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/NCT05965440</url>
    </required_header>
    <id_info>
      <org_study_id>69HCL23_0410</org_study_id>
      <nct_id>NCT05965440</nct_id>
    </id_info>
    <brief_title>Impact of Dapagliflozin on Intestinal Microbiota Composition and on the Metabolites Derived From the Intestinal Microbiota in Non-diabetic Chronic Renal Failure Patients</brief_title>
    <acronym>DAPA-GUT</acronym>
    <official_title>Impact of Dapagliflozin on Intestinal Microbiota Composition and on the Metabolites Derived From the Intestinal Microbiota in Non-diabetic Chronic Renal Failure Patients</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Hospices Civils de Lyon</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Hospices Civils de Lyon</source>
    <oversight_info>
      <has_dmc>No</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>
        Chronic kidney disease (CKD) is a common disease affecting 10-12% of the adult population and&#xD;
        characterize with high-risk cardiovascular morbidity and mortality with progression of CKD.&#xD;
        Treatment with sodium-glucose cotransporter 2 inhibitors (iSGLT2) not only improves&#xD;
        hyperglycemia and type 2 diabetes (T2D) but also results in body-weight loss, a reduction in&#xD;
        blood pressure, and a decrease of cardiovascular events and progression of renal failure in&#xD;
        both diabetes and non-diabetes patients.(Heerspink et al. 2020) Therefore, dapagliflozin is&#xD;
        now associated with the inhibitors of the renin-angiotensin system to reduce kidney events.&#xD;
  &#xD;
        However, the mechanisms underlying the effects of dapagliflozin on the renal function remain&#xD;
        unclear. When renal failure occurs, it impairs the removal of several metabolites called&#xD;
        uremic retention solutes. If these retention solutes exhibit deleterious interferences with&#xD;
        biochemical/physiological functions, they are referred to as uremic toxins as they can&#xD;
        contribute to the manifestations of the uremic syndrome and are associated with a high&#xD;
        cardiovascular morbidity and mortality and with progression of CKD. Many of the uremic toxins&#xD;
        are not produced by the body itself but rather derived from gut microbiota metabolism such as&#xD;
        the well-known trimethylamine-N-oxide (TMAO),p-cresyl sulfate (PCS), phenyl sulfate (PS),&#xD;
        indoxyl sulfate (IS), and indole-3-acetic acid (IAA).The gut microbiota composition in a&#xD;
        uremic context has been the subject of an increasing number of publications and majority of&#xD;
        them confirm a decrease of gut microbiota richness and deep modifications.Recently, an animal&#xD;
        study suggested that dapagliflozin, subtly improve the composition of the gut microbiota in&#xD;
        mice with T2D and another preliminary clinical study didn't observe a modification in the&#xD;
        fecal microbiome after dapagliflozin initiation.But in other study, empagliflozin&#xD;
        significantly reshaped the gut microbiota after 1 month of treatment in T2D patients and be&#xD;
        associated with shifts in plasma metabolites. Similarly, canagliflozin reduces plasma uremic&#xD;
        toxins in a CKD mice model.However, it remains unknown whether treatment with dapagliflozin&#xD;
        alters the gut microbiota in CKD patients without T2D; furthermore, the relationship between&#xD;
        the gut microbiota, uremic toxins production and CKD-related beneficial effects of&#xD;
        dapagliflozin remains elusive.&#xD;
  &#xD;
        Herein, the investigator will investigate the clinical benefits of dapagliflozin and possible&#xD;
        associations between its renal function benefits and alterations in plasmatic gut&#xD;
        microbiota-derived metabolites and the gut microbiota composition in non-T2D CKD patients. To&#xD;
        this end, the investigator will conduct an observational clinical trial in non-T2D CKD&#xD;
        patients with the primary aim of investigating dapagliflozin-induced compositional changes of&#xD;
        intestinal gut microbiota.&#xD;
      </textblock>
    </brief_summary>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 1, 2023</start_date>
    <completion_date type="Anticipated">December 15, 2024</completion_date>
    <primary_completion_date type="Anticipated">December 15, 2024</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Single Group Assignment</intervention_model>
      <primary_purpose>Diagnostic</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Alpha diversity and beta diversity size of the intestinal microbiota after 12 weeks of daily treatment with dapagliflozin compared to alfa and beta diversity size before initiation of treatment.</measure>
      <time_frame>Before and 12 weeks after initiation of treatment with dapagliflozin</time_frame>
      <description>The analysis of the microbiota by 16s sequencing of bacterial DNA will be carried out on the GenEPII platform located at the Croix Rousse hospital, Hospices Civils de Lyon (Pr Sophie JARRAUD).</description>
    </primary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">50</enrollment>
    <condition>Chronic Kidney Diseases</condition>
    <arm_group>
