Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants Less Than 750 Grams Birthweight
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| ClinicalTrials.gov Identifier: NCT00734539 |
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Recruitment Status :
Completed
First Posted : August 14, 2008
Results First Posted : July 17, 2014
Last Update Posted : March 1, 2019
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Candidiasis | Drug: fluconazole Drug: placebo | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 362 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Prevention |
| Official Title: | Fluconazole Prophylaxis for the Prevention of Candidiasis in Infants < 750 Grams Birth |
| Study Start Date : | November 2008 |
| Actual Primary Completion Date : | December 2011 |
| Actual Study Completion Date : | April 2013 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: 1
fluconazole 6mg/kg IV or PO twice weekly for 6 weeks
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Drug: fluconazole
6mg/kg IV/PO twice weekly for a total of up to 12-13 doses
Other Name: Diflucan |
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Placebo Comparator: 2
Placebo IV or PO twice weekly for 6 weeks
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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 |
- Death or Candidiasis [ Time Frame: study day 49 ]
The primary endpoint for the study is death or candidiasis.
- Death prior to study day 49.
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Candidiasis prior to study day 49
- Definite: 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 therapy
AND both:
ii. Thrombocytopenia <150,000/mm3 iii. Positive Candida culture from nonsterile site (ETS, bag urine)
- Neurodevelopmental Impairment [ Time Frame: 18-22 months corrected gestational age ]Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy
- Candidiasis [ Time Frame: prior to hospital discharge, up to 15 ½ months ]Definite or probable
- Stage II or Higher Necrotizing Enterocolitis [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
- Focal Intestinal Perforation [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
- Chronic Lung Disease [ Time Frame: 36 weeks corrected gestational age ]
- Patent Ductus Arterious Requiring Surgical Ligation [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
- Periventricular Leukomalacia [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
- Retinopathy of Prematurity Requiring Laser Surgery [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
- Length of Hospitalization [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
- Positive Bacterial Infection From a Sterile Site [ Time Frame: prior to hospital discharge, up to 15 ½ months ]
- Intraventricular Hemorrhage [ Time Frame: prior to hospital discharge, up to 15 ½ months ]Grade 3 or 4
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| Ages Eligible for Study: | up to 5 Days (Child) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00734539
Show 33 study locations
| Principal Investigator: | Daniel K Benjamin, MD MPH PhD | Duke Univerisity Medical Center, Duke Clinical Research Institute |
| Responsible Party: | Daniel Benjamin, Professor of Pediatrics, Duke University |
| ClinicalTrials.gov Identifier: | NCT00734539 |
| Other Study ID Numbers: |
Pro00001538 1R01HD057956-01 ( U.S. NIH Grant/Contract ) Pro00017720 ( Other Identifier: DUMC ) |
| First Posted: | August 14, 2008 Key Record Dates |
| Results First Posted: | July 17, 2014 |
| Last Update Posted: | March 1, 2019 |
| Last Verified: | February 2019 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| 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). |
| Supporting Materials: |
Study Protocol Statistical Analysis Plan (SAP) Clinical Study Report (CSR) |
| Time Frame: | DASH was published in December 2018. DASH is managed by NICHD for future research. |
| Access Criteria: | DASH is managed by NICHD. |
| URL: | https://dash.nichd.nih.gov/Study/19811 |
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Candida Neonate Fluconazole |
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