<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/NCT03764605</url>
  </required_header>
  <id_info>
    <org_study_id>Eudract2018-000477-77</org_study_id>
    <nct_id>NCT03764605</nct_id>
  </id_info>
  <brief_title>Metformin vs Tolvaptan for Treatment of Autosomal Dominant Polycystic Kidney Disease</brief_title>
  <acronym>METROPOLIS</acronym>
  <official_title>Metformin vs Tolvaptan for Treatment of Autosomal Dominant Polycystic Kidney Disease. A Phase 3a, Indipendent, Multicentre, Two Parallel Arms, Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal&#xD;
      disorder occurring in 1:400-1:1.000 live births and affects 4 to 6 million persons worldwide&#xD;
      and about 205.000 people in Europe (EU). This figure is equivalent to 4 in 10.000 people and&#xD;
      thus below the prevalence threshold of 5 in 10.000 used to designate a disease as rare in EU.&#xD;
&#xD;
      Renal cyst development and expansion in ADPKD involves both fluid secretion and abnormal&#xD;
      proliferation of cyst-lining epithelial cells. The chloride channel of the cystic fibrosis&#xD;
      transmembrane conductance regulator (CFTR) participates in secretion of cyst fluid, and the&#xD;
      mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial&#xD;
      cells. CFTR and mTOR are both negatively regulated by AMP-activated protein kinase (AMPK).&#xD;
      Metformin, a drug widely used, is a pharmacological activator of AMPK. The investigators&#xD;
      found that metformin stimulates AMPK, resulting in inhibition of both CFTR and the mTOR&#xD;
      pathways. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo&#xD;
      models of renal cystogenesis. In addition, metformin administration produces a significant&#xD;
      decrease in the cystic index in two mouse models of ADPKD. These results suggest a possible&#xD;
      role for AMPK activation in slowing renal cystogenesis as well as the potential for&#xD;
      therapeutic application of metformin in the context of ADPKD.&#xD;
&#xD;
      Thus this study aims to evaluate metformin efficacy in slowing renal cystogenesis in ADPKD as&#xD;
      compared to the actual gold standard (Tolvaptan).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objective of the study is to assess if a two-year course of 1500 mg oral metformin is&#xD;
      effective and safe in treatment of ADPKD, as compared to the actual gold-standard therapy,&#xD;
      tolvaptan (Jinarc®) This is a phase 3a, independent, multi-centre, parallel arms, randomized&#xD;
      controlled trial comparing efficacy and safety of metformin and tolvaptan in ADPKD.&#xD;
&#xD;
      This trial will enroll approximately 150 tolvaptan and metformin naïve subjects affected by&#xD;
      Type I-truncating ADPKD, as these subjects have grater probability of progression.&#xD;
&#xD;
      The trial contemplates a 2 weeks screening period (included in a 9 months total recruitment&#xD;
      period) during which 3 visits have to be collected (the 1st and the 2nd in three days, and&#xD;
      the 3rd after biochemical analyses performed during the first two visits have been reviewed).&#xD;
      The subject's eligibility for the trial will be confirmed by the mean of eGFR calculated from&#xD;
      the 2 pre-treatment, central-lab, serum creatinine assessments. Longer screening periods (up&#xD;
      to 4 additional weeks) are acceptable for subjects needing stabilization after changing or&#xD;
      discontinuing other treatments, especially anti-hypertensives and diuretics.&#xD;
&#xD;
      Once eligibility is assessed, patients will undergo non-contrast enhanced CT-scan of kidneys&#xD;
      (if not performed within six months prior to randomization).&#xD;
&#xD;
      Randomization visit will occur on Day -29. During this visit patients will be randomized (in&#xD;
      a ratio 1:1 tolvaptan:metformin) to each arm of treatment and will start an IMP titration&#xD;
      period (3 weeks from -28 to -8). Subjects not tolerating the minimum IMP dose will be&#xD;
      considered &quot;Titration failures&quot; and will complete End of Treatment (EoTx) visit assessments&#xD;
      and will be followed up after 7 days by phone call to assess any ongoing AEs. Subjects&#xD;
      tolerating the minimum IMP dose enter the unblind run-in period (1 week from Day -7 to -1).&#xD;
      During the &quot;Run-in&quot; phase, subjects will continue on a stable IMP dose to confirm&#xD;
      tolerability over a longer period. At the end of the run-in period (Day -1), subjects not&#xD;
      tolerating the minimum IMP dose will be considered &quot;Run-in failures&quot; and will complete EoTx&#xD;
      visit assessments and will be followed up after 7 days by phone call to assess any ongoing&#xD;
      AEs. Subjects completing the run-in will start the open-label 24 months treatment period,&#xD;
      during which visits will be collected three-monthly. At the end of the 24th month, and in&#xD;
      case of early treatment cessation, follow-up period (3 weeks from +8 to +21) will start,&#xD;
      during which 2 visits have to be collected. No IMP will be administered during this period.&#xD;
&#xD;
      This trial will enroll approximately 150 tolvaptan and metformin naïve subjects and will be&#xD;
      conducted in about 11 Italian Hospital Nephrology Departments The investigators plan to&#xD;
      recruit a total of 150 patients which are currently within the reach of the network&#xD;
      coordinated by the proponent and composed by 11 Nephrology Centres. This network treats a&#xD;
      total of 1500 (already genetically studied) patients of which the investigators expect (based&#xD;
      on standard response rates recognized in the population) acceptance to participate in the&#xD;
      study to a value of approximately 40% of patients that will be then allocated to the&#xD;
      experimental and control intervention.&#xD;
&#xD;
      The selected sample is adequate to evaluate a significant reduction in the slope of eGFR at 2&#xD;
      years by 10%, which is a clinically relevant piece of information at the current state of&#xD;
      knowledge, as well as a complete assessment of the benefits-harms trade-off of the two&#xD;
      interventions.&#xD;
&#xD;
      The trial has a 36 months overall duration, that include a 9 months recruitment period; has a&#xD;
      2 weeks duration, it is included in the 9 months recruitment period. The treatment period has&#xD;
      a 25 months duration. Each month lasts 28 days. It includes the 3 weeks titration period and&#xD;
      the 1 week run-in period.&#xD;
&#xD;
      The post-treatment follow-up: lasts 21 days. The total Study Duration is of about 3 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">January 30, 2019</start_date>
  <completion_date type="Anticipated">January 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2021</primary_completion_date>
  <phase>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>Trial will enroll 150 subjects affected by Type I-truncating ADPKD. Their eligibility will be confirmed by the mean of eGFR calculated from the 2 pre-treatment serum creatinine assessments. Once eligibility is assessed, patients will undergo kidneys CTscan. Randomization visit will occur on Day -29. During this visit patients will be randomized (1:1) to each arm of treatment and will start IMP titration. Subjects not tolerating the minimum IMP dose will be considered &quot;Titration failures&quot; and will complete End of Treatment (EoTx) visit and will be followed up after 7 days by phone call. Subjects tolerating the minimum IMP dose enter the unblind run-in period during which, subjects will continue on a stable IMP dose to confirm tolerability over a longer period. At the end of the run-in period subjects not tolerating the minimum IMP dose will be considered &quot;Run-in failures&quot; and will complete EoTx visit. Subjects completing the run-in will start the open-label 24 months treatment period.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Glomerular Filtration Rate (estimated by CKD-Epi formula) variation</measure>
    <time_frame>25 months</time_frame>
    <description>Primary outcome of the study is to evaluate the difference between Metformin and Tolvaptan in annualized slope of eGFR (CKD-EPI) for individual subjects, that will be calculated using an appropriate baseline and post-randomization assessment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Total Kidney Volume variation (measured by non contrast enhanced Kidney CT scan)</measure>
    <time_frame>25 months</time_frame>