      <arm_group_label>impact of Dapagliflozin on Intestinal Microbiota on chronic renal failure patients</arm_group_label>
      <arm_group_type>Other</arm_group_type>
      <description>Addition of 3 blood tubes of 5mL during the collection for the treatment&#xD;
  Collection of fresh urine (7 mL)&#xD;
  Collection of stools by the participant at his home&#xD;
  Collection of fresh stools for patients participating in the ancillary study&#xD;
  Constitution of a biocollection (blood, urine and stool)&#xD;
  Food collection for 3 days with no impact on patient follow-up&#xD;
  Stool appearance sheet to be completed by the patient at each collection</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>impact of Dapagliflozin on Intestinal Microbiota on chronic renal failure patients</intervention_name>
      <description>Analysis of microbiota</description>
      <arm_group_label>impact of Dapagliflozin on Intestinal Microbiota on chronic renal failure patients</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Age between 18 and 80 years old&#xD;
  &#xD;
            -  Non-diabetic patient&#xD;
  &#xD;
            -  Patient with a medical indication for the introduction of dapagliflozin according to&#xD;
               the Marketing Authorization and as part of routine care, ie:&#xD;
  &#xD;
                 -  An estimated GFR between 25 and 60 mL/min/1.73m2 according to the CKD EPI&#xD;
                    formula.&#xD;
  &#xD;
                 -  A urinary albumin/creatinine ratio &gt; 200mg/g and &lt; 5000 mg/g&#xD;
  &#xD;
                 -  Be treated with the maximum tolerated dose of renin-angiotensin system inhibitors&#xD;
                    for at least 4 weeks.&#xD;
  &#xD;
            -  BMI between 18 and 30 kg/m2&#xD;
  &#xD;
            -  Patient not taking dapagliflozin (or any other treatment containing iSGLT2 or iSGLT1)&#xD;
  &#xD;
            -  Very regular bowel movements between 24 and 48 hours&#xD;
  &#xD;
            -  Patient following the dietary recommendations recommended during CKD (a sodium intake&#xD;
               targeting 6g NaCl/day +/-20% and a protein intake of 0.6g/kg/d +/-20%)&#xD;
  &#xD;
            -  Affiliation to social security&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Taking drugs can interfere with the intestinal microbiota (prebiotics, probiotics,&#xD;
               postbiotics, antibiotics) in the last 6 weeks&#xD;
  &#xD;
            -  Patient using high dose laxatives (more than 2 per day, for more than 3 months)&#xD;
  &#xD;
            -  Patient with a foreseeable transplant or dialysis project within the next 6 months.&#xD;
  &#xD;
            -  Patient with a colectomy, a resection of the small intestine or a cholecystectomy&#xD;
  &#xD;
            -  Patient with a progressive and unstabilized inflammatory, infectious, cardiovascular&#xD;
               or neoplastic disease&#xD;
  &#xD;
            -  Inability to understand the nature, follow-up and possible consequences of the study.&#xD;
  &#xD;
            -  Patient in exclusion period from previous study or already participating in a clinical&#xD;
               research protocol having an impact on the endpoints of the study&#xD;
  &#xD;
            -  Patient under guardianship or in safeguard of justice&#xD;
  &#xD;
            -  Pregnant, parturient or breastfeeding women&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Laetitia KOPPE, M.D., Ph. D</last_name>
      <phone>+33 4 72 67 87 15</phone>
      <email>laetitia.koppe@chu-lyon.fr</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Cécile BARNEL</last_name>
      <phone>+33 4 78 86 37 12</phone>
      <email>cecile.barnel@chu-lyon.fr</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Nephrology department, Hôpital Lyon Sud, Hospices Civils de Lyon</name>
        <address>
          <city>Lyon</city>
          <country>France</country>
        </address>
      </facility>
      <contact>
        <last_name>Laetitia KOPPE,, M.D., Ph. D</last_name>
      </contact>
    </location>
    <location_countries>
      <country>France</country>
    </location_countries>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 20, 2023</study_first_submitted>
    <study_first_submitted_qc>July 20, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 28, 2023</study_first_posted>
    <last_update_submitted>July 28, 2023</last_update_submitted>
    <last_update_submitted_qc>July 28, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 1, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <keyword>CKD</keyword>
    <keyword>gliflozine</keyword>
    <keyword>gut microbiota</keyword>
    <keyword>metabolomic</keyword>
    <keyword>uremic toxin</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>Renal Insufficiency</mesh_term>
      <mesh_term>Kidney Failure, Chronic</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Dapagliflozin</mesh_term>
    </intervention_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/NCT05965440
  org study id: 69HCL23_0410
  nct id: NCT05965440
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  Chronic kidney disease (CKD) is a common disease affecting 10-12% of the adult population and
        characterize with high-risk cardiovascular morbidity and mortality with progression of CKD.
        Treatment with sodium-glucose cotransporter 2 inhibitors (iSGLT2) not only improves
        hyperglycemia and type 2 diabetes (T2D) but also results in body-weight loss, a reduction in
        blood pressure, and a decrease of cardiovascular events and progression of renal failure in
        both diabetes and non-diabetes patients.(Heerspink et al. 2020) Therefore, dapagliflozin is
        now associated with the inhibitors of the renin-angiotensin system to reduce kidney events.
  
        However, the mechanisms underlying the effects of dapagliflozin on the renal function remain
        unclear. When renal failure occurs, it impairs the removal of several metabolites called
        uremic retention solutes. If these retention solutes exhibit deleterious interferences with
        biochemical/physiological functions, they are referred to as uremic toxins as they can
        contribute to the manifestations of the uremic syndrome and are associated with a high
        cardiovascular morbidity and mortality and with progression of CKD. Many of the uremic toxins
        are not produced by the body itself but rather derived from gut microbiota metabolism such as
        the well-known trimethylamine-N-oxide (TMAO),p-cresyl sulfate (PCS), phenyl sulfate (PS),
        indoxyl sulfate (IS), and indole-3-acetic acid (IAA).The gut microbiota composition in a
        uremic context has been the subject of an increasing number of publications and majority of
        them confirm a decrease of gut microbiota richness and deep modifications.Recently, an animal
        study suggested that dapagliflozin, subtly improve the composition of the gut microbiota in
        mice with T2D and another preliminary clinical study didn't observe a modification in the
        fecal microbiome after dapagliflozin initiation.But in other study, empagliflozin
        significantly reshaped the gut microbiota after 1 month of treatment in T2D patients and be
        associated with shifts in plasma metabolites. Similarly, canagliflozin reduces plasma uremic
        toxins in a CKD mice model.However, it remains unknown whether treatment with dapagliflozin
        alters the gut microbiota in CKD patients without T2D; furthermore, the relationship between
        the gut microbiota, uremic toxins production and CKD-related beneficial effects of
        dapagliflozin remains elusive.
  
        Herein, the investigator will investigate the clinical benefits of dapagliflozin and possible
        associations between its renal function benefits and alterations in plasmatic gut
        microbiota-derived metabolites and the gut microbiota composition in non-T2D CKD patients. To
        this end, the investigator will conduct an observational clinical trial in non-T2D CKD
        patients with the primary aim of investigating dapagliflozin-induced compositional changes of
        intestinal gut microbiota.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Diagnostic
  masking: None (Open Label)
  measure: Alpha diversity and beta diversity size of the intestinal microbiota after 12 weeks of daily treatment with dapagliflozin compared to alfa and beta diversity size before initiation of treatment.
  time frame: Before and 12 weeks after initiation of treatment with dapagliflozin
  description: The analysis of the microbiota by 16s sequencing of bacterial DNA will be carried out on the GenEPII platform located at the Croix Rousse hospital, Hospices Civils de Lyon (Pr Sophie JARRAUD).
  arm group label: impact of Dapagliflozin on Intestinal Microbiota on chronic renal failure patients
  arm group type: Other
  description: Addition of 3 blood tubes of 5mL during the collection for the treatment
  Collection of fresh urine (7 mL)
  Collection of stools by the participant at his home
  Collection of fresh stools for patients participating in the ancillary study
  Constitution of a biocollection (blood, urine and stool)
  Food collection for 3 days with no impact on patient follow-up
  Stool appearance sheet to be completed by the patient at each collection
  intervention type: Drug
  intervention name: impact of Dapagliflozin on Intestinal Microbiota on chronic renal failure patients
  description: Analysis of microbiota
  arm group label: impact of Dapagliflozin on Intestinal Microbiota on chronic renal failure patients
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 80 Years
  healthy volunteers: Accepts Healthy Volunteers
  last name: Laetitia KOPPE, M.D., Ph. D
  phone: +33 4 72 67 87 15
  email: laetitia.koppe@chu-lyon.fr
  last name: Cécile BARNEL
  phone: +33 4 78 86 37 12
  email: cecile.barnel@chu-lyon.fr
  facility: 
  contact: 
  country: France
  responsible party type: Sponsor
  mesh term: Kidney Diseases
  mesh term: Renal Insufficiency, Chronic
  mesh term: Renal Insufficiency
  mesh term: Kidney Failure, Chronic
  mesh term: Dapagliflozin