<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/NCT03262363</url>
  </required_header>
  <id_info>
    <org_study_id>UIMER002</org_study_id>
    <nct_id>NCT03262363</nct_id>
  </id_info>
  <brief_title>Curcumin on NFE2L2 Gene Expression, Antioxidant Capacity and Renal Function According to rs35652124 in Diabetic Nephropathy</brief_title>
  <acronym>CURCUNRF2</acronym>
  <official_title>Interaction of Polymorphism rs35652124 With Curcumin Supplementation on NFE2L2 Gene Expression, Antioxidant Capacity and Renal Function in Patients With Early Diabetic Nephropathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Unidad de Investigacion Medica en Enfermedades Renales</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Unidad de Investigacion Medica en Enfermedades Renales</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>
      The increase in the prevalence of diabetes mellitus (DM) is one of the greatest public health&#xD;
      challenges worldwide. Epidemiological studies have shown that DM is the leading cause of&#xD;
      chronic kidney disease (CKD) in patients initiating renal replacement therapy. In our&#xD;
      country, diabetes accounts for about 60% of all incidents of dialysis. On the other hand, CKD&#xD;
      is currently considered a noxious disease because patients not only have the likelihood of&#xD;
      progression to end-stage renal disease (ESRD), but because these renal alterations are&#xD;
      associated with an increased risk of cardiovascular complications and premature death for the&#xD;
      same cause. Most studies have focused on traditional risk factors (poor diet, physical&#xD;
      inactivity and obesity) for the development and progression of renal damage, and less&#xD;
      information exists on non-traditional factors such as oxidative stress and mainly, the low&#xD;
      antioxidant response that characterizes both DM and nephropathy. In addition, there is a&#xD;
      great variation in the susceptibility to and progression of kidney disease between different&#xD;
      populations that is not explained by the presence of traditional factors and that could be&#xD;
      triggered by genetic variations and its interaction with other components related to the&#xD;
      environment and lifestyle. Fortunately, there is sufficient scientific evidence that early&#xD;
      detection and modification of negative lifestyle factors can not only delay or halt the&#xD;
      progression of the renal function decline to ESRD but can also significantly reduce the&#xD;
      incidence of cardiovascular disease leading to premature death in most of these patients.&#xD;
      Therefore, it is suggested that this risk may be determined by the interaction of lifestyle&#xD;
      factors with the presence of susceptibility alleles, which may vary from one population to&#xD;
      another. It is now known that hyperglycemia causes a state of oxidative stress and&#xD;
      inflammation that can be counteracted by diet supplementation with some natural antioxidants&#xD;
      such as curcumin. It has been shown that this molecule has multiple pharmacological&#xD;
      properties: antioxidant, anti-inflammatory, cardioprotective, renoprotective, among others.&#xD;
      In clinical trials a positive effect of curcumin has been seen in the treatment of diabetes&#xD;
      and its complications. This has generated a relative optimism in the search for new curcumin&#xD;
      treatment targets where oxidative stress is of great relevance, as is the case with CKD.&#xD;
      However, there are still doubts about its efficacy as an adjuvant in the prevention of CKD.&#xD;
      Additionally, the role played by interindividual variability in genes involved in the&#xD;
      mechanism of action of curcumin is still incipient, more studies in this knowledge area are&#xD;
      necessary.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aim: To evaluate the interaction between rs35652124 polymorphism and curcumin supplementation&#xD;
      on the levels of NFE2L2 gene expression, antioxidant capacity and renal function in patients&#xD;
      with early diabetic nephropathy (EDN).&#xD;
&#xD;
      Subjects and Methods. Parallel clinical trial with randomized and triple blind. From a&#xD;
      database of diabetic patients newly diagnosed with CKD, those with EDN will be identified and&#xD;
      located by telephone to complete a total of 275 subjects over 18 years of age. Subsequently,&#xD;
