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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)

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ClinicalTrials.gov Identifier: NCT00460382
Recruitment Status : Completed
First Posted : April 13, 2007
Last Update Posted : September 17, 2010
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Janssen-Cilag Tibotec
Information provided by:
French National Agency for Research on AIDS and Viral Hepatitis

Study Description
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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.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: raltegravir potassium Drug: darunavir/ritonavir Drug: etravirine Drug: Optimized background regimen Phase 2

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.


Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 103 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : May 2007
Actual Primary Completion Date : March 2008
Actual Study Completion Date : September 2009

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arms and Interventions
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Intervention Details:
  • Drug: raltegravir potassium
    400 mg twice a day
    Other Name: Isentress
  • Drug: darunavir/ritonavir
    2 pills of 300 mg twice a day
    Other Name: Prezista
  • Drug: etravirine
    2 pills of 100 mg twice a day
    Other Name: TMC125
  • Drug: Optimized background regimen
    NRTIs and or enfuvirtide (investigator choice)
    Other Names:
    • OBT
    • enfuvirtide

Outcome Measures
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Primary Outcome Measures :
  1. 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 Measures :
  1. 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 ]
  2. HIV RNA level evolution between baseline and week 48 [ Time Frame: from week 0 to 48 ]
  3. HIV proviral DNA and 2LTR circle HIV DNA between baseline and week 48 [ Time Frame: from week 0 to 48 ]
  4. Number and type of resistance mutations in case of virologic failure occurrence [ Time Frame: from week 0 to 48 ]
  5. CD4 lymphocyte count and proportion evolution between baseline and week 48 [ Time Frame: from week 0 to 48 ]
  6. HIV infection progression [ Time Frame: from week 0 to 48 ]
  7. Frequency of the study regimen modifications and interruption [ Time Frame: from week 0 to 48 ]
  8. Study regimen tolerance [ Time Frame: from week 0 to 48 ]
  9. Study regimen adherence [ Time Frame: from week 0 to 48 ]
  10. 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 ]
  11. Evolution of pharmacokinetics parameters of study drugs in the PK substudy [ Time Frame: betwwen week 1 and 4 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00460382


Locations
France
Hôpital Gustave Dron, Service Maladies Infectieuses
Tourcoing, France, 59208
Sponsors and Collaborators
French National Agency for Research on AIDS and Viral Hepatitis
Merck Sharp & Dohme Corp.
Janssen-Cilag Tibotec
Investigators
Principal Investigator: Yazdan YAZDANPANAH, MD PHD Hôpital Tourcoing FRANCE
Study Director: Geneviève CHENE, MD PHD INSERM U897 BORDEAUX FRANCE
More Information
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Responsible Party: French National Agency for Research on AIDS and Viral Hepatitis
ClinicalTrials.gov Identifier: NCT00460382     History of Changes
Other Study ID Numbers: 2007-000670-23
ANRS 139 TRIO
First Posted: April 13, 2007    Key Record Dates
Last Update Posted: September 17, 2010
Last Verified: September 2010

Keywords provided by French National Agency for Research on AIDS and Viral Hepatitis:
HIV infections
HIV integrase inhibitor
etravirine
darunavir
 MK 0518
raltegravir
Treatment Experienced
Antiviral drug resistance

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Ritonavir
Darunavir
Raltegravir Potassium
Enfuvirtide
Etravirine
HIV Protease Inhibitors
 Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
HIV Integrase Inhibitors
Integrase Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
HIV Fusion Inhibitors
Viral Fusion Protein Inhibitors