Fluconazole Prophylaxis for the Prevention of Candidiasis... | NCT00734539

ID	Type	Description	Link
1R01HD057956-01	U.S. NIH Grant/Contract		View source
Pro00017720	Other Identifier	DUMC

Name	Class
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)	NIH
Thrasher Research Fund	OTHER
Food and Drug Administration (FDA)	FED

Description Module

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.

Label	Type	Description	Intervention Names
1	Experimental	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks	Drug: fluconazole
2	Placebo Comparator	Placebo IV or PO twice weekly for 6 weeks	Drug: placebo

Name	Type	Description	Arm Group Labels	Other Names
fluconazole	Drug	6mg/kg IV/PO twice weekly for a total of up to 12-13 doses	1

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 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)	study day 49

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

Name	Affiliation	Role
Daniel K Benjamin, MD MPH PhD	Duke Univerisity Medical Center, Duke Clinical Research Institute	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
University of Alabama at Birmingham		Birmingham	Alabama	35233	United States
University of Arkansas for Medical Sciences

PubMed Identifier	Type	Citation	Retractions
24794367	Derived	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.
19915602

ID	Title	Description
FG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
FG001	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

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Death or Candidiasis

The primary endpoint for the study is death or candidiasis.

Death prior to study day 49.
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)

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

study day 49

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000188 OG001173

Title

Denominators

Categories

Title	Measurements
	OG00031 OG00137

Secondary

Neurodevelopmental Impairment

Bayley-III cognition composite score of less than 70, blindness, deafness, or cerebral palsy

Attended the follow-up visit and had complete data on composite endpoint

Posted

Number

participants

18-22 months corrected gestational age

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000

Secondary

Candidiasis

Definite or probable

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

prior to hospital discharge, up to 15 ½ months

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000

Secondary

Stage II or Higher Necrotizing Enterocolitis

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

prior to hospital discharge, up to 15 ½ months

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000

Secondary

Focal Intestinal Perforation

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

prior to hospital discharge, up to 15 ½ months

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000

Secondary

Chronic Lung Disease

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

36 weeks corrected gestational age

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000

Secondary

Patent Ductus Arterious Requiring Surgical Ligation

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

prior to hospital discharge, up to 15 ½ months

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000

Secondary

Periventricular Leukomalacia

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

prior to hospital discharge, up to 15 ½ months

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000

Secondary

Retinopathy of Prematurity Requiring Laser Surgery

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

prior to hospital discharge, up to 15 ½ months

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000

Secondary

Length of Hospitalization

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Median

Inter-Quartile Range

days

prior to hospital discharge, up to 15 ½ months

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
OG001	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

Units	Counts
Participants	OG000

Secondary

Positive Bacterial Infection From a Sterile Site

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

prior to hospital discharge, up to 15 ½ months

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6mg/kg IV/PO twice weekly for a total of up to 12-13 doses
OG001	Placebo	Placebo IV or PO twice weekly for 6 weeks placebo: normal saline (IV) or 3 parts Ora Plus oral suspension vehicle and 1 part simethicone suspension (PO): will be given twice weekly for a total of up to 12-13 doses

Units	Counts
Participants	OG000

Secondary

Intraventricular Hemorrhage

Grade 3 or 4

Modified intent-to-treat; only subjects who received at least one dose of study drug.

Posted

Number

participants

prior to hospital discharge, up to 15 ½ months

ID	Title	Description
OG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6mg/kg IV/PO twice weekly for a total of up to 12-13 doses
OG001	Placebo	Placebo IV or PO twice weekly for 6 weeks 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

Units	Counts
Participants	OG000

Serious Adverse Events

Term	Organ System	Statistical Information
Necrotising Enterocolitis Neonatal	Gastrointestinal disorders	EG00027 affected188 at risk EG00128 affected173 at risk
Intestinal Perforation	Gastrointestinal disorders	EG00012 affected188 at risk EG0016 affected173 at risk
Meconium Ileus	Gastrointestinal disorders	EG0002 affected188 at risk EG0010 affected173 at risk
Colonic Stenosis	Gastrointestinal disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Ileal Perforation	Gastrointestinal disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Intestinal Ischaemia	Gastrointestinal disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Intestinal Obstruction	Gastrointestinal disorders	EG0000 affected188 at risk EG0011 affected173 at risk
Peritoneal Haemorrhage	Gastrointestinal disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Pneumoperitoneum	Gastrointestinal disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Rectal Prolapse	Gastrointestinal disorders	EG0000 affected188 at risk EG0011 affected173 at risk
Small Intestinal Perforation	Gastrointestinal disorders	EG0000 affected188 at risk EG0011 affected173 at risk
Sepsis Neonatal	Infections and infestations	EG0005 affected188 at risk EG00112 affected173 at risk
Staphylococcal Sepsis	Infections and infestations	EG0004 affected188 at risk EG0010 affected173 at risk
Osteomyelitis	Infections and infestations	EG0001 affected188 at risk EG0011 affected173 at risk
Arthritis Bacterial	Infections and infestations	EG0001 affected188 at risk EG0010 affected173 at risk
Candida Sepsis	Infections and infestations	EG0000 affected188 at risk EG0011 affected173 at risk
Candidiasis	Infections and infestations	EG0000 affected188 at risk EG0011 affected173 at risk
Group B Streptococcus Neonatal Sepsis	Infections and infestations	EG0001 affected188 at risk EG0010 affected173 at risk
Meningitis	Infections and infestations	EG0000 affected188 at risk EG0011 affected173 at risk
Pneumonia Klebsiella	Infections and infestations	EG0000 affected188 at risk EG0011 affected173 at risk
Neonatal Respiratory Failure	Respiratory, thoracic and mediastinal disorders	EG0009 affected188 at risk EG0012 affected173 at risk
Neonatal Respiratory Arrest	Respiratory, thoracic and mediastinal disorders	EG0003 affected188 at risk EG0010 affected173 at risk
Neonatal Respiratory Distress Syndrome	Respiratory, thoracic and mediastinal disorders	EG0001 affected188 at risk EG0012 affected173 at risk
Pneumothorax	Respiratory, thoracic and mediastinal disorders	EG0002 affected188 at risk EG0010 affected173 at risk
Bronchopleural Fistula	Respiratory, thoracic and mediastinal disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Pleural Effusion	Respiratory, thoracic and mediastinal disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Pulmonary Haemorrhage	Respiratory, thoracic and mediastinal disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Intraventricular Haemorrhage Neonatal	Nervous system disorders	EG0002 affected188 at risk EG0013 affected173 at risk
Hydrocephalus	Nervous system disorders	EG0002 affected188 at risk EG0011 affected173 at risk
Convulsion Neonatal	Nervous system disorders	EG0001 affected188 at risk EG0011 affected173 at risk
Cerebral Ventricle Dilatation	Nervous system disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Bradycardia Neonatal	Cardiac disorders	EG0002 affected188 at risk EG0011 affected173 at risk
Neonatal Cardiac Failure	Cardiac disorders	EG0002 affected188 at risk EG0010 affected173 at risk
Cardio-Respiratory Arrest	Cardiac disorders	EG0000 affected188 at risk EG0011 affected173 at risk
Cardio-Respiratory Arrest Neonatal	Cardiac disorders	EG0000 affected188 at risk EG0011 affected173 at risk
Neonatal Hypotension	Vascular disorders	EG0001 affected188 at risk EG0013 affected173 at risk
Deep Vein Thrombosis	Vascular disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Vena Cava Thrombosis	Vascular disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Venous Thrombosis Limb	Vascular disorders	EG0000 affected188 at risk EG0011 affected173 at risk
Neonatal Multi-Organ Failure	General disorders	EG0001 affected188 at risk EG0013 affected173 at risk
Infusion Site Extravasation	General disorders	EG0000 affected188 at risk EG0011 affected173 at risk
Renal Failure	Renal and urinary disorders	EG0001 affected188 at risk EG0011 affected173 at risk
Renal Failure Neonatal	Renal and urinary disorders	EG0001 affected188 at risk EG0011 affected173 at risk
Renal Failure Acute	Renal and urinary disorders	EG0000 affected188 at risk EG0011 affected173 at risk
Patent Ductus Arteriosus	Congenital, familial and genetic disorders	EG0001 affected188 at risk EG0011 affected173 at risk
Ileal Atresia	Congenital, familial and genetic disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Thrombocytopenia	Blood and lymphatic system disorders	EG0001 affected188 at risk EG0011 affected173 at risk
Adrenal Insufficiency	Endocrine disorders	EG0002 affected188 at risk EG0010 affected173 at risk
Endotracheal Intubation Complication	Injury, poisoning and procedural complications	EG0001 affected188 at risk EG0010 affected173 at risk
Gastrointestinal Stoma Complication	Injury, poisoning and procedural complications	EG0000 affected188 at risk EG0011 affected173 at risk
Bilirubin Conjugated Increased	Investigations	EG0001 affected188 at risk EG0010 affected173 at risk
Oxygen Saturation Decreased	Investigations	EG0001 affected188 at risk EG0010 affected173 at risk
Retinopathy of Prematurity	Eye disorders	EG0000 affected188 at risk EG0011 affected173 at risk
Soft Tissue Necrosis	Musculoskeletal and connective tissue disorders	EG0001 affected188 at risk EG0010 affected173 at risk
Skin Necrosis	Skin and subcutaneous tissue disorders	EG0000 affected188 at risk EG0011 affected173 at risk

ID	Term
D009181	Mycoses
D001423	Bacterial Infections and Mycoses
D007239	Infections

ID	Term
D014230	Triazoles
D001393	Azoles
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds

ID	Title	Description
BG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses
BG001	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
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Fluconazole	fluconazole 6mg/kg IV or PO twice weekly for 6 weeks fluconazole: 6 mg/kg PO/IV twice weekly x 14 doses			83	188	1	188
EG001	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			68	173	1	173

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Hyperbilirubinaemia Neonatal	Hepatobiliary disorders				EG0000 events0 affected188 at risk EG0011 events1 affected173 at risk
Gamma-Glutamyltransferase Increased	Investigations				EG0001 events1 affected188 at risk EG0010 events0 affected173 at risk