<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02969070</url>
  </required_header>
  <id_info>
    <org_study_id>FedericoIIU 259/16</org_study_id>
    <nct_id>NCT02969070</nct_id>
  </id_info>
  <brief_title>Effects of Nutraceutical Therapies on Endothelial Function, Platelet Aggregation, and Coronary Flow Reserve</brief_title>
  <acronym>NUTRENDO</acronym>
  <official_title>Randomized Trial to Evaluate the Effects of Two Different Nutraceutical Therapies on Endothelial Function, Platelet Aggregation, and Coronary Flow Reserve in Hypercholesterolemic Patients at Moderate Cardiovascular Risk</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Federico II University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Federico II University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypercholesterolemia is considered one of the most important cardiovascular risk factors.&#xD;
      Cardiovascular prevention include a class I indication to statins in addition to&#xD;
      non-pharmacologic intervention and prevention strategies in patients deemed to be 'high&#xD;
      risk'. Along with non-pharmacologic intervention and prevention strategies, newer approaches&#xD;
      to reduce cholesterol blood levels currently include nutraceuticals, which are compounds&#xD;
      derived from foods with cholesterol lowering actions. However, it remains unclear if&#xD;
      nutraceuticals yield additive positive effects other than cholesterol lowering. In&#xD;
      particular, there is evidence that Berberine has cardiovascular protective effects and that,&#xD;
      in vitro, Morus Alba, mulberry fruit, modulates platelet function by inhibiting platelet&#xD;
      activation, thromboxane formation, serotonin secretion, aggregation and thrombus formation.&#xD;
      Furthermore, Morus Alba exerts an α-glucosidase inhibitory and antioxidant activity in vitro,&#xD;
      which may reduce postprandial glucose peak, thus improving HbA1c concentration. Accordingly,&#xD;
      we designated a study to evaluate the effects of two commercially available nutraceutical&#xD;
      combined pills [LopiGLIK™, Akademy Pharma, 1 capsule/day containing red yeast rice 220 mg (at&#xD;
      least 3,3 mg of Monacolin K) + Berberine 531,25 mg + Morus Alba 200 mg (at least 4 mg of&#xD;
      Deoxynojirimycin) vs. Armolipid Plus®, Meda Pharma, 1 capsule/day containing Berberis&#xD;
      aristata d.e. 588 mg (equivalent to Berberine chloride 500 mg) + Red yeast rice 200 mg&#xD;
      (equivalent to Monacolin K 3 mg) + Policosanol 10 mg + Folic acid 0.2 mg + Coenzyme Q10 2.0&#xD;
      mg + Astaxanthin 0.5 mg] on lipid and metabolic profile, platelet aggregation, endothelial&#xD;
      function and coronary flow reserve (CFR). For this purpose patients with hypercholesterolemia&#xD;
      not requiring statins or statin intolerant at moderate cardiovascular risk will be subjected&#xD;
      at day 0 and at day 28, after 4 weeks of therapy, to blood sampling to evaluate lipid and&#xD;
      metabolic profile, peripheral arterial tonometry (EndoPAT), platelet aggregation tests with&#xD;
      light transmission aggregometry (LTA), nitric oxide (NO) release, endothelial nitric oxide&#xD;
      synthase (eNOS) phosphorylation on platelets. Only for CFR, patients will be further&#xD;
      evaluated also after two hours from the administration of the first dose of nutraceutical&#xD;
      combined pill. Patients will be randomly assigned to receive therapy with LopiGLIK™ or with&#xD;
      Armolipid Plus®.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cardiovascular diseases (CVD) are the principal cause of death worldwide. Primary prevention&#xD;
      of cardiovascular disease by identifying and treating at-risk individuals remains a major&#xD;
      public-health priority. According to guidelines, the main approach is a healthy life-style,&#xD;
      assisted by pharmaco-therapy. Hypercholesterolemia is considered one of the most important&#xD;
      cardiovascular risk factors. Cardiovascular prevention include a class I indication to&#xD;
      statins in addition to non-pharmacologic intervention and prevention strategies in patients&#xD;
      deemed to be 'high risk'. In the real world, however, statin treatment is often discontinued&#xD;
      due to side effects. In addition, statins are not indicated in those subjects deemed to be&#xD;
      'low risk', in whom only non-pharmacologic intervention and prevention strategies are&#xD;
      currently prescribed. Along with non-pharmacologic intervention and prevention strategies,&#xD;
      newer approaches to reduce cholesterol blood levels currently include nutraceuticals, which&#xD;
      are compounds derived from foods with cholesterol lowering actions. However, it remains&#xD;
      unclear if nutraceuticals yield additive positive effects other than cholesterol lowering. In&#xD;
      particular, there is evidence that Berberine has cardiovascular protective effects and that,&#xD;
      in vitro, Morus Alba, mulberry fruit, modulates platelet function by inhibiting platelet&#xD;
      activation, thromboxane formation, serotonin secretion, aggregation and thrombus formation.&#xD;
      Furthermore, Morus Alba exerts an α-glucosidase inhibitory and antioxidant activity in vitro,&#xD;
      which may reduce postprandial glucose peak, thus improving HbA1c concentration. Accordingly,&#xD;
      we designated a study to evaluate the effects of two commercially available nutraceutical&#xD;
      combined pills [LopiGLIK™, Akademy Pharma, 1 capsule/day containing red yeast rice 220 mg (at&#xD;
      least 3,3 mg of Monacolin K) + Berberine 531,25 mg + Morus Alba 200 mg (at least 4 mg of&#xD;
      Deoxynojirimycin) vs. Armolipid Plus®, Meda Pharma, 1 capsule/day containing Berberis&#xD;
      aristata d.e. 588 mg (equivalent to Berberine chloride 500 mg) + Red yeast rice 200 mg&#xD;
      (equivalent to Monacolin K 3 mg) + Policosanol 10 mg + Folic acid 0.2 mg + Coenzyme Q10 2.0&#xD;
      mg + Astaxanthin 0.5 mg] on lipid and metabolic profile, platelet aggregation, endothelial&#xD;
      function and coronary flow reserve (CFR). For this purpose patients with hypercholesterolemia&#xD;
      not requiring statins or statin intolerant at moderate cardiovascular risk will be subjected&#xD;
      at day 0 and at day 28, after 4 weeks of therapy, to blood sampling to evaluate lipid and&#xD;
      metabolic profile, peripheral arterial tonometry (EndoPAT), platelet aggregation tests with&#xD;
      light transmission aggregometry (LTA), NO release, eNOS phosphorylation on platelets. Only&#xD;
      for CFR, patients will be further evaluated also after two hours from the administration of&#xD;
      the first dose of nutraceutical combined pill. Patients will be randomly assigned to receive&#xD;
      therapy with LopiGLIK™ or with Armolipid Plus®.&#xD;
&#xD;
      STUDY DESIGN&#xD;
&#xD;
      Study procedure For study enrolment, all subjects will undergo a screening to determine the&#xD;
      criteria for inclusion / exclusion in the study. Eligible patients will receive an&#xD;
      information sheet that will give a preview to the family and to General Practitioner, and, if&#xD;
      accept to participate, they must sign a written informed consent.&#xD;
&#xD;
      The information collected for each subject, regarding suitability to the study, will be&#xD;
      retained and stored by Investigators.&#xD;
&#xD;
      Condition Outcomes Intervention&#xD;
&#xD;
      Patients with hypercholesterolemia and moderate cardiovascular risk according to current&#xD;
      European Society of Cardiology (ESC) guidelines Device: Peripheral arterial tonometry&#xD;
      (EndoPAT) Device: Platelet aggregation with LTA Platelet isolation for measurement of eNOS&#xD;
      phosphorylation Device: colorDoppler echocardiography at rest and after cold pressure test&#xD;
      for CFR evaluation 4 weeks of LopiGLIK™ therapy&#xD;
&#xD;
      1 capsule/day or 4 weeks of Armolipid Plus® therapy&#xD;
&#xD;
      1 capsule/day&#xD;
&#xD;
      Study Type: Interventional&#xD;
&#xD;
      Study plan:&#xD;
&#xD;
        -  30 patients will be evaluated at day 0 (anamnesis, cardiovascular risk factors,&#xD;
           medications, EndoPAT + CFR + blood sample (1 yellow tube for biochemistry + 6 light blue&#xD;
           tubes for platelet function)&#xD;
&#xD;
        -  Patients will be randomly assigned to treatment for 4 weeks with 1 capsule/day of&#xD;
           LopiGLIK™ containing red yeast rice 220 mg + Berberine 531,25 mg + Morus Alba 200 mg or&#xD;
           with 1 capsule/day of Armolipid Plus® containing Berberis aristata d.e. 588 mg&#xD;
           (equivalent to Berberine chloride 500 mg) + Red yeast rice 200 mg (equivalent to&#xD;
           Monacolin K 3 mg) + Policosanol 10 mg + Folic acid 0.2 mg + Coenzyme Q10 2.0 mg +&#xD;
           Astaxanthin 0.5 mg&#xD;
&#xD;
        -  Re-evaluation at day 28 of all tests performed at day 0&#xD;
&#xD;
      Primary Outcome Measures:&#xD;
&#xD;
      • Effects on endothelial function as evaluated by Reactive Hyperemia Index (RHI)&#xD;
&#xD;
      Secondary Outcome Measures:&#xD;
&#xD;
        -  Evaluation of treatment tolerability (as evaluated by a specific questionnaire)&#xD;
&#xD;
        -  Reasons for treatment discontinuation&#xD;
&#xD;
        -  Effects on lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol,&#xD;
           triglycerides) and metabolic indexes (glucose levels, insulin plasma levels, insulin&#xD;
           sensitivity index (HOMA index)&#xD;
&#xD;
        -  Effects on platelet aggregation as evaluated by LTA&#xD;
&#xD;
        -  Effects on coronary flow reserve (CFR) as evaluated by echocardiocolorDoppler&#xD;
           visualization of coronary flow in the distal left anterior descending artery at rest and&#xD;
           after cold pressure test (CPT).&#xD;
&#xD;
      STUDY POPULATION&#xD;
&#xD;
      30 patients will be enrolled (15 in each treatment group).&#xD;
&#xD;
      METHODS&#xD;
&#xD;
      Endothelial function Endothelial function will be assessed with the flow-mediated dilation&#xD;
      test (FMD) by digital pulse amplitude, using a fingertip PAT as previously described&#xD;
      [Gargiulo P, et al. Int J Cardiol 2013]. The system (Itamar Medical Ltd., Caesarea, Israel)&#xD;
      consists of a finger probe to assess digital volume changes accompanying pulse waves. All&#xD;
      subjects included in the study were maintained without smoking, alcohol or caffeine from the&#xD;
      night before the evaluation. Reactive hyperaemia was measured as a PAT reactive hyperaemic&#xD;
      index (RHI) calculated as the ratio of the average amplitude of the PAT signal over a 1-min&#xD;
      time interval starting 1-min after cuff deflation divided by the average amplitude of the PAT&#xD;
      signal of a 3.5-min time period before cuff inflation (baseline) and normalized to the RHI of&#xD;
      the control arm. Endothelial dysfunction was defined as a RHI &lt;1.68 calculated by the mean&#xD;
      value minus 2 standard deviations of 20 healthy asymptomatic control individuals without&#xD;
      history of cardiovascular disease and without major cardiovascular risk factors as previously&#xD;
      described.&#xD;
&#xD;
      Platelet function Platelet aggregation will be measured by light transmission aggregometry&#xD;
      (LTA) using a dual channel lumi-aggregometer (model 700; Chrono-Log). Platelets will be&#xD;
      prepared according to a standard procedure. Briefly, platelet-rich plasma (PRP) will be&#xD;
      prepared from blood that was drawn by venipuncture into 3.8% trisodium citrate (w/v)&#xD;
      Vacutainer Blood Collection Tubes. PRP will be obtained by centrifugation of blood at 250 g&#xD;
      at 25°C for 15 minutes. Platelet-poor plasma (PPP) will be obtained by centrifugation of the&#xD;
      rest of the blood at 1400 g at 25°C for 10 minutes.&#xD;
&#xD;
      Platelet aggregation will be monitored at 37°C with constant stirring (1200 rpm) and measured&#xD;
      as the increase in light transmission for 10 minutes, with the addition of adenosine&#xD;
      diphosphate (ADP) 10 μmol/L, collagen 2 μg/ml and arachidonic acid 1 0,5 millimole (mM) as a&#xD;
      proaggregatory stimulus. All measurements will be obtained within 2 hours of sample&#xD;
      collection, and results will be reported as percentage maximum aggregation. Some experiments&#xD;
      will be performed in platelet pre-treated with insulin (15 microIU/mL) for 30 minutes at&#xD;
      37°C. After stimulation, 3 ml of platelet suspension will be centrifuged for 15 minutes at&#xD;
      3000 and the platelet pellet obtained will be used for the measurement of eNOS&#xD;
      phosphorylation and NO levels.&#xD;
&#xD;
      Coronary flow reserve Standard Doppler echocardiography will be performed using a Vivid Seven&#xD;
      machine (GE, Horten, Norway) in the morning after an overnight fast of 12-14 h; subjects will&#xD;
      be instructed to avoid all coffee-containing drinks and theophylline containing medications,&#xD;
      and to abstain from smoking and heavy exercise from 24 h before the study. The color Doppler&#xD;
      visualization of coronary flow in the distal left anterior descending artery will be obtained&#xD;
      with a 5 megahertz (MHz) shallow-focus phased-array transducer. Doppler sample volume will be&#xD;
      placed on the color signal of the left anterior descending artery, and the spectral pulsed&#xD;
      Doppler signal will be recorded to look for the characteristic biphasic flow pattern with a&#xD;
      larger diastolic and a smaller systolic component both at rest and after cold pressure test&#xD;
      (CPT). Coronary diastolic peak flow velocities (cm/s) as well as heart rate and BP will be&#xD;
      measured at rest and soon after CPT, corresponding to maximal hyperemia. CFR will be&#xD;
      calculated as the ratio of hyperemic-to-resting diastolic peak velocities. The CPT will be&#xD;
      performed according to a standardized protocol, by placing the subject's hand and distal part&#xD;
      of the forearm in an ice water slurry for 3 min. The highest three spectral Doppler signals&#xD;
      will be averaged for each parameter. CFR will be evaluated at baseline, 2 hours after&#xD;
      administration of the first nutraceutical combined pill, and after 28 days of therapy.&#xD;
&#xD;
      All images will be recorded on local archives and analyzed off-line by two observers who will&#xD;
      be blinded to the clinical characteristics of the patients.&#xD;
&#xD;
      Sample size calculation Assuming that the standard deviation of the differences in Endo-PAT&#xD;
      indices for the 2 test days would be 0.5 and that we would want to detect a true difference&#xD;
      in means &gt;0.5 with a paired t test conducted at the 0.05 level of significance, we determined&#xD;
      that a sample of 30 subjects (15 for each group) would provide 80% power.&#xD;
&#xD;
      Composition and supply of the nutraceutical treatments Capsules of LopiGLIK™ (containing red&#xD;
      yeast rice 220 mg + Berberine 531,25 mg + Morus Alba 200 mg) and of Armolipid Plus®&#xD;
      (containing Berberis aristata d.e. 588 mg (equivalent to Berberine chloride 500 mg) + Red&#xD;
      yeast rice 200 mg (equivalent to Monacolin K 3 mg) + Policosanol 10 mg + Folic acid 0.2 mg +&#xD;
      Coenzyme Q10 2.0 mg + Astaxanthin 0.5 mg) will be provided free of charge by Akademy Pharma&#xD;
      and Meda Pharma, respectively.&#xD;
&#xD;
      Treatment duration All patients will be treated for a period of 4 weeks.&#xD;
&#xD;
      Data Results of the study will be communicated to all participant at the study end.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2016</start_date>
  <completion_date type="Actual">October 2017</completion_date>
  <primary_completion_date type="Actual">September 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Effects on endothelial function as evaluated by Reactive Hyperemia Index (RHI)</measure>
    <time_frame>28 days</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluation of treatment tolerability</measure>
    <time_frame>28 days</time_frame>
    <description>Self reporting questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reasons for treatment discontinuation</measure>
    <time_frame>28 days</time_frame>
    <description>Self reporting questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effects on lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides)</measure>
    <time_frame>28 days</time_frame>
    <description>mg/dL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effects on metabolic indexes (glucose levels)</measure>
    <time_frame>28 days</time_frame>
    <description>mg/dL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effects on metabolic indexes [insulin plasma levels and insulin sensitivity index (HOMA index)]</measure>
    <time_frame>28 days</time_frame>
    <description>microIU/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effects on platelet aggregation as evaluated by light transmission aggregometry (LTA)</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effects on coronary flow reserve (CFR) as evaluated by echocardiocolorDoppler visualization of coronary flow in the distal left anterior descending artery at rest and after cold pressure test (CPT)</measure>
    <time_frame>28 days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">28</enrollment>
  <condition>Hypercholesterolemia</condition>
  <condition>Endothelial Dysfunction</condition>
  <arm_group>
    <arm_group_label>LopiGLIK™ group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>4 weeks of LopiGLIK™ therapy 1 capsule/day</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Armolipid Plus group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>4 weeks of Armolipid Plus therapy 1 capsule/day</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>LopiGLIK™ therapy</intervention_name>
    <description>4 weeks of LopiGLIK™ therapy 1 capsule/day</description>
    <arm_group_label>LopiGLIK™ group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Armolipid Plus® therapy</intervention_name>
    <description>4 weeks of Armolipid Plus® therapy 1 capsule/day</description>
    <arm_group_label>Armolipid Plus group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 18-70 years old&#xD;
&#xD;
          2. Patients with hypercholesterolemia and moderate cardiovascular risk according to&#xD;
             current ESC guidelines (risk of fatal cardiovascular event of 1-9% at 10 years&#xD;
             according to SCORE risk charts of low-risk populations)&#xD;
&#xD;
          3. Patients giving written Informed Consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Statin treatment indication&#xD;
&#xD;
          2. Previous cardiovascular event&#xD;
&#xD;
          3. Diabetes mellitus&#xD;
&#xD;
          4. Creatinine Clearance &lt;60ml/min/1.73mm2&#xD;
&#xD;
          5. Moderate to severe anemia Hb &lt; 10mg/dl&#xD;
&#xD;
          6. Platelet count &gt;600 x 103/mm3 o &lt;150 x 103/mm3 o hematocrit (HCT) &gt;50% o &lt;25%&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bruno Trimarco, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Federico II University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Naples &quot;Federico II&quot;</name>
      <address>
        <city>Naples</city>
        <zip>80131</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML, Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM, Binno S; ESC Scientific Document Group. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention &amp; Rehabilitation (EACPR). Eur Heart J. 2016 Aug 1;37(29):2315-2381. doi: 10.1093/eurheartj/ehw106. Epub 2016 May 23. No abstract available.</citation>
    <PMID>27222591</PMID>
  </reference>
  <reference>
    <citation>Trimarco V, Izzo R, Stabile E, Rozza F, Santoro M, Manzi MV, Serino F, Schiattarella GG, Esposito G, Trimarco B. Effects of a new combination of nutraceuticals with Morus alba on lipid profile, insulin sensitivity and endotelial function in dyslipidemic subjects. A cross-over, randomized, double-blind trial. High Blood Press Cardiovasc Prev. 2015 Jun;22(2):149-54. doi: 10.1007/s40292-015-0087-2. Epub 2015 Apr 14.</citation>
    <PMID>25870124</PMID>
  </reference>
  <reference>
    <citation>Carrizzo A, Ambrosio M, Damato A, Madonna M, Storto M, Capocci L, Campiglia P, Sommella E, Trimarco V, Rozza F, Izzo R, Puca AA, Vecchione C. Morus alba extract modulates blood pressure homeostasis through eNOS signaling. Mol Nutr Food Res. 2016 Oct;60(10):2304-2311. doi: 10.1002/mnfr.201600233. Epub 2016 Jun 27.</citation>
    <PMID>27234065</PMID>
  </reference>
  <reference>
    <citation>Gargiulo P, Marciano C, Savarese G, D'Amore C, Paolillo S, Esposito G, Santomauro M, Marsico F, Ruggiero D, Scala O, Marzano A, Cecere M, Casaretti L, Perrone Filardi P. Endothelial dysfunction in type 2 diabetic patients with normal coronary arteries: a digital reactive hyperemia study. Int J Cardiol. 2013 Apr 30;165(1):67-71. doi: 10.1016/j.ijcard.2011.07.076. Epub 2011 Aug 17.</citation>
    <PMID>21851998</PMID>
  </reference>
  <reference>
    <citation>Marciano C, Galderisi M, Gargiulo P, Acampa W, D'Amore C, Esposito R, Capasso E, Savarese G, Casaretti L, Lo Iudice F, Esposito G, Rengo G, Leosco D, Cuocolo A, Perrone-Filardi P. Effects of type 2 diabetes mellitus on coronary microvascular function and myocardial perfusion in patients without obstructive coronary artery disease. Eur J Nucl Med Mol Imaging. 2012 Jul;39(7):1199-206. doi: 10.1007/s00259-012-2117-9. Epub 2012 Apr 12.</citation>
    <PMID>22526959</PMID>
  </reference>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>November 13, 2016</study_first_submitted>
  <study_first_submitted_qc>November 17, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2016</study_first_posted>
  <last_update_submitted>February 14, 2019</last_update_submitted>
  <last_update_submitted_qc>February 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Federico II University</investigator_affiliation>
    <investigator_full_name>Bruno Trimarco</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypercholesterolemia</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02969070
org study id: FedericoIIU 259/16
nct id: NCT02969070
lead sponsor: 
has dmc: No
Hypercholesterolemia is considered one of the most important cardiovascular risk factors.
      Cardiovascular prevention include a class I indication to statins in addition to
      non-pharmacologic intervention and prevention strategies in patients deemed to be 'high
      risk'. Along with non-pharmacologic intervention and prevention strategies, newer approaches
      to reduce cholesterol blood levels currently include nutraceuticals, which are compounds
      derived from foods with cholesterol lowering actions. However, it remains unclear if
      nutraceuticals yield additive positive effects other than cholesterol lowering. In
      particular, there is evidence that Berberine has cardiovascular protective effects and that,
      in vitro, Morus Alba, mulberry fruit, modulates platelet function by inhibiting platelet
      activation, thromboxane formation, serotonin secretion, aggregation and thrombus formation.
      Furthermore, Morus Alba exerts an α-glucosidase inhibitory and antioxidant activity in vitro,
      which may reduce postprandial glucose peak, thus improving HbA1c concentration. Accordingly,
      we designated a study to evaluate the effects of two commercially available nutraceutical
      combined pills [LopiGLIK™, Akademy Pharma, 1 capsule/day containing red yeast rice 220 mg (at
      least 3,3 mg of Monacolin K) + Berberine 531,25 mg + Morus Alba 200 mg (at least 4 mg of
      Deoxynojirimycin) vs. Armolipid Plus®, Meda Pharma, 1 capsule/day containing Berberis
      aristata d.e. 588 mg (equivalent to Berberine chloride 500 mg) + Red yeast rice 200 mg
      (equivalent to Monacolin K 3 mg) + Policosanol 10 mg + Folic acid 0.2 mg + Coenzyme Q10 2.0
      mg + Astaxanthin 0.5 mg] on lipid and metabolic profile, platelet aggregation, endothelial
      function and coronary flow reserve (CFR). For this purpose patients with hypercholesterolemia
      not requiring statins or statin intolerant at moderate cardiovascular risk will be subjected
      at day 0 and at day 28, after 4 weeks of therapy, to blood sampling to evaluate lipid and
      metabolic profile, peripheral arterial tonometry (EndoPAT), platelet aggregation tests with
      light transmission aggregometry (LTA), nitric oxide (NO) release, endothelial nitric oxide
      synthase (eNOS) phosphorylation on platelets. Only for CFR, patients will be further
      evaluated also after two hours from the administration of the first dose of nutraceutical
      combined pill. Patients will be randomly assigned to receive therapy with LopiGLIK™ or with
      Armolipid Plus®.
Cardiovascular diseases (CVD) are the principal cause of death worldwide. Primary prevention
      of cardiovascular disease by identifying and treating at-risk individuals remains a major
      public-health priority. According to guidelines, the main approach is a healthy life-style,
      assisted by pharmaco-therapy. Hypercholesterolemia is considered one of the most important
      cardiovascular risk factors. Cardiovascular prevention include a class I indication to
      statins in addition to non-pharmacologic intervention and prevention strategies in patients
      deemed to be 'high risk'. In the real world, however, statin treatment is often discontinued
      due to side effects. In addition, statins are not indicated in those subjects deemed to be
      'low risk', in whom only non-pharmacologic intervention and prevention strategies are
      currently prescribed. Along with non-pharmacologic intervention and prevention strategies,
      newer approaches to reduce cholesterol blood levels currently include nutraceuticals, which
      are compounds derived from foods with cholesterol lowering actions. However, it remains
      unclear if nutraceuticals yield additive positive effects other than cholesterol lowering. In
      particular, there is evidence that Berberine has cardiovascular protective effects and that,
      in vitro, Morus Alba, mulberry fruit, modulates platelet function by inhibiting platelet
      activation, thromboxane formation, serotonin secretion, aggregation and thrombus formation.
      Furthermore, Morus Alba exerts an α-glucosidase inhibitory and antioxidant activity in vitro,
      which may reduce postprandial glucose peak, thus improving HbA1c concentration. Accordingly,
      we designated a study to evaluate the effects of two commercially available nutraceutical
      combined pills [LopiGLIK™, Akademy Pharma, 1 capsule/day containing red yeast rice 220 mg (at
      least 3,3 mg of Monacolin K) + Berberine 531,25 mg + Morus Alba 200 mg (at least 4 mg of
      Deoxynojirimycin) vs. Armolipid Plus®, Meda Pharma, 1 capsule/day containing Berberis
      aristata d.e. 588 mg (equivalent to Berberine chloride 500 mg) + Red yeast rice 200 mg
      (equivalent to Monacolin K 3 mg) + Policosanol 10 mg + Folic acid 0.2 mg + Coenzyme Q10 2.0
      mg + Astaxanthin 0.5 mg] on lipid and metabolic profile, platelet aggregation, endothelial
      function and coronary flow reserve (CFR). For this purpose patients with hypercholesterolemia
      not requiring statins or statin intolerant at moderate cardiovascular risk will be subjected
      at day 0 and at day 28, after 4 weeks of therapy, to blood sampling to evaluate lipid and
      metabolic profile, peripheral arterial tonometry (EndoPAT), platelet aggregation tests with
      light transmission aggregometry (LTA), NO release, eNOS phosphorylation on platelets. Only
      for CFR, patients will be further evaluated also after two hours from the administration of
      the first dose of nutraceutical combined pill. Patients will be randomly assigned to receive
      therapy with LopiGLIK™ or with Armolipid Plus®.

