Trial Outcomes & Findings for Immediate vs. Deferred Empirical Antifungal Treatment With Voriconazole In Neutropenic Patients (NCT NCT00150345)

Results Overview

Number of participants with proven (deep tissue infection, fungemia, or endemic fungal infections) or probable IFI (at least 1 host criterion \[fever, body temperature \<36 or \>38 degrees Celsius, graft-versus-host disease, use of corticosteroids\]; and 1 microbiological criterion \[fungal or yeasts\]; or clinical criteria \[abnormal site consistent with infection\]) as defined by European Organization for Research and Treatment of Cancer Mycosis Study Group (EORTC/MSG) criteria. Complete case analysis: must be evaluable until Day 28 or had developed a proven or probable IFI by the final visit.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

147 participants

Primary outcome timeframe

Day 2 through Day 28

Results posted on

2012-01-19

Participant Flow

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.

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).

Participant milestones

Participant milestones
Measure	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.
Overall Study STARTED	81	66
Overall Study COMPLETED	47	34
Overall Study NOT COMPLETED	34	32

Reasons for withdrawal

Reasons for withdrawal
Measure	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.
Overall Study Death	5	2
Overall Study Adverse Event	8	6
Overall Study Lack of Efficacy	5	4
Overall Study Withdrawal by Subject	3	4
Overall Study Laboratory abnormality	1	2
Overall Study Other	12	14

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Immediate Voriconazole n=81 Participants 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 n=66 Participants 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 n=147 Participants Total of all reporting groups
Age, Customized Between 18 and 44 years	29 participants n=5 Participants	17 participants n=7 Participants	46 participants n=5 Participants
Age, Customized Between 45 and 64 years	31 participants n=5 Participants	35 participants n=7 Participants	66 participants n=5 Participants
Age, Customized >=65 years	21 participants n=5 Participants	14 participants n=7 Participants	35 participants n=5 Participants
Sex: Female, Male Female	39 Participants n=5 Participants	29 Participants n=7 Participants	68 Participants n=5 Participants
Sex: Female, Male Male	42 Participants n=5 Participants	37 Participants n=7 Participants	79 Participants n=5 Participants
Race/Ethnicity, Customized White	81 participants n=5 Participants	65 participants n=7 Participants	146 participants n=5 Participants
Race/Ethnicity, Customized Other	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants
Weight	77.1 kilograms (kg) n=5 Participants	79.2 kilograms (kg) n=7 Participants	78.1 kilograms (kg) n=5 Participants
Height	172.1 centimeters (cm) n=5 Participants	171.9 centimeters (cm) n=7 Participants	172.0 centimeters (cm) n=5 Participants

PRIMARY outcome

Timeframe: Day 2 through Day 28

Population: Modified Intent-to-Treat population (MITT): participants in ITT population (at least 1 dose of study treatment) with valid post-baseline proven or probable IFI, did not have fungemia or other IFI at screening or randomization, no antipyretic analgesics on Day 5 (or Day 9 of open-label voriconazole). N=number of complete case evaluable participants.

Number of participants with proven (deep tissue infection, fungemia, or endemic fungal infections) or probable IFI (at least 1 host criterion \[fever, body temperature \<36 or \>38 degrees Celsius, graft-versus-host disease, use of corticosteroids\]; and 1 microbiological criterion \[fungal or yeasts\]; or clinical criteria \[abnormal site consistent with infection\]) as defined by European Organization for Research and Treatment of Cancer Mycosis Study Group (EORTC/MSG) criteria. Complete case analysis: must be evaluable until Day 28 or had developed a proven or probable IFI by the final visit.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=43 Participants 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 n=35 Participants 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.
Number of Participants With Proven or Probable Invasive Fungal Infections (IFI): Complete Case Analysis	6 participants	9 participants

SECONDARY outcome

Timeframe: Day 5 (96 hours through 120 hours after start of study treatment)

Population: MITT

Number of participants who achieved defervescence (were afebrile). Defervescence stated if all of a participants's body temperatures within 24 hours of evaluation time were \<38.0 degrees C. Defervescence was not stated and participant was discontinued from the study if participant received antipyretics (non-steroidal anti-inflammatory drugs or paracetamol).

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Number of Participants With Defervescence Day 5 (4 Days After Initiation of Study Treatment)	32 participants	28 participants

SECONDARY outcome

Timeframe: Day 9 (192 hours through 216 hours after start of study treatment)

Population: MITT

Number of participants who achieved defervescence (were afebrile). Defervescence stated if all of a participant's body temperatures within 24 hours of evaluation time were \<38.0 degrees C. Defervescence was not stated and participant was discontinued from the study if participant received antipyretics (non-steroidal anti-inflammatory drugs or paracetamol).

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Number of Participants With Defervescence Day 9 (8 Days After Initiation of Study Treatment)	42 particpants	34 particpants

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT

Time (in days) from start of study medication to continuous defervescence. Continuous defervescence stated if participant maintains a body temperature of \<38.0 degrees C for at least 96 hours.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Time to Continuous Defervescence	6.0 days Interval 4.0 to 8.0	5.0 days Interval 4.0 to 7.0

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Number of Participants Per Reason for Lack of Defervescence Fungal infection	3 participants	3 participants
Number of Participants Per Reason for Lack of Defervescence Bacterial infection	7 participants	6 participants
Number of Participants Per Reason for Lack of Defervescence Viral infection	1 participants	0 participants
Number of Participants Per Reason for Lack of Defervescence Unknown	4 participants	4 participants
Number of Participants Per Reason for Lack of Defervescence Other	3 participants	3 participants
Number of Participants Per Reason for Lack of Defervescence Missing evaluation response	0 participants	1 participants

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; N=number of participants evaluable until Day 28 (final visit) or died before the final visit.

Number of participants that died on or before Day 28 after start of study treatment. A participant must be evaluable until Day 28 (final visit) or have died before the final visit.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=43 Participants 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 n=29 Participants 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.
Number of Participants That Died on or Before Day 28 (Mortality)	4 participants	1 participants

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; N=number of participants whose most recent panfungal PCR result prior to start of study medication was positive.

Time (in days) from start of study medication to negative panfungal PCR; assessed for participants whose most recent panfungal PCR result prior to start of study medication was positive. Defined as negative if at least 2 successive and all following panfungal PCR assessments from start of study medication until 24 hours after end of treatment are negative. Measured as first quartile of time (point in time measurement; no median or measure of dispersion calculated); median time was not estimable for deferred voriconazole treatment group.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=10 Participants 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 n=8 Participants 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.
Time to Negative Panfungal Polymerase Chain Reaction (PCR)	4.0 days	5.5 days

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; N=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR.

Percent of positive panfungal PCR assessments during treatment phase of study in association with achievement of continuous defervescence (response=Yes). Continuous defervescence stated if participant maintains a body temperature of \<38.0 degrees C for at least 96 hours. Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=36 Participants 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 n=27 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association of Positive PCR Assessments With Achievement of Continuous Defervescence (Yes)	10.6 percent of positive PCR assessments Standard Deviation 14.11	8.0 percent of positive PCR assessments Standard Deviation 14.71

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; N=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR.

Percent of positive panfungal PCR assessments during treatment phase of study in association with achievement of continuous defervescence (response=No). Continuous defervescence stated if participant maintains a body temperature of \<38.0 degrees C for at least 96 hours. Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=3 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association of Positive PCR Assessments With Achievement of Continuous Defervescence (No)	21.7 percent of positive PCR assessments Standard Deviation 20.21	—

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT. Correlation of positive panfungal PCR assessments with age was not summarized as planned.

Percent of positive panfungal PCR assessments during treatment phase of study in association with age for participants who completed the study and have a non-missing value for percent of positive panfungal PCR.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; (n)=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent of positive panfungal PCR assessments during treatment phase of study in association with gender (Female or Male). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Gender Female (n=21, 12)	12.3 percent of positive PCR assessments Standard Deviation 14.82	4.2 percent of positive PCR assessments Standard Deviation 10.36
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Gender Male (n=18, 15)	10.4 percent of positive PCR assessments Standard Deviation 14.75	11.1 percent of positive PCR assessments Standard Deviation 17.16

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; (n)=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent of positive panfungal PCR assessments during treatment phase of study in association with primary underlying neoplastic disease. Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Primary Underlying Neoplastic Disease Acute lymphatic leukemia (n=6, 6)	13.9 percent of positive PCR assessments Standard Deviation 16.39	9.7 percent of positive PCR assessments Standard Deviation 15.29
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Primary Underlying Neoplastic Disease Acute myeloid leukemia (n=29, 18)	10.5 percent of positive PCR assessments Standard Deviation 14.39	8.8 percent of positive PCR assessments Standard Deviation 15.78

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; (n)=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent of positive panfungal PCR assessments during treatment phase of study in association with allogeneic bone marrow transplant or allogeneic peripheral stem cell transplant (Yes or No). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Planned Allogeneic Transplants Association Yes (n=13, 9)	10.5 percent of positive PCR assessments Standard Deviation 14.88	6.5 percent of positive PCR assessments Standard Deviation 13.03
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Planned Allogeneic Transplants Association No (n=26, 18)	11.9 percent of positive PCR assessments Standard Deviation 14.77	8.8 percent of positive PCR assessments Standard Deviation 15.78

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; (n)=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent positive panfungal PCR assessments during treatment phase of study in association with use of concomitant (prophylaxis) fluconazole (Yes or No). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Concomitant Fluconazole Association No (n=31, 23)	10.9 percent of positive PCR assessments Standard Deviation 14.63	8.3 percent of positive PCR assessments Standard Deviation 15.28
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Concomitant Fluconazole Association Yes (n=8, 4)	13.5 percent of positive PCR assessments Standard Deviation 15.39	6.3 percent of positive PCR assessments Standard Deviation 12.50

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; (n)=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent of positive panfungal PCR assessments during treatment phase of study in association with neutrophil count \>500 uL (Yes or No). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Neutrophil Count >500 uL Association Yes (n=24, 20)	10.9 percent of positive PCR assessments Standard Deviation 14.60	7.9 percent of positive PCR assessments Standard Deviation 15.17
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Neutrophil Count >500 uL Association No (n=15, 7)	12.3 percent of positive PCR assessments Standard Deviation 15.13	8.3 percent of positive PCR assessments Standard Deviation 14.43

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT. Correlation of positive panfungal PCR assessments with c-reactive protein level was not summarized as planned.

Percent of positive panfungal PCR assessments during treatment phase of study in association with c-reactive protein level (measured in milligrams per liter \[mg/L\]) \>1.25 x ULN (Yes or No). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; (n)=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent of positive panfungal PCR assessments during treatment phase of study in association with fungal species (singular \[one species\]=sp; plural \[many species\]=spp) identified (Yes or No). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Aspergillus flavus: No (n=39, 27)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Aspergillus fumig: No (n=38, 27)	11.7 percent of positive PCR assessments Standard Deviation 14.70	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Aspergillus nidulans: No (n=39, 27)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Aspergillus sp: No (n=39, 27)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Aspergillus spp: No (n=37, 27)	11.6 percent of positive PCR assessments Standard Deviation 14.88	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Candida albicans: Yes (n=2, 4)	16.7 percent of positive PCR assessments Standard Deviation 23.57	0.0 percent of positive PCR assessments Standard Deviation 0.0
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Candida albicans: No (n=37, 23)	11.2 percent of positive PCR assessments Standard Deviation 14.45	9.4 percent of positive PCR assessments Standard Deviation 15.55
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Candida glabrata: Yes (n=2, 1)	33.3 percent of positive PCR assessments Standard Deviation 0.00	0.0 percent of positive PCR assessments Standard Deviation 0.0
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Candida glabrata: No (n=37, 26)	10.3 percent of positive PCR assessments Standard Deviation 14.06	8.3 percent of positive PCR assessments Standard Deviation 14.91
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Candida krusei: No (n=39, 26)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.3 percent of positive PCR assessments Standard Deviation 14.91
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Candida spp: No (n=38, 27)	11.7 percent of positive PCR assessments Standard Deviation 14.70	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified Candida tropicalis: No (n=39, 27)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.0 percent of positive PCR assessments Standard Deviation 14.71

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; N=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR.

Percent of positive panfungal PCR assessments during treatment phase of study in association with fungal species (singular \[one species\]=sp; plural \[many species\]=spp) identified (Yes). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=2 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified (Aspergillus Spp=Yes)	8.3 percent of positive PCR assessments Standard Deviation 11.79	—

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; (n)=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent of positive panfungal PCR assessments during treatment phase of study in association with proven or probable IFI (complete cases) between Day 2 and Day 28 (Yes or No). Complete case analysis: participant must be evaluable until Day 28 (final visit) or have developed a proven or probable IFI by the final visit. Participant considered evaluable until Day 28 if participant completed the study and completed an assessment of IFI at Day 28 or final visit. Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Proven or Probable IFI (Complete Cases) Between Day 2 and Day 28 Association Yes (n=2, 2)	0.0 percent of positive PCR assessments Standard Deviation 0.0	16.7 percent of positive PCR assessments Standard Deviation 23.57
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Proven or Probable IFI (Complete Cases) Between Day 2 and Day 28 Association No (n=37, 25)	12.1 percent of positive PCR assessments Standard Deviation 14.77	7.3 percent of positive PCR assessments Standard Deviation 14.30

SECONDARY outcome

Timeframe: Day 5 (96 hours through 120 hours after start of study treatment)

Population: MITT; (n)=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent of positive panfungal PCR assessments during treatment phase of study in association with defervescence (were afebrile) Day 5 (Yes or No). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence Day 5 (4 Days After Initiation of Study Treatment) Association Yes (n=28, 21)	14.5 percent of positive PCR assessments Standard Deviation 14.58	8.3 percent of positive PCR assessments Standard Deviation 15.81
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence Day 5 (4 Days After Initiation of Study Treatment) Association No (n=11, 6)	3.6 percent of positive PCR assessments Standard Deviation 12.06	6.9 percent of positive PCR assessments Standard Deviation 11.08

SECONDARY outcome

Timeframe: Day 2 through Day 9 (192 hours through 216 hours after start of study treatment)

Population: MITT; N=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR.

Percent of positive panfungal PCR assessments during treatment phase of study in association with defervescence (were afebrile) Day 9 (Yes). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=37 Participants 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 n=27 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence (Yes) by Day 9 (8 Days After Initiation of Study Treatment)	11.0 percent of positive PCR assessments Standard Deviation 14.11	8.0 percent of positive PCR assessments Standard Deviation 14.71

SECONDARY outcome

Timeframe: Day 2 through Day 9 (192 hours through 216 hours after start of study treatment)

Population: MITT; N=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR.

Percent of positive panfungal PCR assessments during treatment phase of study in association with defervescence (were afebrile) Day 9 (No). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=2 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence (No) by Day 9 (8 Days After Initiation of Study Treatment)	20.0 percent of positive PCR assessments Standard Deviation 28.28	—

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT. Correlation of positive panfungal PCR assessments with time to defervescence was not summarized as planned.

Percent of positive panfungal PCR assessments during treatment phase of study in association with time to defervescence. Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; (n)=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent of positive panfungal PCR assessments during treatment phase of study in association with lack of continuous defervescence (No). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence (No) Fungal infection: No (n=39, 27)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence (No) Bacterial infection: No (n=39, 27)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence (No) Viral infection: No (n=39, 27)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence (No) Unknown infection: No (n=36, 27)	10.6 percent of positive PCR assessments Standard Deviation 14.11	8.0 percent of positive PCR assessments Standard Deviation 14.71
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence (No) Other infection: No (n=39, 27)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.0 percent of positive PCR assessments Standard Deviation 14.71

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; N=number of participants who completed the study and had a non-missing value for percent of positive panfungal PCR for immediate voriconazole and deferred voriconazole treatment, respectively.

Percent of positive panfungal PCR assessments during treatment phase of study in association with lack of continuous defervescence (Yes). Percent calculated as number of positive PCR assessments divided by number of all PCR assessments in treatment phase multiplied by 100.

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=3 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence: Unknown Infection (Yes)	21.7 percent of positive PCR assessments Standard Deviation 20.21	—

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; participants who completed the study and had a non-missing value for percent of positive panfungal PCR. N=number of participants for category "Alive".

Percent of positive panfungal PCR assessments during treatment phase of study in association with mortality on or before Day 28 after start of study treatment (Alive). A participant must be evaluable until Day 28 (final visit).

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=39 Participants 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 n=27 Participants 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.
Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Mortality by Day 28 (Alive)	11.4 percent of positive PCR assessments Standard Deviation 14.62	8.0 percent of positive PCR assessments Standard Deviation 14.71

SECONDARY outcome

Timeframe: Day 2 through Day 28

Population: MITT; participants who completed the study and had a non-missing value for percent of positive panfungal PCR: no participants met this criteria within the category "Died".

Percent of positive panfungal PCR assessments during treatment phase of study in association with mortality on or before Day 28 after start of study treatment (Died). A participant must have died before Day 28 (final visit).

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 28

Population: MITT

Outcome measures

Outcome measures
Measure	Immediate Voriconazole n=68 Participants 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 n=54 Participants 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.
Number of Participants Assessed as Needing Further Antineoplastic Therapy as Planned	42 participants	32 participants

SECONDARY outcome

Timeframe: Day 28

Population: MITT; data not summarized as planned; data insufficient for analysis due to missing data.

Outcome measures

Outcome data not reported

Adverse Events

Immediate Voriconazole

Serious events: 8 serious events

Other events: 58 other events

Deaths: 0 deaths

Deferred Voriconazole Treatment

Serious events: 8 serious events

Other events: 38 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer, Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER

Measure	Immediate Voriconazole n=81 participants at risk 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 n=66 participants at risk 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.
Cardiac disorders Coronary artery disease	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Gastrointestinal haemorrhage	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
General disorders Chest pain	0.00% 0/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
General disorders Multi-organ failure	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
General disorders Pyrexia	0.00% 0/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Hepatobiliary disorders Cholecystitis acute	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Hepatobiliary disorders Hepatic function abnormal	0.00% 0/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Immune system disorders Anaphylactic reaction	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Abscess	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Bacteraemia	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Bacterial sepsis	0.00% 0/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Cellulitis	0.00% 0/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Encephalitic infection	0.00% 0/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Enterocolitis bacterial	0.00% 0/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Gastroenteritis norovirus	0.00% 0/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Mucormycosis	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Pneumonia	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Sepsis	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	3.0% 2/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Infections and infestations Septic shock	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Renal and urinary disorders Renal failure acute	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Respiratory failure	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Embolism	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	0.00% 0/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.

Measure	Immediate Voriconazole n=81 participants at risk 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 n=66 participants at risk 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.
Eye disorders Visual impairment	6.2% 5/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	3.0% 2/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Abdominal pain	2.5% 2/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	7.6% 5/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Constipation	8.6% 7/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	4.5% 3/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Diarrhoea	27.2% 22/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	19.7% 13/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Nausea	14.8% 12/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	9.1% 6/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Gastrointestinal disorders Vomiting	11.1% 9/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	7.6% 5/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
General disorders Chest pain	2.5% 2/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	7.6% 5/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
General disorders Mucosal inflammation	8.6% 7/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	4.5% 3/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
General disorders Oedema	6.2% 5/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	4.5% 3/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
General disorders Oedema peripheral	7.4% 6/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	1.5% 1/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
General disorders Pyrexia	8.6% 7/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	7.6% 5/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Investigations C-reactive protein increased	1.2% 1/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	6.1% 4/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Metabolism and nutrition disorders Hypokalaemia	9.9% 8/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	3.0% 2/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Nervous system disorders Headache	9.9% 8/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	16.7% 11/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Psychiatric disorders Hallucination	6.2% 5/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	3.0% 2/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Cough	8.6% 7/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	7.6% 5/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Respiratory, thoracic and mediastinal disorders Epistaxis	13.6% 11/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	6.1% 4/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Skin and subcutaneous tissue disorders Rash	17.3% 14/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	9.1% 6/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.
Vascular disorders Hypertension	6.2% 5/81 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.	4.5% 3/66 • Baseline up to 7 days after last dose of study drug Safety population = all randomized participants with at least 1 dose of study treatment. The same event may appear as both an AE and SAE; however, they are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another, or 1 participant may have experienced both a serious and nonserious event during the study.