Characterization of DupEx2 Duchenne Muscular Dystrophy

Muscular Dystrophy, Duchenne Clinical Trial

— DMDDup2  

Official title:

Characterization of the Phenotypic Diversity in DupEx2 Duchenne Muscular Dystrophy and Identification of Predictive/Prognostic Markers

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06337669
• Other study ID #: OSRSCP-GUP21006
• Status: Recruiting
• Start date: January 31, 2022
• Est. completion date: January 31, 2025

Study information

• Verified date: March 2024
• Source: IRCCS San Raffaele
• Contact: Stefano C Previtali, MD
• Phone: 00390226433036
• Email: neuromuscolare[@]hsr.it
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

To characterize the clinical phenotype and possible predictive/prognostic factors of patients with Duchenne muscular dystrophy (DMD) due to duplication of exon 2 (Dup2). Specifically, we aim 1) to describe the progression of motor, respiratory and cardiac function; 2) to enquire if the phenotypic spectrum of Dup2 is milder than classic DMD, 3) to perform whole genome sequencing (WGS) to characterize DNA breakpoints to correlate with the phenotype; 4) to collect material for future proteomic/transcriptomic studies.

Background/Rationale DMD is caused by mutations in the DMD gene and in 11% of cases is due to duplications. The most promising therapeutic approaches include mutation-specific therapies. Notably, there is increasing evidence that specific groups of mutations may underlie different disease trajectories compared to the "average" DMD population. It is thus mandatory to have more information on genotype-phenotype correlations and patterns of progression related to different genotypes.

Dup2 is the most common DMD duplication and the only one for which a AAV-mediated exon skipping study is ongoing. Despite most case series and databases ascribe Dup2 to severe phenotype, our preliminary findings sustain that these patients have collectively a milder progression of the disease and in 1/3 of cases a significantly milder phenotype. Moreover, our attempts to reveal mechanism involved in attenuating the phenotype would confute the hypothesis of alternative spicing transcripts as previously described for DMD with deletion of exon 2.

Research design and methods Clinical information regarding a cohort of 26 Italian Dup2 patients will be collected. Differences in time to loss of ambulation compared to a DMD control group will be achieved. Finally, we will retrieve DNA for correlative WGS studies.

Anticipated output We expect that Dup2 patients present a milder DMD phenotype , which might be predicted by genomic studies.

Description:

The primary clinical endpoint is time to loss of ambulation (LOA).

Secondary endpoints include:

1. The change over time of the following functional measurements:

1.1 Motor function: The 6 Minute Walk test (6MWT) and North Star Ambulatory Assessment (NSAA) including sub-items such as Time to Rise from the floor.

1.2 Respiratory function: Forced Vital Capacity (FVC) Liters (L) and % of predicted; time to FVC% < 50%. Time to Nocturnal Ventilation initiation.

1,3 Cardiac function: Left ventricular ejection fraction (EF) as measured by echocardiogram.

2. To characterize DNA breakpoints in mild vs severe phenotypes

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 26
• Est. completion date: January 31, 2025
• Est. primary completion date: January 31, 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A and older

Eligibility

Inclusion Criteria:

• pediatric and adult DMD patients harboring a genetically confirmed duplication of the exon 2 in the dystrophin gene

Exclusion Criteria:

• patients lacking genetic confirmation of Dup2 mutation

Related Conditions & MeSH terms

• Muscular Dystrophies
• Muscular Dystrophy, Duchenne

Locations

Country	Name	City	State
Italy	Dept. of Neurology, IRCCS Ospedale San Raffaele	Milano

Sponsors (1)

Lead Sponsor	Collaborator
IRCCS San Raffaele

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Age at loss of ambulation	Age at loss of ambulation	12 months
Secondary	Time test for motor function	The 6 Minute Walk test (6MWT) and North Star Ambulatory Assessment (NSAA) including sub-items such as Time to Rise from the floor.	12 months
Secondary	Respiratory function	Forced Vital Capacity (FVC) Liters (L) and % of predicted; time to FVC% < 50%. Time to Nocturnal Ventilation initiation	12 months