    <description>The key secondary endpoint is the percent change from baseline in htTKV as measured by CT-scan at 24 months.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Blood pressure</measure>
    <time_frame>36 months</time_frame>
    <description>mmHg</description>
  </other_outcome>
  <other_outcome>
    <measure>Post void body weight</measure>
    <time_frame>36 months</time_frame>
    <description>Kg</description>
  </other_outcome>
  <other_outcome>
    <measure>Change from serum creatinine baseline</measure>
    <time_frame>36 months</time_frame>
    <description>mg/dl</description>
  </other_outcome>
  <other_outcome>
    <measure>Serum sodium</measure>
    <time_frame>36 months</time_frame>
    <description>mg/dl</description>
  </other_outcome>
  <other_outcome>
    <measure>Blood venous gas lactate levels</measure>
    <time_frame>36 months</time_frame>
    <description>mmol/l</description>
  </other_outcome>
  <other_outcome>
    <measure>Bolood Glucose levels</measure>
    <time_frame>36 months</time_frame>
    <description>mg/dl</description>
  </other_outcome>
  <other_outcome>
    <measure>Vitamin B12 deficency</measure>
    <time_frame>36 months</time_frame>
    <description>pg/ml</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">150</enrollment>
  <condition>ADPKD</condition>
  <arm_group>
    <arm_group_label>Metformin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will take metformin starting from 500 mg a day. They will up-titrate every week, if tolerating IMP, adding one 500 mg dose 8 hours after the former, till reaching 500 mg thrice a day.&#xD;
The minimum tolerated dose requested in order to be admitted to the study is 500 mg twice a day.&#xD;
Those reaching eGFR&lt;45 ml/min will reduce the dose by one third. Those reaching eGFR&lt;30 will drop out the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tolvaptan</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patient will start Tolvaptan in a split dose regimen 45 mg as first dose, followed by 15 mg 8 hours later. Those tolerating this dose will uptitrate to 60/30 mg and then to 90/30 mg a day. Those not tolerating 45/15 mg a day will drop out.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <description>Patieny will be treated by using Metformin from 500 mg a day to 500 mg thrice a day.</description>
    <arm_group_label>Metformin</arm_group_label>
    <other_name>Zuglimet</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tolvaptan</intervention_name>
    <description>Patients will be treated with tolvaptan from 45 mg + 15 mg a day to 90 mg + 30 mg a day</description>
    <arm_group_label>Tolvaptan</arm_group_label>
    <other_name>Jinarc</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Men and women aged between 18 and 50 years&#xD;
&#xD;
          2. eGFR (CKD-EPI) ≥ 45 ml/min/1,73 m2&#xD;
&#xD;
          3. Genetic Diagnosis of Type I ADPKD truncating mutation&#xD;
&#xD;
          4. Signed and dated informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Women of childbearing potential (WOCBP) who do not agree to practice 2 different&#xD;
             methods of birth control or remain abstinent during the trial and for 30 days after&#xD;
             the last dose of IMP. If employing birth control, 2 of the following precautions must&#xD;
             be used: vasectomy of partner, tubal ligation, vaginal diaphragm, intrauterine device,&#xD;
             birth control implant, condom, or sponge with spermicide. Non-childbearing potential&#xD;
             in women is defined as female subjects who are surgically sterile (ie, have undergone&#xD;
             bilateral oophorectomy or hysterectomy) or female subjects who have been&#xD;
             postmenopausal for at least 12 consecutive months.&#xD;
&#xD;
          2. Women who are breast-feeding and/or who have a positive pregnancy test result prior to&#xD;
             receiving investigational medical product (IMP).&#xD;
&#xD;
          3. Treatment with acarbose, guar gum, cimetidin, phenprocoumon, oral anticoagulants,&#xD;
             thrombolytic drugs, diuretics, ranolazin, cephalexin.&#xD;
&#xD;
          4. Evidence of active systemic or localized major infection at the time of screening.&#xD;
&#xD;
          5. Hepatic impairment or liver function abnormalities other than that expected for ADPKD&#xD;
