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A Study Of Maraviroc In HIV Co-Infected Subjects With Hepatitis C And/Or Hepatitis B

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ClinicalTrials.gov Identifier: NCT01327547
Recruitment Status : Completed
First Posted : April 1, 2011
Results First Posted : November 14, 2014
Last Update Posted : December 6, 2017
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
ViiV Healthcare

March 22, 2011
April 1, 2011
April 9, 2014
November 14, 2014
December 6, 2017
May 18, 2011
April 23, 2013   (Final data collection date for primary outcome measure)
Percentage of Participants With Grade 3 and Grade 4 Alanine Aminotransferase (ALT) Abnormalities at Week 48 [ Time Frame: 48 weeks ]
Percentage of participants with Grade 3 or Grade 4 ALT abnormalities defined as >5x upper limit of normal (ULN) for participants whose baseline ALT ≤ULN, or >3.5x baseline for participants whose baseline ALT >ULN, up to and including Week 48 in the maraviroc arm versus the placebo arm. The baseline was defined as the last measurement prior to Day 1 dosing.
Percentage of subjects with Grade 3 and Grade 4 ALT abnormalities defined as >5x upper limit of normal (ULN) for subjects whose baseline ALT ≤ULN, or or >3.5x baseline for subjects whose baseline ALT >ULN. [ Time Frame: 48 weeks ]
At Week 48 in the maraviroc arm versus the placebo arm.
Complete list of historical versions of study NCT01327547 on ClinicalTrials.gov Archive Site
  • Percentage of Participants With Grade 3 and Grade 4 ALT Abnormalities Through Week 144 [ Time Frame: Week 96 and 144 ]
    Percentage of participants with Grade 3 or Grade 4 ALT abnormalities defined as >5x upper limit of normal (ULN) for participants whose baseline ALT ≤ULN, or >3.5x baseline for participants whose baseline ALT >ULN, up to and including Week 96 and Week 144 in the maraviroc arm versus the placebo arm. The baseline was defined as the last measurement prior to Day 1 dosing.
  • Time to Development of Grade 3 and Grade 4 ALT Abnormalities [ Time Frame: 144 weeks ]
    Time taken in days to development of Grade 3 and Grade 4 ALT abnormalities defined as >5x ULN for participants whose baseline ALT ≤ULN, or >3.5x baseline for participants whose baseline ALT >ULN, at Week 144.
  • Percentage of Participants With Grade 3 and Grade 4 ALT Abnormalities Associated With a Change From Baseline ALT >100 IU/L [ Time Frame: 144 weeks ]
    Percentage of participants who had Grade 3 and Grade 4 ALT abnormalities associated with a change from baseline ALT >100 IU/L during the 144-week period. Baseline will be defined as the last measurement prior to Day 1 dosing.
  • Time to Development of Grade 3 and Grade 4 ALT Abnormalities at Week 144 Associated With a Change From Baseline ALT >100 IU/L [ Time Frame: 144 weeks ]
    Time to development of Grade 3 and Grade 4 ALT abnormalities associated with a change from baseline ALT >100 IU/L during the 144-week period. Baseline will be defined as the last measurement prior to Day 1 dosing.
  • Number of Participants With Hy's Law Abnormalities Through Week 144 [ Time Frame: 144 weeks ]
    Hy's law was defined as a total bilirubin >2x ULN with a simultaneous ALT or aspartate transaminase (AST)>3x ULN, excluding participants with an alkaline phosphatase>3x ULN
  • Percentage of Participants With Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Concentration <40 Copies/mL at Week 48, 96 and 144 [ Time Frame: Week 48, 96 and 144 ]
    The Food and Drug Administration (FDA's) snapshot algorithm was used to derive the efficacy endpoint of the proportion of participants with HIV-1 RNA <40 copies/mL at Week 48. This algorithm included the missing data imputation method and used the plasma HIV-1 RNA concentration in the visit window only, followed the "virology-first principle" and considered a participant who had a missing plasma HIV-1 RNA concentration, or switched to a prohibited background anti-retroviral regimen or discontinues from the study or study drug as a failure (MSDF).
  • Mean Change From Baseline in CD4+ and CD8+ Cell Counts at Week 48, 96 and 144 [ Time Frame: Week 48, 96 and 144 ]
    Immunologic response (magnitude of change in CD4+ and CD8+ cell counts from baseline) was measured. Baseline value for CD4 and CD8 is defined as the pre-dose measurement taken at Day 1 visit.
  • Mean Change From Baseline in CD38 Expression on CD4 and CD8 Cells at Weeks 48, 96 and 144 [ Time Frame: 48, 96 and 144 weeks ]
    Plasma samples were used to determine markers of immune activation namely CD38 expression on CD4 and CD8 cells.
  • Mean Change From Baseline in Markers of Immune Activation: C-reactive Protein (CRP) - Week 48, 96 and 144. [ Time Frame: 48, 96 and 144 weeks ]
    Plasma samples were used to determine markers of immune activation namely CRP.
  • Mean Change From Baseline in Markers of Immune Activation: D Dimer - Week 48, 96 and 144 [ Time Frame: 48, 96 and 144 weeks ]
    Plasma samples were used to determine markers of immune activation namely D-Dimer.
  • Mean Change From Baseline in Markers of Immune Activation: Transforming Growth Factor-beta (TGF Beta) - Week 48, 96 and 144 [ Time Frame: 48, 96 and 144 weeks ]
    Plasma samples were used to determine markers of immune activation namely TGF beta.
  • Mean Change From Baseline in Log10 Plasma Hepatitis C Virus (HCV) RNA at Week 48, 96 and 144 [ Time Frame: 48, 96 and 144 weeks ]
    Plasma samples were used to determine HCV RNA using the Roche COBAS Ampliprep/COBAS HCV Taqman assay, RUO version (LOD=15 IU/mL).Baseline value for HCV RNA/HBV DNA is defined as the pre-dose measurement taken at Day 1 visit.
  • Mean Change From Baseline in Plasma Hepatitis B Virus (HBV) DNA at Week 48, 96 and 144 [ Time Frame: 48, 96 and 144 weeks ]
    Plasma samples were used to determine HBV DNA using the Roche COBAS Taqman HBV assay. Baseline value for HCV RNA/HBV DNA is defined as the pre-dose measurement taken at Day 1 visit.
  • Mean Change From Baseline in Enhanced Liver Fibrosis (ELF) Test at Week 48, 96 and 144 [ Time Frame: 48, 96 and 144 weeks ]

    The markers of fibrosis assessed in this test comprised hyaluronic acid (CHA), tissue inhibitor of metalloproteinase (CTIMP1) and procollagen III N-terminal peptide (CP3NP); these are components of the extracellular matrix and basement sinusoidal membrane of the liver and are elevated during activation of the stellate cell. The ELF tests were performed on an ADVIA Centaur XP and the composite score was calculated as follows: ELF score = 2.278 + 0.851 ln(CHA) + 0.751 ln (CP3NP) + 0.394 ln(CTIMP1).

    ELF score < 7.7: no to mild fibrosis; ≥ 7.7 — < 9.8: Moderate fibrosis; ≥ 9.8 — < 11.3: Severe fibrosis; ≥ 11.3: Cirrhosis.

  • Mean Change From Baseline in the Hepatic Elastography (FibroscanTM) at Week 48, 96 and 144 [ Time Frame: 48, 96 and 144 weeks ]
    Participants had transient hepatic elastography using FibroScan technology. It rapidly and non invasively measures hepatic tissue stiffness. Through a probe, a low frequency vibration of low amplitude is transmitted to the liver. The velocity of the wave that is generated during the procedure correlates directly with tissue stiffness as it passes through the liver; the harder or stiffer the liver, the faster the shear wave propagates. Results are reported in kilopascals (kPa). A negative change in the fibroscan values (i.e. decrease in liver stiffness) correlates with a decrease in fibrosis and thus improved outcome.
  • Absolute Fibrosis Score (Ishak) in Liver Biopsy Samples at Baseline and at Week 144 [ Time Frame: Baseline and Week 144 ]
    Samples were processed and sent to a central reader for scoring for fibrosis and other analyses such as Sirius red and α smooth muscle actin staining for activated stellate cells. Samples were collected, processed, stored and shipped in accordance with the procedure documented in a separate handling document. The Ishak fibrosis scoring system was used to score the fibrosis observed, with a minimum score of 0 and maximum score of 6 (where 0 = no fibrosis, 1 = expansion of some portal areas with or without septa, 2 = expansion of most portal areas with or without septa, 3 = expansion of most portal areas with occasional portal or portal bridging, 4 = expansion of portal areas with marked bridging [portal-portal and/or portal-central], 5 = marked bridging with occasional nodules [incomplete cirrhosis], 6 = cirrhosis, probable or definitive). The scores for liver biopsies were summarized based upon the availability of liver biopsy results.
  • Change From Baseline in Fibrosis Score (Ishak) in Liver Biopsy Samples at Week 144 [ Time Frame: Week 144 ]
    Samples were processed and sent to a central reader for scoring for fibrosis and other analyses such as Sirius red and α smooth muscle actin staining for activated stellate cells. Samples were collected, processed, stored and shipped in accordance with the procedure documented in a separate handling document. The Ishak fibrosis scoring system was used to score the fibrosis observed, with a minimum score of 0 and maximum score of 6 (where 0 = no fibrosis, 1 = expansion of some portal areas with or without septa, 2 = expansion of most portal areas with or without septa, 3 = expansion of most portal areas with occasional portal or portal bridging, 4 = expansion of portal areas with marked bridging [portal-portal and/or portal-central], 5 = marked bridging with occasional nodules [incomplete cirrhosis], 6 = cirrhosis, probable or definitive). The scores for liver biopsies were summarized based upon the availability of liver biopsy results.
  • Percentage of Participants Who Were Hospitalized Due to Hepatic Disease Through Week 144 [ Time Frame: 144 Weeks ]
    Healthcare resource utilization data was collected using the Healthcare Resource Utilization Questionnaire at all study visits except Screening and Baseline. Other components of healthcare resource utilization, including length of hospital stay, type of ward, associated investigative and therapeutic procedures and concomitant medications were captured from primary and secondary data sources.
  • Summary of Estimated Maraviroc PK Parameters [ Time Frame: Week 48 ]
    Week 4 and Week 48 clinic visits were scheduled such that a trough sample may be taken within a time window of 8-16 hours after the previous dose (Ctrough). Blood samples (4mL) were collected from all participants at the Week 4 and 48 visits.
  • Exposure-response Relationship Between Change From Baseline in Liver Fibrosis Biomarkers Versus MVC Cavg at Week 48 [ Time Frame: Week 48 ]
    The relationship between change from baseline in liver fibrosis biomarkers (AST, ALT, ALK, BIL, ELF and FSCN) versus MVC Cavg was analyzed using Bayesian methods. P-values were assessed for significance in the relationship between liver fibrosis biomarkers and MVC Cavg. P-value <0.05 was regarded as significantly related.
  • Percentage of subjects with Grade 3 and Grade 4 ALT abnormalities [ Time Frame: 96 weeks ]
  • Percentage of subjects with Grade 3 and Grade 4 ALT abnormalities [ Time Frame: 144 weeks ]
  • Time to development of Grade 3 and Grade 4 ALT abnormalities [ Time Frame: 48 weeks ]
  • Time to development of Grade 3 and Grade 4 ALT abnormalities [ Time Frame: 96 weeks ]
  • Time to development of Grade 3 and Grade 4 ALT abnormalities [ Time Frame: 144 weeks ]
  • Percentage of subjects with Grade 3 and Grade 4 ALT abnormalities associated with a change from baseline ALT >=100 IU/L [ Time Frame: 48 weeks ]
  • Percentage of subjects with Grade 3 and Grade 4 ALT abnormalities associated with a change from baseline ALT >=100 IU/L [ Time Frame: 96 weeks ]
  • Percentage of subjects with Grade 3 and Grade 4 ALT abnormalities associated with a change from baseline ALT >=100 IU/L [ Time Frame: 144 weeks ]
  • Time to development of Grade 3 and Grade 4 ALT test abnormalities associated with a change from baseline ALT >=100 IU/L [ Time Frame: 48 weeks ]
  • Time to development of Grade 3 and Grade 4 ALT test abnormalities associated with a change from baseline ALT >=100 IU/L [ Time Frame: 96 weeks ]
  • Time to development of Grade 3 and Grade 4 ALT test abnormalities associated with a change from baseline ALT >=100 IU/L [ Time Frame: 144 weeks ]
  • Percentage of subjects with Hy's law abnormalities [ Time Frame: 48 weeks ]
  • Percentage of subjects with Hy's law abnormalities [ Time Frame: 96 weeks ]
  • Percentage of subjects with Hy's law abnormalities [ Time Frame: 144 weeks ]
  • Percentage of subjects with plasma HIV-1 RNA concentration <40 copies/mL [ Time Frame: 48 weeks ]
  • Percentage of subjects with plasma HIV-1 RNA concentration <40 copies/mL [ Time Frame: 96 weeks ]
  • Percentage of subjects with plasma HIV-1 RNA concentration <40 copies/mL [ Time Frame: 144 weeks ]
  • Change from baseline in CD4+ and CD8+ cell counts [ Time Frame: 48 weeks ]
  • Change from baseline in CD4+ and CD8+ cell counts [ Time Frame: 96 weeks ]
  • Change from baseline in CD4+ and CD8+ cell counts [ Time Frame: 144 weeks ]
  • Frequency and severity of adverse events and laboratory abnormalities [ Time Frame: 144 weeks ]
  • Change from baseline in markers of immune activation (CD38 expression on CD4 and CD8 cells, C-reactive protein, D-dimer, transforming growth factor-beta [TGF-beta]) [ Time Frame: 48 weeks ]
  • Change from baseline in markers of immune activation (CD38 expression on CD4 and CD8 cells, C-reactive protein, D-dimer, transforming growth factor-beta [TGF-beta]) [ Time Frame: 96 weeks ]
  • Change from baseline in markers of immune activation (CD38 expression on CD4 and CD8 cells, C-reactive protein, D-dimer, transforming growth factor-beta [TGF-beta]) [ Time Frame: 144 weeks ]
  • Change from baseline in plasma HCV RNA [ Time Frame: 48 weeks ]
  • Change from baseline in plasma HCV RNA [ Time Frame: 96 weeks ]
  • Change from baseline in plasma HCV RNA [ Time Frame: 144 weeks ]
  • Change from baseline in plasma HBV DNA [ Time Frame: 48 weeks ]
  • Change from baseline in plasma HBV DNA [ Time Frame: 96 weeks ]
  • Change from baseline in plasma HBV DNA [ Time Frame: 144 weeks ]
  • Change from baseline in Enhanced Liver Fibrosis (ELF) test [ Time Frame: 48 weeks ]
  • Change from baseline in Enhanced Liver Fibrosis (ELF) test [ Time Frame: 96 weeks ]
  • Change from baseline in Enhanced Liver Fibrosis (ELF) test [ Time Frame: 144 weeks ]
  • Change from baseline in the hepatic elastography (FibroscanTM) [ Time Frame: 48 weeks ]
  • Change from baseline in the hepatic elastography (FibroscanTM) [ Time Frame: 96 weeks ]
  • Change from baseline in the hepatic elastography (FibroscanTM) [ Time Frame: 144 weeks ]
  • Change from baseline in fibrosis score (Ishak) in liver biopsy samples at Week 144 (liver biopsy substudy) [ Time Frame: 144 weeks ]
  • Population pharmacokinetic analysis of time versus plasma concentration of maraviroc [ Time Frame: 48 weeks ]
  • Exploratory exposure-response relationship, if any, between maraviroc PK and liver fibrosis biomarkers, any changes from baseline that may be observed in AST and ALT measurements or other laboratory measurements. [ Time Frame: 48 weeks ]
  • Health economic impact, as measured by the utilization of hepatic fibrosis and cirrhosis-related inpatient and outpatient services and associated costs of care. [ Time Frame: 144 weeks ]
Not Provided
Not Provided
 
A Study Of Maraviroc In HIV Co-Infected Subjects With Hepatitis C And/Or Hepatitis B
A Multicenter, Randomized, Blinded, Placebo-controlled Study To Evaluate The Safety Of Maraviroc In Combination With Other Antiretroviral Agents In Hiv-1-infected Subjects Co-infected With Hepatitis C And/or Hepatitis B Virus
To describe liver enzyme elevations in patients who are coinfected with HIV and either Hepatitis C (HCV) and/or Hepatitis B (HBV) receiving maraviroc or placebo in combination with their current suppressive anti-HIV drug therapy.
Not Provided
Interventional
Phase 4
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
HIV Coinfection
  • Drug: Maraviroc
    150mg, 300mg or 600mg twice daily x 144 weeks; dosing dependent on components of the current suppressive anti-HIV therapy
    Other Name: Selzentry, Celsentri
  • Drug: Placebo
    150mg, 300mg or 600mg twice daily x 144 weeks; dosing dependent on components of the current suppressive anti-HIV therapy
  • Experimental: 1.0
    Intervention: Drug: Maraviroc
  • Placebo Comparator: 2
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
138
120
March 24, 2015
April 23, 2013   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV coinfected with HCV and/or HBV.
  • Undetectable HIV-1 RNA for at least 3 months prior to the screening visit
  • Treatment with current antiretroviral therapy (3-6 drugs excluding low-dose ritonavir) for at least 5 months.

Exclusion Criteria:

  • Currently receiving maraviroc.
  • Active opportunistic infections.
  • ALT and/or AST >5x upper limit of normal.
  • Direct bilirubin >1.5x upper limit of normal.
  • Severe or decompensated liver disease.
  • Liver disease unrelated to viral hepatitis infection.
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact information is only displayed when the study is recruiting subjects
Czechia,   France,   Germany,   Hungary,   Poland,   Puerto Rico,   Spain,   United Kingdom,   United States
Czech Republic
 
NCT01327547
A4001098
2010-021994-35 ( EudraCT Number )
Yes
Not Provided
Not Provided
ViiV Healthcare
ViiV Healthcare
Pfizer
Study Director: Pfizer CT.gov Call Center Pfizer
ViiV Healthcare
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP