Clinical trial NCT00734539: Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight
Official title: Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants < 750 Grams Birth
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Candidiasis
Keywords: Candida
Neonate
Fluconazole
Prophylaxis
Colonization
Resistance
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Thrasher Research Fund
name: Food and Drug Administration (FDA)
First posted: 2008-08-14
Enrollment: 362
Sex: ALL
Minimum age (years): 2
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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

Primary outcomes:
measure: Death or Candidiasis
timeFrame: study day 49
Secondary outcomes:
measure: Neurodevelopmental Impairment
timeFrame: 18-22 months corrected gestational age
measure: Candidiasis
timeFrame: prior to hospital discharge, up to 15 ½ months
measure: Stage II or Higher Necrotizing Enterocolitis
timeFrame: prior to hospital discharge, up to 15 ½ months
measure: Focal Intestinal Perforation
timeFrame: prior to hospital discharge, up to 15 ½ months
measure: Chronic Lung Disease
timeFrame: 36 weeks corrected gestational age
measure: Patent Ductus Arterious Requiring Surgical Ligation
timeFrame: prior to hospital discharge, up to 15 ½ months
measure: Periventricular Leukomalacia
timeFrame: prior to hospital discharge, up to 15 ½ months
measure: Retinopathy of Prematurity Requiring Laser Surgery
timeFrame: prior to hospital discharge, up to 15 ½ months
measure: Length of Hospitalization
timeFrame: prior to hospital discharge, up to 15 ½ months
measure: Positive Bacterial Infection From a Sterile Site
timeFrame: prior to hospital discharge, up to 15 ½ months
measure: Intraventricular Hemorrhage
timeFrame: prior to hospital discharge, up to 15 ½ months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Little Rock
country: United States
facility: Arkansas Childrens Hospital
state: Arkansas
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Diego
country: United States
facility: University of California-San Diego
state: California
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: Baptist Medical Center
state: Florida
city: Jacksonville
country: United States
facility: Shands Jacksonville Medical Center
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Indianapolis
country: United States
facility: Riley Hospital
state: Indiana
city: South Bend
country: United States
facility: Memorial Hospital
state: Indiana
city: Wichita
country: United States
facility: Wesley Medical Center
state: Kansas
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University School of Medicine
state: Louisiana
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota, Fairview Medical Center
state: Minnesota
city: Las Vegas
country: United States
facility: University of Nevada School of Medicine
state: Nevada
city: Voorhees
country: United States
facility: West Jersey Hospital - Voorhees
state: New Jersey
city: Brooklyn
country: United States
facility: Brookdale University Medical Center
state: New York
city: Brooklyn
country: United States
facility: Kings County Hospital Center
state: New York
city: Brooklyn
country: United States
facility: SUNY Dowstate Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greenville
country: United States
facility: Pitt County Memorial Hospital
state: North Carolina
city: Akron
country: United States
facility: Akron Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences Center
state: Oregon
city: Philadelphia
country: United States
facility: Pennsylvania Hospital
state: Pennsylvania
city: Memphis
country: United States
facility: University of Tennessee
state: Tennessee
city: Dallas
country: United States
facility: Parkland Memorial Hospital
state: Texas
city: Fort Worth
country: United States
facility: Cooks Children's Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital/Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: University of Texas - Houston
state: Texas
Study officials:
affiliation: Duke Univerisity Medical Center, Duke Clinical Research Institute
name: Daniel K Benjamin, MD MPH PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Benjamin DK Jr, Hudak ML, Duara S, Randolph DA, Bidegain M, Mundakel GT, Natarajan G, Burchfield DJ, White RD, Shattuck KE, Neu N, Bendel CM, Kim MR, Finer NN, Stewart DL, Arrieta AC, Wade KC, Kaufman DA, Manzoni P, Prather KO, Testoni D, Berezny KY, Smith PB; Fluconazole Prophylaxis Study Team. Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA. 2014 May 7;311(17):1742-9. doi: 10.1001/jama.2014.2624.
citation: Moran C, Smith PB, Cohen-Wolkowiez M, Benjamin DK Jr. Clinical trial design in neonatal pharmacology: effect of center differences, with lessons from the Pediatric Oncology Cooperative Research experience. Clin Pharmacol Ther. 2009 Dec;86(6):589-91. doi: 10.1038/clpt.2009.175.