Dolutegravir Antiretroviral Strategy to Promote Improvement and Reduce Drug Exposure

Study Overview
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Brief Summary
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HIV-1 infected subjects with CD4 nadir > 200 cells/mm3, no history of virologic failure and plasma HIV RNA <50 copies/mL for at least 48 weeks while on any United States Department of Health and Human Services (DHHS) recommended or alternative three-drug antiretroviral regimen will be randomized to dolutegravir (DTG) plus lamivudine (Arm 1) or continuation of their current regimen (Arm 2) for 48 weeks. The primary endpoint is virologic failure defined as confirmed plasma HIV-1 RNA > 50 copies/mL before or at Week 24

Detailed Description
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DESIGN HIV-1 infected subjects with CD4 nadir > 200 cells/mm3, no history of virologic failure and plasma HIV RNA <50 copies/mL for at least 48 weeks while on any United States Department of Health and Human Services (DHHS) recommended or alternative three-drug antiretroviral regimen will be randomized to dolutegravir (DTG) plus lamivudine (Arm 1) or continuation of their current regimen (Arm 2) for 48 weeks. The primary endpoint is virologic failure defined as confirmed plasma HIV-1 RNA > 50 copies/mL before or at Week 24 All subjects will undergo routine monitoring including plasma HIV-1 RNA, CD4/CD8 count, hematology, chemistry and fasting lipids. Resistance testing will be done in all patients who experience virologic failure. Single-copy HIV-1 assay will be done to quantify residual viremia. DURATION 48 weeks SAMPLE SIZE 90 subjects POPULATION HIV-1-infected men and women, 18 years and older, with CD4 nadir > 200 cells/mm3, no baseline resistance, no history of virologic failure, and HIV RNA <50 copies/mL for at least 48 weeks prior to study entry while on any DHHS recommended or alternative three-drug regimen REGIMEN Subjects will be randomized (1:1) to: Arm 1: dolutegravir 50 mg plus lamivudine 300 mg once daily OR Arm 2: Continue current DHHS recommended or alternative three-drug antiretroviral regimen

Official Title
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Dolutegravir Antiretroviral Strategy to Promote Improvement and Reduce Drug Exposure (ASPIRE) Study

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: dolutegravir
* Drug: lamivudine
* Drug: Continue current antiretroviral regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV-1 Infection HIV-1 RNA <50 copies/mL on all measurements within 48 weeks prior to study entry while on any DHHS recommended or alternative three-drug antiretroviral regimen. (A history of switching for simplification and/or tolerability is allowed. At least two measurements within the previous 48 weeks are required prior to study screening.) No history of virologic failure, defined as consecutive HIV RNA > 50 copies/mL after 12 months of initiating ART. An isolated (non-consecutive) HIV RNA > 50 copies/mL (but less than 400 copies/mL) is permitted after 12 months of initiating ART but not in the 48-week window prior to study entry. Screening plasma HIV RNA < 20 copies/mL using the COBAS AmpliPrep/COBAS TaqMan HIV-1 Test V2.0, obtained within 45 days prior to study entry Nadir CD4 count >200 cells/mm Pretreatment genotype documenting no mutations in the protease or reverse transcriptase genes No known resistance to integrase inhibitors Laboratory values obtained within 45 days prior to study entry: ANC >750 Hemoglobin >10 g/dL Platelets >50,000 Calculated creatinine clearance (CrCl) >50 mL/min Negative serum or urine pregnancy test Men and women age greater or equal to 18 years. Ability to continue current regimen (i.e, have uninterrupted access) No evidence of chronic hepatitis B Exclusion Criteria: Serious illness or AIDS-related complication within 21 days of screening requiring systemic treatment and/or hospitalization Treatment within 30 days prior to study entry with immune modulators Vaccination within 7 days Active HCV treatment or anticipated need for treatment within study period. (HCV infection alone is not exclusionary) Unstable liver disease or severe hepatic impairment Known allergy or hypersensitivity to DTG or lamivudine. Active drug or alcohol use or dependence that could interfere with adherence to study requirements ALT (alanine aminotransferase) >5 x ULN (upper limit of normal) OR ALT >3 x ULN and total bilirubin >1.5 x ULN (with 35% direct bilirubin)

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 plus lamivudine<br>dolutegravir 50 mg plus lamivudine 300 mg once daily | Drug: dolutegravir<br>* 50 mg tablet by mouth once daily for 48 weeks<br>* Other names: TIVICAY, DTG;Drug: lamivudine<br>* 300 mg tablet by mouth once daily for 48 weeks<br>* Other names: EPIVIR, 3TC;|
| Active Comparator: Continue current ART regimen<br>Continue current DHHS recommended or alternative three-drug antiretroviral regimen | Drug: Continue current antiretroviral regimen<br>* Continue current DHHS recommended or alternative three-drug antiretroviral regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Treatment Failure | Proportion of participants with treatment failure (defined as virologic failure (HIV RNA >50 copies/mL), loss to follow-up, or treatment discontinuation) between those who switch to DTG + lamivudine and those who continue their current ART regimen | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With Virologic Success | Proportion of participants with virologic success (<50 copies/mL) based on FDA snapshot definition | 48 weeks | 
| Change in CD4 Count From Baseline to Week 48 | Change in CD4 count between arms will be presented in the attached statistical analysis table | Baseline and 48 weeks | 
| Change in Total Cholesterol From Baseline to Week 48 | Change in Total Cholesterol between arms will be presented in the attached statistical analysis table | Baseline and 48 weeks | 
| Change in LDL Cholesterol From Baseline to Week 48 | Change in Low-density lipoprotein (LDL) cholesterol between arms will be presented in the attached statistical analysis table | Baseline and Week 48 | 
| Change in Creatinine Clearance From Baseline to Week 48 | Change in Creatinine Clearance between arms will be presented in the attached statistical analysis table | Baseline and Week 48 | 
| Drug Resistance Associated Mutations | Drug resistance mutations measured by HIV genotyping in patients with confirmed virologic failure | 48 weeks |