Phase 3 Multicenter Randomized Double-Blind Placebo-Controlled Trial of Fordadistrogene Movaparvovec in Duchenne Muscular Dystrophy Patients
- Trial ID
- 2023-508510-42-00
- Protocol
- C3391003
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the superior efficacy of treatment with **fordadistrogene movaparvovec** compared to placebo, as measured by the change from baseline in the North Star Ambulatory Assessment (NSAA) in patients with Duchenne Muscular Dystrophy (DMD). This objective is clinically relevant as it aims to establish the therapeutic benefit of fordadistrogene movaparvovec in improving motor function in DMD, a progressive neuromuscular disorder characterized by muscle degeneration and weakness.
Secondary objectives include:
- Quantifying the mini-dystrophin expression level in the muscle of participants treated with fordadistrogene movaparvovec.
- Characterizing the distribution of mini-dystrophin expression in the muscle of participants treated with fordadistrogene movaparvovec.
- Characterizing the change in serum creatine kinase (CK) concentration in participants treated with fordadistrogene movaparvovec compared to placebo.
- Characterizing the skills gained, based on the individual items of the NSAA, in participants treated with PF-06939926 compared to placebo.
- Characterizing the skills either improved or maintained, based on the individual items of the NSAA, in participants treated with fordadistrogene movaparvovec compared to placebo.
- Characterizing the 10-meter run/walk velocity in participants treated with PF-06939926 compared to placebo.
- Characterizing the rise from floor velocity in participants treated with fordadistrogene movaparvovec compared to placebo.
- Characterizing the functional health status in participants treated with fordadistrogene movaparvovec compared to placebo.
These secondary objectives are crucial for understanding the broader impact of fordadistrogene movaparvovec on muscle function and overall health in DMD patients, providing insights into the potential benefits and mechanisms of action of the treatment.
Participants
The clinical trial involves a total of **74 participants** diagnosed with **Duchenne Muscular Dystrophy (DMD)**. The study population consists exclusively of male subjects, aged between 4 and 8 years, who have a confirmed genetic diagnosis of DMD. Participants are required to be ambulatory, with the ability to walk 10 meters unassisted, and must have a North Star Ambulatory Assessment (NSAA) total score between 16 and 30 at screening. All participants are on a stable daily dose of glucocorticoids for at least three months prior to the screening and are expected to maintain this regimen throughout the study. The trial population was selected based on these criteria to ensure a consistent baseline for evaluating the efficacy of the treatment. The study does not include female subjects and involves a vulnerable population due to the young age and specific health condition of the participants. Lifestyle considerations include adherence to scheduled visits, treatment plans, and other study procedures, including potential open muscle biopsies and cardiac MRI under general anesthesia. Participants and their legally acceptable representatives are required to comply with all study requirements and maintain the integrity of the study data by not seeking or sharing sensitive clinical data independently.
Plans and Procedures
The clinical trial is a **Phase 3**, multicenter, randomized, double-blind, placebo-controlled study designed to evaluate the safety and efficacy of **fordadistrogene movaparvovec** for the treatment of **Duchenne muscular dystrophy (DMD)**. The trial aims to demonstrate superior efficacy of the treatment compared to placebo, with the primary endpoint being the change from baseline at Week 52 in the North Star Ambulatory Assessment (NSAA) total score. Secondary endpoints include changes in mini-dystrophin expression levels, serum CK concentration, and various functional assessments over the course of the study.
The trial is expected to last until December 5, 2039, with recruitment having started on November 5, 2020. Participants will be involved in the study for a maximum treatment period of one year. The study includes several key visits: an initial screening visit to confirm eligibility, followed by a series of treatment and follow-up visits, and concluding with an end-of-study visit. The screening visit will ensure participants meet the inclusion criteria, such as being male, aged between 4 and 8 years, having a confirmed diagnosis of DMD, and being on a stable dose of glucocorticoids. Follow-up visits will monitor the participants' response to the treatment and any adverse effects.
Participants will be randomly assigned to receive either the investigational product, **fordadistrogene movaparvovec**, or a placebo, both administered as a **solution for infusion**. The study is double-blind, meaning neither the participants nor the investigators will know which treatment the participants are receiving. The trial includes conditions for early termination, such as significant adverse events or non-compliance with the study protocol. Participants and their legally acceptable representatives must agree to comply with all study procedures and maintain the integrity of the study data by not seeking independent clinical data or sharing trial experiences publicly.
