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

Condition(s) targeted: Candidiasis; Neonate

Intervention: fluconazole (Drug); placebo (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Duke University

Official(s) and/or principal investigator(s):
Daniel K Benjamin, MD MPH PhD, Principal Investigator, Affiliation: Duke Univerisity Medical Center, Duke Clinical Research Institute

Overall contact:
Daniel K Benjamin, MD MPH PhD, Phone: 9196688295, Email: danny.benjamin@duke.edu

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.

This will be accomplished by randomizing 360 neonates, with a birthweight <750g, at 20 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.

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

Study design: Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Primary outcome: Death or candidiasis

Secondary outcome:

Neurodevelopmental impairment

Positive bacterial culture from sterile site

candidiasis

positive Candida culture from non-sterile site

stage II or higher necrotizing enterocolitis

focal intestinal perforation

chronic lung disease

patent ductus arteriosus requiring surgical ligation

periventricular leukomalacia

retinopathy of prematurity requiring laser surgery

length of hospitalization

Candida colonization

Development of resistance among Candida isolates

drug toxicity

Minimum age: N/A. Maximum age: 5 Days. Gender(s): Both.

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

Daniel K Benjamin, MD MPH PhD, Phone: 9196688295, Email: danny.benjamin@duke.edu

University of Alabama at Birmingham, Birmingham, Alabama, United States; Recruiting
Claire Roane, Phone: 205-934-0095
David Randolph, Principal Investigator

University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States; Recruiting
Lee Howard, Phone: 501-364-1418
Ashley Ross, Principal Investigator

Arkansas Childrens Hospital, Little Rock, Arkansas, United States; Not yet recruiting
Lee Howard, Phone: 501-364-1418
Ashley Ross, Principal Investigator

Children's Hospital of Orange County, Orange, California, United States; Recruiting
Kathy Shea, Phone: 714-289-4791
Antonio Arrieta, Principal Investigator

University of California-San Diego, San Diego, California, United States; Recruiting
Wade Rich, Phone: 619-543-5375
Neil Finer, Principal Investigator

University of Florida, Gainesville, Florida, United States; Recruiting
Cindy Miller, Phone: 352-273-8979
David Burchfield, Principal Investigator

Baptist Medical Center, Jacksonville, Florida, United States; Recruiting
Kimberly Barnette, Phone: 904-244-5566
Mark Hudak, Principal Investigator

Shands Jacksonville Medical Center, Jacksonville, Florida, United States; Recruiting
Kimberly Barnette, Phone: 904-244-5023
Mark Hudak, Principal Investigator

University of Miami, Miami, Florida, United States; Recruiting
Karina Lifschitz, Phone: 305-585-6408
Shahnaz Duara, Principal Investigator

Riley Hospital, Indianapolis, Indiana, United States; Recruiting
Leslie Wison, Phone: 317-274-8255
Brenda Poindexter, Principal Investigator

Memorial Hospital, South Bend, Indiana, United States; Recruiting
Mashelle Manhaut, Phone: 574-284-3048
Robert White, Principal Investigator

Wesley Medical Center, Wichita, Kansas, United States; Not yet recruiting
Paula Delmore, Phone: 316-962-8580
Barry Bloom, Principal Investigator

Kosair Children's Hospital, Louisville, Kentucky, United States; Recruiting
Carrrie Schanie, Phone: 502-629-6802
Daniel Stewart, Principal Investigator

Tulane University School of Medicine, New Orleans, Louisiana, United States; Recruiting
Jane Reynolds, Phone: 504-988-2214
Phillip Gordon, Principal Investigator

Wayne State University, Detroit, Michigan, United States; Recruiting
Melanie Lulic, Phone: 373-745-1436
Seetha Shankaran, Principal Investigator

University of Minnesota, Fairview Medical Center, Minneapolis, Minnesota, United States; Recruiting
Marla Mills, Phone: 612-626-3250
Catherine Bendel, Principal Investigator

University of Nevada School of Medicine, Las Vegas, Nevada, United States; Recruiting
Ineaada Jack, Phone: 702-944-2816
Echezona Ezeanolue, Principal Investigator

West Jersey Hospital - Voorhees, Voorhees, New Jersey, United States; Recruiting
Christine Catts, Phone: 856-325-3952
Paresh Pandit, Principal Investigator

SUNY Dowstate Medical Center, Brooklyn, New York, United States; Recruiting
Sara Higgerson, Phone: 347-374-1506
Agnes Perenyi, Principal Investigator

Kings County Hospital Center, Brooklyn, New York, United States; Recruiting
Subhatra Limbu, Phone: 718-245-4753
Gratias Mundakel, Principal Investigator

Brookdale University Medical Center, Brooklyn, New York, United States; Recruiting
Chika Iwuchukwu, Phone: 718-240-5668
Roger Kim, Principal Investigator

Columbia University Medical Center, New York, New York, United States; Recruiting
Erin Humel-Amadori, Phone: 212-305-3677
Natalie Neu, Principal Investigator

Duke University Medical Center, Durham, North Carolina, United States; Recruiting
Wendy Veasey, Phone: 919-681-5859
Margarita Bidegain, Principal Investigator

ECU Brody School of Medicine, Greenville, North Carolina, United States; Recruiting
sherry Moseley, Phone: 252-744-5368
James Cummings, Principal Investigator

Akron Children's Hospital, Akron, Ohio, United States; Recruiting
Judy Ohlinger, Phone: 330-543-8750
Anand Kantak, Principal Investigator

Oregon Health Sciences Center, Portland, Oregon, United States; Recruiting
Gretchen Barron, Phone: 503-494-7601
Robert Schelonka, Principal Investigator

Pennsylvania Hospital, Philadelphia, Pennsylvania, United States; Recruiting
Toni Mancini, Phone: 215-829-7118
Kelly Wade, Principal Investigator

University of Tennessee, Memphis, Tennessee, United States; Recruiting
Gayle Gower, Phone: 901-448-1823
Ramasubbareddy Dhanireddy, Principal Investigator

Parkland Memorial Hospital, Dallas, Texas, United States; Recruiting
Deborah McElroy, Phone: 214-456-8792
Pablo Sanchez, Principal Investigator

Cooks Children's Medical Center, Fort Worth, Texas, United States; Recruiting
Trudy Morris, Phone: 682-885-6718
Jonathan Nedrelow, Principal Investigator

University of Texas Medical Branch, Galveston, Texas, United States; Recruiting
Kristin Pollock, Phone: 409-772-5278
Karen Shattuck, Principal Investigator

University of Texas - Houston, Houston, Texas, United States; Recruiting
Peggy Robichaux, Phone: 713-500-5071
Kathleen Kennedy, Principal Investigator

Texas Children's Hospital/Baylor College of Medicine, Houston, Texas, United States; Recruiting
Inge Wieser, Phone: 832-824-4216
Mahan Venkatesh, Principal Investigator

Starting date: November 2008
Last updated: May 11, 2010