Fosamprenavir in Pts With Hepatic Impairment

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01054586
First received: January 21, 2010
Last updated: May 2, 2013
Last verified: April 2013
  Purpose

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.


Condition Intervention
Infection, Human Immunodeficiency Virus
Drug: Intervention A Standard dose
Drug: Intervention B Reduced Dose
Drug: Intervention C
Drug: Intervention D
Drug: Intervention E

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: HI FPV Study: Using Observational Cohorts to Monitor Safety of Fosamprenavir in Patients With Mild/Moderate Hepatic Impairment

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    An elevation in ALT is defined as a single value >200 IU/I.

  • 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 ] [ Designated as safety issue: No ]
    An elevation in ALT is defined as a single value >200 IU/I.

  • 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 ] [ Designated as safety issue: No ]
    An elevation in ALT is defined as a single value >200 IU/I.

  • 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 ] [ Designated as safety issue: No ]
    An elevation in ALT is defined as a single value >200 IU/I.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV.

  • 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 ] [ Designated as safety issue: No ]
    A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV.

  • 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 ] [ Designated as safety issue: No ]
    A first discontinuation is defined as the first occurrence of stopping FPV/RTV or LPV/RTV

  • 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 ] [ Designated as safety issue: No ]
    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

  • 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 ] [ Designated as safety issue: No ]
    A first discontinuation is defined as the first occurrence of stopping one or more drugs in the FPV/RTV or LPV/RTV-based regime

  • 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 ] [ Designated as safety issue: No ]
    A first discontinuation is defined as the first occurrence of stopping one or more drugs in the FPV/RTV or LPV/RTV-based regime.

  • 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 ] [ Designated as safety issue: No ]
    A first discontinuation is defined as the first occurrence of stopping one or more drugs in the FPV/RTV or LPV/RTV-based regime.

  • 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 ] [ Designated as safety issue: No ]
    Defined as the occurrence of stopping FPV/RTV or LPV/RTV; where the reason for stopping is attributed to adverse events only

  • 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 ] [ Designated as safety issue: No ]
    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).

  • 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 ] [ Designated as safety issue: No ]
    Antiretrovirals discontinued for the first time after starting FPV/r or LPV/r

  • 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 ] [ Designated as safety issue: No ]
    Major reasons for discontinuing one or more drugs in the FPV/r or LPV/r regimen

  • 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 ] [ Designated as safety issue: No ]
    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)

  • 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 ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Median Length of Participant Follow-up and Length of Time on Antiretroviral Therapy (ART) at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Participant characteristics at baseline are presented according to treatment group. ART is used for the treatment of HIV.

  • Cluster of Differentiation (CD4) Count at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Median Aspartate Aminotransferase (AST)-Platelet Ratio Index (APRI) Score at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Median FIB (a Model of End-stage Liver Disease) Score at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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).

  • Median Model of End-stage Liver Disease (MELD) Score at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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.

  • Median ALT and AST Scores at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Participants characteristics at baseline according to treatment group.

  • Median Blood Platelet Count at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Participant characteristics at baseline according to treatment group.

  • Median Bilirubin Level at Baseline [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Participant characteristics at baseline according to treatment group.


Enrollment: 167
Study Start Date: January 2009
Study Completion Date: March 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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.
Drug: Intervention A Standard dose
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.
Drug: Intervention B Reduced Dose
HIV subjects with mild hepatic impairment, defined by receipt of the recommended reduced FPV/RTV dose (700mg BID/100mg QD).
Drug: Intervention C
HIV subjects with moderate hepatic impairment, defined by receipt of FPV 450mg BID/RTV 100mg QD.
Drug: Intervention D
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.
Drug: Intervention E
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.

Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01054586

Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01054586     History of Changes
Other Study ID Numbers: 111949, WEUKSTV2430, EPI40537
Study First Received: January 21, 2010
Results First Received: January 14, 2011
Last Updated: May 2, 2013
Health Authority: United Kingdon: No Health Authority

Keywords provided by GlaxoSmithKline:
antiretroviral therapy
hepatic impairment
HIV

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Acquired Immunodeficiency Syndrome
HIV Infections
Liver Diseases
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Digestive System Diseases
Fosamprenavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014