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)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 80
- 试验地点
- 17
- 主要终点
- Change From Baseline in Double Homeobox 4 (DUX4) Activity in Affected Skeletal Muscle
研究概览
简要总结
This is a study to evaluate the safety and efficacy of Losmapimod in treating patients with Facioscapulohumeral Muscular Dystrophy (FSHD) over 48 weeks.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
This study will be performed in a double-blind fashion. The investigator, study staff, subjects, sponsor and monitor will remain blinded to the treatment until study closure.
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
排除标准
- •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 -
- •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.
研究组 & 干预措施
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.
干预措施: Losmapimod oral tablet (Drug)
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.
干预措施: Placebo oral tablet (Drug)
结局指标
主要结局
Change From Baseline in Double Homeobox 4 (DUX4) Activity in Affected Skeletal Muscle
时间窗: Baseline and Week 16 to Week 36
Skeletal muscle biopsies were collected at Baseline and post-Baseline. DUX4 activity in skeletal muscle biopsies was assessed by measuring expression levels of a panel of 6 genes known to be regulated by DUX4. Expression levels of genes were measured using a validated quantitative RT-PCR assay and expressed as Ct (PCR cycles). Raw Ct for each of the 6 genes was normalized to the specified reference genes to generate a normalized Ct. The DUX4 activity is the average of the normalized Cts of each of the identified 6 genes, where the Ct for each of the 6 genes is first normalized to reference genes before the average is generated. Change in Baseline is calculated as \[average delta Ct across the 6 genes post-baseline\] minus \[average delta Ct across the 6 genes at baseline\].
次要结局
- Plasma Concentration After Administration of Losmapimod(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)
- Number of Participants With Type of Adverse Events (AEs) to Losmapimod(Up to Week 48)
- Number of Participants With Severity of AEs to Losmapimod(Up to Week 48)
- Number of Participants With Relationship of AEs to Losmapimod(Up to Week 48)
- Number of Participants With Adverse Events of Special Interest (AESIs)(Up to Week 48)
- Number of Participants Who Prematurely Discontinued Study Drug Due to a Treatment Emergent Adverse Event (TEAE)(Up to Week 48)
- Change From Baseline in Muscle Fat Fraction (MFF) at Week 12, Week 24 and Week 48(Baseline and at Week 12, Week 24 and Week 48)
- Change From Baseline in Lean Muscle Volume (LMV) at Week 12, Week 24 and Week 48(Baseline and at Week 12, Week 24 and Week 48)
- Change From Baseline in Muscle Fat Infiltration (MFI) at Week 12, Week 24 and Week 48(Baseline and at Week 12, Week 24 and Week 48)
- Concentration of Losmapimod in Skeletal Muscle Biopsy(Baseline, Week 16 and Week 36)
- Percent Change From Baseline in Phosphorylated Heat Shock Protein 27 (pHSP27)/Total Heat Shock Protein 27 (tHSP27)(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)