 52 | 1.37 Score on a scale |
p-value: =0.911695% CI: [-1.46, 1.64]Mixed Models Analysis
Secondary
Change From Baseline in 10 Meter Run/Walk Velocity at Week 52
Velocity was calculated based on the time it took to complete the 10-meter run/walk test.
Time frame: Baseline, Week 52
Population: FAS included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Change From Baseline in 10 Meter Run/Walk Velocity at Week 52 | 0.127 Meter per second |
| Cohort 2 | Change From Baseline in 10 Meter Run/Walk Velocity at Week 52 | 0.206 Meter per second |
p-value: =0.334395% CI: [-0.242, 0.083]Mixed Models Analysis
Secondary
Change From Baseline in Modified Pediatric Outcome Data Collection Instrument (PODCI)- Transfer and Basic Mobility Core Scale at Week 52
Modified PODCI- transfer and basic mobility core scale (parent of pediatric participant) consisted of 11 items that assessed how caregivers of participants evaluated a participant's ability to walk, stand, and perform activities of daily living. The scale produced an independent, standardized score ranging from 0-100, with lower scores representing lower levels of function.
Time frame: Baseline, Week 52
Population: FAS included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Change From Baseline in Modified Pediatric Outcome Data Collection Instrument (PODCI)- Transfer and Basic Mobility Core Scale at Week 52 | 2.18 Score on a scale |
| Cohort 2 | Change From Baseline in Modified Pediatric Outcome Data Collection Instrument (PODCI)- Transfer and Basic Mobility Core Scale at Week 52 | 0.16 Score on a scale |
p-value: =0.21995% CI: [-1.22, 5.24]Mixed Models Analysis
Secondary
Change From Baseline in Modified PODCI- Sports and Physical Functioning Core Scale at Week 52
Modified PODCI- sports and physical functioning core scale (parent of pediatric participant) consisted of 21 items that assessed how caregivers of participants evaluated a participant's ability to perform recreational activities. The scale produced an independent, standardized score ranging from 0-100, with lower scores representing lower levels of function.
Time frame: Baseline, Week 52
Population: FAS included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Change From Baseline in Modified PODCI- Sports and Physical Functioning Core Scale at Week 52 | 2.95 Score on a scale |
| Cohort 2 | Change From Baseline in Modified PODCI- Sports and Physical Functioning Core Scale at Week 52 | 1.84 Score on a scale |
p-value: =0.709695% CI: [-4.79, 7]Mixed Models Analysis
Secondary
Change From Baseline in Percent Normal Dystrophin Expression Level in Muscle Biopsies by Liquid Chromatography Mass Spectrometry (LC-MS) Based on LLQV Peptide at Week 52
The LC-MS assay measured the LLQVAVEDR (LLQV) peptide that detected full-length endogenous dystrophin as well as the mini-dystrophin transgene protein.
Time frame: Baseline, Week 52
Population: FAS through Week 52 included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Change From Baseline in Percent Normal Dystrophin Expression Level in Muscle Biopsies by Liquid Chromatography Mass Spectrometry (LC-MS) Based on LLQV Peptide at Week 52 | 85.88 % normal dystrophin expression level |
| Cohort 2 | Change From Baseline in Percent Normal Dystrophin Expression Level in Muscle Biopsies by Liquid Chromatography Mass Spectrometry (LC-MS) Based on LLQV Peptide at Week 52 | 0.13 % normal dystrophin expression level |
p-value: =0.000295% CI: [49.15, 122.35]ANCOVA
Secondary
Change From Baseline in Percent of Muscle Fibers Expressing Mini-Dystrophin in Muscle Biopsies by Immunofluorescence at Week 52
Muscle fibers expressing mini-dystrophin transgene protein were evaluated by immunofluorescent staining using the mini-dystrophin specific antibody which only recognized the mini-dystrophin transgene protein.
Time frame: Baseline, Week 52
Population: FAS included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Change From Baseline in Percent of Muscle Fibers Expressing Mini-Dystrophin in Muscle Biopsies by Immunofluorescence at Week 52 | 50.15 Percentage of muscle fibers |
| Cohort 2 | Change From Baseline in Percent of Muscle Fibers Expressing Mini-Dystrophin in Muscle Biopsies by Immunofluorescence at Week 52 | -1.31 Percentage of muscle fibers |
p-value: <0.000195% CI: [31.43, 71.49]ANCOVA
Secondary
Change From Baseline in Rise From Floor Velocity at Week 52
Velocity was calculated based on the time it took to rise from floor.
Time frame: Baseline, Week 52
Population: FAS included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Change From Baseline in Rise From Floor Velocity at Week 52 | 0.025 Meter per second |
| Cohort 2 | Change From Baseline in Rise From Floor Velocity at Week 52 | 0.029 Meter per second |
p-value: =0.882695% CI: [-0.052, 0.045]Mixed Models Analysis
Secondary
Change From Baseline in Serum Creatine Kinase (CK) Concentration at Week 52
The CK results were analyzed by the central laboratory.
Time frame: Baseline, Week 52
Population: FAS included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Change From Baseline in Serum Creatine Kinase (CK) Concentration at Week 52 | 0.68 Units per Liter (U/L) |
| Cohort 2 | Change From Baseline in Serum Creatine Kinase (CK) Concentration at Week 52 | 1.06 Units per Liter (U/L) |
p-value: =0.000295% CI: [0.5, 0.81]Mixed Models Analysis
Secondary
Least Square Mean of Proportion of Skills Either Improved or Maintained Based on the Individual Items of the NSAA at Week 52
Proportion of skills either improved or maintained at Week 52 was expressed as a proportion of the number of items at Baseline that could be improved or maintained (numerator was the number of items on NSAA improved or maintained at Week 52 and denominator is number of items on NSAA which is 17). The NSAA was a 17-item test that graded performance of various functional skills using the following scale: 0 (unable to achieve independently), 1 (modified method but achieves goal independent of physical assistance from another), and 2 (normal- no obvious modification of activity). Total score was calculated as the sum of all 17 individual item responses and ranged from 0 (worst) to 34 (fully independent function) with higher scores indicating better function.
Time frame: Baseline, Week 52
Population: FAS included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Least Square Mean of Proportion of Skills Either Improved or Maintained Based on the Individual Items of the NSAA at Week 52 | 0.88 Proportion of skills |
| Cohort 2 | Least Square Mean of Proportion of Skills Either Improved or Maintained Based on the Individual Items of the NSAA at Week 52 | 0.89 Proportion of skills |
p-value: =0.543795% CI: [0.63, 1.28]Binomial Regression
Secondary
Least Square Mean of Proportion of Skills Gained Based on the Individual Items of the NSAA at Week 52
Proportion of skills gained at Week 52 were expressed as a proportion of the number of skills at Baseline that could be gained (numerator was number of items on NSAA gained at Week 52, with response 1 or 2 and denominator was number of items on NSAA with score 0 at baseline). The NSAA was a 17-item test that graded performance of various functional skills using the following scale: 0 (unable to achieve independently), 1 (modified method but achieves goal independent of physical assistance from another), and 2 (normal- no obvious modification of activity). Total score was calculated as the sum of all 17 individual item responses and ranged from 0 (worst) to 34 (fully independent function) with higher scores indicating better function.
Time frame: Baseline, Week 52
Population: FAS included all eligible participants who were randomly assigned and received a single dose of study drug on Day 1 (Year 1 Day 1). Here, Overall Number of Participants signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1 | Least Square Mean of Proportion of Skills Gained Based on the Individual Items of the NSAA at Week 52 | 0.55 Proportion of skills |
| Cohort 2 | Least Square Mean of Proportion of Skills Gained Based on the Individual Items of the NSAA at Week 52 | 0.42 Proportion of skills |
p-value: =0.278495% CI: [0.64, 4.62]Binomial regression