      they will be cited in the office of Biomedical Unit 02, will verify that they meet the&#xD;
      selection criteria, will be informed about the objectives of the study and invited to&#xD;
      participate. Those who agree to participate will be given an informed consent letter, they&#xD;
      will be asked to read it carefully and if they have any doubts, they will be clarified at the&#xD;
      moment. Once they have signed the written consent they will be cited for the first blood&#xD;
      sample collecting (5 mL) to be used for genomic DNA extraction and genotyping for the&#xD;
      rs35652124 polymorphism. All patients entering the study will undergo a physical and dietary&#xD;
      examination and will record the data on a clinical record card. They will be prescribed a&#xD;
      meal plan according to ADA recommendations and K/DOQI guidelines two weeks prior (week &lt;2) at&#xD;
      the start of the clinical trial, which will be maintained throughout the follow-up. They will&#xD;
      then be scheduled monthly for medical and nutritional assessment. At the visits of weeks 2, 0&#xD;
      (start of supplementation), 12, and 24, three peripheral blood tubes (5 mL each) will be&#xD;
      drawn. The first, to extract total mRNA and expression analysis of the NFE2L2 gene, the&#xD;
      second, to determine the levels of NRF2, SOD, GPx and HO1 and the third, to perform renal&#xD;
      function tests and control of possible confounding variables (creatinine, glucose,&#xD;
      glycosylated hemoglobin, lipid profile and uric acid). In addition, they will be asked to&#xD;
      collect a sample of the first morning urine to quantify albuminuria/creatinuria on the same&#xD;
      day that blood samples were taken. The time of the study since the first evaluation is 26&#xD;
      weeks and the total number of medical and nutrition visits will be six, one monthly.&#xD;
      Genotyping will be performed by polymerase chain reaction (PCR) coupled to four pairs of&#xD;
      oligonucleotide primers specific for the alleles of interest. The gene expression assay will&#xD;
      be performed by real-time PCR, while the determination of the concentrations of NRF2, SOD,&#xD;
      GPx and HO1 will be carried out by the ELISA method with kits designed for this purpose. The&#xD;
      analysis of the data includes descriptive statistics expressed in averages and standard or&#xD;
      median deviations according to the parametric or non-parametric distribution, the nominal&#xD;
      variables will be presented as numbers or percentages and the comparison between these will&#xD;
      be by Chi square or Fisher exact. Inferential statistics included U-Mann Whitney or Student t&#xD;
      tests for independent and paired samples as appropriate to evaluate the NRF2, SOD, GPx and&#xD;
      HO1 concentrations with the different interventions and the individuals in the control group.&#xD;
      A covariance analysis will be performed taking into consideration the factor supplementation,&#xD;
      genetic factor and the interaction of both with the concentrations of NRF2. A value of p&lt;0.05&#xD;
      and 95% CI will be considered significant.&#xD;
&#xD;
      Resources and infrastructure. The CIBO and the Medical Research Unit in Renal Diseases have&#xD;
      the human resources to coordinate and develop the present research. Also, they have the&#xD;
      necessary infrastructure and equipment to carry out the procedures contemplated in this&#xD;
      project. The project will be submitted to calls for funding to obtain the necessary resources&#xD;
      for its development.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">August 1, 2018</start_date>
  <completion_date type="Anticipated">April 30, 2019</completion_date>
  <primary_completion_date type="Anticipated">February 28, 2019</primary_completion_date>
  <phase>Phase 2/Phase 3</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 study starts from the classification of patients according to the genotype for the rs35652124 polymorphism (-653G&gt;A) of the NFE2L2 gene. Two Experimental groups and two Control groups will be formed according to the following:&#xD;
Experimental group 1: Diabetic patients with early CKD homozygous for the -653G (G/G) allele of the NFE2L2 gene that will receive curcumin.&#xD;
Experimental group 2: Diabetic patients with early CKD carrying the allele -653A (G/A or A/A) of the NFE2L2 gene that will receive curcumin.&#xD;
Control group 1: Diabetic patients with early CKD homozygous for the -653G (G/G) allele of the NFE2L2 gene receiving placebo.&#xD;
Control group 2: Diabetic patients with early CKD carrying the allele -653A (G/A or A/A) of the NFE2L2 gene who will receive placebo.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Patient Blinding: Patients with EDN will be blinded to the intervention they will receive Evaluator Blinding: The principal investigator will be blinded to the intervention that patients will receive (curcumin or placebo), but will know the genotype distribution in both Experimental and Placebo groups. The external investigator will be blinded to the knowledge of the patients genotype, but will know the intervention group to which each patient was assigned according to a registry (but will not know the identity of the patients). The Doctorate Program Student will be blinded to the distribution of patients genotype and the type of intervention patients will receive.&#xD;
Statistical Blinding: An associated researcher will be blinded to the distribution of patients genotype and the type of intervention patients will receive, but not to the knowledge of the database.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change from Baseline expression Gen NFE2L2 at 3 months</measure>
    <time_frame>Baseline at 3 months</time_frame>
    <description>mRNA and active protein NRF2</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Baseline expression Gen NFE2L2 at 6 months</measure>
    <time_frame>Baseline at 6 months</time_frame>
    <description>mRNA and active protein NRF2</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Antioxidant capacity at 3 months</measure>
    <time_frame>Baseline at 3 months</time_frame>
    <description>Superoxide dismutase, hemoxygenase 1, Glutathion peroxidase using the ELISA technique</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Antioxidant capacity at 6 months</measure>
    <time_frame>Baseline at 6 months</time_frame>
    <description>Superoxide dismutase, hemoxygenase 1, Glutathion peroxidase using the ELISA technique</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Renal Function at 3 months</measure>
    <time_frame>Baseline at 3 months</time_frame>
    <description>Glomerular Filtration Rate (Serum creatinine) and Albuminuria (Albumin/Creatinine Ratio)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change from Renal Function at 6 months</measure>
    <time_frame>Baseline at 6 months</time_frame>
    <description>Glomerular Filtration Rate (Serum creatinine) and Albuminuria (Albumin/Creatinine Ratio)</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">176</enrollment>
  <condition>Chronic Kidney Diseases</condition>
  <condition>Diabetes Mellitus, Type 2</condition>
  <condition>Polymorphism</condition>
  <arm_group>
    <arm_group_label>Curcumin/NFE2L2 A&gt;G</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in Experimental group 1 and 2 will receive 800 mg/day of curcumin (for which a bioavailability of about 90% has been demonstrated and greater than other curcuminoids, administered in two doses of 400 mg each (the presentation will be in capsules containing 400 mg of THC).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo/NFE2L2 A&gt;G</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients in control group 1 and 2, the placebo intervention will consist of administering sucralose capsules (a substance lacking pharmacological action, with no active principle and a lower intake of glucose compared to sucrose). Patients will receive 300 mg/day of sucralose distributed in two doses of 150 mg each.</description>
  </arm_group>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Curcumin/NFE2L2 A&gt;G</intervention_name>
    <description>The administration will be orally and the patient will be instructed to take two capsules per day for one week, one in the morning 15 minutes before breakfast and another at night 15 minutes before dinner, accompanied by a cup of 240 mL of pure water. It will be indicated to continue with their usual medical treatment.</description>
    <arm_group_label>Curcumin/NFE2L2 A&gt;G</arm_group_label>
    <other_name>Curcumin group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Placebo/NFE2L2 A&gt;G</intervention_name>
    <description>The administration will be orally and the patient will be instructed to take two capsules for 24 weeks, one in the morning 15 minutes before breakfast and another in the evening 15 minutes before dinner, accompanied by a 240 mL cup of pure water. They will be advised to continue their usual medical treatment.</description>
    <arm_group_label>Placebo/NFE2L2 A&gt;G</arm_group_label>
    <other_name>Placebo group</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  With T2DM according to the American Diabetes Association&#xD;
&#xD;
          -  With any time of T2DM evolution&#xD;
&#xD;
          -  With CKD stage 1-3a according to the K/DIGO guidelines&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Incomplete evaluations&#xD;
&#xD;
          -  That they have not been attached to the assigned intervention with an established&#xD;
             frequency of &lt;80%&#xD;
&#xD;
          -  Decide to withdraw from the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>LAURA CORTES-SANABRIA, PhD</last_name>
    <phone>(55)3339522038</phone>
    <phone_ext>32204</phone_ext>
    <email>cortes_sanabria@yahoo.com.mx</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>ERIKA FABIOLA GOMEZ-GARCIA, MsC</last_name>
    <phone>(55)3339522038</phone>
    <phone_ext>32204</phone_ext>
    <email>erikaf.gomezg@yahoo.com.mx</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Umae Hospital de Especialidades</name>
      <address>
        <city>Guadalajara</city>
        <state>Jalisco</state>
        <zip>44340</zip>
        <country>Mexico</country>
      </address>
    </facility>
    <contact>
      <last_name>LAURA CORTES-SANABRIA, PhD</last_name>
      <phone>33 3660 3000</phone>
      <phone_ext>32204</phone_ext>
      <email>cortes_sanabria@yahoo.com.mx</email>
    </contact>
    <contact_backup>
      <last_name>ERIKA FABIOLA GOMEZ-GARCIA, MsC</last_name>
      <phone>33 3660 3000</phone>
      <phone_ext>32204</phone_ext>
      <email>erikaf.gomezg@yahoo.com.mx</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <reference>
    <citation>United States Renal Data Sytem. 2016 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Bethesda, MD, 2016.</citation>
  </reference>
  <reference>
    <citation>Gutiérrez JP, Rivera Dommarco J, Shamah Levy T, et al. Encuesta Nacional de Salud y Nutrición 2012. Resultados Nacionales. Cuernavaca, México: Salud Publica Mex; 2012.</citation>
  </reference>
  <reference>
    <citation>Hernández Ávila M, Gutiérrez JP, editores. Diabetes mellitus: la urgencia de reforzar la respuesta en políticas públicas para su prevención y control. Cuernavaca, México: Salud Publica Mex; 2012.</citation>
  </reference>
  <reference>
    <citation>Asociación Latinoamericana de Diabetes (ALAD). Guías ALAD sobre el diagnóstico, control y tratamiento de la diabetes mellitus Tipo 2 con medicina basada en evidencia. 1a ed. Latinoamérica: ALAD; 2013.</citation>
  </reference>
  <reference>
    <citation>Hernández Ávila M, Rivera Dommarco J, Shamah Levy T. Encuesta Nacional de Salud y Nutrición 2016. Resultados Nacionales. Cuernavaca, México: Instituto Nacional de Salud Pública (MX), 2016.</citation>
  </reference>
  <reference>
    <citation>Cueto Manzano AM, Cortés Sanabria L, Martínez Ramírez HR, et al. Enfermedad Renal Crónica Temprana: Prevención, diagnóstico y tratamiento. México: Médica Panamericana; 2013. pp. 250.</citation>
  </reference>
  <reference>
    <citation>Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest. 2004 Dec;34(12):785-96. doi: 10.1111/j.1365-2362.2004.01429.x.</citation>
    <PMID>15606719</PMID>
  </reference>
  <reference>
    <citation>Navarro JF, Milena FJ, Mora C, Leon C, Garcia J. Renal pro-inflammatory cytokine gene expression in diabetic nephropathy: effect of angiotensin-converting enzyme inhibition and pentoxifylline administration. Am J Nephrol. 2006;26(6):562-70. doi: 10.1159/000098004. Epub 2006 Dec 13.</citation>
    <PMID>17167242</PMID>
  </reference>
  <reference>
    <citation>Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H, Negishi T, Sugawara A, Kensler TW, Yamamoto M. The Keap1-Nrf2 system prevents onset of diabetes mellitus. Mol Cell Biol. 2013 Aug;33(15):2996-3010. doi: 10.1128/MCB.00225-13. Epub 2013 May 28.</citation>
    <PMID>23716596</PMID>
  </reference>
  <reference>
    <citation>Gómez García EF, Martínez Ramírez HR, Cortés Sanabria L, et al. Cambios y mejoras en la calidad de la dieta en pacientes con enfermedad renal crónica temprana. En: Conferencia dentro del marco del XLVII Congreso Nacional de Nefrología; 2013 Sep 4-12; Guadalajara, Jalisco. México.</citation>
  </reference>
  <reference>
    <citation>Balagopal P, George D, Patton N, Yarandi H, Roberts WL, Bayne E, Gidding S. Lifestyle-only intervention attenuates the inflammatory state associated with obesity: a randomized controlled study in adolescents. J Pediatr. 2005 Mar;146(3):342-8. doi: 10.1016/j.jpeds.2004.11.033.</citation>
    <PMID>15756217</PMID>
  </reference>
  <reference>
    <citation>Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013 Jun;83(6):1029-41. doi: 10.1038/ki.2012.439. Epub 2013 Jan 16.</citation>
    <PMID>23325084</PMID>
  </reference>
  <reference>
    <citation>Yoh K, Hirayama A, Ishizaki K, Yamada A, Takeuchi M, Yamagishi S, Morito N, Nakano T, Ojima M, Shimohata H, Itoh K, Takahashi S, Yamamoto M. Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Genes Cells. 2008 Nov;13(11):1159-70. doi: 10.1111/j.1365-2443.2008.01234.x.</citation>
    <PMID>19090810</PMID>
  </reference>
  <reference>
    <citation>Choi BH, Kang KS, Kwak MK. Effect of redox modulating NRF2 activators on chronic kidney disease. Molecules. 2014 Aug 20;19(8):12727-59. doi: 10.3390/molecules190812727.</citation>
    <PMID>25140450</PMID>
  </reference>
  <reference>
    <citation>Atul A and Lakhwinder S. Pathogenesis of diabetic nephropathy and potential therapeutic effect of curcumin: A Review. Int J Pharm Bio Sci 2013;4:79-87.</citation>
  </reference>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>August 18, 2017</study_first_submitted>
  <study_first_submitted_qc>August 21, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</study_first_posted>
  <last_update_submitted>May 28, 2018</last_update_submitted>
  <last_update_submitted_qc>May 28, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 30, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>nutrigenomics</keyword>
  <keyword>Diet-gene interaction,</keyword>
  <keyword>Curcumin,</keyword>
  <keyword>Antioxidants,</keyword>
  <keyword>Human NFE2L2 protein,</keyword>
  <keyword>Polymorphism,</keyword>
  <keyword>Diabetes,</keyword>
  <keyword>Chronic kidney disease</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>
    <mesh_term>Diabetic Nephropathies</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Curcumin</mesh_term>
  </intervention_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/NCT03262363
org study id: UIMER002
nct id: NCT03262363
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The increase in the prevalence of diabetes mellitus (DM) is one of the greatest public health
      challenges worldwide. Epidemiological studies have shown that DM is the leading cause of
      chronic kidney disease (CKD) in patients initiating renal replacement therapy. In our
      country, diabetes accounts for about 60% of all incidents of dialysis. On the other hand, CKD
      is currently considered a noxious disease because patients not only have the likelihood of
      progression to end-stage renal disease (ESRD), but because these renal alterations are
      associated with an increased risk of cardiovascular complications and premature death for the
      same cause. Most studies have focused on traditional risk factors (poor diet, physical
      inactivity and obesity) for the development and progression of renal damage, and less
      information exists on non-traditional factors such as oxidative stress and mainly, the low
      antioxidant response that characterizes both DM and nephropathy. In addition, there is a
      great variation in the susceptibility to and progression of kidney disease between different
      populations that is not explained by the presence of traditional factors and that could be
      triggered by genetic variations and its interaction with other components related to the
      environment and lifestyle. Fortunately, there is sufficient scientific evidence that early
      detection and modification of negative lifestyle factors can not only delay or halt the
      progression of the renal function decline to ESRD but can also significantly reduce the
      incidence of cardiovascular disease leading to premature death in most of these patients.
      Therefore, it is suggested that this risk may be determined by the interaction of lifestyle
      factors with the presence of susceptibility alleles, which may vary from one population to
      another. It is now known that hyperglycemia causes a state of oxidative stress and
      inflammation that can be counteracted by diet supplementation with some natural antioxidants
      such as curcumin. It has been shown that this molecule has multiple pharmacological
      properties: antioxidant, anti-inflammatory, cardioprotective, renoprotective, among others.
      In clinical trials a positive effect of curcumin has been seen in the treatment of diabetes
      and its complications. This has generated a relative optimism in the search for new curcumin
      treatment targets where oxidative stress is of great relevance, as is the case with CKD.
      However, there are still doubts about its efficacy as an adjuvant in the prevention of CKD.
      Additionally, the role played by interindividual variability in genes involved in the
      mechanism of action of curcumin is still incipient, more studies in this knowledge area are
      necessary.
Aim: To evaluate the interaction between rs35652124 polymorphism and curcumin supplementation
      on the levels of NFE2L2 gene expression, antioxidant capacity and renal function in patients
      with early diabetic nephropathy (EDN).

      Subjects and Methods. Parallel clinical trial with randomized and triple blind. From a
      database of diabetic patients newly diagnosed with CKD, those with EDN will be identified and
      located by telephone to complete a total of 275 subjects over 18 years of age. Subsequently,
      they will be cited in the office of Biomedical Unit 02, will verify that they meet the
      selection criteria, will be informed about the objectives of the study and invited to
      participate. Those who agree to participate will be given an informed consent letter, they
      will be asked to read it carefully and if they have any doubts, they will be clarified at the
      moment. Once they have signed the written consent they will be cited for the first blood
      sample collecting (5 mL) to be used for genomic DNA extraction and genotyping for the
      rs35652124 polymorphism. All patients entering the study will undergo a physical and dietary
      examination and will record the data on a clinical record card. They will be prescribed a
      meal plan according to ADA recommendations and K/DOQI guidelines two weeks prior (week <2) at
      the start of the clinical trial, which will be maintained throughout the follow-up. They will
      then be scheduled monthly for medical and nutritional assessment. At the visits of weeks 2, 0
      (start of supplementation), 12, and 24, three peripheral blood tubes (5 mL each) will be
      drawn. The first, to extract total mRNA and expression analysis of the NFE2L2 gene, the
      second, to determine the levels of NRF2, SOD, GPx and HO1 and the third, to perform renal
      function tests and control of possible confounding variables (creatinine, glucose,
      glycosylated hemoglobin, lipid profile and uric acid). In addition, they will be asked to
      collect a sample of the first morning urine to quantify albuminuria/creatinuria on the same
      day that blood samples were taken. The time of the study since the first evaluation is 26
      weeks and the total number of medical and nutrition visits will be six, one monthly.
      Genotyping will be performed by polymerase chain reaction (PCR) coupled to four pairs of
      oligonucleotide primers specific for the alleles of interest. The gene expression assay will
      be performed by real-time PCR, while the determination of the concentrations of NRF2, SOD,
      GPx and HO1 will be carried out by the ELISA method with kits designed for this purpose. The
      analysis of the data includes descriptive statistics expressed in averages and standard or
      median deviations according to the parametric or non-parametric distribution, the nominal
      variables will be presented as numbers or percentages and the comparison between these will
      be by Chi square or Fisher exact. Inferential statistics included U-Mann Whitney or Student t
      tests for independent and paired samples as appropriate to evaluate the NRF2, SOD, GPx and
      HO1 concentrations with the different interventions and the individuals in the control group.
      A covariance analysis will be performed taking into consideration the factor supplementation,
      genetic factor and the interaction of both with the concentrations of NRF2. A value of p<0.05
      and 95% CI will be considered significant.

      Resources and infrastructure. The CIBO and the Medical Research Unit in Renal Diseases have
      the human resources to coordinate and develop the present research. Also, they have the
      necessary infrastructure and equipment to carry out the procedures contemplated in this
      project. The project will be submitted to calls for funding to obtain the necessary resources
      for its development.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The study starts from the classification of patients according to the genotype for the rs35652124 polymorphism (-653G>A) of the NFE2L2 gene. Two Experimental groups and two Control groups will be formed according to the following:
Experimental group 1: Diabetic patients with early CKD homozygous for the -653G (G/G) allele of the NFE2L2 gene that will receive curcumin.
Experimental group 2: Diabetic patients with early CKD carrying the allele -653A (G/A or A/A) of the NFE2L2 gene that will receive curcumin.
Control group 1: Diabetic patients with early CKD homozygous for the -653G (G/G) allele of the NFE2L2 gene receiving placebo.
Control group 2: Diabetic patients with early CKD carrying the allele -653A (G/A or A/A) of the NFE2L2 gene who will receive placebo.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Patient Blinding: Patients with EDN will be blinded to the intervention they will receive Evaluator Blinding: The principal investigator will be blinded to the intervention that patients will receive (curcumin or placebo), but will know the genotype distribution in both Experimental and Placebo groups. The external investigator will be blinded to the knowledge of the patients genotype, but will know the intervention group to which each patient was assigned according to a registry (but will not know the identity of the patients). The Doctorate Program Student will be blinded to the distribution of patients genotype and the type of intervention patients will receive.
Statistical Blinding: An associated researcher will be blinded to the distribution of patients genotype and the type of intervention patients will receive, but not to the knowledge of the database.
measure: Change from Baseline expression Gen NFE2L2 at 3 months
time frame: Baseline at 3 months
description: mRNA and active protein NRF2
measure: Change from Baseline expression Gen NFE2L2 at 6 months
time frame: Baseline at 6 months
description: mRNA and active protein NRF2
measure: Change from Antioxidant capacity at 3 months
time frame: Baseline at 3 months
description: Superoxide dismutase, hemoxygenase 1, Glutathion peroxidase using the ELISA technique
measure: Change from Antioxidant capacity at 6 months
time frame: Baseline at 6 months
description: Superoxide dismutase, hemoxygenase 1, Glutathion peroxidase using the ELISA technique
measure: Change from Renal Function at 3 months
time frame: Baseline at 3 months
description: Glomerular Filtration Rate (Serum creatinine) and Albuminuria (Albumin/Creatinine Ratio)
measure: Change from Renal Function at 6 months
time frame: Baseline at 6 months
description: Glomerular Filtration Rate (Serum creatinine) and Albuminuria (Albumin/Creatinine Ratio)
arm group label: Curcumin/NFE2L2 A>G
arm group type: Experimental
description: Patients in Experimental group 1 and 2 will receive 800 mg/day of curcumin (for which a bioavailability of about 90% has been demonstrated and greater than other curcuminoids, administered in two doses of 400 mg each (the presentation will be in capsules containing 400 mg of THC).
arm group label: Placebo/NFE2L2 A>G
arm group type: Placebo Comparator
description: Patients in control group 1 and 2, the placebo intervention will consist of administering sucralose capsules (a substance lacking pharmacological action, with no active principle and a lower intake of glucose compared to sucrose). Patients will receive 300 mg/day of sucralose distributed in two doses of 150 mg each.
intervention type: Combination Product
intervention name: Curcumin/NFE2L2 A>G
description: The administration will be orally and the patient will be instructed to take two capsules per day for one week, one in the morning 15 minutes before breakfast and another at night 15 minutes before dinner, accompanied by a cup of 240 mL of pure water. It will be indicated to continue with their usual medical treatment.
arm group label: Curcumin/NFE2L2 A>G
other name: Curcumin group
intervention type: Combination Product
intervention name: Placebo/NFE2L2 A>G
description: The administration will be orally and the patient will be instructed to take two capsules for 24 weeks, one in the morning 15 minutes before breakfast and another in the evening 15 minutes before dinner, accompanied by a 240 mL cup of pure water. They will be advised to continue their usual medical treatment.
arm group label: Placebo/NFE2L2 A>G
other name: Placebo group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: LAURA CORTES-SANABRIA, PhD
phone: (55)3339522038
phone ext: 32204
email: cortes_sanabria@yahoo.com.mx
last name: ERIKA FABIOLA GOMEZ-GARCIA, MsC
phone: (55)3339522038
phone ext: 32204
email: erikaf.gomezg@yahoo.com.mx
facility: 
contact: 
contact backup: 
country: Mexico
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PMID: 15606719
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PMID: 25140450
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responsible party type: Sponsor
mesh term: Kidney Diseases
mesh term: Renal Insufficiency, Chronic
mesh term: Diabetic Nephropathies
mesh term: Diabetes Mellitus, Type 2
mesh term: Curcumin
sharing ipd: Undecided