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

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants < 750 Grams Birth

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. Demonst

Detailed Summary: 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.
Sponsor: Daniel Benjamin

Current Primary Outcome: Death or Candidiasis [ Time Frame: 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)



Original Primary Outcome: Death or Candidiasis [ Time Frame: study day 49 ]

Current Secondary Outcome:

  • Neurodevelopmental Impairment [ Time Frame: 18-22 months corrected gestational age ]
    Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy
  • Candidiasis [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
    Definite or probable
  • Stage II or Higher Necrotizing Enterocolitis [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
  • Focal Intestinal Perforation [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
  • Chronic Lung Disease [ Time Frame: 36 weeks corrected gestational age ]
  • Patent Ductus Arterious Requiring Surgical Ligation [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
  • Periventricular Leukomalacia [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
  • Retinopathy of Prematurity Requiring Laser Surgery [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
  • Length of Hospitalization [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
  • Positive Bacterial Infection From a Sterile Site [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
  • Intraventricular Hemorrhage [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
    Grade 3 or 4


Original Secondary Outcome:

  • Neurodevelopmental Impairment [ Time Frame: 18-22 months corrected age ]
  • Positive bacterial culture from sterile site [ Time Frame: prior to hospital discharge ]
  • Candidiasis [ Time Frame: prior to hospital discharge ]
  • positive Candida culture from non-sterile site [ Time Frame: prior to hospital discharge ]
  • Stage II or Higher Necrotizing Enterocolitis [ Time Frame: prior to discharge ]
  • Focal Intestinal Perforation [ Time Frame: prior to hospital discharge ]
  • Chronic Lung Disease [ Time Frame: 36 weeks adjusted gestational age ]
  • patent ductus arteriosus requiring surgical ligation [ Time Frame: prior to hospital discharge ]
  • Periventricular Leukomalacia [ Time Frame: prior to hospital discharge ]
  • Retinopathy of Prematurity Requiring Laser Surgery [ Time Frame: prior to hospital discharge ]
  • Length of Hospitalization [ Time Frame: discharge from hospital ]
  • Candida colonization [ Time Frame: Study day 42 ]
  • Development of resistance among Candida isolates [ Time Frame: prior to hospital discharge ]
  • drug toxicity [ Time Frame: within 30 days of last dose of study drug ]


Information By: Duke University

Dates:
Date Received: August 13, 2008
Date Started: November 2008
Date Completion:
Last Updated: July 27, 2014
Last Verified: July 2014