CompletedNCT04495608FLUCOLITHUpdated Jul 12, 2024

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

A Phase 2 interventional study of Fluconazole and Placebo in Nephrolithiasis, Nephrocalcinosis and Hypercalciuria, sponsored by Hospices Civils de Lyon. Completed at 11 sites in France. Open to participants aged 10 Years to 60 Years. Per ClinicalTrials.gov, last updated 2024-07-12.

Sponsored by Hospices Civils de Lyon · Phase 2, Interventional, and Treatment

Phase: Phase 2
Study type: Interventional
Enrollment: 56
Allocation: Randomized
Ages: 10 Years to 60 Years
Sex: All

Study 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 studied

Nephrolithiasis
Nephrocalcinosis
Hypercalciuria

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Keywords

Hypercalciuria
nephrocalcinosis
1,25-dihydroxyvitamin D
1-alpha-hydroxylase
fluconazole

Who can participate

Ages eligible: 10 Years to 60 Years
Sexes eligible: All
Accepts healthy volunteers: No

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

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.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 56 participants (actual)

Study arms

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

Interventions

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

What researchers measure

Primary outcomes

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.
Time frame: Baseline (V1) and 18 weeks of treatment (V7)

Secondary outcomes

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.
Time frame: Baseline (V1), 18 weeks of treatment (V7)
Serum creatinine
Evolution of renal function
Time frame: Baseline (V1), 18 weeks of treatment (V7)
number of lithiasis, nephrocalcinosis
Evolution of renal function
Time frame: Baseline (V1), 18 weeks of treatment (V7)
size of lithiasis, nephrocalcinosis
Evolution of renal function
Time frame: Baseline (V1), 18 weeks of treatment (V7)
Quantity of calcium intakes
Anthropometry
Time frame: 18 weeks
Quantity of sodium intakes
Anthropometry
Time frame: 18 weeks
Quantity of protein intakes
Anthropometry
Time frame: 18 weeks
bone alkaline phosphatases
Bone evaluation with biomarkers
Time frame: 16 weeks
FGF23
Bone evaluation with biomarkers
Time frame: 16 weeks
Klotho
Bone evaluation with biomarkers
Time frame: 18 weeks
femoral neck (FN) assessed with Dual energy x-ray absorptiometry (DXA):
Bone evaluation with biomarkers
Time frame: 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
Time frame: at randomization (day 0)
total body (TB) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):
Bone evaluation with biomarkers
Time frame: at randomization (day 0)
Safety evaluation through the study : cardiac evaluation
Cardiac evaluation : electrocardiogram, corrected QT interval
Time frame: Baseline (V1)
Safety evaluation through the study : cardiac evaluation
Cardiac evaluation : electrocardiogram, corrected QT interval
Time frame: 4 weeks
Safety evaluation through the study : cardiac evaluation
Cardiac evaluation : electrocardiogram, corrected QT interval
Time frame: 10 weeks
Safety evaluation through the study : blood analysis
Hepatic functions : aspartate transaminase
Time frame: 20 weeks
Safety evaluation through the study : blood analysis
Hepatic functions : bilirubin
Time frame: 20 weeks
Safety evaluation through the study : blood analysis
Hepatic functions : gamma-glutamyl-transpeptidase
Time frame: 20 weeks
Safety evaluation through the study : blood analysis
Lactate dehydrogenase
Time frame: 20 weeks
Safety evaluation through the study : blood analysis
phosphoremia
Time frame: 20 weeks
Safety evaluation through the study : blood analysis
Calcemia
Time frame: 20 weeks
Safety evaluation through the study : blood analysis
Serum creatinine
Time frame: 20 weeks
Safety evaluation through the study : blood analysis
Albumin
Time frame: 20 weeks
Safety evaluation through the study : blood analysis
Hepatic functions : alanine aminotransferase
Time frame: 18 weeks
Safety evaluation through the study : blood analysis
Complete blood cell counts
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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)
Time frame: 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).
Time frame: The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7)

Study locations

11 sites

Service de Néphrologie Rhumatologie Dermatologie Pédiatrique
Bron, Bron, France
CHU de Dijon
Dijon, France
Hôpital Edouard Herriot
Lyon, France
APHM - CHU Conception
Marseille, France
CHR Metz-Thionville
Metz, France
CHU de Nantes
Nantes, France
Hôpital Universitaire Necker
Paris, 75743, France
APHP - Hôpital Européen Georges Pompidou HEGP
Paris, France
Hôpital Universitaire Necker-Enfants Malades
Paris, France
CHU Rennes Pontchaillou
Rennes, France
CHU de Strasbourg, hôpital de Hautepierre
Strasbourg, France

References and documents

Publications

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. PubMed 35710560 ↗

Registry details

Key details

Study ID: NCT04495608
Lead sponsor: Hospices Civils de Lyon
Responsible party: Sponsor
First posted: Aug 3, 2020
Start date: Jan 13, 2021
Primary completion: Jul 1, 2024
Completion: Jul 1, 2024
Last update: Jul 12, 2024

Study contacts

Aurélia BERTHOLET-THOMAS, Dr

principal investigator · Hospices Civils de Lyon

Oversight

Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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