Purpose / Objectives

Primary Outcome

• The proportion of subjects with HIV-1 Ribonucleic acid (RNA) <50 copies/millilitre (c/mL) at Maintenance Week 32 [ Time Frame: Week 32 ] [ Designated as safety issue: No ]
  The endpoint at Week 32 is based on the ITT-Maintenance Exposed population using the MSDF (Missing, Switch or Discontinuation = Failure) (Snapshot) algorithm.
• The proportion of subjects with protocol defined virologic failures over time [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  Virologic failure is defined as any of the following: Non-response as indicated by a less than a 1.0 log10 copies/mL decrease in plasma HIV-1 RNA after 4 weeks of starting the Induction Period (subsequently confirmed, unless the plasma HIV-1 RNA is <400 c/mL). Rebound as indicated by two consecutive plasma HIV-1 RNA levels >=200 c/mL after prior suppression to < 200 c/mL. Rebound as indicated by two consecutive plasma HIV-1 RNA that are > 0.5 log10 c/mL increase in plasma HIV-1 RNA from the nadir value on study, where the lowest HIV-1 RNA value is >=200 c/mL.
• Incidence and severity of adverse events (AEs) over time [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product
• Incidence and severity of laboratory abnormalities over time [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  Laboratory tests will include haematology, clinical chemistry, and urinalysis parameters.

Secondary Outcomes

• Proportion of subjects with plasma HIV-1 RNA <200 c/mL and <50 c/mL, for oral dose of GSK744 30 mg plus ABC/3TC [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  The antiviral activity of GSK744 30 mg plus ABC/3TC orally once daily will be evaluated, through the Induction and Maintenance Periods.
• Absolute values and change from Baseline in plasma HIV-1 RNA, for oral dose of GSK744 30 mg plus ABC/3TC [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
  The antiviral activity of GSK744 30 mg plus ABC/3TC oral once daily, by measuring the absolute values and change from Baseline in plasma HIV-1 RNA will be evaluated, through the Induction and Maintenance Periods.
• Absolute values and changes from Baseline in CD4+ cell counts, for oral dose of GSK744 30 mg plus ABC/3TC [ Time Frame: Baseline to Week 96 ] [ Designated as safety issue: No ]
  The antiviral activity of GSK744 30 mg plus ABC/3TC orally once daily will be evaluated, by measuring the absolute values and change from Baseline in CD4+ cell counts, through the Induction and Maintenance Periods.CD4+ lymphocyte count will be obtained by flow cytometry
• Incidence of disease progression for oral dose of GSK744 30 mg plus ABC/3TC [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  The incidence will be evaluated using indicators of clinical disease progression including HIV-associated conditions, acquired immunodeficiency syndrome [AIDS] and death after administration of oral dose of GSK744 30 mg plus ABC/3TC
• Incidence and severity of AEs over time, for oral dose of GSK744 30 mg plus ABC/3TC [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
• The incidence and severity of laboratory abnormalities over time, for oral dose of GSK744 30 mg plus ABC/3TC [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  Laboratory tests will include haematology, clinical chemistry, and urinalysis parameters.
• Absolute values and changes in laboratory parameters over time, for oral dose of GSK744 30 mg plus ABC/3TC [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  Laboratory tests will include haematology, clinical chemistry, and urinalysis parameters.
• Proportion of subjects with plasma HIV-1 RNA <200 c/mL and <50 c/mL over time, for GSK744 LA 400 mg IM plus TMC278 LA 600 mg IM every 4 weeks and GSK744 LA 600 mg IM plus TMC278 LA 900 mg every 8 weeks, relative to GSK744 plus ABC/3TC orally once daily [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  The efficacy, tolerability, and safety will be evaluated through Week 96 of the Maintenance Period. Plasma HIV-1 RNA will be measured by ABBOTT REALTIME™ HIV-1 Assay with LLOD of 40 c/mL. Additional exploratory methods may be used in some cases. ABBOTT REALTIME is a trademark owned by Abbott Laboratories.
• Proportion of subjects with protocol defined virologic failures over time, for GSK744 LA 400 mg IM plus TMC278 LA 600 mg IM every 4 weeks and GSK744 LA 600 mg IM plus TMC278 LA 900 mg every 8 weeks, relative to GSK744 30 mg plus ABC/3TC orally once daily [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  Virologic failure is defined as any of the following: Non-response indicated by a less than a 1.0 log10 copies/mL decrease in plasma HIV-1 RNA after 4 weeks of starting the Induction Period (subsequently confirmed, unless the plasma HIV-1 RNA is <400 c/mL). Rebound as indicated by two consecutive plasma HIV-1 RNA levels >=200 c/mL after prior suppression to < 200 c/mL. Rebound as indicated by two consecutive plasma HIV-1 RNA that are > 0.5 log10 c/mL increase in plasma HIV-1 RNA from the nadir value on study, where the lowest HIV-1 RNA value is >=200 c/mL.
• The absolute values and change from Baseline in plasma HIV-1 RNA, for GSK744 LA 400 mg IM plus TMC278 LA 600 mg IM every 4 weeks and GSK744 LA 600 mg IM plus TMC278 LA 900 mg every 8 weeks, relative to GSK744 30 mg plus ABC/3TC orally once daily [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  Plasma HIV-1 RNA will be measured by Abbott Real time HIV-1 Assay with LLOD of 40 c/mL. Additional exploratory methods may be used in some cases.
• Absolute values and changes from Baseline in CD4+ cell counts, for GSK744 LA 400 mg IM plus TMC278 LA 600 mg IM every 4 weeks and GSK744 LA 600 mg IM plus TMC278 LA 900 mg every 8 weeks, relative to GSK744 30 mg plus ABC/3TC orally once daily [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  CD4+ lymphocyte count will be obtained by flow cytometry
• The incidence of disease progression for GSK744 LA 400 mg IM plus TMC278 LA 600 mg IM every 4 weeks and GSK744 LA 600 mg IM plus TMC278 LA 900 mg every 8 weeks, relative to GSK744 30 mg plus ABC/3TC orally once daily [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  The incidence will be evaluated using indicators of clinical disease progression including HIV-associated conditions, AIDS and death.
• Incidence of disease progression through Week 96 of the Maintenance Period. [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  The incidence will be evaluated using indicators of clinical disease progression including HIV-associated conditions, AIDS and death
• Incidence and severity of AEs, for GSK744 LA 400 mg IM plus TMC278 LA 600 mg IM every 4 weeks and GSK744 LA 600 mg IM plus TMC278 LA 900 mg every 8 weeks, relative to GSK744 30 mg plus ABC/3TC orally once daily [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product
• Incidence and severity of laboratory abnormalities, for GSK744 LA 400 mg IM plus TMC278 LA 600 mg IM every 4 weeks and GSK744 LA 600 mg IM plus TMC278 LA 900 mg every 8 weeks, relative to GSK744 30 mg plus ABC/3TC orally once daily [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  Laboratory tests will include haematology, clinical chemistry, ECGs, and urinalysis parameters
• Absolute values and changes in laboratory parameters, for GSK744 LA 400 mg IM plus TMC278 LA 600 mg IM every 4 weeks and GSK744 LA 600 mg IM plus TMC278 LA 900 mg every 8 weeks, relative to GSK744 30 mg plus ABC/3TC orally once daily [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  Laboratory tests will include haematology, clinical chemistry, ECGs, and urinalysis parameters
• Plasma pharmacokinetic (PK) parameters for GSK744 LA and TMC278 LA during the Maintenance Period [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  PK parameters included (C trough and concentrations post dose [~Cmax])
• Plasma GSK744 and RPV trough concentrations [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  To determine when steady state is achieved for each GSK744 LA and TMC278 LA regimen Concentrations of GSK1265744 and TMC278 will be determined in plasma samples.
• PK-pharmacodynamic (PD) assessment for GSK744 LA and TMC278 LA [ Time Frame: Up to Week 48 ] [ Designated as safety issue: No ]
  The PK-PD relationship will be explored between plasma PK parameters and plasma HIV-1 RNA, CD4+ cell counts and/or occurrence of AEs through Week 48 of the Maintenance Period.
• Incidence of treatment emergent genotypic and phenotypic resistance to GSK1265744, TMC278, and other on-study Antiretroviral Therapy (ART). [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  The development of viral resistance will be assessed in subjects experiencing protocol defined virologic failure.
• The proportion of subjects with plasma HIV-1 RNA <50 c/mL over time. [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  The effect of various demographic Baseline characteristics and adherence on virologic response of GSK1265744 and TMC278 will be explored. Plasma HIV-1 RNA will be measured by Abbott Real time HIV-1 Assay with LLOD of 40 c/mL. Additional exploratory methods may be used in some cases.
• To evaluate the treatment satisfaction for subjects on the long-acting injectable regimens with those on the oral regimen using the HIV Treatment Satisfaction Questionnaire Status (HIVTSQ(s)), through Week 96 of the Maintenance Period. [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  The HIV Treatment Satisfaction Questionnaire (HIVTSQ) will assess change in treatment satisfaction over time (in the same subjects) and compare current satisfaction with previous treatment satisfaction, from an earlier time point. HIVTSQ(s) is the status version of the questionnaire.
• To evaluate the change in treatment satisfaction for subjects using the HIV Treatment Satisfaction Questionnaire Change (HIVTSQ[c]) through Week 32 of the Maintenance Period. [ Time Frame: Up to Week 32 ] [ Designated as safety issue: No ]
  HIVTSQ will assess change in treatment satisfaction over time (in the same subjects) and compare current satisfaction with previous treatment satisfaction, from an earlier time point. HIVTSQ(c) is the revised changed version.
• To evaluate medication adherence over time using the HIV Medication Questionnaire (HIVMQ). [ Time Frame: Up to Week 96/Withdrawal ] [ Designated as safety issue: No ]
  HIVMQ is used to assess medication adherence as reported by the subjects.

