A research study of a new investigational medicinal product for the treatment of Duchenne Muscular Dystrophy patients

• Register: EUCTR
• Last refreshed on: 10 August 2020
• Main ID: EUCTR2015-002069-52-NO
• Date of registration: 30/09/2019
• Prospective Registration: Yes
• Primary sponsor: Sarepta Therapeutics, Inc.
• Public title: A research study of a new investigational medicinal product for the treatment of Duchenne Muscular Dystrophy patients
• Scientific title: A Double-Blind, Placebo-Controlled, Multicenter Study With an Open-Label Extension to Evaluate the Efficacy and Safety of SRP-4045 and SRP-4053 in Patients With Duchenne Muscular Dystrophy - N/A
• Date of first enrolment: 07/04/2020
• Target sample size: 222
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002069-52
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: Patients may participate in an open-label treatment extension period of up to 48 weeks; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Bulgaria, Canada, Chile, Czech Republic, Denmark, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Norway, Poland, Portugal, Russian Federation, Serbia, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Clinical Trials
• Affiliation: Voisin Consulting

• Name: Clinical Trials
• Affiliation: Voisin Consulting

Key inclusion & exclusion criteria

Inclusion criteria:
1. Is a male with an established clinical diagnosis of DMD and an out-offrame 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 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 7 and 13 years of age, inclusive, at randomization.
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), ß 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 business 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 (eg, female oral contraceptives) during this time frame.
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.
Are the trial subjects under 18? yes
Number of subjects for this age range: 222
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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, vamorolone (VBP-15), 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 (NO)-active agents including, but not limited to, metformin and citrulline, isosorbide dinitrate, tadalafil, sildenafil, pentoxyfilline 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.
? 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

Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Patients with Duchenne Muscular Dystrophy Amenable to Exon 45 or 53 Skipping
MedDRA version: 20.0 Level: PT Classification code 10013801 Term: Duchenne muscular dystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Intervention(s)

Product Name: SRP-4045
Product Code: SRP-4045
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Not yet available
CAS Number: 1422958-19-7
Current Sponsor code: SRP-4045
Other descriptive name: Phosphorodiamidate morpholino oligomer for exon 45 skipping
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Product Name: SRP-4053
Product Code: SRP-4053
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Not yet available
CAS Number: 1422959-91-8
Current Sponsor code: SRP-4053
Other descriptive name: Phosphorodiamidate morpholino oligomer for exon 53 skipping
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

Main Objective: 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

Primary end point(s): Double-blind period: Change from Baseline at Week 96 in 6MWT

Secondary Objective: -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

Timepoint(s) of evaluation of this end point: Screening, Baseline, Week 12, 24, 36, 48, 60, 72, 84, 96

Secondary Outcome(s)

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

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), 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), 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

Secondary ID(s)

2015-002069-52-GB

4045-301

NCT02500381

Source(s) of Monetary Support

Sarepta Therapeutics, Inc.

Ethics review

Status: Not Approved
Approval date: 07/04/2020
Contact: