Trial Readiness and Endpoint Assessment in Congenital and Childhood Myotonic Dystrophy (GUP19002)

Children with congenital myotonic dystrophy (CDM) present at birth with respiratory insufficiency, talipes equinovarus, feeding difficulties and hypotonia. There is a 30% mortality rate in the first year of life. Children with childhood onset myotonic dystrophy present with symptoms later on but soon develop behavioural difficulties and learning difficulties and are at risk for autistic features and gastrointestinal symptoms. The ability to conduct a therapeutic trial in children with CDM or ChDM is directly limited by the lack of available data regarding appropriate clinical endpoints and biomarkers. Whereas there is an active Italian collaboration recruiting adults with DM1 to study muscle and multisystem aspects in this population, there is no active network in Italy involved in the pediatric population with DM1. Though the underlying mechanism is the same in adult DM1, in CDM and ChDM there are specific challenges to the pediatric population. The aim of this project is to coordinate the Italian Child Neurologist actively involved with CDM and ChDM in a common effort of standardizing protocols and procedures to be applied in the care of these patients. Specific aims are to collect functional measures and clinical information over time to define clinically meaningful endpoints and outcome measures in preparation for international therapeutic clinical trials. This project will contribute to the ongoing international study in CDM by recruiting additional patients from all over Italy and will extend the investigations to the childhood onset forms as an additional add-on pilot study in view of potential treatment options. The investigators expect that the Italian network, with Telethon support, will provide the necessary backbone for trial readiness in the pediatric population both at the national and international levels.

Study Overview

• Status: Completed
• Conditions: CDM; ChDM

Detailed Description

observational prospective study

• Study Type: Observational
• Enrollment (Actual): 70

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20162
    • Fondazione Serena Onlus - Centro Clinico NeMO Milano

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Please refer to the inclusion and exclusion criteria.

Description

Inclusion criteria, CDM group:

1. Age 0-17 years, 11 months of age
2. A diagnosis of CDM, which is 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).

Inclusion criteria, ChDM group:

1. Age 0-17 years, 11 months of age
2. A diagnosis of ChDM, which is defined as children having symptoms of myotonic dystrophy after day 30 from birth. These may include any delay in psychomotor development, attention deficit disorder, behavioral abnormalities within the spectrum of autistic spectrum disorders, gastrointestinal dysfunction such as persistent constipation or diarrhea and gastroesophageal reflux; 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.

Exclusion criteria, CDM and ChDM groups:

1. Any other non-DM1 illness that would interfere with the ability or results of the study in the opinion of the site investigator
2. Significant trauma within one month
3. Internal metal or devices (exclusion for DEXA component)
4. Unable to walk more than 50 feet if over the age of 3.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Congenital Myotonic Dystrophy (CDM); CDM group: Age 0-17 years, 11 months of age; A diagnosis of CDM, which is 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).
Childhood Muscular Dystrophy (ChDM); ChDM group: Age 0-17 years, 11 months of age; A diagnosis of ChDM, which is defined as children having symptoms of myotonic dystrophy after day 30 from birth. These may include any delay in psychomotor development, attention deficit disorder, behavioral abnormalities within the spectrum of autistic spectrum disorders, gastrointestinal dysfunction such as persistent constipation or diarrhea and gastroesophageal reflux; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Physical function	Measures of right grip strength using hand-held myometry	From Baseline (T0) to Days 1080
Physical function	Oral facial strength as measured by lip-force meter	From Baseline (T0) to Days 1080
Cognitive-behavioral and Quality of Life	Total score and subscores from the CCMDHI	From Baseline (T0) to Days 1080
Cognitive-behavioral and Quality of Life	BRIEF total scores	From Baseline (T0) to Days 1080
Biomarkers	Muscle RNA splicing changes	From Baseline (T0) to Days 1080
Biomarkers	Lean muscle mass	From Baseline (T0) to Days 1080

Collaborators and Investigators

• Sponsor: Fondazione Serena Onlus - Centro Clinico NeMO Milano
• Collaborators: Azienda Ospedaliera Città della Salute e della Scienza di Torino; Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Bambino Gesù Hospital and Research Institute; Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta; Istituto Giannina Gaslini; IRCCS Fondazione Stella Maris; IRCCS Istituto Neurologico Mondino, Pavia, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna

Study record dates

Study Major Dates

• Study Start (Actual): July 8, 2020
• Primary Completion (Actual): April 1, 2024
• Study Completion (Actual): April 1, 2024

Study Registration Dates

• First Submitted: January 15, 2024
• First Submitted That Met QC Criteria: February 21, 2024
• First Posted (Actual): February 23, 2024

Study Record Updates

• Last Update Posted (Actual): July 5, 2024
• Last Update Submitted That Met QC Criteria: July 3, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: congenital myotonic dystrophy; childhood myotonic dystrophy
• Additional Relevant MeSH Terms: Nervous System Diseases; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Muscular Disorders, Atrophic; Heredodegenerative Disorders, Nervous System; Muscular Dystrophies; Myotonic Disorders; Myotonic Dystrophy
• Other Study ID Numbers: NM040-GUP19002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED