Clinical trial NCT06079567: An 18-month Prospective Natural History Study to Gain Insight Into FSHD2 Pathophysiology and Disease Progression
Official title: An 18-month Prospective Natural History Study to Gain Insight Into FSHD2 Pathophysiology and Disease Progression
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Facioscapulohumeral Muscular Dystrophy Type 2
Lead sponsor: Centre Hospitalier Universitaire de Nice
Sponsor class: OTHER
First posted: 2023-10-12
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


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

Primary outcomes:
measure: Minimal clinical importance of the Motor Function Measure-32 (MFM-32) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
Secondary outcomes:
measure: Change of the Italian Severity Score (FCS) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the Clinical Severity Score (CSS) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the Manual Muscle Testing (MMT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the Hand-Held dynamometry (HHD) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the Pinch and Grip test from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the 9-Hole Peg test (9-HPT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the repeated 9-Hole Peg test (r9-HPT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the classic Timed Up and Go test (classic TUG) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the optimized Timed Up and Go test (optimized TUG) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the 6-Minute Walk Test (6MWT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the Sit Up Test (SiUT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the repeated Sit Up Test (r-SiUT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the Stand Up Test (SaUT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the repeated Stand Up Test (r-SaUT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the Bend Over Test (BOT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the repeated Bend Over Test (r-BOT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the Neck Flexion Fatigability Test (NFFT) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the respiratory function (sitting and bedside spirometry) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the muscle composition from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the score for physical function and the impact of physical limitations on daily life (PROMIS57) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the score for the Patient Global Impression of Change (PGIC) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the score for the Upper Extremity Functional Index (UEFI) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the score for the Facial Disability Index (FDI) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the score for the Sydney Swallow Questionnaire (SSQ) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the score for the Swallowing Quality of Life questionnaire (SWAL-QOL) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the score for the Multidimensional Dyspnea Profile (MDP) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the FSHD-Rasch-built overall disability scale (FSHD-RODS) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the fatigue severity scale (FSS) from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the fall and exercise questionnaire from Baseline (V1) to 18 months (V3)
timeFrame: At baseline and 18 months
measure: Change of the cytokines levels in serum from Baseline (V1) to 12 months (V2) and 18 months (V3)
timeFrame: At baseline, 12 and 18 months
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: Leuven University
city: Nice
country: France
facility: Nice University Hospital
state: Alpes M
city: Marseille
country: France
facility: APHM
state: Bouches du Rhone
city: Paris
country: France
facility: Myology Institute
city: Roma
country: Italy
facility: Gemelli University Hospital
state: Latium
city: Milano
country: Italy
facility: Nemo Center
state: Lombardie
city: Pisa
country: Italy
facility: Pisa University
state: Toscane
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Centre Nijmegen
city: Donostia
country: Spain
facility: Donostia University Hospital
state: Guipuscoa
Study officials:
References: