Clinical trial NCT03734211: Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients
Official title: EVOLVD: Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cardiac Allograft Vasculopathy
Keywords: Evolocumab
Heart Transplantation
Vasculopathy
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: Sahlgrenska University Hospital
name: Skane University Hospital
name: Rigshospitalet, Denmark
name: Aarhus University Hospital
name: Helsinki University Central Hospital
First posted: 2018-11-07
Enrollment: 130
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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.

Exclusion Criteria:

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.

Primary outcomes:
measure: Maximal intimal thickness
timeFrame: 12 months
Secondary outcomes:
measure: Cardiac allograft vasculopathy
timeFrame: 12 months
measure: Total atheroma volume
timeFrame: 12 months
measure: The index of microvascular resistance
timeFrame: 12 months
measure: Low-density lipoprotein (LDL) cholesterol
timeFrame: 12 months
measure: Estimated glomerular filtration rate (eGFR)
timeFrame: 12 months
measure: The 36-item short form health survey questionnaire (SF-36)
timeFrame: 12 months
measure: The 3-level version of EQ-5D (EQ-5D-3L) questionnaire
timeFrame: 12 months
measure: The Beck Depression Inventory (BDI)
timeFrame: 12 months
measure: N-terminal pro-B-type natriuretic peptide (NT-proBNP)
timeFrame: 12 months
measure: Cardiac troponin T (TnT)
timeFrame: 12 months
measure: Number of rejections
timeFrame: 12 months
measure: Number of adverse events (AE)
timeFrame: 12 months
measure: Number of major clinical adverse events
timeFrame: 12 months
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Department of Cardiology, Rigshospitalet
city: Skejby
country: Denmark
facility: Department of Cardiology, Aarhus University Hospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital Heart and Lung Center
city: Gothenburg
country: Sweden
facility: Department of Cardiology, Sahlgrenska University Hospital
city: Lund
country: Sweden
facility: The Clinic for Heart Failure and Valvular Disease, Skåne University Hospital and Lund University
Study officials:
affiliation: Oslo University Hospital
name: Lars Gullestad, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Broch K, Gude E, Karason K, Dellgren G, Radegran G, Gjesdal G, Gustafsson F, Eiskjaer H, Lommi J, Pentikainen M, Lemstrom KB, Andreassen AK, Gullestad L. Cholesterol lowering with EVOLocumab to prevent cardiac allograft Vasculopathy in De-novo heart transplant recipients: Design of the randomized controlled EVOLVD trial. Clin Transplant. 2020 Sep;34(9):e13984. doi: 10.1111/ctr.13984. Epub 2020 Aug 6.