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

Study Overview
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Brief Summary
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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.

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

Conditions
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Nephrolithiasis, Nephrocalcinosis, Hypercalciuria

Intervention / Treatment
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* Drug: Fluconazole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who presented in their medical history nephrolithiasis and/or nephrocalcinosis Patients who have at inclusion (V1), a local biological evaluation with: 24-hour urine calcium > 0.1 mmol/kg/day, and 1,25(OH)2D levels ≥ 150 pmol/L, and 25-OH-D levels ≥ 20 nmol/L, and calcemia levels ≤ 2.65 mmol/L. Children from 10 years Adults until 60 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 Patient weight below than 28 kg Patient with BMI >35 Women menopaused 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 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: congenital Long QT syndrome; familial history of sudden cardiac death before 50 years of age; cardiopathy: ischemia or myocardial infarction, congestive cardiac insufficiency, left ventricle hypertrophy, cardiomyopathy, conduction trouble within 6 months preceding the inclusion; arrhythmia history (in particular ventricular arrhythmia, auricular fibrillation or recent rhythm recovery after an auricular fibrillation); electrolytic instabilities: hypokalemia, hypomagnesemia, hypocalcemia ; bradycardia (< 50 beats per minute) ; acute neurological events (i.e. intracranial hemorrhage or sub-arachnoid, cerebrovascular accident, intracranial trauma) within 6 months preceding the inclusion; 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 an estimated 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 Patient with hyperparathyroidism Women who are pregnant or breast feeding, or who have a project of pregnancy before the end of the study 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.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: fluconazole<br>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). | Drug: Fluconazole<br>* 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).<br>|
| Placebo Comparator: placebo<br>Placebo (1, 2, 3 or 4 pills to take daily during 18 weeks), same appearance to experimental drug | Drug: Placebo<br>* Placebo (1, 2, 3 or 4 pills to take daily during 18 weeks), same appearance to experimental drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with normalization of calciuria | 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. | Baseline (V1) and 18 weeks of treatment (V7) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolution over time of the calcium/phosphate metabolism (serum and urines dosages) | 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. | Baseline (V1), 18 weeks of treatment (V7) | 
| Serum creatinine | Evolution of renal function | Baseline (V1), 18 weeks of treatment (V7) | 
| number of lithiasis, nephrocalcinosis | Evolution of renal function | Baseline (V1), 18 weeks of treatment (V7) | 
| size of lithiasis, nephrocalcinosis | Evolution of renal function | Baseline (V1), 18 weeks of treatment (V7) | 
| Quantity of calcium intakes | Anthropometry | 18 weeks | 
| Quantity of sodium intakes | Anthropometry | 18 weeks | 
| Quantity of protein intakes | Anthropometry | 18 weeks | 
| bone alkaline phosphatases | Bone evaluation with biomarkers | 16 weeks | 
| FGF23 | Bone evaluation with biomarkers | 16 weeks | 
| Klotho | Bone evaluation with biomarkers | 18 weeks | 
| femoral neck (FN) assessed with Dual energy x-ray absorptiometry (DXA): | Bone evaluation with biomarkers | at randomization (day 0) | 
| lumbar spine vertebra 2 to 4 (LS2-4) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA): | Bone evaluation with biomarkers | at randomization (day 0) | 
| total body (TB) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA): | Bone evaluation with biomarkers | at randomization (day 0) | 
| Safety evaluation through the study : cardiac evaluation | Cardiac evaluation : electrocardiogram, corrected QT interval | Baseline (V1) | 
| Safety evaluation through the study : cardiac evaluation | Cardiac evaluation : electrocardiogram, corrected QT interval | 4 weeks | 
| Safety evaluation through the study : cardiac evaluation | Cardiac evaluation : electrocardiogram, corrected QT interval | 10 weeks | 
| Safety evaluation through the study : blood analysis | Hepatic functions : aspartate transaminase | 20 weeks | 
| Safety evaluation through the study : blood analysis | Hepatic functions : bilirubin | 20 weeks | 
| Safety evaluation through the study : blood analysis | Hepatic functions : gamma-glutamyl-transpeptidase | 20 weeks | 
| Safety evaluation through the study : blood analysis | Lactate dehydrogenase | 20 weeks | 
| Safety evaluation through the study : blood analysis | phosphoremia | 20 weeks | 
| Safety evaluation through the study : blood analysis | Calcemia | 20 weeks | 
| Safety evaluation through the study : blood analysis | Serum creatinine | 20 weeks | 
| Safety evaluation through the study : blood analysis | Albumin | 20 weeks | 
| Safety evaluation through the study : blood analysis | Hepatic functions : alanine aminotransferase | 18 weeks | 
| Safety evaluation through the study : blood analysis | Complete blood cell counts | 20 weeks | 
| Proportion of patients that developed mycological resistance | 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. | 18 weeks | 
| Proportion of patients that developed mycological resistance | 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. | 18 weeks | 
| Compliance assessment | 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 | every month from Randomization (V2) to 18 weeks of treatment (V7) | 
| Quality of life and treatment satisfaction assessments : adults | Quality of life will be assessed with SF-36 auto-questionnaire (for adult patients) | The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7) | 
| Quality of life and treatment satisfaction assessments : children and adolescents | PedsQL auto-questionnaire (PedsQL 8-12 years for children, and PedsQL 13-18 years for adolescents). | The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypercalciuria, nephrocalcinosis, 1,25-dihydroxyvitamin D, 1-alpha-hydroxylase, fluconazole