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

Summary

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.

Conditions

• Nephrolithiasis
• Nephrocalcinosis
• Hypercalciuria

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

Sponsors & Collaborators

• Hospices Civils de Lyon

  lead OTHER

Principal Investigators

• Aurélia BERTHOLET-THOMAS, Dr · Hospices Civils de Lyon

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

10 Years

Max Age

60 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2021-01-13

Primary Completion

2024-07-01

Completion

2024-07-01

Countries

• France

Study Locations