Risk Of Severe Hepatic Injury In Patients With Invasive Candidiasis Treated With Echinocandins

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01213823
• Collaborator: (none)
• Enrollment: 536
• Duration (Months): 31.9

Study Details

Study Description

Brief Summary

The purpose of this study is to estimate the relative risk of severe hepatic injury in hospitalized patients with invasive candidiasis and candidemia who received anidulafungin, compared to patients who received caspofungin and/or micafungin.

Condition or Disease	Intervention/Treatment	Phase
Invasive Candidiasis; Candidemia	Other: Does not apply; Other: Does not apply

Study Design

• Study Type: Observational
• Actual Enrollment: 536 participants
• Observational Model: Case-Control
• Time Perspective: Retrospective
• Official Title: Risk Of Severe Hepatic Injury In Patients With Invasive Candidiasis Treated With Echinocandins
• Study Start Date: Sep 1, 2008
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Cases Potential cases were defined as patients with a diagnosis of severe hepatic injury identified in the acute-care inpatient cohort using ICD-9 codes associated with the case definition of severe liver injury. Case status was validated by a Consultant Gastroenterologist blinded to study drug exposure via medical record review using an apriori algorithm. Only validated cases were included in the analysis (N=69)	Other: Does not apply; This is a non-interventional study, therefore the intervention type / name do not apply
Controls Controls were defined as patients without a diagnosis of severe hepatic injury (i.e. with no ICD-9 codes associated with the case definition of severe liver injury) selected at random from the same acute-care inpatient cohort as cases (N=467)	Other: Does not apply; This is a non-interventional study, therefore the intervention type / name do not apply

Outcome Measures

Primary Outcome Measures

1. Number of Any Severe Hepatic Injury Cases and Matched Controls [01 June 2006 to 30 June 2008 (up to 25 Months)]

   Severe hepatic injury (acute/subacute necrosis of liver, hepatic coma, hepatorenal syndrome, or hepatitis unspecified) classified as: 1) acute liver failure (associated with encephalopathy and/or coagulopathy in absence of underlying liver disease); 2) Hy's Law Criteria (serum alanine transaminase [ALT] levels greater than [>]3 times the upper limit of normal [ULN] and direct bilirubin >2 times ULN and absence of alkaline phosphatase elevation); 3) ALT levels greater than or equal to (≥) 10 times ULN; 4) ALT levels >3 times ULN and less than (<) 10 times ULN; or 5) classified by clinician. Disease Related Group (DRG) severity of illness coding was reported for severe hepatic injury cases and matched controls.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Acute-care inpatients;

• Aged 18 years or older;

• At least one dose of echinocandin therapy during the hospitalization;

• Primary or secondary ICD-9 discharge diagnosis of invasive candidiasis / candidemia.

Exclusion Criteria:

• < 18 years of age;

• No recorded echinocandin therapy during hospitalization;

• Acetaminophen hepatotoxicity;

• Pre-existing autoimmune hepatitis;

• Autoimmune/metabolic liver disease;

• Primary biliary cirrhosis;

• Primary sclerosing cholangitis and orthotopic liver transplantation.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT01213823
• Other Study ID Numbers: A8851024
• First Posted: Oct 4, 2010
• Last Update Posted: Mar 30, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Pfizer: invasive candidiasis; candidemia; severe hepatic injury; echinocandins; anidulafungin; caspofungin; micafungin
• Additional relevant MeSH terms: Candidiasis; Candidemia; Candidiasis, Invasive

Study Results

Participant Flow

Arm/Group Title	Cases	Controls
Arm/Group Description	Potential cases were to be defined as participants with invasive candidiasis (candidiasis of the lung, disseminated candidiasis, candidal endocarditis, candidal meningitis, candidal enteritis, or candidiasis of unspecified site) with severe hepatic injury (acute/subacute necrosis of liver, hepatic coma, hepatorenal syndrome, or hepatitis unspecified) classified into one of the following categories: 1) acute liver failure (associated with encephalopathy and/or coagulopathy in absence of underlying liver disease); 2) Hy's Law Criteria (serum alanine transaminase [ALT] levels greater than [>]3 times the upper limit of normal [xULN] and total bilirubin >2 xULN, with absence of alkaline phosphatase elevation; 3) serum ALT levels greater than or equal to (≥)10 xULN; 4) ALT levels >3 xULN and less than (<)10 xULN; or 5) as determined by clinician.	Controls were to be defined as participants with invasive candidiasis (candidiasis of the lung, disseminated candidiasis, candidal endocarditis, candidal meningitis, candidal enteritis, or candidiasis of unspecified site) without a diagnosis of severe hepatic injury.
Period Title: Overall Study
STARTED	69	467
COMPLETED	69	467
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cases	Controls	Total
Arm/Group Description	Potential cases were to be defined as participants with invasive candidiasis (candidiasis of the lung, disseminated candidiasis, candidal endocarditis, candidal meningitis, candidal enteritis, or candidiasis of unspecified site) with severe hepatic injury (acute/subacute necrosis of liver, hepatic coma, hepatorenal syndrome, or hepatitis unspecified) classified into one of the following categories: 1) acute liver failure (associated with encephalopathy and/or coagulopathy in absence of underlying liver disease); 2) Hy's Law Criteria (serum alanine transaminase [ALT] levels greater than [>]3 times the upper limit of normal [xULN] and total bilirubin >2 xULN, with absence of alkaline phosphatase elevation; 3) serum ALT levels greater than or equal to (≥)10 xULN; 4) ALT levels >3 xULN and less than (<)10 xULN; or 5) as determined by clinician.	Controls were to be defined as participants with invasive candidiasis (candidiasis of the lung, disseminated candidiasis, candidal endocarditis, candidal meningitis, candidal enteritis, or candidiasis of unspecified site) without a diagnosis of severe hepatic injury.	Total of all reporting groups
Overall Participants	69	467	536
Age, Customized (Number) [Number]
18-24 years	1 1.4%	12 2.6%	13 2.4%
25-34 years	1 1.4%	26 5.6%	27 5%
35-44 years	5 7.2%	42 9%	47 8.8%
45-54 years	15 21.7%	73 15.6%	88 16.4%
55-64 years	16 23.2%	76 16.3%	92 17.2%
65-74 years	18 26.1%	111 23.8%	129 24.1%
Greater than or equal to (>=) 75 years	13 18.8%	127 27.2%	140 26.1%
Sex: Female, Male (Count of Participants)
Female	29 42%	245 52.5%	274 51.1%
Male	40 58%	222 47.5%	262 48.9%

Outcome Measures

1. Primary Outcome

Title	Number of Any Severe Hepatic Injury Cases and Matched Controls
Description	Severe hepatic injury (acute/subacute necrosis of liver, hepatic coma, hepatorenal syndrome, or hepatitis unspecified) classified as: 1) acute liver failure (associated with encephalopathy and/or coagulopathy in absence of underlying liver disease); 2) Hy's Law Criteria (serum alanine transaminase [ALT] levels greater than [>]3 times the upper limit of normal [ULN] and direct bilirubin >2 times ULN and absence of alkaline phosphatase elevation); 3) ALT levels greater than or equal to (≥) 10 times ULN; 4) ALT levels >3 times ULN and less than (<) 10 times ULN; or 5) classified by clinician. Disease Related Group (DRG) severity of illness coding was reported for severe hepatic injury cases and matched controls.
Time Frame	01 June 2006 to 30 June 2008 (up to 25 Months)

Outcome Measure Data

Analysis Population Description

Acute-care participants, with at least 1 dose of echinocandin antifungal therapy and a primary or secondary International Classification of Diseases 9 (ICD-9).

Arm/Group Title	Cases	Controls
Arm/Group Description	Potential cases were to be defined as participants with invasive candidiasis (candidiasis of the lung, disseminated candidiasis, candidal endocarditis, candidal meningitis, candidal enteritis, or candidiasis of unspecified site) with severe hepatic injury (acute/subacute necrosis of liver, hepatic coma, hepatorenal syndrome, or hepatitis unspecified) classified into one of the following categories: 1) acute liver failure (associated with encephalopathy and/or coagulopathy in absence of underlying liver disease); 2) Hy's Law Criteria (serum alanine transaminase [ALT] levels greater than [>]3 times the upper limit of normal [xULN] and total bilirubin >2 xULN, with absence of alkaline phosphatase elevation; 3) serum ALT levels greater than or equal to (≥)10 xULN; 4) ALT levels >3 xULN and less than (<)10 xULN; or 5) as determined by clinician.	Controls were to be defined as participants with invasive candidiasis (candidiasis of the lung, disseminated candidiasis, candidal endocarditis, candidal meningitis, candidal enteritis, or candidiasis of unspecified site) without a diagnosis of severe hepatic injury.
Measure Participants	69	467
DRG Severity Coding 1	0 0%	1 0.2%
DRG Severity Coding 2	0 0%	10 2.1%
DRG Severity Coding 3	1 1.4%	66 14.1%
DRG Severity Coding 4	68 98.6%	389 83.3%

Adverse Events

Adverse Event Reporting Description	In this retrospective observational study, adverse events were not collected as a part of this study.
Arm/Group Title	Cases		Controls
Arm/Group Description	Potential cases were to be defined as participants with invasive candidiasis (candidiasis of the lung, disseminated candidiasis, candidal endocarditis, candidal meningitis, candidal enteritis, or candidiasis of unspecified site) with severe hepatic injury (acute/subacute necrosis of liver, hepatic coma, hepatorenal syndrome, or hepatitis unspecified) classified into one of the following categories: 1) acute liver failure (associated with encephalopathy and/or coagulopathy in absence of underlying liver disease); 2) Hy's Law Criteria (serum alanine transaminase [ALT] levels greater than [>]3 times the upper limit of normal [xULN] and total bilirubin >2 xULN, with absence of alkaline phosphatase elevation; 3) serum ALT levels greater than or equal to (≥)10 xULN; 4) ALT levels >3 xULN and less than (<)10 xULN; or 5) as determined by clinician.		Controls were to be defined as participants with invasive candidiasis (candidiasis of the lung, disseminated candidiasis, candidal endocarditis, candidal meningitis, candidal enteritis, or candidiasis of unspecified site) without a diagnosis of severe hepatic injury.
All Cause Mortality
	Cases		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Cases		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Cases		Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

Study results were invalidated due to lack of temporality, a critical methodological element of the study that was never established for the majority of the cases of severe hepatic injury.

More Information

Certain Agreements

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

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.