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

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.

Conditions

• Candidiasis

Interventions

DRUG

fluconazole

6mg/kg IV/PO twice weekly for a total of up to 12-13 doses

DRUG

placebo

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

Sponsors & Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

  collaborator NIH

• Thrasher Research Fund

  collaborator OTHER

• Food and Drug Administration (FDA)

  collaborator FED

• Daniel Benjamin

  lead OTHER

Principal Investigators

• Daniel K Benjamin, MD MPH PhD · Duke Univerisity Medical Center, Duke Clinical Research Institute

Study Design

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Model

PARALLEL

Eligibility

Min Age

2 Days

Max Age

5 Days

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2008-11-30

Primary Completion

2011-12-31

Completion

2013-04-30

Countries

• United States

Study Locations