<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/NCT04495608</url>
  </required_header>
  <id_info>
    <org_study_id>69HCL20_0071</org_study_id>
    <secondary_id>2020-003011-97</secondary_id>
    <nct_id>NCT04495608</nct_id>
  </id_info>
  <brief_title>Multicenter, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Fluconazole in Hypercalcicuric Patients With Increased 1.25(OH) 2D Levels</brief_title>
  <acronym>FLUCOLITH</acronym>
  <official_title>Multicenter, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Fluconazole in Hypercalcicuric Patients With Increased 1.25(OH) 2D Levels</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>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>
      Hypercalciuria is one of the most frequent metabolic disorders associated with&#xD;
      nephrolithiasis and/or nephrocalcinosis leading to Chronic Kidney Disease (CKD) and bone&#xD;
      complications in adults.&#xD;
&#xD;
      Hypercalciuria can be secondary to increased intestinal absorption and/or increased renal&#xD;
      distal tubular reabsorption of calcium due to increased active vitamin D, i.e. 1,25(OH)2D,&#xD;
      levels. The management of hypercalciuria is challenging. Classic management based on&#xD;
      hyperhydration and dietary advice has low impact on calciuria and therefore on CKD&#xD;
      progression. Other strategies such as hydrochlorothiazide can be proposed, however with an&#xD;
      uncertain medical benefit in view of side effects (hypokalemia, asthenia, potential cutaneous&#xD;
      long-term side effects).&#xD;
&#xD;
      Azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels.&#xD;
      These antifungal drugs are commonly used in neonates, infants and adults; pharmacokinetic&#xD;
      data are well described. Recently, to improve azoles tolerance, fluconazole has been&#xD;
      successfully reported to reduce calciuria in patients with CYP24A1 mutation (1 adult) or&#xD;
      NPTIIc mutations (1 child), while maintaining a stable renal function. Based on these&#xD;
      observations, the investigators hypothesize that fluconazole is effective to decrease and&#xD;
      normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels.&#xD;
&#xD;
      The primary objective is to demonstrate that fluconazole normalizes or decreases calciuria&#xD;
      after 18 weeks of treatment in patients with hypercalciuria and increased 1,25(OH)2D levels.&#xD;
&#xD;
      The secondary objectives aim to describe:&#xD;
&#xD;
        -  the effects of fluconazole on the evolution over time of the calcium/phosphate&#xD;
           metabolism,&#xD;
&#xD;
        -  the evolution of renal function,&#xD;
&#xD;
        -  the cohort at Baseline and after 4 months of treatment period,&#xD;
&#xD;
        -  the safety of fluconazole,&#xD;
&#xD;
        -  the onset of potential mycological resistances,&#xD;
&#xD;
        -  and the treatment compliance. This is a prospective, interventional, national,&#xD;
           randomized in 2 parallel groups (1:1), controlled versus placebo, double blind trial.&#xD;
&#xD;
      This study will involve patients between 10 and 60 years of age suffering from&#xD;
      nephrolithiasis and/or nephrocalcinosis with hypercalciuria (&gt; 0.1 mmol/kg/d) and increased&#xD;
      1,25 (OH)2D levels (≥ 150 pmol/l) and 25-OH-D levels (≥50 nmol/L).&#xD;
&#xD;
      FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not&#xD;
      expensive drug (e.g. fluconazole) in rare renal diseases, the ultimate objective being the&#xD;
      secondary prevention of CKD worsening in these patients.&#xD;
&#xD;
      If the results of this proof-of-concept randomized controlled trial are positive, the&#xD;
      investigators will propose an extension phase to evaluate the long term efficacy and safety&#xD;
      of fluconazole on renal and bone parameters.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 13, 2021</start_date>
  <completion_date type="Anticipated">July 2024</completion_date>
  <primary_completion_date type="Anticipated">July 2024</primary_completion_date>
  <phase>Phase 2</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Blinding procedure will be systematic thanks to the indistinguishable nature of the active product and placebo and their packaging.&#xD;
Only the biostatistician in charge of the production of the randomization list, the Centre Anti-Poison of Lyon, and the main pharmacy (Pharmacy Department Groupement Hospitalier Centre - Edouard Herriot Hospital - Hospices Civils de Lyon (Lyon, France), responsible for packaging, labeling and dispatching of experimental drugs to the sites, will have access to a decoded list.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients with normalization of calciuria</measure>
    <time_frame>Baseline (V1) and 18 weeks of treatment (V7)</time_frame>
    <description>Proportion of patients with normalization of 24-hour calciuria (≤ 0.1 mmol/kg/d) between Baseline (V1) and W18 (V7), or with a relative change of 30% of 24-hour calciuria between Baseline (V1) and W18 (V7) for patients who still have at W18 a 24-hour calciuria&gt; 0.1mmol/kg/d.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evolution over time of the calcium/phosphate metabolism (serum and urines dosages)</measure>
    <time_frame>Baseline (V1), 18 weeks of treatment (V7)</time_frame>
    <description>Serum: calcium, ionized calcium, phosphate, magnesium, PTH, 25-OH-D, 1,25(OH)2D, 24-25 (OH)2 D, 25-OH-D:24-25(OH)2D ratio, total alkaline phosphatase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum creatinine</measure>
    <time_frame>Baseline (V1), 18 weeks of treatment (V7)</time_frame>
    <description>Evolution of renal function</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>number of lithiasis, nephrocalcinosis</measure>
    <time_frame>Baseline (V1), 18 weeks of treatment (V7)</time_frame>
    <description>Evolution of renal function</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>size of lithiasis, nephrocalcinosis</measure>
    <time_frame>Baseline (V1), 18 weeks of treatment (V7)</time_frame>
    <description>Evolution of renal function</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quantity of calcium intakes</measure>
    <time_frame>18 weeks</time_frame>
    <description>Anthropometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quantity of sodium intakes</measure>
    <time_frame>18 weeks</time_frame>
    <description>Anthropometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quantity of protein intakes</measure>
    <time_frame>18 weeks</time_frame>
    <description>Anthropometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>bone alkaline phosphatases</measure>
    <time_frame>16 weeks</time_frame>
    <description>Bone evaluation with biomarkers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FGF23</measure>
    <time_frame>16 weeks</time_frame>
    <description>Bone evaluation with biomarkers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Klotho</measure>
    <time_frame>18 weeks</time_frame>
    <description>Bone evaluation with biomarkers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>femoral neck (FN) assessed with Dual energy x-ray absorptiometry (DXA):</measure>
    <time_frame>at randomization (day 0)</time_frame>
    <description>Bone evaluation with biomarkers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>lumbar spine vertebra 2 to 4 (LS2-4) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):</measure>
    <time_frame>at randomization (day 0)</time_frame>
    <description>Bone evaluation with biomarkers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>total body (TB) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):</measure>
    <time_frame>at randomization (day 0)</time_frame>
    <description>Bone evaluation with biomarkers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : cardiac evaluation</measure>
    <time_frame>Baseline (V1)</time_frame>
    <description>Cardiac evaluation : electrocardiogram, corrected QT interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : cardiac evaluation</measure>
    <time_frame>4 weeks</time_frame>
    <description>Cardiac evaluation : electrocardiogram, corrected QT interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : cardiac evaluation</measure>
    <time_frame>10 weeks</time_frame>
    <description>Cardiac evaluation : electrocardiogram, corrected QT interval</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>20 weeks</time_frame>
    <description>Hepatic functions : aspartate transaminase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>20 weeks</time_frame>
    <description>Hepatic functions : bilirubin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>20 weeks</time_frame>
    <description>Hepatic functions : gamma-glutamyl-transpeptidase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>20 weeks</time_frame>
    <description>Lactate dehydrogenase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>20 weeks</time_frame>
    <description>phosphoremia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>20 weeks</time_frame>
    <description>Calcemia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>20 weeks</time_frame>
    <description>Serum creatinine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>20 weeks</time_frame>
    <description>Albumin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>18 weeks</time_frame>
    <description>Hepatic functions : alanine aminotransferase</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety evaluation through the study : blood analysis</measure>
    <time_frame>20 weeks</time_frame>
    <description>Complete blood cell counts</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients that developed mycological resistance</measure>
    <time_frame>18 weeks</time_frame>
    <description>Mycological urine samples will be collected to evaluate the onset of potential mycological resistances to Candida. A description of the proportion of patients that developed at least one mycological resistance into the study will be performed by treatment arm, with a listing of the given resistances.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients that developed mycological resistance</measure>
    <time_frame>18 weeks</time_frame>
    <description>Mycological buccal samples will be collected to evaluate the onset of potential mycological resistances to Candida. A description of the proportion of patients that developed at least one mycological resistance into the study will be performed by treatment arm, with a listing of the given resistances.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compliance assessment</measure>
    <time_frame>every month from Randomization (V2) to 18 weeks of treatment (V7)</time_frame>
    <description>Compliance under treatment (fluconazole or placebo) will be measured by accountability of returned study treatment and information recorded on patients' diary. Level of compliance will be described separately at several follow-up times</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life and treatment satisfaction assessments : adults</measure>
    <time_frame>The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7)</time_frame>
    <description>Quality of life will be assessed with SF-36 auto-questionnaire (for adult patients)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life and treatment satisfaction assessments : children and adolescents</measure>
    <time_frame>The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7)</time_frame>
    <description>PedsQL auto-questionnaire (PedsQL 8-12 years for children, and PedsQL 13-18 years for adolescents).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Nephrolithiasis</condition>
  <condition>Nephrocalcinosis</condition>
  <condition>Hypercalciuria</condition>
  <arm_group>
    <arm_group_label>fluconazole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Fluconazole 50mg capsule (1, 2, 3 or 4 pills to take daily during 18 weeks, corresponding respectively to 50, 100, 150 or 200 mg of fluconazole).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo (1, 2, 3 or 4 pills to take daily during 18 weeks), same appearance to experimental drug</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fluconazole</intervention_name>
    <description>Fluconazole 50 mg/capsule or placebo, per os during 18 weeks :&#xD;
From W0 to W2 : 1 caps/ day&#xD;
From W2 to W4 : 1 or 2 caps/day&#xD;
From W4 to W6 : 1, 2 or 3 caps/day&#xD;
From W6 to W18 : 1, 2, 3 or 4 caps/day&#xD;
The number of capsules to take will be determined by 24-hours calciuria results performed every 2 weeks during the titration period (W2, W4 and W6).&#xD;
During the titration period, if 24-hours calciuria is &gt; 0.1 mmol/kg/day, fluconazole dose will be increased every 2 weeks to 50 mg per intake, with a maximum dose of 200 mg/day. If 24-hour calciuria is ≤ 0.1mmol/kg/day, fluconazole dose will remain stable.&#xD;
After W6 and until the end of the study, the treatment dose will remain stable (stable period).</description>
    <arm_group_label>fluconazole</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo (1, 2, 3 or 4 pills to take daily during 18 weeks), same appearance to experimental drug</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients who presented in their medical history nephrolithiasis and/or&#xD;
             nephrocalcinosis&#xD;
&#xD;
          -  Patients who have at inclusion (V1), a local biological evaluation with:&#xD;
&#xD;
               -  24-hour urine calcium &gt; 0.1 mmol/kg/day,&#xD;
&#xD;
               -  and 1,25(OH)2D levels ≥ 150 pmol/L,&#xD;
&#xD;
               -  and 25-OH-D levels ≥ 20 nmol/L,&#xD;
&#xD;
               -  and calcemia levels ≤ 2.65 mmol/L.&#xD;
&#xD;
          -  Children from 10 years&#xD;
&#xD;
          -  Adults until 60 years&#xD;
&#xD;
          -  Women of child-bearing potential (including sexually active adolescent females) must&#xD;
             use highly effective methods of contraception (Annex 7 CTFG recommendations) during&#xD;
             the study period. Likewise, partners of male patients of child-bearing potential must&#xD;
             use highly effective methods of contraception. Male patients must use condoms.&#xD;
&#xD;
          -  Patients insured or beneficiary of a health insurance plan&#xD;
&#xD;
          -  Evidence of signed and dated informed consent document(s) indicating that the subject&#xD;
             and/or his parents/legal guardian has/have been informed of all pertinent aspects of&#xD;
             the trial.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patient who already received fluconazole or ketoconazole during the last 6 months&#xD;
             before inclusion&#xD;
&#xD;
          -  Patient weight below than 28 kg&#xD;
&#xD;
          -  Patient with BMI &gt;35&#xD;
&#xD;
          -  Women menopaused&#xD;
&#xD;
          -  Patients who cannot stop hydrochlorothiazide or other diuretics during the screening&#xD;
             and study period&#xD;
&#xD;
          -  Patients who cannot stop vitamin D supplementation and/or calcium supplementation&#xD;
             (drugs, enriched waters, etc.) during the study period&#xD;
&#xD;
          -  Hypersensibility to fluconazole and/or other derivative azoles and/or excipients&#xD;
&#xD;
          -  Due to the presence of lactose excipient, patients presenting rare hereditary&#xD;
             abnormalities of galactose intolerance, of Lapp lactase deficit or of&#xD;
             glucose-galactose malabsorption&#xD;
&#xD;
          -  Patients who need co-administration with other drugs known to prolong the QT interval&#xD;
             and metabolized by cytochrome P450 (CYP) 3A4 (pimozide, quinidine and erythromycin;&#xD;
             the exhaustive list of drugs known to prolong the QTc is available on:&#xD;
             https://crediblemeds.org).&#xD;
&#xD;
          -  Patients with iatrogenic hypercalciuria (vitamin D intoxication, immobilization)&#xD;
&#xD;
