An 18-month Prospective Natural History Study to Gain Ins... | NCT06079567

Status Module

Description Module

Brief Summary

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited myopathies in adults. It is associated with genetic and epigenetic deregulation of the D4Z4 locus on the sub-telomeric region of chromosome 4q35, resulting in abnormal expression of DUX4p. Type 1 FSHD (FSHD1) is the most common form of the disease and accounts for 95% of cases, while Type 2 FSHD (FSHD2) accounts for only 5% of all FSHD cases. FSHD1 and FSHD2 are closely related in terms of genetic and epigenetic foundations, pathophysiology and clinical manifestations. Although initially described as distinct entities based on their genetics, recent information suggests that both forms of myopathy may represent the opposite ends of a spectrum of molecular diseases in which alteration of the genetic and epigenetic factors that govern DUX4 suppression in skeletal muscle have a different impact in both forms of the disease. FSHD1 and FSHD2 are both associated with re-expression of DUX4 leading to muscle atrophy, but the genetics underlying this re-expression are different, depending on whether it is type 1 or type 2. For FSHD1, it is associated with a critical contraction of the D4Z4 region and the 4qA permissive allele, leading to the expression of DUX4. In contrast, FSHD2 is caused by the inheritance of two independent genetic variations. A heterozygous mutation, mainly located on the SMCHD1 (Structural Maintenance of Chromosome flexible Hinge Domain containing 1) gene, results in a loss of function of chromatin D4Z4 repressor. This mutation, combined with the 4qA allele bearing the DU4 polyadenylation site, makes this allele permissive for the expression of the DUX4 topical gene.

Therefore, because the two forms of FSHD are genetically distinct and very few patients have FSHD2, our knowledge of the impact of chromatin D4Z4 repressors, such as SMCHD1, or the progression and severity of the disease remains very limited. It is important to note that a lack of reliable biomarkers specific to the severity and progression of the disease may prevent the development of therapies to treat patients with FSHD2. This study will allow us to better understand the natural progression of FSHD2 over time, to assess the responsiveness of clinical outcome measures (COMs) and to identify and validate inflammatory serum biomarkers predicting the severity and progression of the disease.

Label	Type	Description	Intervention Names
New COMs for FSHD2 patients	Experimental		Diagnostic Test: Validation of new COMs for FSHD2 patients

Name	Type	Description	Arm Group Labels	Other Names
Validation of new COMs for FSHD2 patients	Diagnostic Test	Monitoring of commonly used and new COMs in FSHD2 patients	New COMs for FSHD2 patients

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Minimal clinical importance of the Motor Function Measure-32 (MFM-32) from Baseline (V1) to 18 months (V3)	Within MFM-32, 32 terms will be evaluated to describe patient's motor functions and grouped into 3 sub-scores at baseline and 18 months: D1: standing position and transfer D2: axial and proximal motor function D3: distal motor function The MFM-32 ratings rely on the use of a 4-point Likert scale based on the subject's maximal abilities without assistance (0: cannot initiate the task or maintain the starting position; 1: performs the task partially; 2: performs the task incompletely or imperfectly;3: performs the task fully and normally.)	At baseline and 18 months

Secondary Outcomes

Measure	Description	Time Frame
Change of the Italian Severity Score (FCS) from Baseline (V1) to 18 months (V3)	The Italian Severity Score (FCS) ranks weakness in the face, shoulders, arms, distal, and proximal lower extremities on a 15-points scale	At baseline and 18 months
Change of the Clinical Severity Score (CSS) from Baseline (V1) to 18 months (V3)

Eligibility Module

Eligibility Criteria

Inclusion criteria:

Genetically confirmed FSHD2: pathogenic mutation in SMCHD1 gene and at least one D4Z4 4qA allele;
Age 18-75 years
Symptomatic limb weakness
Clinical severity score of 2 to 5 (RICCI score; range 0-5), inclusive, at screening:
- Group ambulant patient with a RICCI score of 2 to 4
- Group non-ambulant patient with a RICCI score of 5
Patient giving written consent after written and oral information
Patient affiliated to a social security system
If taking over the counter supplements, willing to remain consistent with supplement regimen throughout the course of the study

Non inclusion criteria:

Patients with comorbidity not related to the disease that can modify the natural evolution of the disease or would interfere with safe testing in the opinion of the Investigator
Regular use of available muscle anabolic/catabolic agents such as corticosteroids, oral testosterone or derivatives, or oral beta agonists
Contraindication to muscle MRI as per clinic standard practice
Patients who has been to a tropical or subtropical country during the last 3 months
Patients who has practiced physical exercise within 10 hours before blood test
Patients declaring not to be fasting for at least 10 hours
Patients following a particular diet for medical reasons and after prescription by a doctor or dietitian
Patients who regularly consumes large quantities of alcohol
Patients having consumed an illicit recreational drug during the last 3 months
Patients having been vaccinated during the last 3 months
Patients having received a blood transfusion or immunoglobulins during the last 3 months
Patients declaring to be seropositive for HIV, HBV or HCV
Patients having had an infectious episode during the 3 weeks preceding the visit
Use of an experimental drug in an FSHD clinical trial within the past 30 days
Participation in others clinical trials
Pregnant women, breastfeeding women, women of childbearing age without contraception Pregnancy
Patient with legal protection measures (future protection mandate, family empowerment, guardianship, curators) under Article L. 1122-2 of the French Public Health Code
Patient refusing to participate in the study or expressing opposition to participation