Clinical trial NCT06222827: Study to Evaluate the Efficacy and Safety of Satralizumab in FSHD1
Official title: A Bicentric, Randomized, Double Blind, Placebo-controlled Pilot Study to Evaluate the Efficacy and Safety of Satralizumab in FSHD1
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Facioscapulohumeral Muscular Dystrophy 1
Lead sponsor: Centre Hospitalier Universitaire de Nice
Sponsor class: OTHER
First posted: 2024-01-25
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: First period: two groups of patients who receive either satralizumab, or placebo. Second period: all patients receive satralizumab
Primary purpose: TREATMENT

Brief summary: Facioscapulohumeral muscular dystrophy (FSHD) is characterized by clinical diversity, with FSHD1 being the most common form. It is associated with a toxic gain of function of the Double homeobox 4 (DUX4) gene, leading to muscle cell death and weakness. Despite the lack of approved treatments, recent studies highlight inflammation's role in early FSHD progression, triggered by inappropriate DUX4 expression.

In understanding inflammation's pivotal role in FSHD, a study assessed serum cytokines in 100 adult FSHD1 patients. Out of the 20 cytokines examined, 10 showed significantly altered expression levels compared to healthy controls of similar age and sex. FSHD1 patients exhibited heightened levels of inflammatory cytokines and diminished anti-inflammatory cytokines, signaling chronic inflammation. Notably, Interleukin-6 (IL-6) emerged as a promising disease activity biomarker, displaying robust correlations with established clinical severity and functional scores.

Given the pathological significance of inflammation and the correlation of IL-6 levels with disease severity, the ReInForce study will explore the satralizumab, an IL6-receptor (IL6-R) antagonist, for its efficacy in specifically reducing muscle and systemic inflammation. By antagonizing IL-6R downstream signaling, satralizumab holds promise in mitigating inflammation and potentially curtailing fibrofatty degeneration in FSHD.


Eligibility criteria: Inclusion Criteria:

* Capable of understanding the written informed consent, and providing signed, dated, and witnessed written informed consent.
* Male or female subjects between the ages of 18 and 65 years, inclusive.
* Patient affiliated to a European social security system (Nice center only)
* Genetically confirmed diagnosis of typical FSHD1 with 1 to 9 D4Z4 repeats via assessment of the size of the D4Z4 array on chromosome 4. Genetic confirmation must be obtained before the subject screening assessments, including MRI, and before the baseline. Genetic confirmation can come from previous testing if verified with appropriate documentation from an accredited laboratory. Due to stable transmission of repeat sizes within families, subjects with a clinical diagnosis of FSHD who have a first-degree relative with a genetically confirmed diagnosis of FSHD1 may be entered into the study for screening assessments, including MRI.
* Clinical severity score of 2 to 4 (RICCI score; range 0-5), inclusive.
* Patients with a body weight of below or equal 100 kg
* On initial whole-body MRI, subjects with evidence of muscle fat replacement such that the total lean volume of muscles with an intermediate fat replacement (i.e. muscle with at least 10% of Muscle Fat Infiltration and no more than 50% of Muscle Fat Fraction) is at least 500 ml if there is only one intermediate muscle or 250 ml if there is more than one intermediate muscle.
* Subjects able to walk without support
* Willing to maintain same level of exercise (frequency and intensity) during the study.
* Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
* For female patients of childbearing potential: use adequate contraception during the treatment period and/or until treatment discontinuation.

Exclusion Criteria:

* History of any illness or any clinical condition that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. This may include, but is not limited to, any major comorbidities (diabetes mellitus, cancer, severe autoimmune diseases, chronic renal failure, articular diseases that restricts exercise or participation in study assessments in the physician's opinion...), a history of relevant drug or food allergies; history of cardiovascular, respiratory, central nervous system disease; neuromuscular diseases except FSHD (e.g., myopathy, neuropathy, neuromuscular junction disorders)
* History of malignancy within the last 5 years, including solid tumors, hematologic malignancies and in situ carcinoma (except basal cell and squamous cell carcinomas of the skin, or in situ carcinoma of the cervix uteri that have been completely excised and cured)
* Subjects who are on drug(s) or supplements that may affect muscle function, as determined by the treating physician must be on a stable dose of that drug(s) or supplement for at least 3 months prior to the first dose of study drug and remain on that stable dose for the duration of the study.
* Orthopedic conditions, such as unresolved fracture or arthrosis, interfering or precluding testing of muscle function
* Contraindication to muscle MRI as per clinic standard practice
* Articular contracture limiting movements, scapular fixation or other surgeries, preceding or planned
* Any known hypersensitivity to satralizumab or any of its components and/or history of severe allergic reaction to a biologic agent (e.g., shock, anaphylactic reactions)
* Evidence of latent or active tuberculosis (TB; excluding patients receiving chemoprophylaxis for latent TB infection for at least 4 weeks prior to enrollment), active opportunistic or life-threatening infections
* History of diverticulitis or concurrent severe GI disorders (such as symptomatic diverticulosis) that, in the investigator's opinion, may lead to increased risk of complications such as GI perforation. Infection requiring hospitalization or treatment with IV anti-infective agents within 4 weeks prior to baseline visit or oral anti-infective agents within 2 weeks prior to baseline visit (Visit 1, week 0)
* Positive screen for hepatitis B surface antigen (HbsAg), antibody (anti-HbS), hepatitis C virus (HCV) antibody.
* Acute or chronic history of liver disease
* Abnormal laboratory results with: White blood cells (WBC) \< 3.0x 10\^9/L ; Absolute Neutrophils Counts (ANC)\< 2.0x 10\^9/L ; Platelet count \< 10x10\^4/µl ; Absolute lymphocyte count (ALC) \< 0.8x 10\^3/µl ; Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 1.5 times the upper limit of normal (ULN)
* Severe renal impairment (defined as a glomerular filtration rate of \<30mL/min/1.73m²)
* Vaccination with live or live-attenuated vaccines within the 6 weeks prior to randomization.
* Pregnancy or lactation
* For patients of reproductive potential, a positive result from a serum pregnancy test at screening, or not willing to use reliable means of contraception (physical barrier \[patient or partner\] in conjunction with a spermicidal product, contraceptive pill, patch, injectable, intrauterine device or intrauterine system) during the treatment period and for at least 3 months after the last dose of study drug.
* Any current mental condition (psychiatric disorder, senility, or dementia) that, in the opinion of the investigator, may affect study compliance or prevent understanding of the aims, investigational procedures, or possible consequences of the study.
* Use of another investigational product within 6 months or 5 half-lives (whichever is longer), or currently participating in a prospective study with an investigational product, whether it concerns an experimental drug or a medical device. Note: concurrent participation in natural history studies (non-drug, non-device studies) is not allowed during the course of the study.
* Any prior treatment with any agent targeting the IL-6 inhibition pathway (e.g. tocilizumab, sarilumab), alemtuzumab treatment, total body irradiation, or bone marrow transplantation; treatment in the past 24 weeks with an anti-B-lymphocyte antigen CD20 (e.g. rituximab, ocrelizumab), eculizumab, anti-B-lymphocyte stimulator, or any other multiple sclerosis disease-modifying treatment; treatment in the past 2 years with an anti-T-cell surface glycoprotein CD4, cladribine, cyclophosphamide, or mitoxantrone; or treatment with any other investigational drug within 3 months prior to baseline. See section 4.4.4 for details on the vaccination and immunization.
* Subject, or close relative of the subject, is the investigator or a coinvestigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site.
* Patient protected by law, under guardianship or curator ship, or not able to participate in a clinical study according to the article L.1121-16 of the French Public Health Code.

Primary outcomes:
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on whole body muscle MRI.
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on RICCI clinical severity scale score.
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on Reachable Work Space (RWS) results with and without weights.
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on muscle strength, determined by quantitative isometric dynamometry
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on FSHD-Composite Outcome Measure (FSHD-COM) total score, sub-scale scores and individual items.
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on FSHD-Rasch-built overall disability scale (FSHD-RODS) total score
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the proportion of participants with an improvement in the FSHD Patient Global Impression of Change scale (FSHD-PGIC) during the Double Blind period (week 0 to week 48)
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the proportion of participants with an improvement in FSHD Clinical Global Impressions of Change scale (FSHD-CGIC) during the Double Blind period (week 0 to week 48)
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on the number of falls reported.
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on Neuromuscular Disease Independence Scale-Upper Limb Module (NMDIS-ULM) total score
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on Neuromuscular Disease Independence Scale-Ambulatory (NMDIS-Amb) total score.
timeFrame: From baseline to week 48
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during the Double Blind (DB) period (week 0 to week 48) on inflammation, and specifically on molecular biomarkers associated with inflammation.
timeFrame: From baseline to week 48
measure: The study will evaluate the safety and tolerability of satralizumab compared to placebo, measured by the type, frequency, severity, seriousness, and relationship of Adverse Events to satralizumab during the Double Blind (DB) period (week 0 to week 48).
timeFrame: From baseline to week 48
measure: The study will evaluate the safety and tolerability of satralizumab compared to placebo, measured by the incidence of Adverse events of special interest (AESIs) and selected AEs during the Double Blind (DB) period (week 0 to week 48).
timeFrame: From baseline to week 48
measure: The study will evaluate the safety and tolerability of satralizumab compared to placebo, measured by the number of subjects discontinuing study drug due to an AE during the Double Blind (DB) period (week 0 to week 48).
timeFrame: From baseline to week 48
measure: The study will evaluate safety and tolerability of satralizumab compared to placebo, measured by frequency of clinically significant changes from baseline in laboratory test, vital signs, and physical examination results during the Double Blind period
timeFrame: From baseline to week 48
Secondary outcomes:
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96) on whole body muscle MRI.
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96) on RICCI clinical severity scale score
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96) on Reachable Work Space (RWS) results with and without weights.
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96) on muscle strength, determined by quantitative isometric dynamometry
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind and Open-label periods on FSHD-Composite Outcome Measure (FSHD-COM) total score, sub-scale scores and individual items
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96) on FSHD-Rasch-built overall disability scale (FSHD-RODS) total score
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the proportion of participants with an improvement in the FSHD Patient Global Impression of Change scale (FSHD-PGIC) during Double Blind and Open-label periods
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the proportion of participants with an improvement in the FSHD Clinical Global Impressions of Change scale (FSHD-CGIC) during Double Blind and Open-label periods
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96) on the number of falls reported
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind (DB) and Open-label (OL) periods on Neuromuscular Disease Independence Scale-Upper Limb Module (NMDIS-ULM) total score.
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96) on Neuromuscular Disease Independence Scale-Ambulatory (NMDIS-Amb) total score
timeFrame: From baseline to week 96
measure: The study will evaluate the efficacy of satralizumab compared to placebo, measured by the change during Double Blind (DB) and Open-label (OL) periods on inflammation, and specifically on molecular biomarkers associated with inflammation
timeFrame: From baseline to week 96
measure: The study will evaluate the safety and tolerability of satralizumab compared to placebo, measured by the type, frequency, severity, seriousness, and relationship of Adverse Events to satralizumab during Double Blind and Open-label periods
timeFrame: From baseline to week 96
measure: The study will evaluate the safety and tolerability of satralizumab compared to placebo, measured by the incidence of Adverse events of special interest (AESIs) and selected AEs during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96)
timeFrame: From baseline to week 96
measure: The study will evaluate the safety and tolerability of satralizumab compared to placebo, measured by the number of subjects discontinuing study drug due to an AE during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96)
timeFrame: From baseline to week 96
measure: The study will evaluate safety/tolerability of satralizumab versus placebo, measured by frequency of clinically significant changes from baseline in laboratory test, vital signs, and physical examination results during Double Blind and Open-label periods
timeFrame: From baseline to week 96
Other outcomes:
Locations:
city: Ottawa
country: Canada
facility: CHEO Research Institute Ottawa
state: Ontario
city: Nice
country: France
facility: CHU de Nice
state: Alpes Maritimes
Study officials:
References: