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

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

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.

Study Overview

• Status: Completed
• Conditions: Candidiasis
• Intervention / Treatment: Drug: fluconazole; Drug: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 362
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • University of Arkansas for Medical Sciences
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Childrens Hospital
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Diego, California, United States, 92103
      • University of California-San Diego
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Jacksonville, Florida, United States, 32209
      • Baptist Medical Center
    • Jacksonville, Florida, United States, 32209
      • Shands Jacksonville Medical Center
    • Miami, Florida, United States, 33136
      • University of Miami
  • Indiana
    • Indianapolis, Indiana, United States, 46601
      • Riley Hospital
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Wesley Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kosair Children's Hospital
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University School of Medicine
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, Fairview Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • University of Nevada School of Medicine
  • New Jersey
    • Voorhees, New Jersey, United States, 08043
      • West Jersey Hospital - Voorhees
  • New York
    • Brooklyn, New York, United States, 11203
      • Brookdale University Medical Center
    • Brooklyn, New York, United States, 11203
      • Kings County Hospital Center
    • Brooklyn, New York, United States, 11203
      • SUNY Dowstate Medical Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 27834
      • Pitt County Memorial Hospital
  • Ohio
    • Akron, Ohio, United States, 44313
      • Akron Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97201
      • Oregon Health Sciences Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Pennsylvania Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38130
      • University of Tennessee
  • Texas
    • Dallas, Texas, United States, 75235
      • Parkland Memorial Hospital
    • Fort Worth, Texas, United States, 76104
      • Cooks Children's Medical Center
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030
      • Texas Children's Hospital/Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • University of Texas - Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 days to 5 days (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; fluconazole 6mg/kg IV or PO twice weekly for 6 weeks	Drug: fluconazole; 6mg/kg IV/PO twice weekly for a total of up to 12-13 doses; Other Names: Diflucan
Placebo Comparator: 2; Placebo IV or PO twice weekly for 6 weeks	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death or Candidiasis	The primary endpoint for the study is death or candidiasis.; Death prior to study day 49.; Candidiasis prior to study day 49Definite: 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 therapyAND both:ii. Thrombocytopenia <150,000/mm3 iii. Positive Candida culture from nonsterile site (ETS, bag urine)	study day 49

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neurodevelopmental Impairment	Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy	18-22 months corrected gestational age
Candidiasis	Definite or probable	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
Patent Ductus Arterious Requiring Surgical Ligation		prior to hospital discharge, up to 15 ½ months
Periventricular Leukomalacia		prior to hospital discharge, up to 15 ½ months
Retinopathy of Prematurity Requiring Laser Surgery		prior to hospital discharge, up to 15 ½ months
Length of Hospitalization		prior to hospital discharge, up to 15 ½ months
Positive Bacterial Infection From a Sterile Site		prior to hospital discharge, up to 15 ½ months
Intraventricular Hemorrhage	Grade 3 or 4	prior to hospital discharge, up to 15 ½ months

Collaborators and Investigators

• Sponsor: Daniel Benjamin
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Food and Drug Administration (FDA); Thrasher Research Fund
• Investigators: Principal Investigator: Daniel K Benjamin, MD MPH PhD, Duke Univerisity Medical Center, Duke Clinical Research Institute

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): April 1, 2013

Study Registration Dates

• First Submitted: August 13, 2008
• First Submitted That Met QC Criteria: August 13, 2008
• First Posted (Estimate): August 14, 2008

Study Record Updates

• Last Update Posted (Actual): March 1, 2019
• Last Update Submitted That Met QC Criteria: February 14, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Fluconazole; Resistance; Prophylaxis; Neonate; Candida; Colonization
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Mycoses; Candidiasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Fluconazole
• Other Study ID Numbers: Pro00001538; 1R01HD057956-01 (U.S. NIH Grant/Contract); Pro00017720 (Other Identifier: DUMC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: 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).
• IPD Sharing Time Frame: DASH was published in December 2018. DASH is managed by NICHD for future research.
• IPD Sharing Access Criteria: DASH is managed by NICHD.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No