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Capacity of the Dual Combination Raltegravir/Etravirine to Maintain Virological Success in HIV-1 Infected Patients of at Least 45 Years of Age- ANRS 163 ETRAL

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Janssen-Cilag Ltd.
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:
NCT02212379
First received: July 30, 2014
Last updated: August 17, 2016
Last verified: August 2016
  Purpose
This multicenter, international, non randomized (single arm), open, phase II trial aims to evaluate the capacity of the dual combination raltegravir/etravirine to maintain virological success in virologically suppressed HIV-1 infected patients, of at least 45 years of age, switching from a boosted PI-containing regimen. Patients will be followed for 96 weeks. Measurement of primary endpoint will be at 48 weeks. Virological success is defined as the absence of 2 consecutive plasma viral load >50 copies/mL within 2 to 4 weeks of a dual raltegravir/etravirin regimen. Raltegravir/etravirine will be considered acceptable if the percentage of patients in virological success at week 48 is significantly above 90 %. Assuming a 95 % virological success rate, by including 160 individuals and considering the strategy to be acceptable if no more than 8 individuals have virological failure; investigators will have a 95 % probability to discard a combination for which efficacy is smaller than 90 % and investigators will select with a power of 80 % the strategy for which the efficacy is above or equal to 95 %. The principal secondary endpoint is the proportion of patients in therapeutic success up to week 48 and 96.

Condition Intervention Phase
HIV-1 Infection
Drug: raltegravir and etravirine
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Non-comparative Phase II Trial Evaluating the Capacity of the Dual Combination Raltegravir/Etravirine to Maintain Virological Success in HIV-1 Infected Patients of at Least 45 Years of Age With an HIV-RNA Plasma Viremia Below 50 Copies/mL Under a Current Boosted Protease Inhibitor Containing Regimen (ANRS 163 ETRAL)

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:
  • To evaluate the capacity to maintain virological success in HIV-1 infected patients, of at least 45 years of age, with suppressed plasma viremia switching from a boosted PI-containing regimen. [ Time Frame: week 48 ] [ Designated as safety issue: Yes ]
    Virological success is defined as the absence of 2 consecutive plasma viral loads (VL) > 50 copies/mL within 2 to 4 weeks of a dual raltegravir/etravirine regimen


Secondary Outcome Measures:
  • Tolerability [ Time Frame: From day 0 to week 48 and week 96 ] [ Designated as safety issue: Yes ]
    • Incidence of clinical and biological adverse effects
    • Incidence of clinical and biological adverse events (grade 3 or 4)

  • Seminal sub-study [ Time Frame: week 48 ] [ Designated as safety issue: No ]
    • Assessment of HIV-RNA viral load and Cmin (Minimal Drug Concentration) of raltegravir and etravirine in human male genital compartment (20 patients)

  • Immunological outcome [ Time Frame: at each time point from day 0 ] [ Designated as safety issue: No ]
    - Evolution of CD4+, CD8+ T cells counts and CD4/CD8 ratio

  • Evolution of cardiovascular risk [ Time Frame: from day 0 to week 48 and week 96 ] [ Designated as safety issue: Yes ]
    • Evolution of the calibrated Framingham risk score and of the SCORE risk equation including HDL (High Density Lipoprotein) cholesterol

  • Evolution of renal function [ Time Frame: from day 0 to week 96 ] [ Designated as safety issue: Yes ]
    • Evolution of renal function evaluated using proteinuria and the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Calculator) formula to estimate the Glomerular Filtration Rate (GFR)

  • Health-related, quality of life [ Time Frame: from day 0 to week 48 and week 96 ] [ Designated as safety issue: No ]
    • Evaluation of health-related quality of life with a self-assessment questionnaire

  • Metabolic parameters [ Time Frame: from day 0 to week 48 and week 96 ] [ Designated as safety issue: No ]
    • Evolution of metabolic parameters (fasting triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol and fasting glycemia)

  • Sub-study: evolution of peripheral and central body fat distribution [ Time Frame: from day 0 to week 48 and week 96 ] [ Designated as safety issue: No ]
    • Evolution of limb lean, limb fat, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), measured by DXA scan (Dual-energy X-Ray Absorptiometry), from D0 to W48 and W96 (DXA scan sub-study, 80 patients)

  • Compliance [ Time Frame: at week-6/ week -4, week 48, and week 96 ] [ Designated as safety issue: No ]
    • Evaluation of the compliance with a self-assessment questionnaire

  • Virological success [ Time Frame: from day 0 to week 48 and week 96 ] [ Designated as safety issue: Yes ]
    • percentage of patients remaining in therapeutic success
    • percentage of patients in virological success (plasma HIV-RNA <=50 cp/mL)

  • Treatment interruption [ Time Frame: from day 0 to week 96 ] [ Designated as safety issue: Yes ]
    • Percentage of patients with trial treatment interruption

  • Virological failure [ Time Frame: from day 0 to week 96 ] [ Designated as safety issue: Yes ]
    • Percentage of patients with plasma HIV-RNA viral load between 51 and 200 copies/mL

  • Virological failure [ Time Frame: at time of virological failure ] [ Designated as safety issue: Yes ]
    • Percentage of patients with plasma HIV-RNA VL ˃ 200 copies/mL

  • Virological failure [ Time Frame: between day 0 and week 96 ] [ Designated as safety issue: Yes ]
    • Median time of virological failure (time limit between the date of the study treatment initiation and the date of virological failure)

  • Virological failure: resistance mutations [ Time Frame: between day 0 and week 96 ] [ Designated as safety issue: Yes ]
    • Percentage of patients with RAL and/or ETR resistance mutations in case of virological failure
    • Percentage of patients with resistant viruses to all study drug's class in case of virological failure

  • Virological failure: associated factors [ Time Frame: between day 0 and week 96 ] [ Designated as safety issue: Yes ]
    • Factors associated with the occurrence of plasma HIV-RNA viral load > 50 copies/mL (genotype history, pre-cART viral load, plasma drug concentration (etravirine, raltegravir) at the virological rebound, viral reservoir measured by HIV-DNA at day 0 and adherence assessed with a self-questionnaire)

  • total HIV-DNA [ Time Frame: from day 0 to week 48 and week 96 ] [ Designated as safety issue: No ]
    • Evolution of total cell-associated HIV-DNA

  • Inflammatory parameters [ Time Frame: from day 0 to week 48, and week 96 ] [ Designated as safety issue: No ]
    • Evolution of the inflammation markers (IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin) on frozen plasma aliquots

  • Sub-study: bone mineral density [ Time Frame: from day 0, to week 48 and week 96 ] [ Designated as safety issue: No ]
    • Evolution of bone mineral density measured by DXA scans (DXA scan sub-study, 80 patients)


Estimated Enrollment: 160
Study Start Date: January 2015
Estimated Study Completion Date: January 2019
Estimated Primary Completion Date: January 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: raltegravir and etravirine Drug: raltegravir and etravirine

Raltegravir (RAL, ISENTRESS®) 400 mg tablets will be administered as one 400 mg oral tablet PO twice daily (800 mg per day) after a meal.

Etravirine (ETR, INTELENCE®) 200 mg tablets will be administered as one 200 mg oral tablet PO twice daily (400 mg per day) after a meal.


  Eligibility

Ages Eligible for Study:   45 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Documented HIV-1 infection
  • Age ≥ 45 years
  • Naïve to integrase inhibitor and etravirine
  • At least 6 months of stable antiretroviral therapy (ART) including a boosted protease inhibitor, whatever the number of combined drugs
  • HIV-RNA plasma VL ≤ 50 copies/mL during the last 24 months prior to screening visit (Week-6/Week-4), documented by at least 4 time-points with no more than one blip in HIV-RNA plasma viral load between 51 and 200 copies/mL
  • HIV-RNA plasma VL ≤ 50 copies/mL at screening visit (Week-6/Week-4)
  • A genotype is available (on amplified DNA at Week-6/Week-4 Visit and/or on RNA in the medical history of the patient) and shows a virus sensitive to ETR OR no genotype is available (amplification failure on DNA at Week-6/Week-4 Visit and no genotype in the medical history of the patient), there are no virological failure on NNRTI in the medical history
  • CD4+ lymphocytes > 200 cells/mm3
  • Creatinine < 2.5 x ULN
  • CPK (Creatine Phospho Kinase) < 6 ULN (Upper Limit of Normal)
  • AST (Aspartate Aminotransferase), ALT (Alanine Aminotransferase) < 5 ULN
  • Hemoglobin > 10 g/dL
  • Platelets > 100 000/mm3
  • Negative urinary pregnancy test and use of efficient contraception for women of childbearing potential
  • For French participants only: subject enrolled in or a beneficiary of a Social Security programme (State Medical Aid or AME is not a Social Security programme), article L1121-11 of the Public heatlh code
  • Patients with a coverage from a social health
  • Signed informed consent

Exclusion Criteria:

  • Previous exposure to raltegravir or etravirine
  • Presence of any documented integrase inhibitor mutation on DNA genotype at Week-6/Week-4 and/or on RNA in the medical history of the patient
  • Positive hepatitis B HBsAg or Positive HBc Ac and negative HBs Ac
  • HIV-2 infection
  • Active viral hepatitis C requiring a specific treatment during the 24 months of the trial
  • Patient with a history of non-compliance or irregular follow-up
  • Initiation of a concomitant anti-hypercholesterolemia (e.g. statins) or antidiabetic treatment within the last 3 months prior the screening visit (Week-6 /Week-4)
  • Patient using: Clopidogrel (Plavix®), Prasugrel (Effient®), Ticagrelor (Brilinta®), Ticlopidine (Ticlid®), Flurbiprofen (Antadys® - Cebutid®), Rifampin (Rifampicin® - Rifadin® - RofactMC - Rifater®), Rifapentine (Priftin®), St John's wort, Carbamazepine (Tegretol®), Phenobarbital, Phenytoin (Dilantin®),Avanafil (Stendra™), Triazolam (Halcion®)
  • Concomitant treatment using interferon, interleukins or any other immunetherapy or chemotherapy
  • Concomitant prophylactic or curative treatment for an opportunistic infection
  • All conditions (use of alcohol, drugs, etc.) judged by the investigator to possibly interfere with trial protocol compliance, adherence and/or trial treatment tolerance
  • Subjects under "sauvegarde de justice" (judicial protection due to temporarily and slightly diminished mental or physical faculties), or under legal guardianship
  • Subjects participating in another clinical trial evaluating different therapies and including an exclusion period that is still in force during the screening phase
  • Pregnant women or breastfeeding women
  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: NCT02212379

Locations
France
Hôpital Avicenne
Bobigny, France, 93000
Hôpital Jean Verdier
Bondy, France, 93140
Hôpital Saint André
Bordeaux, France, 33076
Hôpital Bicêtre
Le Kremlin Bicêtre, France, 94275
Hôpital Croix Rousse
Lyon, France, 69317
Hôpital Sainte marguerite
Marseille, France, 13009
Hôpital Gui de Chauliac
Montpellier, France, 34000
CHU Hôtel Dieu
Nantes, France, 44093
Hôpital de l'Archet
Nice, France, 06202
Hôpital Saint Louis
Paris, France, 75010
Hôpital Pitié-Salpétrière
Paris, France, 75013
Hôpital Cochin
Paris, France, 75014
Hôpital Necker
Paris, France, 75015
Hôpital Bichat Claude Bernard
Paris, France, 75018
Hôpital Européen Georges Pompidou
Paris, France, 75908
Hôpital Bretonneau
Tours, France, 37044
Spain
Hospital de Bellvitge
Barcelona, Spain, 08000
Hospital de la santa Creu i San Pau
Barcelona, Spain, 08025
Hospital Clinic
Barcelona, Spain, 08036
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.
Janssen-Cilag Ltd.
Investigators
Principal Investigator: Christine Katlama, MD Service des Maladies Infectieuses et Tropicales, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
Study Chair: Jacques Reynes, MD Département des Maladies Infectieuses et Tropicales Hôpital Gui de Chauliac, CHU de Montpellier France
Study Director: Dominique Costagliola, PhD Inserm UMR S 1136 Université Pierre et Marie Curie Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Paris, France
  More Information

Additional Information:
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: NCT02212379     History of Changes
Other Study ID Numbers: 2014-000828-24  ANRS 163 ETRAL 
Study First Received: July 30, 2014
Last Updated: August 17, 2016
Health Authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
Spain: Spanish Agency of Medicines

Keywords provided by French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS):
Raltegravir
Etravirine
aged, 45 and over
Viral load
Efficacy
Safety

Additional relevant MeSH terms:
Raltegravir Potassium
Etravirine
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
HIV Integrase Inhibitors
Integrase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on September 28, 2016