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

Hepatitis C Clinical Trial

— LIVERAL  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01289951
• Other study ID #: LIVERAL
• Status: Completed
• Phase: Phase 1
• First received: February 1, 2011
• Last updated: January 31, 2013
• Start date: December 2010
• Est. completion date: October 2011

Study information

• Verified date: January 2013
• Source: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of Medicines
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: October 2011
• Est. primary completion date: June 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acquired Immunodeficiency Syndrome
• Hepatitis
• Hepatitis A
• Hepatitis C
• HIV Infections
• Human Immunodeficiency Virus
• Immunologic Deficiency Syndromes
• Liver Cirrhosis

Intervention

Drug:
• Raltegravir 400 mg/12hours

• Raltegravir 400 mg/12hours

Locations

Country	Name	City	State
Spain	Hospital Universitario Ramón y Cajal.	Madrid

Sponsors (2)

Lead Sponsor	Collaborator
Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	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	On the fifth day of treatment with raltegravir	No
Secondary	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).	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.	On day 1, 5 and 15	No