Duchenne Muscular Dystrophy MedDRA version: 20.1 Level: PT Classification code 10052655 Term: Duchenne muscular dystrophy gene carrier System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Trade Name: Exondys 51
Product Name: Eteplirsen
Product Code: AVI-4658
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: ETEPLIRSEN
CAS Number: 1173755-55-9
Current Spons
Sponsors
Sarepta Therapeutics, Inc.
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: A patient must meet all of the following criteria to be eligible to participate in this study. 1. Be a male with an established clinical diagnosis of DMD and an out-of-frame deletion mutation of the DMD gene amenable to exon 51 skipping (for example, deletions of exons 45-50, 47-50, 48-50, 49-50, 50, 52, and 52-63). 2. Be aged 7 to 13 years, inclusive 3. Have achieved a mean 6-minute walk test (6MWT) distance of =300 and =450 meters (without assistance) at both the screening and baseline visits for the double-blind. 4. Have intact right and left biceps muscles (the preferred biopsy site) or an alternative upper arm muscle group that will allow for sufficiently sized (1 cm3) muscle biopsies to be obtained prior to and on treatment. 5. Have been on a stable dose or dose equivalent of oral corticosteroids for at least 24 weeks prior to randomization, and the dose is expected to remain constant (except for modifications to accommodate changes in weight) throughout the study. 6. Have stable pulmonary function (forced vital capacity =50% of predicted and no requirement for nocturnal ventilation) that, in the Investigator’s opinion, is unlikely to decompensate significantly over the duration of the study. 7. If sexually active, agree 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 (ie, female oral contraceptives) during this timeframe. 8. Have (a) parent(s) or legal guardian(s) who is (are) able to understand and comply with all the study requirements. 9. 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: 152 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
Exclusion criteria: A patient who meets any of the following criteria will be excluded from this study: 1. Use of any pharmacologic treatment (other than corticosteroids) within 12 weeks prior to randomization that may have an effect on muscle strength or function. Growth hormone for short stature and testosterone for delayed puberty are permitted if an endocrinologist has documented the diagnosis and medical necessity of treatment and if the patient has been on a stable dose for at least 24 weeks prior to randomization. 2. Current or previous treatment with any other experimental pharmacologic treatment for DMD or any prior exposure to antisense oligonucleotide, gene therapy or gene editing; exceptions are listed in number 3 below. 3. Previous treatment with drisapersen, ezutromid, or domagrozumab in the last 24 weeks prior to study enrollment. 4. Major surgery within 3 months prior to randomization or planned surgery for any time during this study, except for allowed protocol-specified surgery, as applicable. 5. Presence of any other significant neuromuscular or genetic disease other than DMD (eg, dwarfism). 6. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease or malignancy. 7. Has evidence of cardiomyopathy, as defined by LVEF <50% on the screening ECHO or the Fridericia’s correction formula (QTcF) =450 milliseconds based on the screening ECGs. 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. 9. Is, in the Investigator’s opinion, unable or unwilling to comply with the study procedures.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Open-label Dose Escalation Evaluate the safety and tolerability of weekly IV doses of 100 and 200 mg/kg of eteplirsen. Double-blind Dose Finding: Evaluate the PK, PD (exon skipping quantitation), safety and tolerability of doses higher than 30 mg/kg of eteplirsen, to select a single higher dose of eteplirsen for Dose Comparison Double-blind Dose Comparison: Comparison of a selected high dose of eteplirsen with 30 mg/kg IV weekly To investigate the effect of a selected high dose of eteplirsen (100 mg/kg or 200 mg/kg) as compared with 30 mg/kg, administered weekly IV, on motor function in ambulant Duchenne muscular dystrophy (DMD) patients with confirmed deletion genotypes amenable to exon 51 skipping;Secondary Objective: Double-blind Dose Comparison: Comparison of a selected high dose of eteplirsen with 30 mg/kg IV weekly on: -Ambulatory performance -Pulmonary function -Dystrophin expression To evaluate safety and tolerability of a selected high dose as compared with 30 mg/kg of eteplirsen, administered weekly IV ;Primary end point(s): Open-label Dose Escalation Incidence of AEs, adverse events of special interest (AESIs) serious adverse events (SAEs), Safety laboratory assessments, ECGs and ECHO Double-blind Dose Finding Dystrophin expression in biopsied muscle tissue Plasma PK parameters of 30, 100, and 200 mg/kg of eteplirsen, administered IV weekly Incidence of AEs, AESIs and SAEs Abnormal changes from baseline or worsening of vitals or physical examination findings Safety laboratory assessments ECGs and ECHO Tissue concentration of eteplirsen from biopsied muscle tissue Dose Comparison Change from baseline at Week 144 in North Star Ambulatory Assessment (NSAA) total score;Timepoint(s) of evaluation of this end point: Open-label Dose Escalation At the completion of every 2-week treatment by 4 subjects at each dose level. Double-blind Dose Finding At baseline all patients undergo muscle biopsy pre-dose. One additional muscle biopsy at eith | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Change from baseline at Week 144 in o 6 MWT o 10 meter walk/run time o Timed 4 step stair ascend test o Time to rise from floor Annual decline rate in FVC % predicted Time to LOA Change from baseline at Week 48 (also at Week 12 if Dose Finding is not necessary, based on Dose Escalation, and Week 24 if dose selection is at Week 12) in skeletal muscle dystrophin expression by: o Western blot (quantitation) o IHC fiber intensity o Exon skipping quantitation by PCR IIncidence of AEs Incidence of AESIs Incidence of SAEs Safety laboratory assessments ECGs ECHO;Timepoint(s) of evaluation of this end point: Change from baseline at Week 144 Change from baseline at Week 48 (also at Week 12 if Dose Finding is not necessary, based on Dose Escalation, and Week 24 if dose selection is at Week 12) AE assessment at baseline and continuous throughout the study. ECG at screening, week 1, 4, 8, and 12, and every 12 weeks thereafter. ECHO at screening, week 48, 96, and 144. | — |
Countries
Argentina, Australia, Belgium, Canada, Chile, Colombia, Czech Republic, Denmark, France, Germany, Greece, Hong Kong, Hungary, Ireland, Italy, Korea, Republic of, Netherlands, New Zealand, Norway, Peru, Poland, Romania, Russian Federation, Slovenia, Spain, Sweden, Taiwan, Turkey, United Kingdom
Contacts
Public ContactCarolyn Mills
Syneos Health
Outcome results
None listed