| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Duchenne Muscular Dystrophy Amenable to Exon 45 or 53 Skipping |
|
| 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 | 20.0 |
| 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 |
| Double-blind period: Evaluate the effect of SRP-4045 and SRP-4053 (combined-active group) compared to placebo on ambulation, endurance, and muscle function, as measured by the 6MWT |
|
| E.2.2 | Secondary objectives of the trial |
-Double-blind period:
Evaluate the effect of SRP-4045 and SRP-4053 (combined-active group) on:
1) Dystrophin protein expression in biopsied muscle tissue as measured by:
•Western blot (quantification)
•Immunohistochemistry (IHC) fiber intensity
2) Functional status as measured by:
•Ability to rise independently from the floor (without external support)
•Loss of ambulation (LOA)
•North Star Ambulatory Assessment (NSAA)
•Respiratory muscle function as measured by forced vital capacity (FVC)% predicted
3) Safety and tolerability of SRP-4045 and SRP-4053
-Open-label period:
4) Evaluate the long-term effects of SRP-4045 and SRP-4053 treatment on functional status up to 144 weeks
5) Evaluate the long-term safety and tolerability of SRP-4045 and SRP-4053
-Pharmacokinetics:
6) Evaluate the PK properties of SRP-4045 and SRP-4053 via a population PK model |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is a male with an established clinical diagnosis of DMD and an out-of-frame deletion amenable to:
● Exon 45 skipping (including but not limited to deletions of exons such as 12-44, 18-44, 44, 46-47, 46-48, 46-49, 46-51, 46-53, or 46-55) OR
● Exon 53 skipping (including but not limited to deletions of exons such as 42-52, 45-52, 47-52, 48-52,49-52, 50-52, 52, or 54-58) as documented as prior to screening by a genetic report from an accredited laboratory defining deletion endpoints by multiplex ligation-dependent probe amplification or sequencing. The patient's amenability to exon 45 or exon 53 skipping must be confirmed prior to first dose using the genotyping results obtained during Screening.
2. Is between 6 and 13 years of age, inclusive, at randomization for patients amenable to exon 53 skipping; or is between 7 and 13 years of age, inclusive, at randomization for patients amenable to exon 45 skipping.
3. Has stable pulmonary function (FVC % of predicted ≥50% and no requirement for nocturnal ventilation) that, in the Investigator’s opinion, is unlikely to decompensate over the duration of the study.
4. Has intact right and left biceps brachii muscles (the preferred biopsy site) or 2 alternative upper arm muscle groups.
5. Has been on a stable dose or dose equivalent of oral corticosteroids for at least 24 weeks prior to Week 1 and the dose is expected to remain constant throughout the study(except for modifications to accommodate changes in weight).
6. If taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), β adrenergic blockers, aldosterone receptor antagonists, potassium or coenzyme Q, has been on a stable dose for at least 12 weeks prior to Week 1 and the dose is expected to remain constant throughout the study (except for modifications to accommodate changes in weight).
7. Achieved a mean 6MWT distance of ≥300 to ≤450 meters (without assistance) at both the Screening and Baseline visits (prior to Week 1). The mean 6MWT distance at the Screening and Baseline visits is the average of 2 separate assessments on 2 consecutive days at each visit. The Baseline mean (average of Baseline Days 1 and 2) must be within 15% of the Screening mean distance (average of Screening Days 1 and 2).
8. If sexually active, agrees to use a male condom during such activity for the entire duration of the study and for 90 days after the last dose. The sexual partner must also use a medically acceptable form of contraceptive (e.g., female oral contraceptives) during this time frame. Acceptable methods of contraception include combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal); progesterone -only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion, vasectomized partner; sexual abstinence (True abstinence: when this is in line with thepreferred and usual lifestyle of the subject. Periodic abstinence: such as calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception); or condom in combination with either cap, diaphragm, or sponge with spermicide (double-barrier contraception).
9. Has (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the study requirements.
10. Is willing to provide informed assent (if applicable) and has (a) parent(s) or legal guardian(s) who is (are) willing to provide written informed consent for the patient to participate in the study. |
|
| E.4 | Principal exclusion criteria |
1. Treatment with any of the following investigational therapies according to the time frames specified:
● At any time:
- Utrophin upregulating agents (except for Ezutromid)
- CRISPR/Cas9, or any other form of gene editing
- Gene therapy
- Cell-based therapy (e.g., stem cell transplantation)
- Any form of nucleic acid antisense therapy, except PRO045 (BMN 045) or PRO053 (BMN 053) (see below)
- Exon Skipping Therapies
- Drisapersen within 36 weeks prior to Week 1
- PRO045 (BMN 045) Within 24 weeks prior to Week 1
- PRO053 (BMN 053) Within 24 weeks prior to Week 1
- PRO051 (BMN 051) Within 24 weeks prior to Week 1
● All Anti-Myostatin Therapies within 24 Weeks prior to Week 1 including but not limited to:
- Domagrozumab (PF-06252616)
- RG-6206 (formally RO-7239361 and BMS-986089)
● Small Molecule Therapies:
- Ezutromid (SMT C1100) within 1 week prior to Week 1
● Within 24 weeks prior to Week 1:
- Anti-fibrotic or anti-inflammatory agents including but not limited to: rimeporide, epigallocatechin-gallate, TAS-205, edasalonexent (CAT-1004), FG-3019, and halofuginone (HT-100)
- Mast cell activation inhibitor (e.g., CRD007 [pemirolast sodium])
- Idebenone (Raxone®)
● Within 12 weeks prior to Week 1:
- Nitric oxide -active agents including, but not limited to, metformin and citrulline, isosorbide dinitrate, tadalafil, sildenafil, pentoxifylline if taken as part of a DMD clinical trial and not for a medical indication. If taken for a medical indication, must be on a stable dose for at least 12 weeks prior to Week 1.
- Vamorolone (VBP-15)
● For any experimental treatment not otherwise specified in Exclusion Criterion 1, consult the medical monitor.
2. Treatment with any of the following non-investigational therapies according to the time frames specified:
● Within 12 weeks prior to Week 1:
- Any pharmacologic treatment (other than corticosteroids) that may have an effect on muscle strength or function. Growth hormone for short stature and testosterone for delayed puberty are permitted if a physician has documented the diagnosis and medical necessity of treatment, and the patient started dosing at least 24 weeks prior to Week 1.
● Within 12 weeks prior to Week 1 or anticipated need during the study:
- Statins
- Aminoglycoside antibiotics
3. Major surgery within 3 months prior to Week 1 or planned surgery for any time during this study, except for protocol-specified surgery, as applicable.
4. Presence of any other significant genetic disease other than DMD (e.g., dwarfism).
5. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease, or malignancy.
6. LVEF <50% on the Screening echocardiogram (ECHO) or QTcF ≥450 msec based on the Screening and Baseline electrocardiogram (ECG).
7. Dorsiflexion range of motion will be measured bilaterally and recorded as degrees from neutral (see figure). The subject will be excluded if the average loss of dorsiflexion of both extremities is > -10 degrees. For example, if the subject has -8 degrees on one side and -12 degrees on the other side, then he would still qualify because the average of the 2 sides is -10 degrees.
8. Prior or ongoing medical condition that could, in the Investigator's opinion, adversely affect the safety of the patient, make it unlikely that the course of treatment would be completed, or impair the assessment of study results. Additionally, patients who seem unable / unwilling to comply with the study procedures, in the Investigator's opinion, are to be excluded.
9. Known hypersensitivity to the study drug or to any of its components. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Double-blind period: Change from Baseline at Week 96 in 6MWT |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Screening, Baseline, Week 12, 24, 36, 48, 60, 72, 84, 96 |
|
| E.5.2 | Secondary end point(s) |
1) ●Change from Baseline at Weeks 48 or 96 in the quantity of dystrophin protein expression as measured by Western blot of biopsied muscle tissue
●Change from Baseline at Weeks 48 or 96 in the intensity of dystrophin expression in biopsied muscle tissue, as measured by IHC
2) ● Ability to rise independently from the floor (without external support) at Week 96, as indicated by an NSAA subscore of "2" (without modification) or "1" (Gower's maneuver)
● Time to LOA from randomization through Week 96
● Change from Baseline at Week 96 in:
- NSAA total score
- FVC% predicted
3) Review and evaluation of:
• AEs, SAEs, deaths, and discontinuations due to AEs
• Laboratory testing including hematology, coagulation, chemistry (including serum cystatin C), electrolytes (including magnesium), and urinalysis (including urinary kidney injury molecule-1 [KIM-1])
• Immunogenicity
• Electrocardiogram (ECG)
• Vital signs
• Physical examination findings
4) • Change from Baseline at Week 144 (Week 48 of the OL period) in 6MWT
• Ability to rise independently from the floor (without external support) at Week 144, as indicated by an NSAA subscore of "2" (without modification) or "1" (Gower's maneuver)
• Time to LOA from randomization through Week 144
• Change from Baseline at Week 144 in:
− NSAA total score
− FVC% predicted
5) Review and evaluation of:
• AEs, SAEs, deaths, and discontinuations due to AEs
• Laboratory testing including hematology, coagulation, chemistry (including serum cystatin C), electrolytes (including magnesium), and urinalysis (including urinary kidney injury molecule-1 [KIM-1])
• Immunogenicity
• Electrocardiogram (ECG)
• Vital signs
• Physical examination findings
6) Standard population PK parameters will be estimated by population PK analysis. The effects of potential covariates such as standard dosing, demographic characteristics, concomitant medications, laboratory values, and others on SRP-4045 and SRP-4053 PK will be evaluated |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
● Quantity of dystrophin protein expression: Baseline, weeks 48 or 96
● 6MWT: weeks 108, 120, 132 and 144
● Intensity of dystrophin expression: Baseline, weeks 48 or 96
● Ability to rise independently from the floor: Screening, Baseline, Week 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, and 144
● LOA status: Week 96 and Week 144
● NSAA total score and FVC% predicted: Week 96 and Week 144 |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Patients may participate in an open-label treatment extension period of up to 48 weeks |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| 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 |
| Argentina |
| Ukraine |
| Taiwan |
| Australia |
| Canada |
| Israel |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Serbia |
| United Kingdom |
| United States |
| Belgium |
| Bulgaria |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Netherlands |
| Poland |
| 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
|
- National end of trial: confirmation that enrollment is closed in the
country, or decision to close the site/country early, or last patient last
visit in the country, whichever is later
- Global end of trial: last patient last visit worldwide. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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