<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/NCT03779529</url>
  </required_header>
  <id_info>
    <org_study_id>1</org_study_id>
    <nct_id>NCT03779529</nct_id>
  </id_info>
  <brief_title>EVOO Coratina Intervention on Lipids in Non-diabetic Hypertensive Patients Undergoing Hemodialysis (EVOOC-3H)</brief_title>
  <acronym>EVOOC-3H</acronym>
  <official_title>EVOO-coratina Intervention on Lipids in Non-diabetic Hypertensive (h) Patients With Hyperlipidemia (h) Undergoing Periodic Hemodialysis (h)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fondazione Schena</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Bari</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Fondazione Schena</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Twenty-four non-diabetic hypertensive and hyperlipidemic patients undergoing periodic chronic&#xD;
      hemodialysis will be enrolled for receiving extravirgin olive oil (EVOO) Coratina (12&#xD;
      patients) or refined olive oil (12 patients). Aim of the study is to evaluate the effect of&#xD;
      EVOO-C on serum lipid levels. Randomization will be done centrally with appropriate&#xD;
      stratification. Sample size is opportunistic because this is a pilot study. Dietary and&#xD;
      clinical monitoring will be done by nephrologists, cardiologists and dieticians.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Detailed Description: EXTRAVIRGIN OLIVE OIL CORATINA INTERVENTION ON LIPIDS IN NON-DIABETIC&#xD;
      HYPERTENSIVE (H) PATIENTS WITH HYPERLIPIDEMIA (H)UNDERGOING PERIODIC HEMODIALYSIS (H)&#xD;
      (EVOOC-3H) INTRODUCTION What is known. The primary causes of death in patients undergoing&#xD;
      chronic hemodialysis (HD) are the cardiovascular events.&#xD;
&#xD;
      Cardiovascular risk factors(hypertension, type 2 diabetes, obesity, high levels of low&#xD;
      density lipoprotein (LDL) , low levels of high density lipoprotein cholesterol (HDL), smoking&#xD;
      and reduced physical activity) are almost universally present in people on HD. Evidence from&#xD;
      randomized clinical trials demonstrate that statin administration in patients undergoing HD&#xD;
      does not reduce the risk of adverse vascular outcomes. In the general population, there is&#xD;
      growing evidence that the Mediterranean diet supplemented with olive oil implies&#xD;
      cardiovascular and survival advantage. The favorable effects of the extravirgin olive oil&#xD;
      (EVOO) are due to the combination of high content of monounsaturated fatty acids (MUFA) and&#xD;
      polyphenols. The EVOO Coratina (EVOOC), produced in the Puglia Region within the Bari&#xD;
      Province, is characterized by high values of polyphenols ranging between 400 and 1000 mg/kg&#xD;
      of EVOO.&#xD;
&#xD;
      What is unknown. The potential effects of EVOOC in people on HD have not been formally&#xD;
      explored both for surrogate and patient level endpoints.&#xD;
&#xD;
      Why this study. The investigators want to evaluate the effects of EVOOC in non-diabetic&#xD;
      hypertensive patients undergoing chronic HD on a series of surrogate endpoints.&#xD;
&#xD;
      AIM OF THE PROPOSAL The investigators will investigate the effects of EVOOC with high content&#xD;
      of polyphenols compared with refined olive oil (ROO) on lipid levels in HD patients.&#xD;
&#xD;
      STUDY DESIGN&#xD;
&#xD;
      Participants:&#xD;
&#xD;
      The investigators will enroll non-diabetic hypertensive and hyperlipidemic patients&#xD;
      undergoing chronic HD Hypertension will be defined as systolic blood pressure &gt;130 mmHg and&#xD;
      diastolic blood pressure &gt;80 mmHg or having any antihypertensive agents.&#xD;
&#xD;
      Hyperlipidemia will be defined as LDL cholesterol values more than 70 mg/dl or receiving&#xD;
      statins at any dose.&#xD;
&#xD;
      Eligible patients may be of age. (40-80 years old)&#xD;
&#xD;
      The following patients will be excluded:&#xD;
&#xD;
        1. Baseline disease other than diabetic kidney disease or hypertensive kidney disease&#xD;
&#xD;
        2. Severe heart failure (NYHA class III or IV)&#xD;
&#xD;
        3. Patients with low compliance&#xD;
&#xD;
        4. Smoking, intake of antioxidant supplements (eg, carotenoids, vitamin C, vitamin E and&#xD;
           glutathione), aspirin, or any other drug with established antioxidant properties,&#xD;
           hyperlipidemia, obesity (body mass index &gt;30 kg/m2), diabetes, celiac or other&#xD;
           intestinal disease, life-threatening&#xD;
&#xD;
        5. Life expectancy &lt;6 months based on managing physicians assessment&#xD;
&#xD;
        6. Inability to participate in the trial based on managing physician assessment&#xD;
&#xD;
      Interventions:&#xD;
&#xD;
      The experimental intervention will be EVOOC. Participants will ingest two tablespoons of&#xD;
      olive oil during the day: one spoon containing 10g of EVOOC (&gt;5mg of total biophenols/kg of&#xD;
      EVOOC) at lunch and one at dinner. Total biophenols ingested per day will be &gt;10mg.&#xD;
&#xD;
      Comparator:&#xD;
&#xD;
      The control will be refined olive oil (ROO). Participants will ingest two tablespoons of ROO&#xD;
      during the day: one spoon containing 10g of ROO at lunch and one at dinner.&#xD;
&#xD;
      Cointerventions:&#xD;
&#xD;
      Patients may be receiving any drug for anemia, bone disease, nutrition and other including&#xD;
      dietary advice towards a Mediterranean dietary pattern.&#xD;
&#xD;
      Patients may be on either chronic HD or hemodiafiltration (HDF). All treatments will be high&#xD;
      flux.&#xD;
&#xD;
      CASE REPORT FORM This includes demographic findings and laboratory data at each time visit&#xD;
      during the follow-up. Moreover, inclusion and exclusion criteria will be present at&#xD;
      randomization time Daily food and individual quantities will be recorded on 'ad hoc' designed&#xD;
      case report form. The intake of food will be analyzed and converted into nutrients using the&#xD;
      useful software Medisystems (Anthropometric variable -weight) will be measured during the&#xD;
      study.&#xD;
&#xD;
      Physical activity will be evaluated by the Minnesota Leisure Time Physical Activity&#xD;
      Questionnaire. No restriction of physical activity will be given.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      This study will be a centrally randomized trial with blinding of participants, investigators&#xD;
      and outcome assessors, based on the intention to treat principle.&#xD;
&#xD;
      Organizational aspects:&#xD;
&#xD;
      The study will be conducted by the Schena Foundation in collaboration with the Renal Unit at&#xD;
      Policlinic,University of Bari, and the MED&amp;FOOD spin-off of the University of Bari.&#xD;
&#xD;
      Follow-up duration will be 12 weeks. Clinical visit and laboratory control will be done every&#xD;
      4 weeks for 3 consecutive months.&#xD;
&#xD;
      Randomization:&#xD;
&#xD;
      Randomization will be performed centrally at the Schena Foundation, with appropriate&#xD;
      stratification.&#xD;
&#xD;
      Sample size:&#xD;
&#xD;
      Sample size is opportunistic. The investigators will recruit a total of 24 individuals of&#xD;
      whom 12 will receive EVOOC and 12 will receive ROO, based on the pilot nature of this study.&#xD;
      There are, therefore, no formal sample size calculations.&#xD;
&#xD;
      FOLLOW- UP Dietary and clinical monitoring will be done by nephrologists, cardiologists and&#xD;
      dieticians. Participants in both groups will receive dietary counseling. The counseling will&#xD;
      be accompanied by written information with detailed description of typical ingested foods and&#xD;
      the use of specific questionnaires: 1) the 14-items for the adherence to the Mediterranean&#xD;
      diet; 2) the 137-items for the food frequency; 3) the Minnesota questionnaire for the&#xD;
      physical activity; 4) the short-form-36 for the quality of life.&#xD;
&#xD;
      CARDIOLOGY INVESTIGATIONS&#xD;
&#xD;
        -  Intima-media thickness study will be done by the measurement of the carotid-wall&#xD;
           intima-media thickness (cIMT). Echo-measurements will be made in three zones: (a)&#xD;
           proximal zone: about 2 cm before the flow-divider; (b) distal zone: about ½ cm before&#xD;
           the flow-divider; (c) middle zone. These data will be used to obtain the arithmetical&#xD;
           mean cIMT value.&#xD;
&#xD;
        -  Brachial artery reactivity study will be carried out by the ultrasonographic assessment&#xD;
           of endothelial dependent flow-mediated vasodilation of the brachial artery. ECG&#xD;
&#xD;
        -  24 hours ECG Holter monitoring&#xD;
&#xD;
        -  2D Color Doppler Echocardiography Cardiological investigations will be held during the&#xD;
           long intradialytic period except for the ECG Holter monitoring that will be done at&#xD;
           least one hour before and four hours after dialysis.&#xD;
&#xD;
      OUTCOMES&#xD;
&#xD;
      Outcomes will be:&#xD;
&#xD;
        -  cardiovascular event onset&#xD;
&#xD;
        -  composite outcome: myocardial infarction, revascularization, ischemic stroke, peripheral&#xD;
           artery disease, cardiovascular death&#xD;
&#xD;
        -  blood concentration of LDL and HDL cholesterol, total cholesterol,&#xD;
&#xD;
        -  blood pressure METHODS Blood samples will be drown in the morning after 12 hours of&#xD;
           fasting. Urine sample will be collected from the first spot morning micturition in&#xD;
           presence of residual diuresis.&#xD;
&#xD;
      Blood and urine sample will be collected at the randomization visit and at each intervention&#xD;
      period (every 4 weeks for a total of 3 months) after the short interval between two dialysis&#xD;
      sessions.&#xD;
&#xD;
      Peripheral blood mononuclear cells (PBMCs) will be collected for the genome study. Serum&#xD;
      samples will be collected for the measurement of pro-inflammatory (IL-1b, IL-6, TNFa) and&#xD;
      anti-inflammatory (IL4, IL-10) cytokines and CRP.&#xD;
&#xD;
      A few ml of urine will be collected for tyrosol and hydroxytyrosol determinations by&#xD;
      mass-spectrometry. In addition, other metabolites will be measured by nuclear magnetic&#xD;
      resonance.&#xD;
&#xD;
      Oxidative stress evaluation. The investigators will evaluate at T0 and after 12 weeks ROS&#xD;
      serum concentrations by spectrophotometric method using commercially available kit (dROMs&#xD;
      Test Diacron). The investigators will also assess the measurement of serum 8-oxodG, a marker&#xD;
      of oxidative DNA damage by ELISA (Trevigen). The investigators will identify the nature of&#xD;
      ROS generated in PBMCs by the peroxide-sensitive fluorescent probe&#xD;
      2',7'-dichlorodihydrofluorescin diacetate (DCFH, Molecular Probes). Kinetic measurements of&#xD;
      mitochondrial ROS generation will be evaluated by measuring the linear fluorescence increase&#xD;
      caused by the H2O2-dependent oxidation of DCFH. NADPH-dependent superoxide generation will be&#xD;
      measured by lucigenin-enhanced chemiluminescence methods in PBMCs isolated from HD patients.&#xD;
      In parallel, the investigators will prepare RIPA lysates of the PBMCs and evaluate the&#xD;
      expression of the various NADPH oxidase subunits by Western blot analysis. The antibodies for&#xD;
      gp91phox/Nox2 or Rac1 antibodies will be furnished by Upstate/Millipore; p22phox, p47phox or&#xD;
      p67phox will be purchased from Santa Cruz Biotechnologies. Additionally, the activity of the&#xD;
      small GTPase Rac will be evaluated by affinity precipitation using the p21-activated kinase&#xD;
      (PAK-1) binding domain linked to glutathione S-transferase (GST-PAK-1-PBD) on&#xD;
      glutathione-agarose beads (Millipore/Upstate Biotech.).&#xD;
&#xD;
      STATISTICAL ANALYSIS Normality of variable distribution will be assessed by analysis of&#xD;
      skewness and kurtosis. One-factor ANOVA and Kruskall-Wallis test will be used to analyze the&#xD;
      differences among the two groups (case-control).&#xD;
&#xD;
      The general linear model for repeated measurements will be used with multiple paired&#xD;
      comparisons in order to assess differences between the groups.&#xD;
&#xD;
      Linearity of values across refined OO and EVOO will be determined for testing the&#xD;
      dose-response effect of biophenolic compounds.&#xD;
&#xD;
      Sample size and power calculations are not applicable given the pilot nature of the study&#xD;
      with recruitment of an opportunistic sample.&#xD;
&#xD;
      Primary statistical analysis: All analyses will be carried out on an intention-to-treat&#xD;
      basis. Statistical significance will be defined as p&lt;0.05 for a two-sided test.&#xD;
&#xD;
      CHARACTERISTICS OF EVOOC AND ROO EVOOC: This olive oil is obtained by Coratina cultivar trees&#xD;
      that are DNA certificated.&#xD;
&#xD;
      ROO: This olive oil used as placebo is a mixture of refined OO. Fatty acid composition and&#xD;
      polyphenol content have been determined by gas chromatography and HPLC, respectively.&#xD;
&#xD;
      Polyphenols are undetectable in ROO. The characteristics of EVOOC and ROO (nutraceutic label)&#xD;
      are enclosed in this protocol.&#xD;
&#xD;
      The OOs will be provided by the MED&amp;FOOD spin-off, University of Bari.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 1, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2020</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>
    <intervention_model_description>The general linear model for repeated measurements will be used with multiple paired comparisons in order to assess differences between the groups.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The olive oils will be administered as oil A or B with content unknown to participants, investigators and outcome assessors</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Serum levels of LDL cholesterol</measure>
    <time_frame>1st month</time_frame>
    <description>Blood measurement</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum levels of LDL cholesterol</measure>
    <time_frame>2nd month</time_frame>
    <description>Blood measurement</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum levels of LDL cholesterol</measure>
    <time_frame>3rd month</time_frame>
    <description>Blood measurement</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum levels of HDL cholesterol,</measure>
    <time_frame>1st month</time_frame>
    <description>Blood measurement</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum levels of HDL cholesterol,</measure>
    <time_frame>2nd month</time_frame>
    <description>Blood measurement</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum levels of HDL cholesterol,</measure>
    <time_frame>3rd month</time_frame>
    <description>Blood measurement</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum levels of total cholesterol</measure>
    <time_frame>1st month</time_frame>
    <description>Blood measurement</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum levels of total cholesterol</measure>
    <time_frame>2nd month</time_frame>
    <description>Blood measurement</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serum levels of total cholesterol</measure>
    <time_frame>3rd month</time_frame>
    <description>Blood measurement</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>number of participants with high blood pressure</measure>
    <time_frame>1st month</time_frame>
    <description>Monitoring of blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of participants with high blood pressure</measure>
    <time_frame>2nd month</time_frame>
    <description>Monitoring of blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of participants with high blood pressure</measure>
    <time_frame>3rd month</time_frame>
    <description>Monitoring of blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of participants with myocardial infarction</measure>
    <time_frame>Measurement will be done at 1st month</time_frame>
    <description>Trop-1 measurement</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of participants with myocardial infarction</measure>
    <time_frame>Measurement will be done at 2nd month</time_frame>
    <description>Trop-1 measurement</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of participants with myocardial infarction</measure>
    <time_frame>Measurement will be done at 3rd month</time_frame>
    <description>Trop-1 measurement</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">24</enrollment>
  <condition>Chronic Kidney Disease Stage V</condition>
  <arm_group>
    <arm_group_label>Arm label extra-vergin olive oil (EVOO)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will ingest two tablespoons of extra-vergin olive oil (EVOO) Coratina during the day: one spoon containing 10g of olive oil (&gt;5mg of total biophenols/kg of olive oil) at lunch and one at dinner. The total biophenols ingested per day will be &gt;10mg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm label refined olive oil (ROO)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Participants will ingest two tablespoons of refined olive oil during the day: one spoon containing 10 g of refined olive oil at lunch and one at dinner.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Olive oil</intervention_name>
    <description>Intervention includes dosage and amount of biophenols administered daily</description>
    <arm_group_label>Arm label extra-vergin olive oil (EVOO)</arm_group_label>
    <arm_group_label>Arm label refined olive oil (ROO)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  The investigators will enroll non-diabetic hypertensive and hyperlipidemic patients&#xD;
             undergoing chronic HD&#xD;
&#xD;
          -  Hypertension will be defined as having a systolic blood pressure of &gt;130 mmHg and a&#xD;
             diastolic blood pressure &gt;80 mmHg or having any antihypertensive agents.&#xD;
&#xD;
          -  Hyperlipidemia will be defined as having LDL cholesterol values more than 100 mg/dl or&#xD;
             receiving statins at any dose.&#xD;
&#xD;
          -  Eligible patients may be of any age.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diabetes mellitus type 1 or 2&#xD;
&#xD;
          -  Severe heart failure (NYHA class IV)&#xD;
&#xD;
          -  Patients with low compliance or severe psychiatric illnesses&#xD;
&#xD;
          -  Smoking, intake of antioxidant supplements (eg, carotenoids, vitamin C, vitamin E and&#xD;
             glutathione), aspirin, or any other drug with established antioxidant properties,&#xD;
             hyperlipidemia, obesity (body mass index &gt;30 kg/m2), diabetes, celiac or other&#xD;
             intestinal disease, life-threatening&#xD;
&#xD;
          -  Survival expectancy &lt;6 months based on managing physicians assessment&#xD;
&#xD;
          -  Inability to participate in the trial based on managing physicians assessment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Francesco P Schena, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fondazione Schena</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Francesco P Schena, MD</last_name>
    <phone>3336771291</phone>
    <phone_ext>+39</phone_ext>
    <email>paolo.schena@uniba.it</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Giovanni B Pertosa, MD</last_name>
    <phone>3476013674</phone>
    <phone_ext>+39</phone_ext>
    <email>giovannibattista.pertosa@uniba.it</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Fondazione Schena</name>
      <address>
        <city>Valenzano</city>
        <state>Bari</state>
        <zip>70010</zip>
        <country>Italy</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Francesco P Schena, MD</last_name>
      <phone>+393336771291</phone>
      <email>paolo.schena@uniba.it</email>
    </contact>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012 Aug 21;157(4):263-75. doi: 10.7326/0003-4819-157-4-201208210-00007.</citation>
    <PMID>22910937</PMID>
  </reference>
  <reference>
    <citation>Estruch R, Martinez-Gonzalez MA, Corella D, Salas-Salvado J, Ruiz-Gutierrez V, Covas MI, Fiol M, Gomez-Gracia E, Lopez-Sabater MC, Vinyoles E, Aros F, Conde M, Lahoz C, Lapetra J, Saez G, Ros E; PREDIMED Study Investigators. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006 Jul 4;145(1):1-11. doi: 10.7326/0003-4819-145-1-200607040-00004. Erratum In: Ann Intern Med. 2018 Aug 21;169(4):270-271.</citation>
    <PMID>16818923</PMID>
  </reference>
  <reference>
    <citation>Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, Gomez-Gracia E, Ruiz-Gutierrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pinto X, Basora J, Munoz MA, Sorli JV, Martinez JA, Martinez-Gonzalez MA. Retraction and Republication: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90. N Engl J Med. 2018 Jun 21;378(25):2441-2442. doi: 10.1056/NEJMc1806491. Epub 2018 Jun 13. No abstract available.</citation>
    <PMID>29897867</PMID>
  </reference>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>August 28, 2018</study_first_submitted>
  <study_first_submitted_qc>December 17, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>December 4, 2020</last_update_submitted>
  <last_update_submitted_qc>December 4, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 7, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fondazione Schena</investigator_affiliation>
    <investigator_full_name>Francesco Paolo Schena</investigator_full_name>
    <investigator_title>President and scientif director</investigator_title>
  </responsible_party>
  <keyword>olive oil</keyword>
  <keyword>hemodialysis</keyword>
  <keyword>lipids</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Renal Insufficiency, Chronic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>the IPD are shared with other researchers</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>2 years</ipd_time_frame>
    <ipd_access_criteria>publications or reports</ipd_access_criteria>
    <ipd_url>http://www.fondazioneschena.org</ipd_url>
  </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/NCT03779529
org study id: 1
nct id: NCT03779529
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Twenty-four non-diabetic hypertensive and hyperlipidemic patients undergoing periodic chronic
      hemodialysis will be enrolled for receiving extravirgin olive oil (EVOO) Coratina (12
      patients) or refined olive oil (12 patients). Aim of the study is to evaluate the effect of
      EVOO-C on serum lipid levels. Randomization will be done centrally with appropriate
      stratification. Sample size is opportunistic because this is a pilot study. Dietary and
      clinical monitoring will be done by nephrologists, cardiologists and dieticians.
Detailed Description: EXTRAVIRGIN OLIVE OIL CORATINA INTERVENTION ON LIPIDS IN NON-DIABETIC
      HYPERTENSIVE (H) PATIENTS WITH HYPERLIPIDEMIA (H)UNDERGOING PERIODIC HEMODIALYSIS (H)
      (EVOOC-3H) INTRODUCTION What is known. The primary causes of death in patients undergoing
      chronic hemodialysis (HD) are the cardiovascular events.

      Cardiovascular risk factors(hypertension, type 2 diabetes, obesity, high levels of low
      density lipoprotein (LDL) , low levels of high density lipoprotein cholesterol (HDL), smoking
      and reduced physical activity) are almost universally present in people on HD. Evidence from
      randomized clinical trials demonstrate that statin administration in patients undergoing HD
      does not reduce the risk of adverse vascular outcomes. In the general population, there is
      growing evidence that the Mediterranean diet supplemented with olive oil implies
      cardiovascular and survival advantage. The favorable effects of the extravirgin olive oil
      (EVOO) are due to the combination of high content of monounsaturated fatty acids (MUFA) and
      polyphenols. The EVOO Coratina (EVOOC), produced in the Puglia Region within the Bari
      Province, is characterized by high values of polyphenols ranging between 400 and 1000 mg/kg
      of EVOO.

      What is unknown. The potential effects of EVOOC in people on HD have not been formally
      explored both for surrogate and patient level endpoints.

      Why this study. The investigators want to evaluate the effects of EVOOC in non-diabetic
      hypertensive patients undergoing chronic HD on a series of surrogate endpoints.

      AIM OF THE PROPOSAL The investigators will investigate the effects of EVOOC with high content
      of polyphenols compared with refined olive oil (ROO) on lipid levels in HD patients.

      STUDY DESIGN

      Participants:

      The investigators will enroll non-diabetic hypertensive and hyperlipidemic patients
      undergoing chronic HD Hypertension will be defined as systolic blood pressure >130 mmHg and
      diastolic blood pressure >80 mmHg or having any antihypertensive agents.

      Hyperlipidemia will be defined as LDL cholesterol values more than 70 mg/dl or receiving
      statins at any dose.

      Eligible patients may be of age. (40-80 years old)

      The following patients will be excluded:

        1. Baseline disease other than diabetic kidney disease or hypertensive kidney disease

        2. Severe heart failure (NYHA class III or IV)

        3. Patients with low compliance

        4. Smoking, intake of antioxidant supplements (eg, carotenoids, vitamin C, vitamin E and
           glutathione), aspirin, or any other drug with established antioxidant properties,
           hyperlipidemia, obesity (body mass index >30 kg/m2), diabetes, celiac or other
           intestinal disease, life-threatening

        5. Life expectancy <6 months based on managing physicians assessment

        6. Inability to participate in the trial based on managing physician assessment

      Interventions:

      The experimental intervention will be EVOOC. Participants will ingest two tablespoons of
      olive oil during the day: one spoon containing 10g of EVOOC (>5mg of total biophenols/kg of
      EVOOC) at lunch and one at dinner. Total biophenols ingested per day will be >10mg.

      Comparator:

      The control will be refined olive oil (ROO). Participants will ingest two tablespoons of ROO
      during the day: one spoon containing 10g of ROO at lunch and one at dinner.

      Cointerventions:

      Patients may be receiving any drug for anemia, bone disease, nutrition and other including
      dietary advice towards a Mediterranean dietary pattern.

      Patients may be on either chronic HD or hemodiafiltration (HDF). All treatments will be high
      flux.

      CASE REPORT FORM This includes demographic findings and laboratory data at each time visit
      during the follow-up. Moreover, inclusion and exclusion criteria will be present at
      randomization time Daily food and individual quantities will be recorded on 'ad hoc' designed
      case report form. The intake of food will be analyzed and converted into nutrients using the
      useful software Medisystems (Anthropometric variable -weight) will be measured during the
      study.

      Physical activity will be evaluated by the Minnesota Leisure Time Physical Activity
      Questionnaire. No restriction of physical activity will be given.

      Methods:

      This study will be a centrally randomized trial with blinding of participants, investigators
      and outcome assessors, based on the intention to treat principle.

      Organizational aspects:

      The study will be conducted by the Schena Foundation in collaboration with the Renal Unit at
      Policlinic,University of Bari, and the MED&FOOD spin-off of the University of Bari.

      Follow-up duration will be 12 weeks. Clinical visit and laboratory control will be done every
      4 weeks for 3 consecutive months.

      Randomization:

      Randomization will be performed centrally at the Schena Foundation, with appropriate
      stratification.

      Sample size:

      Sample size is opportunistic. The investigators will recruit a total of 24 individuals of
      whom 12 will receive EVOOC and 12 will receive ROO, based on the pilot nature of this study.
      There are, therefore, no formal sample size calculations.

      FOLLOW- UP Dietary and clinical monitoring will be done by nephrologists, cardiologists and
      dieticians. Participants in both groups will receive dietary counseling. The counseling will
      be accompanied by written information with detailed description of typical ingested foods and
      the use of specific questionnaires: 1) the 14-items for the adherence to the Mediterranean
      diet; 2) the 137-items for the food frequency; 3) the Minnesota questionnaire for the
      physical activity; 4) the short-form-36 for the quality of life.

      CARDIOLOGY INVESTIGATIONS

        -  Intima-media thickness study will be done by the measurement of the carotid-wall
           intima-media thickness (cIMT). Echo-measurements will be made in three zones: (a)
           proximal zone: about 2 cm before the flow-divider; (b) distal zone: about ½ cm before
           the flow-divider; (c) middle zone. These data will be used to obtain the arithmetical
           mean cIMT value.

        -  Brachial artery reactivity study will be carried out by the ultrasonographic assessment
           of endothelial dependent flow-mediated vasodilation of the brachial artery. ECG

        -  24 hours ECG Holter monitoring

        -  2D Color Doppler Echocardiography Cardiological investigations will be held during the
           long intradialytic period except for the ECG Holter monitoring that will be done at
           least one hour before and four hours after dialysis.

      OUTCOMES

      Outcomes will be:

        -  cardiovascular event onset

        -  composite outcome: myocardial infarction, revascularization, ischemic stroke, peripheral
           artery disease, cardiovascular death

        -  blood concentration of LDL and HDL cholesterol, total cholesterol,

        -  blood pressure METHODS Blood samples will be drown in the morning after 12 hours of
           fasting. Urine sample will be collected from the first spot morning micturition in
           presence of residual diuresis.

      Blood and urine sample will be collected at the randomization visit and at each intervention
      period (every 4 weeks for a total of 3 months) after the short interval between two dialysis
      sessions.

      Peripheral blood mononuclear cells (PBMCs) will be collected for the genome study. Serum
      samples will be collected for the measurement of pro-inflammatory (IL-1b, IL-6, TNFa) and
      anti-inflammatory (IL4, IL-10) cytokines and CRP.

      A few ml of urine will be collected for tyrosol and hydroxytyrosol determinations by
      mass-spectrometry. In addition, other metabolites will be measured by nuclear magnetic
      resonance.

      Oxidative stress evaluation. The investigators will evaluate at T0 and after 12 weeks ROS
      serum concentrations by spectrophotometric method using commercially available kit (dROMs
      Test Diacron). The investigators will also assess the measurement of serum 8-oxodG, a marker
      of oxidative DNA damage by ELISA (Trevigen). The investigators will identify the nature of
      ROS generated in PBMCs by the peroxide-sensitive fluorescent probe
      2',7'-dichlorodihydrofluorescin diacetate (DCFH, Molecular Probes). Kinetic measurements of
      mitochondrial ROS generation will be evaluated by measuring the linear fluorescence increase
      caused by the H2O2-dependent oxidation of DCFH. NADPH-dependent superoxide generation will be
      measured by lucigenin-enhanced chemiluminescence methods in PBMCs isolated from HD patients.
      In parallel, the investigators will prepare RIPA lysates of the PBMCs and evaluate the
      expression of the various NADPH oxidase subunits by Western blot analysis. The antibodies for
      gp91phox/Nox2 or Rac1 antibodies will be furnished by Upstate/Millipore; p22phox, p47phox or
      p67phox will be purchased from Santa Cruz Biotechnologies. Additionally, the activity of the
      small GTPase Rac will be evaluated by affinity precipitation using the p21-activated kinase
      (PAK-1) binding domain linked to glutathione S-transferase (GST-PAK-1-PBD) on
      glutathione-agarose beads (Millipore/Upstate Biotech.).

      STATISTICAL ANALYSIS Normality of variable distribution will be assessed by analysis of
      skewness and kurtosis. One-factor ANOVA and Kruskall-Wallis test will be used to analyze the
      differences among the two groups (case-control).

      The general linear model for repeated measurements will be used with multiple paired
      comparisons in order to assess differences between the groups.

      Linearity of values across refined OO and EVOO will be determined for testing the
      dose-response effect of biophenolic compounds.

      Sample size and power calculations are not applicable given the pilot nature of the study
      with recruitment of an opportunistic sample.

      Primary statistical analysis: All analyses will be carried out on an intention-to-treat
      basis. Statistical significance will be defined as p<0.05 for a two-sided test.

      CHARACTERISTICS OF EVOOC AND ROO EVOOC: This olive oil is obtained by Coratina cultivar trees
      that are DNA certificated.

      ROO: This olive oil used as placebo is a mixture of refined OO. Fatty acid composition and
      polyphenol content have been determined by gas chromatography and HPLC, respectively.

      Polyphenols are undetectable in ROO. The characteristics of EVOOC and ROO (nutraceutic label)
      are enclosed in this protocol.

      The OOs will be provided by the MED&FOOD spin-off, University of Bari.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The general linear model for repeated measurements will be used with multiple paired comparisons in order to assess differences between the groups.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The olive oils will be administered as oil A or B with content unknown to participants, investigators and outcome assessors
measure: Serum levels of LDL cholesterol
time frame: 1st month
description: Blood measurement
measure: Serum levels of LDL cholesterol
time frame: 2nd month
description: Blood measurement
measure: Serum levels of LDL cholesterol
time frame: 3rd month
description: Blood measurement
measure: Serum levels of HDL cholesterol,
time frame: 1st month
description: Blood measurement
measure: Serum levels of HDL cholesterol,
time frame: 2nd month
description: Blood measurement
measure: Serum levels of HDL cholesterol,
time frame: 3rd month
description: Blood measurement
measure: Serum levels of total cholesterol
time frame: 1st month
description: Blood measurement
measure: Serum levels of total cholesterol
time frame: 2nd month
description: Blood measurement
measure: Serum levels of total cholesterol
time frame: 3rd month
description: Blood measurement
measure: number of participants with high blood pressure
time frame: 1st month
description: Monitoring of blood pressure
measure: number of participants with high blood pressure
time frame: 2nd month
description: Monitoring of blood pressure
measure: number of participants with high blood pressure
time frame: 3rd month
description: Monitoring of blood pressure
measure: number of participants with myocardial infarction
time frame: Measurement will be done at 1st month
description: Trop-1 measurement
measure: number of participants with myocardial infarction
time frame: Measurement will be done at 2nd month
description: Trop-1 measurement
measure: number of participants with myocardial infarction
time frame: Measurement will be done at 3rd month
description: Trop-1 measurement
arm group label: Arm label extra-vergin olive oil (EVOO)
arm group type: Active Comparator
description: Participants will ingest two tablespoons of extra-vergin olive oil (EVOO) Coratina during the day: one spoon containing 10g of olive oil (>5mg of total biophenols/kg of olive oil) at lunch and one at dinner. The total biophenols ingested per day will be >10mg.
arm group label: Arm label refined olive oil (ROO)
arm group type: Active Comparator
description: Participants will ingest two tablespoons of refined olive oil during the day: one spoon containing 10 g of refined olive oil at lunch and one at dinner.
intervention type: Dietary Supplement
intervention name: Olive oil
description: Intervention includes dosage and amount of biophenols administered daily
arm group label: Arm label extra-vergin olive oil (EVOO)
arm group label: Arm label refined olive oil (ROO)
criteria: 
gender: All
gender based: Yes
minimum age: 40 Years
maximum age: 80 Years
healthy volunteers: No
last name: Francesco P Schena, MD
role: Principal Investigator
affiliation: Fondazione Schena
last name: Francesco P Schena, MD
phone: 3336771291
phone ext: +39
email: paolo.schena@uniba.it
last name: Giovanni B Pertosa, MD
phone: 3476013674
phone ext: +39
email: giovannibattista.pertosa@uniba.it
facility: 
status: Recruiting
contact: 
country: Italy
citation: Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012 Aug 21;157(4):263-75. doi: 10.7326/0003-4819-157-4-201208210-00007.
PMID: 22910937
citation: Estruch R, Martinez-Gonzalez MA, Corella D, Salas-Salvado J, Ruiz-Gutierrez V, Covas MI, Fiol M, Gomez-Gracia E, Lopez-Sabater MC, Vinyoles E, Aros F, Conde M, Lahoz C, Lapetra J, Saez G, Ros E; PREDIMED Study Investigators. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med. 2006 Jul 4;145(1):1-11. doi: 10.7326/0003-4819-145-1-200607040-00004. Erratum In: Ann Intern Med. 2018 Aug 21;169(4):270-271.
PMID: 16818923
citation: Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, Gomez-Gracia E, Ruiz-Gutierrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pinto X, Basora J, Munoz MA, Sorli JV, Martinez JA, Martinez-Gonzalez MA. Retraction and Republication: Primary Prevention of Cardiovascular Disease with a Mediterranean Diet. N Engl J Med 2013;368:1279-90. N Engl J Med. 2018 Jun 21;378(25):2441-2442. doi: 10.1056/NEJMc1806491. Epub 2018 Jun 13. No abstract available.
PMID: 29897867
responsible party type: Principal Investigator
investigator affiliation: Fondazione Schena
investigator full name: Francesco Paolo Schena
investigator title: President and scientif director
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
sharing ipd: Yes
ipd description: the IPD are shared with other researchers
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: 2 years
ipd access criteria: publications or reports
ipd url: http://www.fondazioneschena.org