Treatment
The clinical trial involves the administration of **Fordadistrogene Movaparvovec**, an experimental medication designed for the treatment of Duchenne Muscular Dystrophy. This investigational product is a **solution for infusion** and is administered via **intravenous use**. The active substance, **fordadistrogene movaparvovec**, is a recombinant adeno-associated viral vector serotype 9 containing the human mini-dystrophin gene. The maximum daily and total dose is set at 200 trillion vector genomes (vg)/mL, with a treatment period limited to one day. This product is classified as an Advanced Therapy Investigational Medicinal Product (ATIMP) and is not formulated for pediatric use.
The study also includes a **placebo** comparator, referred to as "Placebo for PF-06939926". The placebo is used to maintain the double-blind nature of the trial, ensuring unbiased assessment of the investigational product's efficacy. The placebo does not contain any active substance and is not associated with any specific pharmaceutical form or route of administration.
Additionally, **Eculizumab** is included as a non-experimental treatment in the study. Eculizumab is a **concentrate for solution for infusion** and is administered as a solution for infusion. The active substance, **eculizumab**, is provided at a maximum daily and total dose of 1200 mg, with a treatment period of one day. This product is not formulated for pediatric use and is designated as an orphan drug under the number EU/3/09/653.
Efficacy
The efficacy of the investigational product, **fordadistrogene movaparvovec**, in the treatment of Duchenne Muscular Dystrophy will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline at Week 52 in the North Star Ambulatory Assessment (NSAA) total score. This assessment will provide a quantitative measure of motor function improvement in participants.
Secondary endpoints include several measures to further evaluate the efficacy of the treatment. These include the change from baseline in percent normal mini-dystrophin expression level in biceps brachii muscle biopsies at Day 360, assessed using a liquid chromatography mass spectrometry (LC-MS) assay, and the change in the percent of muscle fibers expressing mini-dystrophin in biceps brachii muscle biopsies at Day 360, assessed by immunofluorescence. Additional secondary endpoints involve changes from baseline at Week 52 in serum creatine kinase (CK) concentration, the number of skills gained or maintained based on individual items of the NSAA, and changes in the 10-meter run/walk velocity and rise from floor velocity. Furthermore, changes in the Modified Pediatric Outcomes Data Collection Instrument (PODCI) scores, specifically the Transfer and Basic Mobility Core Scale and the Sports and Physical Functioning Core Scale, will be evaluated at Week 52.
The efficacy assessments will be conducted at specified time points, including baseline, Week 52, and Day 360, using validated scales and laboratory tests. These assessments will provide comprehensive data on the therapeutic impact of **fordadistrogene movaparvovec** on muscle function and dystrophin expression in patients with Duchenne Muscular Dystrophy.
Inclusion and Exclusion Criteria
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 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).
Exclusion Criteria
- Prior treatment with gene therapy, defined as any therapy introducing exogenous DNA or intended to permanently alter the endogenous DNA. Gene therapy (other than IP) will be prohibited for the duration of the study.
- 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). These treatments will also be prohibited during the period between Screening (Visit 1) and Day 1 (Visit 3) and for the first 52 weeks of the study. Please note that for participants who are eligible for these treatments: Participants may be enrolled who have previously experienced lack of efficacy, or intolerance, as long as they received their last dose more than 6 months before screening (Visit 1), or who have refused these treatments. Participants receiving these treatments from which there is believed to be benefit should not discontinue them in order to meet this exclusion criterion and enroll in the study.
- Previous administration with an investigational drug or investigational vaccine within 30 days (or as determined by the local requirement) or 5 half-lives (whichever is longer) at Screening (Visit 1). These treatments will also be prohibited during the period between Screening (Visit 1) 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 (Visit 1).
- Any nonhealed injury at Screening (Visit 1) 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 (Visit 1).
- Positive test for NAb to AAV9, based on the threshold determined by the Central Laboratory, from a sample taken at Screening (Visit 1)
- Receipt of a live attenuated vaccination within 30 days prior to Screening (Visit 1). 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 (Visit 1). 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 (Visit 1), 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 8.2.13) 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 (Visit 1) 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 the Screening Visit (Visit 1), 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 (Visit 1): 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 (Visit 1).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 05 Nov 2020 | 5 |
 France | Not Recruiting | 05 Nov 2020 | 5 |
 Germany | Not Recruiting | 05 Nov 2020 | 4 |
 Italy | Not Recruiting | 05 Nov 2020 | 13 |
 Spain | Not Recruiting | 05 Nov 2020 | 21 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Fordadistrogene Movaparvovec | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | 200000000000000 | 1 | PRD10928501 |
ECULIZUMAB | Other | — | SOLUTION FOR INFUSION | 1200 | 1 | SUB25187 |
Placebo for PF-06939926 | Placebo | N/A | — | — | — | N/A |