             with typical cystic liver disease during the screening period as defined by:&#xD;
&#xD;
               -  AST O ALT &gt;8x UNL&#xD;
&#xD;
               -  AST O ALT &gt;5x UNL &gt;2 WEEKS&#xD;
&#xD;
               -  AST O ALT &gt;3x UNL E BT &gt;2x UNL OR INR &gt;1,5&#xD;
&#xD;
               -  AST O ALT &gt;3x UNL E SIGNS AND SYMPTOMS OF LIVER DAMAGE (fatigue, anorexy, nausea,&#xD;
                  vomiting, right hypocondrium pain, fever, jaundice, skin rash, itching)&#xD;
&#xD;
          6. Acute or chronic disease causing tissue hypoxia (e.g.: myocardial failure, severe&#xD;
             arythmias, myocardial infarction, respiratory failure, liver failure, alcohol acute&#xD;
             intoxication, alcoholism, dehydration).&#xD;
&#xD;
          7. Previously diagnosed diabetes already in treatment with other hypoglycemic drugs.&#xD;
&#xD;
          8. Ongoing breast feeding.&#xD;
&#xD;
          9. Use of any other investigational drug or treatment up to 4 weeks before enrollment and&#xD;
             during the treatment phase.&#xD;
&#xD;
         10. Known hypersensitivity to metformin and its derivatives.&#xD;
&#xD;
         11. Psychiatric disorders and any condition that might prevent full comprehension of the&#xD;
             purposes and risks of the study.&#xD;
&#xD;
         12. Malignancies within three years before enrolment in the study.&#xD;
&#xD;
         13. HIV, HBV, HCV infection.&#xD;
&#xD;
         14. Urinary tract obstruction.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Loreto Gesualdo</last_name>
    <role>Principal Investigator</role>
    <affiliation>AOUConsorziale Policlinico di Bari</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Loreto Gesualdo</last_name>
    <phone>+390805594040</phone>
    <email>loretoge60@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>AOUC &quot;Policlinico&quot;</name>
      <address>
        <city>Bari</city>
        <zip>70124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AOUConsorziale Policlinico Di Bari</name>
      <address>
        <city>Bari</city>
        <zip>70124</zip>
        <country>Italy</country>
      </address>
    </facility>
    <contact>
      <last_name>Loreto Gesualdo</last_name>
      <phone>+390805594040</phone>
      <email>trialnefrobari@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Giovanni Piscopo</last_name>
      <phone>+393299664404</phone>
      <email>giopiscopo@gmail.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>November 29, 2018</study_first_submitted>
  <study_first_submitted_qc>December 3, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 5, 2018</study_first_posted>
  <last_update_submitted>December 5, 2018</last_update_submitted>
  <last_update_submitted_qc>December 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 7, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari</investigator_affiliation>
    <investigator_full_name>Loreto GESUALDO</investigator_full_name>
    <investigator_title>Head of Nephrology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Kidney Diseases</mesh_term>
    <mesh_term>Polycystic Kidney Diseases</mesh_term>
    <mesh_term>Polycystic Kidney, Autosomal Dominant</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
    <mesh_term>Tolvaptan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 31, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/05/NCT03764605/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03764605
org study id: Eudract2018-000477-77
nct id: NCT03764605
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal
      disorder occurring in 1:400-1:1.000 live births and affects 4 to 6 million persons worldwide
      and about 205.000 people in Europe (EU). This figure is equivalent to 4 in 10.000 people and
      thus below the prevalence threshold of 5 in 10.000 used to designate a disease as rare in EU.

      Renal cyst development and expansion in ADPKD involves both fluid secretion and abnormal
      proliferation of cyst-lining epithelial cells. The chloride channel of the cystic fibrosis
      transmembrane conductance regulator (CFTR) participates in secretion of cyst fluid, and the
      mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial
      cells. CFTR and mTOR are both negatively regulated by AMP-activated protein kinase (AMPK).
      Metformin, a drug widely used, is a pharmacological activator of AMPK. The investigators
      found that metformin stimulates AMPK, resulting in inhibition of both CFTR and the mTOR
      pathways. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo
      models of renal cystogenesis. In addition, metformin administration produces a significant
      decrease in the cystic index in two mouse models of ADPKD. These results suggest a possible
      role for AMPK activation in slowing renal cystogenesis as well as the potential for
      therapeutic application of metformin in the context of ADPKD.

      Thus this study aims to evaluate metformin efficacy in slowing renal cystogenesis in ADPKD as
      compared to the actual gold standard (Tolvaptan).
Objective of the study is to assess if a two-year course of 1500 mg oral metformin is
      effective and safe in treatment of ADPKD, as compared to the actual gold-standard therapy,
      tolvaptan (Jinarc®) This is a phase 3a, independent, multi-centre, parallel arms, randomized
      controlled trial comparing efficacy and safety of metformin and tolvaptan in ADPKD.

      This trial will enroll approximately 150 tolvaptan and metformin naïve subjects affected by
      Type I-truncating ADPKD, as these subjects have grater probability of progression.

      The trial contemplates a 2 weeks screening period (included in a 9 months total recruitment
      period) during which 3 visits have to be collected (the 1st and the 2nd in three days, and
      the 3rd after biochemical analyses performed during the first two visits have been reviewed).
      The subject's eligibility for the trial will be confirmed by the mean of eGFR calculated from
      the 2 pre-treatment, central-lab, serum creatinine assessments. Longer screening periods (up
      to 4 additional weeks) are acceptable for subjects needing stabilization after changing or
      discontinuing other treatments, especially anti-hypertensives and diuretics.

      Once eligibility is assessed, patients will undergo non-contrast enhanced CT-scan of kidneys
      (if not performed within six months prior to randomization).

      Randomization visit will occur on Day -29. During this visit patients will be randomized (in
      a ratio 1:1 tolvaptan:metformin) to each arm of treatment and will start an IMP titration
      period (3 weeks from -28 to -8). Subjects not tolerating the minimum IMP dose will be
      considered "Titration failures" and will complete End of Treatment (EoTx) visit assessments
      and will be followed up after 7 days by phone call to assess any ongoing AEs. Subjects
      tolerating the minimum IMP dose enter the unblind run-in period (1 week from Day -7 to -1).
      During the "Run-in" phase, subjects will continue on a stable IMP dose to confirm
      tolerability over a longer period. At the end of the run-in period (Day -1), subjects not
      tolerating the minimum IMP dose will be considered "Run-in failures" and will complete EoTx
      visit assessments and will be followed up after 7 days by phone call to assess any ongoing
      AEs. Subjects completing the run-in will start the open-label 24 months treatment period,
      during which visits will be collected three-monthly. At the end of the 24th month, and in
      case of early treatment cessation, follow-up period (3 weeks from +8 to +21) will start,
      during which 2 visits have to be collected. No IMP will be administered during this period.

      This trial will enroll approximately 150 tolvaptan and metformin naïve subjects and will be
      conducted in about 11 Italian Hospital Nephrology Departments The investigators plan to
      recruit a total of 150 patients which are currently within the reach of the network
      coordinated by the proponent and composed by 11 Nephrology Centres. This network treats a
      total of 1500 (already genetically studied) patients of which the investigators expect (based
      on standard response rates recognized in the population) acceptance to participate in the
      study to a value of approximately 40% of patients that will be then allocated to the
      experimental and control intervention.

      The selected sample is adequate to evaluate a significant reduction in the slope of eGFR at 2
      years by 10%, which is a clinically relevant piece of information at the current state of
      knowledge, as well as a complete assessment of the benefits-harms trade-off of the two
      interventions.

      The trial has a 36 months overall duration, that include a 9 months recruitment period; has a
      2 weeks duration, it is included in the 9 months recruitment period. The treatment period has
      a 25 months duration. Each month lasts 28 days. It includes the 3 weeks titration period and
      the 1 week run-in period.

      The post-treatment follow-up: lasts 21 days. The total Study Duration is of about 3 years.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Trial will enroll 150 subjects affected by Type I-truncating ADPKD. Their eligibility will be confirmed by the mean of eGFR calculated from the 2 pre-treatment serum creatinine assessments. Once eligibility is assessed, patients will undergo kidneys CTscan. Randomization visit will occur on Day -29. During this visit patients will be randomized (1:1) to each arm of treatment and will start IMP titration. Subjects not tolerating the minimum IMP dose will be considered "Titration failures" and will complete End of Treatment (EoTx) visit and will be followed up after 7 days by phone call. Subjects tolerating the minimum IMP dose enter the unblind run-in period during which, subjects will continue on a stable IMP dose to confirm tolerability over a longer period. At the end of the run-in period subjects not tolerating the minimum IMP dose will be considered "Run-in failures" and will complete EoTx visit. Subjects completing the run-in will start the open-label 24 months treatment period.
primary purpose: Treatment
masking: None (Open Label)
measure: Glomerular Filtration Rate (estimated by CKD-Epi formula) variation
time frame: 25 months
description: Primary outcome of the study is to evaluate the difference between Metformin and Tolvaptan in annualized slope of eGFR (CKD-EPI) for individual subjects, that will be calculated using an appropriate baseline and post-randomization assessment.
measure: Total Kidney Volume variation (measured by non contrast enhanced Kidney CT scan)
time frame: 25 months
description: The key secondary endpoint is the percent change from baseline in htTKV as measured by CT-scan at 24 months.
measure: Blood pressure
time frame: 36 months
description: mmHg
measure: Post void body weight
time frame: 36 months
description: Kg
measure: Change from serum creatinine baseline
time frame: 36 months
description: mg/dl
measure: Serum sodium
time frame: 36 months
description: mg/dl
measure: Blood venous gas lactate levels
time frame: 36 months
description: mmol/l
measure: Bolood Glucose levels
time frame: 36 months
description: mg/dl
measure: Vitamin B12 deficency
time frame: 36 months
description: pg/ml
arm group label: Metformin
arm group type: Experimental
description: Patients will take metformin starting from 500 mg a day. They will up-titrate every week, if tolerating IMP, adding one 500 mg dose 8 hours after the former, till reaching 500 mg thrice a day.
The minimum tolerated dose requested in order to be admitted to the study is 500 mg twice a day.
Those reaching eGFR<45 ml/min will reduce the dose by one third. Those reaching eGFR<30 will drop out the study.
arm group label: Tolvaptan
arm group type: Active Comparator
description: Patient will start Tolvaptan in a split dose regimen 45 mg as first dose, followed by 15 mg 8 hours later. Those tolerating this dose will uptitrate to 60/30 mg and then to 90/30 mg a day. Those not tolerating 45/15 mg a day will drop out.
intervention type: Drug
intervention name: Metformin
description: Patieny will be treated by using Metformin from 500 mg a day to 500 mg thrice a day.
arm group label: Metformin
other name: Zuglimet
intervention type: Drug
intervention name: Tolvaptan
description: Patients will be treated with tolvaptan from 45 mg + 15 mg a day to 90 mg + 30 mg a day
arm group label: Tolvaptan
other name: Jinarc
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: No
last name: Loreto Gesualdo
role: Principal Investigator
affiliation: AOUConsorziale Policlinico di Bari
last name: Loreto Gesualdo
phone: +390805594040
email: loretoge60@gmail.com
facility: 
facility: 
contact: 
contact backup: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari
investigator full name: Loreto GESUALDO
investigator title: Head of Nephrology
mesh term: Kidney Diseases
mesh term: Polycystic Kidney Diseases
mesh term: Polycystic Kidney, Autosomal Dominant
mesh term: Metformin
mesh term: Tolvaptan
sharing ipd: No
provided document: 