Diagnosis

• HIV-1

Target population

Age

18-99

Inclusion criteria

• Subjects screened for this study must be HIV-1 infected and >=18 years of age.
• A female subject is eligible to enter and participate in the study if she: is of non-child-bearing potential defined as either post-menopausal (12 months of spontaneous amenorrhea and >=45 years of age) or physically incapable of becoming pregnant with documented tubal ligation, hysterectomy or bilateral oophorectomy or; is of child-bearing potential with a negative pregnancy test at both Screening and first day of the Induction Period and agrees to use one of the following methods of contraception to avoid pregnancy 2 weeks prior to administration of IP, throughout the study, and for at least 2 weeks after discontinuation of all oral study medications and for at least 52 weeks after discontinuation of GSK744 LA and TMC278 LA: Complete abstinence from intercourse (where this is the subject's preferred and usual lifestyle); double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide); approved hormonal contraception; any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year; male partner sterilization prior to the female subject's entry into the study, and this male is the sole partner for that subject; any other method with published data showing that the lowest expected failure rate is <1% per year; any contraception method must be used consistently and in accordance with the approved product label. All subjects participating in the study must follow safer sexual practices including the use of effective barrier methods (e.g. male condom/spermicide) to minimize risk of HIV transmission.
• HIV-1 infection as documented by Screening plasma HIV-1 RNA>=1000 c/mL.
• CD4+ cell count >=200 cells/mm^3 (or higher as local guidelines dictate).
• ART-naive defined as having no more than 10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection. Any previous exposure to an HIV integrase inhibitor or non-nucleoside reverse transcriptase inhibitor will be exclusionary.
• French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion criteria

