Trial Readiness and Endpoint Assessment in Pediatric Myotonic Dystrophy Extension

Virginia Commonwealth University200 enrolled

Overview

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.

Study Type

OBSERVATIONAL

Enrollment

200

Conditions

Congenital Myotonic Dystrophy Childhood Myotonic Dystrophy Myotonic Dystrophy

Eligibility

Sex: ALLMin age: 3 YearsMax age: 17 Years

Medical Language ↔ Plain English

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)

Locations (1)

Virginia Commonwealth University

Richmond, Virginia, United States

RECRUITING

Outcomes

Primary Outcomes

Change in ambulation over 24 months as measured by the 10-Meter Walk/Run Test (10M WRT)

The participant will be timed walking or running along a 10-meter course. It is scored by recording the total time taken to ambulate 6 meters (m) is recorded to the nearest hundredth of a second. 6 m is then divided by the total time (in seconds) taken to ambulate and recorded in m/s.

Time frame: Baseline, Month 12 and Month 24 visits

Change in mobility (100-meter timed test)

Mobility will be measured using the 100 Meter Timed Test (100m) in which the participant is asked to complete 2 laps around 2 cones set 25 meters apart as quickly as safely possible, running if able. The total time in seconds is recorded from when the participant starts walking until they break the plane of the 100 meter mark (i.e., when any part of the body passes the 100 meter mark).

Time frame: Baseline, Month 12 and Month 24 visits

Change in Time to Stand (SUPINE TO STAND test)

Participant will be timed transitioning from a supine position to standing. The participant will complete one trial of this test. The test measures the participant's ability to quickly rise from a supine position on the floor with arms at their sides, to full upright posture with arms at their sides. This should be performed without external support from another person, a device, or furniture. Results will be reported in seconds.

Time frame: Baseline, Month 12 and Month 24 visits

Change in Gross Motor Function (GMFM-88)

The Gross Motor Function Measure (GMFM-88) is an assessment tool originally designed and evaluated to measure changes in gross motor function over time or with intervention in children with cerebral palsy. The GMFM assesses functional abilities including; lying/rolling, sitting, crawling/kneeling, standing, and walking/running/jumping. A four-point ordinal scale of measurement is used to assess each item, higher scores denote better performance. A score of 4 on an item indicates a consistently normal response, a score \> 4 indicates persistent hypertonus, and a score \< 4 indicates various degrees of hypotonus.

Central Contacts

Ruby Langeslay, MPH

CONTACT

804-828-6318 Ruby.Langeslay@vcuhealth.org

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Time frame: Baseline, Month 12 and Month 24 visits

Change in Handheld Dynamometry and Grip HAND-HELD DYNAMOMETRY (HHD)

Maximum hand and grip strength will be assessed using a myometer. The participant will be asked to squeeze a handheld tool. When performing a hand-held dynamometry (HHD) test, you generally want a high score as it indicates greater muscle strength in the tested area; a higher number signifies a stronger muscle contraction.

Time frame: Baseline, Month 12 and Month 24 visits

9-HOLE PEGBOARD TEST (9HPT)

The Nine-Hole Peg Test (9-HPT) is a standardized, quantitative assessment used to measure finger dexterity. Test is measured in seconds.

Time frame: Baseline, Month 12 and Month 24 visits

VIDEO HAND OPENING TIME (vHOT)

. The participant will squeeze the hand for three seconds then open the hand as quickly as possible. A video recording of the procedure will be obtained showing the forearm and hand but not the face. Recordings will later be assessed by a blinded reviewer to determine the hand opening time. The time is recorded in seconds.

Time frame: Baseline, Month 12 and Month 24 visits

IOWA PERFORMANCE INSTRUMENT (IOPI)

The IOPI consists of a pressure bulb attached to a manometer. The pressure bulb will be placed on the participant's tongue. Participants are asked to push the bulb against the hard palate on the alveolar ridge just behind the upper central incisors for 3-5 seconds. This test should be repeated 3 times with a 30-second interval between trials. The maximum pressure is recorded.

Time frame: Baseline, Month 12 and Month 24 visits

CLINICAL EVALUATION OF LANGUAGE FUNDAMENTALS, 5th edition (CELF-5)

The mean score is 100, with a standard deviation of 15, meaning that standard scores between 85-115 are within the normal range. You can calculate the level of severity for delayed skills according to how many deviations below the mean a client's score is: Mild: 70-85, Moderate 55-70 , Severe: 55 and lower.

Time frame: Baseline, Month 12 and Month 24 visits

TIMED WATER SWALLOW TEST (TWST)

Participants will be given 3 ounces (90 mL) of water to drink from a clear cup. Safety of completing this test will be determined by the site PI with input from the parents/caregivers. Participants will be asked to drink the water as they normally would, without interruption. Straws may be used, if that is preferred. Participants will be asked to say aloud "I'm done" when they feel they've completed the task with a written cue provided as a reminder.26,27 Testing will be recorded for later quantification of time needed for test, volume ingested, volume/swallow, time/swallow, and swallow capacity (mL/swallow).

Time frame: Baseline, Month 12 and Month 24 visits

DOMAIN DELTA QUESTIONNAIRE

A "domain delta questionnaire" is a patient-reported questionnaire used in clinical research to assess how much a patient perceives their health status has changed across specific domains (like mobility, overall health, or upper limb function) between two points in time, essentially asking them if they feel they have gotten better, worse, or stayed the same in each area compared to a baseline measurement; it's a way to measure perceived change in health related quality of life over time.

Time frame: Baseline, Month 12 and Month 24 visits

INTELLIGIBILITY IN CONTEXT SCALE (ICS)

The ICS is a brief, 7-question, caregiver proxy instrument that rates relative intelligibility of a child with a variety of familiar and unfamiliar communication partners. It uses a 5-point Likert scale to rate the approximate level of intelligibility. ICS scores indicate a child's level of functional intelligibility, ranging from a score of 1.00 (low intelligibility) to a score of 5.00 (high intelligibility). If a child achieves an average score of 3.5, then it may be appropriate to indicate that the child is usually to sometimes understood.

Time frame: Baseline, Month 12 and Month 24 visits

PEDIATRIC QUALITY OF LIFE (PEDS QL) - GENERIC CORE SCALES

The PedsQL evaluates a child's health-related quality of life (HRQoL) with respect to social, emotional, physical, and school functioning. he PedsQL 4.0 Generic Core Scales consist of four scales measuring HRQoL in four domains: Physical, Emotional, Social, and School functioning. Scores of 81 or higher on the PedsQL™ SCD pain scales should be considered good HRQL functioning. These children likely have had less pain that was less severe than children with lower scores and/or are managing their symptoms well.

Time frame: Baseline, Month 12 and Month 24 visits

PEDIATRIC DAYTIME SLEEPINESS SCALE (PDSS)

SS is an 8-item scale that assesses daytime sleepiness in children as a PRO that has been used in sleep disordered breathing and epilepsy studies. 5 points Likert scale (0-4) for 8 questions concerning to sleepiness. Higher scores on PDSS were associated with reduced total sleep time, poorer school achievement, poorer anger control, and frequent illness.

Time frame: Baseline, Month 12 and Month 24 visits

BEHAVIOR RATING INVENTORY OF EXECUTIVE FUNCTION -2 (BRIEF2)

The BRIEF2 gives you the information you need to help children and adolescents with executive dysfunction. It digs deeper than similar measures and pinpoints exactly where and why children struggle, so therapists and schools can make informed and impactful intervention and accommodation recommendations. For all BRIEF2 clinical scales and indexes, T scores from 60 to 64 are considered mildly elevated, and T scores from 65 to 69 are considered potentially clinically elevated. T scores at or above 70 are considered clinically elevated.

Time frame: Baseline, Month 12 and Month 24 visits

VINELAND ADAPTIVE BEHAVIOR SCALES THIRD EDITION (VINELAND-3)

Vineland Adaptive Behavior Scales 3rd Edition is a leading instrument for diagnosing intellectual and developmental disabilities, providing valuable information for educational and treatment plans. Higher Internalizing and Externalizing v-scale scores indicate more problem behavior. If qualitative descriptors are desired, scores of 1 to 17 may be considered Average, 18 to 20 Elevated, and 21 to 24 Clinically Significant.

Time frame: Baseline, Month 12 and Month 24 visits

WECHSLER INTELLIGENCE SCALE FOR CHILDREN (WISC-V)

Wechsler Intelligence Scale for Children (WISC-V) is an intelligence test that measures a child's intellectual ability and 5 cognitive domains that impact performance. Low Average: 80-89. Students who test in this range may struggle to keep up in school, but are not generally eligible for special education or assistance. Average: 90-109. Students who test in this range are average and may or may not struggle to keep up in school.

Time frame: Baseline, Month 12 and Month 24 visits

AUTISM SPECTRUM SCREENING QUESTIONNAIRE (ASSQ)

Results consist of a total score between 0 and 54, where higher scores indicate that many characteristics of ASD were reported. A score of 13 and above indicates ASD is probable, with a true positive rate of 90% and a false positive rate of 22%.

Time frame: Baseline, Month 12 and Month 24 visits

REPETITIVE BEHAVIOR SCALE - REVISED (RBS-R)

The RBS-R is a questionnaire that focuses exclusively on RRBs. It includes 43 items rated on a four-point Likert scale: 0=behavior does not occur; 1=behavior occurs and is a mild problem; 2=behavior occurs and is a moderate problem; and 3=behavior occurs and is a severe problem.

Time frame: Baseline, Month 12 and Month 24 visits