FSHD Muscle disease
Conditions
Interventions
None listed
Sponsors
Fulcrum Therapeutics
Eligibility
Age
18 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1.FSHD1 subjects age 18-65 years., 2.Subject will sign and date an informed consent form (ICF)., 3.3. Subjects will have a confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the D4Z4 array on chromosome 4 using the calculator provided by the sponsor. Genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy; genetic confirmation can come from previous testing if verified with appropriate documentation. 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 and MRI. During screening, a confirmatory genetic diagnosis is conducted. If genetic testing during screening is necessary, the 4-week screening window will not start until the results are obtained and verified by the principal investigator. , 4.Subject will be willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, scheduled needle muscle biopsies, and other study procedures., 5.Male or female subjects:, a.A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhoea or if of childbearing potential is using a highly effective method for avoidance of pregnancy (refer to Section 5.5) for the duration of the clinical trial and until 90 days following the last dose. The decision to include or exclude women of childbearing potential may be made at the discretion of the investigator and in accordance with local practice in relation to adequate contraception., b.Male subjects must agree to use one of the contraception methods listed in Section 5.5. This criterion must be followed from the time of the first dose of study medication until 90 days after the last study drug dose., 6. Subject has a Clinical Severity Score between 2 and 4 on Ricci*s scale (scale range is from 0 to 5). Patients that use a wheelchair or walker for any activity are not permitted to enroll in the study., 7. Subject commitment to complete the 2 visits for skeletal muscle needle biopsy and all visits for whole body MRI., 8. Subject is able to complete the RWS, TUG, and FSHD PROs (FSHD-RODS and FSHD HI) at the screening visit., 9. Subject has an MRI-eligible muscle for biopsy as determined by the central reader.
Exclusion criteria
Exclusion criteria: 1. Subject has a 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, history of relevant drug or food allergies; history of cardiovascular or central nervous system disease; history or presence of clinically significant pathology; clinically significant history of mental disease; and history of cancer, except for squamous cell skin cancer, basal cell skin cancer, and Stage 0 cervical carcinoma in situ (all 3 with no recurrence for the last 5 years)., 2. Subject has a known or clinically suspected infection with human immunodeficiency virus or hepatitis B or C viruses., 3. Subject has current clinically significant liver or kidney dysfunction., 4. Subject screens positive for hepatitis B surface antigen, hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency viruses 1 and 2 (HIV 1/HIV 2 antibodies)., 5. Subject has any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy, or other gastrointestinal tract surgery, except appendectomy)., 6. Subject has a standard 12-lead ECG demonstrating QT interval by Fredericia (QTcF) >450 msec for male subjects and QTcF >470 msec for female subjects at Screening. If QTcF exceeds 450 msec for males or 470 msec for females, the ECG will be repeated 2 more times, and the average of the 3 QTcF values will be used to determine the subject*s eligibility., 7. Subject has a history of cardiac dysrhythmias requiring anti-arrhythmia treatment(s); or history or evidence of abnormal ECGs that, in the opinion of the investigator or Medical Monitor, would preclude the subject*s participation in the study., 8. Male subject has a female partner who is planning to become pregnant during the study or within 90 days after the last study drug dose., 9. Subject has donated blood (of approximately 1 pint [500 mL] or more) or has had any significant loss of blood within 90 days before the first study drug dose, as determined by the investigator., 10. Vaccination with a live attenuated vaccine within 6 weeks of randomization., 11. Subject has a history of alcohol, analgesic/opioid, and/or illicit drug abuse as defined by the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, in the last 6 months before screening, or a positive test for drugs of abuse at screening. 12. Subject has participated in a clinical trial in which they have received an investigational product within the following time period prior to enrolment in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever was longer)., 13. For subjects that are on drug(s) or supplements that may affect muscle function as determined by the treating physician or included in the list of drugs presented in Appendix 15.1: subjects must be on a stable dose of that drug(s) or supplement for at least 3 months prior to enrolment in the study and remain on that stable dose for the duration of the study (list of drugs presented in Appendix 15.1). Changes to the dose or treatment discontinuation during the study can only be done for strict medical reasons
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Assessment of safety and tolerability based on adverse events (AEs), serious adverse events (SAEs), clinically significant laboratory test results, electrocardiograms (ECGs), and vital signs (safety endpoint) Extension: The primary endpoint is the assessment of the efficacy of treatment with losmapimod as evaluated by skeletal muscle echogenicity by ultrasound (selected muscles). | — |
Secondary
| Measure | Time frame |
|---|---|
| Change from baseline in pHSP27 and ratio of pHSP27/total HSP27 as measured by sorbitol stimulated peripheral whole blood and change from baseline in the ratio of pHSP27/total HSP27 in muscle (PD endpoint) and concentration losmapimod in blood and muscle (PK endpoint). Exploratoty Endpoints: Changes from baseline during the dosing period in the following: 1. DUX4 activity by quantitative polymerase chain reaction (qPCR) of skeletal muscle using a subset of DUX4 regulated gene transcripts 2. Other disease transcripts by qPCR of skeletal muscle 3. Skeletal muscle lean tissue volume by whole-body MRI 4. Skeletal muscle tissue replacement by fat using whole-body MRI 5. Skeletal muscle echogenicity by ultrasound (selected muscles) 6. Reachable Work Space (RWS) with and without weights 7. Ambulatory function by classic and FSHD-optimised TUG 8. Physical function by Motor Function Measure (MFM) domain 1 9. Muscle strength by quantitative manual dynamometry 10. Disease impact by subject report using FSHD-Rasch-built Overall Disability Scale (FSHD RODS) 11. Disease impact by subject report using FSHD-HI 12. Disease impact by subject report using Patient Global Impression of Change (PGIC) 13. Upper and lower limb mobility in the outpatient setting using wearables 14. Change in ambulation as measured by the 6-minute walking test (6-MWT) 15. Change in lung ventilatory function as measured by Spirometry Extension: Secondary Endpoints 1. Assessment of the efficacy of treatment with losmapimod as evaluated by whole body skeletal muscle MRI parameters. 2. Assessment of safety and tolerability based on AEs, SAEs, clinically significant laboratory test results, ECGs, and vital signs (safety endpoint). 3. Changes from baseline during treatment in pHSP27 and the ratio of pHSP27/total HSP27 as measured by sorbitol stimulated peripheral whole blood (pharmacodynamic [PD] endpoint). Exploratory Endpoints 1. RWS with and without weights 2. Ambulatory funct | — |
Countries
Netherlands
Outcome results
None listed