Immediate vs. Deferred Empirical Antifungal Treatment With Voriconazole In Neutropenic Patients (IDEA)

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
810 participants screened; 81 assigned to immediate voriconazole treatment and 66 to deferred voriconazole treatment. Study should be considered a pilot study; planned sample size (n=200) was not based on statistical power considerations.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Screening phase started with cytoreductive treatment; screening phase ended at onset of fever or if reconstitution of leukocytes to >1000 per microliter (1000/uL) or neutrophils to >500/uL. Randomization occurred within 18 hours after onset of fever (if febrile or had positive polymerase chain reaction (PCR) assay prior to onset of fever).

Reporting Groups

	Description
Immediate Voriconazole	Voriconazole intravenous (IV) loading dose of 6 milligrams per kilogram (mg/kg) every 12 hours on Day 1 for the first 2 doses followed by 4 mg/kg IV every 12 hours (maintenance dose) for at least 4 days (up to Day 5). Continued treatment with oral (PO) voriconazole 200 mg twice a day (BID) through Day 28. Treatment ended if the participant was afebrile (< 38.0 degrees Celsius [C]) for 7 days with neutrophil counts < 500 per microliter (500/uL) or if participant was afebrile (< 38.0 degrees C) for 2 days with neutrophil counts > 500/uL.
Deferred Voriconazole Treatment	Placebo IV loading dose of 6 mg/kg every 12 hours on Day 1 for the first 2 doses followed by 4 mg/kg IV every 12 hours (maintenance dose) for at least 4 days (up to Day 5). On Day 5, voriconazole IV loading dose of 6 mg/kg every 12 hours for at least 4 days (up to Day 9). Continued treatment with PO voriconazole 200 mg BID through Day 28. Treatment ended if the participant was afebrile (< 38.0 degrees C) for 7 days with neutrophil counts < 500/uL or if participant was afebrile (< 38.0 degrees C) for 2 days with neutrophil counts > 500/uL.

Participant Flow:   Overall Study

	Immediate Voriconazole	Deferred Voriconazole Treatment
STARTED	81	66
COMPLETED	47	34
NOT COMPLETED	34	32
Death	5	2
Adverse Event	8	6
Lack of Efficacy	5	4
Withdrawal by Subject	3	4
Laboratory abnormality	1	2
Unspecified	12	14

Reporting Groups

	Description
Immediate Voriconazole	Voriconazole intravenous (IV) loading dose of 6 milligrams per kilogram (mg/kg) every 12 hours on Day 1 for the first 2 doses followed by 4 mg/kg IV every 12 hours (maintenance dose) for at least 4 days (up to Day 5). Continued treatment with oral (PO) voriconazole 200 mg twice a day (BID) through Day 28. Treatment ended if the participant was afebrile (< 38.0 degrees Celsius [C]) for 7 days with neutrophil counts < 500 per microliter (500/uL) or if participant was afebrile (< 38.0 degrees C) for 2 days with neutrophil counts > 500/uL.
Deferred Voriconazole Treatment	Placebo IV loading dose of 6 mg/kg every 12 hours on Day 1 for the first 2 doses followed by 4 mg/kg IV every 12 hours (maintenance dose) for at least 4 days (up to Day 5). On Day 5, voriconazole IV loading dose of 6 mg/kg every 12 hours for at least 4 days (up to Day 9). Continued treatment with PO voriconazole 200 mg BID through Day 28. Treatment ended if the participant was afebrile (< 38.0 degrees C) for 7 days with neutrophil counts < 500/uL or if participant was afebrile (< 38.0 degrees C) for 2 days with neutrophil counts > 500/uL.
Total	Total of all reporting groups

Baseline Measures

	Immediate Voriconazole	Deferred Voriconazole Treatment	Total
Number of Participants   [units: participants]	81	66	147
Age, Customized   [units: participants]
Between 18 and 44 years	29	17	46
Between 45 and 64 years	31	35	66
>=65 years	21	14	35
Gender   [units: participants]
Female	39	29	68
Male	42	37	79
Race/Ethnicity, Customized   [units: participants]
White	81	65	146
Other	0	1	1
Weight   [units: kilograms (kg)] Mean ( Full Range )	77.1     ( 42.0 to 112.5 )	79.2     ( 45.3 to 152.0 )	78.1     ( 42.0 to 152.0 )
Height   [units: centimeters (cm)] Mean ( Full Range )	172.1     ( 150.0 to 196.0 )	171.9     ( 153.0 to 198.0 )	172.0     ( 150.0 to 198.0 )

