Sarepta 4045-301

Principal Investigator: Russell Butterfield
Keywords: MDA , Duchenne , DMD , Clinical Trial , Exon 51 , Exon 53 , Skipping , Pediatrics Department: Pediatric Administration
IRB Number: 00083978 Co Investigator: Nicholas Johnson
Specialty: Neurology
Sub Specialties: Muscular Dystrophy
Recruitment Status: Recruiting

Contact Information

Brittney Holmberg
brittneyh@genetics.utah.edu
801-585-9055

Brief Summary

The primary objective of this study is to evaluate the effect of SRP-4045 and SRP-4053 (combined-active group) compared to
placebo on ambulation, endurance and muscle function at week 96, as measured by the 6-Minute Walk Test (6MWT).
Secondary Objectives

The secondary objectives are to evaluate the effect of SRP-4045 and SRP-4053 (combined-active group) on:

  • Dystrophin protein expression in biopsied muscle tissue as measured by:
  • Western blot (quantification)
  • Immunohistochemistry (IHC) fiber intensity
  • 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
  • Frequency of falls
  • Cardiac function, as measured by left ventricular ejection fraction (LVEF)
  • Safety and tolerability of SRP-4045 and SRP-4053.
Additional Efficacy Objectives:
-Characterize dystrophin protein expression in biopsied muscle tissues as measured by IHC (percent dystrophin-positive fibers)
-Evaluate the effect of SRP-4045 and SRP 4053 (combined active group) on endurance and muscle function, as measured by:
    -10-meter walk/run time (seconds) assessed by NSAA
    -Timed 4-step test
    -9-hole peg test
    -Performance of Upper Limb
  • Quantitative muscle testing (QMT) by hand -held myometry/dynamometry at all Hub Sites, and maximum voluntary isometric contraction testing (MVICT) at a subset of Hub Sites with MVICT capabilities.
  • Evaluate the effect of SRP-4045 and SRP-4053 (combined-active group) on respiratory muscle function, as measured by percent predicted maximal inspiratory pressure (MIP%p) and percent predicted maximal expiratory pressure (MEP%p). 
  • Evaluate the effect of SRP-4045 and SRP-4053 (combined-active group) on patient quality of life (QoL) as measured by Pediatric Outcomes Data Collection Instrument (PODCI).
  • Evaluate the psychometric characteristics of 2 DMD-specific instruments evaluating physical functioning as well as the effect of SRP-4045 and SRP-4053 on physical functioning as measured by these instruments.
 
Open-Label Study Period Objectives of the OL study period:
  1. Evaluate the long-term effects of SRP-4045 and SRP-4053 treatment on functional status up to 192 weeks.
  2. Evaluate the long-term safety and tolerability of SRP-4045 and SRP-4053.
  3. Evaluate the psychometric characteristics of 2 DMD-specific instruments evaluating physical functioning as well as the effect of SRP-4045 and SRP-4053 on physical functioning as measured these instruments. 
 
Pharmacokinetic Objective:
The PK objective is to evaluate the PK properties of SRP-4045 and SRP-4053 using a population PK model.

Inclusion Criteria

Inclusion Criteria:
A patient must meet all of the following criteria to be eligible for this study.
  1. Is a male with DMD and has an out-of-frame deletion that may be corrected by one of the following criteria:
    1. Exon 45 skipping (e.g., deletions of exons such as 12-44, 18-44, 44, 46-47, 46-48, 46-49, 46-51, 46-53, or 46-55) OR 
    2. Exon 53 skipping (e.g., deletions of exons such as 42-52, 45-52, 47-52, 48-52, 49-52, 50-52, 52, or 54-58) as documented by a genetic report from an accredited laboratory confirming deletion endpoints by multiplex ligation-dependent probe amplification or sequencing.
  2.  Is 7 to 13 years of age, inclusive, at randomization
  3. Has stable pulmonary function (forced vital capacity % of predicted [FVC %] ≥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 bicep muscles (preferred biopsy site) or two 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 (except for modifications to accommodate
changes in weight) throughout the study.
6. If taking angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocking agents (ARBs), β adrenergic blockers, potassium, and coenzyme Q, provided they have been on a stable dose for 12 weeks prior to Week 1 and the dose is expected to remain constant throughout the study. (except for modifications to accomodate 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 (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.

Exclusion Criteria

Exclusion Criteria
A patient who meets any of the following criteria will be excluded from this study.
  1. Treatment with any of the following investigational therapies according to the time frames specified:
  • At any time:
  • Utrophin upregulating agents (eg, ezutromid [SMT C1100] or other)
  • Anti-myostatin agents (eg, BMS-986089, domagrazumab [PF-062552616] or other)
  • CRISPR/Cas9, or any other form of gene editing
  • Gene therapy
  • Cell-based therapy (eg, stem cell transplantation)
  • Any form of nucleic acid antisense therapy, except PRO045 (BMN 045) or PRO053 (BMN 053) (see below)
    • Within 24 weeks prior to Week 1:
      o PRO045 (BMN 045)
      o PRO053 (BMN 053)
      o 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)
      o Mast cell activation inhibitor (eg, CRD007 [pemirolast sodium])
      o Idebenone (Raxone®)
      • Within 12 weeks prior to Week 1:
        o 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
    • o 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:
    • o Statins
    • o Aminoglycoside antibiotic

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 (eg, 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 on the Screening and
Baseline 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.