A bicentric, randomized, double blind, placebo-controlled pilot study to evaluate the efficacy and safety of satralizumab in FSHD1

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nice

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

15 Jan 2024 → ongoing

Decision date (initial)

2023-09-15

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the efficacy and safety of satralizumab compared with placebo in patients with FSHD1

Secondary objectives 1

1. To assess the long-term safety and efficacy of satralizumab during the open-label (OL) period

Conditions and MedDRA coding

Type 1 facioscapulohumeral muscular dystrophy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Capable of understanding the written informed consent, and providing signed, dated, and witnessed written informed consent
2. Male or female subjects between the ages of 18 and 65 years, inclusive
3. Patient affiliated to a European social security system (Nice center only)
4. 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
5. Clinical severity score of 2 to 4 (RICCI score; range 0-5), inclusive
6. 6Patients with a body weight of below or equal 100 kg
7. On initial whole-body MRI, subjects with: a. At least one muscle in lower limbs showing STIR or T2-Dixon positive signal ; b. 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.
8. Subjects able to walk without support
9. Willing to maintain same level of exercise (frequency and intensity) during the study
10. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures
11. For female patients of childbearing potential: use adequate contraception during the treatment period and/or until tratment discontinuation

Exclusion criteria 21

1. 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
2. History of malignancy within the last 5 years
3. Subjects who are on drug(s) or supplements that may affect muscle function
4. Orthopedic conditions, such as unresolved fracture or arthrosis, interfering or precluding testing of muscle function
5. Contraindication to muscle MRI as per clinic standard practice
6. Articular contracture limiting movements, scapular fixation or other surgeries, preceding or planned
7. 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)
8. 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
9. 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)
10. Positive screen for hepatitis B surface antigen (HbsAg), antibody (anti-HbS), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV-1/HIV-2)
11. Acute or chronic history of liver disease
12. Abnormal laboratory results with : White blood cells (WBC) < 3.0x 10^9/L ; Absolute Neutrophils Counts (ANC) < 2.0x 10^9/L ; Platelet count < 10x 10^4/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)
13. Severe renal impairment (defined as a glomerular filtration rate of <30mL/min/1.73m²)
14. Vaccination with live or live-attenuated vaccines within the 6 weeks prior to randomization
15. Pregnancy or lactation
16. 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
17. 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
18. Use of another investigational product within 6 months or 5 half-lives (whichever is longer), or according to local regulations, 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) may be acceptable if confirmed in writing by the sponsor. In the case of patients treated with Losmapimod, the wash out period will be 5 half-lives.
19. 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
20. Subject, or close relative of the subject, is the investigator or a subinvestigator, research assistant, pharmacist, study coordinator, or other staff directly involved with the conduct of the study at that site
21. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 16

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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 (DB) period (week 0 to week 48)
8. 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 the Double Blind (DB) period (week 0 to week 48)
9. 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.
10. 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.
11. 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.
12. 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 (e.g. IFN-γ, IL-1β, IL-6, TNF-α, VEGF, IL1-RA, IL-6-R, sICAM-1, sVCAM-1, SAA…).
13. 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 (AEs) to satralizumab during the Double Blind (DB) period (week 0 to week 48).
14. 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).
15. 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).
16. The study will evaluate the safety and tolerability of satralizumab compared to placebo, measured by the frequency of clinically significant changes from baseline in laboratory test, vital signs, and physical examination results during the Double Blind (DB) period (week 0 to week 48).

Secondary endpoints 16

1. 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.
2. 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.
3. 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.
4. 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.
5. 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-Composite Outcome Measure (FSHD-COM) total score, sub-scale scores and individual items.
6. 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.
7. 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 (DB) and Open-label (OL) periods (week 0 to week 96)
8. 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 (DB) and Open-label (OL) periods (week 0 to week 96)
9. 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.
10. 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-Upper Limb Module (NMDIS-ULM) total score.
11. 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
12. 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 inflammation, and specifically on molecular biomarkers associated with inflammation (e.g. IFN-γ, IL-1β, IL-6, TNF-α, VEGF, IL1-RA, IL-6-R, sICAM-1, sVCAM-1, SAA…).
13. 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 (AEs) to satralizumab during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96)
14. 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)
15. 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)
16. The study will evaluate the safety and tolerability of satralizumab compared to placebo, measured by the frequency of clinically significant changes from baseline in laboratory test, vital signs, and physical examination results during Double Blind (DB) and Open-label (OL) periods (week 0 to week 96)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nice

Sponsor organisation

Centre Hospitalier Universitaire De Nice

Address

4 Avenue Reine Victoria

City

Nice

Postcode

06000

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nice

Contact name

Pr Sabrina SACCONI

Public contact point

Organisation

Centre Hospitalier Universitaire De Nice

Contact name

Céline HIVELIN

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 54 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications