Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight
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.
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|Official Title:||Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants < 750 Grams Birth|
- Death or Candidiasis [ Time Frame: study day 49 ] [ Designated as safety issue: Yes ]
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).
i. > 5 days of consecutive antifungal therapy
ii. Thrombocytopenia <150,000/mm3 iii. Positive Candida culture from nonsterile site (ETS, bag urine)
- Neurodevelopmental Impairment [ Time Frame: 18-22 months corrected gestational age ] [ Designated as safety issue: No ]Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy
- Candidiasis [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: Yes ]Definite or probable
- Stage II or Higher Necrotizing Enterocolitis [ Time Frame: prior to discharge ] [ Designated as safety issue: Yes ]
- Focal Intestinal Perforation [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: Yes ]
- Chronic Lung Disease [ Time Frame: 36 weeks corrected gestational age ] [ Designated as safety issue: No ]
- Patent Ductus Arterious Requiring Surgical Ligation [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: Yes ]
- Periventricular Leukomalacia [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: Yes ]
- Retinopathy of Prematurity Requiring Laser Surgery [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: Yes ]
- Length of Hospitalization [ Time Frame: discharge from hospital ] [ Designated as safety issue: No ]
- Positive Bacterial Infection From a Sterile Site [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: Yes ]
- Intraventricular Hemorrhage [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: Yes ]Grade 3 or 4
|Study Start Date:||November 2008|
|Study Completion Date:||April 2013|
|Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
fluconazole 6mg/kg IV or PO twice weekly for 6 weeks
6mg/kg IV/PO twice weekly for a total of up to 12-13 doses
Other Name: Diflucan
Placebo Comparator: 2
Placebo IV or PO twice weekly for 6 weeks
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
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00734539
Show 33 Study Locations
|Principal Investigator:||Daniel K Benjamin, MD MPH PhD||Duke Univerisity Medical Center, Duke Clinical Research Institute|