Clinical trial NCT04003974: Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Facioscapulohumeral Muscular Dystrophy (FSHD)
Keywords: FSHD, FSHD1
Muscular Dystrophies
Muscular Dystrophy
Facioscapulohumeral Muscular Disorders
Musculoskeletal Diseases
Neuromuscular Diseases
Lead sponsor: Fulcrum Therapeutics
Sponsor class: INDUSTRY
First posted: 2019-07-01
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This study is a randomized, double-blind, placebo-controlled, 48-week parallel-group study.
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change From Baseline in Double Homeobox 4 (DUX4) Activity in Affected Skeletal Muscle
timeFrame: Baseline and Week 16 to Week 36
Secondary outcomes:
measure: Number of Participants With Type of Adverse Events (AEs) to Losmapimod
timeFrame: Up to Week 48
measure: Number of Participants With Severity of AEs to Losmapimod
timeFrame: Up to Week 48
measure: Number of Participants With Relationship of AEs to Losmapimod
timeFrame: Up to Week 48
measure: Number of Participants With Adverse Events of Special Interest (AESIs)
timeFrame: Up to Week 48
measure: Number of Participants Who Prematurely Discontinued Study Drug Due to a Treatment Emergent Adverse Event (TEAE)
timeFrame: Up to Week 48
measure: Change From Baseline in Muscle Fat Fraction (MFF) at Week 12, Week 24 and Week 48
timeFrame: Baseline and at Week 12, Week 24 and Week 48
measure: Change From Baseline in Lean Muscle Volume (LMV) at Week 12, Week 24 and Week 48
timeFrame: Baseline and at Week 12, Week 24 and Week 48
measure: Change From Baseline in Muscle Fat Infiltration (MFI) at Week 12, Week 24 and Week 48
timeFrame: Baseline and at Week 12, Week 24 and Week 48
measure: Plasma Concentration After Administration of Losmapimod
timeFrame: Pre dose, 4 hours post dose, Week 4 pre dose, Week 4: 4 hours post dose, Week 12, Week 16 pre dose, Week 16: 4 hours post dose, Week 24, Week 36 pre dose, Week 36: 4 hours post dose, Week 48
measure: Concentration of Losmapimod in Skeletal Muscle Biopsy
timeFrame: Baseline, Week 16 and Week 36
measure: Percent Change From Baseline in Phosphorylated Heat Shock Protein 27 (pHSP27)/Total Heat Shock Protein 27 (tHSP27)
timeFrame: Baseline and at Day 1: 4 hours post dose, Week 16: pre dose, Week 16: 4 hours post dose, Week 36 pre dose, Week 36: 4 hours post dose
Other outcomes:
measure: Change From Baseline in Reachable Work Space (RWS) Dominant and Non-dominant Total Relative Surface Area (RSA) With Weight Quintant (Q)1 to Q5
timeFrame: Baseline and Week 4, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in Classic Timed Up and Go (TUG) Average Completion Time
timeFrame: Baseline and at Week 4, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in Facioscapulohumeral Muscular Dystrophy (FSDH) TUG Average Completion Time
timeFrame: Baseline and at Week 4, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in All Muscles Total Average Strength as Assessed by Hand-held Dynamometry
timeFrame: Baseline and at Week 4, Week 12, Week 24, Week 36 and Week 48
measure: Change From Baseline in Motor Function Measure (MFM) Domain 1 Score
timeFrame: Baseline and at Week 48
measure: Change From Baseline in FSHD Health Index (HI)
timeFrame: Baseline and at Week 48
measure: Number of Participants With Improved and Not Improved Response to Patients' Global Impression of Change (PGIC)
timeFrame: At Week 48
Locations:
city: Irvine
country: United States
facility: University of California Irvine
state: California
city: Los Angeles
country: United States
facility: University of California Los Angeles (UCLA)
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baltimore
country: United States
facility: Kennedy Krieger Institute
state: Maryland
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: University of Washinton Medical Center
state: Washington
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Montréal
country: Canada
facility: Montreal Neurological Institute and Hospital
state: Quebec
city: Nice
country: France
facility: CHU de NICE- CHU pasteur2
city: Barcelona
country: Spain
facility: Hospital de la Sta Creu i St Pau
city: Valencia
country: Spain
facility: Hospital UiP La Fe
Study officials:
affiliation: Fulcrum Therapeutics
name: Michelle Mellion, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
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.
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.
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.
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.
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.
citation: 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.