| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Duchenne Muscular Dystrophy | |
| E.1.1.1 | Medical condition in easily understood language | | Duchenne Muscular Dystrophy | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10052655 | | E.1.2 | Term | Duchenne muscular dystrophy gene carrier | | E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10013801 | | E.1.2 | Term | Duchenne muscular dystrophy | | E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders | |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To evaluate the effect of SRP-9001 on physical function in Part 1 as assessed by the Performance Upper Limb (PUL) (Version 2.0 [V2.0]) | |
| E.2.2 | Secondary objectives of the trial | To evaluate the effect of SRP-9001 on respiratory function in Part 1 as assessed by:
o Forced vital capacity (FVC) percent predicted
o Peak expiratory flow (PEF) percent predicted
To evaluate micro-dystrophin expression from SRP-9001 at 12 weeks (Part 1) as measured by western blot of biopsied muscle tissue
To evaluate subject and parent/caregiver proxy reported Upper Extremity Function, using the Patient-Reported Outcomes Measurement Information System (PROMIS®) tool
To evaluate the safety of SRP-9001
For Cohort 2 only: To evaluate the effect of SRP-9001 on physical function as assessed by the North Star Ambulatory assessment (NSAA) score
To evaluate cardiac strain over time by cardiac magnetic resonance imaging (cMRI) | |
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives | Select sites will participate in a musculoskeletal sub-study to undergo musculoskeletal imaging
assessments at the time points indicated in Section 3.3. A musculoskeletal MRI will be
performed to evaluate the structure and function of skeletal muscles as well as lean body mass.
A subset of subjects will have a muscle biopsy performed at Week 12.
The biopsy will be of the biceps muscle, preferably on the left arm. If the biceps muscle is not viable, prior approval from the Sponsor is required for using an alternate muscle of the upper extremity.
A subset of parents/caregivers will be invited to participate in a qualitative interview sub-study
which will involve a pre-interview questionnaire and a 60-minute telephone interview after the
Part 1 Week 72 (or early termination from Part 1) visit to provide a better understanding of
individuals’ experiences with DMD and the study drug and identify potential improvements with
the study drug. Participants must be willing and able to participate in qualitative semi-structured
interviews. The interviews will be conducted by trained interviewers from RTI Health Solutions
or their qualitative research partner following a semi structured interview guide | |
| E.3 | Principal inclusion criteria | A subject must meet the following criteria to be eligible to participate in this study:
1. Is male at birth and has a definitive diagnosis of DMD prior to Screening based on documentation of clinical findings and prior confirmatory genetic testing using a clinical diagnostic genetic test. Genetic report must describe a frameshift deletion, frameshift duplication, premature stop (“nonsense”), canonical splice mutation, or other pathogenic variant in the DMD gene fully contained between exons 18 to 79 (inclusive) that is expected to lead to complete absence of dystrophin protein.
• Mutations fully or partially contained within exons 1-17 (inclusive) are not eligible.
2. Cohort 1 only (non-ambulatory):
a. Has been non-ambulatory for a minimum of 6 months with onset of non-ambulatory status defined as participant- or caregiver-reported age at continuous wheelchair use, approximated to the nearest month, with an NSAA walk score of "0" and inability to perform the 10MWR at the Screening visit.
b. Has a PUL entry item score ≥ 2 at the Screening visit.
c. Has a total PUL score of ≥ 20 and ≤ 40 at the Screening visit.
3. Cohort 2 only (ambulatory ≥ 8 years to < 18 years of age):
a. ≥ 8 to < 18 years of age at the time of Screening.
b. Has a PUL entry item score > 3 and < 6 at the Screening visit.
c. Has a total PUL score of ≥ 20 and ≤ 40 at the Screening visit.
d. Has an NSAA score ≥ 12 and ≤ 26 at the Screening visit.
4. Able to cooperate with motor assessment testing.
5. Has been on a stable dose of oral corticosteroids for at least 12 weeks before Screening and the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study. Note that no use of corticosteroids is considered a stable dose (ie, 0 mg).
6. Has rAAVrh74 antibody titers < 1:400 (ie, not elevated) as determined by an ELISA.
7. Subjects who are sexually active must agree to use, for the entire duration of the study, a condom and the female sexual partner must also use a medically acceptable form of birth control (eg, oral contraceptive). Refer to Appendix 1 for guidance on highly effective contraceptive methods.
8. Has (a) parent(s) or legal caregiver(s) or is a subject who is ≥ 18 years of age who is (are) able to understand and comply with the study visit schedule and all other protocol requirements.
9. Is willing to provide informed assent or consent (if applicable) and has (a) parent(s) or legal guardian(s) or is a subject ≥18 years of age who is (are) willing to provide informed consent for the subject to participate in the study.
| |
| E.4 | Principal exclusion criteria | A subject who meets any of the following criteria will be excluded from this study:
1. Has left ventricular ejection fraction < 40% on the Screening ECHO or clinical signs and/or symptoms of cardiomyopathy.
2. Forced vital capacity < 40% of predicted value at Screening.
3. Major surgery within 3 months prior to Day 1 or planned surgery or procedure that would interfere with the conduct of the study for any time during this study.
4. Presence of any other clinically significant illness, including cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or infection or malignancy or concomitant illness or requirement for chronic drug treatment that in the opinion of the Investigator creates unnecessary risks for gene transfer therapy or a medical condition or extenuating circumstance that, in the opinion of the Investigator, might compromise the subject’s ability to comply with the protocol required testing or procedures or compromise the subject’s wellbeing, safety, or clinical interpretability.
5. Has serological evidence of current, chronic, or active human immunodeficiency virus, hepatitis C, or hepatitis B infection.
6. Has a symptomatic infection (eg, upper respiratory tract infection, pneumonia, pyelonephritis, meningitis) within 4 weeks prior to Day 1.
7. Demonstrates cognitive delay or impairment that could confound motor development in the opinion of the Investigator.
8. Treatment with any of the following therapies according to the time frames specified:
• Any time:
− Gene therapy
− Cell based therapy (eg, stem cell transplantation)
− CRISPR/Cas9, or any other form of gene editing
• Within 12 weeks of Day 1 and anytime during the study:
− Use of human growth factor or vamorolone
• Within 6 months of Day 1 and anytime during the study:
− Any investigational medication
− Any treatment designed to increase dystrophin expression (eg, Translarna™, EXONDYS 51™, VILTEPSO™)
9. Has received a live virus vaccine within 4 weeks or inactive vaccine within 2 weeks of the Day 1 visit or expects to receive a vaccination during the first 3 months after Day 1.
10. Has abnormal laboratory values considered clinically significant including but not limited
to:
• Gamma-glutamyl transferase (GGT) > 2 × ULN
• Glutamate dehydrogenase (GLDH) >15 U/L
• Total bilirubin > ULN. Note that elevations in total bilirubin confirmed to be due toGilbert's syndrome are not exclusionary.
• White blood cell count > 18,500 per µL
• Platelets ≤ 150,000 per µL
11. Has a known hypersensitivity to SRP-9001 or its excipients
12. Subject or family does not want to disclose subject’s study participation with general practitioner/primary care physician and other medical providers.
13. In the opinion of the Investigator, the subject is not likely to be compliant with the study protocol.
| |
| E.5 End points |
| E.5.1 | Primary end point(s) | Change in PUL (V2.0) total score
| |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | From Baseline to Week 72 (Part 1) | |
| E.5.2 | Secondary end point(s) | •Change in PEF% predicted from Baseline to Week 72 (Part 1)
•Change in FVC% predicted from Baseline to Week 72 (Part 1)
•The quantity of micro-dystrophin protein expression at Week 12 (Part 1) as measured by western blot
•Change in PROMIS score per domain from Baseline to 72 weeks (Part 1)
For Cohort 2 only •Change in the NSAA score from Baseline to
Week 72 (Part 1) and Week 52 (Part 2)
•Incidence of treatment-emergent adverse events (TEAEs)
•Incidence of adverse events of special interest (AESIs)
•Clinically significant changes in vital signs and physical examination findings
•Incidence of serious adverse events (SAEs)
•Clinically significant changes in safety laboratory assessments, electrocardiograms (ECGs), echocardiograms (ECHOs)
•Change in global circumferential strain from baseline to Week 72 (Part 1). | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | •Change in PEF% predicted from Baseline to Week 72 (Part 1)
•Change in FVC% predicted from Baseline to Week 72 (Part 1)
•Quantity of micro-dystrophin protein expression at Week 12 (Part 1) as measured by western blot
•Change in PROMIS score per domain from Baseline to 72 weeks (Part 1)
For Cohort 2 only •Change in the NSAA score from Baseline to Week 72 (Part 1)
•Incidence of treatment-emergent adverse events
•Incidence of adverse events of special interest
•Clinically significant changes in vital signs and physical examination findings
•Incidence of serious adverse events
•Clinically significant changes in safety laboratory assessments, electrocardiograms (ECGs), echocardiograms (ECHOs)
•Change in global circumferential strain from baseline to Week 72 (Part 1). | |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Australia | | Israel | | Japan | | United Kingdom | | United States | | Belgium | | France | | Germany | | Italy | | Spain | | Sweden | |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
