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Clinical Trial to Assess the Efficacy of Darunavir/Ritonavir (DRV/r), Etravirine (ETV) and Raltegravir (MK-0518) in HIV Patients With Resistant Viruses (ANRS139 TRIO)

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
raltegravir potassium
darunavir/ritonavir
etravirine
Optimized background regimen
Sponsored by
French National Agency for Research on AIDS and Viral Hepatitis
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring HIV infections, HIV integrase inhibitor, etravirine, darunavir, MK 0518, raltegravir, Treatment Experienced, Antiviral drug resistance

Eligibility Criteria

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

Inclusion Criteria:

  • Age: 18 years and above
  • Documented HIV-1 infection.
  • History of virological failure on NNRTIs (patients with a history of toxicity to nevirapine and efavirenz may be enrolled in this study).
  • On a combination antiretroviral therapy for at least 8 weeks prior to the screening visit (if on tipranavir, or enfuvirtide these drugs should have been introduced more than 8 weeks before the screening visit).
  • Patient naive to darunavir, etravirine and to integrase inhibitors
  • Plasma viral load at screening visit over 1000 copies/ml, (no CD4 restriction).

  • Genotypic resistance testing at the screening visit:

    • Protease inhibitor mutations: over or equal to 3 primary protease inhibitor mutations among: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54M, L76V, V82A/F/L/T/S, I84V, N88S and L90M (IAS list 2006) but below or equal to 3 mutations among the following: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V et L89V (virus sensitivity to darunavir/ritonavir).
    • Reverse transcriptase mutations: over or equal to 3 NRTI mutations (among IAS list) and below or equal to 3 mutations among: A98G, L100I, K101Q/P/E, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/I/V/C/H/L, Y188C/H/L, G190A/C/E/Q/S, P225H, F227C/L, M230I/L, P236L, K238N/T and Y318F (virus sensitivity to etravirine)

Exclusion Criteria:

  • Non effective barrier contraception in women of child bearing potential
  • Pregnant women or women who are breastfeeding
  • Opportunistic infection at the acute phase
  • Decompensated cirrhosis (stage B or C of Child-Pugh score)
  • Malignancy requiring chemotherapy or radiotherapy
  • Contraindicated medications being taken by the patient (listed in protocol)
  • Allergy to the active substances and expedients of darunavir, etravirine and raltegravir.
  • Haemoglobin < 7g/dl, neutrophil cell count < 500/mm3, platelets < 50,000/mm3, creatinine clearance < 50 ml/mn, P. alkaline, AST, ALT or total bilirubin over or equal to 3 times normal values.
  • Patients receiving experimental agents with an exclusion period for participation in other studies applicable at the screening visit of the current study.

Sites / Locations

  • Hôpital Gustave Dron, Service Maladies Infectieuses

Outcomes

Primary Outcome Measures

Proportion of patients with HIV RNA levels of less than 50 copies/ml in an intent to treat analysis at week 24

Secondary Outcome Measures

Proportions of patients with HIV RNA levels of less than 50 copies/ml at week 48, with HIV RNA levels of less than 400 copies/ml at weeks 24 and 48
HIV RNA level evolution between baseline and week 48
HIV proviral DNA and 2LTR circle HIV DNA between baseline and week 48
Number and type of resistance mutations in case of virologic failure occurrence
CD4 lymphocyte count and proportion evolution between baseline and week 48
HIV infection progression
Frequency of the study regimen modifications and interruption
Study regimen tolerance
Study regimen adherence
Association between study drugs' minimum concentrations at week 4 and week 12 and virologic success at week 24
Evolution of pharmacokinetics parameters of study drugs in the PK substudy

Full Information

First Posted
April 12, 2007
Last Updated
September 16, 2010
Sponsor
French National Agency for Research on AIDS and Viral Hepatitis
Collaborators
Merck Sharp & Dohme LLC, Janssen-Cilag Tibotec
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1. Study Identification

