Clinical trial NCT04022967: ANRS 12372 MODERATO Study
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: HIV-1-infection
Keywords: Africa
Antiretroviral Treatment
HIV-1
Adults
Dual maintenance therapy
Dolutegravir
Atazanavir
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Mylan Laboratories
First posted: 2019-07-17
Enrollment: 480
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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)

Eligibility criteria: 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

Primary outcomes:
measure: The treatment success, as defined by using the FDA snapshot algorithm
timeFrame: 90 to 102 weeks
Secondary outcomes:
measure: Failure combined endpoint
timeFrame: Between Day 0 and Week 96
measure: Plasma HIV-1 RNA
timeFrame: Between Day 0 and Week 96
measure: Virological success
timeFrame: Between Day 0 and Week 96
measure: CD4 lymphocyte
timeFrame: Between Day 0 and Week 96
measure: Virological failure and new resistance mutations
timeFrame: Week 48 and Week 96
measure: New HIV-1 drug resistance mutations
timeFrame: Week 48 and Week 96
measure: WHO stage 3-4 morbidity
timeFrame: Between Day 0 and Week 96
measure: ANRS grade 3-4 overall morbidity
timeFrame: Between Day 0 and Week 96
measure: ANRS grade 3-4 renal morbidity
timeFrame: Between Day 0 and Week 96
measure: ANRS grade 3-4 neurologic morbidity
timeFrame: Between Day 0 and Week 96
measure: ANRS grade 3-4 hepatic morbidity
timeFrame: Between Day 0 and Week 96
measure: Creatinine clearance
timeFrame: Between Day 0 and Week 96
measure: Grade 1,2,3 or 4 renal disorders
timeFrame: Between Day 0 and Week 96
measure: Grade 1,2,3 or 4 hepatic liver disorders or abnormalities
timeFrame: Between Day 0 and Week 96
measure: Grade 1,2,3 or 4 CNS disorders
timeFrame: Between Day 0 and Week 96
measure: Bone mineral density
timeFrame: Between Day 0 and Week 96
measure: Adherence to treatment using a self-questionnaire
timeFrame: Between Day 0 and Week 96
measure: Life quality
timeFrame: Between Day 0 and Week 96
measure: Symptoms
timeFrame: Between Day 0 and Week 96
measure: ARV drug plasma concentrations in participants with treatment failure
timeFrame: Between Day 0 and Week 96
measure: Switched back to triple therapy
timeFrame: Between Day 0 and Week 96
measure: Cost-effectiveness of the 3 ARV strategies
timeFrame: Week 96
Other outcomes:
Locations:
city: Bobo-Dioulasso
country: Burkina Faso
facility: Hôpital de jour, Service des maladies infectieuses, CHU Sourô Sanou
city: Ouagadougou
country: Burkina Faso
facility: Service de médecine interne, CHU Yalgado Ouédraogo
city: Yaoundé
country: Cameroon
facility: Service des Maladies Infectieuses, Hôpital du jour, Hôpital Central
city: Abidjan
country: Côte D'Ivoire
facility: Centre de Prise en Charge et de Formation (CePReF), Association ACONDA
city: Abidjan
country: Côte D'Ivoire
facility: Service des Maladies Infectieuses et Tropicales (SMIT), CHU de Treichville
Study officials:
affiliation: Service des Maladies Infectieuses et Tropicales, CHU de Treichville, Abidjan, Côte d'Ivoire
name: Serge P. Eholié, MD, MSc, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut de Médecine et d'Epidémiologie Appliquée - Hôpital Bichat Claude Bernard, Paris, France
name: Roland Landman, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Inserm 1219, Université de Bordeaux, France
name: Xavier Anglaret, MD, PhD
role: STUDY_DIRECTOR
affiliation: Infectious Diseases Department, University Hospital Saint Antoine, Paris, France
name: Pierre-Marie Girard, MD, PhD
role: STUDY_CHAIR
References: