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

Daniel Benjamin

Status and phase

Completed

Phase 3

Conditions

Candidiasis

Treatments

Drug: placebo

Drug: fluconazole

Study type

Interventional

Funder types

Other

Other U.S. Federal agency

NIH

Identifiers

NCT00734539

Pro00001538

Pro00017720 (Other Identifier)

1R01HD057956-01 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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.

Enrollment

362 patients

Sex

All

Ages

2 to 5 days old

Volunteers

No Healthy Volunteers

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