Fosamprenavir in Pts With Hepatic Impairment

May 2, 2013 updated by: GlaxoSmithKline

HI FPV Study: Using Observational Cohorts to Monitor Safety of Fosamprenavir in Patients With Mild/Moderate Hepatic Impairment

APV10017 was a pharmacokinetic study that evaluated the pharmacokinetics, safety and tolerability of fosamprenavir/ritonavir (FPV/RTV) at reduced doses over 14 days in HIV-infected subjects with mild to moderate hepatic impairment (HI). Based on these data, two new regimens have recently been approved by the EMEA and FDA in these patient groups; FPV 700mg BID/RTV 100mg QD for those with mild HI (Child-Pugh score 4-6) and FPV 450mg BID/RTV 100mg QD for those with moderate HI (Child Pugh score 7-9). The Committee for Medicinal Products for Human Use (CHMP) has requested longer-term safety data among this hepatically impaired HIV-infected population who have received the recently updated FPV/RTV dosing regimens.

An observational cohort study will be conducted using routinely collected data in three European HIV patient cohorts with a high proportion of hepatitis co-infected individuals. Patients who received FPV/RTV will be followed to address the following objectives.

Primary: To assess the safety and tolerability of FPV/RTV-based ART in subjects with mild to moderate hepatic impairment.

Secondary: A). To compare the safety and tolerability of FPV/RTV-based ART in subjects with mild to moderate hepatic impairment when compared to FPV/RTV-based ART in hepatitis B (HBV) or hepatitis C (HCV) co-infected subjects with normal hepatic function. B). To compare the safety and tolerability of FPV/RTV-based ART to lopinavir/ritonavir LPV/RTV-based ART in subjects with mild to moderate hepatic impairment.

Study Overview

Detailed Description

Patients were not recruited for nor enrolled in this study. This study is a retrospective observational study. Data from medical records or insurance claims databases are anonymised and used to develop a patient cohort. All diagnoses and treatment are recorded in the course of routine medical practice.

Study Type

Observational

Enrollment (Actual)

167

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

The source population is from three HIV patient cohorts; ICONA, HEPAVIH and MASTER cohort in Europe. Data from these cohorts are comprised of the clinical records (or a defined subset thereof) of HIV infected patients. The ICONA Foundation study collects data on HIV infected individuals from 67 infectious disease centres across Italy and has been established since 1997. The ICONA cohort only includes patients who are treatment naïve at initial presentation. HEPAVIH is a cohort of HIV-hepatitis co-infected patients, identified from three other ongoing French HIV cohorts: RIBAVIC, SEROCO and AQUITAINE and an additional 12 clinical departments. The MASTER cohort collects data on HIV infected individuals from centres across Italy and includes treatment-experienced and naive patients.

Description

Inclusion Criteria:

  • HIV infected patients with or without hepatic impairment coinfected with HBV or HCV who started FPV/RTV-based therapy on or after January 1, 2008. The FPV/RTV exposed patients will be stratified into four groups for analysis (see interventions A-D for label/description above), according to their degree of baseline hepatic impairment, which will be defined according to FPV/RTV dose received (and APRI score for interventions A and D). The LPV/RTV intervention group must have started this therapy at approved standard doses on or after January 1, 2008.

Exclusion Criteria:

  • Receipt of FPV/RTV or LPV/RTV within the year preceding the baseline visit.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
HIV pts w/ HBV or HCV, w/ or w/o mild to moderate HI
Patients with HIV coinfected with HBV or HCV with or without mild to moderate HI who are enrolled in one of the participating HIV patient cohorts. These patients will be exposed to FPV/RTV or LPV/RTV.
HIV subjects with HBV or HCV co-infection but normal hepatic function, defined by receipt of FPV 700mg BID/RTV 100mg BID and a baseline AST-platelet ratio index (APRI) score of <2.0.
HIV subjects with mild hepatic impairment, defined by receipt of the recommended reduced FPV/RTV dose (700mg BID/100mg QD).
HIV subjects with moderate hepatic impairment, defined by receipt of FPV 450mg BID/RTV 100mg QD.
HIV subjects receiving the standard dose of FPV/RTV despite evidence of abnormal hepatic function according to APRI score: HIV subjects with HBV or HCV co-infection, receipt of FPV 700mg BID/RTV 100mg BID and a baseline APRI score of ≥2.0.
HIV subjects coinfected with HBV or HCV who have initiated standard doses of LPV 400mg/RTV 100mg and enrolled in the same cohorts as the FPV/RTV exposed subjects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Events of ALT Elevation After Baseline, Controlling for APRI Score and Other Variables
Time Frame: The incidence of these events was assessed over time during Year 1, censoring participants' follow-up at date of last ALT
An elevation in ALT is defined as a single value >200 IU/I.
The incidence of these events was assessed over time during Year 1, censoring participants' follow-up at date of last ALT
Number of Events of an Elevation in ALT After Baseline by Treatment Group, Controlling for APRI-score, and Other Variables
Time Frame: Incidence of these events was assessed over time during Year 1, censoring patients' follow-up at date of last ALT
An elevation in ALT is defined as a single value >200 IU/I.
Incidence of these events was assessed over time during Year 1, censoring patients' follow-up at date of last ALT
Number of Events of an Elevation in ALT After Baseline by Treatment Group, Controlling for FIB-score, and Other Variables
Time Frame: Incidence was assessed over time during Year 1
An elevation in ALT is defined as a single value >200 IU/I.
Incidence was assessed over time during Year 1
Number of Events of an Elevation in ALT After Baseline by Treatment Group, Controlling for Current Values of CD4 and Platelet Counts
Time Frame: Incidence was assessed over time during Year 1
An elevation in ALT is defined as a single value >200 IU/I.
Incidence was assessed over time during Year 1

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Events of First Discontinuation of FPV/RTV or LPV/RTV Alone by Treatment Group, Controlling for APRI-score, and Other Variables
Time Frame: Incidence was assessed over time during Year 1
A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV.
Incidence was assessed over time during Year 1
Number of Events of First Discontinuation of FPV/RTV or LPV/RTV Alone by Treatment Group, Controlling for FIB-score, and Other Variables
Time Frame: Incidence was assessed over time during Year 1
A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV.
Incidence was assessed over time during Year 1
Number of Events of First Discontinuation of FPV/RTV- or LPV/RTV Alone by Treatment Group, Controlling for Current Values of CD4 and Platelet Counts
Time Frame: Incidence was assessed over time during Year 1
A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV
Incidence was assessed over time during Year 1
Number of Events of First Discontinuation of FPV/RTV or LPV/RTV Alone Due to Adverse Events Only
Time Frame: Incidence was assessed over time during Year 1
A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV; where the reason for stopping is attritubed to adverse events only
Incidence was assessed over time during Year 1
Number of Events of First Discontinuation of One or More Drugs Included in the FPV/RTV- or LPV/RTV-based Regimen by Treatment Group, Controlling for APRI-score and Other Variables (See Comments)
Time Frame: Incidence was assessed over time during Year 1
A first discontinuation is defined as the first occurrence of stopping one or more drugs in the FPV/RTV or LPV/RTV-based regime
Incidence was assessed over time during Year 1
Number of Events of First Discontinuation of One or More Drugs Included in the FPV/RTV- or LPV/RTV-based Regimen by Treatment Group, Controlling for FIB-score and Other Variables
Time Frame: Incidence was assessed over time during Year 1
A first discontinuation is defined as the first occurrence of stopping one or more drugs in the FPV/RTV or LPV/RTV-based regime.
Incidence was assessed over time during Year 1
Number of Events of First Discontinuation of One or More Drugs Included in the FPV/RTV- or LPV/RTV-based Regimen by Treatment Group, Controlling Current Values of CD4 and Platelet Counts
Time Frame: Incidence was assessed over time during Year 1
A first discontinuation is defined as the first occurrence of stopping one or more drugs in the FPV/RTV or LPV/RTV-based regime.
Incidence was assessed over time during Year 1
Number of Events of Discontinuation of One or More Drugs in the FPV/RTV- or LPV/RTV Regimen Due to Adverse Events Only
Time Frame: Incidence was assessed over time during Year 1
Defined as the occurrence of stopping FPV/RTV or LPV/RTV; where the reason for stopping is attributed to adverse events only
Incidence was assessed over time during Year 1
Number of Events of First Discontinuation of FPV/RTV or LPV/RTV Alone Due to the Indicated Adverse Events
Time Frame: Incidence was assessed over time during Year 1
Defined as the first occurrence of stopping FPV/RTV or LPV/RTV; where the reason for stopping is attributed to adverse events only. Adverse events can only be attributed to the body system stated (no further specificity is available).
Incidence was assessed over time during Year 1
Number of Participants Who Discontinued the Indicated Antiretrovirals for the First Time After Starting FPV/r or LPV/r
Time Frame: Assessed over time during Year 1
Antiretrovirals discontinued for the first time after starting FPV/r or LPV/r
Assessed over time during Year 1
Number of Participants With the Indicated Major Reasons for Discontinuing One or More Drugs in the FPV/r or LPV/r Regimen
Time Frame: Assessed over time during Year 1
Major reasons for discontinuing one or more drugs in the FPV/r or LPV/r regimen
Assessed over time during Year 1
Number of Participants for Which the Reason for Discontinuation of One or More Drugs in the FPV/RTV or LPV/RTV Regimen Was Due to Adverse Events Only
Time Frame: The incidence of these events was assessed over time during Year 1
Number of participants for which the reason for discontinuation of one or more drugs in the FPV/RTV or LPV/RTV regimen was due to adverse events only. Adverse events can only be attributed to the body system stated (no further specificity is available)
The incidence of these events was assessed over time during Year 1
Incidence Rates Per 100 Person-years of Follow-up (PYFU) of Study Main Outcome Measures
Time Frame: Incidence of these events was assessed over time during Year 1
Incidence rates per 100 person-years of follow-up of study primary outcome. The numbers analyzed in the category titles represent the number of patients with each event. Incidence rate is the number of new cases per population in a given time period, where the denominator is the sum of the person-time of the at-risk population.
Incidence of these events was assessed over time during Year 1

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Median Length of Participant Follow-up and Length of Time on Antiretroviral Therapy (ART) at Baseline
Time Frame: Baseline
Participant characteristics at baseline are presented according to treatment group. ART is used for the treatment of HIV.
Baseline
Cluster of Differentiation (CD4) Count at Baseline
Time Frame: Baseline
Participant characteristics at baseline according to treatment group. CD4 count is a measurement of how many functional CD4 T-cells are circulating in the blood. The lower the absolute CD4 count, the weaker the immune system.
Baseline
Median Aspartate Aminotransferase (AST)-Platelet Ratio Index (APRI) Score at Baseline
Time Frame: Baseline
The APRI score (AST to platelet ratio index) is an index comprised of biochemical values and is used to determine the degree of hepatic fibrosis. It is calculated as follows: APRI score = ([AST level/Upper Limit Normal]/Platelet counts) x 100. AST = Aspartate aminotransferase. In general, APRI scores range from 0 to >2.0, where scores <0.5 indicate no significant fibrosis, scores >1.5 indicate significant fibrosis, and scores >2.0 have been shown to be best correlated with the presence of cirrhosis.
Baseline
Median FIB (a Model of End-stage Liver Disease) Score at Baseline
Time Frame: Baseline
The FIB-4 score is an index that combines biochemical values (platelets, ALT, AST) and age to determine the degree of hepatic fibrosis. FIB-4 = (Age x AST)/(Platelet counts x ALT1/2). The FIB-4 score ranges between values of 0 to 13. A score of <1.45 indicates no/moderate fibrosis (F0-F1-F2-F3 in the ISHAK classification of fibrosis), whereas a score >3.25 is indicative of extensive fibrosis or cirrhosis (F4-F5-F6). The ISHAK classification of fibrosis is a commonly used scoring system that stages fibrosis from 0-6 (1-2, portal fibrotic expansion; 3-4, bridging fibrosis; 5-6, cirrhosis).
Baseline
Median Model of End-stage Liver Disease (MELD) Score at Baseline
Time Frame: Baseline
MELD is a scoring system for assessing the severity of chronic liver disease and is used to predict participant survival. It is calculated using biochemical values as follows: MELD = (0.957 x Log[Creatinine]) + (0.378 x Log[Bilirubin]) + (1.120 x Log[INR]) + 0.6431. INR = International Normalized Ratio for prothrombin time. MELD scores range between 0 and 40, with 40 being the most severe, i.e., 100% mortality. In interpreting the MELD score in hospitalized participants, the 3-month mortality is: score >=40, 100% mortality; 30-39, 83% mortality; 20-29, 76% mortality; 10-19, 27% mortality.
Baseline
Median ALT and AST Scores at Baseline
Time Frame: Baseline
Participants characteristics at baseline according to treatment group.
Baseline
Median Blood Platelet Count at Baseline
Time Frame: Baseline
Participant characteristics at baseline according to treatment group.
Baseline
Median Bilirubin Level at Baseline
Time Frame: Baseline
Participant characteristics at baseline according to treatment group.
Baseline

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2009

Primary Completion (Actual)

March 1, 2012

Study Completion (Actual)

March 1, 2012

Study Registration Dates

First Submitted

January 21, 2010

First Submitted That Met QC Criteria

January 21, 2010

First Posted (Estimate)

January 22, 2010

Study Record Updates

Last Update Posted (Estimate)

May 7, 2013

Last Update Submitted That Met QC Criteria

May 2, 2013

Last Verified

April 1, 2013

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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