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

This study has been completed.
Thrasher Research Fund
Food and Drug Administration (FDA)
Information provided by (Responsible Party):
Daniel Benjamin, Duke University Medical Center
ClinicalTrials.gov Identifier:
First received: August 13, 2008
Last updated: April 16, 2013
Last verified: April 2013

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.

Condition Intervention Phase
Drug: fluconazole
Drug: placebo
Phase 3

Study Type: Interventional
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

Resource links provided by NLM:

Further study details as provided by Duke University:

Primary Outcome Measures:
  • Death or candidiasis [ Time Frame: study day 49 ] [ Designated as safety issue: No ]

    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:
  • Neurodevelopmental impairment [ Time Frame: 18-22 months corrected age ] [ Designated as safety issue: No ]
  • Positive bacterial culture from sterile site [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: No ]
  • candidiasis [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: No ]
  • positive Candida culture from non-sterile site [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: No ]
  • stage II or higher necrotizing enterocolitis [ Time Frame: prior to discharge ] [ Designated as safety issue: No ]
  • focal intestinal perforation [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: No ]
  • chronic lung disease [ Time Frame: 36 weeks adjusted gestational age ] [ Designated as safety issue: No ]
  • patent ductus arteriosus requiring surgical ligation [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: No ]
  • periventricular leukomalacia [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: No ]
  • retinopathy of prematurity requiring laser surgery [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: No ]
  • length of hospitalization [ Time Frame: discharge from hospital ] [ Designated as safety issue: No ]
  • Candida colonization [ Time Frame: Study day 42 ] [ Designated as safety issue: No ]
  • Development of resistance among Candida isolates [ Time Frame: prior to hospital discharge ] [ Designated as safety issue: No ]
  • drug toxicity [ Time Frame: within 30 days of last dose of study drug ] [ Designated as safety issue: Yes ]

Enrollment: 362
Study Start Date: November 2008
Study Completion Date: April 2013
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
fluconazole 6mg/kg IV or PO twice weekly for 6 weeks
Drug: fluconazole
6 mg/kg PO/IV twice weekly x 14 doses
Other Name: Diflucan
Placebo Comparator: 2
Placebo IV or PO twice weekly for 6 weeks
Drug: placebo
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 14 doses

Detailed Description:

362 subjects were randomized to the study at 33 US sites. Month 18-22 corrected age long term follow up visit and data cleaning are ongoing. Study database is anticipated to be locked in March 2013, followed by data analysis.


Ages Eligible for Study:   up to 5 Days
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00734539

  Show 33 Study Locations
Sponsors and Collaborators
Daniel Benjamin
Thrasher Research Fund
Food and Drug Administration (FDA)
Principal Investigator: Daniel K Benjamin, MD MPH PhD Duke Univerisity Medical Center, Duke Clinical Research Institute
  More Information

No publications provided by Duke University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Daniel Benjamin, Professor of Pediatrics, Duke University Medical Center
ClinicalTrials.gov Identifier: NCT00734539     History of Changes
Other Study ID Numbers: Pro00001538, 1R01HD057956-01, Pro00017720
Study First Received: August 13, 2008
Last Updated: April 16, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Duke University:

Additional relevant MeSH terms:
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
14-alpha Demethylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 16, 2014