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

Candidiasis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00734539
• Other study ID #: Pro00001538
• Secondary ID: 1R01HD057956-01P
• Status: Completed
• Phase: Phase 3
• Start date: November 2008
• Est. completion date: April 2013

Study information

• Verified date: February 2019
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 362
• Est. completion date: April 2013
• Est. primary completion date: December 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 5 Days

Eligibility

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

Related Conditions & MeSH terms

• Candidiasis

Intervention

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

Locations

Country	Name	City	State
United States	Akron Children's Hospital	Akron	Ohio
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Brookdale University Medical Center	Brooklyn	New York
United States	Kings County Hospital Center	Brooklyn	New York
United States	SUNY Dowstate Medical Center	Brooklyn	New York
United States	Parkland Memorial Hospital	Dallas	Texas
United States	Wayne State University	Detroit	Michigan
United States	Duke University Medical Center	Durham	North Carolina
United States	Cooks Children's Medical Center	Fort Worth	Texas
United States	University of Florida	Gainesville	Florida
United States	University of Texas Medical Branch	Galveston	Texas
United States	Pitt County Memorial Hospital	Greenville	North Carolina
United States	Texas Children's Hospital/Baylor College of Medicine	Houston	Texas
United States	University of Texas - Houston	Houston	Texas
United States	Riley Hospital	Indianapolis	Indiana
United States	Baptist Medical Center	Jacksonville	Florida
United States	Shands Jacksonville Medical Center	Jacksonville	Florida
United States	University of Nevada School of Medicine	Las Vegas	Nevada
United States	Arkansas Childrens Hospital	Little Rock	Arkansas
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	University of Tennessee	Memphis	Tennessee
United States	University of Miami	Miami	Florida
United States	University of Minnesota, Fairview Medical Center	Minneapolis	Minnesota
United States	Tulane University School of Medicine	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	Pennsylvania Hospital	Philadelphia	Pennsylvania
United States	Oregon Health Sciences Center	Portland	Oregon
United States	University of California-San Diego	San Diego	California
United States	Memorial Hospital	South Bend	Indiana
United States	West Jersey Hospital - Voorhees	Voorhees	New Jersey
United States	Wesley Medical Center	Wichita	Kansas

Sponsors (4)

Lead Sponsor	Collaborator
Daniel Benjamin	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Food and Drug Administration (FDA), Thrasher Research Fund

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Death or Candidiasis	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).; 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)	study day 49
Secondary	Neurodevelopmental Impairment	Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy	18-22 months corrected gestational age
Secondary	Candidiasis	Definite or probable	prior to hospital discharge, up to 15 ½ months
Secondary	Stage II or Higher Necrotizing Enterocolitis		prior to hospital discharge, up to 15 ½ months
Secondary	Focal Intestinal Perforation		prior to hospital discharge, up to 15 ½ months
Secondary	Chronic Lung Disease		36 weeks corrected gestational age
Secondary	Patent Ductus Arterious Requiring Surgical Ligation		prior to hospital discharge, up to 15 ½ months
Secondary	Periventricular Leukomalacia		prior to hospital discharge, up to 15 ½ months
Secondary	Retinopathy of Prematurity Requiring Laser Surgery		prior to hospital discharge, up to 15 ½ months
Secondary	Length of Hospitalization		prior to hospital discharge, up to 15 ½ months
Secondary	Positive Bacterial Infection From a Sterile Site		prior to hospital discharge, up to 15 ½ months
Secondary	Intraventricular Hemorrhage	Grade 3 or 4	prior to hospital discharge, up to 15 ½ months