      STUDY DESIGN

      Study procedure For study enrolment, all subjects will undergo a screening to determine the
      criteria for inclusion / exclusion in the study. Eligible patients will receive an
      information sheet that will give a preview to the family and to General Practitioner, and, if
      accept to participate, they must sign a written informed consent.

      The information collected for each subject, regarding suitability to the study, will be
      retained and stored by Investigators.

      Condition Outcomes Intervention

      Patients with hypercholesterolemia and moderate cardiovascular risk according to current
      European Society of Cardiology (ESC) guidelines Device: Peripheral arterial tonometry
      (EndoPAT) Device: Platelet aggregation with LTA Platelet isolation for measurement of eNOS
      phosphorylation Device: colorDoppler echocardiography at rest and after cold pressure test
      for CFR evaluation 4 weeks of LopiGLIK™ therapy

      1 capsule/day or 4 weeks of Armolipid Plus® therapy

      1 capsule/day

      Study Type: Interventional

      Study plan:

        -  30 patients will be evaluated at day 0 (anamnesis, cardiovascular risk factors,
           medications, EndoPAT + CFR + blood sample (1 yellow tube for biochemistry + 6 light blue
           tubes for platelet function)

        -  Patients will be randomly assigned to treatment for 4 weeks with 1 capsule/day of
           LopiGLIK™ containing red yeast rice 220 mg + Berberine 531,25 mg + Morus Alba 200 mg or
           with 1 capsule/day of Armolipid Plus® containing Berberis aristata d.e. 588 mg
           (equivalent to Berberine chloride 500 mg) + Red yeast rice 200 mg (equivalent to
           Monacolin K 3 mg) + Policosanol 10 mg + Folic acid 0.2 mg + Coenzyme Q10 2.0 mg +
           Astaxanthin 0.5 mg

        -  Re-evaluation at day 28 of all tests performed at day 0

      Primary Outcome Measures:

      • Effects on endothelial function as evaluated by Reactive Hyperemia Index (RHI)

      Secondary Outcome Measures:

        -  Evaluation of treatment tolerability (as evaluated by a specific questionnaire)

        -  Reasons for treatment discontinuation

        -  Effects on lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol,
           triglycerides) and metabolic indexes (glucose levels, insulin plasma levels, insulin
           sensitivity index (HOMA index)

        -  Effects on platelet aggregation as evaluated by LTA

        -  Effects on coronary flow reserve (CFR) as evaluated by echocardiocolorDoppler
           visualization of coronary flow in the distal left anterior descending artery at rest and
           after cold pressure test (CPT).

      STUDY POPULATION

      30 patients will be enrolled (15 in each treatment group).

      METHODS

      Endothelial function Endothelial function will be assessed with the flow-mediated dilation
      test (FMD) by digital pulse amplitude, using a fingertip PAT as previously described
      [Gargiulo P, et al. Int J Cardiol 2013]. The system (Itamar Medical Ltd., Caesarea, Israel)
      consists of a finger probe to assess digital volume changes accompanying pulse waves. All
      subjects included in the study were maintained without smoking, alcohol or caffeine from the
      night before the evaluation. Reactive hyperaemia was measured as a PAT reactive hyperaemic
      index (RHI) calculated as the ratio of the average amplitude of the PAT signal over a 1-min
      time interval starting 1-min after cuff deflation divided by the average amplitude of the PAT
      signal of a 3.5-min time period before cuff inflation (baseline) and normalized to the RHI of
      the control arm. Endothelial dysfunction was defined as a RHI <1.68 calculated by the mean
      value minus 2 standard deviations of 20 healthy asymptomatic control individuals without
      history of cardiovascular disease and without major cardiovascular risk factors as previously
      described.

      Platelet function Platelet aggregation will be measured by light transmission aggregometry
      (LTA) using a dual channel lumi-aggregometer (model 700; Chrono-Log). Platelets will be
      prepared according to a standard procedure. Briefly, platelet-rich plasma (PRP) will be
      prepared from blood that was drawn by venipuncture into 3.8% trisodium citrate (w/v)
      Vacutainer Blood Collection Tubes. PRP will be obtained by centrifugation of blood at 250 g
      at 25°C for 15 minutes. Platelet-poor plasma (PPP) will be obtained by centrifugation of the
      rest of the blood at 1400 g at 25°C for 10 minutes.

      Platelet aggregation will be monitored at 37°C with constant stirring (1200 rpm) and measured
      as the increase in light transmission for 10 minutes, with the addition of adenosine
      diphosphate (ADP) 10 μmol/L, collagen 2 μg/ml and arachidonic acid 1 0,5 millimole (mM) as a
      proaggregatory stimulus. All measurements will be obtained within 2 hours of sample
      collection, and results will be reported as percentage maximum aggregation. Some experiments
      will be performed in platelet pre-treated with insulin (15 microIU/mL) for 30 minutes at
      37°C. After stimulation, 3 ml of platelet suspension will be centrifuged for 15 minutes at
      3000 and the platelet pellet obtained will be used for the measurement of eNOS
      phosphorylation and NO levels.

      Coronary flow reserve Standard Doppler echocardiography will be performed using a Vivid Seven
      machine (GE, Horten, Norway) in the morning after an overnight fast of 12-14 h; subjects will
      be instructed to avoid all coffee-containing drinks and theophylline containing medications,
      and to abstain from smoking and heavy exercise from 24 h before the study. The color Doppler
      visualization of coronary flow in the distal left anterior descending artery will be obtained
      with a 5 megahertz (MHz) shallow-focus phased-array transducer. Doppler sample volume will be
      placed on the color signal of the left anterior descending artery, and the spectral pulsed
      Doppler signal will be recorded to look for the characteristic biphasic flow pattern with a
      larger diastolic and a smaller systolic component both at rest and after cold pressure test
      (CPT). Coronary diastolic peak flow velocities (cm/s) as well as heart rate and BP will be
      measured at rest and soon after CPT, corresponding to maximal hyperemia. CFR will be
      calculated as the ratio of hyperemic-to-resting diastolic peak velocities. The CPT will be
      performed according to a standardized protocol, by placing the subject's hand and distal part
      of the forearm in an ice water slurry for 3 min. The highest three spectral Doppler signals
      will be averaged for each parameter. CFR will be evaluated at baseline, 2 hours after
      administration of the first nutraceutical combined pill, and after 28 days of therapy.

      All images will be recorded on local archives and analyzed off-line by two observers who will
      be blinded to the clinical characteristics of the patients.

      Sample size calculation Assuming that the standard deviation of the differences in Endo-PAT
      indices for the 2 test days would be 0.5 and that we would want to detect a true difference
      in means >0.5 with a paired t test conducted at the 0.05 level of significance, we determined
      that a sample of 30 subjects (15 for each group) would provide 80% power.

      Composition and supply of the nutraceutical treatments Capsules of LopiGLIK™ (containing red
      yeast rice 220 mg + Berberine 531,25 mg + Morus Alba 200 mg) and of Armolipid Plus®
      (containing Berberis aristata d.e. 588 mg (equivalent to Berberine chloride 500 mg) + Red
      yeast rice 200 mg (equivalent to Monacolin K 3 mg) + Policosanol 10 mg + Folic acid 0.2 mg +
      Coenzyme Q10 2.0 mg + Astaxanthin 0.5 mg) will be provided free of charge by Akademy Pharma
      and Meda Pharma, respectively.

      Treatment duration All patients will be treated for a period of 4 weeks.

      Data Results of the study will be communicated to all participant at the study end.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Effects on endothelial function as evaluated by Reactive Hyperemia Index (RHI)
time frame: 28 days
measure: Evaluation of treatment tolerability
time frame: 28 days
description: Self reporting questionnaire
measure: Reasons for treatment discontinuation
time frame: 28 days
description: Self reporting questionnaire
measure: Effects on lipid profile (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides)
time frame: 28 days
description: mg/dL
measure: Effects on metabolic indexes (glucose levels)
time frame: 28 days
description: mg/dL
measure: Effects on metabolic indexes [insulin plasma levels and insulin sensitivity index (HOMA index)]
time frame: 28 days
description: microIU/mL
measure: Effects on platelet aggregation as evaluated by light transmission aggregometry (LTA)
time frame: 28 days
measure: Effects on coronary flow reserve (CFR) as evaluated by echocardiocolorDoppler visualization of coronary flow in the distal left anterior descending artery at rest and after cold pressure test (CPT)
time frame: 28 days
arm group label: LopiGLIK™ group
arm group type: Active Comparator
description: 4 weeks of LopiGLIK™ therapy 1 capsule/day
arm group label: Armolipid Plus group
arm group type: Active Comparator
description: 4 weeks of Armolipid Plus therapy 1 capsule/day
intervention type: Dietary Supplement
intervention name: LopiGLIK™ therapy
description: 4 weeks of LopiGLIK™ therapy 1 capsule/day
arm group label: LopiGLIK™ group
intervention type: Dietary Supplement
intervention name: Armolipid Plus® therapy
description: 4 weeks of Armolipid Plus® therapy 1 capsule/day
arm group label: Armolipid Plus group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Bruno Trimarco, MD
role: Principal Investigator
affiliation: Federico II University
facility: 
country: Italy
citation: Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML, Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM, Binno S; ESC Scientific Document Group. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016 Aug 1;37(29):2315-2381. doi: 10.1093/eurheartj/ehw106. Epub 2016 May 23. No abstract available.
PMID: 27222591
citation: Trimarco V, Izzo R, Stabile E, Rozza F, Santoro M, Manzi MV, Serino F, Schiattarella GG, Esposito G, Trimarco B. Effects of a new combination of nutraceuticals with Morus alba on lipid profile, insulin sensitivity and endotelial function in dyslipidemic subjects. A cross-over, randomized, double-blind trial. High Blood Press Cardiovasc Prev. 2015 Jun;22(2):149-54. doi: 10.1007/s40292-015-0087-2. Epub 2015 Apr 14.
PMID: 25870124
citation: Carrizzo A, Ambrosio M, Damato A, Madonna M, Storto M, Capocci L, Campiglia P, Sommella E, Trimarco V, Rozza F, Izzo R, Puca AA, Vecchione C. Morus alba extract modulates blood pressure homeostasis through eNOS signaling. Mol Nutr Food Res. 2016 Oct;60(10):2304-2311. doi: 10.1002/mnfr.201600233. Epub 2016 Jun 27.
PMID: 27234065
citation: Gargiulo P, Marciano C, Savarese G, D'Amore C, Paolillo S, Esposito G, Santomauro M, Marsico F, Ruggiero D, Scala O, Marzano A, Cecere M, Casaretti L, Perrone Filardi P. Endothelial dysfunction in type 2 diabetic patients with normal coronary arteries: a digital reactive hyperemia study. Int J Cardiol. 2013 Apr 30;165(1):67-71. doi: 10.1016/j.ijcard.2011.07.076. Epub 2011 Aug 17.
PMID: 21851998
citation: Marciano C, Galderisi M, Gargiulo P, Acampa W, D'Amore C, Esposito R, Capasso E, Savarese G, Casaretti L, Lo Iudice F, Esposito G, Rengo G, Leosco D, Cuocolo A, Perrone-Filardi P. Effects of type 2 diabetes mellitus on coronary microvascular function and myocardial perfusion in patients without obstructive coronary artery disease. Eur J Nucl Med Mol Imaging. 2012 Jul;39(7):1199-206. doi: 10.1007/s00259-012-2117-9. Epub 2012 Apr 12.
PMID: 22526959
responsible party type: Principal Investigator
investigator affiliation: Federico II University
investigator full name: Bruno Trimarco
investigator title: Professor
mesh term: Hypercholesterolemia
sharing ipd: Undecided