Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD)

Facioscapulohumeral Muscular Dystrophy (FSHD) Clinical Trial

— FSHD  

Official title:

A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 48-Week, Parallel-Group Study of the Efficacy and Safety of Losmapimod in Treating Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04003974
• Other study ID #: FIS-002-2019
• Status: Completed
• Phase: Phase 2
• Start date: August 9, 2019
• Est. completion date: January 28, 2021

Study information

• Verified date: February 2022
• Source: Fulcrum Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a study to evaluate the safety and efficacy of Losmapimod in treating patients with Facioscapulohumeral Muscular Dystrophy (FSHD) over 48 weeks.

Description:

This study is a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, multicenter study designed to evaluate the efficacy and safety of losmapimod in treating patients with Facioscapulohumeral Muscular Dystrophy (FSHD) over 48 weeks. Patients will participate in this study for approximately 53 weeks. This will include a 4-week screening period, a 48-week, placebo-controlled treatment period and a 7 day safety follow-up period. Patients must have a confirmed diagnosis of FSHD1 and genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy. Patients will be randomized to receive 15 mg of losmapimod or placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily for 48 weeks. All patients will be asked to attend the study clinic for each scheduled visit.

The primary endpoint of the study is to evaluate the efficacy of losmapimod in inhibiting or reducing expression of DUX4, as measured by a subset of DUX4-regulated gene transcripts in skeletal muscle biopsies of FSHD patients. Secondary endpoints include evaluation of the safety and tolerability of losmapimod, the plasma concentrations of losmapimod, levels of losmapimod in skeletal muscle and losmapimod target engagement in blood and skeletal muscle in FSHD patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 80
• Est. completion date: January 28, 2021
• Est. primary completion date: January 28, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• The patient must have consented to participate and must have provided signed, dated and witnessed IRB-approved informed consent form that conforms to federal and institutional guidelines.

• Male or female subjects

• Patients must be between 18 and 65 years of age, inclusive

• Confirmed diagnosis of FSHD1 with 1 to 9 repeats via assessment of the size of the D4Z4 array on chromosome 4. Genetic confirmation must be obtained prior to the screening MRI and baseline muscle biopsy.

• Clinical severity score of 2 to 4 (RICCI Score; Range 0-5), inclusive at screening

• Must have a MRI-eligible muscle for biopsy

• Must be willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines and other study procedures.

• Will practice an approved method of birth control

Exclusion Criteria:

• 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.

• For subjects who are on drug(s) or supplements that may affect muscle function, as determined by the treating physician, or that are included in the list of drugs presented in the protocol, 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.

• 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.

• Known severe renal impairment (defined as a glomerular filtration rate of <30 mL/min/1.73m2).

• Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or antibodies against human immunodeficiency virus (HIV)-1 and -2.

• Male subjects with a female partner who is planning to become pregnant during the study or within 90 days after the last dose of study drug.

• Use of another investigational product within 30 days or 5 half-lives (whichever is longer), or according to local regulations, or currently participating in a study with an investigational product. Note: concurrent participation in other non-drug studies may be acceptable if confirmed in writing by the sponsor.

Related Conditions & MeSH terms

• Facioscapulohumeral Muscular Dystrophy (FSHD)
• Muscular Dystrophies
• Muscular Dystrophy, Facioscapulohumeral

Intervention

Drug:
• Losmapimod
This study includes a 48 week treatment period. Patients will receive Losmapimod 15 mg twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily. The study drug should be taken with food and the date and time of each dose taken recorded in the subject diary.
• Placebo oral tablet
This study includes a 48 week treatment period. Patients will receive Placebo twice daily given as two 7.5 mg tablets per dose by mouth; for a total of 4 pills or 30 mg daily. The placebo tablets are identical to the Losmapimod tablets. Placebo should be taken with food and the date and time of each dose taken recorded in the subject diary.

Locations

Country	Name	City	State
Canada	Montreal Neurological Institute and Hospital	Montréal	Quebec
Canada	Ottawa Hospital Research Institute	Ottawa	Ontario
France	CHU de NICE- CHU pasteur2	Nice
Spain	Hospital de la Sta Creu i St Pau	Barcelona
Spain	Hospital UiP La Fe	Valencia
United States	Kennedy Krieger Institute	Baltimore	Maryland
United States	Ohio State University	Columbus	Ohio
United States	University of Florida	Gainesville	Florida
United States	University of California Irvine	Irvine	California
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of California Los Angeles (UCLA)	Los Angeles	California
United States	Virginia Commonwealth University	Richmond	Virginia
United States	University of Rochester Medical Center	Rochester	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	University of Washinton Medical Center	Seattle	Washington
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Fulcrum Therapeutics

Countries where clinical trial is conducted

United States,  Canada,  France,  Spain, 

References & Publications (7)

Barbour AM, Sarov-Blat L, Cai G, Fossler MJ, Sprecher DL, Graggaber J, McGeoch AT, Maison J, Cheriyan J. Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers. Br J Clin Pharmacol. 2013 Jul;76(1):99-106. doi: 10.1111/bcp.12063. — View Citation

Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Mäki-Petäjä KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation. 2011 Feb 8;123(5):515-23. doi: 10.1161/CIRCULATIONAHA.110.971986. Epub 2011 Jan 24. — View Citation

de Greef JC, Lemmers RJ, van Engelen BG, Sacconi S, Venance SL, Frants RR, Tawil R, van der Maarel SM. Common epigenetic changes of D4Z4 in contraction-dependent and contraction-independent FSHD. Hum Mutat. 2009 Oct;30(10):1449-59. doi: 10.1002/humu.21091. — View Citation

