ANRS0392s ELDORADO : Phase III, open-label, randomized, multicenter trial EvaLuating the non-inferiority of DORAvirine versus DOlutegravir based antiretroviral regimens in treatment-naïve people living with HIV-1 infection
- Conditions
- HIV-1 infection
- Interventions
- Registration Number
- 2023-508626-10-00
- Lead Sponsor
- Inserm
- Brief Summary
To assess the non-inferiority of doravirine (DOR) in association with tenofovir (TDF) and lamivudine (3TC), compared to dolutegravir (DTG) in association with tenofovir (TDF) and lamivudine (3TC) or emtricitabine (FTC), in terms of virologic efficacy at week 48, measured by the proportion of subjects achieving HIV 1 RNA <50 copies/mL, in HIV-1 infected, treatment-naive subjects with pre-treatment viral load (HIV-1 RNA) ≥ 1,000 copies/mL.
- Detailed Description
Phase III, multicenter, open-label, randomized, non-inferiority clinical trial which aims to assess the non-inferiority of doravirine in association with tenofovir and lamivudine, as compared to dolutegravir in association with tenofovir and lamivudine or emtricitabine.
This trial will be implemented in Brazil, Cameroon, Côte d'Ivoire, France, Mozambique and Thailand.
Six hundred and ten patients will be enrolled and followed for 96 weeks after entry in the trial (=ART initiation).
Primary endpoint will assess virological efficacy at Week 48, measured by the proportion of subjects achieving HIV-1 RNA \<50 copies/mL, in HIV-1 infected, treatment-naive subjects with pre-treatment viral load (HIV-1 RNA) ≥ 1,000 copies/mL.
Secondary endpoints are planned at W48 and W96.
Recruitment & Eligibility
- Status
- Ongoing, recruiting
- Sex
- Not specified
- Target Recruitment
- 60
Be at least 18 years of age on the day of signing the informed consent
Be HIV-1 positive as determined according to national testing strategies
Have a plasma HIV-1 RNA ≥1000 copies/mL within 30 days prior to the randomization
Have HIV treatment indication based on physician assessment according to local treatment guidelines
Be naïve to antiretroviral therapy (ART) for the treatment of HIV infection including investigational antiretroviral agents
For women or transgender men of childbearing potential i.e. of childbearing age who are not menopausal, or permanently sterilized (e.g. tubal occlusion, hysterectomy, bilateral salpingectomy) or not refraining from sexual activity: negative urinary test for pregnancy and acceptance to use contraceptive methods
Understand the study procedures and voluntarily agree to participate by giving written informed consent for the trial
For patients in France, be affiliated to a Social Security program, CMU (Universal Health Cover) or AME (State Medical Aid)
Has ongoing (pulmonary or extra-pulmonary) tuberculosis
Requires or is anticipated to require any of the prohibited or contraindicated medications noted in the trial protocol
Has significant hypersensitivity or other contraindication to any of the components of the study drugs
Is pregnant, breastfeeding, or expecting to conceive at any time during the study
Has any condition, which might, in the investigator’s opinion, compromise the safety of treatment and/or patient’s adherence to study procedures
Is a person under guardianship or deprived of freedom by a judicial or administrative decision
Has any other history or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study or interfere with the subject’s participation for the full duration of the study, such that it is not in the best interest of the subject to participate
Is infected with HIV-2 or co-infected with HIV-1 and HIV-2
Has received cabotegravir long acting or dapivirine pre-exposure prophylaxis (PrEP)
Has received oral pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP) in the past three months or has had no negative HIV-1 serology performed
Has documented or known resistance or possible resistance to study drugs (in France and where national guidelines recommend screening for primary resistance before starting first-line ART), as defined below by the ANRS-MIE AC43 Resistance group: DTG: G118R, F121Y, E138A/K/T, G140A/C/S, N144D, Q148H/K/R, V151L, S153F/Y, N155H, S230R, R263K, T66K+L74M, L74I+E92Q, T66K and at least 3 mutations among: L74M, E92Q, T97A, S147G TDF: K65R/E/N, K70E, T69INS, at least 3 mutations among M41L, E44D, D67N, T69D/N/S, L74V/I, L210W, T215A/C/D/E/G/H/I/L/N/S/V/Y/F DOR: V106A, V106M, Y188L, G190E/S, F227C, F227L/R, M230L, L100I+K103N, K103N+Y181C, K103N+P225H, at least 2 mutations among: A98G, L100I, K101E, V106I, E138K, Y181C/V, G190A or H221Y 3TC/FTC: K65R, 69INS, M184V/I, Q151M
Has the following laboratory values at screening visit, within 30 days prior to the randomization: AST (SGOT) and ALT (SGPT) >4.0 x upper limit of normal (ULN) and/or estimated glomerular filtration rate at time of screening <60 mL/min/1.73m², based on the CKD-EPI equation
Has participated in a study with an investigational compound/device within 30 days prior to signing informed consent or anticipates participating in such a study involving an investigational compound/device during the course of this study
Has used systemic immunosuppressive therapy or immune modulators within 30 days prior to treatment in this study or is anticipated to need them during the course of the study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Arm && Interventions
Group Intervention Description Doravirine arm Doravirine + tenofovir DF + lamivudine Doravirine (100 mg) + tenofovir DF (300 mg) + lamivudine (300mg) administered daily Dolutegravir arm Dolutegravir + tenofovir DF + lamivudine or emtricitabine Dolutegravir (50 mg) + tenofovir DF 300 mg + XTC (300 mg if lamivudine or 200 mg if emtricitabine) administered daily
- Primary Outcome Measures
Name Time Method Proportion of subjects in virologic success defined as achieving HIV-1 RNA <50 copies/mL at week 48 under allocated treatment using the FDA snapshot algorithm (window period of 42-54 weeks). Proportion of subjects in virologic success defined as achieving HIV-1 RNA <50 copies/mL at week 48 under allocated treatment using the FDA snapshot algorithm (window period of 42-54 weeks).
- Secondary Outcome Measures
Name Time Method Occurrence of obesity at Week 48 and at Week 96. Obesity will be defined as having BMI≥30 kg/m² for Caucasian and African population and BMI≥27.5 kg/m² for Asian populations. Occurrence of obesity at Week 48 and at Week 96. Obesity will be defined as having BMI≥30 kg/m² for Caucasian and African population and BMI≥27.5 kg/m² for Asian populations.
Proportion of subjects with newly measured HOMA≥2 at Week 48 and Week 96 as compared to baseline Proportion of subjects with newly measured HOMA≥2 at Week 48 and Week 96 as compared to baseline
Proportion of subjects with hypertension newly detected at Week 48 and Week 96 compared to baseline. Hypertension will be defined as either being prescribed new anti-hypertension medication and/or by having diastolic blood pressure >90 mmHg AND/OR systolic blood pressure >140 mmHg during visit and confirmed during subsequent visit > 15 days after. Proportion of subjects with hypertension newly detected at Week 48 and Week 96 compared to baseline. Hypertension will be defined as either being prescribed new anti-hypertension medication and/or by having diastolic blood pressure >90 mmHg AND/OR systolic blood pressure >140 mmHg during visit and confirmed during subsequent visit > 15 days after.
Proportion of subjects in virologic success defined as achieving HIV-1 RNA <50 copies/mL at week 96 under allocated treatment using the FDA snapshot algorithm with a window period of 90 to 102 weeks Proportion of subjects in virologic success defined as achieving HIV-1 RNA <50 copies/mL at week 96 under allocated treatment using the FDA snapshot algorithm with a window period of 90 to 102 weeks
Change from baseline in CD4 cell count, CD4 percentage, CD8 cell count, CD8 percentage, CD4/CD8 ratio, at Week 48 and at Week 96 Change from baseline in CD4 cell count, CD4 percentage, CD8 cell count, CD8 percentage, CD4/CD8 ratio, at Week 48 and at Week 96
Proportion of confirmed virological failures occurring up to Week 48 and up to Week 96. Virological failure will be defined as 1) confirmed HIV-1 RNA ≥ 200 copies/mL after initial response with HIV-1 RNA < 50 copies/mL at any time during the study or 2) non-response defined as either confirmed HIV-1 RNA ≥ 200 copies/mL at Week 24 or Week 36 (or any other unscheduled visit in-between) or confirmed HIV-1 RNA ≥ 50 copies/mL at Week 48, W72 and Week 96 (or any other unscheduled visit in-between). Proportion of confirmed virological failures occurring up to Week 48 and up to Week 96. Virological failure will be defined as 1) confirmed HIV-1 RNA ≥ 200 copies/mL after initial response with HIV-1 RNA < 50 copies/mL at any time during the study or 2) non-response defined as either confirmed HIV-1 RNA ≥ 200 copies/mL at Week 24 or Week 36 (or any other unscheduled visit in-between) or confirmed HIV-1 RNA ≥ 50 copies/mL at Week 48, W72 and Week 96 (or any other unscheduled visit in-between).
Frequency of HIV-1 drug resistances in patients with a confirmed virological failure. Drug resistances will be defined according to the last version of the ANRS algorithm and to the last version of the Stanford algorithm. Frequency of HIV-1 drug resistances in patients with a confirmed virological failure. Drug resistances will be defined according to the last version of the ANRS algorithm and to the last version of the Stanford algorithm.
Proportion of subjects achieving HIV 1 RNA<200 copies/mL under allocated treatment at Week 48 and Week 96 Proportion of subjects achieving HIV 1 RNA<200 copies/mL under allocated treatment at Week 48 and Week 96
Proportion of subjects achieving HIV 1 RNA<1000 copies/mL under allocated treatment at Week 48 and Week 96 Proportion of subjects achieving HIV 1 RNA<1000 copies/mL under allocated treatment at Week 48 and Week 96
Frequency of RT and integrase mutations at baseline and impact on the virological response at Week 48 and Week 96 Frequency of RT and integrase mutations at baseline and impact on the virological response at Week 48 and Week 96
Occurrence of combined overweight and obesity at Week 48 and at Week 96. Combined overweight and obesity will be defined as having BMI≥25 kg/m² for Caucasian and African populations and BMI≥23 kg/m² for Asian populations Occurrence of combined overweight and obesity at Week 48 and at Week 96. Combined overweight and obesity will be defined as having BMI≥25 kg/m² for Caucasian and African populations and BMI≥23 kg/m² for Asian populations
Proportion of subjects with ≥10% absolute weight gain from baseline at Week 48 and Week 96 Proportion of subjects with ≥10% absolute weight gain from baseline at Week 48 and Week 96
Change from baseline in absolute weight at Week 48 and at Week 96. Absolute weight gain will be calculated by simply subtracting the follow-up weight from baseline weight measured according to protocol procedures Change from baseline in absolute weight at Week 48 and at Week 96. Absolute weight gain will be calculated by simply subtracting the follow-up weight from baseline weight measured according to protocol procedures
Proportion of subjects with diabetes newly detected at Week 48 and Week 96 compared to baseline. Diabetes will be defined as either being prescribed new medication for diabetes mellitus and/or having a fasting glycemia ≥1.26g/L during visit and confirmed during subsequent visit > 15 days after and/or in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dL (11.1mmol/L). Proportion of subjects with diabetes newly detected at Week 48 and Week 96 compared to baseline. Diabetes will be defined as either being prescribed new medication for diabetes mellitus and/or having a fasting glycemia ≥1.26g/L during visit and confirmed during subsequent visit > 15 days after and/or in a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dL (11.1mmol/L).
