Angiotensin II Receptor Blockade in Vascular Ehlers Danlos Syndrome: a Double Blind, Randomized, Placebo Controlled, Multicenter Trial.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 61
- 试验地点
- 15
- 主要终点
- Cardiovascular morbidity and mortality
研究概览
简要总结
This study aims to verify the hypothesis that patients with Vascular Ehlers Danlos syndrome (vEDS) should benefit of the blockade of angiotensin (Ang) II noxious effects on their vasculature affected by a defect in type III collagen in addition to the effects celiprolol. This randomized, double blind, placebo controlled trial compares the administration of the Ang II type I receptor blocker (ARB) - irbesartan- to placebo over a 2-year period in vEDS patients with the main objective to reduce the incidence of both symptomatic and asymptomatic vascular events.
详细描述
vEDS is a rare life-threatening inherited condition due to mutations at the COL3A1 gene encoding the pro-alpha 1 chain of type III procollagen (OMIM #130050) with unpredictable and recurring arterial dissections/aneurysms starting in the early adulthood. The investigators have previously shown that a treatment with 200-400 mg per day of celiprolol, reduces both fatal and non-fatal vascular events in patients with vEDS. If tolerated, the treatment is now the standard treatment for vEDS. However, despite celiprolol , symptomatic and asymptomatic arterial events continue to occur in vEDS patients. Recent findings suggest a possible deleterious effect of endogenous Angiotensin II on medium size arteries in vEDS patients. The hypothesis of this study is that the blockade of endogenous Ang II will provide supplemental vascular protection and thus reduce recurrence of arterial events in vEDS patients.
The primary objective of this study is to determine in patients with molecularly proven vEDS, whether an Ang II receptor blocker, prescribed at an optimally tolerated dose combined with the reference celiprolol treatment, decreases the 24 months rate of both asymptomatic and symptomatic cardiovascular (CV) events when compared to placebo.
Methodology:
Multicenter, double-blind, randomized (1:1), placebo-controlled, parallel group, study with blind endpoint evaluation in adult vEDS patients.
Main criteria for inclusion:
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
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with genetically-proven vEDS (presence of a pathogenic mutation at the COL3A1 gene);
- •Age ≥18 years and <70 years;
- •Men and women with reliable contraception or negative beta-HCG at screening;
- •Celiprolol at the optimal tolerated dose since at least 12 weeks;
- •vEDS patient fully intolerant to celiprolol but not treated with any other drug active on the vascular system, except another beta-blocker;
- •No compelling indication for ARB therapy (renal infarction, hypertension, proteinuric nephropathy, chronic heart failure, myocardial infarction, stroke);
- •Estimated glomerular filtration rate (GFR) ≥ 30ml/min/1,73m2 (MDRD Formula);
- •Normal or clinically acceptable 12-lead ECG;
- •Written informed consent to participate in the study.
排除标准
- •General criteria
- •Unlikely to co-operate in the study and/or poor compliance anticipated by the investigator, e.g., uncooperative attitude, inability to return for follow-up visit, and unlikelihood of completing the study;
- •Participation in another interventional therapeutic study at the same time or within 3 months prior to the beginning of the present study;
- •Participant not affiliated to the French social security;
- •No written informed consent;
- •Severe contrast media allergy, not amenable to pre-treatment Medical and therapeutic criteria
- •History of previous symptomatic visceral complication (any CV event, pulmonary or digestive event) in the 3 months preceding the inclusion;
- •Formal indication for an antihypertensive medication (office BP ≥140/90 mmHg on celiprolol on at least two separated visits, confirmed by daytime ambulatory BP or home BP ≥ 135/85 mmHg);
- •Concomitant treatment with renin-angiotensin-aldosterone system blocking agents apart from the study drug, e.g. ACEI, ARB or aldosterone-antagonist or any renin inhibitor, if given for an elective indication (heart failure, renal infarction, chronic kidney disease, proteinuria, myocardial infarction, stroke);
- •Any cardiac condition that justifies a specific medical care (i.e. second or third degree auriculo-ventricular block, potentially life threatening arrhythmia or other uncontrolled arrhythmia or persistent arrhythmia, clinically significant valvular heart disease);
- •Known significant renal artery stenosis with evidence of renal ischemia (on Duplex ultrasound, CTA, or other exam);
- •Any concurrent life threatening condition other than vEDS with a life expectancy less than 2 years;
- •Likely allergy or hypersensitivity to irbesartan, based on known allergies to drugs of the same class, or which in the opinion of the investigator suggests an increased potential for an adverse hypersensitivity as well as known or suspected contraindications to the study drug;
- •Any condition that in the opinion of the investigator would jeopardize the evaluation of efficacy or safety;
- •Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive Human Chorionic Gonadotropin (hCG) laboratory test (>5 mIU/ml);
- •Women of child-bearing potential (WOCBP) without reliable contraception.
研究组 & 干预措施
Irbesartan
Irbesartan: 150 or 300 mg o.d. for 2 years.The up-titration of irbesartan from 150 mg to 300 mg o.d. occurs during the first 8 weeks following randomization and will be driven by clinical, hemodynamic and biological (plasma creatinine and K) tolerability.
干预措施: Irbesartan (Drug)
Placebo
Placebo once or twice per day for 2 years.
干预措施: Placebo (Drug)
结局指标
主要结局
Cardiovascular morbidity and mortality
时间窗: 2 years
Total number of any non-fatal and fatal cardiovascular events or events related to vEDS
Arterial lesions
时间窗: 2 years
number and severity of arterial lesions detected by CTA
次要结局
- Time to first symptomatic clinical morbid and fatal events(2 years)
- Total number of arterial lesions worsened during follow-up(2 years)
- Rate of any symptomatic cardiovascular event(2 years)
- Occurrence of new asymptomatic arterial lesions (aneurysm, dissection), detected by a systematic CTA(2 years)
- Number of unplanned hospitalization for any vEDS related event(2 years)
- Total number of arterial lesions detected by vascular DUS(2 years)
- Changes in PWV (Pulse Wave Velocity)(2 years)
- Changes in large arteries properties (diameter, wall stress, stiffness)(2 years)
- Decrease in office systolic/diastolic BP(2 years)
- Change in estimated glomerular filtration rate (MDRD)(2 years)
- Tolerability and safety of the irbesartan assessed by orthostatic hypotension, plasma creatinine, plasma K+ evaluated at each visit(2 years)
- Compliance to treatment(2 years)
- Quality of life(2 years)