Efficacy and Safety of a Dolutegravir-based Regimen for the Initial Management of HIV Infected Adults in Resource-limited Settings (NAMSAL)

A Phase III Randomized, Open Label Trial to Evaluate Dolutegravir Versus Efavirenz 400 mg, Both Combined With Tenofovir Disoproxil Fumarate + Lamivudine for the Initial Management of HIV Infected Adults in Resource-limited Settings

Several reports indicate that treatment failure due to HIV resistance or to adverse event-related discontinuation could compromise the effectiveness of scaling-up antiretroviral treatment (ART), especially when lack of access to viral load is a concern. Combined with other nucleoside reverse transcriptase inhibitor, Dolutegravir (DTG) is a very promising alternative to the current first-line non nucleoside reverse transcriptase inhibitor-based regimens.

Initial evaluations of DTG conducted in high income countries showed excellent efficacy and safety and indicated high genetic barrier thus preserving second line treatment. As a consequence, DTG-based regimens have been recently included in the first-line options in the national guidelines for ART of several high-income countries. However, the clinical trials evaluating DTG-based regimens have been conducted in highly controlled conditions, including baseline resistance testing and regular viral load monitoring. Moreover, these trials included a high proportion of men with rare co-morbidities.

There is need to evaluate how a DTG-based regimen will perform in real-world conditions within resources-constrained settings, where viral load monitoring is limited, and where the majority of HIV patients are women with important family planning consideration and NAMSAL trial is a randomized clinical trial which aims to evaluate efficacy and safety over 48, 96 and 192 weeks of DTG + tenofovir disoproxil fumarate/lamivudine versus Efavirenz (EFV) + tenofovir disoproxil fumarate/lamivudine in 606 ART-naïve HIV-1-infected adults in Cameroon. A set of efficacy and safety endpoints will be compared over 48, 96 and 192 weeks between the two arms including the proportion of patients with viral load <50 copies/mL and incidence of severe adverse events.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: Dolutegravir 50 mg; Drug: Tenofovir disoproxil fumarate 300 mg / lamivudine 300 mg; Drug: Efavirenz 400 mg

• Study Type: Interventional
• Enrollment (Actual): 616
• Phase: Phase 3

Contacts and Locations

Study Locations

• Cameroon
  • Yaoundé, Cameroon
    • Cité Verte Hospital
  • Yaoundé, Cameroon
    • Hôpital Central
  • Yaoundé, Cameroon
    • Military Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• HIV-1 infected
• Age ≥ 18 years
• Abtiretroviral-naïve, including above 7 days of cumulative prior antiretroviral therapy at any time prior to study entry.
• For women of childbearing potential: acceptance to use effective contraceptive methods
• Provision of written informed consent

Exclusion Criteria:

• Infection with HIV-1 group O, N, P
• Infection or co-infection with HIV-2
• Absolute neutrophil count (ANC) < 500 cells/mm3
• Hemoglobin < 7.0 g/dL
• Platelet count < 50,000 cells/mm3
• AST and/or ALT > 5 x Upper Limit of Normal (ULN)
• Calculated creatinine clearance < 50 mL/min
• Active opportunistic or severe disease not under adequate control
• For women of childbearing age : Pregnancy/breastfeeding
• History or presence of allergy and/or contraindications to the trial drugs or their components
• Severe psychiatric illness
• Severe hepatic failure Patients co-infected with tuberculosis (TB), receiving a TB treatment and with stable clinical condition will not be excluded.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dolutegravir; Dolutegravir 50 mg Quaque die (QD) + tenofovir disoproxil fumarate/lamivudine 300 mg/ 300 mg Fixed Dose Combination (FDC) QD	Drug: Dolutegravir 50 mg; 1 tablet once a day; Other Names: DTG; Drug: Tenofovir disoproxil fumarate 300 mg / lamivudine 300 mg; Fixed dose combination, 1 tablet once a day; Other Names: TDF / 3TC
Active Comparator: Efavirenz; Efavirenz 400 mg QD + tenofovir disoproxil fumarate/lamivudine 300 mg/ 300 mg FDC QD	Drug: Tenofovir disoproxil fumarate 300 mg / lamivudine 300 mg; Fixed dose combination, 1 tablet once a day; Other Names: TDF / 3TC; Drug: Efavirenz 400 mg; 1 tablets once a day; Other Names: EFV400

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with Viral Load (VL) <50 cp/mL	Proportion of patients with Viral Load (VL) <50 cp/mL at week 48 (FDA snapshot algorithm)	week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with Viral Load (VL) <50 cp/mL	Proportion of patients with Viral Load (VL) <50 cp/mL at week 96 (FDA snapshot algorithm)	week 96
Proportion of patients with Viral Load (VL) <50 cp/mL	Proportion of patients with VL< 50 cp/mL at week 24 (FDA snapshot algorithm)	week 24
Proportion of patients with Viral Load (VL) < 200 cp/mL	Proportion of patients with VL< 200 cp/mL (FDA snapshot algorithm)	week 24, week 48, week 96, week 144, week 192
Time to virologic failure	Time to virologic failure	week 48, week 96, week 144, week 192
Changes in Cluster of differentiation 4 (CD4)-cell count from baseline to endpoints week-48, -96, -144, -192	Changes in Cluster of differentiation 4 (CD4)-cell count from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Time to death or to disease progression	Time to death or to disease progression	week 48, week 96, week 144, week 192
Time to first toxicity failure	Time to first toxicity failure	week 48, week 96, week 144, week 192
Incidence of first grade 3 or 4 clinical adverse event	Incidence of first grade 3 or 4 clinical adverse event	week 48, week 96, week 144, week 192
Incidence of first grade 3 or 4 laboratory adverse event	Incidence of first grade 3 or 4 laboratory adverse event	week 48, week 96, week 144, week 192
AE and SAE	Incidence of adverse events (AE) and serious adverse event (SAE)	week 48, week 96, week 144, week 192
Time to treatment discontinuation	Time to treatment discontinuation	week 48, week 96, week 144, week 192
Hemoglobine changes from baseline to endpoints week-48, -96, -144, -192	Changes in hemoglobin Time to virologic failure from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Changes in creatinine from baseline to endpoints week-48, -96, -144, -192	Changes in creatinine from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Changes in estimated glomerular filtration rate from baseline to endpoints week-48, -96, -144, -192	Changes in estimated glomerular filtration rate from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Changes in Aspartate Aminotransferase (AST) ffrom baseline to endpoints week-48, -96, -144, -192	Changes in Aspartate Aminotransferase (AST) from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Changes in Alanine Aminotransferase (ALT) from baseline to endpoints week-48, -96, -144, -192	Changes in Alanine Aminotransferase (ALT) from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Changes in level of fasting glucose from baseline to endpoints week-48, -96, -144, -192	Changes in level of fasting glucose from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Changes in level of total cholesterol from baseline to endpoints week-48, -96, -144, -192	Changes in level of total cholesterol from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Changes in level of triglycerides from baseline to endpoints week-48, -96, -144, -192	Changes in level of triglycerides from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Changes in level of HDL from baseline to endpoints week-48, -96, -144, -192	Changes in level of HDL from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96, week 144, week 192
Proportion of patients defaulting clinic schedule	Proportion of patients defaulting clinic schedule	week 48, week 96, week 144, week 192
Mean medication adherence level from baseline to endpoints week-48, -96, -144, -192	Mean medication adherence level from baseline to endpoints week-48, -96, -144, -192	week 48, week 96, week 144, week 192
Mean change in Depression Anxiety Stress Scale from baseline to endpoints week-48, -96, -144, -192	Mean change in Depression Anxiety Stress Scale from baseline to endpoints week-48, -96, -144, -192; Depression Normal 0-9, Mild 10-13, Moderate 14-20, Severe 21-27, Extremely Severe +28; Anxiety Normal 0-7, Mild 8-9, Moderate 10-14, Severe 15-19, Extremely Severe +20; Stress Normal 0-14, Mild 15-18, Moderate 19-25, Severe 26-33, Extremely Severe +34	Baseline, week 48, week 96, week 144, week 192
Mean change in Quality of life score assessed by the Short Form health survey from baseline to endpoints week-48, -96, -144, -192	Mean change in Quality of life score assessed by the Short Form health survey from baseline to endpoints week-48, -96, -144, -192 (Score varies according to the items, in order to test the vigilance of the patient. Reading the results provides a semantic appreciation)	Baseline, week 48, week 96, week 144, week 192
Mean change in EFV-related symptoms questionnaire score from baseline to endpoints week-48, -96, -144, -192	Mean change in EFV-related symptoms questionnaire score from baseline to endpoints week-48, -96, -144, -192	Baseline, week 48, week 96
Tobacco status consumtion	The status of tobacco smoker / non-smoker will be requested.	week 192
HbA1c	Levels of glycated hemoglobin	week 192
hsPCR	Levels of high sensitivity protein C reactive	week 192
Lipodistrophia	Qualitative and quantitative measurements of soft tissue composition = Lipodistrophia	week 192
CIMT	Mesures of Carotid Intima-Media Thickness	week 192
PWV	Mesures of Pulse Wave Velocity	week 192
Levels of adiponectin	Levels of adiponectin	Baseline, week 48, week 96, week 144, week 192
Levels of leptin	Levels of leptin	Baseline, week 48, week 96, week 144, week 192
Levels of ghrelin	Levels of ghrelin	Baseline, week 48, week 96, week 144, week 192

Collaborators and Investigators

• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: UNITAID; Institut de Recherche pour le Developpement
• Investigators: Principal Investigator: Eric Delaporte, MD, PhD, IRD, INSERM, University Montpellier; Principal Investigator: Charles Kouanfack, MD, PhD, Central Hospital

Publications and helpful links

General Publications

• Bousmah MA, Nishimwe ML, Tovar-Sanchez T, Lantche Wandji M, Mpoudi-Etame M, Maradan G, Omgba Bassega P, Varloteaux M, Montoyo A, Kouanfack C, Delaporte E, Boyer S; New Antiretroviral and Monitoring Strategies in HIV-infected Adults in Low-Income Countries (NAMSAL) ANRS 12313 Study Group. Cost-Utility Analysis of a Dolutegravir-Based Versus Low-Dose Efavirenz-Based Regimen for the Initial Treatment of HIV-Infected Patients in Cameroon (NAMSAL ANRS 12313 Trial). Pharmacoeconomics. 2021 Mar;39(3):331-343. doi: 10.1007/s40273-020-00987-3. Epub 2020 Dec 23.
• Calmy A, Tovar Sanchez T, Kouanfack C, Mpoudi-Etame M, Leroy S, Perrineau S, Lantche Wandji M, Tetsa Tata D, Omgba Bassega P, Abong Bwenda T, Varloteaux M, Tongo M, Mpoudi-Ngole E, Montoyo A, Mercier N, LeMoing V, Peeters M, Reynes J, Delaporte E; New Antiretroviral and Monitoring Strategies in HIV-infected Adults in Low-Income Countries (NAMSAL) ANRS 12313 Study Group. Dolutegravir-based and low-dose efavirenz-based regimen for the initial treatment of HIV-1 infection (NAMSAL): week 96 results from a two-group, multicentre, randomised, open label, phase 3 non-inferiority trial in Cameroon. Lancet HIV. 2020 Oct;7(10):e677-e687. doi: 10.1016/S2352-3018(20)30238-1.
• NAMSAL ANRS 12313 Study Group, Kouanfack C, Mpoudi-Etame M, Omgba Bassega P, Eymard-Duvernay S, Leroy S, Boyer S, Peeters M, Calmy A, Delaporte E. Dolutegravir-Based or Low-Dose Efavirenz-Based Regimen for the Treatment of HIV-1. N Engl J Med. 2019 Aug 29;381(9):816-826. doi: 10.1056/NEJMoa1904340. Epub 2019 Jul 24.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2016
• Primary Completion (Actual): July 1, 2018
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: March 1, 2016
• First Submitted That Met QC Criteria: May 17, 2016
• First Posted (Estimate): May 19, 2016

Study Record Updates

• Last Update Posted (Actual): August 31, 2021
• Last Update Submitted That Met QC Criteria: August 26, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Dolutegravir; Efavirenz-low-dose
• 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; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Integrase Inhibitors; Integrase Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Tenofovir; Lamivudine; Efavirenz; Dolutegravir
• Other Study ID Numbers: ANRS 12313 NAMSAL