A Randomized, Double-Blind, Placebo-Controlled, Multiple Dose Study With an Open-Label Extension to Determine the Safety, Pharmacokinetics and Efficacy of Oral Ifetroban in Subjects With Duchenne Muscular Dystrophy
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 46
- 试验地点
- 10
- 主要终点
- Incidence of Treatment-Emergent Adverse Events
研究概览
简要总结
Duchenne muscular dystrophy (DMD) is a devastating X-linked disease which leads to loss of ambulation between ages 7 and 13, respiratory failure and cardiomyopathy (CM) at any age, and inevitably premature death of affected young men in their late twenties. DMD is the most common fatal genetic disorder diagnosed in childhood. It affects approximately 1 in every 3,500 live male births across all races and cultures, and results in 20,000 new cases each year worldwide.Significant advances in respiratory care have unmasked CM as the leading cause of death. As there are yet no specific cardiac treatments to extend life, the current study aims to address this unmet medical need using a new therapeutic strategy for patients with DMD.
Funding Source - FDA OOPD
详细描述
This is a phase 2 randomized, double-blind, placebo-controlled, multiple dose study with an optional open-label extension to determine the safety, pharmacokinetics (PK) and efficacy of two doses of oral ifetroban in subjects with DMD. DMD patients who meet the inclusion criteria and none of the exclusion criteria will receive oral ifetroban or placebo once daily for 12 months. Subjects will be enrolled into one of three treatment groups, low-dose ifetroban, high-dose ifetroban or placebo. Each dose level will be evaluated by eight subjects with early stage (LVEF > 45%) DMD-associated cardiomyopathy and eight subjects with more advanced stage (LVEF 35-45%) cardiac disease as there may be differences in the treatment effect based on cardiac involvement. Each subject treated will be evaluated for first-dose and steady-state exposure PK. All subjects who receive treatment will be assessed for safety. All subjects with at least one efficacy assessment post-baseline will be evaluated for efficacy. Blood and urine will be collected for standard and novel cardiac biomarkers. Target enrollment met for early-stage subjects (LVEF > 45%); study closed to enrollment prior to meeting target enrollment in the late-stage cohort (LVEF 35-45%). All subjects who complete the 12-month study are eligible to enter an optional open label extension period consisting of treatment with high-dose ifetroban only. Subjects in the open label extension will be evaluated for safety and cardiac efficacy every 12 months.
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
Each individual bottle is labelled with a unique numeric code that identifies the contents to the unblinded sponsor representative.
入排标准
- 年龄范围
- 7 Years 至 —（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Males 7 years of age and older with the diagnosis of DMD, defined as phenotype consistent with DMD and either positive genotype, first degree relative with positive genotype, or confirmatory muscle biopsy.
- •Stable dose of oral corticosteroids for at least 8 weeks or has not received corticosteroids for at least 30 days.
- •Stable cardiac function defined as change in left ventricular ejection fraction (LVEF) of < 15% and no heart failure admission over the last 12 months; LVEF 35% or greater by cine cardiac magnetic resonance imaging (MRI) or echocardiography; myocardial damage in one or more left ventricular segments evident by late gadolinium enhancement allowed; concurrent angiotensin-converting enzyme inhibitors (ACEI), beta-blocker (BB) or angiotensin receptor blocker (ARB) therapy allowed (selection of which dictated by clinical care) if started three months or greater from first dose of IMP without change in dose. Aldosterone receptor antagonists (eg. Spironolactone or eplerenone) allowed if started 12 months or greater from first dose of Investigational Medicinal Product (IMP). No changes throughout the study allowed, except in the event of a decline in left ventricular ejection fraction (LVEF) >5% following the baseline CMR as measured by a subsequent CMR at the same center. Should this occur, changes in cardiac medications are allowed on the study.
- •a. Late-stage cohort: Subjects are eligible for the late-stage cohort if the subject has: i. LVEF 35%-45% by cine cardiac magnetic resonance imaging (MRI) or echocardiography or ii. historically documented LVEF 35%-45% by cine cardiac magnetic resonance imaging (MRI) or echocardiography and if their baseline MRI is less than 50%.
- •Subjects aged 18 years and older, informed consent obtained directly. For subjects ages 7-17 years old (yo), both assent from the subject and permission from a parent or guardian.
排除标准
- •Clinically significant illness other than DMD
- •Clinically significant laboratory abnormality not associated with DMD
- •Major surgery within six weeks prior to the first dose of study drug, or planned surgery during this study which would interfere with the ability to perform study procedures
- •Require antiarrhythmic therapy and/or initiation of diuretic therapy for management of acute heart failure in the last 6 months
- •A LVEF of < 35% by Cardiac Magnetic Resonance Imaging (CMR) and/or fractional shortening of < 15% based on echocardiography (ECHO) during screening
- •A known bleeding disorder or has received anticoagulant treatment within 2 weeks of study entry
- •Allergy to gadolinium contrast or known renal insufficiency defined as abnormal cystatin C or creatinine above the upper limit of normal for age. The male serum reference ranges as follows:
- •Age 7-9 years - 0.2-0.6 mg/dL
- •Age 10-11 years - 0.3-0.7 mg/dL
- •Age 12-13 years - 0.4-0.8 mg/dL
- •Age 14-15 years - 0.5-0.9 mg/dL
- •Age 16 years or older - 0.8-1.3 mg/dL
- •Non-MR compatible implants (e.g. neurostimulator, automatic implantable cardioverter-defibrillator [AICD])
- •Subjects who participated in a therapeutic clinical trial within 30 days or five half-lives (whichever is longer) of study entry
- •Any other condition that could interfere with the subject's participation
研究组 & 干预措施
Oral Ifetroban - Low Dose
Weight based, once daily oral ifetroban
干预措施: Ifetroban (Drug)
Oral Ifetroban - High Dose
Weight based, once daily oral ifetroban
干预措施: Ifetroban (Drug)
Placebos
Matching Placebo
干预措施: Placebo (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events
时间窗: Baseline through 12 months
Percentage of subjects with one or more treatment emergent adverse event
次要结局
- Pharmacokinetics Area Under the Curve(Pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post-dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7)
- Pharmacokinetics Maximum Serum Concentration (Cmax)(Pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7)
- Pharmacokinetics Time to Reach Cmax (Tmax) Concentration(Pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7)
- Pharmacokinetics Plasma Terminal Half-life Concentration(Pre-dose and at 0.5, 1.0, 4.0, 8.0 and 24.0 h post dose on Day 0 and pre-dose and 0.5 h post-dose on Day 7)
- Change From Baseline in Left Ventricular Ejection Fraction(Baseline visit and Month 12 visit)
- Change From Baseline in FEV1(Baseline through month 12)
- Change From Baseline in Percent Predicted FEV1(Baseline through month 12)
- Change From Baseline in FVC(Baseline through month 12)
- Change From Baseline in Percent Predicted FVC(Baseline through month 12)
- Change From Baseline in Maximal Expiratory Pressure(Baseline through month 12)
- Change From Baseline in Maximal Inspiratory Pressure(Baseline through month 12)
- Change From Baseline in Peak Expiratory Flow Rate(Baseline through month 12)
- Change From Baseline in Percent Predicted Peak Expiratory Flow Rate(Baseline through month 12)
- Change From Baseline in Quality-of-life(Baseline through 12 months)