Clinical trial NCT04495608: Multicenter, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Fluconazole in Hypercalcicuric Patients With Increased 1.25(OH) 2D Levels
Official title: 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nephrolithiasis
Nephrocalcinosis
Hypercalciuria
Keywords: Hypercalciuria
nephrocalcinosis
1,25-dihydroxyvitamin D
1-alpha-hydroxylase
fluconazole
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2020-08-03
Enrollment: 56
Sex: ALL
Minimum age (years): 10
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of patients with normalization of calciuria
timeFrame: Baseline (V1) and 18 weeks of treatment (V7)
Secondary outcomes:
measure: Evolution over time of the calcium/phosphate metabolism (serum and urines dosages)
timeFrame: Baseline (V1), 18 weeks of treatment (V7)
measure: Serum creatinine
timeFrame: Baseline (V1), 18 weeks of treatment (V7)
measure: number of lithiasis, nephrocalcinosis
timeFrame: Baseline (V1), 18 weeks of treatment (V7)
measure: size of lithiasis, nephrocalcinosis
timeFrame: Baseline (V1), 18 weeks of treatment (V7)
measure: Quantity of calcium intakes
timeFrame: 18 weeks
measure: Quantity of sodium intakes
timeFrame: 18 weeks
measure: Quantity of protein intakes
timeFrame: 18 weeks
measure: bone alkaline phosphatases
timeFrame: 16 weeks
measure: FGF23
timeFrame: 16 weeks
measure: Klotho
timeFrame: 18 weeks
measure: femoral neck (FN) assessed with Dual energy x-ray absorptiometry (DXA):
timeFrame: at randomization (day 0)
measure: lumbar spine vertebra 2 to 4 (LS2-4) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):
timeFrame: at randomization (day 0)
measure: total body (TB) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):
timeFrame: at randomization (day 0)
measure: Safety evaluation through the study : cardiac evaluation
timeFrame: Baseline (V1)
measure: Safety evaluation through the study : cardiac evaluation
timeFrame: 4 weeks
measure: Safety evaluation through the study : cardiac evaluation
timeFrame: 10 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 20 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 20 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 20 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 20 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 20 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 20 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 20 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 20 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 18 weeks
measure: Safety evaluation through the study : blood analysis
timeFrame: 20 weeks
measure: Proportion of patients that developed mycological resistance
timeFrame: 18 weeks
measure: Proportion of patients that developed mycological resistance
timeFrame: 18 weeks
measure: Compliance assessment
timeFrame: every month from Randomization (V2) to 18 weeks of treatment (V7)
measure: Quality of life and treatment satisfaction assessments : adults
timeFrame: The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7)
measure: Quality of life and treatment satisfaction assessments : children and adolescents
timeFrame: The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7)
Other outcomes:
Locations:
city: Bron
country: France
facility: Service de Néphrologie Rhumatologie Dermatologie Pédiatrique
city: Dijon
country: France
facility: CHU de Dijon
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Marseille
country: France
facility: APHM - CHU Conception
city: Metz
country: France
facility: CHR Metz-Thionville
city: Nantes
country: France
facility: CHU de Nantes
city: Paris
country: France
facility: Hôpital Universitaire Necker
city: Paris
country: France
facility: APHP - Hôpital Européen Georges Pompidou HEGP
city: Paris
country: France
facility: Hôpital Universitaire Necker-Enfants Malades
city: Rennes
country: France
facility: CHU Rennes Pontchaillou
city: Strasbourg
country: France
facility: CHU de Strasbourg, hôpital de Hautepierre
Study officials:
affiliation: Hospices Civils de Lyon
name: Aurélia BERTHOLET-THOMAS, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bertholet-Thomas A, Portefaix A, Flammier S, Dhelens C, Subtil F, Dubourg L, Laudy V, Le Bouar M, Boussaha I, Ndiaye M, Molin A, Lemoine S, Bacchetta J. Fluconazole in hypercalciuric patients with increased 1,25(OH)2D levels: the prospective, randomized, placebo-controlled, double-blind FLUCOLITH trial. Trials. 2022 Jun 16;23(1):499. doi: 10.1186/s13063-022-06302-z.