Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight
3 other identifiers
interventional
362
1 country
33
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Nov 2008
Typical duration for phase_3
33 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 13, 2008
CompletedFirst Posted
Study publicly available on registry
August 14, 2008
CompletedStudy Start
First participant enrolled
November 1, 2008
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 1, 2011
CompletedStudy Completion
Last participant's last visit for all outcomes
April 1, 2013
CompletedResults Posted
Study results publicly available
July 17, 2014
CompletedMarch 1, 2019
February 1, 2019
3.1 years
August 13, 2008
June 17, 2014
February 14, 2019
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Death or Candidiasis
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)
study day 49
Secondary Outcomes (11)
Neurodevelopmental Impairment
18-22 months corrected gestational age
Candidiasis
prior to hospital discharge, up to 15 ½ months
Stage II or Higher Necrotizing Enterocolitis
prior to hospital discharge, up to 15 ½ months
Focal Intestinal Perforation
prior to hospital discharge, up to 15 ½ months
Chronic Lung Disease
36 weeks corrected gestational age
- +6 more secondary outcomes
Study Arms (2)
1
EXPERIMENTALfluconazole 6mg/kg IV or PO twice weekly for 6 weeks
2
PLACEBO COMPARATORPlacebo IV or PO twice weekly for 6 weeks
Interventions
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
Eligibility Criteria
You may qualify if:
- 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
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Daniel Benjaminlead
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)collaborator
- Thrasher Research Fundcollaborator
- Food and Drug Administration (FDA)collaborator
Study Sites (33)
University of Alabama at Birmingham
Birmingham, Alabama, 35233, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, 72202, United States
Arkansas Childrens Hospital
Little Rock, Arkansas, 72205, United States
Children's Hospital of Orange County
Orange, California, 92868, United States
University of California-San Diego
San Diego, California, 92103, United States
University of Florida
Gainesville, Florida, 32610, United States
Baptist Medical Center
Jacksonville, Florida, 32209, United States
Shands Jacksonville Medical Center
Jacksonville, Florida, 32209, United States
University of Miami
Miami, Florida, 33136, United States
Riley Hospital
Indianapolis, Indiana, 46601, United States
Memorial Hospital
South Bend, Indiana, 46601, United States
Wesley Medical Center
Wichita, Kansas, 67214, United States
Kosair Children's Hospital
Louisville, Kentucky, 40202, United States
Tulane University School of Medicine
New Orleans, Louisiana, 70112, United States
Wayne State University
Detroit, Michigan, 48201, United States
University of Minnesota, Fairview Medical Center
Minneapolis, Minnesota, 55455, United States
University of Nevada School of Medicine
Las Vegas, Nevada, 89109, United States
West Jersey Hospital - Voorhees
Voorhees Township, New Jersey, 08043, United States
Brookdale University Medical Center
Brooklyn, New York, 11203, United States
Kings County Hospital Center
Brooklyn, New York, 11203, United States
SUNY Dowstate Medical Center
Brooklyn, New York, 11203, United States
Columbia University Medical Center
New York, New York, 10032, United States
Duke University Medical Center
Durham, North Carolina, 27705, United States
Pitt County Memorial Hospital
Greenville, North Carolina, 27834, United States
Akron Children's Hospital
Akron, Ohio, 44313, United States
Oregon Health Sciences Center
Portland, Oregon, 97201, United States
Pennsylvania Hospital
Philadelphia, Pennsylvania, 19107, United States
University of Tennessee
Memphis, Tennessee, 38130, United States
Parkland Memorial Hospital
Dallas, Texas, 75235, United States
Cooks Children's Medical Center
Fort Worth, Texas, 76104, United States
University of Texas Medical Branch
Galveston, Texas, 77555, United States
Texas Children's Hospital/Baylor College of Medicine
Houston, Texas, 77030, United States
University of Texas - Houston
Houston, Texas, 77030, United States
Related Publications (2)
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.
PMID: 24794367DERIVEDMoran 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.
PMID: 19915602DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Daniel K. Benjamin Jr
- Organization
- Duke Univiersity Medical Center
Study Officials
- PRINCIPAL INVESTIGATOR
Daniel K Benjamin, MD MPH PhD
Duke Univerisity Medical Center, Duke Clinical Research Institute
Publication Agreements
- PI is Sponsor Employee
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- QUADRUPLE
- Who Masked
- PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
- Purpose
- PREVENTION
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR INVESTIGATOR
- PI Title
- Professor of Pediatrics
Study Record Dates
First Submitted
August 13, 2008
First Posted
August 14, 2008
Study Start
November 1, 2008
Primary Completion
December 1, 2011
Study Completion
April 1, 2013
Last Updated
March 1, 2019
Results First Posted
July 17, 2014
Record last verified: 2019-02
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, SAP, CSR
- Time Frame
- DASH was published in December 2018. DASH is managed by NICHD for future research.
- Access Criteria
- DASH is managed by NICHD.
In December 2018, after receiving IRB's approval, the team submitted the de-identified study dataset and redacted study documents to the NICHD Data and Specimen Hub (DASH).