1.  Primary:

Number of Participants With Proven or Probable Invasive Fungal Infections (IFI): Complete Case Analysis   [ Time Frame: Day 2 through Day 28 ]

2.  Secondary:

Number of Participants With Defervescence Day 5 (4 Days After Initiation of Study Treatment)   [ Time Frame: Day 5 (96 hours through 120 hours after start of study treatment) ]

3.  Secondary:

Number of Participants With Defervescence Day 9 (8 Days After Initiation of Study Treatment)   [ Time Frame: Day 9 (192 hours through 216 hours after start of study treatment) ]

4.  Secondary:

Time to Continuous Defervescence   [ Time Frame: Day 2 through Day 28 ]

5.  Secondary:

Number of Participants Per Reason for Lack of Defervescence   [ Time Frame: Day 2 through Day 28 ]

6.  Secondary:

Number of Participants That Died on or Before Day 28 (Mortality)   [ Time Frame: Day 2 through Day 28 ]

7.  Secondary:

Time to Negative Panfungal Polymerase Chain Reaction (PCR)   [ Time Frame: Day 2 through Day 28 ]

8.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association of Positive PCR Assessments With Achievement of Continuous Defervescence (Yes)   [ Time Frame: Day 2 through Day 28 ]

9.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association of Positive PCR Assessments With Achievement of Continuous Defervescence (No)   [ Time Frame: Day 2 through Day 28 ]

10.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Age   [ Time Frame: Day 2 through Day 28 ]

11.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Gender   [ Time Frame: Day 2 through Day 28 ]

12.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Primary Underlying Neoplastic Disease   [ Time Frame: Day 2 through Day 28 ]

13.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Planned Allogeneic Transplants   [ Time Frame: Day 2 through Day 28 ]

14.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Concomitant Fluconazole   [ Time Frame: Day 2 through Day 28 ]

15.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Neutrophil Count >500 uL   [ Time Frame: Day 2 through Day 28 ]

16.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With C-reactive Protein Level >1.25 Times the Upper Limit of Normal (x ULN)   [ Time Frame: Day 2 through Day 28 ]

17.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified   [ Time Frame: Day 2 through Day 28 ]

18.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified (Aspergillus Spp=Yes)   [ Time Frame: Day 2 through Day 28 ]

19.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Proven or Probable IFI (Complete Cases) Between Day 2 and Day 28   [ Time Frame: Day 2 through Day 28 ]

20.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence Day 5 (4 Days After Initiation of Study Treatment)   [ Time Frame: Day 5 (96 hours through 120 hours after start of study treatment) ]

21.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence (Yes) by Day 9 (8 Days After Initiation of Study Treatment)   [ Time Frame: Day 2 through Day 9 (192 hours through 216 hours after start of study treatment) ]

22.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence (No) by Day 9 (8 Days After Initiation of Study Treatment)   [ Time Frame: Day 2 through Day 9 (192 hours through 216 hours after start of study treatment) ]

23.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Time to Defervescence   [ Time Frame: Day 2 through Day 28 ]

24.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence (No)   [ Time Frame: Day 2 through Day 28 ]

25.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence: Unknown Infection (Yes)   [ Time Frame: Day 2 through Day 28 ]

26.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Mortality by Day 28 (Alive)   [ Time Frame: Day 2 through Day 28 ]

27.  Secondary:

Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Mortality by Day 28 (Died)   [ Time Frame: Day 2 through Day 28 ]

28.  Secondary:

Number of Participants Assessed as Needing Further Antineoplastic Therapy as Planned   [ Time Frame: Day 28 ]

29.  Secondary:

Number of Participants With Reasons Why Antineoplastic Therapy Not Continued as Planned   [ Time Frame: Day 28 ]