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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

Tracking Information
First Submitted Date  ICMJE April 12, 2007
First Posted Date  ICMJE April 13, 2007
Last Update Posted Date September 17, 2010
Study Start Date  ICMJE May 2007
Actual Primary Completion Date March 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 1, 2008)
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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: April 12, 2007)
Proportion of patients with HIV RNA levels of less than 50 copies/ml in an intent to treat analysis at W24.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 1, 2008)
  • 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 ]
  • HIV RNA level evolution between baseline and week 48 [ Time Frame: from week 0 to 48 ]
  • HIV proviral DNA and 2LTR circle HIV DNA between baseline and week 48 [ Time Frame: from week 0 to 48 ]
  • Number and type of resistance mutations in case of virologic failure occurrence [ Time Frame: from week 0 to 48 ]
  • CD4 lymphocyte count and proportion evolution between baseline and week 48 [ Time Frame: from week 0 to 48 ]
  • HIV infection progression [ Time Frame: from week 0 to 48 ]
  • Frequency of the study regimen modifications and interruption [ Time Frame: from week 0 to 48 ]
  • Study regimen tolerance [ Time Frame: from week 0 to 48 ]
  • Study regimen adherence [ Time Frame: from week 0 to 48 ]
  • 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 ]
  • Evolution of pharmacokinetics parameters of study drugs in the PK substudy [ Time Frame: betwwen week 1 and 4 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 12, 2007)
  • 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 virologic success at week 24
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Clinical Trial to Assess the Efficacy of Darunavir/Ritonavir (DRV/r), Etravirine (ETV) and Raltegravir (MK-0518) in HIV Patients With Resistant Viruses
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV Infections
Intervention  ICMJE
  • 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
Study Arms  ICMJE Not Provided
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 1, 2008)
103
Original Enrollment  ICMJE
 (submitted: April 12, 2007)
90
Actual Study Completion Date  ICMJE September 2009
Actual Primary Completion Date March 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00460382
Other Study ID Numbers  ICMJE 2007-000670-23
ANRS 139 TRIO
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party French National Agency for Research on AIDS and Viral Hepatitis
Study Sponsor  ICMJE French National Agency for Research on AIDS and Viral Hepatitis
Collaborators  ICMJE
  • Merck Sharp & Dohme Corp.
  • Janssen-Cilag Tibotec
Investigators  ICMJE
Principal Investigator: Yazdan YAZDANPANAH, MD PHD Hôpital Tourcoing FRANCE
Study Director: Geneviève CHENE, MD PHD INSERM U897 BORDEAUX FRANCE
PRS Account French National Agency for Research on AIDS and Viral Hepatitis
Verification Date September 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP