Invasive Candidiasis
Conditions
Keywords
candidemia, invasive candidiasis, preemptive antifungal therapy, surveillance, β-D-Glucan (BDG)
Brief summary
This is a single center, prospective, open label assessment of β-D-glucan surveillance with preemptive anidulafungin therapy versus standard care for the prevention of invasive candidiasis in at-risk surgical intensive care unit (SICU) patients. Subjects will be stratified by APACHE II score and randomized in 3:1 fashion to either biweekly surveillance using the β-D-glucan assay or standard care. Subjects in the active monitoring arm will receive intravenous anidulafungin should the β-D-glucan exceed 60 pg/mL on a single determination. Subjects in the standard care arm will have biweekly blood draws for β-D-glucan, but the specimens will be batched and tested retrospectively. Antifungal use in the standard care arm is at the discretion of the treating physicians. The primary study end-points are the feasibility of a preemptive antifungal strategy in a SICU setting, β-D-glucan test characteristics, and the safety and tolerability of preemptive anidulafungin. Risks associated with study participation include the risks associated with blood draws, study drug related side effects, and the potential for loss of confidentiality.
Interventions
DRUGPreemptive Therapy with Anidulafungin
Subjects in the active surveillance arm who develop a single positive β-D-glucan test will receive preemptive anidulafungin intravenously. Preemptive therapy will include a loading dose of 200mg followed by 100mg maintenance therapy once a day. The loading and maintenance doses are derived from the FDA cleared schedule for Invasive Candidiasis and candidemia. Preemptive therapy will continue for 14 days.
DRUGEmpiric antifungal therapy based on physician discretion.
Patients in the standard care group may receive antifungal prophylaxis and/or treatment at any time based on the discretion of the treating physician.
Sponsors
Pfizer
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years * Admission to the intensive care unit for ≥ 72 hours and expected to stay an additional 48 hours * IV access for administration of study drug * Subject (or subject's legal representative) able to give written informed consent
Exclusion criteria
* History of hypersensitivity or intolerance to echinocandin antifungals * Liver function test (ALT, AST (aspartate aminotransferase), and/or total bilirubin) greater than 10 times the upper limits of normal (ULN) * Pregnant or lactating women * Treatment with systemic antifungal therapy within the preceding 7 days * Documented invasive fungal infection at baseline/screening * Life expectancy less than 2 days or moribund
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients. | Participants were followed until ICU discharge, an average of 17 days | Clinical utility was defined as β-D-glucan test performance. Biweekly βDG testing used a threshold of ≥ 60 pg/ml to indicate a positive test for invasive candidiasis. True and false positives, and true and false negatives were confirmed using a composite clinical definition of invasive candidiasis that combines physical symptom/signs and microbiology. Cases of proven/probable invasive fungal infection (IFI) were adjudicated by a single reviewer blinded to group assignment and BDG results. |
| Safety and Tolerability of Preemptive Anidulafungin | weekly until ICU discharge | reported as the Number of Adverse Events Possibly Related to Study Drug |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Validate Gene Expression Signatures Predictive of IC | Study Completion, an average of 17 days | — |
| Incidence of Proven or Probable Invasive Fungal Infection (IFI) | Participants were followed until ICU discharge, an average of 17 days | Institution specific criteria were used to establish a diagnosis of proven or probable invasive candidiasis. Other IFIs were classified according to the European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria. However, BDG results were not factored into the EORTC/MSG criteria. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from June 2008 to December 2010 on three intensive care units.
