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

NCT ID: NCT00734539

Last Updated: 2019-03-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 362 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-11-30
• Study Completion Date: 2013-04-30

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.

Conditions

Candidiasis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

1

fluconazole 6mg/kg IV or PO twice weekly for 6 weeks

Group Type: EXPERIMENTAL

fluconazole

Intervention Type: DRUG

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

2

Placebo IV or PO twice weekly for 6 weeks

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

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

Interventions

fluconazole

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

Intervention Type: DRUG

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

Intervention Type: DRUG

Other Intervention Names

Diflucan

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

• Minimum Eligible Age: 2 Days
• Maximum Eligible Age: 5 Days
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

Thrasher Research Fund

OTHER

Sponsor Role: collaborator

Food and Drug Administration (FDA)

FED

Sponsor Role: collaborator

Daniel Benjamin

OTHER

Sponsor Role: lead

Responsible Party

Daniel Benjamin

Professor of Pediatrics

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Daniel K Benjamin, MD MPH PhD

Role: PRINCIPAL_INVESTIGATOR

Duke Univerisity Medical Center, Duke Clinical Research Institute

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States

Arkansas Childrens Hospital

Little Rock, Arkansas, United States

Children's Hospital of Orange County

Orange, California, United States

University of California-San Diego

San Diego, California, United States

University of Florida

Gainesville, Florida, United States

Baptist Medical Center

Jacksonville, Florida, United States

Shands Jacksonville Medical Center

Jacksonville, Florida, United States

University of Miami

Miami, Florida, United States

Riley Hospital

Indianapolis, Indiana, United States

Memorial Hospital

South Bend, Indiana, United States

Wesley Medical Center

Wichita, Kansas, United States

Kosair Children's Hospital

Louisville, Kentucky, United States

Tulane University School of Medicine

New Orleans, Louisiana, United States

Wayne State University

Detroit, Michigan, United States

University of Minnesota, Fairview Medical Center

Minneapolis, Minnesota, United States

University of Nevada School of Medicine

Las Vegas, Nevada, United States

West Jersey Hospital - Voorhees

Voorhees Township, New Jersey, 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

Columbia University Medical Center

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Pitt County Memorial Hospital

Greenville, North Carolina, United States

Akron Children's Hospital

Akron, Ohio, United States

Oregon Health Sciences Center

Portland, Oregon, United States

Pennsylvania Hospital

Philadelphia, Pennsylvania, United States

University of Tennessee

Memphis, Tennessee, United States

Parkland Memorial Hospital

Dallas, Texas, United States

Cooks Children's Medical Center

Fort Worth, Texas, United States

University of Texas Medical Branch

Galveston, Texas, United States

Texas Children's Hospital/Baylor College of Medicine

Houston, Texas, United States

University of Texas - Houston

Houston, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 24794367 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 19915602 (View on PubMed)

Other Identifiers

1R01HD057956-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

Pro00017720

Identifier Type: OTHER

Identifier Source: secondary_id

Pro00001538

Identifier Type: -

Identifier Source: org_study_id