Fluconazole in Hypercalciuric Patients With Increased 1,25(OH)2D Levels

Overview

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 4 months 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 50 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.

Full Title of Study: “Fluconazole as a New Therapeutic Tool in Hypercalciuric Patients With Increased 1,25(OH)2D Levels”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: June 13, 2023

Interventions

  • Drug: Fluconazole
    • 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).
  • Drug: Placebo
    • Placebo (1, 2, 3 or 4 pills to take daily during 18 weeks), same appearance to experimental drug

Arms, Groups and Cohorts

  • Experimental: fluconazole
    • 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).
  • Placebo Comparator: placebo
    • Placebo (1, 2, 3 or 4 pills to take daily during 18 weeks), same appearance to experimental drug

Clinical Trial Outcome Measures

Primary Measures

  • Proportion of patients with normalization of calciuria
    • Time Frame: Baseline (V1) and 16 weeks of treatment (V8)
    • Proportion of patients with normalization of 24-hour calciuria (≤ 0.1 mmol/kg/d) between Baseline (V1) and W16 (V8), or with a relative change of 30% of 24-hour calciuria between Baseline (V1) and W16 (V8) for patients who still have at W16 a 24-hour calciuria> 0.1mmol/kg/d.

Secondary Measures

  • Evolution over time of the calcium/phosphate metabolism (serum and urines dosages)
    • Time Frame: Baseline (V1), 16 weeks of treatment (V8)
    • 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.
  • Serum creatinine
    • Time Frame: Baseline (V1), 16 weeks of treatment (V8)
    • Evolution of renal function
  • number of lithiasis, nephrocalcinosis
    • Time Frame: Baseline (V1), 18 weeks of treatment (V9)
    • Evolution of renal function
  • size of lithiasis, nephrocalcinosis
    • Time Frame: Baseline (V1), 18 weeks of treatment (V9)
    • Evolution of renal function
  • Quantity of calcium intakes
    • Time Frame: 18 weeks
    • Anthropometry
  • Quantity of sodium intakes
    • Time Frame: 18 weeks
    • Anthropometry
  • Quantity of protein intakes
    • Time Frame: 18 weeks
    • Anthropometry
  • bone alkaline phosphatases
    • Time Frame: 16 weeks
    • Bone evaluation with biomarkers
  • FGF23
    • Time Frame: 16 weeks
    • Bone evaluation with biomarkers
  • Klotho
    • Time Frame: 16 weeks
    • Bone evaluation with biomarkers
  • femoral neck (FN) assessed with Dual energy x-ray absorptiometry (DXA):
    • Time Frame: at randomization (day 0)
    • Bone evaluation with biomarkers
  • 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)
    • Bone evaluation with biomarkers
  • total body (TB) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):
    • Time Frame: at randomization (day 0)
    • Bone evaluation with biomarkers
  • Safety evaluation through the study : cardiac evaluation
    • Time Frame: 18 weeks
    • Cardiac evaluation : electrocardiogram, corrected QT interval
  • Safety evaluation through the study : blood analysis
    • Time Frame: 20 weeks
    • Hepatic functions : aspartate transaminase
  • Safety evaluation through the study : blood analysis
    • Time Frame: 20 weeks
    • Hepatic functions : bilirubin
  • Safety evaluation through the study : blood analysis
    • Time Frame: 20 weeks
    • Hepatic functions : gamma-glutamyl-transpeptidase
  • Safety evaluation through the study : blood analysis
    • Time Frame: 20 weeks
    • Lactate dehydrogenase
  • Safety evaluation through the study : blood analysis
    • Time Frame: 20 weeks
    • phosphoremia
  • Safety evaluation through the study : blood analysis
    • Time Frame: 20 weeks
    • Calcemia
  • Safety evaluation through the study : blood analysis
    • Time Frame: 20 weeks
    • Serum creatinine
  • Safety evaluation through the study : blood analysis
    • Time Frame: 20 weeks
    • Albumin
  • Safety evaluation through the study : blood analysis
    • Time Frame: 18 weeks
    • Hepatic functions : alanine aminotransferase
  • Safety evaluation through the study : blood analysis
    • Time Frame: 20 weeks
    • Complete blood cell counts
  • Proportion of patients that developed mycological resistance
    • Time Frame: 18 weeks
    • 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.
  • Proportion of patients that developed mycological resistance
    • Time Frame: 18 weeks
    • 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.
  • Compliance assessment
    • Time Frame: every month from Randomization (V2) to 18 weeks of treatment (V9)
    • 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
  • 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 (V9)
    • Quality of life will be assessed with SF-36 auto-questionnaire (for adult patients)
  • 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 (V9)
    • PedsQL auto-questionnaire (PedsQL 8-12 years for children, and PedsQL 13-18 years for adolescents).

Participating in This Clinical Trial

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.

Gender Eligibility: All

Minimum Age: 10 Years

Maximum Age: 50 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Hospices Civils de Lyon
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Aurélia BERTHOLET-THOMAS, Dr, Principal Investigator, Hospices Civils de Lyon
  • Overall Contact(s)
    • Aurélia BERTHOLET-THOMAS, Dr, 4 27 85 61 04, aurelia.bertholet-thomas@chu-lyon.fr

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.