A research study to compare different doses of a new investigational medicinal product for treatment of certain patients with Duchenne muscular dystrophy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sarepta Therapeutics Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

9 Dec 2021 → ongoing

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Sarepta Therapeutics, Inc.

External identifiers

EU CT number

2024-511492-15-00

EudraCT number

2018-001762-42

ClinicalTrials.gov

NCT03992430

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacodynamic, Others, Efficacy, Dose response, Pharmacokinetic

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 and Dose Comparison Part:
• To investigate the effect of high doses of eteplirsen (100 mg/kg and 200 mg/kg) as compared with 30 mg/kg, administered weekly IV, on motor function in ambulant DMD patients with confirmed deletion genotypes amenable to Exon 51 skipping
• To evaluate higher doses of eteplirsen (100mg/kg and 200 mg/kg) for dose comparison

Secondary objectives 1

1. Double-Blind Dose Finding and Dose Comparison Part : • To evaluate the effect of high doses as compared with 30 mg/kg of eteplirsen, administered weekly IV, on o Ambulatory performance o Pulmonary function o Dystrophin expression • To evaluate the PK and PD of doses (100mg/kg and 200mg/kg) higher than 30 mg/kg of eteplirsen • To evaluate safety and tolerability of doses (100mg/kg and 200mg/kg) higher than 30 mg/kg of eteplirsen administered weekly IV

Conditions and MedDRA coding

Duchenne Muscular Dystrophy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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 4 to 13 years, inclusive 3. Ambulatory patient, able to perform TTRISE in 10 seconds or less at the time of screening visit. 4. Able to walk independently without assistive devices. 5. Has 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 (for patients in the double-blind part of the study). 6. Has been on a stable dose or dose equivalent of oral corticosteroids for at least 12 weeks prior to randomization, and the dose is expected to remain constant (except for modifications to accommodate changes in weight and stress-related needs as per the recently published guidelines [Birnkrant 2018, Kinnett 2017]) throughout the study). 7. For ages 7 years and older, has 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. For ages 4 to 6 years , does not require support from ventilator or non- invasive ventilation at time of screening. 8. 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. 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; intra-uterine hormone-releasing system; bilateral tubal occlusion; vasectomized partner; sexual abstinence (True abstinence: When this is in line with the preferred and usual lifestyle of the patient. 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 informed consent for the patient to participate in the study.

Exclusion criteria 1

1. 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 physician 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; except the following: Ezutromid administered at least 12 weeks prior to first dose. Drisapersen administered at least 36 weeks prior to first dose. Suvodirsen administered at least 12 weeks prior to first dose. Vamorolone administered at least 12 weeks prior to first dose. Eteplirsen (previous or current use) Tamoxifen administered at least 4 weeks prior to first dose. 3. 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. 4. Presence of any significant neuromuscular or genetic disease other than DMD (eg, dwarfism). 5. Gamma-glutamyl transpeptidase (GGT) > 3 × the upper limit of normal (ULN) or serum bilirubin > ULN unexplained by Gilbert's Syndrome. 6. Any known impairment of renal function (eg, estimated glomerular filtration rate [eGFR] ≤ 60 mL/min as assessed by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] cystatin C based equation [Inker, 2012, Filler 2012]), or dipstick protein result +2, or persistent and unexplained dipstick protein result +1 7. Platelet count < the lower limit of normal. 8. Presence of other clinically significant illness including significant cardiac, pulmonary, hepatic, renal, hematologic, immunologic, or behavioral disease or malignancy. 9. Has evidence of cardiomyopathy, as defined by left ventricular ejection fraction <50% on the screening ECHO or the Fridericia's correction formula (QTcF) ≥450 milliseconds based on the screening ECGs. 10. 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. 11. Known hypersensitivity to eteplirsen or any excipients of eteplirsen. 12. Is, in the Investigator's opinion, unable or unwilling to comply with the study procedures.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Open-Label Dose Escalation: Incidence of AEs, Incidence of adverse events of special interest (AESIs), Abnormal changes from Baseline or worsening of vitals or physical examination findings, Incidence of SAEs, Safety laboratory assessments, Electrocardiograms (ECGs) and Echocardiograms (ECHO).
2. Double-Blind Dose Finding and Dose Comparison Part: -Change from Baseline at Week 72 or Week 96 in NSAA total score (for conditional efficacy interim analysis) -Change from Baseline at Week 144 in NSAA total score (for final analysis)

Secondary endpoints 6

1. • Change from Baseline at Week 144 in o Time to rise (TTRISE) from floor o 10-meter walk/run time o 6-minute walk test (6MWT) o Timed 4-step stair ascend test o Forced vital capacity percent predicted (FVC%p)
2. • Time to Loss of Ambulation (LOA) through Week 144
3. • Change from Baseline at Week 24, Week 48, or Week 144 in skeletal muscle dystrophin expression by: o Western blot (quantitation) o Immunohistochemistry (IHC) fiber intensity by Immunofluorescence o Exon skipping quantitation by droplet digital polymerase chain reaction (ddPCR) o Percent dystrophin-positive fibers (PDPF) by Immunofluorescence
4. PK parameters (plasma and muscle biopsy)
5. • Incidence of AEs • Incidence of AESIs • Incidence of SAEs • Safety laboratory assessments
6. • ECGs • ECHO • Abnormal changes from Baseline or worsening of vital signs and physical examination findings

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sarepta Therapeutics Inc.

Sponsor organisation

Sarepta Therapeutics Inc.

Address

215 1st Street

City

Cambridge

Postcode

02142-1213

Country

United States

Scientific contact point

Organisation

Sarepta Therapeutics Inc.

Contact name

Patient Recruitment

Public contact point

Organisation

Sarepta Therapeutics Inc.

Contact name

Patient Recruitment

Third parties 30

Locations

13 EU/EEA countries · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 157 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

20 submissions — initial application plus substantial / non-substantial modifications