Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients (EVOLVD)
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|ClinicalTrials.gov Identifier: NCT03734211|
Recruitment Status : Not yet recruiting
First Posted : November 7, 2018
Last Update Posted : April 19, 2019
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).
|Condition or disease||Intervention/treatment||Phase|
|Cardiac Allograft Vasculopathy||Drug: Evolocumab Drug: Placebo||Phase 3|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||130 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||EVOLVD: Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients|
|Estimated Study Start Date :||May 15, 2019|
|Estimated Primary Completion Date :||October 31, 2021|
|Estimated Study Completion Date :||December 1, 2021|
420 mg evolocumab will be administered subcutaneously by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector.
Other Name: Repatha
|Placebo Comparator: Placebo||
Placebo will be administered subcutaneously by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector.
- Maximal intimal thickness [ Time Frame: 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.
- Cardiac allograft vasculopathy [ Time Frame: 12 months ]Incidence of cardiac allograft vasculopathy, defined as mean a maximal intimal thickness ≥0.5 mm over the entire matched segment, will be measured by intravascular ultrasound 12 months after randomization.
- Total atheroma volume [ Time Frame: 12 months ]The total atheroma volume will be measured by intravascular ultrasound.
- The index of microvascular resistance [ Time Frame: 12 months ]The index of microcirculatory resistance will be obtained at the time of routine coronary angiography after heart transplantation at baseline (4-10 weeks) and at the end of treatment 12 months after randomization.
- Low-density lipoprotein (LDL) cholesterol [ Time Frame: 12 months ]Blood lipids must be assessed after end-of treatment only, to avoid what will effectively amount to study drug allocation unblinding. To avoid bias, the investigators will be blinded to the lipid analyses.
- Estimated glomerular filtration rate (eGFR) [ Time Frame: 12 months ]The glomerular filtration rate (in in ml/min/1.73 m2) will be estimated by the MDRD formula: 175 x (SCr)-1.154 x (age)-0.203 x 0.742 [if female] x 1.212 [if black], where SCr is serum creatinine in mg/dl, and age is measured in years.
- The 36-item short form health survey questionnaire (SF-36) [ Time Frame: 12 months ]The SF-36 Health Survey is a 36-item, patient-reported survey of patient health.
- The 3-level version of EQ-5D (EQ-5D-3L) questionnaire [ Time Frame: 12 months ]The EQ-5D-3L descriptive system comprises the following five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, and extreme problems.
- The Beck Depression Inventory (BDI) [ Time Frame: 12 months ]The BDI is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression.
- N-terminal pro-B-type natriuretic peptide (NT-proBNP) [ Time Frame: 12 months ]NT-proBNP values will be used for endpoint analyses.
- Cardiac troponin T (TnT) [ Time Frame: 12 months ]Troponin T-values will be used for endpoint analyses.
- Number of rejections [ Time Frame: 12 months ]Number of all rejections will be recorded through the duration of the study.
- Number of adverse events (AE) [ Time Frame: 12 months ]The standard time period for collecting and recording AE and SAEs will begin at the start of study treatment and will continue for 30 day after end-of treatment (at which time approximately 30 days will have passed since the last study drug injection.
- Number of major clinical adverse events [ Time Frame: 12 months ]The number of major clinical adverse events, defined as death, myocardial infarction, percutaneous coronary intervention/coronary bypass surgery, cerebral stroke, cancer, end stage renal disease (exploratory endpoint).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03734211
|Contact: Kaspar Broch, MD, PhDemail@example.com|
|Contact: Elisabeth Bjørkelund, BN||UXBJEQ@ous-hf.no|
|Department of Cardiology, Rigshospitalet||Not yet recruiting|
|Copenhagen, Denmark, 2100|
|Contact: Finn Gustafsson, MD, PhD firstname.lastname@example.org|
|Department of Cardiology, Aarhus University Hospital|
|Skejby, Denmark, 8200|
|Helsinki University Hospital Heart and Lung Center||Not yet recruiting|
|Helsinki, Finland, 00029|
|Contact: Karl Lemström, MD, PhD +358504272281 email@example.com|
|Department of Cardiology, Sahlgrenska University Hospital||Not yet recruiting|
|Gothenburg, Sweden, SE-41345|
|Contact: Kristjan Karason, MD, PhD 0736254552 firstname.lastname@example.org|
|The Clinic for Heart Failure and Valvular Disease, Skåne University Hospital and Lund University||Not yet recruiting|
|Lund, Sweden, 22185|
|Contact: Gøran Rådegran, MD, PhD Goran.Radegran@skane.se|
|Principal Investigator:||Lars Gullestad, MD, PhD||Oslo University Hospital|