Effect of Evolocumab on Vascular Function
Condition: Atherosclerotic Cardiovascular Disease
MeSH terms: Cardiovascular Diseases; Atherosclerosis
Study type: Interventional
Phase: Phase 4

Summary: 
      This is a phase IV, randomized (1:1), prospective, double-blind, placebo controlled,
      parallel-group, single center study at the Clinical Research Unit (CRC) of the Department of
      Nephrology and Hypertension, with its two separate locations:

        -  Nürnberg, Kreuzburger Str. 2, 90471 Nürnberg, and

        -  Erlangen, Ulmenweg 18, 91054 Erlangen

      The results of this study provide strong support for the concept that it is lower LDL-C
      levels that is key to achieving better outcomes, and that it is possible to achieve these on
      top of statin therapy (despite the much debated potential "pleiotropic" effects of statins).

      At least 65 patients will be randomized (1:1) and included (informed consent) in order to
      obtain 58 fully evaluable subjects (29 with evolocumab, 29 with placebo).

      Patients will be simultaneously recruited from investigator's outpatient clinics, referring
      physicians, and advertisement in local newspapers, and social media. Those patients that
      appear to potentially fulfill the inclusion criteria will be invited to a screening visit.
      After providing informed consent, patients will be tested for inclusion/exclusion criteria
      and for feasibility of vascular measurements (in particular to ensure that adequate imaging
      of the brachial artery is possible). Patients will provide a blood sample for laboratory
      testing. If the patient then fulfills inclusion criteria and in the absence of exclusion
      criteria, the patient will be enrolled into the trial, and the study visits will be
      scheduled. Randomization will take place at the latest one day prior to the study visit 2
      (e.g. at the latest at visit 2a).

      At visit 2, baseline vascular function parameters will be obtained and the patient will be
      given an SC injection of the study drug (either SC 420 mg evolocumab or SC placebo). At visit
      4, the second injection of study drug will be administered. After 1, 4 and 8 weeks of
      treatment (visits 3, 4 and 5), testing of vascular function will be repeated. At visit 6, a
      final close out visits will be performed to gather additional safety information.
    

Detailed description: 
      The recently published IMPROVE-IT trial was the first to demonstrate that in high-risk
      patients, reduction of low density cholesterol (LDL-C) beyond current treatment goals by
      addition of ezetimibe to statin therapy leads to a further improvement of cardiovascular (CV)
      outcomes. The results of this study provide strong support for the concept that it is lower
      LDL-C levels that is key to achieving better outcomes, and that it is possible to achieve
      these on top of statin therapy (despite the much debated potential "pleiotropic" effects of
      statins). However, ezetimibe has only limited ability to reduce LCL-C further (-24% lower
      compared with statin alone in the IMPROVE-IT trial). Proprotein convertase subtilisin/kexin
      type 9 (PCSK9) inhibition is a new treatment paradigm for hypercholesterolemia. The normal
      function of PCSK9 is to bind to the low density cholesterol (LDL-C) receptor, and to promote
      its lysosomal destruction in the hepatocyte. Thus, inhibition of PCSK9 protects the LDL-C
      receptor from lysosomal destruction, resulting in increased recirculation of the LDL-C
      receptor to the hepatocyte cell surface, and as a consequence, increased hepatic uptake and
      lower circulating levels of LDL-C.

      The PCSK9 inhibitor evolocumab has been approved in 2015 for the treatment of patients with
      homocygote familial hypercholesterolemia (FH), as well as for treatment of patients with
      heterocygote familial or non-familial hypercholesterolemia in which target LDL-C levels
      cannot be achieved by standard cholesterol-lowering therapy, or who are statin-intolerant.
      Evolocumab achieves a reduction in LDL-C regardless of background therapy in the order of
      50-70% (including those on a statin). This therapy substantially increases the number of
      patients achieving lower LCL-C target levels. Recently, the results of a large prospective
      study (FOURIER) in 27.500 patients at high CV risk have been published. This study showed
      that evolocumab lowered LDL cholesterol in patients already on optimized lipid lowering
      therapy including a statin to a median of 30 mg per deciliter and substantially reduced CV
      events (hazard ratio 0.85, confidence interval 0.79 to 0.92; P<0.001). However, the
      mechanisms mediating the improvement of CV outcomes under therapy with evolocumab are unclear
      at present.

      Intact function of the endothelium is a key component of vascular health. Conversely,
      impaired endothelial function has been linked with increased future CV event rates. Intact
      endothelium has many protective and anti-atherosclerotic effects on the vasculature. At least
      in part, these protective effects are due to endothelial release of nitric oxide (NO). A
      well-established and non-invasive method of assessing endothelial function in humans is by
      measurement of flow-mediated vasodilation (FMD). In addition, recent evidence suggests
      concurrent assessment of low flow-mediated vasoconstriction (L-FMC) improves characterization
      of underlying CV and coronary disease compared with each parameter alone. Further,
      endothelial function has been found to impact large artery function. Endothelial dysfunction
      leads to vasoconstriction, greater peripheral wave reflection and arterial stiffness, and as
      a consequence, augmentation of central (aortic) systolic blood pressure (BP). This is of
      prognostic relevance, since aortic stiffness (e.g. determined by pulse wave velocity [PWV]),
      central systolic BP (cSBP) and central BP augmentation have been identified as strong and
      independent predictors of CV events in several patient cohorts. Exciting technical
      developments of recent years have now made the ambulatory (24-h) measurement of arterial
      stiffness possible.

      The investigator group has been amongst the first to show that statin treatment improves
      endothelial function in patients with elevated LDL-C, which at least in part serves to
      explain the beneficial effects of statins on CV outcomes. The investigator Group was also
      able to show that an improvement in endothelial function during statin therapy is linked with
      an improvement of pulse wave reflection. Rapid improvement of endothelial and large artery
      function is considered to be particularly important in patients at high CV risk, such as
      those that have suffered a recent CV event. The investigator Group hypothesize that the
      beneficial effects of evolocumab, such as recently demonstrated in the FOURIER trial, are
      linked to a rapid improvement of endothelial and large artery function, even in patients
      already on optimized lipid lowering therapy including a statin. Of note, improvement of basal
      NO activity in the renal circulation and NO-dependent vasodilation of the peripheral
      vasculature occurs already 3 days after initiating treatment of statins. In the current study
      we focus on FMD of the brachial artery as the primary objective parameter. This parameter,
      which is widely accepted as an integrated measure of vascular function, is partly dependent
      on endothelial NO production. These data would help to explain the results of IMPROVE-IT and
      FOURIER, and add to the evidence that it is lower cholesterol levels that matter most for CV
      outcomes.
    

Intervention name(s): Evolocumab Prefilled Syringe; Placebos
Intervention type(s): Drug; Drug
Intervention description(s): Injection of study drug; Injection of placebo
Intervention MeSH terms: Evolocumab
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: randomized (1:1), prospective, double-blind, placebo controlled, parallel-group
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: CVD; LDL; heart failure; PCSK9