Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight
- Registration Number
- NCT00734539
- Lead Sponsor
- Daniel Benjamin
- Brief 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.
- Detailed 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 362
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 2 placebo Placebo IV or PO twice weekly for 6 weeks 1 fluconazole fluconazole 6mg/kg IV or PO twice weekly for 6 weeks
- Primary Outcome Measures
Name Time Method Death or Candidiasis study day 49 The primary endpoint for the study is death or candidiasis.
1. Death prior to study day 49.
2. Candidiasis prior to study day 49
1. Definite: isolation of Candida from normally sterile body fluid (blood, CSF, urine \[obtained via sterile catheterization or suprapubic tap\], peritoneal fluid).
2. 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)
- Secondary Outcome Measures
Name Time Method Focal Intestinal Perforation prior to hospital discharge, up to 15 ½ months Neurodevelopmental Impairment 18-22 months corrected gestational age Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy
Candidiasis prior to hospital discharge, up to 15 ½ months Definite or probable
Stage II or Higher Necrotizing Enterocolitis prior to hospital discharge, up to 15 ½ months Chronic Lung Disease 36 weeks corrected gestational age Patent Ductus Arterious Requiring Surgical Ligation prior to hospital discharge, up to 15 ½ months Retinopathy of Prematurity Requiring Laser Surgery prior to hospital discharge, up to 15 ½ months Periventricular Leukomalacia prior to hospital discharge, up to 15 ½ months Length of Hospitalization prior to hospital discharge, up to 15 ½ months Positive Bacterial Infection From a Sterile Site prior to hospital discharge, up to 15 ½ months Intraventricular Hemorrhage prior to hospital discharge, up to 15 ½ months Grade 3 or 4
Trial Locations
- Locations (33)
University of California-San Diego
🇺🇸San Diego, California, United States
Riley Hospital
🇺🇸Indianapolis, Indiana, United States
West Jersey Hospital - Voorhees
🇺🇸Voorhees, New Jersey, United States
Pennsylvania Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Parkland Memorial Hospital
🇺🇸Dallas, Texas, United States
Texas Children's Hospital/Baylor College of Medicine
🇺🇸Houston, Texas, United States
University of Nevada School of Medicine
🇺🇸Las Vegas, Nevada, United States
Cooks Children's Medical Center
🇺🇸Fort Worth, Texas, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
SUNY Dowstate Medical Center
🇺🇸Brooklyn, New York, United States
University of Texas Medical Branch
🇺🇸Galveston, Texas, United States
Baptist Medical Center
🇺🇸Jacksonville, Florida, United States
Arkansas Childrens Hospital
🇺🇸Little Rock, Arkansas, United States
Pitt County Memorial Hospital
🇺🇸Greenville, North Carolina, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
University of Texas - Houston
🇺🇸Houston, Texas, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Memorial Hospital
🇺🇸South Bend, Indiana, United States
Tulane University School of Medicine
🇺🇸New Orleans, Louisiana, United States
Brookdale University Medical Center
🇺🇸Brooklyn, New York, United States
University of Minnesota, Fairview Medical Center
🇺🇸Minneapolis, Minnesota, United States
Wesley Medical Center
🇺🇸Wichita, Kansas, United States
Shands Jacksonville Medical Center
🇺🇸Jacksonville, Florida, United States
Kings County Hospital Center
🇺🇸Brooklyn, New York, United States
University of Tennessee
🇺🇸Memphis, Tennessee, United States
Akron Children's Hospital
🇺🇸Akron, Ohio, United States
University of Florida
🇺🇸Gainesville, Florida, United States
University of Miami
🇺🇸Miami, Florida, United States
Children's Hospital of Orange County
🇺🇸Orange, California, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Wayne State University
🇺🇸Detroit, Michigan, United States
Oregon Health Sciences Center
🇺🇸Portland, Oregon, United States
Kosair Children's Hospital
🇺🇸Louisville, Kentucky, United States