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)

Civil Hospices of Lyon

Status and phase: Completed; Phase 2

Conditions: Nephrocalcinosis; Hypercalciuria; Nephrolithiasis

Treatments: Drug: Fluconazole; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT04495608

69HCL20_0071

2020-003011-97 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 56 patients

Sex: All

Ages: 10 to 60 years old

Volunteers: No Healthy Volunteers

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:

  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 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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56 participants in 2 patient groups, including a placebo group

fluconazole

Experimental group

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).

Treatment:

Drug: Fluconazole

placebo

Placebo Comparator group

Description:

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

Treatment:

Drug: Placebo