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

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

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.


Condition or disease Intervention/treatment Phase
HIV-1 Infection Drug: Dolutegravir 50 mg Drug: Tenofovir disoproxil fumarate 300 mg / lamivudine 300 mg Drug: Efavirenz 400 mg Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 616 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 2016
Actual Primary Completion Date : July 2018
Actual Study Completion Date : July 2021


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 Name: DTG

Drug: Tenofovir disoproxil fumarate 300 mg / lamivudine 300 mg
Fixed dose combination, 1 tablet once a day
Other Name: 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 Name: TDF / 3TC

Drug: Efavirenz 400 mg
1 tablets once a day
Other Name: EFV400




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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)

  2. 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)

  3. 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)

  4. Time to virologic failure [ Time Frame: week 48, week 96, week 144, week 192 ]
    Time to virologic failure

  5. 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

  6. Time to death or to disease progression [ Time Frame: week 48, week 96, week 144, week 192 ]
    Time to death or to disease progression

  7. Time to first toxicity failure [ Time Frame: week 48, week 96, week 144, week 192 ]
    Time to first toxicity failure

  8. 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

  9. 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

  10. AE and SAE [ Time Frame: week 48, week 96, week 144, week 192 ]
    Incidence of adverse events (AE) and serious adverse event (SAE)

  11. Time to treatment discontinuation [ Time Frame: week 48, week 96, week 144, week 192 ]
    Time to treatment discontinuation

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. Proportion of patients defaulting clinic schedule [ Time Frame: week 48, week 96, week 144, week 192 ]
    Proportion of patients defaulting clinic schedule

  22. 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

  23. 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

  24. 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)

  25. 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

  26. Tobacco status consumtion [ Time Frame: week 192 ]
    The status of tobacco smoker / non-smoker will be requested.

  27. HbA1c [ Time Frame: week 192 ]
    Levels of glycated hemoglobin

  28. hsPCR [ Time Frame: week 192 ]
    Levels of high sensitivity protein C reactive

  29. Lipodistrophia [ Time Frame: week 192 ]
    Qualitative and quantitative measurements of soft tissue composition = Lipodistrophia

  30. CIMT [ Time Frame: week 192 ]
    Mesures of Carotid Intima-Media Thickness

  31. PWV [ Time Frame: week 192 ]
    Mesures of Pulse Wave Velocity

  32. Levels of adiponectin [ Time Frame: Baseline, week 48, week 96, week 144, week 192 ]
    Levels of adiponectin

  33. Levels of leptin [ Time Frame: Baseline, week 48, week 96, week 144, week 192 ]
    Levels of leptin

  34. Levels of ghrelin [ Time Frame: Baseline, week 48, week 96, week 144, week 192 ]
    Levels of ghrelin



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02777229


Locations
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Cameroon
Cité verte Hospital
Yaoundé, Cameroon
Hopital Central
Yaoundé, Cameroon
Military Hospital
Yaoundé, Cameroon
Sponsors and Collaborators
ANRS, Emerging Infectious Diseases
Institut de Recherche pour le Developpement
UNITAID
Investigators
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Principal Investigator: Eric Delaporte, MD, PhD IRD, INSERM, University Montpellier
Principal Investigator: Charles Kouanfack, MD, PhD Central Hospital
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: ANRS, Emerging Infectious Diseases
ClinicalTrials.gov Identifier: NCT02777229    
Other Study ID Numbers: ANRS 12313 NAMSAL
First Posted: May 19, 2016    Key Record Dates
Last Update Posted: August 31, 2021
Last Verified: February 2021
Keywords provided by ANRS, Emerging Infectious Diseases:
Dolutegravir
Efavirenz-low-dose
Additional relevant MeSH terms:
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Tenofovir
Lamivudine
Efavirenz
Dolutegravir
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Cytochrome P-450 CYP2C9 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Cytochrome P-450 CYP2C19 Inhibitors
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP3A Inducers
HIV Integrase Inhibitors
Integrase Inhibitors