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

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00150345
• Collaborator: Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) (Other)
• Enrollment: 147
• Locations: 28
• Arms: 2
• Duration (Months): 51
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A well-known side-effect of cytostatics (drugs against malignancies) is a decrease in the number of white blood cells, especially of the so-called neutrophil granulocytes, which are very important for the defense against infections. Hence their decrease (called "neutropenia") leads to a predisposition to infections.

Since infections during neutropenia can be very dangerous, the patients are treated with antibiotics from the very first signs of such an infection (usually fever). If the antibiotics (drugs against bacteria) do not lead to a normalization of the body temperature within four days, a drug against fungi is added.

In the IDEA study, one half of the patients receive the antifungal drug voriconazole (as usual) only in case the antibiotics alone do not lead to a normalization of the body temperature (current standard of care). The other half of the patients receive voriconazole immediately after onset of fever (concomitantly with the antibiotics).

The research question is, whether in the "early-treatment" group fewer manifest fungal infections will be observed than in the "late-treatment" group.

Condition or Disease	Intervention/Treatment	Phase
Possible Fungal Infection	Drug: voriconazole (Vfend); Drug: voriconazole (Vfend)	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 147 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Immediate vs. Deferred Empirical Antifungal Treatment With Voriconazole In High-Risk Neutropenic Patients With Fever And A Positive Panfungal Polymerase Chain Reaction Assay (IDEA Study)
• Study Start Date: Jan 1, 2005
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Early treatment Voriconazole starts within 18 hours of onset of fever intravenously with a loading dose of 6 mg/kg q12h for the first two doses followed by 4 mg/kg q12h (maintenance dose). Switched to oral treatment (200 mg BID) is possible after at least four days. Treatment will be ended if the patient is afebrile (< 38.0 °C) for 7 days with neutrophil counts < 500/µL, or if the patient is afebrile (< 38.0 °C) for 2 days with neutrophil counts > 500/µL.	Drug: voriconazole (Vfend); voriconazole, early treatment
Other: Deferred treatment Treatment with voriconazole (for dosage see "early treatment arm") is initiated only if a patient is persistently febrile on day 5 after the onset of fever despite antibiotic treatment.	Drug: voriconazole (Vfend); voriconazole, deferred treatment

Outcome Measures

Primary Outcome Measures

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

   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.

Secondary Outcome Measures

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

   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).

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

   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).

3. Time to Continuous Defervescence [Day 2 through Day 28]

   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.

4. Number of Participants Per Reason for Lack of Defervescence [Day 2 through Day 28]

5. Number of Participants That Died on or Before Day 28 (Mortality) [Day 2 through Day 28]

   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.

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

   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.

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

   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.

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

   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.

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

   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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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.

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

    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).

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

    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).

27. Number of Participants Assessed as Needing Further Antineoplastic Therapy as Planned [Day 28]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Acute leukemia, aggressive lymphoma, bone marrow or stem cell transplantation;

• Neutropenia (<500 neutrophils/µL) of at least 10 days;

• Newly diagnosed fever;

• Positive panfungal polymerase chain reaction assay

Exclusion Criteria:

• Documented bacterial infection during screening or at randomization

• Fungemia or other documented invasive fungal infection during screening or at randomization.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Augsburg		Germany	86156
2	Pfizer Investigational Site	Berlin		Germany	10117
3	Pfizer Investigational Site	Berlin		Germany	12200
4	Pfizer Investigational Site	Berlin		Germany	13353
5	Pfizer Investigational Site	Bielefeld		Germany	33611
6	Pfizer Investigational Site	Bremen		Germany	28177
7	Pfizer Investigational Site	Chemnitz		Germany	09113
8	Pfizer Investigational Site	Dresden		Germany	01307
9	Pfizer Investigational Site	Erlangen		Germany	91054
10	Pfizer Investigational Site	Essen		Germany	45239
11	Pfizer Investigational Site	Frankfurt (Oder)		Germany	15236
12	Pfizer Investigational Site	Freiburg		Germany	79106
13	Pfizer Investigational Site	Goettingen		Germany	37075
14	Pfizer Investigational Site	Hannover		Germany	30623
15	Pfizer Investigational Site	Homburg/Saar		Germany	66421
16	Pfizer Investigational Site	Kiel		Germany	24116
17	Pfizer Investigational Site	Koeln		Germany	50937
18	Pfizer Investigational Site	Leipzig		Germany	04103
19	Pfizer Investigational Site	Ludwigshafen		Germany	67063
20	Pfizer Investigational Site	Luebeck		Germany	23538
21	Pfizer Investigational Site	Mainz		Germany	55101
22	Pfizer Investigational Site	Muenchen		Germany	81675
23	Pfizer Investigational Site	Muenchen		Germany	81737
24	Pfizer Investigational Site	Potsdam		Germany	14467
25	Pfizer Investigational Site	Stuttgart		Germany	70376
26	Pfizer Investigational Site	Trier		Germany	54290
27	Pfizer Investigational Site	Wiesbaden		Germany	65191
28	Pfizer Investigational Site	Wuerzburg		Germany	97070

Sponsors and Collaborators

• Pfizer
• Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00150345
• Other Study ID Numbers: A1501029
• First Posted: Sep 8, 2005
• Last Update Posted: Jan 19, 2012
• Last Verified: Jan 1, 2012

• Keywords provided by Pfizer: Neutropenia; Fever of unknown origin; Empirical treatment; Voriconazole
• Additional relevant MeSH terms: Mycoses; Voriconazole

Study Results

Participant Flow

Recruitment Details	810 participants screened; 81 assigned to immediate voriconazole treatment and 66 to deferred voriconazole treatment. Study should be considered a pilot study; planned sample size (n=200) was not based on statistical power considerations.
Pre-assignment Detail	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).

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	81	66
COMPLETED	47	34
NOT COMPLETED	34	32

Baseline Characteristics

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment	Total
Arm/Group Description	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.	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 of all reporting groups
Overall Participants	81	66	147
Age, Customized (participants) [Number]
Between 18 and 44 years	29 35.8%	17 25.8%	46 31.3%
Between 45 and 64 years	31 38.3%	35 53%	66 44.9%
>=65 years	21 25.9%	14 21.2%	35 23.8%
Sex: Female, Male (Count of Participants)
Female	39 48.1%	29 43.9%	68 46.3%
Male	42 51.9%	37 56.1%	79 53.7%
Race/Ethnicity, Customized (participants) [Number]
White	81 100%	65 98.5%	146 99.3%
Other	0 0%	1 1.5%	1 0.7%
Weight (kilograms (kg)) [Mean (Full Range) ]
Mean (Full Range) [kilograms (kg)]	77.1	79.2	78.1
Height (centimeters (cm)) [Mean (Full Range) ]
Mean (Full Range) [centimeters (cm)]	172.1	171.9	172.0

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	43	35
Number [participants]	6 7.4%	9 13.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Voriconazole, Deferred Voriconazole Treatment
	Comments	Hypothesis: H0: rv - rp = 0 vs H1: rv - rp does not equal 0, where ri is rate of IFI (i=v for voriconazole group, i=p for deferred voriconazole group). Logit model (including important covariates) used. The adjusted odds ratio and 95 percent (%) confidence interval (CI) for adjusted odds ratio calculated. If 95% CI around odds ratio does not contain a value of 1, then the null hypothesis of equal rates of IFI between immediate voriconazole and deferred voriconazole to be rejected.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.258
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.493
	Confidence Interval	(2-Sided) 95%; 0.129 to 1.755
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio computed from the logistic regression (logit model) including terms for treatment arm, concomitant fluconazole, and positive PCR before randomization. Event IFI=yes is modeled.

