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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Tenofovir disoproxil fumarate 300 mg / lamivudine 300 mg
* Drug: Efavirenz 400 mg
* Drug: Dolutegravir 50 mg


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dolutegravir, Efavirenz-low-dose