ANRS 12372 MODERATO Study (MODERATO)

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

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

Study Overview

• Status: Active, not recruiting
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: dolutegravir; Drug: Lamivudine; Drug: atazanavir boosted with ritonavir; Drug: tenofovir + lamivudine +efavirenz or dolutegravir + lamivudine + tenofovir

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)

• Study Type: Interventional
• Enrollment (Actual): 480
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Fadiga Fatoumata, MD; Phone Number: +225 21755960; Email: fatoumata.fadiga@pacci.ci
• Study Contact Backup: Name: Raoul Moh, MD, PhD; Phone Number: +225 21755960; Email: raoul.moh@pacci.ci

Study Locations

• Burkina Faso
  • Bobo-Dioulasso, Burkina Faso
    • Hôpital de jour, Service des maladies infectieuses, CHU Sourô Sanou
  • Ouagadougou, Burkina Faso
    • Service de médecine interne, CHU Yalgado Ouédraogo
• Cameroon
  • Yaoundé, Cameroon
    • Service des Maladies Infectieuses, Hôpital du jour, Hôpital Central
• Côte D'Ivoire
  • Abidjan, Côte D'Ivoire
    • Centre de Prise en Charge et de Formation (CePReF), Association ACONDA
  • Abidjan, Côte D'Ivoire
    • Service des Maladies Infectieuses et Tropicales (SMIT), CHU de Treichville

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: Mylan Laboratories
• Investigators: Principal Investigator: Serge P. Eholié, MD, MSc, Pr, Service des Maladies Infectieuses et Tropicales, CHU de Treichville, Abidjan, Côte d'Ivoire; Principal Investigator: Roland Landman, MD, Institut de Médecine et d'Epidémiologie Appliquée - Hôpital Bichat Claude Bernard, Paris, France; Study Director: Xavier Anglaret, MD, PhD, Inserm 1219, Université de Bordeaux, France; Study Chair: Pierre-Marie Girard, MD, PhD, Infectious Diseases Department, University Hospital Saint Antoine, Paris, France

Publications and helpful links

Helpful Links

• Related Info
• Sponsor site

Study record dates

Study Major Dates

• Study Start (Actual): September 21, 2020
• Primary Completion (Estimated): February 5, 2025
• Study Completion (Estimated): February 5, 2025

Study Registration Dates

• First Submitted: July 12, 2019
• First Submitted That Met QC Criteria: July 15, 2019
• First Posted (Actual): July 17, 2019

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: September 5, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: HIV-1; Adults; Africa; Atazanavir; Dolutegravir; Antiretroviral Treatment; Dual maintenance therapy
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Ritonavir; Lamivudine; Atazanavir Sulfate; Efavirenz; Dolutegravir
• Other Study ID Numbers: ANRS 12372 MODERATO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No