Phase 3 Randomized Double-Blind Placebo-Controlled Study on Losmapimod Efficacy and Safety in Facioscapulohumeral Muscular Dystrophy Patients
- Trial ID
- 2024-512737-33-00
- Protocol
- 1821-FSH-301
- Sponsor
- Fulcrum Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of losmapimod in treating patients with **Facioscapulohumeral Muscular Dystrophy (FSHD)** by assessing disease progression. This is measured through RWS quantification of total RSA Q1-Q5 with a 500 g wrist weight averaged over both arms. Additionally, the study aims to assess the long-term safety and tolerability of losmapimod in patients with FSHD. The clinical relevance of this objective lies in potentially providing a therapeutic option that could slow disease progression and improve patient outcomes in FSHD, a condition characterized by progressive muscle weakness.
Secondary objectives for Part A include: - Evaluating the Patient Global Impression of Change (PGIC) relative to placebo. - Assessing the efficacy of losmapimod in slowing the accumulation of fat in muscle using Muscle Fat Infiltration (MFI) with Whole-Body Musculoskeletal MRI relative to placebo. - Evaluating the relative change from baseline in shoulder strength using hand-held quantitative dynamometry relative to placebo. - Assessing the change in Neuro-QoL Upper Extremity (UE) relative to placebo. - Evaluating the safety and tolerability of losmapimod in patients with FSHD.
Participants
The clinical trial involves a total of **116 participants** diagnosed with **Facioscapulohumeral Muscular Dystrophy (FSHD)**, a genetic muscle disorder. The study population includes both male and female subjects, aged between 18 and 65 years. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of FSHD1 or FSHD2 through genetic testing and a Clinical Severity Score of 2 to 4. The trial population is not limited to any specific lifestyle considerations such as diet or physical activity, but participants must be willing and able to comply with scheduled visits and study procedures. The study does not include individuals who are wheelchair-dependent or reliant on a walker for activities. Both male and female participants are required to adhere to contraceptive guidelines during the study and for a specified period after the last dose of the study drug. The trial aims to evaluate the efficacy and long-term safety of losmapimod in treating FSHD.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of **losmapimod** in treating patients with **Facioscapulohumeral Muscular Dystrophy (FSHD)**. The trial is structured as a parallel-group study with a duration of 48 weeks. Participants will be randomly assigned to receive either losmapimod or a placebo, with the treatment administered orally in tablet form. The primary objective is to assess the change from baseline in average total RSA Q1-Q5 with a 500 g wrist weight at Week 48, while secondary endpoints include various measures of muscle function and safety assessments.
The trial will commence with an inclusion (screening) visit, where potential participants will undergo genetic testing to confirm a diagnosis of FSHD1 or FSHD2, and other eligibility criteria will be assessed. Randomization will be stratified to ensure balanced treatment allocation. Participants will be required to have a Clinical Severity Score of 2 to 4 and meet other specific criteria, including age and reproductive status requirements. Following the screening, participants will enter Part A of the study, which involves 48 weeks of treatment. Those who complete Part A may continue into Part B, focusing on the long-term safety and tolerability of losmapimod.
Study visits will occur at regular intervals throughout the trial to monitor efficacy and safety. These visits will include assessments such as clinical laboratory tests, ECGs, vital signs, and physical examinations. The end-of-study visit will mark the conclusion of the participant's involvement, with final evaluations conducted to assess the primary and secondary endpoints. The expected length of participant involvement is up to 48 weeks, with conditions for early termination including non-compliance with the study protocol or the occurrence of adverse events that warrant discontinuation.
Treatment
The clinical trial involves the administration of **Losmapimod**, a chemical compound developed by Fulcrum Therapeutics, Inc. Losmapimod is provided in tablet form for **oral use**. Each tablet contains 15 mg of the active substance, and the maximum daily dose is 30 mg. The total dose over the treatment period can reach up to 30,240 mg, with a maximum treatment duration of 144 weeks. The dosing schedule is designed to ensure consistent administration, and participant compliance is monitored throughout the study to maintain the integrity of the trial data.
In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo tablets are visually identical to the active Losmapimod tablets, ensuring that neither the participants nor the investigators can distinguish between the two. This placebo is also administered orally and matches the 15 mg dosage of the active treatment. The use of a placebo is critical in assessing the efficacy and safety of Losmapimod in treating patients with **Facioscapulohumeral Muscular Dystrophy (FSHD)**, as it allows for a controlled comparison of outcomes between the treatment and non-treatment groups.