Unique Protocol Identification Number
NCT00460382
Brief Title
Clinical Trial to Assess the Efficacy of Darunavir/Ritonavir (DRV/r), Etravirine (ETV) and Raltegravir (MK-0518) in HIV Patients With Resistant Viruses
Acronym
ANRS139 TRIO
Official Title
Prospective Clinical Trial to Assess Safety and Efficacy of DRV/r(TMC 114/r), ETV(TMC 125) and MK-0518 in Addition to OBT in HIV-1 Infected Patients With Limited to No Treatment Options ANRS 139 TRIO
Study Type
Interventional

2. Study Status

Record Verification Date
September 2010
Overall Recruitment Status
Completed
Study Start Date
May 2007 (undefined)
Primary Completion Date
March 2008 (Actual)
Study Completion Date
September 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
French National Agency for Research on AIDS and Viral Hepatitis
Collaborators
Merck Sharp & Dohme LLC, Janssen-Cilag Tibotec

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to look at the safety and efficacy of a combination of 3 new antiretroviral drugs: darunavir, etravirine and MK-0518 (raltegravir) in patients who have multi-resistant viruses and limited treatment options. An optimized background regimen that may include nucleoside reverse transcriptase inhibitors (NRTIs) and enfuvirtide can be added, if possible, to this combination. Patients will undergo treatment for 48 weeks and virological efficacy will be evaluated at week 24.
Detailed Description
Methods: A phase II pilot, prospective, open label, single arm multicentric clinical trial assessing a darunavir/ritonavir, etravirine and MK-0518-containing regimen, if possible associated to an optimized background regimen that may include NRTIs and enfuvirtide, in HIV-1 infected patients failing combination antiretroviral therapy with multi-resistant viruses. Treatment strategy: Patients will receive raltegravir (MK-0518), darunavir/ritonavir (TMC114/r) and etravirine (TMC125) and if possible an optimized background therapy. raltegravir (MK-0518) (400 mg x 2/d = one 400 mg pill twice daily) darunavir (600 mg x 2/d= two 300 mg pills twice daily with meal) ritonavir (100 mg x 2/d = one 100 mg pill twice daily with meal) etravirine (200 mg x 2/d = two 100 mg pills twice daily with meal) if possible an optimized background therapy: may include NRTI(s) and enfuvirtide but not nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). NRTIs choice is left to the clinician's discretion. Enfuvirtide is highly recommended in enfuvirtide-naive patients but is left to the clinician. Main outcome: proportion of patients with HIV RNA levels of less than 50 copies/ml in an intent to treat analysis at W24. Secondary outcomes: proportions of patients with HIV RNA levels of less than 50 copies/ml at week 48, with HIV RNA levels of less than 400 copies/ml at week 24 and 48; HIV RNA level evolution between baseline and week 48; HIV proviral DNA and 2LTR circle HIV DNA between baseline and week 48; number and type of resistance mutations in case of virologic failure occurrence; CD4 lymphocyte count and proportion evolution between baseline and week 48; HIV infection progression; frequency of the study regimen modifications and interruption; study regimen tolerance; study regimen adherence; association between study drugs' minimum concentrations at week 4 and virologic success at week 24; evolution of pharmacokinetic parameters of study drugs between week 1 and week 4 in the Pharmacokinetic substudy. Sample size: 103 patients Enrollment period: 24 weeks Patient's participation duration: 52 weeks An extended follow-up (from week 52 to week 96) has been added in April 2008.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections
Keywords
HIV infections, HIV integrase inhibitor, etravirine, darunavir, MK 0518, raltegravir, Treatment Experienced, Antiviral drug resistance

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
103 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
raltegravir potassium
Other Intervention Name(s)
Isentress
Intervention Description
400 mg twice a day
Intervention Type
Drug
Intervention Name(s)
darunavir/ritonavir
Other Intervention Name(s)
Prezista
Intervention Description
2 pills of 300 mg twice a day
Intervention Type
Drug
Intervention Name(s)
etravirine
Other Intervention Name(s)
TMC125
Intervention Description
2 pills of 100 mg twice a day
Intervention Type
Drug
Intervention Name(s)
Optimized background regimen
Other Intervention Name(s)
OBT, enfuvirtide
Intervention Description
NRTIs and or enfuvirtide (investigator choice)
Primary Outcome Measure Information:
Title
Proportion of patients with HIV RNA levels of less than 50 copies/ml in an intent to treat analysis at week 24
Time Frame
week 24
Secondary Outcome Measure Information:
Title
Proportions of patients with HIV RNA levels of less than 50 copies/ml at week 48, with HIV RNA levels of less than 400 copies/ml at weeks 24 and 48
Time Frame
week 24 and 48
Title
HIV RNA level evolution between baseline and week 48
Time Frame
from week 0 to 48
Title
HIV proviral DNA and 2LTR circle HIV DNA between baseline and week 48
Time Frame
from week 0 to 48
Title
Number and type of resistance mutations in case of virologic failure occurrence
Time Frame
from week 0 to 48
Title
CD4 lymphocyte count and proportion evolution between baseline and week 48
Time Frame
from week 0 to 48
Title
HIV infection progression
Time Frame
from week 0 to 48
Title
Frequency of the study regimen modifications and interruption
Time Frame
from week 0 to 48
Title
Study regimen tolerance
Time Frame
from week 0 to 48
Title
Study regimen adherence
Time Frame
from week 0 to 48
Title
Association between study drugs' minimum concentrations at week 4 and week 12 and virologic success at week 24
Time Frame
from week 4 to 24
Title
Evolution of pharmacokinetics parameters of study drugs in the PK substudy
Time Frame
betwwen week 1 and 4

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age: 18 years and above Documented HIV-1 infection. History of virological failure on NNRTIs (patients with a history of toxicity to nevirapine and efavirenz may be enrolled in this study). On a combination antiretroviral therapy for at least 8 weeks prior to the screening visit (if on tipranavir, or enfuvirtide these drugs should have been introduced more than 8 weeks before the screening visit). Patient naive to darunavir, etravirine and to integrase inhibitors Plasma viral load at screening visit over 1000 copies/ml, (no CD4 restriction). Genotypic resistance testing at the screening visit: Protease inhibitor mutations: over or equal to 3 primary protease inhibitor mutations among: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54M, L76V, V82A/F/L/T/S, I84V, N88S and L90M (IAS list 2006) but below or equal to 3 mutations among the following: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V et L89V (virus sensitivity to darunavir/ritonavir). Reverse transcriptase mutations: over or equal to 3 NRTI mutations (among IAS list) and below or equal to 3 mutations among: A98G, L100I, K101Q/P/E, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/I/V/C/H/L, Y188C/H/L, G190A/C/E/Q/S, P225H, F227C/L, M230I/L, P236L, K238N/T and Y318F (virus sensitivity to etravirine) Exclusion Criteria: Non effective barrier contraception in women of child bearing potential Pregnant women or women who are breastfeeding Opportunistic infection at the acute phase Decompensated cirrhosis (stage B or C of Child-Pugh score) Malignancy requiring chemotherapy or radiotherapy Contraindicated medications being taken by the patient (listed in protocol) Allergy to the active substances and expedients of darunavir, etravirine and raltegravir. Haemoglobin < 7g/dl, neutrophil cell count < 500/mm3, platelets < 50,000/mm3, creatinine clearance < 50 ml/mn, P. alkaline, AST, ALT or total bilirubin over or equal to 3 times normal values. Patients receiving experimental agents with an exclusion period for participation in other studies applicable at the screening visit of the current study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yazdan YAZDANPANAH, MD PHD
Organizational Affiliation
Hôpital Tourcoing FRANCE
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Geneviève CHENE, MD PHD
Organizational Affiliation
INSERM U897 BORDEAUX FRANCE
Official's Role
Study Director
Facility Information:
Facility Name
Hôpital Gustave Dron, Service Maladies Infectieuses
City
Tourcoing
ZIP/Postal Code
59208
Country
France

12. IPD Sharing Statement

Learn more about this trial

Clinical Trial to Assess the Efficacy of Darunavir/Ritonavir (DRV/r), Etravirine (ETV) and Raltegravir (MK-0518) in HIV Patients With Resistant Viruses

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