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

HIV Coinfection Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01327547
• Other study ID #: A4001098
• Secondary ID: 2010-021994-35
• Status: Completed
• Phase: Phase 4
• First received: March 22, 2011
• Last updated: November 2, 2017
• Start date: May 18, 2011
• Est. completion date: March 24, 2015

Study information

• Verified date: November 2017
• Source: ViiV Healthcare
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 138
• Est. completion date: March 24, 2015
• Est. primary completion date: April 23, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Coinfection
• Hepatitis
• Hepatitis A
• Hepatitis B
• Hepatitis C
• HIV Coinfection

Intervention

Drug:
• Maraviroc
150mg, 300mg or 600mg twice daily x 144 weeks; dosing dependent on components of the current suppressive anti-HIV therapy
• Placebo
150mg, 300mg or 600mg twice daily x 144 weeks; dosing dependent on components of the current suppressive anti-HIV therapy

Locations

Country	Name	City	State
Czechia	Fakultni nemocnice Brno	Brno
France	Hopital de la Croix Rousse	Lyon cedex 4
France	Hopital Tenon, Service des Maladies Infectieuses	Paris
France	Centre Hospitalier Cochin Saint Vincent de Paul	Paris CEDEX 14
Germany	EPIMED - Gesellschaft fuer epidemiologische und klinische Forschung in der Medizin mbH	Berlin
Germany	Universitaetsklinikum Bonn, Immunologische Ambulanz HIV	Bonn
Germany	ifi - Studien und Projekte GmbH	Hamburg
Germany	Universitaetsklinikum Hamburg-Eppendorf	Hamburg
Germany	Klinikum der Universitaet zu Koeln	Koeln
Germany	Ludwig-Maximilians-Universitaet	Muenchen
Hungary	Egyesített Szent István és Szent László Kórház Rendelointézet	Budapest
Poland	Wojewodzki Szpital Obserwacyjno - Zakazny im. Tadeusza Browicza w Bydgoszczy	Bydgoszcz
Poland	SPZOZ Wojewodzki Szpital Zakazny	Warszawa
Poland	EMC Instytut Medyczny S.A. Przychodnia przy ul. Lowieckiej	Wroclaw	Dolnoslaskie
Puerto Rico	Ararat Research Center	Ponce
Puerto Rico	Farmacia UPR-CTU	San Juan
Puerto Rico	University of Puerto Rico - School of Medicine	San Juan
Spain	Hospital Universitari Vall dHebron	Barcelona
Spain	Hospital Reina Sofia Hospital Provincial	Cordoba
Spain	Hospital Carlos Iii	Madrid
Spain	Hospital Nuestra Señora de Valme	Sevilla
Spain	Consorcio Hospital General Universitario de Valencia	Valencia
United Kingdom	Harrison Wing Research Office, Guys and St. Thomas NHS Foundation Trust	London
United Kingdom	St Stephen's AIDS Trust	London
United States	Georgia Regents Medical Center	Augusta	Georgia
United States	The Office of Dr. Franco Antonio Felizarta, M.D.	Bakersfield	California
United States	I.D. Consultants, P.A.	Charlotte	North Carolina
United States	Kaiser Permanente Sunnybrook Medical Office	Clackamas	Oregon
United States	Southwest Infectious Disease Clinical Research Inc.	Dallas	Texas
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Henry Ford Hospital	Detroit	Michigan
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	AIDS Research Alliance	Los Angeles	California
United States	Community AIDS Resource Inc dba Care Resource	Miami	Florida
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Mount Sinai Faculty Practice Associates	New York	New York
United States	The Mount Sinai Hospital	New York	New York
United States	Saint Michael's Medical Center	Newark	New Jersey
United States	Alameda Health System - Highland Hospital	Oakland	California
United States	Kaiser Permanente Northwest	Portland	Oregon
United States	University of California	Sacramento	California
United States	University of California Davis Research	Sacramento	California
United States	University Health Care Center Downtown	San Antonio	Texas
United States	University of California, San Francisco - Hepatitis/HIV Clinical Trials Group (HHCTG)	San Francisco	California
United States	University of California, San Francisco - Mt. Zion Hospital	San Francisco	California
United States	University of South Florida Health - HIV Clinical Research Unit	Tampa	Florida
United States	New York Medical College	Valhalla	New York
United States	Rowan Tree Medical, P.A.	Wilton Manors	Florida

Sponsors (2)

Lead Sponsor	Collaborator
ViiV Healthcare	Pfizer

Countries where clinical trial is conducted

United States,  Czechia,  France,  Germany,  Hungary,  Poland,  Puerto Rico,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Grade 3 and Grade 4 Alanine Aminotransferase (ALT) Abnormalities at Week 48	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.	48 weeks
Secondary	Percentage of Participants With Grade 3 and Grade 4 ALT Abnormalities Through Week 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.	Week 96 and 144
Secondary	Time to Development of Grade 3 and Grade 4 ALT Abnormalities	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.	144 weeks
Secondary	Percentage of Participants With Grade 3 and Grade 4 ALT Abnormalities Associated With a Change From Baseline ALT >100 IU/L	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.	144 weeks
Secondary	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 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.	144 weeks
Secondary	Number of Participants With Hy's Law Abnormalities Through Week 144	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	144 weeks
Secondary	Percentage of Participants With Plasma Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Concentration <40 Copies/mL at 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).	Week 48, 96 and 144
Secondary	Mean Change From Baseline in CD4+ and CD8+ Cell Counts at 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.	Week 48, 96 and 144
Secondary	Mean Change From Baseline in CD38 Expression on CD4 and CD8 Cells at Weeks 48, 96 and 144	Plasma samples were used to determine markers of immune activation namely CD38 expression on CD4 and CD8 cells.	48, 96 and 144 weeks
Secondary	Mean Change From Baseline in Markers of Immune Activation: C-reactive Protein (CRP) - Week 48, 96 and 144.	Plasma samples were used to determine markers of immune activation namely CRP.	48, 96 and 144 weeks
Secondary	Mean Change From Baseline in Markers of Immune Activation: D Dimer - Week 48, 96 and 144	Plasma samples were used to determine markers of immune activation namely D-Dimer.	48, 96 and 144 weeks
Secondary	Mean Change From Baseline in Markers of Immune Activation: Transforming Growth Factor-beta (TGF Beta) - Week 48, 96 and 144	Plasma samples were used to determine markers of immune activation namely TGF beta.	48, 96 and 144 weeks
Secondary	Mean Change From Baseline in Log10 Plasma Hepatitis C Virus (HCV) RNA at Week 48, 96 and 144	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.	48, 96 and 144 weeks
Secondary	Mean Change From Baseline in Plasma Hepatitis B Virus (HBV) DNA at Week 48, 96 and 144	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.	48, 96 and 144 weeks
Secondary	Mean Change From Baseline in Enhanced Liver Fibrosis (ELF) Test at Week 48, 96 and 144	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.	48, 96 and 144 weeks
Secondary	Mean Change From Baseline in the Hepatic Elastography (FibroscanTM) at Week 48, 96 and 144	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.	48, 96 and 144 weeks
Secondary	Absolute Fibrosis Score (Ishak) in Liver Biopsy Samples at Baseline and at Week 144	Samples were processed and sent to a central reader for scoring for fibrosis and other analyses such as Sirius red and a 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.	Baseline and Week 144
Secondary	Change From Baseline in Fibrosis Score (Ishak) in Liver Biopsy Samples at Week 144	Samples were processed and sent to a central reader for scoring for fibrosis and other analyses such as Sirius red and a 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.	Week 144
Secondary	Percentage of Participants Who Were Hospitalized Due to Hepatic Disease Through Week 144	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.	144 Weeks
Secondary	Summary of Estimated Maraviroc PK Parameters	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.	Week 48
Secondary	Exposure-response Relationship Between Change From Baseline in Liver Fibrosis Biomarkers Versus MVC Cavg at 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.	Week 48

External Links

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