|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Facioscapulohumeral Muscular Dystrophy
|Medical condition in easily understood language
|Diseases [C] - Musculoskeletal Diseases [C05]
|E.1.2 Medical condition or disease under investigation
|Facioscapulohumeral muscular dystrophy
|System Organ Class
|10010331 - Congenital, familial and genetic disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|The primary objective of this study is to evaluate the efficacy of losmapimod in inhibiting or reducing expression of DUX4, the root cause of FSHD, as measured by a subset of DUX4-regulated gene transcripts in skeletal muscle biopsies from FSHD subjects.
|Secondary objectives of the trial
|The secondary objectives of this study are:
• To evaluate the safety and tolerability of losmapimod in FSHD subjects
• To evaluate the plasma concentrations of losmapimod and its metabolite GSK198602 in FSHD subjects
• To evaluate the levels of losmapimod and GSK198602 in skeletal muscle in FSHD subjects
• To evaluate losmapimod target engagement in blood and in skeletal muscle in FSHD subjects
|Trial contains a sub-study
|Principal inclusion criteria
|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. 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. Randomization will be stratified to ensure that treatment allocation is balanced across FSHD repeat number categories (ie, 1 to 3 repeats versus 4 to 9 repeats). 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. Clinical severity score of 2 to 4 (RICCI score; range 0-5), inclusive, at screening.
5. Has a MRI-eligible muscle for biopsy, as determined by a central reader.
6. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
7. Willing to practice an approved method of birth control:
• A female subject is eligible to participate if she is of non-child-bearing potential, defined as premenopausal females with permanent sterilization (includes hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a female subject of any age); or postmenopausal, defined as 12 months of spontaneous amenorrhea; or, if of child-bearing potential, if she is using a highly effective method for avoidance of pregnancy and will continue to use these methods for the duration of the study and until 90 days after the last dose of study drug. The decision to include or exclude women of child-bearing potential may be made at the discretion of the investigator and in accordance with local practice in relation to adequate contraception.
• Male subjects must agree to use a contraception method. This criterion must be followed for the duration of the study and until 90 days after the last dose of study drug.
|Principal exclusion criteria
|1. 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, a history of relevant drug or food allergies; history of cardiovascular or central nervous system disease; neuromuscular diseases except FSHD (eg, myopathy, neuropathy, neuromuscular junction disorders); or clinically significant history of mental disease.
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 subjects who are on drug(s) or supplements that may affect muscle function, as determined by the treating physician: subjects 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. Changes to the dose or treatment discontinuation during the study can only be done for strict medical reasons by the treating physician with clear documentation and notification to the sponsor.
4. History of febrile illness within 5 days before randomization. Subjects who were healthy during screening but develop febrile illness in the 5 days before randomization need to have the baseline visit postponed until the febrile illness is fully resolved. Once the febrile illness is fully resolved, the subject’s baseline visit can be scheduled. The duration of the screening visit in such cases can be extended for up to 35 days.
5. Known active tuberculosis, active opportunistic, or life-threatening infections.
6. Acute or chronic history of liver disease or known to have current alanine aminotransferase ≥2 × upper limit of normal (ULN) or total bilirubin >1.5 × ULN, or known history of hepatitis B or C.
7. Known severe renal impairment (defined as a glomerular filtration rate of <30 mL/min/1.73m2).
8. Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency virus (HIV)-1 and -2.
9. Standard 12-lead ECG demonstrating QTcF >450 msec for male subjects or 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.
10. 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.
11. Blood donation (of approximately 1 pint [500 mL] or more) or any significant loss of blood within 90 days before the first dose of study drug, as determined by the investigator.
12. Vaccination with a live attenuated vaccine within 6 weeks of randomization.
|E.5 End points
|Primary end point(s)
|The primary endpoint of this study is the change from baseline in DUX4 activity in affected skeletal muscle at 16 weeks, as measured by QRT-PCR in a panel of DUX4-regulated gene transcripts.
|Timepoint(s) of evaluation of this end point
|Secondary end point(s)
|• Adverse events, SAEs, laboratory tests, ECGs, vital signs, and physical examinations
• Plasma concentrations of losmapimod and its metabolite GSK198602
• Concentrations of losmapimod and its metabolite in skeletal muscle biopsy at steady state
• Target engagement parameters in blood and skeletal muscle biopsy
|Timepoint(s) of evaluation of this end point
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The end of the study is defined as the date on which the last subject completes the last visit (includes the safety follow-up visit).
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months
|In all countries concerned by the trial days