Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients

• ClinicalTrials.gov Identifier: NCT01396239
• Recruitment Status: Completed
• First Posted: July 18, 2011
• Results First Posted: November 9, 2015
• Last Update Posted: March 30, 2020
• Sponsor: Sarepta Therapeutics, Inc.
• Information provided by (Responsible Party): Sarepta Therapeutics, Inc.

Tracking Information

• First Submitted Date: July 8, 2011
• First Posted Date: July 18, 2011
• Results First Submitted Date: July 2, 2013
• Results First Posted Date: November 9, 2015
• Last Update Posted Date: March 30, 2020
• Study Start Date: July 2011
• Actual Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 12, 2015)

Change in the Number (%) of Dystrophin Positive Fibers [ Time Frame: After 12 weeks for 4 patients who received 50 mg/kg and 2 patients who received placebo. After 24 weeks for 4 patients who received 30 mg/kg and 2 patients who received placebo. ]

The primary efficacy endpoint will be based on the pre-treatment and post-treatment change in the number (%) of dystrophin positive fibers as measured in the muscle biopsy tissue on immunohistochemistry (IHC).

Original Primary Outcome Measures (submitted: July 15, 2011)

Dystrophin positive fibers as measured in the muscle biopsy tissue on IHC [ Time Frame: 24 weeks ]

The primary efficacy endpoint will be based on the pre-treatment and post-treatment percent of dystrophin positive fibers as measure in the muscle biopsy tissue on IHC.

Current Secondary Outcome Measures (submitted: October 12, 2015)

• Change From Baseline: 6 Minute Walk Test (6MWT) - Intent to Treat Population (ITT) [ Time Frame: 24 weeks ]
  A key secondary efficacy endpoint will be based on the pre-treatment and post-treatment Change from baseline: 6 Minute Walk Test (6MWT) - Intent to Treat population (ITT)
• Change From Baseline: 6 Minute Walk Test (6MWT) - Modified Intent to Treat Population (mITT) [ Time Frame: 24 weeks ]
  A key secondary efficacy endpoint will be based on the pre-treatment and post-treatment of the 6-MWT distance. Change from baseline: 6 Minute Walk Test (6MWT) - modified Intent-to-Treat population (mITT).

Original Secondary Outcome Measures (submitted: July 15, 2011)

Key secondary: CD3, CD4, and CD8 lymphocyte counts as measured in the muscle biopsy tissue [ Time Frame: 24 weeks ]

A key secondary efficacy endpoint will be based on the pre-treatment and post-treatment CD3, CD4, and CD8 lymphocyte counts as measured in the muscle biopsy tissue.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy Study of AVI-4658 to Induce Dystrophin Expression in Selected Duchenne Muscular Dystrophy Patients
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Efficacy, Safety, Tolerability and Pharmacokinetics Study of AVI-4658(Eteplirsen),in the Treatment of Ambulant Subjects With Duchenne Muscular Dystrophy
• Brief Summary: This study is designed to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of AVI-4658 (eteplirsen) in both 50.0 mg/kg and 30.0 mg/kg doses administered over 24 weeks in subjects diagnosed with Duchenne muscular dystrophy (DMD).
• Detailed Description: For details regarding the roll-over extension study 4658-us-202, please refer to NCT01540409.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Duchenne Muscular Dystrophy

Intervention

• Drug: AVI-4658 (Eteplirsen)
  Treatment group 1 (n=4): 50.0 mg/kg eteplirsen once weekly x 24 weeks via a 60-minute i.v. infusion Treatment group 2 (n=4): 30.0 mg/kg eteplirsen once weekly x 24 weeks via a 60-minute i.v. infusion Treatment group 3 (n=4): matching placebo once weekly x 24 weeks via a 60-minute i.v. infusion; treatment group 3a will match two placebo subjects to 50.0 mg/kg eteplirsen; treatment group 3b will match two placebo subjects to 30.0 mg/kg eteplirsen
  Other Name: Eteplirsen- Phosphorodiamidate Morphilino Oligomer
• Other: Placebo
  sterile, isotonic, clear, colorless phosphate buffered saline solution of eteplirsen at a concentration of 100 mg/mL in single-use vials containing a nominal volume of 1.0 mL without preservatives.
  Other Name: Phosphate buffered saline

Study Arms

• Experimental: AVI-4658 (Eteplirsen)
  1. 50 mg/kg eteplirsen for 28 weeks
  2. 30 mg/kg eteplirsen for 28 weeks
  Intervention: Drug: AVI-4658 (Eteplirsen)
• Placebo Comparator: Placebo / Delayed Treatment

  3a. Placebo 50 mg/kg phosphate buffered saline solution identical in appearance to eteplirsen for 24 weeks followed by 50 mg/kg of eteplirsen for 4 weeks.

  3b. Placebo 30 mg/kg phosphate buffered saline solution identical in appearance to eteplirsen for 24 weeks followed by 30 mg/kg of eteplirsen for 4 weeks.

  Intervention: Other: Placebo

Publications *

• Mendell JR, Goemans N, Lowes LP, Alfano LN, Berry K, Shao J, Kaye EM, Mercuri E; Eteplirsen Study Group and Telethon Foundation DMD Italian Network. Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy. Ann Neurol. 2016 Feb;79(2):257-71. doi: 10.1002/ana.24555. Epub 2016 Jan 8.
• Mendell JR, Rodino-Klapac LR, Sahenk Z, Roush K, Bird L, Lowes LP, Alfano L, Gomez AM, Lewis S, Kota J, Malik V, Shontz K, Walker CM, Flanigan KM, Corridore M, Kean JR, Allen HD, Shilling C, Melia KR, Sazani P, Saoud JB, Kaye EM; Eteplirsen Study Group. Eteplirsen for the treatment of Duchenne muscular dystrophy. Ann Neurol. 2013 Nov;74(5):637-47. doi: 10.1002/ana.23982. Epub 2013 Sep 10.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 15, 2011): 12
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: June 2012
• Actual Primary Completion Date: February 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Major Inclusion and Exclusion Criteria:

Inclusion Criteria:

A subject must meet all of the following criteria to be eligible for this study.

• Be a male with DMD and have an out-of-frame deletion(s) that may be corrected by skipping exon 51 [e.g., deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63], as confirmed in a Clinical Laboratory Improvement Act-accredited laboratory by any of the peer-reviewed and published methodology that evaluates all exons (including, but not limited to, multiplex ligation-dependent probe, comparative genomic hybridization, and single condition amplification/internal primer analysis).
• Be between the ages of 7 and 13 years, inclusive.
• Have stable cardiac function and stable pulmonary function (forced vital capacity [FVC] ≥50% of predicted and not require supplemental oxygen) that, in the Investigator's opinion, is unlikely to decompensate over the duration of the study.
• Be receiving treatment with oral corticosteroids and have been on a stable dose for at least 24 weeks before study entry. Subjects may be allowed to take other (non-RNA antisense or gene therapy) medication (including angiotensin-converting enzyme [ACE] inhibitors, β blockers, losartan potassium, and coenzyme Q) as long as they have been on a stable dose of the medication for 24 weeks before the screening visit (Visit 1) and the dose will remain constant throughout the study.
• Have intact right and left biceps muscles or an alternative upper arm muscle group.
• Achieve an average distance within 200m and 400m ±10% (i.e. within 180m and 440m) while walking independently over six minutes.
• Have a left ventricular ejection fraction (LVEF) of >40% based on the ECHO that is obtained at the screening visit (Visit 1). A subject who has abnormal ECHO findings but who has an LVEF of >40% may be enrolled in the study at the Investigator's discretion; however, the subject must have been receiving stable doses of ACE inhibitors or β blockers for at least 24 weeks before study entry.
• Have a parent(s) or legal guardian(s) who is able to understand and comply with the all of the study procedure requirements.
• Be willing to provide informed assent and have a parent(s) or legal guardian(s) who is willing to provide written informed consent for the subject to participate in the study.

Exclusion Criteria:

A subject who meets any of the following criteria will be excluded from this study.

• Use of any pharmacologic treatment, other than corticosteroids, that might have an effect on muscle strength or function within 12 weeks before study entry (e.g., growth hormone, anabolic steroids).
• Previous treatment with the experimental agents eteplirsen, BMN-195, or PRO051.
• Previous treatment with any other experimental agents or participation in any other DMD interventional clinical study within 12 weeks before entry into this study; including use of the shock training system or "STS," or planned use during this study.
• Surgery within 3 months before study entry or planned surgery at any time during this study.
• Presence of other clinically significant illness at the time of study entry, including significant renal dysfunction (as measured by urinary cystatin C, KIM-1, or urinary total protein), or average heart rate during screening Holter monitoring in excess of 110 bpm (unless subsequently treated and confirmed controlled and stable on a β-blocker) or QTc >450 ms.
• Use of any aminoglycoside antibiotic within 12 weeks before the screening visit (Visit 1) or need for use of an aminoglycoside antibiotic during the study (unless discussed and agreed with the Principal Investigator and medical monitor).
• Prior or ongoing medical condition that, in the Investigator's opinion, could adversely affect the safety of the subject or that makes it unlikely that the course of treatment or follow-up would be completed or could impair the assessment of study results.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 7 Years to 13 Years (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01396239
• Other Study ID Numbers: 4658-us-201; 07-2484 ( Other Identifier: Office of Orphan Drug Development )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Sarepta Therapeutics, Inc.
• Study Sponsor: Sarepta Therapeutics, Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Sarepta Therapeutics, Inc.

• PRS Account: Sarepta Therapeutics, Inc.
• Verification Date: March 2020