Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Cholesterol Lowering With EVOLocumab to Prevent Cardiac Allograft Vasculopathy in De-novo Heart Transplant Recipients (EVOLVD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03734211
Recruitment Status : Not yet recruiting
First Posted : November 7, 2018
Last Update Posted : April 19, 2019
Sponsor:
Collaborators:
Sahlgrenska University Hospital, Sweden
Skane University Hospital
Rigshospitalet, Denmark
Aarhus University Hospital
Helsinki University Central Hospital
Information provided by (Responsible Party):
Lars Gullestad, Oslo University Hospital

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).


Condition or disease Intervention/treatment Phase
Cardiac Allograft Vasculopathy Drug: Evolocumab Drug: Placebo Phase 3

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
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


Arm Intervention/treatment
Experimental: Evolocumab Drug: Evolocumab
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 Drug: Placebo
Placebo will be administered subcutaneously by giving 3 injections consecutively within 30 minutes using the single-use prefilled autoinjector.




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. Total atheroma volume [ Time Frame: 12 months ]
    The total atheroma volume will be measured by intravascular ultrasound.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. N-terminal pro-B-type natriuretic peptide (NT-proBNP) [ Time Frame: 12 months ]
    NT-proBNP values will be used for endpoint analyses.

  10. Cardiac troponin T (TnT) [ Time Frame: 12 months ]
    Troponin T-values will be used for endpoint analyses.

  11. Number of rejections [ Time Frame: 12 months ]
    Number of all rejections will be recorded through the duration of the study.

  12. 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.

  13. 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

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


Contacts
Layout table for location contacts
Contact: Kaspar Broch, MD, PhD +4723073555 sbbrok@ous-hf.no
Contact: Elisabeth Bjørkelund, BN UXBJEQ@ous-hf.no

Locations
Layout table for location information
Denmark
Department of Cardiology, Rigshospitalet Not yet recruiting
Copenhagen, Denmark, 2100
Contact: Finn Gustafsson, MD, PhD       finng@dadlnet.dk   
Department of Cardiology, Aarhus University Hospital
Skejby, Denmark, 8200
Finland
Helsinki University Hospital Heart and Lung Center Not yet recruiting
Helsinki, Finland, 00029
Contact: Karl Lemström, MD, PhD    +358504272281    karl.lemstrom@helsinki.fi   
Sweden
Department of Cardiology, Sahlgrenska University Hospital Not yet recruiting
Gothenburg, Sweden, SE-41345
Contact: Kristjan Karason, MD, PhD    0736254552    kristjan.karason@vgregion.se   
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   
Sponsors and Collaborators
Lars Gullestad
Sahlgrenska University Hospital, Sweden
Skane University Hospital
Rigshospitalet, Denmark
Aarhus University Hospital
Helsinki University Central Hospital
Investigators
Layout table for investigator information
Principal Investigator: Lars Gullestad, MD, PhD Oslo University Hospital

Layout table for additonal information
Responsible Party: Lars Gullestad, Professor, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT03734211     History of Changes
Other Study ID Numbers: 2017-005097-19
First Posted: November 7, 2018    Key Record Dates
Last Update Posted: April 19, 2019
Last Verified: April 2019

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Lars Gullestad, Oslo University Hospital:
Evolocumab
Heart Transplantation
Vasculopathy
Additional relevant MeSH terms:
Layout table for MeSH terms
Vascular Diseases
Cardiovascular Diseases
Evolocumab
Antibodies, Monoclonal
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Immunologic Factors
Physiological Effects of Drugs