Pharmacokinetic Study of Raltegravir in Human Immunodeficiency Virus/Hepatitis C Virus (HIV/VHC) Coinfected Patients With Advanced (Child-Pugh C) Hepatic Cirrhosis (LIVERAL)

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
ClinicalTrials.gov Identifier:
NCT01289951
First received: February 1, 2011
Last updated: January 31, 2013
Last verified: January 2013
  Purpose

Raltegravir is the first integrase inhibitor used in humans. It has been shown to be highly efficacious and well tolerated in phase III clinical trials in multidrug experienced human immunodeficiency virus(HIV)-infected patients, as well as initial therapy in untreated patients. Pharmacokinetic studies in healthy adult subjects indicate that the major mechanism of clearance of the drug is glucuronidation mediated by UGT1A1, with a minor contribution of renal excretion of unchanged parent compound. Unlike CYP-based metabolism, glucuronidation is generally found to be relatively unaffected by hepatic disease. A single dose pharmacokinetic study of raltegravir in patients with mild to moderate hepatic insufficiency (Steigbigel et al. 2008) found no clinically important effect on the drug pharmacokinetic profile, with no dosage adjustment being necessary. The liver safety and tolerability of boosted atazanavir (ATV/r) has been evaluated in human immunodeficiency virus and hepatitis C virus (HIV/HCV) coinfected patients with advanced liver disease (decompensated cirrhosis) (Hermida JM et al. 4th IAS: Sidney, 2007). Similar to Raltegravir, ATV is also mainly metabolized by conjugation through UGT1A1. There is an urgent need for potent and efficacious ARV drugs with a clean safety liver profile even in patients with severe liver disease. The investigators hypothesized that pharmacokinetics will not be altered in HIV/HCV patients with advanced (Child-Pugh grade C) cirrhosis or in those with no histologic liver damage.


Condition Intervention Phase
Human Immunodeficiency Virus
Hepatitis C
Drug: Raltegravir 400 mg/12hours
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I, Open Label, Unicentric Study of Multiple-dose Pharmacokinetics of Raltegravir in Patients Infected With Human Immunodeficiency Virus and Hepatitis C Virus With and Without Advanced (Child-Pugh C) Hepatic Cirrhosis.

Resource links provided by NLM:


Further study details as provided by Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal:

Primary Outcome Measures:
  • The area under the curve (AUC0-12) calculated from plasma concentrations, the maximum concentration (Cmax) and the the minimum concentration (Cmin) of Raltegravir 400 mg/12 hours in the steady state for both arms. [ Time Frame: On the fifth day of treatment with raltegravir ] [ Designated as safety issue: No ]
    On the fifth day of treatment, patient will be hospitalized in the clinical trial unit in order to obtaine plasma concentrations previous to the administration of the corresponding dose (basal) and at the following times post-administration: 30min, 1h, 1h30min, 2h, 3h, 4h, 6h, 8h, and 12h. With these measures, (AUC0-12), Cmax and Cmin will be calculated in order to describe the pharmacokinetic of Raltegravir 400 mgBID in the steady state in both arms


Secondary Outcome Measures:
  • Change from baseline in hematology and biochemistry parameters at day 5 and 15, number of adverse events (serious and non serious) notified and number of patients who discontinue the study (drop-out rate). [ Time Frame: On day 1, 5 and 15 ] [ Designated as safety issue: No ]
    Hematology and biochemistry parameters, adverse events notified during the study and drop-out rate will be recorded in order to evaluate the safety and tolerability of multiple doses of raltegravir in HIV/HCV coinfected patients, with no liver damage and with advanced cirrhosis.


Enrollment: 10
Study Start Date: December 2010
Study Completion Date: October 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Patients with Child-Pugh C hepatic-cirrhosis.
VIH/VHC coinfected patients with advanced (Child-Pugh C) hepatic cirrhosis.
Drug: Raltegravir 400 mg/12hours
Active Comparator: VIH/VHC coinfected patients without liver damage. Drug: Raltegravir 400 mg/12hours

  Eligibility

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

Inclusion Criteria:

  • Adults, clinically stable HIV/HCV coinfected patients on HAART with controlled viremia (<50 copies/ml) for at least 6 months. HAART will be based on a boosted protease inhibitor (lopinavir, fosamprenavir or darunavir). Hepatic Stability is defined by the absence of new events of descompensation (Child-Pugh score) in the previous six weeks with no data of progressive hepatic insufficiency.
  • Liver biopsy performed during the previous year showing no liver damage (F0-F1 in the Metavir score) or by elastometry results ≤ 6 Kpa, to classify patients in group B.
  • Liver cirrhosis guided by biopsy (F4 in the Metavir score) or elastometry: results ≥ 14 Kpa, to classify patients in group A.
  • Body mass index (BMI) in the range of 19-35 kg/m2.

Exclusion Criteria:

  • HBV surface antigen positive.
  • Clinical demonstration of a new descompensation event in the previous 6 weeks.
  • Alcohol abuse as an average daily consumption > 20g.
  • Treatment with boosted atazanavir, saquinavir or indinavir.
  • Concomitant treatment with phenytoin, phenobarbital and rifampinor other UGT1A1 inhibitors.
  • Use of any investigational agents (other than ART on expanded access) within 90 days of randomization.
  • Active or previous HCV treatment with Ribavirin and /or Peg-interferon if sustained virological response achieved.
  • Women taking oral contraceptives
  • Pregnancy and lactancy.
  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: NCT01289951

Locations
Spain
Hospital Universitario Ramón y Cajal.
Madrid, Spain, 28034
Sponsors and Collaborators
Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Santiago Moreno Guillen, MD Hospital Universitario Ramón y Cajal. Madrid
  More Information

No publications provided by Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
ClinicalTrials.gov Identifier: NCT01289951     History of Changes
Other Study ID Numbers: LIVERAL
Study First Received: February 1, 2011
Last Updated: January 31, 2013
Health Authority: Spain: Spanish Agency of Medicines

Keywords provided by Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal:
HIV
VHC
Advanced hepatic cirrhosis
Pharmacokinetic
Raltegravir

Additional relevant MeSH terms:
Acquired Immunodeficiency Syndrome
HIV Infections
Hepatitis
Hepatitis A
Virus Diseases
Hepatitis C
Immunologic Deficiency Syndromes
Liver Cirrhosis
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Immune System Diseases
Lentivirus Infections
Retroviridae Infections
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases

ClinicalTrials.gov processed this record on October 01, 2014