β-D-Glucan (BDG) Surveillance With Preemptive Anidulafungin vs. Standard Care for Invasive Candidiasis in Surgical Intensive Care Unit (SICU) Patients

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00672841
• Collaborator: Pfizer (Industry)
• Enrollment: 64
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 2.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Invasive Candidiasis	Drug: Preemptive Therapy with Anidulafungin; Drug: Empiric antifungal therapy based on physician discretion.	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Comparison of β-D-Glucan Surveillance With Preemptive Anidulafungin Versus Standard Care for the Management of Invasive Candidiasis in Surgical Intensive Care Unit Patients
• Study Start Date: Jun 1, 2008
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 2 Standard care/empiric therapy group	Drug: Empiric 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.
Experimental: 1 Active surveillance/ preemptive therapy group	Drug: Preemptive 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.; Other Names: Eraxis

Outcome Measures

Primary Outcome Measures

1. 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.

2. Safety and Tolerability of Preemptive Anidulafungin [weekly until ICU discharge]

   reported as the Number of Adverse Events Possibly Related to Study Drug

Secondary Outcome Measures

1. Validate Gene Expression Signatures Predictive of IC [Study Completion, an average of 17 days]

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University
• Pfizer

Investigators

• Principal Investigator: Kimberly E Hanson, MD, Utah
• Principal Investigator: Barbara D Alexander, MD, Duke
• Principal Investigator: John Perfect, MD, Duke

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00672841
• Other Study ID Numbers: Pro00003161; GA88517X
• First Posted: May 6, 2008
• Last Update Posted: Feb 6, 2015
• Last Verified: Nov 1, 2012

• Keywords provided by Duke University: candidemia; invasive candidiasis; preemptive antifungal therapy; surveillance; β-D-Glucan (BDG)
• Additional relevant MeSH terms: Candidiasis; Candidiasis, Invasive; Antifungal Agents; Clotrimazole; Miconazole; Anidulafungin

Study Results

Participant Flow

Recruitment Details	Patients were recruited from June 2008 to December 2010 on three intensive care units.

Arm/Group Title	Standard Care, Empiric Treatment	Active Surveillance, Preemptive Therapy
Arm/Group Description	Standard care group. Empiric antifungal therapy initiated by physician preference for the treatment of suspected invasive candidiasis.	Active surveillance group. Preemptive therapy (i.e., intravenous anidulafungin 200mg on day one, then 100mg daily x 14 days) initiated in response to a positive 1,3-beta-D glucan test for the presumptive early treatment of invasive candidiasis
Period Title: Overall Study
STARTED	17	47
COMPLETED	16	32
NOT COMPLETED	1	15

Baseline Characteristics

Arm/Group Title	Standard Care, Empiric Treatment	Active Surveillance, Preemptive Therapy	Total
Arm/Group Description	Standard care group. Empiric antifungal therapy initiated by physician preference for the treatment of suspected invasive candidiasis.	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	Total of all reporting groups
Overall Participants	17	47	64
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 64.7%	30 63.8%	41 64.1%
>=65 years	6 35.3%	17 36.2%	23 35.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53 (19)	53 (20)	53 (19)
Sex: Female, Male (Count of Participants)
Female	4 23.5%	16 34%	20 31.3%
Male	13 76.5%	31 66%	44 68.8%
Region of Enrollment (participants) [Number]
United States	17 100%	47 100%	64 100%

Outcome Measures

1. Primary Outcome

Title	Clinical Utility of Biweekly β-D-glucan (BDG) Testing in At-risk Intensive Care Unit (ICU) Patients.
Description	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

Outcome Measure Data

Analysis Population Description

Two study subjects in the preemptive therapy arm were excluded from the analysis of assay sensitivity and specific due to icteric serum specimens.

Arm/Group Title	Active Surveillance, Preemptive Therapy	Standard Care, Empiric Treatment
Arm/Group Description	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	Standard care group. Empiric antifungal therapy initiated by physician preference for the treatment of suspected invasive candidiasis.
Measure Participants	45	17
True BDG Positives	3 17.6%	3 6.4%
True BDG Negative	19 111.8%	9 19.1%
False BDG Positives	23 135.3%	5 10.6%
False BGD Negatives	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Surveillance, Preemptive Therapy, Standard Care, Empiric Treatment
	Comments	Clinical sensitivity of the BDG test was calculated for both study groups combined
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Sensitivity
	Estimated Value	100
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Sensitivity [1] = (True positives [n=6]/ True positives + False negatives [n=6])

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Surveillance, Preemptive Therapy, Standard Care, Empiric Treatment
	Comments	Clinical specificity of the BDG test was calculated for the study groups combined
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Specificity
	Estimated Value	50
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Specificity [0.50]= True negatives [n=28]/ True negatives + False positives [56])

2. Secondary Outcome

Title	Validate Gene Expression Signatures Predictive of IC
Time Frame	Study Completion, an average of 17 days

Outcome Measure Data

Analysis Population Description

Data was not collected for this outcome measure.

Arm/Group Title	Active Surveillance, Preemptive Therapy	Standard Care, Empiric Treatment
Arm/Group Description	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	Standard care group. Empiric antifungal therapy initiated by physician preference for the treatment of suspected invasive candidiasis.
Measure Participants	0	0

3. Secondary Outcome

Title	Incidence of Proven or Probable Invasive Fungal Infection (IFI)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Standard Care, Empiric Treatment	Active Surveillance, Preemptive Therapy
Arm/Group Description	Standard care group. Empiric antifungal therapy initiated by physician preference for the treatment of suspected invasive candidiasis.	Active surveillance group. Preemptive therapy initiated in response to a positive 1,3-beta-D glucan (BDG) test for the presumptive early treatment of invasive candidiasis
Measure Participants	17	41
Number [participants]	3 17.6%	3 6.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active Surveillance, Preemptive Therapy, Standard Care, Empiric Treatment
	Comments	The clinic sensitivity of the BDG test was calculated for both study groups combined
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent Sensitivity
	Estimated Value	100
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Sensitivity = (true positives [n=6]/true positives + false negative [n=6])

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Active Surveillance, Preemptive Therapy, Standard Care, Empiric Treatment
	Comments	The clinical specificity of the BDG test was calculated for both study groups combined
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent Specificity
	Estimated Value	52
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Specificity [0.52]= (True negatives [n=30]/True negatives + false positives [n=58])

4. Primary Outcome

Title	Safety and Tolerability of Preemptive Anidulafungin
Description	reported as the Number of Adverse Events Possibly Related to Study Drug
Time Frame	weekly until ICU discharge

Outcome Measure Data

Analysis Population Description

Subjects receiving at least 1 dose of anidulafungin were assessed.

Arm/Group Title	Standard Care, Empiric Treatment	Active Surveillance, Preemptive Therapy
Arm/Group Description	Standard care group. Empiric antifungal therapy initiated by physician preference for the treatment of suspected invasive candidiasis.	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
Measure Participants	17	45
Number [events]	0	10

Adverse Events

Arm/Group Title	Standard Care, Empiric Treatment		Active Surveillance, Preemptive Therapy
Arm/Group Description	Standard care group. Empiric antifungal therapy initiated by physician preference for the treatment of suspected invasive candidiasis.		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
All Cause Mortality
	Standard Care, Empiric Treatment		Active Surveillance, Preemptive Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Standard Care, Empiric Treatment		Active Surveillance, Preemptive Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/47 (0%)
Other (Not Including Serious) Adverse Events
	Standard Care, Empiric Treatment		Active Surveillance, Preemptive Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		10/47 (21.3%)
Blood and lymphatic system disorders
Thrombocytopenia	0/5 (0%)	0	2/21 (9.5%)	2
Hepatobiliary disorders
Abnormal liver function tests	0/5 (0%)	0	9/21 (42.9%)	9
Metabolism and nutrition disorders
Hypocalcemia	0/5 (0%)	0	2/21 (9.5%)	2

Limitations/Caveats

This study represents a 1st attempt at preemptive antifungal therapy based on the fungal biomarker 1,3-Beta-D-Glucan in the intensive care unit. Main limitation: the small number of subjects with proven/probable invasive candidiasis.

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.