          -  Relating to the risk of QT interval prolongation:&#xD;
&#xD;
               1. congenital Long QT syndrome;&#xD;
&#xD;
               2. familial history of sudden cardiac death before 50 years of age;&#xD;
&#xD;
               3. cardiopathy: ischemia or myocardial infarction, congestive cardiac insufficiency,&#xD;
                  left ventricle hypertrophy, cardiomyopathy, conduction trouble within 6 months&#xD;
                  preceding the inclusion;&#xD;
&#xD;
               4. arrhythmia history (in particular ventricular arrhythmia, auricular fibrillation&#xD;
                  or recent rhythm recovery after an auricular fibrillation);&#xD;
&#xD;
               5. electrolytic instabilities: hypokalemia, hypomagnesemia, hypocalcemia ;&#xD;
&#xD;
               6. bradycardia (&lt; 50 beats per minute) ;&#xD;
&#xD;
               7. acute neurological events (i.e. intracranial hemorrhage or sub-arachnoid,&#xD;
                  cerebrovascular accident, intracranial trauma) within 6 months preceding the&#xD;
                  inclusion;&#xD;
&#xD;
               8. adult patients with a QT interval/corrected QT interval &gt; 470ms for women and &gt;&#xD;
                  450ms for men at the ECG performed at the inclusion visit (V1). For children from&#xD;
                  10 years, the QT interval/corrected QT interval should be &gt; 460ms for girls and &gt;&#xD;
                  450ms for boys.&#xD;
&#xD;
          -  Children with a history of cardiac pathology&#xD;
&#xD;
          -  Patients with an estimated glomerular filtration rate &lt; 60 mL/min/1.73m²&#xD;
&#xD;
          -  Patients with a liver disease or an abnormality in the initial liver lab test&#xD;
&#xD;
          -  Patients with enuresis&#xD;
&#xD;
          -  Patients with another cause of identified lithiasis&#xD;
&#xD;
          -  Patients suffering from granulomatosis pathology such as sarcoidosis&#xD;
&#xD;
          -  Patient with hyperparathyroidism&#xD;
&#xD;
          -  Women who are pregnant or breast feeding, or who have a project of pregnancy before&#xD;
             the end of the study&#xD;
&#xD;
          -  Patients with a project of travelling in a sunny area during the study period&#xD;
&#xD;
          -  Immunodeficient patients&#xD;
&#xD;
          -  Patients with other diseases or disorders that could preclude assessment&#xD;
&#xD;
          -  Patient who is participating in another research study that may interfere with the&#xD;
             results or conclusions of this study&#xD;
&#xD;
          -  Patients under judicial protection.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>10 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Aurélia BERTHOLET-THOMAS, Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospices Civils de Lyon</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Aurélia BERTHOLET-THOMAS, Dr</last_name>
    <phone>4 27 85 61 04</phone>
    <phone_ext>+33</phone_ext>
    <email>aurelia.bertholet-thomas@chu-lyon.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Justine BACCHETTA, Pr</last_name>
    <email>justine.bacchetta@chu-lyon.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Service de Néphrologie Rhumatologie Dermatologie Pédiatrique</name>
      <address>
        <city>Bron</city>
        <zip>Bron</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Aurélia BERTHOLET-THOMAS</last_name>
      <phone>4 27 85 61 04</phone>
      <phone_ext>+33</phone_ext>
      <email>aurelia.bertholet-thomas@chu-lyon.fr</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Hôpital Edouard Herriot</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Sandrine LEMOINE, Dr</last_name>
      <email>sandrine.lemoine@chu-lyon.fr</email>
    </contact>
    <investigator>
      <last_name>Sandrine LEMOINE, Dr</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Hôpital Universitaire Necker</name>
      <address>
        <city>Paris</city>
        <zip>75743</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bertrand KNEBELMANN, Pr</last_name>
      <email>bertrand.knebelmann@aphp.fr</email>
    </contact>
    <investigator>
      <last_name>Bertrand KNEBELMANN, Pr</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>July 23, 2020</study_first_submitted>
  <study_first_submitted_qc>July 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 3, 2020</study_first_posted>
  <last_update_submitted>August 31, 2023</last_update_submitted>
  <last_update_submitted_qc>August 31, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Hypercalciuria</keyword>
  <keyword>nephrocalcinosis</keyword>
  <keyword>1,25-dihydroxyvitamin D</keyword>
  <keyword>1-alpha-hydroxylase</keyword>
  <keyword>fluconazole</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nephrolithiasis</mesh_term>
    <mesh_term>Kidney Calculi</mesh_term>
    <mesh_term>Nephrocalcinosis</mesh_term>
    <mesh_term>Hypercalciuria</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fluconazole</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04495608
org study id: 69HCL20_0071
secondary id: 2020-003011-97
nct id: NCT04495608
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Hypercalciuria is one of the most frequent metabolic disorders associated with
      nephrolithiasis and/or nephrocalcinosis leading to Chronic Kidney Disease (CKD) and bone
      complications in adults.

      Hypercalciuria can be secondary to increased intestinal absorption and/or increased renal
      distal tubular reabsorption of calcium due to increased active vitamin D, i.e. 1,25(OH)2D,
      levels. The management of hypercalciuria is challenging. Classic management based on
      hyperhydration and dietary advice has low impact on calciuria and therefore on CKD
      progression. Other strategies such as hydrochlorothiazide can be proposed, however with an
      uncertain medical benefit in view of side effects (hypokalemia, asthenia, potential cutaneous
      long-term side effects).

      Azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels.
      These antifungal drugs are commonly used in neonates, infants and adults; pharmacokinetic
      data are well described. Recently, to improve azoles tolerance, fluconazole has been
      successfully reported to reduce calciuria in patients with CYP24A1 mutation (1 adult) or
      NPTIIc mutations (1 child), while maintaining a stable renal function. Based on these
      observations, the investigators hypothesize that fluconazole is effective to decrease and
      normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels.

      The primary objective is to demonstrate that fluconazole normalizes or decreases calciuria
      after 18 weeks of treatment in patients with hypercalciuria and increased 1,25(OH)2D levels.

      The secondary objectives aim to describe:

        -  the effects of fluconazole on the evolution over time of the calcium/phosphate
           metabolism,

        -  the evolution of renal function,

        -  the cohort at Baseline and after 4 months of treatment period,

        -  the safety of fluconazole,

        -  the onset of potential mycological resistances,

        -  and the treatment compliance. This is a prospective, interventional, national,
           randomized in 2 parallel groups (1:1), controlled versus placebo, double blind trial.

      This study will involve patients between 10 and 60 years of age suffering from
      nephrolithiasis and/or nephrocalcinosis with hypercalciuria (> 0.1 mmol/kg/d) and increased
      1,25 (OH)2D levels (≥ 150 pmol/l) and 25-OH-D levels (≥50 nmol/L).

      FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not
      expensive drug (e.g. fluconazole) in rare renal diseases, the ultimate objective being the
      secondary prevention of CKD worsening in these patients.

      If the results of this proof-of-concept randomized controlled trial are positive, the
      investigators will propose an extension phase to evaluate the long term efficacy and safety
      of fluconazole on renal and bone parameters.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Blinding procedure will be systematic thanks to the indistinguishable nature of the active product and placebo and their packaging.
Only the biostatistician in charge of the production of the randomization list, the Centre Anti-Poison of Lyon, and the main pharmacy (Pharmacy Department Groupement Hospitalier Centre - Edouard Herriot Hospital - Hospices Civils de Lyon (Lyon, France), responsible for packaging, labeling and dispatching of experimental drugs to the sites, will have access to a decoded list.
measure: Proportion of patients with normalization of calciuria
time frame: Baseline (V1) and 18 weeks of treatment (V7)
description: Proportion of patients with normalization of 24-hour calciuria (≤ 0.1 mmol/kg/d) between Baseline (V1) and W18 (V7), or with a relative change of 30% of 24-hour calciuria between Baseline (V1) and W18 (V7) for patients who still have at W18 a 24-hour calciuria> 0.1mmol/kg/d.
measure: Evolution over time of the calcium/phosphate metabolism (serum and urines dosages)
time frame: Baseline (V1), 18 weeks of treatment (V7)
description: Serum: calcium, ionized calcium, phosphate, magnesium, PTH, 25-OH-D, 1,25(OH)2D, 24-25 (OH)2 D, 25-OH-D:24-25(OH)2D ratio, total alkaline phosphatase.
measure: Serum creatinine
time frame: Baseline (V1), 18 weeks of treatment (V7)
description: Evolution of renal function
measure: number of lithiasis, nephrocalcinosis
time frame: Baseline (V1), 18 weeks of treatment (V7)
description: Evolution of renal function
measure: size of lithiasis, nephrocalcinosis
time frame: Baseline (V1), 18 weeks of treatment (V7)
description: Evolution of renal function
measure: Quantity of calcium intakes
time frame: 18 weeks
description: Anthropometry
measure: Quantity of sodium intakes
time frame: 18 weeks
description: Anthropometry
measure: Quantity of protein intakes
time frame: 18 weeks
description: Anthropometry
measure: bone alkaline phosphatases
time frame: 16 weeks
description: Bone evaluation with biomarkers
measure: FGF23
time frame: 16 weeks
description: Bone evaluation with biomarkers
measure: Klotho
time frame: 18 weeks
description: Bone evaluation with biomarkers
measure: femoral neck (FN) assessed with Dual energy x-ray absorptiometry (DXA):
time frame: at randomization (day 0)
description: Bone evaluation with biomarkers
measure: lumbar spine vertebra 2 to 4 (LS2-4) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):
time frame: at randomization (day 0)
description: Bone evaluation with biomarkers
measure: total body (TB) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):
time frame: at randomization (day 0)
description: Bone evaluation with biomarkers
measure: Safety evaluation through the study : cardiac evaluation
time frame: Baseline (V1)
description: Cardiac evaluation : electrocardiogram, corrected QT interval
measure: Safety evaluation through the study : cardiac evaluation
time frame: 4 weeks
description: Cardiac evaluation : electrocardiogram, corrected QT interval
measure: Safety evaluation through the study : cardiac evaluation
time frame: 10 weeks
description: Cardiac evaluation : electrocardiogram, corrected QT interval
measure: Safety evaluation through the study : blood analysis
time frame: 20 weeks
description: Hepatic functions : aspartate transaminase
measure: Safety evaluation through the study : blood analysis
time frame: 20 weeks
description: Hepatic functions : bilirubin
measure: Safety evaluation through the study : blood analysis
time frame: 20 weeks
description: Hepatic functions : gamma-glutamyl-transpeptidase
measure: Safety evaluation through the study : blood analysis
time frame: 20 weeks
description: Lactate dehydrogenase
measure: Safety evaluation through the study : blood analysis
time frame: 20 weeks
description: phosphoremia
measure: Safety evaluation through the study : blood analysis
time frame: 20 weeks
description: Calcemia
measure: Safety evaluation through the study : blood analysis
time frame: 20 weeks
description: Serum creatinine
measure: Safety evaluation through the study : blood analysis
time frame: 20 weeks
description: Albumin
measure: Safety evaluation through the study : blood analysis
time frame: 18 weeks
description: Hepatic functions : alanine aminotransferase
measure: Safety evaluation through the study : blood analysis
time frame: 20 weeks
description: Complete blood cell counts
measure: Proportion of patients that developed mycological resistance
time frame: 18 weeks
description: Mycological urine samples will be collected to evaluate the onset of potential mycological resistances to Candida. A description of the proportion of patients that developed at least one mycological resistance into the study will be performed by treatment arm, with a listing of the given resistances.
measure: Proportion of patients that developed mycological resistance
time frame: 18 weeks
description: Mycological buccal samples will be collected to evaluate the onset of potential mycological resistances to Candida. A description of the proportion of patients that developed at least one mycological resistance into the study will be performed by treatment arm, with a listing of the given resistances.
measure: Compliance assessment
time frame: every month from Randomization (V2) to 18 weeks of treatment (V7)
description: Compliance under treatment (fluconazole or placebo) will be measured by accountability of returned study treatment and information recorded on patients' diary. Level of compliance will be described separately at several follow-up times
measure: Quality of life and treatment satisfaction assessments : adults
time frame: The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7)
description: Quality of life will be assessed with SF-36 auto-questionnaire (for adult patients)
measure: Quality of life and treatment satisfaction assessments : children and adolescents
time frame: The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7)
description: PedsQL auto-questionnaire (PedsQL 8-12 years for children, and PedsQL 13-18 years for adolescents).
arm group label: fluconazole
arm group type: Experimental
description: Fluconazole 50mg capsule (1, 2, 3 or 4 pills to take daily during 18 weeks, corresponding respectively to 50, 100, 150 or 200 mg of fluconazole).
arm group label: placebo
arm group type: Placebo Comparator
description: Placebo (1, 2, 3 or 4 pills to take daily during 18 weeks), same appearance to experimental drug
intervention type: Drug
intervention name: Fluconazole
description: Fluconazole 50 mg/capsule or placebo, per os during 18 weeks :
From W0 to W2 : 1 caps/ day
From W2 to W4 : 1 or 2 caps/day
From W4 to W6 : 1, 2 or 3 caps/day
From W6 to W18 : 1, 2, 3 or 4 caps/day
The number of capsules to take will be determined by 24-hours calciuria results performed every 2 weeks during the titration period (W2, W4 and W6).
During the titration period, if 24-hours calciuria is > 0.1 mmol/kg/day, fluconazole dose will be increased every 2 weeks to 50 mg per intake, with a maximum dose of 200 mg/day. If 24-hour calciuria is ≤ 0.1mmol/kg/day, fluconazole dose will remain stable.
After W6 and until the end of the study, the treatment dose will remain stable (stable period).
arm group label: fluconazole
intervention type: Drug
intervention name: Placebo
description: Placebo (1, 2, 3 or 4 pills to take daily during 18 weeks), same appearance to experimental drug
arm group label: placebo
criteria: 
gender: All
minimum age: 10 Years
maximum age: 60 Years
healthy volunteers: No
last name: Aurélia BERTHOLET-THOMAS, Dr
role: Principal Investigator
affiliation: Hospices Civils de Lyon
last name: Aurélia BERTHOLET-THOMAS, Dr
phone: 4 27 85 61 04
phone ext: +33
email: aurelia.bertholet-thomas@chu-lyon.fr
last name: Justine BACCHETTA, Pr
email: justine.bacchetta@chu-lyon.fr
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: Nephrolithiasis
mesh term: Kidney Calculi
mesh term: Nephrocalcinosis
mesh term: Hypercalciuria
mesh term: Fluconazole