Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight
Condition: Candidiasis
MeSH terms: Candidiasis
Intervention: fluconazole; placebo
Intervention description: 6mg/kg IV/PO twice weekly for a total of up to 12-13 doses; normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly PO/IV for a total of up to 12-13 doses
Intervention MeSH terms: Fluconazole
Phase: Phase 3
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 362.0
Sex: All
Minimum age: 2 Days
Maximum age: 5 Days
Healthy volunteers: No
Keywords: Candida; Neonate; Fluconazole; Prophylaxis; Colonization; Resistance

Summary:

      The most common etiology of infection-related death or neurodevelopmental impairment in
      neonates with birthweight <750 g is invasive candidiasis. Over 70% of the premature neonates
      who develop invasive candidiasis will die or suffer severe, permanent neurologic impairment.
      Fluconazole has been commonly used off-label in the neonatal intensive care unit, but
      definitive recommendations for its use in the nursery have been hampered by the limited
      number of well-designed trials. In neonates weighing <750 g, appropriate dosing is not known,
      definitive safety and long-term follow up trials have not been completed, and there have not
      been well-powered trials conducted to establish the efficacy of the product using mortality
      as part of the primary endpoint. Three recent proof-of-concept studies suggest that
      fluconazole will be safe and effective, and a recently completed pharmacokinetic study is
      providing data to give preliminary dosing guidance. The next logical step in drug development
      is proposed by this research: to conduct a pivotal trial to determine the safety and efficacy
      of fluconazole in premature neonates with 2-year neurodevelopmental follow-up assessment.

      362 neonates, with a birthweight <750g, were randomized at 33 US centers, to twice weekly
      fluconazole (6 mg/kg) or placebo for the first 6 weeks of life. The primary efficacy endpoint
      will be Candida-free survival at study day 49. The research will establish definitive dosing,
      safety, and efficacy of fluconazole; it will also provide critical information on the effects
      of fluconazole on neurodevelopmental impairment and antifungal resistance.

      Potential Impact:

      Approximately 17,000 neonates are born <750 grams each year in the United States. Over 5000
      will die or develop invasive Candida infections. Demonstrating safety and efficacy of
      fluconazole in preterm neonates will improve the survivability and long term outcomes for
      these neonates.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Informed consent from the legally authorized representative.

          -  > 48 hours of age and < 120 hours old at time of first drug administration

          -  < 750 g birth weight

          -  Negative blood cultures for Candida

        Exclusion Criteria:

          -  History of a hypersensitivity or severe vasomotor reaction to any azole

          -  receiving antifungal therapy for suspected/proven invasive fungal infection

          -  medical condition, in the opinion of the Investigator, may create an unacceptable
             additional risk

          -  diagnosed with invasive candidiasis or congenital Candida infection.

          -  liver failure (AST and ALT > 250 U/L)

          -  renal failure (creatinine > 2 mg/dL)

          -  major lethal congenital or genetic anomalies

          -  triplet or higher multiple gestations