Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Thrasher Research Fund, Food and Drug Administration (FDA)

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.

362 subjects were randomized to the study at 33 US sites. Final study visits of Month 18-22 corrected age long term follow up were completed. Study database is locked.

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

The primary endpoint for the study is death or candidiasis. Death prior to study day 49. Candidiasis prior to study day 49 Definite: isolation of Candida from normally sterile body fluid (blood, CSF, urine [obtained via sterile catheterization or suprapubic tap], peritoneal fluid). Probable: i. > 5 days of consecutive antifungal therapy AND both: ii. Thrombocytopenia <150,000/mm3 iii. Positive Candida culture from nonsterile site (ETS, bag urine)

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

In December 2018, after receiving IRB's approval, the team submitted the de-identified study dataset and redacted study documents to the NICHD Data and Specimen Hub (DASH).

Benjamin DK Jr, Hudak ML, Duara S, Randolph DA, Bidegain M, Mundakel GT, Natarajan G, Burchfield DJ, White RD, Shattuck KE, Neu N, Bendel CM, Kim MR, Finer NN, Stewart DL, Arrieta AC, Wade KC, Kaufman DA, Manzoni P, Prather KO, Testoni D, Berezny KY, Smith PB; Fluconazole Prophylaxis Study Team. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014 May 7;311(17):1742-9. doi: 10.1001/jama.2014.2624.

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