A Simplification Study of Unboosted Reyataz With Epzicom (ASSURE)

Study Overview
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Brief Summary
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This study is designed to compare the efficacy and safety of simplifying therapy from a regimen of atazanavir (ATV) + ritonavir (RTV) + tenofovir/emtricitabine (TDF/FTC) to a regimen of ATV + abacavir sulfate/lamivudine (ABC/3TC) without RTV in virologically suppressed, HIV-1 infected, HLA-B*5701 negative subjects for 48 weeks.

Detailed Description
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A prospective, randomized, multicenter, open-label study to compare the efficacy and safety of simplifying from a regimen of atazanavir (ATV) + ritonavir (RTV) + tenofovir/emtricitabine (TDF/FTC) to ATV + abacavir sulfate/lamivudine (ABC/3TC) without RTV for 48 weeks in virologically suppressed, HIV-1 infected, HLA-B*5701 negative subjects. ViiV Healthcare is the new sponsor of this study, and GlaxoSmithKline is in the process of updating systems to reflect the change in sponsorship.

Official Title
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A Prospective, Randomized, Multicenter, Open-Label Study to Compare the Efficacy and Safety of Simplifying From a Regimen of Atazanavir (ATV) + Ritonavir (RTV) + Tenofovir/Emtricitabine to ATV + Abacavir/Lamivudine Without RTV in Virologically Suppressed, HIV-1 Infected, HLA-B*5701 Negative Subjects

Conditions
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Infection, Human Immunodeficiency Virus

Intervention / Treatment
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* Drug: Reyataz + Norvir + Truvada
* Drug: Reyataz + Epzicom


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is an adult (greater than or equal to 18 years) with documented HIV-1 infection Subject is a male or female of non-childbearing potential (physiologically incapable of becoming pregnant, is pre-menarchal or post-menopausal) or child-bearing potential with a negative pregnancy test who agrees to avoid pregnancy by sexual abstinence or utilization of a highly effective method of birth control throughout the study period Subject is receiving a once-daily regimen of ATV (300mg) + RTV (100mg) + TDF/FTC (300mg/200mg) for at least 6 months prior to or by the first day of screening. ATV + RTV + TDF/FTC must be the subejct's INITIAL regimen or FIRST or SECOND SWITCH regimen. If ATV + RTV + TDF/FTC is subject's first or second switch regimen, then subject may ONLY have received the following prior regimens: a) any currently licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) + TDF/FTC or ZDV/3TC; b) RTV-boosted PI with TDF/FTC or ZDV/3TC; or c) an alternative regimen not listed above after approval by Sponsor. Subject is virologically suppressed on ATV + RTV + TDF/FTC defined as HIV-1 RNA </=75 copies/mL at 2 consecutive timepoints, one of which is at Screening and the other at least 28 days prior to Screening Exclusion Criteria: Subject has evidence of virologic failure Subject has any known HIV genotyping results indicating HIV virus contains any of the following resistance mutations in reverse transcriptase including K65R, K70E, L74V, M184I/V or Y115F, a combination of two or more thymidine analog mutations including M41L, D67N, K70R, K219Q or E that include changes at either L210 or T215), or 3 or more of the following HIV-1 protease mutations associated with atazanavir resistance: D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90 Subject is HLA-B*5701 positive Subject has hypersensitivity to any component of the study drugs SUbject is pregnant or breastfeeding Subject is enrolled in one or more investigational drug protocols within 30 days of screening Subject has an active Center for Disease Control and Prevention (CDC) Category C disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy during the trial Subject has ongoing clinically relevant hepatitis at screening and/or positive for Hepatitis B (+ HbsAg) Subject has a creatinine clearance <50 mL/min via the Cockcroft-Gault method Subject has a verified Grade 4 laboratory abnormality at screening unless the Investigator can provide a compelling explanation (e.g. elevated CPK due to exercise) for the laboratory result(s) and has the assent of the Sponsor Subject has any other laboratory abnormality or medical condition at screening, which, in the opinion of the investigator, would preclude the subject's participation in the study Subject has had an immunization within 30 days prior to first dose of investigational product Subject has had any exposure to treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, or interferons) or receipt of an HIV-1 immunotherapeutic vaccine within 90 days prior to screening. Subjects using inhaled corticosteroids or short-course systemic corticosteroids (less than or equal to 14 days) are eligible for enrollment. Subject has had treatment with radiation therapy or cytotoxic chemotherapeutic agents within 90 days prior to screening, or has an anticipated need for these agents within the study period Subject has had treatment within 30 days prior to first dose of investigational product for or an anticipated need during the study of any medications which can have interactions with the study medications, TDF, FTC, ABC, 3TC, ATV and/or RTV, as described in current product labelling Subject has had treatment with any previous abacavir-containing regimen

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: ATV + ABC/3TC<br>Subjects will change to ATV 400mg administered as two 200mg capsules orally, once daily and to the fixed-dose combination tablet of ABC 600mg/3TC 300mg (EPZICOM) administered as one tablet orally, once daily for 48 weeks. The subject's pre-study RTV will be discontinued. | Drug: Reyataz + Epzicom<br>* atazanavir 400mg + abacavir 600mg/lamivudine 300mg<br>|
| Active Comparator: ATV + RTV + TDF/FTC<br>Subjects will continue their pre-study therapy, un-modified, of ATV 300mg administered as one capsule orally, once daily plus RTV 100mg administered orally, once daily plus fixed dose combination tablet tenofovir 300mg/emtricitabine 200mg administered as one tablet orally, once daily for 48 weeks. | Drug: Reyataz + Norvir + Truvada<br>* atazanavir 300mg + ritonavir 100mg + tenofovir 300mg/emtricitabine 200mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <50 Copies (c)/Milliliter (mL) at the Week 24 Visit: TLOVR Analysis | The percentage of PAR with HIV-1 RNA virus <50 c/mL determined from blood samples drawn at Week 24 was tabulated by treatment arm with stratification by initial antiretroviral treatment. Per TLOVR algorithm, responders were PAR with confirmed viral load <50 c/mL who had not met any non-responder criterion. Non-responders were PAR who never achieved confirmed HIV RNA <50 c/mL, prematurely discontinued study or study medication for any reason, had confirmed rebound to at least 50 c/mL, or had an unconfirmed HIV RNA of at least 50 c/mL at the last visit. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <50 c/mL at the Week 24 Visit: Observed, M/D=F, and SNAPSHOT Analyses | The percentage of PAR with HIV-1 RNA virus <50 c/mL determined from blood samples drawn through Week 24 was tabulated by treatment arm with stratification by initial antiretroviral treatment using specific analysis methods. | Week 24 | 
| Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <50 c/mL at the Week 48 Visit: TLOVR, Observed, M/D=F, and SNAPSHOT Analyses | The percentage of PAR with HIV-1 RNA virus <50 c/mL determined from blood samples drawn at Week 48 was tabulated by treatment arm with stratification by initial antiretroviral treatment using specific analysis methods. | Week 48 | 
| Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <400 c/mL at the Week 24 Visit: TLOVR Analysis | The percentage of PAR with HIV-1 RNA virus <400 c/mL determined from blood samples drawn at Week 24 was tabulated by treatment arm with stratification by initial antiretroviral treatment. Per TLOVR algorithm, responders were PAR with confirmed viral load <400 c/mL who had not met any non-responder criterion. Non-responders were PAR who never achieved confirmed HIV RNA <400 c/mL, prematurely discontinued study or study medication for any reason, had confirmed rebound to at least 400 c/mL, or had an unconfirmed HIV RNA of at least 400 c/mL at the last visit. | Week 24 | 
| Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <400 c/mL at the Week 48 Visit: TLOVR Analysis | The percentage of PAR with HIV-1 RNA virus <400 c/mL determined from blood samples drawn at Week 48 was tabulated by treatment arm with stratification by initial antiretroviral treatment. Per TLOVR algorithm, responders were PAR with confirmed viral load <400 c/mL who had not met any non-responder criterion. Non-responders were PAR who never achieved confirmed HIV RNA <400 c/mL, prematurely discontinued study or study medication for any reason, had confirmed rebound to at least 400 c/mL, or had an unconfirmed HIV RNA of at least 400 c/mL at the last visit. | Week 48 | 
| Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <400 c/mL at the Week 24 Visit: Observed, MD=F, and SNAPSHOT Analyses | The percentage of PAR with HIV-1 RNA virus <400 c/mL determined from blood samples drawn at Week 24 was tabulated by treatment arm with stratification by initial antiretroviral treatment using specific analysis methods. | Week 24 | 
| Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <400 c/mL at the Week 48 Visit: Observed, MD=F, and SNAPSHOT Analyses | The percentage of PAR with HIV-1 RNA virus <400 c/mL determined from blood samples drawn at Week 48 was tabulated by treatment arm with stratification by initial antiretroviral treatment using specific analysis methods. | Week 48 | 
| Change From Baseline in HIV-1 RNA at Week 24 | Change from Baseline was calculated as the Week 24 value minus the Baseline value. Blood was drawn to analyze for plasma HIV viral load. | Baseline and Week 24 | 
| Change From Baseline in HIV-1 RNA at Week 48 | Change from Baseline was calculated as the Week 48 value minus the Baseline value. Blood was drawn to analyze for plasma HIV viral load. | Baseline and Week 48 | 
| Change From Baseline in CD4+ Cell Count at Week 24 | Blood was drawn to analyze for CD4+ cell count. A CD4+ cell is a T lymphocyte that carries the CD4 antigen. Immunologic response was assessed by CD4+ counts. Change from Baseline was calculated as the Week 24 value minus the Baseline value. | Baseline and Week 24 | 
| Change From Baseline in CD4+ Cell Count at Week 48 | Blood was drawn to analyze for CD4+ cell count. A CD4+ cell is a T lymphocyte that carries the CD4 antigen. Immunologic response was assessed by CD4+ counts. Change from Baseline was calculated as the Week 48 value minus the Baseline value. | Baseline and Week 48 | 
| Change From Baseline in Fasting Triglycerides, Total Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Low-density Lipoprotein (LDL) Cholesterol at Week 24 | Triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol levels were measured at Week 24. A Fasting blood sample was drawn to analyze for lipids. Change from Baseline was calculated as the Week 24 value minus the Baseline value for each parameter. | Baseline and Week 24 | 
| Change From Baseline in Cholesterol/HDL Ratio at Week 24 | A Fasting blood sample was drawn to analyze for lipids. Change from Baseline was calculated as the Week 24 value minus the Baseline value. | Baseline and Week 24 | 
| Change From Baseline in Fasting Triglycerides, Total Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Low-density Lipoprotein (LDL) Cholesterol at Week 48 | Triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol levels were measured or calculated at Week 48. A fasting blood sample was drawn to analyze for lipids. Change from Baseline was calculated as the Week 48 value minus the Baseline value for each parameter. | Baseline and Week 48 | 
| Change From Baseline in Cholesterol/HDL Ratio at Week 48 | A fasting blood sample was drawn to analyze for lipids. Change from Baseline was calculated as the Week 48 value minus the Baseline value for each parameter. | Baseline and Week 48 | 
| Number of Participants Who Met the Protocol-defined Confirmed Viral Failure Criteria Through Week 24 | The number of participants that failed to remain virologically suppressed through 24 weeks on treatment was assessed. Viral failure is defined per protocol as confirmed HIV-1 RNA >=400 c/mL. | From Baseline to Week 24 | 
| Number of Participants Who Met the Protocol-defined Confirmed Viral Failure Criteria Through Week 48 | The number of participants that failed to remain virologically suppressed from baseline through 48 weeks on treatment was assessed. Viral failure is defined per protocol as confirmed HIV-1 RNA >=400 c/mL. | From Baseline to Week 48 | 
| Number of Participants Who Experienced Death and/or Disease Progression | Death and clinical disease progression (as per CDC classification) were assessed from Baseline through Week 48. Disease progression is defined as progression from CDC Class A to B, Class A to C, or from Class B to C. AIDS CDC classifications are: Class A, Asymptomatic/lymphadenopathy/acute HIV; Class B, Symptomatic, not AIDS; Class C, AIDS indicator conditions. The CDC categorization of HIV/AIDS is based on the lowest documented CD4 cell count (Class A, >=500 cells per microliter [µl]; Class B, 200-499 cells/µl; Class C, <200 cells/µl) and on previously diagnosed HIV-related conditions. | From Baseline to Week 48 | 
| Number of Confirmed Virologic Failure (VF) Participants (PAR) With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Baseline Through Week 24 | A blood sample was drawn for particiapants with confirmed VF >=400 c/mL. For each participant, the mutations found at the time of failure were compared with any mutations found in the blood sample at Baseline. New resistance-associated viral mutations defined by the International Acquired Immunodeficiency Syndrome Society-United States of America guidelines present at the time of failure were tabulated by drug class. NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. | From Baseline to Week 24 | 
| Number of Confirmed Virologic Failure (VF) Participants (PAR) With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Baseline Through Week 48 | A blood sample was drawn for particiapants with confirmed VF >=400 c/mL. For each participant, the mutations found at the time of failure were compared with any mutations found in the blood sample at Baseline. New resistance-associated viral mutations defined by the International Acquired Immunodeficiency Syndrome Society-United States of America guidelines present at the time of failure were tabulated by drug class. NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. | From Baseline to Week 48 | 
| Number of Confirmed Virologic Failure Participants (PAR) From Baseline Through Week 24 With the Indicated Treatment-emergent Reductions in Susceptibility to Abacavir, Lamivudine, Tenofovir, Emtricitabine, Atazanavir, or Ritonavir | A blood sample was drawn for participants failing to respond to therapy, and changes in drug susceptibility for HIV isolated from the participants for each drug used in the study were assessed. For each participant, the changes in drug susceptibility detected by phenotypic assay in virus from the sample collected at the time of failure was compared with drug susceptibility in the virus from the blood sample at Baseline. | From Baseline to Week 24 | 
| Number of Confirmed Virologic Failure Participants (PAR) From Baseline Through Week 48 With the Indicated Treatment-emergent Reductions in Susceptibility to Abacavir, Lamivudine, Tenofovir, Emtricitabine, Atazanavir, or Ritonavir | A blood sample was drawn for participants failing to respond to therapy, and changes in drug susceptibility for HIV isolated from the participants for each drug used in the study were assessed. For each participant, the changes in drug susceptibility detected by phenotypic assay in virus from the sample collected at the time of failure was compared with drug susceptibility in the virus from the blood sample at Baseline. | From Baseline to Week 48 | 
| Number of Participants With the Indicated Grade 2 to Grade 4 Adverse Events (AEs) Occurring at a Frequency of >=3% in Either Treatment Group | The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 is a descriptive terminology that can be utilized for AE reporting. A grading (severity) scale is provided for each AE. Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1, mild AE; Grade 2, moderate AE; Grade 3, severe AE; Grade 4, life-threatening or disabling AE; Grade 5, death related to the AE. | From Baseline to Week 24 | 
| Number of Participants With the Indicated Grade 2 to Grade 4 Adverse Events (AEs) Occurring at a Frequency of >=3% in Either Treatment Group | The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 is a descriptive terminology that can be utilized for AE reporting. A grading (severity) scale is provided for each AE. Grade refers to the severity of the adverse event (AE). The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1, mild AE; Grade 2, moderate AE; Grade 3, severe AE; Grade 4, life-threatening or disabling AE; Grade 5, death related to the AE. | From Baseline to Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV-1, HIV