Clinical trial NCT02212379: 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
Official title: Dual Therapy Combining Raltegravir With Etravirine Maintains a High Level of Viral Suppression Over 96 Weeks in Long-term Experienced HIV-infected Individuals Over 45 Years on a PI-based Regimen: Results From the Phase II ANRS 163 ETRAL Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Keywords: Raltegravir
Etravirine
aged, 45 and over
Viral load
Efficacy
Safety
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Merck Sharp & Dohme LLC
name: Janssen-Cilag Ltd.
First posted: 2014-08-08
Enrollment: 170
Sex: ALL
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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. The primary endpoint was the proportion of participants with virological success at 48 weeks. Virological success is defined as the absence of 2 consecutive plasma viral load \>50 copies/mL within 2 to 4 weeks apart. The study was designed to show an efficacy \>90%, assuming a success rate \>95%, with a power of 80% and a 5%type-1 error. A total of 160 individuals was required to achieve the objective. The principal secondary endpoint is the proportion of patients in therapeutic success up to week 48 and 96.


Eligibility 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 health 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 immunotherapy 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 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

Primary outcomes:
measure: Percentage of Participants With Successful Virological Suppression at Weeks 48 and 96
timeFrame: at week48 and at week 96
Secondary outcomes:
measure: Percentage of Patients With Therapeutic Success at Week 48 and Week 96
timeFrame: weeks 48 and 96
measure: Percentage of Patients With Trial Treatment Interruption at Week 48 and Week 96
timeFrame: weeks 48 and 96
measure: Percentage of Patients With With Grade Virological Failure (HIV-RNA Plasma VL Between 51 and 200 Copies/mL)
timeFrame: weeks 48 and 96
measure: Median Time of Virological Failure
timeFrame: week 96
measure: Percentage of Patients With High Grade of Virological Failure Defined as HIV RNA > 200 Copies/mL
timeFrame: weeks 48 and 96
measure: Number of Patients With RAL and/or ETR Resistance Mutations Among Those With Virological Failure
timeFrame: week 96
measure: Factors Associated With the Occurrence of Plasma HIV-RNA Viral Load > 50 Copies/mL
timeFrame: week 96
measure: Evolution of Total Cell-associated HIV-DNA
timeFrame: from day 0 to week 48 and week 96
measure: Evolution of CD4+, CD8+ T Cells Counts and CD4/CD8 Ratio
timeFrame: from day 0 to week 48 and week 96
measure: Number of Participants Experiencing Adverse Events and Effects
timeFrame: From day 0 to week 48 and week 96
measure: Evolution of Metabolic Parameters (Fasting Triglycerides, Total Cholesterol, HDL-cholesterol, LDL-cholesterol and Fasting Glycemia)
timeFrame: from day 0 to week 96
measure: Evolution of the Calibrated 5-year Framingham Risk Score
timeFrame: from day 0 to week 48 and at week 96
measure: Percent Change of Renal Function
timeFrame: from day 0 to week 96
measure: Evolution of Body Fat Distribution From Day 0 to W96 (DXA Scan Sub-study, 80 Patients)
timeFrame: from day 0 to week 96
measure: Sub-study: Bone Mineral Density
timeFrame: from day 0, to week 48 and week 96
measure: Percentage of Participants With Detectable Seminal HIV-RNA Viral Load at Week 48
timeFrame: week 48
measure: Inflammatory Parameters
timeFrame: from day 0 to week 96
measure: Percentage of Participants Reporting a Very Good or an Excellent Quality of Life at Day 0, Weeks 48 and 96
timeFrame: day 0 and weeks 48 and 96
measure: Percentage of Participants Compliant With Treatment Program.
timeFrame: at week 0, week 48, and week 96
measure: Evolution of the Ovarian Reserve From D0 to W48 Measured by AMH on Frozen Aliquots
timeFrame: from day 0, to week 48
measure: Evolution of the Level of MCP1 From D0 to W48 on Frozen Samples
timeFrame: from day 0, to week 48
measure: Sub-study in Women : Comparison of the Metabolic/Inflammatory Profile in Women According to Their Ovarian Reserve and Menopausal Status at D0 and Its Evolution up to Week 96
timeFrame: from day 0, to week 96
measure: Sub-study in Women : Comparison of the Evolution Fat Distribution Measured by DXA Scan and Body Weight According to AMH Status
timeFrame: from day 0, to week 96
Other outcomes:
Locations:
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Bondy
country: France
facility: Hôpital Jean Verdier
city: Bordeaux
country: France
facility: Hôpital Saint André
city: Le Kremlin Bicêtre
country: France
facility: Hôpital Bicêtre
city: Lyon
country: France
facility: Hôpital Croix Rousse
city: Marseille
country: France
facility: Hôpital Sainte marguerite
city: Montpellier
country: France
facility: Hôpital Gui de Chauliac
city: Nantes
country: France
facility: CHU Hôtel Dieu
city: Nice
country: France
facility: Hôpital de l'Archet
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hôpital Pitié-Salpétrière
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Hôpital Necker
city: Paris
country: France
facility: Hôpital Bichat Claude Bernard
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Tours
country: France
facility: Hôpital Bretonneau
city: Barcelona
country: Spain
facility: Hospital de Bellvitge
city: Barcelona
country: Spain
facility: Hospital de la santa Creu i San Pau
city: Barcelona
country: Spain
facility: Hospital Clinic
Study officials:
affiliation: Service des Maladies Infectieuses et Tropicales, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
name: Christine Katlama, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Département des Maladies Infectieuses et Tropicales Hôpital Gui de Chauliac, CHU de Montpellier France
name: Jacques Reynes, MD
role: STUDY_CHAIR
affiliation: Inserm UMR S 1136 Université Pierre et Marie Curie Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l'infection à VIH, Paris, France
name: Dominique Costagliola, PhD
role: STUDY_DIRECTOR
References: