xml: <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/NCT06005142</url>
    </required_header>
    <id_info>
      <org_study_id>SaoPSU23</org_study_id>
      <nct_id>NCT06005142</nct_id>
    </id_info>
    <brief_title>Therapeutic Intervention of Eriomin Associated With Metformin in the Control of Hyperglycemia in Pre-Diabetic Patients</brief_title>
    <acronym>Eriomin+Met</acronym>
    <official_title>Therapeutic Intervention of Nutraceutical Eriomin Associated With Metformin to Improve the Control of Hyperglycemia in Patients With Prediabetes: A Double-blind, Randomized, Placebo-controlled Crossover Clinical Trial</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Thais Cesar</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Ingredients by Nature TM</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>São Paulo State University</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>
        Citrus bioflavonoids, such as eriocitrin, hesperidin and naringin, have been shown improved&#xD;
        hyperglycemia, insulin resistance and systemic inflammation, related to the development of&#xD;
        type 2 diabetes. The nutraceutical Eriomin, a lemon flavonoid extract composed mainly by&#xD;
        eriocitrin (70%) and other flavonoids (30%), improved the control of moderate hyperglycemia&#xD;
        in pre-diabetic and diabetic patients without drug therapy. However, most patients with&#xD;
        pre-diabetes are on oral biguanide (metformin) therapy, despite its limited efficacy (30-40%)&#xD;
        on glycemic control and its undesirable gastrointestinal effects.&#xD;
  &#xD;
        Therefore, in the current study, Eriomin will be administered at a dose of 250 mg/d to adults&#xD;
        diagnosed with pre-diabetes and being treated with metformin (1,000 mg/d). This clinical&#xD;
        trial was designed as a placebo-control, double-blind, two-arm, crossover design. Clinical&#xD;
        characteristics, body composition, food consumption, metabolic and inflammatory biomarkers&#xD;
        and the microbiota of all patients will be evaluated before, during and at the end of the&#xD;
        12-week period (arm). Biochemical and metabolic parameters associated with prediabetes are&#xD;
        expected to improve or return to normal with Eriomin in combination with metformin. At the&#xD;
        same time, an increase in beneficial intestinal bacteria is expected, reducing pre-diabetic&#xD;
        dysbiosis, and perhaps a noticeable improvement in body composition.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Recent evidence shows that bioflavonoids from citrus fruits and herbs can reduce&#xD;
        hyperglycemia, dyslipidemia, insulin resistance and the systemic inflammatory process related&#xD;
        to type 2 diabetes (T2D). Although they can be found in fruits and herbs, bioflavonoid&#xD;
        supplements and nutraceuticals can provide sufficient and safe amounts of bioactive compounds&#xD;
        to prevent the development of metabolic disorders, such as metabolic syndrome, diabetes,&#xD;
        obesity and others. Eriocitrin flavanone, present in lemons, limes and oranges, has&#xD;
        demonstrated anti-inflammatory, anti-hyperglycemic and antioxidant properties and is an&#xD;
        integral part of lemon bioflavonoid supplements that have been widely marketed.&#xD;
  &#xD;
        Eriocitrin metabolism, similar to hesperidin, is resistant to pancreatic enzymes and are&#xD;
        mostly deglycosylated by intestinal bacteria (Bacteroides distasonis or Bacteroides&#xD;
        uniformis) to eriodictyol before absorption. A minimal amount can be absorbed as glycosylated&#xD;
        in the upper intestine. Eriodictyol, the aglycon of eriocitrin, can be metabolized by&#xD;
        intestinal bacteria (with 3,4-dihydroxycinnamic acid formation) to homoeriodictyol and&#xD;
        hesperetin through methoxylation. In the liver, eriodictyol is metabolized into glucuronides&#xD;
        and conjugated sulfates of eriodictyol, homoeriodictyol, and hesperitin, through sulfation,&#xD;
        glucuronidation and methylation, and later released into the circulation to exert biological&#xD;
        activity.&#xD;
  &#xD;
        Eriocitrin can increase the total antioxidant capacity, leading to a decrease in inflammatory&#xD;
