A Double-Blind, Placebo-controlled Study on the Effects of MIN-102 on Biochemical, Imaging, Neurophysiological, and Clinical Markers in Patients With Friedreich's Ataxia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 39
- 试验地点
- 5
- 主要终点
- Change from Baseline in spinal cord area cervical segment C2-C3 [mm²]
研究概览
简要总结
Randomized, double-blind, placebo-controlled study on the effects of MIN-102 on Biochemical, Imaging, neurophysiological, and clinical markers in patients with Friedreich's Ataxia
详细描述
This study investigated whether treatment with MIN-102 was able to influence clinical, neurophysiological, and imaging parameters, as well as various peripheral and central nervous system biochemical markers related to mitochondrial dysfunction, in patients with Friedreich's ataxia (FRDA), over a period of 48 weeks in a double-blind, placebo-controlled design.
Patients were screened following written consent (and assent if the patient was a minor) at the Screening visit (V-1). Eligible patients attended a Baseline visit (V0) within a maximum of 28 days after V-1 and were randomized in a 2:1 ratio to receive an individualized starting dose of MIN-102 or placebo, which they took daily for 48 weeks. Patients received individualized starting doses based on gender and age, which were subsequently modified based on pharmacokinetic (PK) parameters obtained from blood samples at V1 to achieve a target MIN-102 exposure of 170 μg.hr/mL.
In addition to the Screening visit (V-1) and Baseline visit (V0), patients were evaluated at 2 interim safety visits (ISV) occurring 2 and 8 weeks after V0 (ISV1 and ISV2; permitted to be home visits performed by a Good Clinical Practice [GCP]-certified nurse), and at 4 weeks (V1), 12 weeks (V2), 24 weeks (V3), 36 weeks (V4), and 48 weeks (V5) after V0.
Results of all scheduled assessments were made available to the investigator as soon as possible. Patients received regularly scheduled phone calls at 6, 10, 16, 20, 28, 32, 40, and 44 weeks after V0 to review changes in concomitant medications and adverse events (AEs), particularly for symptoms possibly indicative of cardiac failure. A Final Follow-up Visit (FUV) took place 4 weeks after the last dose of study drug.
Evaluations consisted of imaging evaluations at V0, V3, and V5, evaluations of clinical status using the Scale for the Assessment and Rating of Ataxia (SARA), cerebellar composite functional scale (CCFS), global clinical rating scales, and patient questionnaires at V0, V3, and V5, assessment of biochemical markers in plasma at V0, V2, V3, and V5, and blood sampling for plasma levels of MIN-102 and its main metabolite (M3) at all scheduled on-site visits (except for ISV1 and ISV2). Assessments for safety and tolerability included collection of AEs, as well as electrocardiograms (ECGs), echocardiograms, and laboratory tests. Palatability was assessed at V0, V1, V2, V3, and V4. Measurements of motor evoked potentials (MEPs) and assessment of biochemical markers in cerebrospinal fluid (CSF) were optional evaluations at V0, V3, and V5. All assessments for safety, tolerability, and biochemical markers in plasma were also performed at premature discontinuation.
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 12 Years 至 60 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female subjects aged ≥12 and ≤60 years, inclusive, with a genetically confirmed diagnosis of Friedreich's Ataxia.
- •Be able to walk >10 meters with support (two special sticks, stroller, or accompanying person).
- •Total score on the Scale for the Assessment and Rating of Ataxia (SARA) of <25.
排除标准
- •Age of onset of disease ≥25 years.
- •Higher degree of cardiomyopathy assessed by echocardiogram.
- •Diabetes.
研究组 & 干预措施
MIN-102
MIN-102 (5-[[4-[2-[5-(1-Hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione hydrochloride (1:1)). Dosing is once daily at approximately the same time each morning throughout the entire treatment phase (48 weeks).
干预措施: MIN-102 (Drug)
Placebo
Matches MIN-102 visually and by taste. Dosing is once daily at approximately the same time each morning throughout the entire treatment phase (48 weeks).
干预措施: Placebo (Drug)
结局指标
主要结局
Change from Baseline in spinal cord area cervical segment C2-C3 [mm²]
时间窗: Baseline to 48 weeks
Spinal cord area cervical segment C2-C3 area was assessed at Baseline, Week 24, and Week 48 by morphometric magnetic resonance imaging (MRI) measurements. Morphometric changes in MRI parameters are associated with measures of clinical decline. In normal disease etiology, the spinal cord exhibits an initial decrease in area, and then reaches a plateau after 7-8 years from disease onset.
次要结局
- Change from Baseline in quantitative susceptibility mapping (QSM) for iron concentration (ppb) at Week 48(Baseline to 48 weeks)
- Change from Baseline in dentate nuclei volume at Week 48(Baseline to 48 weeks)
- Change from Baseline in fixel-based analysis (FBA) of the brain at Week 48: fiber cross-section (FC)(Baseline to 48 weeks)
- Change from Baseline in fixel-based analysis (FBA) of the brain at Week 48: fiber density (FD)(Baseline to 48 weeks)
- Change from Baseline in SARA total score at Week 48(Baseline to 48 weeks)
- Change from Baseline in cervical spinal cord (C2-C7) in fractional anisotropy at Week 48(Baseline to 48 weeks)
- Change from Baseline in cervical spinal cord (C2-C7) in mean, axial, and radial diffusivity (10-³ mm²/s) at Week 48(Baseline to 48 weeks)
- Change from Baseline in spinal cord total N-acetylaspartate concentration/myo-inositol (tNAA/mIns) ratio as assessed by magnetic resonance spectroscopy (MRS) at Week 48(Baseline to 48 weeks)
- Change from Baseline in fixel-based analysis (FBA) of the brain at Week 48: fiber density and cross-section (FDC)(Baseline to 48 weeks)
- Change from Baseline in Cerebellar Composite Functional Scale (CCFS) at Week 48(Baseline to 48 weeks)
- Change from Baseline in quality of life as measured by European Quality of Life 5 Dimensions (EQ-5D-5L) at Week 48(Baseline to 48 weeks)
- Change from Baseline in fatigue severity scale (FSS) at Week 48(Baseline to 48 weeks)
- Change from Baseline in Activities of Daily Living subscale of Friedreich's Ataxia Rating Scale (FARS) at Week 48(Baseline to 48 weeks)
- Change from Baseline in Clinician Global Impression of Severity (CGI-S) at Week 48(Baseline to 48 weeks)
- Assessment from Baseline in Clinician Global Impression of Improvement (CGI-I) at Week 48(24 weeks and 48 weeks)
- Assessment from Baseline in Patient Global Impression of Improvement (PGI-I) at Week 48(24 weeks and 48 weeks)
- Percentage of patients responding to palatability of study drug questions(Baseline, Week 4, Week 12, Week 24, and Week 36)
- Frequency and severity of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs)(Baseline to Final Follow-up Visit (approximately 52 weeks))
- Vital signs: percentage change from Baseline in body weight (kg)(Baseline to Final Follow-up Visit (approximately 52 weeks))
- Vital signs: change from Baseline in blood pressure (mmHg)(Baseline to Final Follow-up Visit (approximately 52 weeks))
- Vital signs: change from Baseline in pulse rate (beats/min)(Baseline to Final Follow-up Visit (approximately 52 weeks))
- Vital signs: change from Baseline in body temperature (°C)(Baseline to Final Follow-up Visit (approximately 52 weeks))
- Number of patients with abnormal, clinically significant electrocardiogram (ECG) and echocardiogram interpretations(Baseline to Final Follow-up Visit (approximately 52 weeks))
- Number of patients with abnormal, clinically significant physical examination findings(Screening to Final Follow-up Visit (approximately 56 weeks))