Fever, Hematologic Neoplasms, Neutropenia
Conditions
Keywords
Hematological neoplasms, Neutropenia, Fever, Itraconazole, Sporanox, Antifungal prophylaxis, Defeverscence
Brief summary
The purpose of this observational study is to investigate whether a sufficient concentration of itraconazole can influence disappearance of a fever (defeverscence) when intravenous (into the vein) itraconazole is administered for resolving unknown neutropenic fever of participants who are given itraconazole oral solution as a prophylaxis under general treatment conditions.
Detailed description
This is a prospective (study following patients forward in time), open-label (all people know the identity of the intervention), multi-center (conducted in more than one center) observational study to examine the correlation between a sufficient blood concentration of itraconazole and disappearance of a fever (defeverscence) when itraconazole injection is administered for resolving unknown neutropenic fever of participants who are given itraconazole oral solution as a prophylaxis under general treatment conditions. The recommended dose of the drug will be 200 milligram (mg), which will be administered intravenously, twice daily for 2 days (a total of 4 doses) and then 200 mg once daily for 12 days. After the administration for a total of 14 days, itraconazole oral solution 200 mg (which is equivalent to 20 ml) twice daily will be continued for a total of 14 days until clinically significant neutropenia is resolved.
Interventions
DRUGItraconazole
Itraconazole will be administered as an infusion (a fluid or a medicine delivered into a vein by way of a needle) over one hour at the dose of 200 milligram (mg) per dose twice daily for 2 days, followed by 200 mg once daily for 12 days, followed by itraconazole oral solution at the dose of 200 mg per dose twice daily for 14 days until clinically significant neutropenia is recovered.
Sponsors
Janssen Korea, Ltd., Korea
Study design
Observational model
CASE_ONLY
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Immunocompromised participants with neutropenic fever who have been treated with itraconazole oral solution as prophylaxis * Female participants who are postmenopausal or received contraceptive operation or refrain from sexual relations and women of childbearing potential should conduct an effective method of birth control (oral contraceptives, injections, intrauterine device, double barrier method, contraceptive patch and male partner's sterilization) before participation and during the study * Male participants who will not have a baby within 2 months after the completion of itraconazole therapy
Exclusion criteria
* Fever due to documented deep-seated fungal infection at the entry into the study, but documented candidemia will be included * Participants with kidney function related abnormalities with calculated creatinine clearance of 30 milliliter per minute (mL/min) or lower * Aminotransferase level 5 times or higher of normal limit and total bilirubin level 5 milliliter per deciliter (mL/dL) or higher due to hepatic dysfunction * Participants with dementia (mental decline) related to head injury and hypoxic brain injury * Participants with mental illness which may interfere with cooperation in treatment and monitoring condition of the clinical study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Plasma Level of Itraconazole at 1000 Nanogram Per Milliliter (ng/mL) or Higher After Administration of Study Treatment | Day 5 | Percentage of participants who achieved more than or equal to 1000 ng/ml level after administration of study treatment were reported. Plasma level of itraconazole was defined as the sum of itraconazole concentration (IC) and hydroxyitraconazole concentration (HIC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Time to Defervescence in Participants Who Received the Study Treatment | Day 0 up to Day 14 | The mean time to defervescence was reported in participants who received the study treatment. Defervescence was defined as fall of the body temperature below 38.0 degree C at least once after starting to receive the study treatment. |
| Duration of Neutropenia | Day 0 up to Day 14 | The duration of neutropenia was reported. Neutropenia was defined as neutrophil count less than or equal to (\<=) 500 cells per cubic millimeter (cells/mm\^3), or neutrophil count \<=1000 cells/mm\^3 and anticipated to decrease to \<=500 cells/mm\^3 within several days. |
| Absolute Neutrophil Count (ANC) | Baseline (Day 0) | The mean values for ANC based on blood tests performed on Day 0 (before starting the study treatment) constitute a Baseline measure for ANC. |
| Percentage of Participants With Deferevescence After Administration of Study Treatment | Day 0 up to Day 14 | Defervescence was defined as fall of the body temperature below 38.0 degree Celsius (C) at least once after starting to receive the study treatment. |
| Plasma Concentration of Itraconazole by Overall Success Rate (OSR) in Participants Who Received the Study Treatment | Day 5 | Plasma level of itraconazole was defined as the sum of IC and HIC. The OSR was defined based on satisfaction of the following criteria: (1) participants if treated for baseline fungal infection, there was either eradication (removal of fungus in culture), or presumed eradication; no evidence in culture but appeared to be treated clinically, (2) absence of breakthrough fungal infection during the treatment and for 7 days after completing the treatment, (3) survival for 7 days after completing the treatment, (4) absence of early withdrawal due to adverse events or lack of efficacy, and (5) defervescence. The presence and absence of OS was reported. |
| Percentage of Participants With Baseline Fungal Infection | Baseline (Day 0) | Blood cultures (a laboratory test on a sample of blood) were assessed to identify fungus. Percentage of participants with presence or absence of fungus before starting the study drug were calculated. |
| Plasma Concentration of Itraconazole by Breakthrough Fungal Infection | Day 5 | Plasma level of itraconazole was defined as the sum of IC and HIC. A breakthrough fungal infection was defined as any fungal infection that was diagnosed more than (\>) 3 days on or during therapy or within 7 days after completion of therapy. Blood cultures were assessed to identify fungus. |
| Percentage of Participants With Defervescence by Plasma Level of Itraconazole | Day 5 | Defervescence was defined as fall of the body temperature below 38.0 degree C at least once after starting to receive the study treatment. Plasma level of itraconazole was defined as the sum of IC and HIC. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Itraconazole Participants who had been receiving itraconazole were observed prospectively. Itraconazole was administered as an infusion (a fluid or a medicine delivered into a vein by way of a needle) over one hour at the dose of 200 milligram (mg) per dose twice daily for 2 days, followed by 200 mg once daily for 12 days, and then itraconazole oral solution at the dose of 200 mg per dose twice daily for 14 days until clinically significant neutropenia was recovered. | 150 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lack of Efficacy | 12 |
| Overall Study | Other | 8 |
| Overall Study | Recovery of neutrophil count | 51 |
Baseline characteristics
| Characteristic | Itraconazole |
|---|---|
| Age Continuous | 52.2 Years STANDARD_DEVIATION 15 |
| Sex: Female, Male Female | 65 Participants |
| Sex: Female, Male Male | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 49 / 203 |
| serious Total, serious adverse events | 28 / 203 |
Outcome results
Primary
Percentage of Participants Achieving Plasma Level of Itraconazole at 1000 Nanogram Per Milliliter (ng/mL) or Higher After Administration of Study Treatment
Percentage of participants who achieved more than or equal to 1000 ng/ml level after administration of study treatment were reported. Plasma level of itraconazole was defined as the sum of itraconazole concentration (IC) and hydroxyitraconazole concentration (HIC).
Time frame: Day 5
Population: The intent-to-treat (ITT) population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itraconazole | Percentage of Participants Achieving Plasma Level of Itraconazole at 1000 Nanogram Per Milliliter (ng/mL) or Higher After Administration of Study Treatment | 68.0 Percentage of Participants |
Secondary
Absolute Neutrophil Count (ANC)
The mean values for ANC based on blood tests performed on Day 0 (before starting the study treatment) constitute a Baseline measure for ANC.
Time frame: Baseline (Day 0)
Population: The ITT population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once. Here, 'N' (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itraconazole | Absolute Neutrophil Count (ANC) | 56.26 Cells/mm^3 | Standard Deviation 127.91 |
Secondary
Duration of Neutropenia
The duration of neutropenia was reported. Neutropenia was defined as neutrophil count less than or equal to (\<=) 500 cells per cubic millimeter (cells/mm\^3), or neutrophil count \<=1000 cells/mm\^3 and anticipated to decrease to \<=500 cells/mm\^3 within several days.
Time frame: Day 0 up to Day 14
Population: The ITT population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itraconazole | Duration of Neutropenia | 2.64 Days | Standard Deviation 1.96 |
Secondary
Mean Time to Defervescence in Participants Who Received the Study Treatment
The mean time to defervescence was reported in participants who received the study treatment. Defervescence was defined as fall of the body temperature below 38.0 degree C at least once after starting to receive the study treatment.
Time frame: Day 0 up to Day 14
Population: The ITT population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once. Here, 'N' (number of participants analyzed) signifies participants who were evaluable for this measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Itraconazole | Mean Time to Defervescence in Participants Who Received the Study Treatment | 3.14 Days | Standard Deviation 1.57 |
Secondary
Percentage of Participants With Baseline Fungal Infection
Blood cultures (a laboratory test on a sample of blood) were assessed to identify fungus. Percentage of participants with presence or absence of fungus before starting the study drug were calculated.
Time frame: Baseline (Day 0)
Population: The ITT population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Itraconazole | Percentage of Participants With Baseline Fungal Infection | 5.3 Percentage of Participants | 1185.2 |
Secondary
Percentage of Participants With Deferevescence After Administration of Study Treatment
Defervescence was defined as fall of the body temperature below 38.0 degree Celsius (C) at least once after starting to receive the study treatment.
Time frame: Day 0 up to Day 14
Population: The ITT population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Itraconazole | Percentage of Participants With Deferevescence After Administration of Study Treatment | 87.3 Percentage of Participants |
Secondary
Percentage of Participants With Defervescence by Plasma Level of Itraconazole
Defervescence was defined as fall of the body temperature below 38.0 degree C at least once after starting to receive the study treatment. Plasma level of itraconazole was defined as the sum of IC and HIC.
Time frame: Day 5
Population: The ITT population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once. Here, 'n' signifies participants who were evaluable for this measure at given time points.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Itraconazole | Percentage of Participants With Defervescence by Plasma Level of Itraconazole | IC+HIC < 1000ng/mL (n=48) | 70.8 Percentage of Participants |
| Itraconazole | Percentage of Participants With Defervescence by Plasma Level of Itraconazole | IC+HIC >= 1000ng/mL (n=102) | 95.1 Percentage of Participants |
Secondary
Plasma Concentration of Itraconazole by Breakthrough Fungal Infection
Plasma level of itraconazole was defined as the sum of IC and HIC. A breakthrough fungal infection was defined as any fungal infection that was diagnosed more than (\>) 3 days on or during therapy or within 7 days after completion of therapy. Blood cultures were assessed to identify fungus.
Time frame: Day 5
Population: The ITT population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once. Here, 'N' (number of participants analyzed) = participants evaluable for this measure and 'n' = participants evaluable for given category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Itraconazole | Plasma Concentration of Itraconazole by Breakthrough Fungal Infection | Presence of Breakthrough Fungal infection (n=128) | 2155.70 ng/mL | Standard Deviation 1529.2 |
| Itraconazole | Plasma Concentration of Itraconazole by Breakthrough Fungal Infection | Absence of Breakthrough Fungal infection (n=6) | 1864.20 ng/mL | Standard Deviation 1509.8 |
Secondary
Plasma Concentration of Itraconazole by Overall Success Rate (OSR) in Participants Who Received the Study Treatment
Plasma level of itraconazole was defined as the sum of IC and HIC. The OSR was defined based on satisfaction of the following criteria: (1) participants if treated for baseline fungal infection, there was either eradication (removal of fungus in culture), or presumed eradication; no evidence in culture but appeared to be treated clinically, (2) absence of breakthrough fungal infection during the treatment and for 7 days after completing the treatment, (3) survival for 7 days after completing the treatment, (4) absence of early withdrawal due to adverse events or lack of efficacy, and (5) defervescence. The presence and absence of OS was reported.
Time frame: Day 5
Population: The ITT population included the participants who satisfied the eligibility criteria, received the study drug at least once, and in whom the primary efficacy endpoint was measured at least once. Here, 'N' (number of participants analyzed) = participants evaluable for this measure and 'n' = participants evaluable for given category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Itraconazole | Plasma Concentration of Itraconazole by Overall Success Rate (OSR) in Participants Who Received the Study Treatment | Presence of OS (n=95) | 2328.10 ng/mL | Standard Deviation 1612 |
| Itraconazole | Plasma Concentration of Itraconazole by Overall Success Rate (OSR) in Participants Who Received the Study Treatment | Absence of OS (n=39) | 1690.90 ng/mL | Standard Deviation 1185.2 |