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

Phase 3

Completed

Conditions: Possible Fungal Infection

Interventions: Drug: voriconazole (Vfend)

Registration Number: NCT00150345

Lead Sponsor: Pfizer

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 147

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Early treatment	voriconazole (Vfend)	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.
Deferred treatment	voriconazole (Vfend)	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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).
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).
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.
Number of Participants Per Reason for Lack of Defervescence	Day 2 through Day 28
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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).
Number of Participants Assessed as Needing Further Antineoplastic Therapy as Planned	Day 28
Number of Participants With Reasons Why Antineoplastic Therapy Not Continued as Planned	Day 28