Multicenter, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Fluconazole in Hypercalcicuric Patients With Increased 1.25(OH) 2D Levels (FLUCOLITH)

This is an interventional treatment trial for Nephrolithiasis focused on measuring Hypercalciuria, nephrocalcinosis, 1,25-dihydroxyvitamin D, 1-alpha-hydroxylase, fluconazole Read More

Inclusion Criteria:

• Patients who presented in their medical history nephrolithiasis and/or nephrocalcinosis
• Patients who had, at least 4 weeks (±2 weeks) before inclusion and at inclusion (V1), a local biological evaluation with:
• 24-hour urine calcium > 0.1 mmol/kg/day,
• 1,25(OH)2D levels ≥150 pmol/L,
• 25-OH-D levels ≥ 50 nmol/L,
• calcemia levels ≤ 2.65 mmol/L.
• Children from 10 years
• Adults until 50 years
• Women of child-bearing potential (including sexually active adolescent females) must use highly effective methods of contraception (Annex 7 CTFG recommendations) during the study period. Likewise, partners of male patients of child-bearing potential must use highly effective methods of contraception. Male patients must use condoms.
• Patients insured or beneficiary of a health insurance plan
• Evidence of signed and dated informed consent document(s) indicating that the subject and/or his parents/legal guardian has/have been informed of all pertinent aspects of the trial.

Exclusion Criteria:

• Patient who already received fluconazole or ketoconazole during the last 6 months before inclusion
• Patients weight below than 28 kg
• Patients who cannot stop hydrochlorothiazide or other diuretics during the screening and study period
• Patients who cannot stop vitamin D supplementation and/or calcium supplementation (drugs, enriched waters, etc.) during the screening and the study period
• Hypersensibility to fluconazole and/or other derivative azoles and/or excipients
• Due to the presence of lactose excipient, patients presenting rare hereditary abnormalities of galactose intolerance, of Lapp lactase deficit or of glucose-galactose malabsorption
• Patients who need co-administration with other drugs known to prolong the QT interval and metabolized by cytochrome P450 (CYP) 3A4 (pimozide, quinidine and erythromycin; the exhaustive list of drugs known to prolong the QTc is available on: https://crediblemeds.org).
• Patients with iatrogenic hypercalciuria (vitamin D intoxication, immobilization)

• Relating to the risk of QT interval prolongation:

  1. congenital Long QT syndrome;
  2. familial history of sudden cardiac death before 50 years of age;
  3. cardiopathy: ischemia or myocardial infarction, congestive cardiac insufficiency, left ventricle hypertrophy, cardiomyopathy, conduction trouble within 6 months preceding the inclusion;
  4. arrhythmia history (in particular ventricular arrhythmia, auricular fibrillation or recent rhythm recovery after an auricular fibrillation);
  5. electrolytic instabilities: hypokalemia, hypomagnesemia, hypocalcemia ;
  6. bradycardia (< 50 beats per minute) ;
  7. acute neurological events (i.e. intracranial hemorrhage or sub-arachnoid, cerebrovascular accident, intracranial trauma) within 6 months preceding the inclusion;
  8. adult patients with a QT interval/corrected QT interval > 470ms for women and > 450ms for men at the ECG performed at the inclusion visit (V1). For children from 10 years, the QT interval/corrected QT interval should be > 460ms for girls and > 450ms for boys.
• Children with a history of cardiac pathology
• Patients with a glomerular filtration rate < 60 mL/min/1.73m²
• Patients with a liver disease or an abnormality in the initial liver lab test
• Patients with enuresis
• Patients with another cause of identified lithiasis
• Patients suffering from granulomatosis pathology such as sarcoidosis
• Women who are pregnant or breast feeding, or who have a project of pregnancy
• Women menopaused
• Patients with a project of travelling in a sunny area during the study period
• Immunodeficient patients
• Patients with other diseases or disorders that could preclude assessment
• Patient who is participating in another research study that may interfere with the results or conclusions of this study
• Patients under judicial protection.