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Fluconazole in Hypercalciuric Patients With Increased 1,25(OH)2D Levels (FLUCOLITH)

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ClinicalTrials.gov Identifier: NCT04495608
Recruitment Status : Not yet recruiting
First Posted : August 3, 2020
Last Update Posted : August 4, 2020
Sponsor:
Information provided by (Responsible Party):
Hospices Civils de Lyon

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 4 months 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 50 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.


Condition or disease Intervention/treatment Phase
Nephrolithiasis Nephrocalcinosis Hypercalciuria Drug: Fluconazole Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

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.

Primary Purpose: Treatment
Official Title: Fluconazole as a New Therapeutic Tool in Hypercalciuric Patients With Increased 1,25(OH)2D Levels
Estimated Study Start Date : January 1, 2021
Estimated Primary Completion Date : June 1, 2023
Estimated Study Completion Date : July 1, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Fluconazole

Arm Intervention/treatment
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

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).


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




Primary Outcome Measures :
  1. Proportion of patients with normalization of calciuria [ Time Frame: Baseline (V1) and 16 weeks of treatment (V8) ]
    Proportion of patients with normalization of 24-hour calciuria (≤ 0.1 mmol/kg/d) between Baseline (V1) and W16 (V8), or with a relative change of 30% of 24-hour calciuria between Baseline (V1) and W16 (V8) for patients who still have at W16 a 24-hour calciuria> 0.1mmol/kg/d.


Secondary Outcome Measures :
  1. Evolution over time of the calcium/phosphate metabolism (serum and urines dosages) [ Time Frame: Baseline (V1), 16 weeks of treatment (V8) ]
    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.

  2. Quantity of calcium intakes [ Time Frame: 18 weeks ]
    Anthropometry

  3. Quantity of sodium intakes [ Time Frame: 18 weeks ]
    Anthropometry

  4. Quantity of protein intakes [ Time Frame: 18 weeks ]
    Anthropometry

  5. Safety evaluation through the study : cardiac evaluation [ Time Frame: 18 weeks ]
    Cardiac evaluation : electrocardiogram, corrected QT interval

  6. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    Hepatic functions : aspartate transaminase

  7. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    Hepatic functions : bilirubin

  8. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    Hepatic functions : gamma-glutamyl-transpeptidase

  9. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    Lactate dehydrogenase

  10. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    phosphoremia

  11. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    Calcemia

  12. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    Serum creatinine

  13. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    Albumin

  14. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    Hepatic functions : alanine aminotransferase

  15. Safety evaluation through the study : blood analysis [ Time Frame: 18 weeks ]
    Complete blood cell counts

  16. Proportion of patients that developed mycological resistance [ Time Frame: 18 weeks ]
    Mycological stool 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.

  17. Compliance assessment [ Time Frame: every month from Randomization (V2) to 18 weeks of treatment (V9) ]
    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

  18. Quality of life and treatment satisfaction assessments : adults [ Time Frame: The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V9) ]
    Quality of life will be assessed with SF-36 auto-questionnaire (for adult patients)

  19. Quality of life and treatment satisfaction assessments : children and adolescents [ Time Frame: The endpoint will be the variation of total score between Randomization (V2) and 18 weeks of treatment (V9) ]
    PedsQL auto-questionnaire (PedsQL 8-12 years for children, and PedsQL 13-18 years for adolescents).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   10 Years to 50 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients who presented in their medical history nephrolithiasis and/or nephrocalcinosis
  • Patients who had, at least 4 weeks (±2 weeks) before inclusion and at inclusion (V1), a local biological evaluation with:
  • 24-hour urine calcium > 0.1 mmol/kg/day,
  • 1,25(OH)2D levels ≥150 pmol/L,
  • 25-OH-D levels ≥ 50 nmol/L,
  • calcemia levels ≤ 2.65 mmol/L.
  • Children from 10 years
  • Adults until 50 years
  • Women using effective methods of contraception during the study period
  • 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:

  • 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)
  • Patients with iatrogenic hypercalciuria (vitamin D intoxication, immobilization)
  • Patients with a congenital or inherited Long QT syndrome
  • Patients with a corrected QT interval > 450 ms
  • Patients who presented heart rhythm disorder
  • Patients with a 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 calcemia levels above 2.65 mmol/L
  • Patients who cannot stop hydrochlorothiazide or other diuretics during the screening and study period
  • Patients with another cause of lithiasis
  • Hypersensibility to fluconazole and/or excipients
  • Women who are pregnant or breast feeding, or who have a project of pregnancy
  • Menopausal woman
  • Patients with a project of travelling in a sunny area during the study period
  • Alcohol addiction
  • 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
  • Patient who already received fluconazole or ketoconazole during the last 6 months before inclusion
  • Patients under judicial protection.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04495608


Contacts
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Contact: Aurélia BERTHOLET-THOMAS 4 27 85 61 04 ext +33 aurelia.bertholet-thomas@chu-lyon.fr
Contact: Justine BACCHETTA justine.bacchette@chu-lyon.fr

Locations
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France
Service de Néphrologie Rhumatologie Dermatologie Pédiatrique
Bron, France, Bron
Sponsors and Collaborators
Hospices Civils de Lyon
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Responsible Party: Hospices Civils de Lyon
ClinicalTrials.gov Identifier: NCT04495608    
Other Study ID Numbers: 69HCL20_0071
First Posted: August 3, 2020    Key Record Dates
Last Update Posted: August 4, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Hospices Civils de Lyon:
Hypercalciuria
nephrocalcinosis
1,25-dihydroxyvitamin D
1-alpha-hydroxylase
fluconazole
Additional relevant MeSH terms:
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Nephrolithiasis
Kidney Calculi
Nephrocalcinosis
Hypercalciuria
Kidney Diseases
Urologic Diseases
Urolithiasis
Urinary Calculi
Calculi
Pathological Conditions, Anatomical
Urological Manifestations
Calcinosis
Calcium Metabolism Disorders
Metabolic Diseases
Fluconazole
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors