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

NCT04495608 | Completed Phase 2 DMC

• 2 other identifiers: 69HCL20_00712020-003011-97
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 11

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.

Conditions

Nephrolithiasis; Nephrocalcinosis; Hypercalciuria

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline (V1) and 18 weeks of treatment (V7)

Secondary Outcomes (31)

• Evolution over time of the calcium/phosphate metabolism (serum and urines dosages)

  Baseline (V1), 18 weeks of treatment (V7)

• Serum creatinine

  Baseline (V1), 18 weeks of treatment (V7)

• number of lithiasis, nephrocalcinosis

  Baseline (V1), 18 weeks of treatment (V7)

• size of lithiasis, nephrocalcinosis

  Baseline (V1), 18 weeks of treatment (V7)

• Quantity of calcium intakes

  18 weeks

Study Arms (2)

fluconazole

EXPERIMENTAL

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

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Fluconazole DRUG

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).

fluconazole

Placebo DRUG

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

placebo

Eligibility Criteria

• Age: 10 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Patients who presented in their medical history nephrolithiasis and/or nephrocalcinosis
• 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.

You may not qualify if:

• 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:
• congenital Long QT syndrome;
• familial history of sudden cardiac death before 50 years of age;
• arrhythmia history (in particular ventricular arrhythmia, auricular fibrillation or recent rhythm recovery after an auricular fibrillation);
• electrolytic instabilities: hypokalemia, hypomagnesemia, hypocalcemia ;
• bradycardia (\< 50 beats per minute) ;

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (11)

Service de Néphrologie Rhumatologie Dermatologie Pédiatrique

Bron, Bron, France

Location

CHU de Dijon

Dijon, France

Location

Hôpital Edouard Herriot

Lyon, France

Location

APHM - CHU Conception

Marseille, France

Location

CHR Metz-Thionville

Metz, France

Location

CHU de Nantes

Nantes, France

Location

Hôpital Universitaire Necker

Paris, 75743, France

Location

APHP - Hôpital Européen Georges Pompidou HEGP

Paris, France

Location

Hôpital Universitaire Necker-Enfants Malades

Paris, France

Location

CHU Rennes Pontchaillou

Rennes, France

Location

CHU de Strasbourg, hôpital de Hautepierre

Strasbourg, France

Location

Related Publications (1)

• 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.

  PMID: 35710560 DERIVED

MeSH Terms

Conditions

Nephrolithiasis; Nephrocalcinosis; Hypercalciuria

Interventions

Fluconazole

Condition Hierarchy (Ancestors)

Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urolithiasis; Male Urogenital Diseases; Calcinosis; Calcium Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Urological Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Aurélia BERTHOLET-THOMAS, Dr

  Hospices Civils de Lyon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Blinding procedure will be systematic thanks to the indistinguishable nature of the active product and placebo and their packaging. Only the biostatistician in charge of the production of the randomization list, the Centre Anti-Poison of Lyon, and the main pharmacy (Pharmacy Department Groupement Hospitalier Centre - Edouard Herriot Hospital - Hospices Civils de Lyon (Lyon, France), responsible for packaging, labeling and dispatching of experimental drugs to the sites, will have access to a decoded list.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 23, 2020
• First Posted: August 3, 2020
• Study Start: January 13, 2021
• Primary Completion: July 1, 2024
• Study Completion: July 1, 2024
• Last Updated: July 12, 2024

Record last verified: 2024-07

Locations

FR (11)