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

MITT

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Number [participants]	32 39.5%	28 42.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Voriconazole, Deferred Voriconazole Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.596
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.822
	Confidence Interval	(2-Sided) 95%; 0.398 to 1.696
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio computed from the logistic regression (logit model) including terms for treatment arm, concomitant fluconazole, and positive PCR before randomization. Event defervescence=yes is modeled.

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

MITT

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Number [particpants]	42	34

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Voriconazole, Deferred Voriconazole Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.864
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.936
	Confidence Interval	(2-Sided) 95%; 0.441 to 1.988
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio computed from the logistic regression (logit model) including terms for treatment arm, concomitant fluconazole, and positive PCR before randomization. Event defervescence=yes is modeled.

4. Secondary Outcome

Title	Time to Continuous Defervescence
Description	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.
Time Frame	Day 2 through Day 28

Outcome Measure Data

Analysis Population Description

MITT

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Median (95% Confidence Interval) [days]	6.0	5.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Voriconazole, Deferred Voriconazole Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.955
	Comments
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Number of Participants Per Reason for Lack of Defervescence
Time Frame	Day 2 through Day 28

Outcome Measure Data

Analysis Population Description

MITT

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Fungal infection	3 3.7%	3 4.5%
Bacterial infection	7 8.6%	6 9.1%
Viral infection	1 1.2%	0 0%
Unknown	4 4.9%	4 6.1%
Other	3 3.7%	3 4.5%
Missing evaluation response	0 0%	1 1.5%

6. Secondary Outcome

Title	Number of Participants That Died on or Before Day 28 (Mortality)
Description	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.
Time Frame	Day 2 through Day 28

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	43	29
Number [participants]	4 4.9%	1 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Voriconazole, Deferred Voriconazole Treatment
	Comments	Difference in proportions expressed as a percent: immediate voriconazole versus (vs) deferred voriconazole treatment
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in % participants that died
	Estimated Value	5.85
	Confidence Interval	(2-Sided) 95%; -5.08 to 16.78
	Parameter Dispersion	Type: Value:
	Estimation Comments	Approximate 2-sided confidence interval (CI).

7. Secondary Outcome

Title	Time to Negative Panfungal Polymerase Chain Reaction (PCR)
Description	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.
Time Frame	Day 2 through Day 28

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	10	8
Number [days]	4.0	5.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Voriconazole, Deferred Voriconazole Treatment
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.190
	Comments
	Method	Log Rank
	Comments

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	36	27
Mean (Standard Deviation) [percent of positive PCR assessments]	10.6 (14.11)	8.0 (14.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Voriconazole, Deferred Voriconazole Treatment
	Comments	Continuous defervescence achieved=Yes
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments	SAS PROC REG with SELECTION=STEPWISE option of SLENTRY=0.05 and SLSTAY=0.10 utilized. Stepwise option combined forward stepping (with a 0.05 level to enter) with elimination of variables already in model that do not stay significant at 0.10 level.
	Method	Regression, Linear
	Comments	Variables: association with age, c-reactive protein, and time to continuous defervescence not significant at 0.05 level; not included in final model
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-22.031
	Confidence Interval	(2-Sided) 95%; -44.004 to -0.059
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 10.888
	Estimation Comments

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	3	0
Mean (Standard Deviation) [percent of positive PCR assessments]	21.7 (20.21)

10. Secondary Outcome

Title	Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Age
Description	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.
Time Frame	Day 2 through Day 28

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	0	0

11. Secondary Outcome

Title	Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Gender
Description	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.
Time Frame	Day 2 through Day 28

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Female (n=21, 12)	12.3 (14.82)	4.2 (10.36)
Male (n=18, 15)	10.4 (14.75)	11.1 (17.16)

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Acute lymphatic leukemia (n=6, 6)	13.9 (16.39)	9.7 (15.29)
Acute myeloid leukemia (n=29, 18)	10.5 (14.39)	8.8 (15.78)

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Association Yes (n=13, 9)	10.5 (14.88)	6.5 (13.03)
Association No (n=26, 18)	11.9 (14.77)	8.8 (15.78)

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Association Yes (n=8, 4)	13.5 (15.39)	6.3 (12.50)
Association No (n=31, 23)	10.9 (14.63)	8.3 (15.28)

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Association Yes (n=24, 20)	10.9 (14.60)	7.9 (15.17)
Association No (n=15, 7)	12.3 (15.13)	8.3 (14.43)

16. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	0	0

17. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Aspergillus flavus: No (n=39, 27)	11.4 (14.62)	8.0 (14.71)
Aspergillus fumig: No (n=38, 27)	11.7 (14.70)	8.0 (14.71)
Aspergillus nidulans: No (n=39, 27)	11.4 (14.62)	8.0 (14.71)
Aspergillus sp: No (n=39, 27)	11.4 (14.62)	8.0 (14.71)
Aspergillus spp: No (n=37, 27)	11.6 (14.88)	8.0 (14.71)
Candida albicans: Yes (n=2, 4)	16.7 (23.57)	0.0 (0.0)
Candida albicans: No (n=37, 23)	11.2 (14.45)	9.4 (15.55)
Candida glabrata: Yes (n=2, 1)	33.3 (0.00)	0.0 (0.0)
Candida glabrata: No (n=37, 26)	10.3 (14.06)	8.3 (14.91)
Candida krusei: No (n=39, 26)	11.4 (14.62)	8.3 (14.91)
Candida spp: No (n=38, 27)	11.7 (14.70)	8.0 (14.71)
Candida tropicalis: No (n=39, 27)	11.4 (14.62)	8.0 (14.71)

18. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	2	0
Mean (Standard Deviation) [percent of positive PCR assessments]	8.3 (11.79)

19. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Association Yes (n=2, 2)	0.0 (0.0)	16.7 (23.57)
Association No (n=37, 25)	12.1 (14.77)	7.3 (14.30)

20. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voricoazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Association Yes (n=28, 21)	14.5 (14.58)	8.3 (15.81)
Association No (n=11, 6)	3.6 (12.06)	6.9 (11.08)

21. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	37	27
Mean (Standard Deviation) [percent of positive PCR assessments]	11.0 (14.11)	8.0 (14.71)

22. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	2	0
Mean (Standard Deviation) [percent of positive PCR assessments]	20.0 (28.28)

23. Secondary Outcome

Title	Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Time to Defervescence
Description	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.
Time Frame	Day 2 through Day 28

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	0	0

24. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Fungal infection: No (n=39, 27)	11.4 (14.62)	8.0 (14.71)
Bacterial infection: No (n=39, 27)	11.4 (14.62)	8.0 (14.71)
Viral infection: No (n=39, 27)	11.4 (14.62)	8.0 (14.71)
Unknown infection: No (n=36, 27)	10.6 (14.11)	8.0 (14.71)
Other infection: No (n=39, 27)	11.4 (14.62)	8.0 (14.71)

25. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	3	0
Mean (Standard Deviation) [percent of positive PCR assessments]	21.7 (20.21)

26. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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".

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	39	27
Mean (Standard Deviation) [percent of positive PCR assessments]	11.4 (14.62)	8.0 (14.71)

27. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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".

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	0	0

28. Secondary Outcome

Title	Number of Participants Assessed as Needing Further Antineoplastic Therapy as Planned
Time Frame	Day 28

Outcome Measure Data

Analysis Population Description

MITT

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	68	54
Number [participants]	42 51.9%	32 48.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Voriconazole, Deferred Voriconazole Treatment
	Comments	Difference in proportions expressed as a percent: immediate voriconazole vs deferred voriconazole treatment
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Difference in percentages
	Estimated Value	2.51
	Confidence Interval	(2-Sided) 95%; -14.96 to 19.97
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Immediate Voriconazole	Deferred Voriconazole Treatment
Arm/Group Description	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.	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.
Measure Participants	0	0

Adverse Events

Time Frame	Baseline up to 7 days after last dose of study drug
Adverse Event Reporting Description	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.
Arm/Group Title	Immediate Voriconazole		Deferred Voriconazole Treatment
Arm/Group Description	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.		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.
All Cause Mortality
	Immediate Voriconazole		Deferred Voriconazole Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Immediate Voriconazole		Deferred Voriconazole Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/81 (9.9%)		8/66 (12.1%)
Cardiac disorders
Coronary artery disease	1/81 (1.2%)		0/66 (0%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/81 (1.2%)		1/66 (1.5%)
General disorders
Chest pain	0/81 (0%)		1/66 (1.5%)
Multi-organ failure	1/81 (1.2%)		0/66 (0%)
Pyrexia	0/81 (0%)		1/66 (1.5%)
Hepatobiliary disorders
Cholecystitis acute	1/81 (1.2%)		0/66 (0%)
Hepatic function abnormal	0/81 (0%)		1/66 (1.5%)
Immune system disorders
Anaphylactic reaction	1/81 (1.2%)		0/66 (0%)
Infections and infestations
Abscess	1/81 (1.2%)		0/66 (0%)
Bacteraemia	1/81 (1.2%)		0/66 (0%)
Bacterial sepsis	0/81 (0%)		1/66 (1.5%)
Cellulitis	0/81 (0%)		1/66 (1.5%)
Encephalitic infection	0/81 (0%)		1/66 (1.5%)
Enterocolitis bacterial	0/81 (0%)		1/66 (1.5%)
Gastroenteritis norovirus	0/81 (0%)		1/66 (1.5%)
Mucormycosis	1/81 (1.2%)		0/66 (0%)
Pneumonia	1/81 (1.2%)		0/66 (0%)
Sepsis	1/81 (1.2%)		2/66 (3%)
Septic shock	1/81 (1.2%)		0/66 (0%)
Renal and urinary disorders
Renal failure acute	1/81 (1.2%)		0/66 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/81 (1.2%)		0/66 (0%)
Vascular disorders
Embolism	1/81 (1.2%)		0/66 (0%)
Other (Not Including Serious) Adverse Events
	Immediate Voriconazole		Deferred Voriconazole Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/81 (71.6%)		38/66 (57.6%)
Eye disorders
Visual impairment	5/81 (6.2%)		2/66 (3%)
Gastrointestinal disorders
Abdominal pain	2/81 (2.5%)		5/66 (7.6%)
Constipation	7/81 (8.6%)		3/66 (4.5%)
Diarrhoea	22/81 (27.2%)		13/66 (19.7%)
Nausea	12/81 (14.8%)		6/66 (9.1%)
Vomiting	9/81 (11.1%)		5/66 (7.6%)
General disorders
Chest pain	2/81 (2.5%)		5/66 (7.6%)
Mucosal inflammation	7/81 (8.6%)		3/66 (4.5%)
Oedema	5/81 (6.2%)		3/66 (4.5%)
Oedema peripheral	6/81 (7.4%)		1/66 (1.5%)
Pyrexia	7/81 (8.6%)		5/66 (7.6%)
Investigations
C-reactive protein increased	1/81 (1.2%)		4/66 (6.1%)
Metabolism and nutrition disorders
Hypokalaemia	8/81 (9.9%)		2/66 (3%)
Nervous system disorders
Headache	8/81 (9.9%)		11/66 (16.7%)
Psychiatric disorders
Hallucination	5/81 (6.2%)		2/66 (3%)
Respiratory, thoracic and mediastinal disorders
Cough	7/81 (8.6%)		5/66 (7.6%)
Epistaxis	11/81 (13.6%)		4/66 (6.1%)
Skin and subcutaneous tissue disorders
Rash	14/81 (17.3%)		6/66 (9.1%)
Vascular disorders
Hypertension	5/81 (6.2%)		3/66 (4.5%)

Limitations/Caveats

One participant in the Immediate Voriconazole treatment group was incorrectly included in the original Primary efficacy analysis and has now been excluded; IFI was identified on the day study treatment started (not prior to study treatment).

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.