Han JJ, Kurillo G, Abresch RT, de Bie E, Nicorici A, Bajcsy R. Reachable workspace in facioscapulohumeral muscular dystrophy (FSHD) by Kinect. Muscle Nerve. 2015 Feb;51(2):168-75. doi: 10.1002/mus.24287. Epub 2014 Nov 19. — View Citation

Jagannathan S, Shadle SC, Resnick R, Snider L, Tawil RN, van der Maarel SM, Bradley RK, Tapscott SJ. Model systems of DUX4 expression recapitulate the transcriptional profile of FSHD cells. Hum Mol Genet. 2016 Oct 15;25(20):4419-4431. doi: 10.1093/hmg/ddw271. — View Citation

Statland JM, Tawil R. Risk of functional impairment in Facioscapulohumeral muscular dystrophy. Muscle Nerve. 2014 Apr;49(4):520-7. doi: 10.1002/mus.23949. Epub 2014 Feb 10. — View Citation

Wang LH, Friedman SD, Shaw D, Snider L, Wong CJ, Budech CB, Poliachik SL, Gove NE, Lewis LM, Campbell AE, Lemmers RJFL, Maarel SM, Tapscott SJ, Tawil RN. MRI-informed muscle biopsies correlate MRI with pathology and DUX4 target gene expression in FSHD. Hum Mol Genet. 2019 Feb 1;28(3):476-486. doi: 10.1093/hmg/ddy364. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Reachable Work Space (RWS)	Subjects are seated in front of a 3D camera and asked to perform a standardized upper extremity movement protocol under the supervision of a study clinical evaluator with and without weights.	Weeks 4, 12, 24 and 36
Other	Timed Up and Go (TUG).	Subjects are timed as they start from a seated or laying position, rise to a standing position, walk a total of 6 meters and then return to either a seated or laying position.	Weeks 4, 12, 24 and 36
Other	Muscle Strength	Muscle strength will be assessed by Hand-Held Quantitative Dynamometry.	Weeks 4, 12, 24, 36 and 48
Other	Motor Function Measure (MFM) Domain 1.	The MFM domain 1 is a validated evaluator administered functional measure for neuromuscular disorders, with 13 items related to standing and transfers.	Weeks 12, 24, 36 and 48
Other	FSHD Health Index (FSHD-HI).	The HI is a 15 domain questionnaire designed and based on patient interviews to measure total FSHD health-related quality-of-life, including both motor impairment and the social and emotional impact of FSHD. 116 questions are combined into a total score, the score is transformed onto a percentage scale, with 100 representing maximal disability, and lower scores representing decreasing disability.	Weeks 4, 12, 24, 36 and 48
Other	Patients' Global Impression of Change (PGIC).	The PGIC is a single question that assesses on a scale of 1-7 if there has been an improvement, decline or no change in clinical status.	Weeks 4, 12, 16, 24, 36 and 48
Other	Muscle Disease Transcripts	To evaluate the change from baseline in inflammatory, immune, apoptotic, and muscle disease transcripts in muscle biopsies by quantitative PCR analysis.	Week 16 or Week 36
Other	Circulating Proteins	To evaluate the change from baseline in circulating proteins in plasma and serum by ELISA analysis.	Weeks 4, 12, 16, 24, 36 and 48
Primary	DUX4 activity	Change from baseline in DUX4 activity will be measured by quantitative polymerase chain reaction (qPCR) of skeletal muscle using a subset of DUX4-regulated gene transcripts.	Week 16 or Week 36 if the biopsy could not be obtained at Week 16 due to COVID-19
Secondary	Treatment-Emergent Adverse Events	To evaluate the safety and tolerability of Losmapimod, the incidence of treatment-emergent adverse events will be assessed by clinically significant laboratory test results, ECGs, and vital signs.	Date of enrollment and Weeks 4, 12, 16, 24, 36, 48 and 7 days after the last dose of study drug
Secondary	Muscle Fat Fraction	The change from baseline in muscle fat fraction (MFF) will be measured by musculoskeletal (MSK) magnetic resonance imaging (MRI).	Week 12, Week 24 if applicable and Week 48
Secondary	Lean Muscle Volume	The change from baseline in skeletal lean muscle lean volume will be measured by musculoskeletal (MSK) magnetic resonance imaging (MRI).	Week 12, Week 24 if applicable and Week 48
Secondary	Muscle Fat Infiltration	The change from baseline in skeletal muscle tissue replacement by fat will be measured by musculoskeletal (MSK) magnetic resonance imaging (MRI).	Week 12, Week 24 if applicable and Week 48
Secondary	Plasma Concentrations of Losmapimod	Blood samples will be collected to measure the plasma concentration of losmapimod at specified timepoints.	Weeks 4, 12, 16, 24, 36 and 48
Secondary	Concentration of Losmapimod in Skeletal Muscle	Muscle biopsies will be collected at two specified timepoints to measure the concentration of losmapimod in skeletal muscle.	Week 16 or Week 36 if the biopsy could not be obtained at Week 16 due to COVID-19
Secondary	Target Engagement	Change from baseline in phospho-HSP27 and ratio of pHSP27/total HSP27 will be measured in peripheral whole blood and muscle.	Week 16 or Week 36