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

• ClinicalTrials.gov Identifier: NCT02777229
• Recruitment Status: Completed
• First Posted: May 19, 2016
• Last Update Posted: August 31, 2021
• Sponsor: ANRS, Emerging Infectious Diseases
• Collaborators: Institut de Recherche pour le Developpement; UNITAID
• Information provided by (Responsible Party): ANRS, Emerging Infectious Diseases

Tracking Information

• First Submitted Date: March 1, 2016
• First Posted Date: May 19, 2016
• Last Update Posted Date: August 31, 2021
• Actual Study Start Date: July 2016
• Actual Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 23, 2021)

Proportion of patients with Viral Load (VL) <50 cp/mL [ Time Frame: week 48 ]

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

• Original Primary Outcome Measures (submitted: May 17, 2016): Proportion of patients with Viral Load (VL) <50 cp/mL at week 48 (FDA snapshot algorithm) [ Time Frame: week 48 ]

Current Secondary Outcome Measures (submitted: August 26, 2021)

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

Original Secondary Outcome Measures (submitted: May 17, 2016)

• Proportion of patients with VL< 50 cp/mL at week 24 (FDA snapshot algorithm) [ Time Frame: week 24 ]
• Proportion of patients with VL< 200 cp/mL at week 48 (FDA snapshot algorithm) [ Time Frame: week 48 ]
• Proportion of patients with VL< 200 cp/mL at week 24 (FDA snapshot algorithm) [ Time Frame: week 24 ]
• Time to virologic failure [ Time Frame: 48 weeks ]
• Changes in Cluster of differentiation 4 (CD4)-cell count from baseline to week 48 [ Time Frame: Baseline and 48 weeks ]
• Time to death or to disease progression [ Time Frame: up to 48 weeks ]
• Time to first toxicity failure [ Time Frame: up to 48 weeks ]
• Incidence of first grade 3 or 4 clinical adverse event [ Time Frame: up to 48 weeks ]
• Incidence of first grade 3 or 4 laboratory adverse event [ Time Frame: up to 48 weeks ]
• Incidence of adverse events (AE) and serious adverse event (SAE) [ Time Frame: up to 48 weeks ]
• Time to treatment discontinuation [ Time Frame: 48 weeks ]
• Change from baseline to week 48 in hemoglobin [ Time Frame: Baseline and 48 weeks ]
• Change from baseline to week 48 in creatinine [ Time Frame: Baseline and 48 weeks ]
• Change from baseline to week 48 in estimated glomerular filtration rate [ Time Frame: Baseline and 48 weeks ]
• Change from baseline to week 48 in Aspartate Aminotransferase (AST) [ Time Frame: Baseline and 48 weeks ]
• Change from baseline to week 48 in Alanine Aminotransferase (ALT) [ Time Frame: Baseline and 48 weeks ]
• Change from baseline to week 48 in level of fasting glucose [ Time Frame: Baseline and 48 weeks ]
• Change from baseline to week 48 in level of total cholesterol [ Time Frame: Baseline and 48 weeks ]
• Change from baseline to week 48 in level of triglycerides [ Time Frame: Baseline and 48 weeks ]
• Change from baseline to week 48 in level of HDL [ Time Frame: Baseline and 48 weeks ]
• Proportion of patients defaulting clinic schedule [ Time Frame: 48 weeks ]
• Mean adherence level overall [ Time Frame: 48 weeks ]
• Mean change in Depression Anxiety Stress Scale [ Time Frame: Baseline and 48 weeks ]
• Mean change in Quality of life score assessed by the Short Form health survey [ Time Frame: Baseline and 48 weeks ]
  composite score
• Mean change in EFV-related symptoms questionnaire score [ Time Frame: Baseline and 48 weeks ]
  composite score

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV-1 Infection

Intervention

• Drug: Dolutegravir 50 mg
  1 tablet once a day
  Other Name: DTG
• Drug: Tenofovir disoproxil fumarate 300 mg / lamivudine 300 mg
  Fixed dose combination, 1 tablet once a day
  Other Name: TDF / 3TC
• Drug: Efavirenz 400 mg
  1 tablets once a day
  Other Name: EFV400

Study Arms

• Experimental: Dolutegravir
  Dolutegravir 50 mg Quaque die (QD) + tenofovir disoproxil fumarate/lamivudine 300 mg/ 300 mg Fixed Dose Combination (FDC) QD
  Interventions:

  • Drug: Dolutegravir 50 mg
  • Drug: Tenofovir disoproxil fumarate 300 mg / lamivudine 300 mg
• Active Comparator: Efavirenz
  Efavirenz 400 mg QD + tenofovir disoproxil fumarate/lamivudine 300 mg/ 300 mg FDC QD
  Interventions:

  • Drug: Tenofovir disoproxil fumarate 300 mg / lamivudine 300 mg
  • Drug: Efavirenz 400 mg

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 2, 2018): 616
• Original Estimated Enrollment (submitted: May 17, 2016): 606
• Actual Study Completion Date: July 2021
• Actual Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Cameroon

Administrative Information

• NCT Number: NCT02777229
• Other Study ID Numbers: ANRS 12313 NAMSAL
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: ANRS, Emerging Infectious Diseases
• Original Responsible Party: Same as current
• Current Study Sponsor: ANRS, Emerging Infectious Diseases
• Original Study Sponsor: Same as current

Collaborators

• Institut de Recherche pour le Developpement
• UNITAID

Investigators

• Principal Investigator: Eric Delaporte, MD, PhD; IRD, INSERM, University Montpellier
• Principal Investigator: Charles Kouanfack, MD, PhD; Central Hospital

• PRS Account: ANRS, Emerging Infectious Diseases
• Verification Date: February 2021