Candidiasis
Conditions
Keywords
Candida, Neonate, Fluconazole, Prophylaxis, Colonization, Resistance
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.
Interventions
DRUGfluconazole
6mg/kg IV/PO twice weekly for a total of up to 12-13 doses
DRUGplacebo
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
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Thrasher Research Fund
Food and Drug Administration (FDA)
Daniel Benjamin
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Days to 5 Days
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death or Candidiasis | study day 49 | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Candidiasis | prior to hospital discharge, up to 15 ½ months | Definite or probable |
| 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 | — |
| Neurodevelopmental Impairment | 18-22 months corrected gestational age | Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy |
| 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 | prior to hospital discharge, up to 15 ½ months | Grade 3 or 4 |
| Periventricular Leukomalacia | prior to hospital discharge, up to 15 ½ months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fluconazole fluconazole 6mg/kg IV or PO twice weekly for 6 weeks
fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses | 188 |
| Placebo Placebo IV or PO twice weekly for 6 weeks
placebo: 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 14 doses | 173 |
| Total | 361 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Main Study | Death | 33 | 32 |
| Main Study | Enrolled in error; ineligible | 1 | 0 |
| Main Study | Physician Decision | 2 | 0 |
| Main Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Total | Placebo | Fluconazole |
|---|---|---|---|
| Age, Continuous | 3 days | 3 days | 3 days |
| birth weight | 650 grams | 640 grams | 653 grams |
| Ethnicity (NIH/OMB) Hispanic or Latino | 46 Participants | 25 Participants | 21 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 315 Participants | 148 Participants | 167 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gestational Age at Birth | 25 weeks | 25 weeks | 25 weeks |
| Race (NIH/OMB) American Indian or Alaska Native | 17 Participants | 7 Participants | 10 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 196 Participants | 94 Participants | 102 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 143 Participants | 70 Participants | 73 Participants |
| Sex: Female, Male Female | 207 Participants | 98 Participants | 109 Participants |
| Sex: Female, Male Male | 154 Participants | 75 Participants | 79 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 188 | 1 / 173 |
| serious Total, serious adverse events | 83 / 188 | 68 / 173 |
Outcome results
Primary
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)
Time frame: study day 49
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Death or Candidiasis | 31 participants |
| Placebo | Death or Candidiasis | 37 participants |
Secondary
Candidiasis
Definite or probable
Time frame: prior to hospital discharge, up to 15 ½ months
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Candidiasis | 8 participants |
| Placebo | Candidiasis | 19 participants |
Secondary
Chronic Lung Disease
Time frame: 36 weeks corrected gestational age
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Chronic Lung Disease | 114 participants |
| Placebo | Chronic Lung Disease | 93 participants |
Secondary
Focal Intestinal Perforation
Time frame: prior to hospital discharge, up to 15 ½ months
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Focal Intestinal Perforation | 16 participants |
| Placebo | Focal Intestinal Perforation | 9 participants |
Secondary
Intraventricular Hemorrhage
Grade 3 or 4
Time frame: prior to hospital discharge, up to 15 ½ months
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Intraventricular Hemorrhage | 33 participants |
| Placebo | Intraventricular Hemorrhage | 31 participants |
Secondary
Length of Hospitalization
Time frame: prior to hospital discharge, up to 15 ½ months
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fluconazole | Length of Hospitalization | 113 days |
| Placebo | Length of Hospitalization | 107 days |
Secondary
Neurodevelopmental Impairment
Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy
Time frame: 18-22 months corrected gestational age
Population: Attended the follow-up visit and had complete data on composite endpoint
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Neurodevelopmental Impairment | 27 participants |
| Placebo | Neurodevelopmental Impairment | 23 participants |
Secondary
Patent Ductus Arterious Requiring Surgical Ligation
Time frame: prior to hospital discharge, up to 15 ½ months
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Patent Ductus Arterious Requiring Surgical Ligation | 46 participants |
| Placebo | Patent Ductus Arterious Requiring Surgical Ligation | 43 participants |
Secondary
Periventricular Leukomalacia
Time frame: prior to hospital discharge, up to 15 ½ months
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Periventricular Leukomalacia | 10 participants |
| Placebo | Periventricular Leukomalacia | 6 participants |
Secondary
Positive Bacterial Infection From a Sterile Site
Time frame: prior to hospital discharge, up to 15 ½ months
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Positive Bacterial Infection From a Sterile Site | 109 participants |
| Placebo | Positive Bacterial Infection From a Sterile Site | 100 participants |
Secondary
Retinopathy of Prematurity Requiring Laser Surgery
Time frame: prior to hospital discharge, up to 15 ½ months
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Retinopathy of Prematurity Requiring Laser Surgery | 29 participants |
| Placebo | Retinopathy of Prematurity Requiring Laser Surgery | 25 participants |
Secondary
Stage II or Higher Necrotizing Enterocolitis
Time frame: prior to hospital discharge, up to 15 ½ months
Population: Modified intent-to-treat; only subjects who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fluconazole | Stage II or Higher Necrotizing Enterocolitis | 25 participants |
| Placebo | Stage II or Higher Necrotizing Enterocolitis | 23 participants |