EXpanded Combination of Evolocumab Plus Empagliflozin on Diabetes: EXCEED-BHS3 Trial
Condition: Dyslipidemia Associated With Type II Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypertension Arterial
MeSH terms: Hypertension; Diabetes Mellitus; Diabetes Mellitus, Type 2; Dyslipidemias
Study type: Interventional
Phase: Phase 4

Summary: 
      Based on the current evidence, empagliflozin could reduce cardiovascular morbidity and
      mortality in Diabetes Mellitus Type 2 (T2DM). Anti-PCSK9 therapy (evolocumab) can reduce the
      major cardiovascular events incidence in secondary prevention individuals, some of them
      presenting T2DM. The beneficial effect of the combined use of these two agents in T2DM
      remains unknown. Evaluating the effect of evolocumab on top of the best of care therapy for
      T2DM, including empaglifozin, on endothelial function may indicate the existence of some
      benefit related to cardiovascular outcomes.
    

Detailed description: 
      Study design: Randomized, parallel-group, open, comparative, prospective clinical study.

      Eligibility criteria will be: T2DM between 40 and 70 years old; adequate glycemic control;
      (HbA1c 7 to 9%) after run-in phase; adequate blood pressure control (SBP ≤ 140 mm Hg);
      maximal tolerated dose of statins and LDL-C between 70 and 100 mg/dL.

      Volunteers' convocation -Investigators will announce in radio, television and newspapers
      inviting volunteers with T2DM for this study. Those who contact us with an interest in
      participating by email or whatsapp will be enrolled for the first telephone screening
      evaluation. These volunteers will be contacted by phone and after a detailed explanation
      about the objectives, procedures, and shared responsibilities between the parties those
      willing to participate will be summoned to a Screening Visit (SV) in which inclusion and
      exclusion criteria will be further verified. The screening FMD will be measured in this
      occasion.

      Run-In - In the following two weeks after the screening visit, patients must return to
      another consultation in which antidiabetic, antihypertensive and lipid-lowering therapies
      adjustment will be performed. The adjustment period must be ended at 16 weeks and if this is
      not so patients will be excluded.

      Pre-randomization exams - In the two weeks preceding the Randomization Visit, patients will
      undergo laboratory tests (urea, creatinine, blood glucose, total cholesterol, HDL-c, LDL-col,
      HbA1c, triglycerides).

      Randomization Phase - At the Randomization Visit (RV): Blood samples will be collected and
      frozen at -250oC for laboratory analysis at the end of the trial. Patients will be submitted
      to a protocol for assessing endothelial function (FMD).

      Thereafter, patients will be assigned to evolocumab (140 mg every two weeks) on top of the
      standard of care therapy (SOC) or to the exclusive use of the SOC.

      At thirty days (Visit 1), 4 weeks (Visit 2), 8 weeks (Visit 3), 12 weeks (Visit 4) and 16
      weeks (Visit 5) post-randomization, patients will be seen at the outpatient clinic for
      evaluation of overall clinical status, treatment adherence through count of tablets, adverse
      events and use of concomitant medications. Evolocumab will be administered at study center
      every 15 days.

      At the Visits 3 and 5, FMD will be reassessed and new blood samples will be collected and
      stored.

      Protocol of Endothelial Function Assessment: Brachial artery measurements will be performed
      using a high-resolution ultrasound (Vivid q, GE Medical System, Milwaukee, WI, USA), obtained
      by physicians with long experience in this exam. The procedure will take place after
      over-night fasting and withdrawal of any vasoactive medications for the previous 24 hours.
      After ten minutes of quiet resting in a room with controlled temperature (around 25°C), the
      brachial artery will be located above the antecubital fossa, and a longitudinal image of 6 to
      8 cm of the artery will be considered as the baseline scan. A size appropriate blood pressure
      cuff will be placed around the forearm and inflated up to 50 mmHg above the systolic blood
      pressure for five minutes and the cuff will be then deflated. The FMD scan will be obtained
      for 5 minutes. An adjustable stereotaxic clamp will stabilize the probe. Percentage change in
      diameter for FMD will be calculated in relation to the respective baseline scans. Video clips
      will be recorded for 1 minute before cuff inflation and then restarted 1 minute before cuff
      deflation until 5 minutes after deflation.

      Laboratory methods - At randomization, 8th and 16th week, blood samples will be obtained for
      measuring: Glucose, C Reactive protein, HbA1c, triglycerides. At the same time points, blood
      samples will also be obtained before and after the two FMD measurements (pre and
      post-ischemia) and will be assessed for VCAM-1 and NO. NO and its metabolites, i.e. nitrite
      and nitrate (NOx), will be measured by an NO chemiluminescence analyzer (model NOA, Sievers
      Instruments, Boulder, CO). Isoprostane will be measured by ELISA at randomization, 8th and
      16th week of therapy.

      Lipoproteins fractions isolation by gradient ultracentrifugation - Lipid profile will be
      assessed at admission, at the 8th week and at the 16th week by gradient ultracentrifugation.
      VLDL, LDL (1 to 5 subfractions) and HDL (2b to 3a subfractions) will be isolated through
      density gradient ultracentrifugation using a SW41Ti rotor. Isolated lipoproteins content in
      cholesterol will be measured using commercially available enzymatic kits total cholesterol
      (TC) (CHOD-PAP, Roche Diagnostics® reagents, Mannheim, Germany)], in the microplate reader
      Power Wave XS (BioTek®, Winooski, USA).

      Sample size and Statistical Analysis - Investigators are not aware of any studies that have
      evaluated the effect of evolocumab or other anti-PCSK9 antibody on FMD. However, two trials
      with similar characteristics to this design were performed testing the effects of
      atorvastatin 80 mg/day or rosuvastatin 40 mg/day on conventional FMD. A difference of 3%
      after treatment was noticed in both trials, with a mean pre-treatment value of 5.5% and a
      standard deviation of 3.9%.

      Considering an alpha value of 0.05 and beta of 90%, this study would require 49 patients per
      arm. Accounting for dropout and exclusion of patients during the pre-randomization phase and
      the trial, investigators propose 12% of drop-off, equivalent to 110 patients, 55 in each arm.
      Investigators used G-Power to calculate sample size. Covariance analysis (ANCOVA) will be
      used to evaluate the effect of treatments on the mean change in FMD at the 16th week, the
      primary endpoint. The assumptions of ANCOVA models (linearity, distribution normality and
      equal variance) will be verified using histograms, normal probability plots and residual
      scatter plots. Age, gender and baseline FMD values will be included as covariables in all
      ANCOVA models. The adjustment for the baseline values is intended to adjust for the possible
      regression to the mean bias. Non-normal continuous variables will be transformed by logarithm
      to correct dispersion. If after transformation they persist not normal, these variables will
      be analyzed by the Kruskal-Wallis test.

      Statistical significance in the secondary endpoints will only be considered if the primary
      outcome is statistically significant. All of the exploratory endpoints will be reported with
      95% CIs. In order to assure the quality of measurements, inter- and intra-patient variability
      of FMD will be obtained in a set of patients from the screening phase of the study.

      Randomization - Stratified randomization will be used in this study. Individuals will be
      allocated in one of the four groups generated by the following parameters that could
      interfere on endothelial function: gender and age (40 -55 or 56 - 70 years old).

      Adverse Events will be collected from time of signature of informed consent, throughout the
      treatment period until the last visit. Serious Adverse Events (SAEs) will be recorded from
      the time of informed consent.

      Reporting of serious adverse events - All SAEs have to be reported in the CRF, whether or not
      considered causally related to the investigational product or to the study procedure(s).
      According to local sanitary (ANVISA) and ethics (CEP/CONEP) regulations, SAEs must be
      reported to the regulatory authority and AMGEN at the same time.
    

Intervention name(s): Evolocumab 140 MG/ML
Intervention type(s): Drug
Intervention description(s): Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that targets LDL receptors for degradation and thereby reduces the liver's ability to remove LDL-C.
Other intervention name(s): Control
Intervention MeSH terms: Evolocumab
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Patients will be assigned to evolocumab (140 mg every two weeks) on top of the standard of care, SOC therapy ( SGLT2 inhibitors, maximal statin dose and ideal control of blood glucose (HbA1c 6.5% to 7%) and blood pressure (SBP <140 mm Hg). Or to the exclusive use of the SOC therapy.
Masking: Single (Participant)
Primary purpose: Diagnostic
Keywords: Dyslipidemia; Diabetes Mellitus, Type 2; Hypertension Arterial