Raltegravir in Patients With End Stage Liver Disease and in Transplant Recipients (LIVERAL)

This study has been completed.
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier:
NCT01022476
First received: November 26, 2009
Last updated: July 17, 2013
Last verified: July 2013
  Purpose

This phase I/II, multi-center study is designed to determine the pharmacokinetic profile of Raltegravir in patients with end stage liver disease and to assess drug-drug interaction when Raltegravir is combined with immunosuppressive therapy in liver transplant recipients.


Condition Intervention Phase
HIV Infection
Liver Failure
Evidence of Liver Transplantation
Drug: Raltegravir potassium
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Pharmacokinetics, Tolerance and Efficacy of Raltegravir Combined to Two Fully Active Molecules Among Nucleosi(ti)de Analogs and Enfuvirtide Before and After Liver Transplant in HIV Infected Patients With End Stage Liver Disease (ANRS 148 LIVERAL)

Resource links provided by NLM:


Further study details as provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):

Primary Outcome Measures:
  • Pharmacokinetic parameters of raltegravir in patients with severe liver dysfunction and after a liver transplantation when combined to immunosuppressive therapy. Pharmacokinetic parameters of immunosuppressive drugs with or without raltegravir [ Time Frame: at month 1 for period 1 and day 7-month 1 for period 2 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To assess the maintenance of the virological efficacy on HIV of raltegravir combined with two fully active molecules among NRTI (or NRTI + enfuvirtide). Follow-up over a 3-months period before and after transplantation [ Time Frame: from day 0 to month 3 for period 1 and period 2 ] [ Designated as safety issue: Yes ]
  • To assess the safety of raltegravir before transplantation in patients with impaired liver function, and after transplantation in combination with immunosuppressive treatment [ Time Frame: from day 0 to month 3 for period 1 and period 2 ] [ Designated as safety issue: Yes ]
  • To describe the clinical outcome of patients (such as the onset of opportunistic infections, relapse of HCV infection, morphological and metabolic disorders outcomes) [ Time Frame: from day 0 to month 3 for period 1 and period 2 ] [ Designated as safety issue: No ]
  • To describe the changes in liver function (evaluation of liver function during treatment) before and after liver transplantation [ Time Frame: from day 0 to month 3 for period 1 and period 2 ] [ Designated as safety issue: No ]

Enrollment: 14
Study Start Date: May 2010
Study Completion Date: May 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Raltegravir potassium
raltegravir 400 mg twice a day
Drug: Raltegravir potassium
one pill of raltegravir 400 mg twice a day
Other Name: ISENTRESS

Detailed Description:

HIV infected patients with stable plasma HIV-RNA below 50 copies per mL and severe liver dysfunction will be switched from their antiretroviral regimen to a combination of raltegravir (one 400 mg pill twice daily) and two fully active molecules among nucleosi(ti)de analogs and enfuvirtide for a first period of at least 3 months and a second period of at least 3 months after liver transplantation, if need be, when a steady state of the anticalcineurin will be reached. Pharmacokinetic parameters of raltegravir will be calculated during severe liver dysfunction period and after liver transplantation. Pharmacokinetic parameters of cyclosporine (or tacrolimus if contra indication to cyclosporine) will be compared when administrated alone or combined with raltegravir. Patients will be followed up according to standard of care. This study will be divided in two distinct periods (1 and 2) lasting 3 months each. Period 1 will start from the inclusion in the study and will generally include the switch to raltegravir. Period 2 will start from liver transplantation.

  Eligibility

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

Inclusion Criteria:

  • Age ≥ 18
  • Documented HIV-1 infection, hepatitis B or C co-infection is allowed
  • Plasma viral load at screening visit below 50 copies per mL for at least 6 months
  • Patient with severe liver failure (Meld Score ≥ 15 and/or refractory ascites and/or haemorrhage of digestive tract and/or hepatic encephalopathy) for taking part into period 1
  • Patient eligible for the liver transplant waiting list or immediate post transplantation for taking part into period 2
  • Abstinence from alcohol intake for at least 6 months (WHO norm)
  • Withdrawal from intravenous drug use for at least 6 months (methadone substitution is permitted)
  • No ongoing class C opportunistic infection (1993 CDC classification)
  • Patient whose clinical and immunovirological condition allows triple therapy with raltegravir + 2 NRTI or raltegravir + NRTI + enfuvirtide
  • Patient whose HIV population, according to cumulative genotypes carried out on viral RNA together with treatment history (if available and interpreted as per the ANRS-AC11 algorithm version no.19) does not present a profile of mutations associated with resistance to raltegravir and is sensitive to at least two fully active* agents selected among nucleoside/nucleotide reverse transcriptase analogs NRTI (abacavir, lamivudine, emtricitabine, tenofovir) or enfuvirtide

    *An ARV agent is considered to be fully active if the cumulative genotypes do not show any mutation associated with resistance or any mutation associated with "possible resistance"

  • Patient not having experienced viral escape during treatment combining 3TC, FTC or raltegravir
  • Patient registered with or covered by a social security scheme
  • For women of child-bearing potential, use of a barrier contraceptive method during sexual intercourse and negative pregnancy test (plasma ß-HCG ) at screening visit
  • Informed consent form signed at screening visit at the latest

Exclusion Criteria:

  • More than two virological failures during antiretroviral treatment
  • Currently receiving treatment with an agent in development (apart from an authorization for temporary use)
  • Plasma viral load at screening visit ≥ 50 copies per mL during at least the last 6 months
  • Pregnant women, or women liable to become pregnant, breast-feeding women, no contraception, or refusal to use contraception
  • All conditions (including but not limited to alcohol intake and drug use) liable to compromise, in the investigator's opinion, the safety of treatment and/or the patient's compliance with the protocol
  • Patient not having any effective options for NRTI +/- enfuvirtide (defined in the inclusion criteria)
  • Ongoing treatment with interferon-alpha or ribavirin for hepatitis C
  • Concomitant medication including one or more agents liable to induce UGT1A1 and reduce raltegravir concentrations:

    • anti-infective agents: rifampicin/rifampin
    • psychotropic/antiepileptic agents: phenytoin, phenobarbital, carbamazepine
    • steroidal anti-inflammatory drug: dexamethasone
  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: NCT01022476

Locations
France
Service de Médecine Interne, Hôpital de Bicêtre
LE KREMLIN-BICETRE cedex, France, 94275
Sponsors and Collaborators
French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Elina TEICHER, MD Hôpital de Bicêtre - LE KREMLIN-BICETRE - FRANCE
Study Chair: Jean-Pierre ABOULKER, MD INSERM SC10 VILLEJUIF FRANCE
  More Information

Additional Information:
No publications provided

Responsible Party: French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)
ClinicalTrials.gov Identifier: NCT01022476     History of Changes
Other Study ID Numbers: 2009-014616-36, ANRS 148 LIVERAL
Study First Received: November 26, 2009
Last Updated: July 17, 2013
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):
Pharmacokinetics
Raltegravir
Immunosuppressive Agents
Severe hepatic insufficiency
Liver Transplantation
Additional Keywords
HIV Infection
Hepatocarcinoma
Hepatitis C
Hepatitis B

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Liver Diseases
Liver Failure
End Stage Liver Disease
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Digestive System Diseases
Hepatic Insufficiency
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 26, 2014