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

HIV-1 Infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02212379
• Other study ID #: 2014-000828-24
• Secondary ID: ANRS 163 ETRAL
• Status: Completed
• Phase: Phase 2
• Start date: January 2015
• Est. completion date: April 2018

Study information

• Verified date: March 2021
• Source: ANRS, Emerging Infectious Diseases
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 170
• Est. completion date: April 2018
• Est. primary completion date: October 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years and older

Eligibility

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

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

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.

Locations

Country	Name	City	State
France	Hôpital Avicenne	Bobigny
France	Hôpital Jean Verdier	Bondy
France	Hôpital Saint André	Bordeaux
France	Hôpital Bicêtre	Le Kremlin Bicêtre
France	Hôpital Croix Rousse	Lyon
France	Hôpital Sainte marguerite	Marseille
France	Hôpital Gui de Chauliac	Montpellier
France	CHU Hôtel Dieu	Nantes
France	Hôpital de l'Archet	Nice
France	Hôpital Bichat Claude Bernard	Paris
France	Hôpital Cochin	Paris
France	Hôpital Européen Georges Pompidou	Paris
France	Hôpital Necker	Paris
France	Hôpital Pitié-Salpétrière	Paris
France	Hôpital Saint Louis	Paris
France	Hôpital Bretonneau	Tours
Spain	Hospital Clinic	Barcelona
Spain	Hospital de Bellvitge	Barcelona
Spain	Hospital de la santa Creu i San Pau	Barcelona

Sponsors (3)

Lead Sponsor	Collaborator
ANRS, Emerging Infectious Diseases	Janssen-Cilag Ltd., Merck Sharp & Dohme Corp.

Countries where clinical trial is conducted

France,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Successful Virological Suppression at Weeks 48 and 96	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.; The proportion of patients who maintained viral suppression under raltegravir plus etravirine was 99.4% (95% confidence interval (95% CI:95.6 -99.9) at week 48 and 98.7% (95% CI: 95.0 -99.7) at week 96	at week48 and at week 96
Secondary	Percentage of Patients With Therapeutic Success at Week 48 and Week 96	Therapeutic success was defined as the absence of virological failure (i.e. 2 consecutive plasma viral loads (VL) > 50 copies/mL within 2 to 4 weeks) and the absence of treatment interruption due to adverse event judged by DSMB as related to the study treatment or procedure	weeks 48 and 96
Secondary	Percentage of Patients With Trial Treatment Interruption at Week 48 and Week 96		weeks 48 and 96
Secondary	Percentage of Patients With With Grade Virological Failure (HIV-RNA Plasma VL Between 51 and 200 Copies/mL)		weeks 48 and 96
Secondary	Median Time of Virological Failure	Time between the date of the study treatment initiation and the date of virological failure	week 96
Secondary	Percentage of Patients With High Grade of Virological Failure Defined as HIV RNA > 200 Copies/mL		weeks 48 and 96
Secondary	Number of Patients With RAL and/or ETR Resistance Mutations Among Those With Virological Failure		week 96
Secondary	Factors Associated With the Occurrence of Plasma HIV-RNA Viral Load > 50 Copies/mL		week 96
Secondary	Evolution of Total Cell-associated HIV-DNA		from day 0 to week 48 and week 96
Secondary	Evolution of CD4+, CD8+ T Cells Counts and CD4/CD8 Ratio		from day 0 to week 48 and week 96
Secondary	Number of Participants Experiencing Adverse Events and Effects	Number of all clinical and biological adverse events effects. Number of grade 3 or 4 clinical and biological adverse events and effects.	From day 0 to week 48 and week 96
Secondary	Evolution of Metabolic Parameters (Fasting Triglycerides, Total Cholesterol, HDL-cholesterol, LDL-cholesterol and Fasting Glycemia)		from day 0 to week 96
Secondary	Evolution of the Calibrated 5-year Framingham Risk Score	The Framingham risk score is expressed as a percentage. Higher scores mean a worse outcome and lower scores mean better outcome.; Median percent change expressed as median (interquartile range (IQR))	from day 0 to week 48 and at week 96
Secondary	Percent Change of Renal Function	Percent change of the estimated Glomerular Filtration Rate (eGFR) calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration Calculator) formula	from day 0 to week 96
Secondary	Evolution of Body Fat Distribution From Day 0 to W96 (DXA Scan Sub-study, 80 Patients)	Evolution of total fat mass, limb fat and trunk fat from day 0 to week 96	from day 0 to week 96
Secondary	Sub-study: Bone Mineral Density	• Evolution of bone mineral density (BMD) measured by DXA scans (DXA scan sub-study, 81 patients); Lumbar spine BMD, mg/cm2; Total hip BMD, mg/cm2	from day 0, to week 48 and week 96
Secondary	Percentage of Participants With Detectable Seminal HIV-RNA Viral Load at Week 48	• Assessment of HIV-RNA viral load in human male genital compartment (20 patients) at week 48	week 48
Secondary	Inflammatory Parameters	• Evolution of the inflammation markers (IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin) on frozen plasma aliquots	from day 0 to week 96
Secondary	Percentage of Participants Reporting a Very Good or an Excellent Quality of Life at Day 0, Weeks 48 and 96		day 0 and weeks 48 and 96
Secondary	Percentage of Participants Compliant With Treatment Program.	The compliance rate was estimated as the number of pills consumed (recorded using the self-reported 90 questionnaire) divided by the number of pills theoretically consumed, classified as low (80%), medium (80%-95%) or high (95%).	at week 0, week 48, and week 96
Secondary	Evolution of the Ovarian Reserve From D0 to W48 Measured by AMH on Frozen Aliquots	We measured the Anti-mullerian Hormone (AMH) level to evaluate the ovarian reserve (from D0 to W48)	from day 0, to week 48
Secondary	Evolution of the Level of MCP1 From D0 to W48 on Frozen Samples		from day 0, to week 48
Secondary	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	Metabolic markers measures are total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides.; Inflammatory and innate immune activation markers measures are: IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, hsCRP and Insulin.; Ovarian reserve measure is AMH	from day 0, to week 96
Secondary	Sub-study in Women : Comparison of the Evolution Fat Distribution Measured by DXA Scan and Body Weight According to AMH Status	BMI, Hip circumference, Waist circumference, waist/hip ratio, Limb fat, Trunk fat, Total fat, Limb lean, Trunk lean, and Total lean	from day 0, to week 96

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