|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|DUCHENNE MUSCULAR DYSTROPHY (DMD)
|Medical condition in easily understood language
|DMD is a severe, X-linked, progressive neuromuscular disease affecting approximately one
in 3600 to 9300 live male births
|Diseases [C] - Musculoskeletal Diseases [C05]
|E.1.2 Medical condition or disease under investigation
|Duchenne muscular dystrophy
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|To demonstrate superior efficacy of treatment with fordadistrogene
movaparvovec as compared to placebo based on change from Baseline in the North Star Ambulatory Assessment (NSAA).
|Secondary objectives of the trial
|- To quantify the mini-dystrophin expression level in the muscle of participants treated with fordadistrogene
- To characterize the distribution of mini-dystrophin expression in the muscle of participants treated with fordadistrogene
- To characterize the change in serum creatine kinase (CK) concentration in participants treated with fordadistrogene
movaparvovec as compared to placebo.
|Trial contains a sub-study
|Principal inclusion criteria
|- Male participants who are ≥4 and <8 years of age at Screening (Visit 1).
- Confirmed diagnosis of DMD by prior genetic testing demonstrating the presence of a mutation in the dystrophin gene consistent with DMD at Screening (Visit 1). If the Investigator determines that the results are inconclusive, a repeat genetic testing will be allowed through the central laboratory at Screening (Visit 1).
- Receipt of a stable daily dose of glucocorticoids (≥0.5 mg/kg/day prednisone, prednisolone, or ≥0.75 mg/kg/day deflazacort) for at least 3 months prior to Screening (Visit 1) and during the period between Screening (Visit 1) and Day 1 (Visit 3). In order to comply with protocol procedures, there should also be a reasonable expectation that this daily dose of glucocorticoids will remain stable for the first 2 years of the study. A stable dose is defined as one in which any change is ≤0.2 mg/kg
- A NSAA total score >16 and <30 at Screening (Visit 1).
- Ambulatory, defined as being able to walk 10 meters unassisted, at Screening (Visit 1).
- Participants/legally acceptable representatives who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures including, potentially, open and/or needle muscle biopsies under general anesthesia and cardiac MRI under general anesthesia.
- Participants/legally acceptable representatives who are capable of giving assent/signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the assent/informed consent document (ICD) and in this protocol.
- Participants/legally acceptable representatives who are willing to protect the integrity of the study data by not actively seeking sensitive clinical data (eg, CK, ALT, AST, NAb to AAV9) through independent laboratory tests and by not sharing trial experiences with other participants or publicly (eg, through social media).
|Principal exclusion criteria
|- Prior treatment with gene therapy, defined as any therapy introducing exogenous DNA or intended to permanently alter the endogenous DNA.
- Exposure within 6 months prior to Screening (Visit 1) to any treatment designed to increase dystrophin expression (including, but not limited to exon-skipping and nonsense read-through).
- Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives (whichever is longer) at Screening. These treatments will also be prohibited during the period between Screening and Day 1 (Visit 3) and for the first 2 years of the study.
- Known cognitive impairment or behavioral issues that would impede the ability to follow instructions, in the judgment of the Investigator, at Screening.
- Any nonhealed injury at Screening which, in the opinion of the Investigator, may impact functional testing; additionally, lower limb fractures must have been healed for at least 3 months prior to Screening.
- Positive test for NAb to AAV9, based on the threshold determined by the Central Laboratory, from a sample taken at Screening.
- Receipt of a live attenuated vaccination within 30 days prior to Screening. Receipt of a live attenuated vaccination will also be prohibited for 90 days before Day 1 (Visit 3), for 90 days prior to Year 2 IP administration, and for the first 2 months after each IP administration.
-Abnormality in hematology or chemistry profiles at Screening. A single repeat for value(s) outside allowable limits is permitted to re-assess eligibility:
a. Absolute neutrophil count <1000 cells/mm3;
b. Platelets <150 x 103/µl;
c. Cystatin C >1.2 x ULN;
d. Positive hepatitis A virus (anti-HAV) immunoglobulin M, hepatitis B surface
antigen (HBsAg), and/or hepatitis C antibody (HCVAb);
e. Markers of hepatic inflammation or overt or occult cirrhosis as evidenced by one
or more of the following:
1. Prothrombin time (PT) > upper limit of normal (ULN); prolonged
international normalized ratio (INR) >ULN;
2. GLDH >2 x ULN;
3. Total bilirubin >1.5 x ULN(unless the participant has a history of Gilbert
disease) and direct bilirubin >0.5 mg/dL;
4. Gamma-glutamyl transferase (GGT) >1.5 x ULN.
-Other acute or chronic medical or psychiatric condition at Screening, including recent (within the past year) or active suicidal ideation or behavior (using screening by the Child Behavior Check List (CBCL) and determined by the Investigator, as described in Section 8.2.11) or laboratory abnormality that may increase the risk associated with study participation or IP administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the participant inappropriate for entry into this study.
-Acute infection at Screening or Baseline (Visit 2) that, in the judgement of the Investigator is not expected to be fully resolved at least 2 weeks before Day 1 (Visit 3). At Day 1 (Visit 3), participants must have been infection-free for at least 2 weeks prior to IP administration. Delay of IP administration for up to 14 days is permitted to enable infections to become fully resolved.
-Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or Pfizer employees, including their family members, directly involved in the conduct of the study.
- Known hypersensitivity to any of the components of the IP or solution for infusion, such as hypersensitivity to albumin or a diagnosis of HFI. Symptoms suggestive of HFI include nausea, vomiting, bloating, stomach cramps, or diarrhea following the ingestion of sweet foods or drinks, or a pattern of avoiding sweet foods or drinks.
- Contraindication to the use of eculizumab, as per the local prescribing information.
- LVEF <50% on echocardiogram performed at Screening Visit, as evaluated by the central reader.
-Participants with the following genetic abnormalities in the dystrophin gene as confirmed by the investigator based on the review of DMD genetic testing:
a.Any mutation (exon deletion, exon duplication, insertion, or point mutation) affecting any exon between exon 9 and exon 13, inclusive; OR
b.A deletion that affects both exon 29 and exon 30; OR
c.A deletion that affects any exons between 56-71, inclusive.
- Cardiac pathologies, as evaluated by a pediatric cardiologist at the Screening Visit:
a. Diagnosis of myocarditis (eg, viral): either based on prior medical history or based on findings in cardiac imaging tests;
b. Any other cardiac history, and/or condition and/or abnormalities in cardiac imaging, that determine that the participant should not be included in the study, as per the cardiologist.
- Not a candidate for mechanical cardiac or respiratory support, or any other invasive intervention, if indicated for management of an acute event as determined by the cardiologist in consultation with the investigator at the Screening Visit.
|E.5 End points
|Primary end point(s)
|Change from Baseline at Week 52 in the NSAA total score.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|- Change from Baseline in percent normal mini-dystrophin expression level in biceps brachii muscle biopsies at Day 360 using an LC-MS assay.
- Change from Baseline in percent of muscle fibers expressing mini-dystrophin in biceps brachii muscle biopsies at Day 360 as assessed by immunofluorescence.
- Change from Baseline at Week 52 in serum CK concentration.
- Number of skills gained at Week 52 based on the individual items of the NSAA.
- Number of skills either improved or maintained at Week 52 based on the individual items of the NSAA.
-Change from Baseline at Week 52 in the 10 meter run/walk velocity.
-Change from Baseline at Week 52 in the rise from floor velocity.
-Change from Baseline at Week 52 in the Modified Pediatric Outcomes Data Collection Instrument (PODCI): Transfer and Basic Mobility Core Scale (Pediatric Parent).
- Change from Baseline at Week 52 in the Modified PODCI: Sports and Physical Functioning Core Scale (Pediatric Parent).
|Timepoint(s) of evaluation of this end point
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Korea, Republic of
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The end of the study is defined as the date of the last visit of the last participant in the study.
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days