A Double-blind, Randomized, Placebo-controlled, Clinical Trial to Test the Efficacy of Epoetin Alfa on Physical Performance of Friedreich Ataxia Patients.
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 56
- 试验地点
- 3
- 主要终点
- Peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test (CPET)
研究概览
简要总结
Friedreich's ataxia (FRDA) is a rare genetic disorder characterised by severe neurological disability and cardiomyopathy. Friedreich's ataxia is the consequence of frataxin deficiency. Although several drugs have been proposed, there is no available treatment. Four trials recently demonstrated that erythropoietin can increase the intracellular levels of frataxin. The present project is aimed at testing a long term therapeutic approach using erythropoietin, which is an already available and commercialised drug. The study will test the effect of erythropoietin on exercise capacity, which is reduced in patients with FRDA. Additional objectives of the study will be the drug's safety and tolerability, and its effect on frataxin, blood vessel reactivity, heart functional indexes, and disease progression.
详细描述
Friedreich's ataxia (FA) is an autosomal recessive ataxia caused by a trinucleotide GAA expansion in the first intron of the FXN gene. The gene encodes for a 210aa mitochondrial protein called frataxin, whose mRNA and protein levels are severely reduced in FA. It has been suggested that frataxin is involved in iron-sulphur cluster and heme biogenesis, iron binding/storage, and chaperone activity. Clinically, the age of onset is generally around puberty and, as the disease progresses, there is increasing ataxia of the limbs, and eventually most patients are wheelchair bound by the twenties. Cardiomyopathy with myocardial hypertrophy occurs very often and is the predominant cause of death. Type II diabetes, scoliosis, foot deformities, optic atrophy, and deafness are other relatively frequent symptoms.
Erythropoietin (EPO) is a glycoprotein that acts as a main regulator for erythropoiesis. Evidence suggests that both EPO and its receptor are expressed in the nervous tissue, and neuroprotective effects have been shown in animal models of cerebral ischemic damage. EPO increases frataxin levels in cultured human lymphocytes from FRDA patients. However, frataxin protein increase is not preceded by mRNA increase, suggesting that a post-transcriptional mechanism is involved. To date, four phase II clinical trials have been published regarding the use of EPO in FRDA patients.
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)
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Molecular diagnosis of Friedreich Ataxia
- •Age ≥12 years
- •Body weight ≥30, ≤90 Kg
- •SARA score ≤30
- •Patient able to read and sign the informed consent
- •Patients able to perform a cardiopulmonary test
排除标准
- •Treatment with Erythropoietin in the previous 12 months
- •Treatment with Idebenone
- •Contraindications to CPET: cardiac valve disease, ischemic cardiomyopathy, atrial fibrillation, asthma, chronic obstructive pulmonary disease, other arrhythmias judged as not compatible with exercise.
- •Any Cardiac and/or Hepatic and/or Renal disease judged as clinically relevant by the investigator
- •Any clinically relevant ECG abnormalities that may interfere with the study
- •Any abnormal and clinically relevant laboratory exams at screening visit that may interfere with the trial
- •Anemia with Hemoglobin <10 g/dL
- •Positive history for venous and/or arterial thrombosis
- •Drug-resistant arterial hypertension
- •Positive history for drug-resistant epilepsy
- •Patients in treatment with not allowed study drugs (starting from 3 months prior to screening)
- •Any acute/chronic disease that might interfere with the clinical trial, as judged by the investigator
- •Hypersensitivity to Epoetin alfa or any other component of the study drug
- •Patients not able to comply to the study
- •For female patients (Sexually not active, hysterectomized, sterilized, menopause patients are excluded from the following criteria): pregnancy and/or breastfeeding and/or inadequate contraception.
研究组 & 干预措施
Epoetin alfa
Patients will be treated with Epoetin alfa 1200 IU/Kg s.c. every 12 weeks
干预措施: Epoetin alfa (Drug)
Placebo
Placebo 1200 IU/Kg s.c. every 12 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
Peak oxygen uptake (VO2 max) at the cardiopulmonary exercise test (CPET)
时间窗: 48 weeks
Patients will undergo a complete CPET as described in the methods section. CPET will be performed at baseline (Visit 2), at 24 weeks (Visit 5), and at 48 weeks (Visit 7).
次要结局
- Vascular reactivity(24 and 48 weeks)
- Secondary outcome variables at the CPET (anaerobic threshold, ventilatory efficiency, exercise duration, and power output).(24 and 48 weeks)
- Frataxin levels in peripheral blood mononuclear cells (PBMCs).(all timepoints)
- Echocardiography(24, and 48 weeks)
- Neurological progression(24 and 48 weeks)
- Quality of life(24 and 48 weeks)
- Safety and tolerability(all visits)
研究者
Alessandro Filla
Principal Investigator
Federico II University