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

Primary Purpose

HIV Infection, Liver Failure, Evidence of Liver Transplantation

Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
Raltegravir potassium
Sponsored by
ANRS, Emerging Infectious Diseases
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infection focused on measuring Pharmacokinetics, Raltegravir, Immunosuppressive Agents, Severe hepatic insufficiency, Liver Transplantation, Additional Keywords, HIV Infection, Hepatocarcinoma, Hepatitis C, Hepatitis B

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Service de Médecine Interne, Hôpital de Bicêtre

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Raltegravir potassium

Arm Description

raltegravir 400 mg twice a day

Outcomes

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

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
To assess the safety of raltegravir before transplantation in patients with impaired liver function, and after transplantation in combination with immunosuppressive treatment
To describe the clinical outcome of patients (such as the onset of opportunistic infections, relapse of HCV infection, morphological and metabolic disorders outcomes)
To describe the changes in liver function (evaluation of liver function during treatment) before and after liver transplantation

Full Information

First Posted
November 26, 2009
Last Updated
July 17, 2013
Sponsor
ANRS, Emerging Infectious Diseases
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT01022476
Brief Title
Raltegravir in Patients With End Stage Liver Disease and in Transplant Recipients
Acronym
LIVERAL
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)
Study Type
Interventional

2. Study Status

Record Verification Date
July 2013
Overall Recruitment Status
Completed
Study Start Date
May 2010 (undefined)
Primary Completion Date
May 2013 (Actual)
Study Completion Date
May 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ANRS, Emerging Infectious Diseases
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infection, Liver Failure, Evidence of Liver Transplantation
Keywords
Pharmacokinetics, Raltegravir, Immunosuppressive Agents, Severe hepatic insufficiency, Liver Transplantation, Additional Keywords, HIV Infection, Hepatocarcinoma, Hepatitis C, Hepatitis B

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Raltegravir potassium
Arm Type
Experimental
Arm Description
raltegravir 400 mg twice a day
Intervention Type
Drug
Intervention Name(s)
Raltegravir potassium
Other Intervention Name(s)
ISENTRESS
Intervention Description
one pill of raltegravir 400 mg twice a day
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
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
Title
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
Title
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
Title
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Elina TEICHER, MD
Organizational Affiliation
Hôpital de Bicêtre - LE KREMLIN-BICETRE - FRANCE
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jean-Pierre ABOULKER, MD
Organizational Affiliation
INSERM SC10 VILLEJUIF FRANCE
Official's Role
Study Chair
Facility Information:
Facility Name
Service de Médecine Interne, Hôpital de Bicêtre
City
LE KREMLIN-BICETRE cedex
ZIP/Postal Code
94275
Country
France

12. IPD Sharing Statement

Links:
URL
http://www.anrs.fr/
Description
Agence nationale de recherches sur le sida et les hépatites virales

Learn more about this trial

Raltegravir in Patients With End Stage Liver Disease and in Transplant Recipients

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