Efficacy
The efficacy of losmapimod in treating patients with **Facioscapulohumeral Muscular Dystrophy (FSHD)** will be assessed through a Phase 3, randomized, double-blind, placebo-controlled, 48-week study. The primary efficacy endpoint for Part A of the trial is the change from baseline in the average total RSA Q1-Q5 with a 500 g wrist weight at Week 48, averaged over both arms. Secondary efficacy endpoints include the Patient Global Impression of Change (PGIC) at Week 48, change from baseline in whole-body longitudinal composite muscle function index (MFI) of B muscles at Week 48, relative change from baseline in average shoulder abductor strength by hand-held quantitative dynamometry at Week 48, and change from baseline in Neuro-QoL upper extremity (UE) at Week 48. Efficacy assessments will be conducted using validated scales and instruments at specified timepoints, ensuring a comprehensive evaluation of losmapimod's impact on disease progression and patient-reported outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Part A: 1. Patient will sign and date an ICF 2. Patients will have a diagnosis of FSHD1 or FSHD2 verified by genetic testing − Randomization will be stratified for FSHD1 to ensure that treatment allocation is balanced across FSHD repeat number categories (ie, 1 to 3 repeats versus 4 to 9 repeats). − Randomization will be stratified for FSHD2 to ensure that an equal number of patients will be allocated to treatment and placebo. 3. Patients will have a Clinical Severity Score of 2 to 4 (Ricci score; range 0 to 5) at screening. Patients who are wheelchair-dependent or dependent on walker or wheelchair for activities are not permitted to enroll in the study. 4. Patients with screening total RSA (Q1-Q4) without weight in the dominant UE assessed by RWS ≥ 0.2 and ≤ 0.7. 5. Willing and able to comply with scheduled visits, treatment plan and other study procedures 6. No contraindications to MRI 7. Patients (male and female) will be between the ages of 18 and 65 years at the time of consent, inclusive − A female patient is eligible to participate if she is of non-child bearing potential, defined as pre-menopausal females with a documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy; if she is postmenopausal, defined as no menses for 12 months without an alternative medical cause; OR − if of child-bearing potential, she is using a highly effective method for avoidance of pregnancy for the duration of dosing and until 90 days after the last dose of study drug − Male patients must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication and until 90 days after the last dose of study drug Part B: 1. Patient completed 48 weeks of treatment during Part A. 2. Patient will sign and date an ICF. 3. Patient is willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures. 4. Patient agrees to the following methods of contraception: - Female patients of childbearing potential agree to continue using a highly effective method for avoidance of pregnancy for the duration of dosing and until 90 days after the last dose. - Male patients must agree to use one of the contraception methods listed in Section 5.5.1 of the protocol. This criterion must be followed from the time of the first dose of study medication and until 90 days after the last dose of study drug.
Exclusion Criteria
- Part A: 1. History of any illness or any clinical condition that might confound the results of the study or pose an additional risk in administering study drug to the patient. 2. Previously diagnosed cancer that has not been in complete remission for at least 5 years. Localized carcinomas of the skin and carcinoma in situ of the cervix that have been resected or ablated for cure are not exclusionary. 3. For patients who are on drug(s) or supplements that may affect muscle function or that are included in the list of drugs presented in Appendix 3 of the Protocol: pt 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. 4. History of febrile illness within 5 days before the first study drug dose 5. Known active opportunistic or life-threatening infections including HIV and hepatitis B or C 6. Known active or inactive tuberculosis infection. 7. Current acute liver disease or chronic liver disease as defined by any of the following: current ALT ≥2 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN (unless participant has Gilbert's syndrome characterized by the combination of total bilirubin < 3 × ULN, direct bilirubin within the normal range and normal ALT and AST, or the presence of mutations in the UDP-glucuronosyltransferase 1 gene, indicative of Gilbert's syndrome); or Positive for hepatitis B or surface antigen; or Positive for hepatitis C antibody unless additional testing for hepatitis C viral RNA is negative, ALT is < 2 × ULN and total bilirubin is ≤1.5 × ULN, indicating inactive/resolved hepatitis C infection 8. Known severe renal impairment (defined as a glomerular filtration rate of < 30 mL/min/1.73 m2). 9. Standard 12-lead ECG demonstrating QTcF >450 msec for male patients and QTcF >470 msec for female patients 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 patient's eligibility. 10. History of cardiac dysrhythmias requiring anti-arrhythmia treatment(s); or history or evidence of abnormal ECGs 11. Male patients with a female partner who is planning to become pregnant during the study or within 90 days after the last study drug dose
- Concomitant use of cytotoxic chemotherapy for cancer or known ongoing or anticipated use of chronic severe immunosuppressive agents. 13. Positive pregnancy test or known to be pregnant or lactating or planning to become pregnant during study drug administration and until 90 days after last dose 14. Any current mental condition (psychiatric disorder, senility or dementia) 15. Patient has any condition possibly affecting drug absorption 16. History of alcohol, analgesic/opioid, and/or illicit drug abuse, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (American Psychiatric Association, 2013), in the last 6 months before screening or a positive test for drugs of abuse at screening. Use of CBD/THC is permitted 17. Use of another IP within 30 days or 5 half-lives 18. Current or anticipated participation in a natural hx study. 19. Known hypersensitivity or intolerance to losmapimod or any of its excipients 20. Previous participation in a Fulcrum-sponsored FSHD losmapimod study 21. Anticipated inability to comply with any study procedures, study visits according to the visit schedule through 48 weeks. 22. Abnormal laboratory results indicative of any significant medical disease 23. Pt, or close relative of the patient to staff directly involved with the conduct of the study 24. Pt is vulnerable (i.e., deprived of freedom), including inmates of psychiatric wards and prison or state institutions, patients with commitments to an institution, or a patient who is detained or committed to an institution by a law court or by legal authorities. 25. For Italy only: Vaccination with a live attenuated vaccine within 6 weeks prior to randomization until the safety follow-up visit Part B: 1. 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 patient. 2. Male patients with a female partner who is planning to become pregnant during the study or within 90 days after the last study drug dose. 3. Anticipated inability to comply with any study procedures, including participation in study visits.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 31 Aug 2022 | 12 |
 France | Not Recruiting | 31 Aug 2022 | 22 |
 Germany | Not Recruiting | 31 Aug 2022 | 39 |
 Italy | Not Recruiting | 31 Aug 2022 | 8 |
 The Netherlands | Not Recruiting | 31 Aug 2022 | — |
 Spain | Not Recruiting | 31 Aug 2022 | 37 |
| Netherlands | — | — | 26 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
PL1 - Placebo to match losmapimod tablets are tablets for oral administration and visually match the active losmapimod tablets, 15 mg. | Placebo | N/A | — | — | — | N/A |
Losmapimod | Test | TABLET | ORAL USE | 30 | 144 | PRD11470016 |