        markers (IL-6, MCP-1 and us-CRP) in the blood and organs of mice supplemented with the&#xD;
        flavonoid. Eriocitrin also increased catalase and glutathione enzymes in the liver of&#xD;
        diabetic rats, and decreased lipid peroxidation in blood, liver and kidney. Furthermore, oral&#xD;
        administration of eriodictyol to diabetic rats improved glucose metabolism in the blood,&#xD;
        liver and kidney, and suppressed diabetes by upregulating PPARγ29 mRNA expression.&#xD;
  &#xD;
        Based on this experimental evidence, the nutraceutical Eriomin, composed of lemon&#xD;
        bioflavonoids, was tested as a dietary supplement to control mild to moderate hyperglycemia&#xD;
        in pre-diabetic and diabetic patients. After three months of therapy, there was a decrease in&#xD;
        hyperglycemia, improvement in insulin resistance and a decrease in HbA1c.&#xD;
  &#xD;
        Thus, the hypothesis of the current study is to use the nutraceutical Eriomin as a&#xD;
        co-adjuvant to oral biguanide (metformin) therapy, improving control of hyperglycemia and&#xD;
        insulin resistance, while increasing efficacy with a low dosage (250 mg/d) of the&#xD;
        nutraceutical. It is expected to improve the quality of the microbiota, the glucose&#xD;
        metabolism and body composition, in addition to reducing the side effects associated with the&#xD;
        continuous use of metformin.&#xD;
  &#xD;
        Therefore, the main objective of this study is to evaluate the effects of Eriomin (250mg/day)&#xD;
        associated with metformin on glycemic control, insulin resistance and other metabolic,&#xD;
        inflammatory and clinical parameters. Furthermore, it will evaluate changes in the microbiota&#xD;
        of pre-diabetic patients.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">July 15, 2023</start_date>
    <completion_date type="Anticipated">December 30, 2024</completion_date>
    <primary_completion_date type="Anticipated">April 30, 2024</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>Crossover Assignment</intervention_model>
      <intervention_model_description>A crossover, randomized, placebo-controlled, double-blind clinical trial will be conducted for 12 weeks, with a two-week washout interval, followed by another 12 weeks, totaling 26 weeks.&#xD;
  All participants must be under oral biguanide (metformin) (1000 mg/day) regimen by at least two weeks before the intervention, and they will be measure for glycemia, HbA1c and OGTT, and an interview with an MD and Nutritionist in order to confirm eligibility, according to the inclusion/exclusion criteria.&#xD;
  The selected individuals will be randomly distributed into 2 groups, and they will receive alternately Eriomin (or placebo), followed by 2-weeks of washout, and placebo (or Eriomin) for 12 weeks.&#xD;
  At the beginning of the first, 12th, 14th, and 26th weeks, all subjects will be evaluated for the following: Glycemia, OGTT, HbA1c, Insulin, Lipids, TEAC, MDA, GLP-1, inflammatory, hepatic, kidney, and anthropometric parameters, and microbiota composition.</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
      <masking_description>All subjects and the principal investigator will remain blinded to treatment until data analysis is complete. Eriomin (lemon flavonoids extract) and Placebo (composed of microcrystalline corn starch) were encapsulated in tablets of the same size, shape, and color, by a registered pharmacist.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Fasting Glycemia</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of glycemia concentration (mg/dL) before and after intervention with Eriomin/placebo</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Oral Glucose Tolerance Test (OGTT)</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Changes in blood glucose 2 hours after the oral glucose tolerance test (mg/dL) before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>HbA1c</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of glycated hemoglobin (%) in the blood serum/plasma before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Insulin</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of Insulin (µU/mL) in the blood serum/plasma before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Blood Lipids profile</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of cholesterol (mg/dL), HDL-cholesterol (mg/dL) and triglycerides (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Antioxidant Capacity</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of Trolox equivalent antioxidant capacity (TEAC) (μM) in the blood serum/plasma before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Lipid Peroxidation</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of Malondialdehyde (MDA) (mM) the blood serum/plasma before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Glucagon-like peptide-1 (GLP-1)</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of GLP-1 (pmol/L) the blood serum/plasma before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Inflammatory parameters</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of C Reactive Protein (CRP) (mg/dL), TNF-alpha (mg/dL), IL-6 (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Hepatic Enzymes</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>dosages of alkaline phosphatase (U/L), gamma glutamyl transferase (U/L), aspartate aminotransferase (U/L), and alanine aminotransferase (U/L) in the blood serum/plasma before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Kidney Blood Parameters</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of urea (mg/dL) and creatinine (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Anthropometric Parameters</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Measurements of body weight (kg), muscle mass (kg), fat mass (kg) before and after intervention with Eriomin/placebo</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Microbiota composition by 16S rRNA gene sequencing</measure>
      <time_frame>0-12-18-26 week</time_frame>
      <description>Dosages of the main bacteria groups by Operational Taxonomic Units (OTU) and % of relative abundance by group</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">60</enrollment>
    <condition>Pre-diabetes</condition>
    <arm_group>
      <arm_group_label>Eriomin/Placebo</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Group A will receive Eriomin (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then placebo (250 mg/day) for 12 weeks.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo/Eriomin</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>Group B will receive placebo (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then Eriomin (250 mg/day) for 12 weeks.</description>
    </arm_group>
    <intervention>
      <intervention_type>Dietary Supplement</intervention_type>
      <intervention_name>Eriomin</intervention_name>
      <description>Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day capsule of Eriomin for 12 weeks.</description>
      <arm_group_label>Eriomin/Placebo</arm_group_label>
      <arm_group_label>Placebo/Eriomin</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Dietary Supplement</intervention_type>
      <intervention_name>Washout</intervention_name>
      <description>After 12 weeks of treatment with the active component (Eriomin) or placebo, the participants will follow a washout for 2 weeks.</description>
      <arm_group_label>Eriomin/Placebo</arm_group_label>
      <arm_group_label>Placebo/Eriomin</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Dietary Supplement</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day placebo capsule for 12 weeks.</description>
      <arm_group_label>Eriomin/Placebo</arm_group_label>
      <arm_group_label>Placebo/Eriomin</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Glycemia of 6.1 to 7.0 mmol / L&#xD;
  &#xD;
            -  Glycated hemoglobin with values between 5.7 and 6.4%&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  use of drugs, vitamins and dietary supplements, alcohol consumption (&gt; 20 g&#xD;
               alcohol/d), and intense physical activity (&gt; 5 hours/week).&#xD;
  &#xD;
            -  History of cardiovascular disease, diabetes mellitus, liver, kidney or pancreatic&#xD;
               disease&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>35 Years</minimum_age>
      <maximum_age>65 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Thais B Cesar, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Sao Paulo State University</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Maria Rita M De Oliveira, PhD</last_name>
      <role>Study Director</role>
      <affiliation>Sao Paulo State University</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Valeria Cristina Samdrim, PhD</last_name>
      <role>Study Chair</role>
      <affiliation>Sao Paulo State University</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Katia Sivieri, PhD</last_name>
      <role>Study Chair</role>
      <affiliation>Sao Paulo State University</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Adriana Lucia Mendes, PhD</last_name>
      <role>Study Chair</role>
      <affiliation>Sao Paulo State University</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Gabriela A Meira, Nutrition</last_name>
      <role>Study Chair</role>
      <affiliation>Sao Paulo State University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Thais B Cesar, PhD</last_name>
      <phone>+1 (352) 978-7557</phone>
      <email>thais.cesar@unesp.br</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Maria Rita M De Oliveira, PhD</last_name>
      <email>maria-rita.oliveira@unesp.br</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Centro de Estudos e Praticas em Nutrição (CEPRAN)</name>
        <address>
          <city>Botucatú</city>
          <state>SP</state>
          <zip>18618-689</zip>
          <country>Brazil</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Maria Rita M de Oliveira, PhD</last_name>
        <phone>(14) 98154-1509</phone>
        <email>maria-rita.oliveira@unesp.br</email>
      </contact>
      <contact_backup>
        <last_name>Valeria Cristina Sandrim, PhD</last_name>
        <phone>(14) 98154-1509</phone>
        <email>valeria.sandrim@unesp.br</email>
      </contact_backup>
      <investigator>
        <last_name>Thais B Cesar, PhD</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Brazil</country>
    </location_countries>
    <reference>
      <citation>Testa R, Bonfigli AR, Genovese S, De Nigris V, Ceriello A. The Possible Role of Flavonoids in the Prevention of Diabetic Complications. Nutrients. 2016 May 20;8(5):310. doi: 10.3390/nu8050310.</citation>
      <PMID>27213445</PMID>
    </reference>
    <reference>
      <citation>Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: a cellular mechanism review. Nutr Metab (Lond). 2015 Dec 23;12:60. doi: 10.1186/s12986-015-0057-7. eCollection 2015.</citation>
      <PMID>26705405</PMID>
    </reference>
    <reference>
      <citation>Minato K, Miyake Y, Fukumoto S, Yamamoto K, Kato Y, Shimomura Y, Osawa T. Lemon flavonoid, eriocitrin, suppresses exercise-induced oxidative damage in rat liver. Life Sci. 2003 Feb 21;72(14):1609-16. doi: 10.1016/s0024-3205(02)02443-8.</citation>
      <PMID>12551749</PMID>
    </reference>
    <reference>
      <citation>Hiramitsu M, Shimada Y, Kuroyanagi J, Inoue T, Katagiri T, Zang L, Nishimura Y, Nishimura N, Tanaka T. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. Sci Rep. 2014 Jan 15;4:3708. doi: 10.1038/srep03708.</citation>
      <PMID>24424211</PMID>
    </reference>
    <reference>
      <citation>Miyake Y, Shimoi K, Kumazawa S, Yamamoto K, Kinae N, Osawa T. Identification and antioxidant activity of flavonoid metabolites in plasma and urine of eriocitrin-treated rats. J Agric Food Chem. 2000 Aug;48(8):3217-24. doi: 10.1021/jf990994g.</citation>
      <PMID>10956094</PMID>
    </reference>
    <reference>
      <citation>Ferreira PS, Spolidorio LC, Manthey JA, Cesar TB. Citrus flavanones prevent systemic inflammation and ameliorate oxidative stress in C57BL/6J mice fed high-fat diet. Food Funct. 2016 Jun 15;7(6):2675-81. doi: 10.1039/c5fo01541c. Epub 2016 May 16.</citation>
      <PMID>27182608</PMID>
    </reference>
    <reference>
      <citation>Ribeiro CB, Ramos FM, Manthey JA, Cesar TB. Effectiveness of Eriomin(R) in managing hyperglycemia and reversal of prediabetes condition: A double-blind, randomized, controlled study. Phytother Res. 2019 Jul;33(7):1921-1933. doi: 10.1002/ptr.6386. Epub 2019 Jun 11.</citation>
      <PMID>31183921</PMID>
    </reference>
    <reference>
      <citation>Cesar TB, Ramos FMM, Ribeiro CB. Nutraceutical Eriocitrin (Eriomin) Reduces Hyperglycemia by Increasing Glucagon-Like Peptide 1 and Downregulates Systemic Inflammation: A Crossover-Randomized Clinical Trial. J Med Food. 2022 Nov;25(11):1050-1058. doi: 10.1089/jmf.2021.0181. Epub 2022 Jul 7.</citation>
      <PMID>35796695</PMID>
    </reference>
    <reference>
      <citation>Flory J, Lipska K. Metformin in 2019. JAMA. 2019 May 21;321(19):1926-1927. doi: 10.1001/jama.2019.3805.</citation>
      <PMID>31009043</PMID>
    </reference>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>March 27, 2023</study_first_submitted>
    <study_first_submitted_qc>August 21, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 22, 2023</study_first_posted>
    <last_update_submitted>August 21, 2023</last_update_submitted>
    <last_update_submitted_qc>August 21, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 24, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>São Paulo State University</investigator_affiliation>
      <investigator_full_name>Thais Cesar</investigator_full_name>
      <investigator_title>Principal Investigator</investigator_title>
    </responsible_party>
    <keyword>citrus flavonoids</keyword>
    <keyword>Eriomin</keyword>
    <keyword>oral antidiabetic biguanide (metformin)</keyword>
    <keyword>hyperglycemia</keyword>
    <keyword>microbiota</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Hyperglycemia</mesh_term>
      <mesh_term>Prediabetic State</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06005142
  org study id: SaoPSU23
  nct id: NCT06005142
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  Citrus bioflavonoids, such as eriocitrin, hesperidin and naringin, have been shown improved
        hyperglycemia, insulin resistance and systemic inflammation, related to the development of
        type 2 diabetes. The nutraceutical Eriomin, a lemon flavonoid extract composed mainly by
        eriocitrin (70%) and other flavonoids (30%), improved the control of moderate hyperglycemia
        in pre-diabetic and diabetic patients without drug therapy. However, most patients with
        pre-diabetes are on oral biguanide (metformin) therapy, despite its limited efficacy (30-40%)
        on glycemic control and its undesirable gastrointestinal effects.
  
        Therefore, in the current study, Eriomin will be administered at a dose of 250 mg/d to adults
        diagnosed with pre-diabetes and being treated with metformin (1,000 mg/d). This clinical
        trial was designed as a placebo-control, double-blind, two-arm, crossover design. Clinical
        characteristics, body composition, food consumption, metabolic and inflammatory biomarkers
        and the microbiota of all patients will be evaluated before, during and at the end of the
        12-week period (arm). Biochemical and metabolic parameters associated with prediabetes are
        expected to improve or return to normal with Eriomin in combination with metformin. At the
        same time, an increase in beneficial intestinal bacteria is expected, reducing pre-diabetic
        dysbiosis, and perhaps a noticeable improvement in body composition.
  Recent evidence shows that bioflavonoids from citrus fruits and herbs can reduce
        hyperglycemia, dyslipidemia, insulin resistance and the systemic inflammatory process related
        to type 2 diabetes (T2D). Although they can be found in fruits and herbs, bioflavonoid
        supplements and nutraceuticals can provide sufficient and safe amounts of bioactive compounds
        to prevent the development of metabolic disorders, such as metabolic syndrome, diabetes,
        obesity and others. Eriocitrin flavanone, present in lemons, limes and oranges, has
        demonstrated anti-inflammatory, anti-hyperglycemic and antioxidant properties and is an
        integral part of lemon bioflavonoid supplements that have been widely marketed.
  
        Eriocitrin metabolism, similar to hesperidin, is resistant to pancreatic enzymes and are
        mostly deglycosylated by intestinal bacteria (Bacteroides distasonis or Bacteroides
        uniformis) to eriodictyol before absorption. A minimal amount can be absorbed as glycosylated
        in the upper intestine. Eriodictyol, the aglycon of eriocitrin, can be metabolized by
        intestinal bacteria (with 3,4-dihydroxycinnamic acid formation) to homoeriodictyol and
        hesperetin through methoxylation. In the liver, eriodictyol is metabolized into glucuronides
        and conjugated sulfates of eriodictyol, homoeriodictyol, and hesperitin, through sulfation,
        glucuronidation and methylation, and later released into the circulation to exert biological
        activity.
  
        Eriocitrin can increase the total antioxidant capacity, leading to a decrease in inflammatory
        markers (IL-6, MCP-1 and us-CRP) in the blood and organs of mice supplemented with the
        flavonoid. Eriocitrin also increased catalase and glutathione enzymes in the liver of
        diabetic rats, and decreased lipid peroxidation in blood, liver and kidney. Furthermore, oral
        administration of eriodictyol to diabetic rats improved glucose metabolism in the blood,
        liver and kidney, and suppressed diabetes by upregulating PPARγ29 mRNA expression.
  
        Based on this experimental evidence, the nutraceutical Eriomin, composed of lemon
        bioflavonoids, was tested as a dietary supplement to control mild to moderate hyperglycemia
        in pre-diabetic and diabetic patients. After three months of therapy, there was a decrease in
        hyperglycemia, improvement in insulin resistance and a decrease in HbA1c.
  
        Thus, the hypothesis of the current study is to use the nutraceutical Eriomin as a
        co-adjuvant to oral biguanide (metformin) therapy, improving control of hyperglycemia and
        insulin resistance, while increasing efficacy with a low dosage (250 mg/d) of the
        nutraceutical. It is expected to improve the quality of the microbiota, the glucose
        metabolism and body composition, in addition to reducing the side effects associated with the
        continuous use of metformin.
  
        Therefore, the main objective of this study is to evaluate the effects of Eriomin (250mg/day)
        associated with metformin on glycemic control, insulin resistance and other metabolic,
        inflammatory and clinical parameters. Furthermore, it will evaluate changes in the microbiota
        of pre-diabetic patients.
  allocation: Randomized
  intervention model: Crossover Assignment
  intervention model description: A crossover, randomized, placebo-controlled, double-blind clinical trial will be conducted for 12 weeks, with a two-week washout interval, followed by another 12 weeks, totaling 26 weeks.
  All participants must be under oral biguanide (metformin) (1000 mg/day) regimen by at least two weeks before the intervention, and they will be measure for glycemia, HbA1c and OGTT, and an interview with an MD and Nutritionist in order to confirm eligibility, according to the inclusion/exclusion criteria.
  The selected individuals will be randomly distributed into 2 groups, and they will receive alternately Eriomin (or placebo), followed by 2-weeks of washout, and placebo (or Eriomin) for 12 weeks.
  At the beginning of the first, 12th, 14th, and 26th weeks, all subjects will be evaluated for the following: Glycemia, OGTT, HbA1c, Insulin, Lipids, TEAC, MDA, GLP-1, inflammatory, hepatic, kidney, and anthropometric parameters, and microbiota composition.
  primary purpose: Treatment
  masking: Triple (Participant, Investigator, Outcomes Assessor)
  masking description: All subjects and the principal investigator will remain blinded to treatment until data analysis is complete. Eriomin (lemon flavonoids extract) and Placebo (composed of microcrystalline corn starch) were encapsulated in tablets of the same size, shape, and color, by a registered pharmacist.
  measure: Fasting Glycemia
  time frame: 0-12-18-26 week
  description: Dosages of glycemia concentration (mg/dL) before and after intervention with Eriomin/placebo
  measure: Oral Glucose Tolerance Test (OGTT)
  time frame: 0-12-18-26 week
  description: Changes in blood glucose 2 hours after the oral glucose tolerance test (mg/dL) before and after intervention with Eriomin/placebo
  measure: HbA1c
  time frame: 0-12-18-26 week
  description: Dosages of glycated hemoglobin (%) in the blood serum/plasma before and after intervention with Eriomin/placebo
  measure: Insulin
  time frame: 0-12-18-26 week
  description: Dosages of Insulin (µU/mL) in the blood serum/plasma before and after intervention with Eriomin/placebo
  measure: Blood Lipids profile
  time frame: 0-12-18-26 week
  description: Dosages of cholesterol (mg/dL), HDL-cholesterol (mg/dL) and triglycerides (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo
  measure: Antioxidant Capacity
  time frame: 0-12-18-26 week
  description: Dosages of Trolox equivalent antioxidant capacity (TEAC) (μM) in the blood serum/plasma before and after intervention with Eriomin/placebo
  measure: Lipid Peroxidation
  time frame: 0-12-18-26 week
  description: Dosages of Malondialdehyde (MDA) (mM) the blood serum/plasma before and after intervention with Eriomin/placebo
  measure: Glucagon-like peptide-1 (GLP-1)
  time frame: 0-12-18-26 week
  description: Dosages of GLP-1 (pmol/L) the blood serum/plasma before and after intervention with Eriomin/placebo
  measure: Inflammatory parameters
  time frame: 0-12-18-26 week
  description: Dosages of C Reactive Protein (CRP) (mg/dL), TNF-alpha (mg/dL), IL-6 (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo
  measure: Hepatic Enzymes
  time frame: 0-12-18-26 week
  description: dosages of alkaline phosphatase (U/L), gamma glutamyl transferase (U/L), aspartate aminotransferase (U/L), and alanine aminotransferase (U/L) in the blood serum/plasma before and after intervention with Eriomin/placebo
  measure: Kidney Blood Parameters
  time frame: 0-12-18-26 week
  description: Dosages of urea (mg/dL) and creatinine (mg/dL) in the blood serum/plasma before and after intervention with Eriomin/placebo
  measure: Anthropometric Parameters
  time frame: 0-12-18-26 week
  description: Measurements of body weight (kg), muscle mass (kg), fat mass (kg) before and after intervention with Eriomin/placebo
  measure: Microbiota composition by 16S rRNA gene sequencing
  time frame: 0-12-18-26 week
  description: Dosages of the main bacteria groups by Operational Taxonomic Units (OTU) and % of relative abundance by group
  arm group label: Eriomin/Placebo
  arm group type: Active Comparator
  description: Group A will receive Eriomin (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then placebo (250 mg/day) for 12 weeks.
  arm group label: Placebo/Eriomin
  arm group type: Placebo Comparator
  description: Group B will receive placebo (250 mg/day) for 12 weeks, followed by a 2-week washout period, and then Eriomin (250 mg/day) for 12 weeks.
  intervention type: Dietary Supplement
  intervention name: Eriomin
  description: Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day capsule of Eriomin for 12 weeks.
  arm group label: Eriomin/Placebo
  arm group label: Placebo/Eriomin
  intervention type: Dietary Supplement
  intervention name: Washout
  description: After 12 weeks of treatment with the active component (Eriomin) or placebo, the participants will follow a washout for 2 weeks.
  arm group label: Eriomin/Placebo
  arm group label: Placebo/Eriomin
  intervention type: Dietary Supplement
  intervention name: Placebo
  description: Pre-diabetic patients on oral biguanide (metformin) (1000 mg/day) will receive a 250 mg/day placebo capsule for 12 weeks.
  arm group label: Eriomin/Placebo
  arm group label: Placebo/Eriomin
  criteria: 
  gender: All
  minimum age: 35 Years
  maximum age: 65 Years
  healthy volunteers: No
  last name: Thais B Cesar, PhD
  role: Principal Investigator
  affiliation: Sao Paulo State University
  last name: Maria Rita M De Oliveira, PhD
  role: Study Director
  affiliation: Sao Paulo State University
  last name: Valeria Cristina Samdrim, PhD
  role: Study Chair
  affiliation: Sao Paulo State University
  last name: Katia Sivieri, PhD
  role: Study Chair
  affiliation: Sao Paulo State University
  last name: Adriana Lucia Mendes, PhD
  role: Study Chair
  affiliation: Sao Paulo State University
  last name: Gabriela A Meira, Nutrition
  role: Study Chair
  affiliation: Sao Paulo State University
  last name: Thais B Cesar, PhD
  phone: +1 (352) 978-7557
  email: thais.cesar@unesp.br
  last name: Maria Rita M De Oliveira, PhD
  email: maria-rita.oliveira@unesp.br
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  investigator: 
  country: Brazil
  citation: Testa R, Bonfigli AR, Genovese S, De Nigris V, Ceriello A. The Possible Role of Flavonoids in the Prevention of Diabetic Complications. Nutrients. 2016 May 20;8(5):310. doi: 10.3390/nu8050310.
  PMID: 27213445
  citation: Vinayagam R, Xu B. Antidiabetic properties of dietary flavonoids: a cellular mechanism review. Nutr Metab (Lond). 2015 Dec 23;12:60. doi: 10.1186/s12986-015-0057-7. eCollection 2015.
  PMID: 26705405
  citation: Minato K, Miyake Y, Fukumoto S, Yamamoto K, Kato Y, Shimomura Y, Osawa T. Lemon flavonoid, eriocitrin, suppresses exercise-induced oxidative damage in rat liver. Life Sci. 2003 Feb 21;72(14):1609-16. doi: 10.1016/s0024-3205(02)02443-8.
  PMID: 12551749
  citation: Hiramitsu M, Shimada Y, Kuroyanagi J, Inoue T, Katagiri T, Zang L, Nishimura Y, Nishimura N, Tanaka T. Eriocitrin ameliorates diet-induced hepatic steatosis with activation of mitochondrial biogenesis. Sci Rep. 2014 Jan 15;4:3708. doi: 10.1038/srep03708.
  PMID: 24424211
  citation: Miyake Y, Shimoi K, Kumazawa S, Yamamoto K, Kinae N, Osawa T. Identification and antioxidant activity of flavonoid metabolites in plasma and urine of eriocitrin-treated rats. J Agric Food Chem. 2000 Aug;48(8):3217-24. doi: 10.1021/jf990994g.
  PMID: 10956094
  citation: Ferreira PS, Spolidorio LC, Manthey JA, Cesar TB. Citrus flavanones prevent systemic inflammation and ameliorate oxidative stress in C57BL/6J mice fed high-fat diet. Food Funct. 2016 Jun 15;7(6):2675-81. doi: 10.1039/c5fo01541c. Epub 2016 May 16.
  PMID: 27182608
  citation: Ribeiro CB, Ramos FM, Manthey JA, Cesar TB. Effectiveness of Eriomin(R) in managing hyperglycemia and reversal of prediabetes condition: A double-blind, randomized, controlled study. Phytother Res. 2019 Jul;33(7):1921-1933. doi: 10.1002/ptr.6386. Epub 2019 Jun 11.
  PMID: 31183921
  citation: Cesar TB, Ramos FMM, Ribeiro CB. Nutraceutical Eriocitrin (Eriomin) Reduces Hyperglycemia by Increasing Glucagon-Like Peptide 1 and Downregulates Systemic Inflammation: A Crossover-Randomized Clinical Trial. J Med Food. 2022 Nov;25(11):1050-1058. doi: 10.1089/jmf.2021.0181. Epub 2022 Jul 7.
  PMID: 35796695
  citation: Flory J, Lipska K. Metformin in 2019. JAMA. 2019 May 21;321(19):1926-1927. doi: 10.1001/jama.2019.3805.
  PMID: 31009043
  responsible party type: Sponsor-Investigator
  investigator affiliation: São Paulo State University
  investigator full name: Thais Cesar
  investigator title: Principal Investigator
  mesh term: Hyperglycemia
  mesh term: Prediabetic State