Trial Readiness and Endpoint Assessment in Pediatric Myotonic Dystrophy Extension

Trial Readiness and Endpoint Assessment in Pediatric Myotonic Dystrophy Extension

This is a natural history study to improve the types of assessments and biological samples that will be used in clinical drug trials in both congenital myotonic dystrophy and childhood myotonic dystrophy.

Congenital Myotonic Dystrophy (CDM) is a multi-systemic, dominantly inherited disorder caused by a trinucleotide repeat expansion (CTGn) in the DMPK gene. Children with CDM present at birth with respiratory insufficiency, talipes equiovarus, feeding difficulties and hypotonia. There is a 30% mortality rate in the first year of life. As children grow, they are at risk for intellectual impairment, autistic features, gastrointestinal symptoms, and motor delay. Childhood onset myotonic dystrophy (ChDM) is similarly multisystem and is classified as onset after birth but before 10 years of age. It likely represents a less severe form of CDM.

Currently, there is an ongoing therapeutic trial in adults with DM1 using an antisense oligonucleotide to target the destruction of the CTG repeat. The ability to conduct this trial in children is directly limited by the lack of available data regarding appropriate clinical endpoints and biomarkers. Although the underlying mechanism is the same in adult DM1 and CDM, there are specific challenges to directly transferring outcome measures into the CDM population. First, our cross-sectional data demonstrates age-related improvement in several functional outcome measures, such as the 6-minute walk. Second, in the adult DM1 clinical trial, RNA splicing changes in the tibialis anterior muscle are a primary endpoint because they correlate with functional measures. However, our pilot data with described splicing changes does not clearly correlate with the adult clinical phenotype.

This study is designed to establish valid and reliable clinical outcome assessments for children with congenital and childhood myotonic dystrophy, and to develop biomarkers for the condition.

This study will enroll up to 200 children with CDM and ChDM at participating sites. No treatment will be administered as part of this study. Patients will receive standard of care as determined by their treating physician. Study visits will occur at Baseline, Month 12, and Month 24.

Inclusion Criteria (Congenital Myotonic Dystrophy Group):

• Age 5-17 years, 11 months at enrollment. Lower age limit not applicable for participants who have completed ASPIRE-DM1 protocol. Upper age limit not applicable for participants who previously participated in TREAT-01-001 (TREAT-CDM) study
• A diagnosis of CDM, defined as: children having symptoms of myotonic dystrophy in the newborn period (<30 days), such as hypotonia, feeding or respiratory difficulty, requiring hospitalization to a ward or to the neonatal intensive care unit for more than 72 hours; and a genetic test confirming an expanded trinucleotide (CTG) repeat in the DMPK gene in the child or mother. An expanded CTG repeat size in the child is considered greater than 200 repeats or E1-E4 classification (E1= 200-500, E2=500-1,000, E3=1,000-1,500, E4>1,500).
• Written, voluntary informed consent must be obtained before any study related procedures are conducted.

Inclusion Criteria (Childhood Myotonic Dystrophy Group):

• Age 3-17 years, 11 months at enrollment. Upper age limit not applicable for participants who previously participated in TREAT-01-001 (TREAT-CDM) study.
• A diagnosis of ChDM, defined as: children having cognitive deficits, muscle weakness, myotonia that developed after age 1 and prior to age 10 and a genetic test confirming an expanded trinucleotide (CTG) repeat in the DMPK gene in the child or mother. An expanded CTG repeat size in the child is considered greater than 200 repeats or E1-E4 classification (E1= 200-500, E2=500-1,000, E3=1,000-1,500, E4>1,500).
• Written, voluntary informed consent must be obtained before any study related procedures are conducted.

Exclusion Criteria:

• Any other non-DM1 illness that would interfere with the ability to undergo safe testing or would affect the interpretation of the results, in the opinion of the site investigator
• Significant trauma within the past month
• Internal metal or devices (exclusion for DEXA component)
• Use of anticoagulants, such as warfarin or a direct oral anticoagulant (e.g., dabigatran) due to the increased risk of bleeding with biopsy
• Platelet count <50,000
• History of a bleeding disorder
• Participation in a clinical trial involving an investigational product
• History of adverse reaction to lidocaine (if participating in muscle biopsy)