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NephrolithiasisPhase 2FLUCOLITHNCT04495608

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 study testing Fluconazole in people with Nephrolithiasis and Nephrocalcinosis, run by Hospices Civils de Lyon at 11 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 10 to 60 years
Conditions the study is for
Nephrolithiasis, Nephrocalcinosis, Hypercalciuria
What is being tested?
Fluconazole
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
56 participants
Where
11 sitesFrance
Study dates
13 Jan 2021to 1 Jul 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 10 to 60 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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.
Show all 11Show fewer
  • 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.

Who cannot join

  • 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
Show all 32Show fewer
  • 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;
  • cardiopathy: ischemia or myocardial infarction, congestive cardiac insufficiency, left ventricle hypertrophy, cardiomyopathy, conduction trouble within 6 months preceding the inclusion;
  • 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) ;
  • acute neurological events (i.e. intracranial hemorrhage or sub-arachnoid, cerebrovascular accident, intracranial trauma) within 6 months preceding the inclusion;
  • 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 locations and contacts

11 sites in 1 country.

11 sites in 1 country

France11 sites

  • Service de Néphrologie Rhumatologie Dermatologie Pédiatrique

    Bron, Bron

  • CHU de Dijon

    Dijon

  • Hôpital Edouard Herriot

    Lyon

  • APHM - CHU Conception

    Marseille

  • CHR Metz-Thionville

    Metz

  • CHU de Nantes

    Nantes

  • Hôpital Universitaire Necker

    Paris, 75743

  • APHP - Hôpital Européen Georges Pompidou HEGP

    Paris

  • Hôpital Universitaire Necker-Enfants Malades

    Paris

  • CHU Rennes Pontchaillou

    Rennes

  • CHU de Strasbourg, hôpital de Hautepierre

    Strasbourg

Other trials in France

About this study

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).

Read more

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.

Being tested
Fluconazole, Placebo
Keywords
Hypercalciuria, nephrocalcinosis, 1,25-dihydroxyvitamin D, 1-alpha-hydroxylase, fluconazole
Medical subject headings
Nephrolithiasis, Nephrocalcinosis, Hypercalciuria

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • FluconazoleDrug

    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).

  • PlaceboDrug

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

Study groups in NCT04495608
Study groupRoleWhat they receive
fluconazoleExperimentalFluconazole 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).
Receives: Drug: Fluconazole
placeboPlacebo comparatorPlacebo (1, 2, 3 or 4 pills to take daily during 18 weeks), same appearance to experimental drug
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (31)

  1. 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.

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

  2. Serum creatinine

    Evolution of renal function

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

  3. number of lithiasis, nephrocalcinosis

    Evolution of renal function

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

  4. size of lithiasis, nephrocalcinosis

    Evolution of renal function

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

  5. Quantity of calcium intakes

    Anthropometry

    Measured: 18 weeks

  6. Quantity of sodium intakes

    Anthropometry

    Measured: 18 weeks

  7. Quantity of protein intakes

    Anthropometry

    Measured: 18 weeks

  8. bone alkaline phosphatases

    Bone evaluation with biomarkers

    Measured: 16 weeks

  9. FGF23

    Bone evaluation with biomarkers

    Measured: 16 weeks

  10. Klotho

    Bone evaluation with biomarkers

    Measured: 18 weeks

  11. femoral neck (FN) assessed with Dual energy x-ray absorptiometry (DXA):

    Bone evaluation with biomarkers

    Measured: at randomization (day 0)

  12. lumbar spine vertebra 2 to 4 (LS2-4) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):

    Bone evaluation with biomarkers

    Measured: at randomization (day 0)

  13. total body (TB) areal bone mineral density assessed with Dual energy x-ray absorptiometry (DXA):

    Bone evaluation with biomarkers

    Measured: at randomization (day 0)

  14. Safety evaluation through the study : cardiac evaluation

    Cardiac evaluation : electrocardiogram, corrected QT interval

    Measured: Baseline (V1)

  15. Safety evaluation through the study : cardiac evaluation

    Cardiac evaluation : electrocardiogram, corrected QT interval

    Measured: 4 weeks

  16. Safety evaluation through the study : cardiac evaluation

    Cardiac evaluation : electrocardiogram, corrected QT interval

    Measured: 10 weeks

  17. Safety evaluation through the study : blood analysis

    Hepatic functions : aspartate transaminase

    Measured: 20 weeks

  18. Safety evaluation through the study : blood analysis

    Hepatic functions : bilirubin

    Measured: 20 weeks

  19. Safety evaluation through the study : blood analysis

    Hepatic functions : gamma-glutamyl-transpeptidase

    Measured: 20 weeks

  20. Safety evaluation through the study : blood analysis

    Lactate dehydrogenase

    Measured: 20 weeks

  21. Safety evaluation through the study : blood analysis

    phosphoremia

    Measured: 20 weeks

  22. Safety evaluation through the study : blood analysis

    Calcemia

    Measured: 20 weeks

  23. Safety evaluation through the study : blood analysis

    Serum creatinine

    Measured: 20 weeks

  24. Safety evaluation through the study : blood analysis

    Albumin

    Measured: 20 weeks

  25. Safety evaluation through the study : blood analysis

    Hepatic functions : alanine aminotransferase

    Measured: 18 weeks

  26. Safety evaluation through the study : blood analysis

    Complete blood cell counts

    Measured: 20 weeks

  27. 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.

    Measured: 18 weeks

  28. 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.

    Measured: 18 weeks

  29. 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

    Measured: every month from Randomization (V2) to 18 weeks of treatment (V7)

  30. Quality of life and treatment satisfaction assessments : adults

    Quality of life will be assessed with SF-36 auto-questionnaire (for adult patients)

    Measured: The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7)

  31. 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).

    Measured: The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V7)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted3 Aug 2020
  2. Study start13 Jan 2021
  3. Primary completion1 Jul 2024
  4. Study completion1 Jul 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
56 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04495608
Sponsor's protocol ID
69HCL20_0071
Other IDs
2020-003011-97
Acronym
FLUCOLITH
Status last verified
Jul 2024
First submitted
23 Jul 2020
Last updated
12 Jul 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

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

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Fluconazole in people with Nephrolithiasis and Nephrocalcinosis, run by Hospices Civils de Lyon at 11 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 12 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of patients with normalization of calciuria (time frame: Baseline (V1) and 18 weeks of treatment (V7)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04495608, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jul 2024.

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