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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Possible Fungal Infection

Intervention / Treatment
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* Drug: voriconazole (Vfend)
* Drug: voriconazole (Vfend)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early treatment<br>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)<br>* voriconazole, early treatment<br>|
| Other: Deferred treatment<br>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)<br>* voriconazole, deferred treatment<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Defervescence Day 5 (4 Days After Initiation 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). | Day 5 (96 hours through 120 hours after start of study treatment) | 
| Number of Participants With Defervescence Day 9 (8 Days After Initiation 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). | Day 9 (192 hours through 216 hours after start of study treatment) | 
| Time to Continuous Defervescence | 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. | Day 2 through Day 28 | 
| 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) | 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. | Day 2 through Day 28 | 
| Time to Negative Panfungal Polymerase Chain Reaction (PCR) | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association of Positive PCR Assessments With Achievement of Continuous Defervescence (Yes) | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association of Positive PCR Assessments With Achievement of Continuous Defervescence (No) | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Age | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Gender | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Primary Underlying Neoplastic Disease | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Planned Allogeneic Transplants | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Concomitant Fluconazole | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Neutrophil Count >500 uL | 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. | Day 2 through Day 28 | 
| 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) | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Fungal Species Identified (Aspergillus Spp=Yes) | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Proven or Probable IFI (Complete Cases) Between Day 2 and 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence Day 5 (4 Days After Initiation 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. | Day 5 (96 hours through 120 hours after start of study treatment) | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence (Yes) by Day 9 (8 Days After Initiation 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. | Day 2 through Day 9 (192 hours through 216 hours after start of study treatment) | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Defervescence (No) by Day 9 (8 Days After Initiation 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. | Day 2 through Day 9 (192 hours through 216 hours after start of study treatment) | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Time to Defervescence | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence (No) | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Reasons for Lack of Continuous Defervescence: Unknown Infection (Yes) | 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. | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Mortality by Day 28 (Alive) | Percent of positive panfungal PCR assessments during treatment phase of study in association with mortality on or before Day 28 after start of study treatment (Alive). A participant must be evaluable until Day 28 (final visit). | Day 2 through Day 28 | 
| Course of Positive Panfungal PCR Assessments to Explanatory Variables: Association With Mortality by Day 28 (Died) | Percent of positive panfungal PCR assessments during treatment phase of study in association with mortality on or before Day 28 after start of study treatment (Died). A participant must have died before Day 28 (final visit). | Day 2 through Day 28 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neutropenia, Fever of unknown origin, Empirical treatment, Voriconazole