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

NCT ID: NCT04003974

Last Updated: 2024-07-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-08-09
• Study Completion Date: 2021-01-28

Brief Summary

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

Detailed 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.

This study was conducted during the Coronavirus Disease-2019 (COVID-19) Pandemic. The pandemic restrictions limited some assessments in the FSHD1 population in the clinic, including collection of some data for Week 24.

Conditions

Facioscapulohumeral Muscular Dystrophy (FSHD)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Treatment

FSHD1 patients with genetic confirmation 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 for 48 weeks.

Group Type: EXPERIMENTAL

Losmapimod oral tablet

Intervention Type: DRUG

Losmapimod will be administered with food when possible.

Placebo

FSHD1 patients with genetic confirmation will receive a 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.

Group Type: PLACEBO_COMPARATOR

Placebo oral tablet

Intervention Type: DRUG

Placebo will be administered with food when possible

Interventions

Losmapimod oral tablet

Losmapimod will be administered with food when possible.

Intervention Type: DRUG

Placebo oral tablet

Placebo will be administered with food when possible

Intervention Type: DRUG

Other Intervention Names

Placebo

Eligibility Criteria

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
• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fulcrum Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Michelle Mellion, MD

Role: STUDY_DIRECTOR

Fulcrum Therapeutics

Locations

University of California Irvine

Irvine, California, United States

University of California Los Angeles (UCLA)

Los Angeles, California, United States

University of Florida

Gainesville, Florida, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Kennedy Krieger Institute

Baltimore, Maryland, United States

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts, United States

Washington University School of Medicine

St Louis, Missouri, United States

University of Rochester Medical Center

Rochester, New York, United States

Ohio State University

Columbus, Ohio, United States

University of Utah

Salt Lake City, Utah, United States

Virginia Commonwealth University

Richmond, Virginia, United States

University of Washinton Medical Center

Seattle, Washington, United States

Ottawa Hospital Research Institute

Ottawa, Ontario, Canada

Montreal Neurological Institute and Hospital

Montreal, Quebec, Canada

CHU de NICE- CHU pasteur2

Nice, , France

Hospital de la Sta Creu i St Pau

Barcelona, , Spain

Hospital UiP La Fe

Valencia, , Spain

Countries

United States; Canada; France; Spain

References

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Reference Type: BACKGROUND

PMID: 23215699 (View on PubMed)

Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Maki-Petaja 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.

Reference Type: BACKGROUND

PMID: 21262998 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19728363 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 24828906 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28171552 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23873337 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30312408 (View on PubMed)

Tawil R, Wagner KR, Hamel JI, Leung DG, Statland JM, Wang LH, Genge A, Sacconi S, Lochmuller H, Reyes-Leiva D, Diaz-Manera J, Alonso-Perez J, Muelas N, Vilchez JJ, Pestronk A, Gibson S, Goyal NA, Hayward LJ, Johnson N, LoRusso S, Freimer M, Shieh PB, Subramony SH, van Engelen B, Kools J, Leinhard OD, Widholm P, Morabito C, Moxham CM, Cadavid D, Mellion ML, Odueyungbo A, Tracewell WG, Accorsi A, Ronco L, Gould RJ, Shoskes J, Rojas LA, Jiang JG. Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2024 May;23(5):477-486. doi: 10.1016/S1474-4422(24)00073-5.

Reference Type: DERIVED

PMID: 38631764 (View on PubMed)

Jagannathan S, de Greef JC, Hayward LJ, Yokomori K, Gabellini D, Mul K, Sacconi S, Arjomand J, Kinoshita J, Harper SQ. Meeting report: the 2021 FSHD International Research Congress. Skelet Muscle. 2022 Jan 17;12(1):1. doi: 10.1186/s13395-022-00287-8.

Reference Type: DERIVED

PMID: 35039091 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

FIS-002-2019

Identifier Type: -

Identifier Source: org_study_id