Participants by arm
| Arm | Count |
|---|---|
| Standard Care, Empiric Treatment Standard care group. Empiric antifungal therapy initiated by physician preference for the treatment of suspected invasive candidiasis. | 17 |
| Active Surveillance, Preemptive Therapy Active surveillance group. Preemptive therapy initiated in response to a positive 1,3-beta-D glucan test for the presumptive early treatment of invasive candidiasis | 47 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 |
| Overall Study | Antifungal therapy, negative glucan | 0 | 4 |
| Overall Study | Comfort care | 1 | 4 |
| Overall Study | icteric specimens | 0 | 3 |
| Overall Study | Pregnancy | 0 | 1 |
Baseline characteristics
| Characteristic | Active Surveillance, Preemptive Therapy | Standard Care, Empiric Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 17 Participants | 6 Participants | 23 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants | 11 Participants | 41 Participants |
| Age, Continuous | 53 years STANDARD_DEVIATION 20 | 53 years STANDARD_DEVIATION 19 | 53 years STANDARD_DEVIATION 19 |
| Region of Enrollment United States | 47 participants | 17 participants | 64 participants |
| Sex: Female, Male Female | 16 Participants | 4 Participants | 20 Participants |
| Sex: Female, Male Male | 31 Participants | 13 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 17 | 10 / 47 |
| serious Total, serious adverse events | 0 / 17 | 0 / 47 |
Outcome results
Primary
Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients.
Clinical utility was defined as β-D-glucan test performance. Biweekly βDG testing used a threshold of ≥ 60 pg/ml to indicate a positive test for invasive candidiasis. True and false positives, and true and false negatives were confirmed using a composite clinical definition of invasive candidiasis that combines physical symptom/signs and microbiology. Cases of proven/probable invasive fungal infection (IFI) were adjudicated by a single reviewer blinded to group assignment and BDG results.
Time frame: Participants were followed until ICU discharge, an average of 17 days
Population: Two study subjects in the preemptive therapy arm were excluded from the analysis of assay sensitivity and specific due to icteric serum specimens.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Active Surveillance, Preemptive Therapy | Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients. | True BDG Positives | 3 participants |
| Active Surveillance, Preemptive Therapy | Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients. | True BDG Negative | 19 participants |
| Active Surveillance, Preemptive Therapy | Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients. | False BDG Positives | 23 participants |
| Active Surveillance, Preemptive Therapy | Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients. | False BGD Negatives | 0 participants |
| Standard Care, Empiric Treatment | Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients. | False BGD Negatives | 0 participants |
| Standard Care, Empiric Treatment | Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients. | True BDG Positives | 3 participants |
| Standard Care, Empiric Treatment | Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients. | False BDG Positives | 5 participants |
| Standard Care, Empiric Treatment | Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients. | True BDG Negative | 9 participants |
Comparison: Clinical sensitivity of the BDG test was calculated for both study groups combinedSensitivity %
Comparison: Clinical specificity of the BDG test was calculated for the study groups combined% Specificity
Primary
Safety and Tolerability of Preemptive Anidulafungin
reported as the Number of Adverse Events Possibly Related to Study Drug
Time frame: weekly until ICU discharge
Population: Subjects receiving at least 1 dose of anidulafungin were assessed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Surveillance, Preemptive Therapy | Safety and Tolerability of Preemptive Anidulafungin | 0 events |
| Standard Care, Empiric Treatment | Safety and Tolerability of Preemptive Anidulafungin | 10 events |
Secondary
Incidence of Proven or Probable Invasive Fungal Infection (IFI)
Institution specific criteria were used to establish a diagnosis of proven or probable invasive candidiasis. Other IFIs were classified according to the European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria. However, BDG results were not factored into the EORTC/MSG criteria.
Time frame: Participants were followed until ICU discharge, an average of 17 days
Population: 4 subjects in the preemptive therapy were excluded from this analysis. These subjects were treated with empiric antifungal therapy despite repeatedly negative glucan results.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Surveillance, Preemptive Therapy | Incidence of Proven or Probable Invasive Fungal Infection (IFI) | 3 participants |
| Standard Care, Empiric Treatment | Incidence of Proven or Probable Invasive Fungal Infection (IFI) | 3 participants |
Comparison: The clinic sensitivity of the BDG test was calculated for both study groups combinedSensitivity
Comparison: The clinical specificity of the BDG test was calculated for both study groups combinedSpecificity
Secondary
Validate Gene Expression Signatures Predictive of IC
Time frame: Study Completion, an average of 17 days
Population: Data was not collected for this outcome measure.