ANRS 12372 MODERATO Study

Study Overview
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Brief Summary
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MODERATO is a phase III, open-label, randomized, multicenter, non-inferiority trial conducted in West and Central Africa (Cameroon, Côte d'Ivoire, Burkina Faso). HIV-1 infected adults receiving first line ART with TDF+XTC+EFV or DTG+XTC+TDF virologically suppressed will be recruited and followed during 100 weeks. The objective is to assess the non-inferiority of a strategy consisting of switching to a dual maintenance therapy (DTG+3TC or ATV/r+3TC), comparing to WHO standard first line regimen (TDF+3TC+EFV or DTG+3TC+TDF), in terms of virological success at 96 weeks

Detailed Description
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In HIV-1 infected adults receiving first line ART with TDF+XTC+EFV or DTG+XTC+TDF virologically suppressed (viral load < detection limit of the technique used) for at least two years: to assess the non-inferiority of a strategy consisting of switching to a dual maintenance therapy (DTG+ 3TC or ATV/r+3TC), comparing to WHO standard first line regimen (TDF+3TC+EFV or DTG+3TC+TDF), in terms of virological success at 96 weeks, in Cameroon, Côte d'Ivoire and Burkina Faso. This is a trial including two strategies (dual maintenance therapy and triple reference therapy) and three ART regimens (DTG+3TC and ATV/r+3TC used in the maintenance strategy and TDF+3TC+EFV/ DTG+3TC+TDF used in the reference strategy). The primary analysis will compare the two strategies. Secondary analyses will compare the three ART regimens two by two. In order to make these secondary analyses possible, participants will be randomly assigned, at inclusion, to each of the three ART regimens (arm 1: DTG+3TC; arm 2: ATV/r+3TC; arm 3: TDF+3TC+EFV / DTG+3TC+TDF). The maintenance strategy will include arm 1 and 2. The reference strategy will include arm 3 Number of participants : 480 (160 in each ART regimen, ie 320 in the dual maintenance therapy strategy and 160 in the triple therapy reference strategy) The primary endpoint is treatment success, as defined by using the FDA snapshot algorithm : patients who are still continuing the assigned strategy and whose last available plasma HIV-1 RNA in the the window analysis (90 to 102 weeks) is <50 copies/ml at the end of the window analysis (90 to 102 weeks)

Official Title
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Randomized, Non-inferiority Trial Comparing a Dual Maintenance Therapy Strategy With Dolutegravir + Lamivudine (DTG/3TC) or Atazanavir/Ritonavir + Lamivudine (ATV/r+3TC) Versus the Standard WHO First Line Triple Therapy Tenofovir + Lamivudine + Efavirenz (TDF+3TC+EFV) or Dolutegravir + Lamivudine + Tenofovir (DTG+3TC+TDF) in West and Central African HIV-1 Infected Patients

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: dolutegravir
* Drug: atazanavir boosted with ritonavir
* Drug: tenofovir + lamivudine +efavirenz or dolutegravir + lamivudine + tenofovir
* Drug: Lamivudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 infection Age of legal majority CD4 > 200 cells/mm3 at pre-inclusion Start first-line ART with non-nucleotide reverse transcriptase inhibitors including TDF+XTC+EFV for at least two years without a past history of virological failure, OR Be on TDF+XTC+EFV for at least two years then DTG+XTC+TDF without a past history of virological failure, OR Be on DTG+XTC+TDF (1st line regimen) for at least two years without a past history of virological failure Absence of past history of virological failure (viral load above the threshold corresponding to the test used); two blips between 50 and 200 copies/ml are allowed. At least 2 consecutive HIV-1 RNA < 50 copies/ml within past 2 years, including HIV-1 RNA at pre-inclusion Women with pregnancy potential are required to use an effective contraceptive method throughout the study follow up. Signed informed consent Exclusion Criteria: HIV-2 infection or HIV-1+2 infection CD4 nadir <100 cells/mm3 Chronic Hepatitis B (HBs Ag positive in the pre-inclusion balance) Ongoing active Tuberculosis Ongoing severe opportunistic infection Ongoing chemotherapy or immunotherapy Grade > 2 hemoglobin, neutrophil or platelet disorder ALT≥ 3 times the upper limit of normal value Creatinine clearance < 50 ml/min (CKD-EPI) Allergy to a trial drugs or drug component Ongoing pregnancy or Refusal of contraception Patient at risk of non-compliance Ongoing treatment with a drug that should not be associated with one of the drugs used in the study (cf appendix E page 77) Any symptoms or biological findings suggestive of a systemic disorder (renal, hepatic, cardiovascular, pulmonary) or other medical conditions that may interfere with the interpretation of test results or jeopardize the health of patients

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 : Dual maintenance therapy DTG+3TC<br> | Drug: dolutegravir<br>* One daily tablet (50mg) during 96 weeks<br>Drug: Lamivudine<br>* One daily tablet (300mg) during 96 weeks<br>|
| Experimental: Arm 2 : Dual maintenance therapy ATV/r+3TC<br> | Drug: atazanavir boosted with ritonavir<br>* One daily tablet with atazanavir (300 mg) boosted with ritonavir (100 mg) during 96 weeks<br>Drug: Lamivudine<br>* One daily tablet (300mg) during 96 weeks<br>|
| Active Comparator: Arm 3 : Reference triple therapy TDF+3TC+EFV or DTG+3TC+TDF<br> | Drug: tenofovir + lamivudine +efavirenz or dolutegravir + lamivudine + tenofovir<br>* One daily tablet with tenofovir 245 mg + lamivudine (300 mg) + efavirenz (400 mg) during 96 weeks OR One daily tablet with dolutegravir 50 mg + lamivudine (300 mg) + tenofovir (300 mg) during 96 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The treatment success, as defined by using the FDA snapshot algorithm | Success : The proportion of patients who are still continuing the assigned strategy and whose last available plasma HIV-1 RNA in the the window analysis is <50 copies/ml at the end of the window analysis. Failure : patients who have discontinued the assigned strategy or whose last available plasma HIV-1 RNA in the window analysis (90 to 102 weeks) is ≥ 50 copies/ml or with no available HIV-1 RNA in the window analysis | 90 to 102 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure combined endpoint | Percentage of participants who reach the following combined endpoint : new drug-resistant resistance mutations observed, decline of at least 20% in creatinine clearance and occurrence of at least one grade 3-4 neuropsychiatric disorder | Between Day 0 and Week 96 | 
| Plasma HIV-1 RNA | Evolution of plasma HIV-1 RNA | Between Day 0 and Week 96 | 
| Virological success | Evolution of the percentage of participants with virological success (VL< 50 copies/Ml) | Between Day 0 and Week 96 | 
| CD4 lymphocyte | Evolution of CD4 lymphocyte absolute count and percentage | Between Day 0 and Week 96 | 
| Virological failure and new resistance mutations | Percentage of participants with virological failure and new resistance mutations | Week 48 and Week 96 | 
| New HIV-1 drug resistance mutations | Profile of new HIV-1 drug resistance mutations observed in participants with virological failure | Week 48 and Week 96 | 
| WHO stage 3-4 morbidity | Incidence of WHO stage 3-4 morbidity ( AIDS events and non AIDS severe morbidity) | Between Day 0 and Week 96 | 
| ANRS grade 3-4 overall morbidity | Incidence of ANRS grade 3-4 overall morbidity (toxicity) | Between Day 0 and Week 96 | 
| ANRS grade 3-4 renal morbidity | Incidence of ANRS grade 3-4 renal morbidity | Between Day 0 and Week 96 | 
| ANRS grade 3-4 neurologic morbidity | Incidence of ANRS grade 3-4 neurologic morbidity | Between Day 0 and Week 96 | 
| ANRS grade 3-4 hepatic morbidity | Incidence of ANRS grade 3-4 hepatic morbidity | Between Day 0 and Week 96 | 
| Creatinine clearance | Evolution of creatinine clearance | Between Day 0 and Week 96 | 
| Grade 1,2,3 or 4 renal disorders | Evolution of the percentage of patients with grade 1,2,3 or 4 renal disorders | Between Day 0 and Week 96 | 
| Grade 1,2,3 or 4 hepatic liver disorders or abnormalities | Evolution of the percentage of patients with grade 1,2,3 or 4 hepatic liver disorders or abnormalities | Between Day 0 and Week 96 | 
| Grade 1,2,3 or 4 CNS disorders | Evolution of the percentage of patients with grade 1,2,3 or 4 CNS disorders | Between Day 0 and Week 96 | 
| Bone mineral density | Evolution of bone mineral density measured using CT bone density scan | Between Day 0 and Week 96 | 
| Adherence to treatment using a self-questionnaire | Evolution of adherence to treatments measured using a self-questionnaire | Between Day 0 and Week 96 | 
| Life quality | Evolution of quality of life measured using the ProQOL questionnaire | Between Day 0 and Week 96 | 
| Symptoms | Evolution of symptoms using the symptoms experienced questionnaire | Between Day 0 and Week 96 | 
| ARV drug plasma concentrations in participants with treatment failure | ARV drug plasma concentrations in participants with treatment failure | Between Day 0 and Week 96 | 
| Switched back to triple therapy | Percentage of patients on dual therapy who switched back to triple therapy | Between Day 0 and Week 96 | 
| Cost-effectiveness of the 3 ARV strategies | Cost-effectiveness of the 3 ARV strategies | Week 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Africa, Antiretroviral Treatment, HIV-1, Adults, Dual maintenance therapy, Dolutegravir, Atazanavir