EVOLVD: Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 130
- 试验地点
- 5
- 主要终点
- Maximal intimal thickness
研究概览
简要总结
The main goal of this study is to evaluate the effect of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab on cardiac allograft vasculopathy in de novo heart transplant recipients.
Secondary objectives are to assess the impact of treatment on: i) cholesterol levels, ii) renal function, iii) inflammation, iv) quality of life, v) cardiac function as assessed by biomarkers and echocardiography, vi) the number of rejections, and (vii) safety and tolerability. As an exploratory outcome, the investigators will asses the effect of treatment on clinical events (death, myocardial infarction, cerebral stroke, cancer, end stage renal disease).
详细描述
Cardiac allograft vasculopathy is an important cause of morbidity and mortality in heart transplant recipients. Previous data show that, although clinical coronary artery disease often manifests years after heart transplantation, there are substantial changes in the coronary artery intima thickness over the first year after transplantation, suggesting that the adverse process starts shortly after transplantation. Moreover, the investigator's previous data have suggested that, whereas early intervention can prevent the long-term progression of cardiac allograft vasculopathy, the same intervention is less effective when administered late after heart transplantation. Thus, there seems to be a window of opportunity for preventive measures against cardiac allograft vasculopathy in de-novo transplant recipients.
The strong association between cholesterol levels and coronary heart disease in the general population, the high cholesterol levels in heart transplant recipients, the high prevalence of vasculopathy in the cardiac allograft, and the association between cholesterol levels and cardiac allograft vasculopathy together provide a strong rationale for aggressive cholesterol lowering in heart transplant recipients. Statins improve outcomes in heart transplant recipients, but their limited effect on post-transplant cholesterol levels, adverse effects, and drug interactions contribute to their not providing sufficient prophylaxis against post-transplant atherosclerotic disease.
Evolocumab is a well-tested drug with a favourable safety profile. It effectively reduces cholesterol levels on top of statin therapy in patients with coronary heart disease. The investigators hypothesise that evolocumab on top of statin therapy will significantly lower low density lipoprotein (LDL) levels in de novo heart transplant recipients. The investigators assume that this reduction in cholesterol levels will manifest as a reduced burden of cardiac allograft vasculopathy as measured by intracoronary ultrasound. Ultimately, the investigators believe that a reduced burden of vasculopathy will translate to reduced morbidity and long-term mortality in heart transplant recipients. The EVOLVD trial is a randomised, placebo-controlled, double-blind study designed to test the hypothesis that treatment with evolocumab can ameliorate cardiac allograft vasculopathy in heart transplant recipients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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 will be screened for eligibility during routine follow-up 4 - 8 weeks after heart transplantation. All of the following conditions must apply prior to administering the investigational medicinal product:
- •Heart transplant recipient within the last 4 - 8 weeks.
- •Age between 18 and 70 years.
- •Informed consent obtained and documented according to Good Clinical Practice (GCP), and national/regional regulations.
- •No contraindications to coronary angiography with intravascular ultrasound
- •Estimated glomerular filtration rate > 20 ml/min/1.73 m2 as assessed by the MDRD formula.
排除标准
- •Patients will be excluded from the study if they meet any of the following criteria:
- •Decompensated liver disease (Child-Pugh class C)
- •Severe renal failure, i.e. eGFR < 20 ml/min/1.73 m2 or on renal replacement therapy
- •Ongoing rejections or infections
- •Known sensitivity or intolerance to evolocumab or any of the excipients of Repatha®
- •Prior use of PCSK9 inhibition treatment
- •Alcohol or drug abuse within 3 months of informed consent that would interfere with trial participation or any ongoing condition leading to decreased compliance with study procedures or study drug intake
- •Participation in another clinical trial involving an investigational drug and/or follow-up within 30 days prior to enrolment.
- •Pregnancy.
- •Female subject who has either (1) not used at least one highly effective method of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment and for an additional 15 weeks after the end of treatment, unless the subject is sterilised or postmenopausal.
研究组 & 干预措施
Evolocumab
Evolocumab (Repatha®) will be administered subcutaneously once monthly in the abdomen, thigh, or upper arm for the duration of the treatment period (one year). The 420 mg evolocumab/placebo will be administered by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector.
干预措施: Evolocumab (Drug)
Placebo
The placebo is presented in an identical prefilled autoinjector. It is supplied as a sterile, single-use, preservative-free solution for subcutaneous injection in a disposable, spring-based prefilled autoinjector. The prefilled autoinjector contains a 1.0 mL deliverable volume of 1.1% (w/v) sodium carboxymethylcellulose, 250 mM proline, 10 mM acetate, and 0.01% (w/v) polysorbate 80, pH 5.0.
干预措施: Placebo (Drug)
结局指标
主要结局
Maximal intimal thickness
时间窗: 12 months
The maximal intimal thickness will be measured by coronary intravascular ultrasound at 12 months after randomization. The maximal intima thickness is defined as the largest distance (in mm) from the intimal leading edge to the external elastic membrane.
次要结局
- Low-density lipoprotein (LDL) cholesterol(12 months)
- Total atheroma volume(12 months)
- The index of microvascular resistance(12 months)
- Number of adverse events (AE)(12 months)
- Cardiac allograft vasculopathy(12 months)
- Estimated glomerular filtration rate (eGFR)(12 months)
- The 36-item short form health survey questionnaire (SF-36)(12 months)
- Number of rejections(12 months)
- Number of major clinical adverse events(12 months)
- N-terminal pro-B-type natriuretic peptide (NT-proBNP)(12 months)
- The 3-level version of EQ-5D (EQ-5D-3L) questionnaire(12 months)
- The Beck Depression Inventory (BDI)(12 months)
- Cardiac troponin T (TnT)(12 months)
研究者
Lars Gullestad
Professor
Oslo University Hospital