Any adverse event of any grade at Week 48 and Week 96 Any adverse event of any grade at Week 48 and Week 96
Change from baseline in EQ-5D-3L score at Week 48 and Week 96 Change from baseline in EQ-5D-3L score at Week 48 and Week 96
Change from baseline in waist and hip circumferences and waist-to-hip ratio at Week 48 and Week 96 Change from baseline in waist and hip circumferences and waist-to-hip ratio at Week 48 and Week 96
Change from baseline in fasting glycemia and insulin at Week 48 and at Week 96 Change from baseline in fasting glycemia and insulin at Week 48 and at Week 96
Change from baseline in fasting serum lipids at Week 48 and at Week 96 Change from baseline in fasting serum lipids at Week 48 and at Week 96
Change from baseline in creatinine clearance at Week 48 and at Week 96. Creatinine clearance will be calculated using the CKD-EPI equation Change from baseline in creatinine clearance at Week 48 and at Week 96. Creatinine clearance will be calculated using the CKD-EPI equation
Proportion of subjects with AIDS, defined as having CDC stage 3 or WHO stage 4 and tuberculosis, IRIS or death at Week 48 and Week 96 Proportion of subjects with AIDS, defined as having CDC stage 3 or WHO stage 4 and tuberculosis, IRIS or death at Week 48 and Week 96
Adherence to ART by 1) pill count (considering a pill count adherence ratio <95% as sub-optimal adherence), 2) 4-days and 1-month recall questions at every trial visit, and 3) by TFV-DP quantification in dry blood spots (LC/MS) at Week 48 and Week 96 Adherence to ART by 1) pill count (considering a pill count adherence ratio <95% as sub-optimal adherence), 2) 4-days and 1-month recall questions at every trial visit, and 3) by TFV-DP quantification in dry blood spots (LC/MS) at Week 48 and Week 96
Type and frequency of variants alleles in the gene coding for CYP3A5 and impact on pharmacokinetics of DOR and DTG, virological response and side-effects Type and frequency of variants alleles in the gene coding for CYP3A5 and impact on pharmacokinetics of DOR and DTG, virological response and side-effects
Assess additional polymorphism of UGT1A1, ABCB1 at baseline Assess additional polymorphism of UGT1A1, ABCB1 at baseline
Metabolic substudy endpoint: change from baseline in truncal fat distribution at Week 48 and Week 96 Metabolic substudy endpoint: change from baseline in truncal fat distribution at Week 48 and Week 96
Metabolic substudy endpoint: change from baseline in adipose tissue markers (adiponectin, leptin) and immune activation markers (sCD14, sCD163) at Week 48 and Week 96 Metabolic substudy endpoint: change from baseline in adipose tissue markers (adiponectin, leptin) and immune activation markers (sCD14, sCD163) at Week 48 and Week 96
Metabolic substudy endpoint: change from baseline (by abdominal subcutaneous surgical biopsy) in fat pathology, gene expression and global transcriptome analysis (RT-PCR and RNAseq) at Week 48 Metabolic substudy endpoint: change from baseline (by abdominal subcutaneous surgical biopsy) in fat pathology, gene expression and global transcriptome analysis (RT-PCR and RNAseq) at Week 48
Trial Locations
- Locations (9)
Hôpital La Colombière
🇫🇷Montpellier, France
Hôpital de la Pitié Salpêtrière
🇫🇷Paris, France
Pellegrin Hospital
🇫🇷Bordeaux, France
Hopital Saint Antoine
🇫🇷Paris Cedex 12, France
Hôpital Lariboisière - APHP
🇫🇷Paris, France
Hôpital Saint André
🇫🇷Bordeaux, France
APHP Bichat-Claude Bernard
🇫🇷Paris, France
Hopital Saint Louis
🇫🇷Paris, France
CHU Nantes
🇫🇷Nantes, France
Hôpital La Colombière🇫🇷Montpellier, FranceAlain MakinsonSite contact0467339510a-makinson@chu-montpellier.fr