Clinical trial NCT02777229: Efficacy and Safety of a Dolutegravir-based Regimen for the Initial Management of HIV Infected Adults in Resource-limited Settings
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1 Infection
Keywords: Dolutegravir
Efavirenz-low-dose
Lead sponsor: ANRS, Emerging Infectious Diseases
Sponsor class: OTHER_GOV
Collaborators: name: Institut de Recherche pour le Developpement
name: UNITAID
First posted: 2016-05-19
Enrollment: 616
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: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of patients with Viral Load (VL) <50 cp/mL
timeFrame: week 48
Secondary outcomes:
measure: Proportion of patients with Viral Load (VL) <50 cp/mL
timeFrame: week 96
measure: Proportion of patients with Viral Load (VL) <50 cp/mL
timeFrame: week 24
measure: Proportion of patients with Viral Load (VL) < 200 cp/mL
timeFrame: week 24, week 48, week 96, week 144, week 192
measure: Time to virologic failure
timeFrame: week 48, week 96, week 144, week 192
measure: Changes in Cluster of differentiation 4 (CD4)-cell count from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Time to death or to disease progression
timeFrame: week 48, week 96, week 144, week 192
measure: Time to first toxicity failure
timeFrame: week 48, week 96, week 144, week 192
measure: Incidence of first grade 3 or 4 clinical adverse event
timeFrame: week 48, week 96, week 144, week 192
measure: Incidence of first grade 3 or 4 laboratory adverse event
timeFrame: week 48, week 96, week 144, week 192
measure: AE and SAE
timeFrame: week 48, week 96, week 144, week 192
measure: Time to treatment discontinuation
timeFrame: week 48, week 96, week 144, week 192
measure: Hemoglobine changes from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Changes in creatinine from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Changes in estimated glomerular filtration rate from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Changes in Aspartate Aminotransferase (AST) ffrom baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Changes in Alanine Aminotransferase (ALT) from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Changes in level of fasting glucose from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Changes in level of total cholesterol from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Changes in level of triglycerides from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Changes in level of HDL from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Proportion of patients defaulting clinic schedule
timeFrame: week 48, week 96, week 144, week 192
measure: Mean medication adherence level from baseline to endpoints week-48, -96, -144, -192
timeFrame: week 48, week 96, week 144, week 192
measure: Mean change in Depression Anxiety Stress Scale from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Mean change in Quality of life score assessed by the Short Form health survey from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Mean change in EFV-related symptoms questionnaire score from baseline to endpoints week-48, -96, -144, -192
timeFrame: Baseline, week 48, week 96
measure: Tobacco status consumtion
timeFrame: week 192
measure: HbA1c
timeFrame: week 192
measure: hsPCR
timeFrame: week 192
measure: Lipodistrophia
timeFrame: week 192
measure: CIMT
timeFrame: week 192
measure: PWV
timeFrame: week 192
measure: Levels of adiponectin
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Levels of leptin
timeFrame: Baseline, week 48, week 96, week 144, week 192
measure: Levels of ghrelin
timeFrame: Baseline, week 48, week 96, week 144, week 192
Other outcomes:
Locations:
city: Yaoundé
country: Cameroon
facility: Cité verte Hospital
city: Yaoundé
country: Cameroon
facility: Hopital Central
city: Yaoundé
country: Cameroon
facility: Military Hospital
Study officials:
affiliation: IRD, INSERM, University Montpellier
name: Eric Delaporte, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Central Hospital
name: Charles Kouanfack, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.