• Women who are breastfeeding.
• Any evidence at screening of an active Center for Disease and Prevention Control (CDC) Category C disease, except cutaneous Kaposi's sarcoma not requiring systemic therapy.
• Subjects with known moderate to severe hepatic impairment.
• Any pre-existing physical or mental condition (including substance abuse disorder) which, in the opinion of the Investigator, may interfere with the subject's ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the subject.
• Subject who, in the investigator's judgment, poses a significant suicide risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk.
• The subject has a tattoo or other dermatological condition overlying the gluteus region which may interfere with interpretation of injection site reactions.
• History of ongoing or clinically relevant hepatitis within the previous 6 months, including chronic Hepatitis B virus (HBV) infection (HBsAg positive). Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be excluded, however Investigators must carefully assess if therapy specific for HCV infection is required; subjects who are anticipated to require such therapy during the randomized portion of the study must be excluded.
• History of liver cirrhosis with or without hepatitis viral co-infection.
• Ongoing or clinically relevant pancreatitis.
• History of the following cardiac diseases: myocardial infarction, congestive heart failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia.
• Personal or known family history of prolonged QT syndrome.
• Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug or render the subject unable to receive study medication.
• History or presence of allergy or intolerance to the study drugs or their components or drugs of their class. In addition, if heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia must not be enrolled.
• Current or anticipated need for chronic anti-coagulation.
• Any evidence of primary resistance based on the presence of any major resistance-associated mutation in the Screening result or, if known, any historical resistance test result.
• Any verified Grade 4 laboratory abnormality.
• Any acute laboratory abnormality at Screening, which, in the opinion of the Investigator, would preclude the subject's participation in the study of an investigational compound.
• Subject has estimated creatinine clearance <50 mL/min via Cockcroft-Gault method.
• Alanine aminotransferase (ALT) >=5 times Upper limit of normal (ULN). Subjects with ALT >2xULN but <5xULN may participate in the study, if in the opinion of the Investigator and GlaxoSmithKline (GSK) medical monitor the lab abnormality will not interfere with the study procedures or compromise subject safety.
• Alanine aminotransferase (ALT) >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin).
• Any clinically significant finding on screening or Baseline electrocardiograph (ECG), specifically: Heart rate <45 and >100 beats per minute (bpm) (Males) and <50 and >100 bpm (Females) (100 to 110 bpm can be rechecked within 30 minutes to verify eligibility), QRS duration >120 milliseconds (msec), QTc interval (B or F) >450 msec; non-sustained (>=3 consecutive beats) or sustained ventricular tachycardia; sinus pauses >2.5 seconds; 2nd degree (Type II) or higher atrio-ventricular (AV) block; evidence of WPW (Wolff- Parkinson-White) syndrome (ventricular pre-excitation); pathologic Q waves defined as Q wave >40msec OR depth >0.4 mV; any significant arrhythmia (either on ECG or by history) which, in the opinion of the Investigator and GSK medical monitor, will interfere with the safety for the individual subject.
• Subjects who are human leukocyte antigen (HLA)-B*5701 positive and unable to use an alternative nucleoside reverse transcriptase inhibitor (NRTI) backbone (subjects who are HLA-B*5701 positive may be enrolled if they use an alternative NRTI backbone that does not contain abacavir).
• Exposure to an experimental drug and/or experimental vaccine within 28 days or 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of IP.
• Treatment with any of the following agents within 28 days of Screening; radiation therapy, cytotoxic chemotherapeutic agents, tuberculosis therapy and Immunomodulators that alter immune responses (such as systemic corticosteroids, interleukins, or interferons)
• Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.
• Treatment with any agent, except recognized ART as allowed above, with documented activity against HIV-1 within 28 days of the first dose of IP.

Study design

• Phase IIb
• Multicenter
• Three-arm
• Open Label
• Randomized

Intervention

Miscellaneous

Study Design:

Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label

Documents (password protected)

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Responsibilities in overall study

Sponsor

ViiV Healthcare

• Tel. +44 (0)20 8380 6200