A Phase IIb Study to Evaluate a Long-Acting Intramuscular Regimen for Maintenance of Virologic Suppression (Following Induction With an Oral Regimen of GSK1265744 and Abacavir/Lamivudine) in Human Immunodeficiency Virus Type 1 (HIV-1) Infected, Antiretroviral Therapy-Naive Adult Subjects
Condition: Infection, Human Immunodeficiency Virus; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes
Intervention: GSK744; GSK744 LA; TMC278 LA; ABC/3TC; RPV
Intervention description: White to almost white oval shaped film coated 30 mg tablets for oral administration.; Sterile white to slightly colored suspension containing 200 mg/mL of GSK744 as free acid (GSK1265744 free acid), polysorbate 20, polyethylene glycol 3350, mannitol, and water for injection, packaged in a 3 mL USP Type I glass vial, for administration by IM injection; Sterile white suspension containing 300 mg/mL of TMC278 as free base, poloxamer 338, sodium dihydrogen phosphate monohydrate, citric acid monohydrate, glucose monohydrate, sodium hydroxide, water for injection, packaged in a 2 mL USP Type I glass vial, for administration by IM injection.; ABC/3TC fixed dose combination (FDC) oral tablet, containing 600 mg of ABC (as abacavir sulfate) and 300 mg of 3TC; Off-white, round, biconvex, film-coated 25 mg Rilpivirine (RPV) tablets for oral administration. Eligible subjects switching from the oral regimen to the IM regimen in the Extension Period will receive 2 weeks of RPV 25 mg once daily, from Week 102 through Week 104
Intervention MeSH terms: Rilpivirine; Cabotegravir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 309.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: bi-monthly; GSK744; injectable; long acting; maintenance; abacavir; every other month; rilpivirine; HIV-1 infection; integrase inhibitor; TMC278 LA; RPV; non-nucleoside reverse transcriptase inhibitor; LA; once monthly; GSK1265744; induction; treatment satisfication; once daily; lamivudine; adherence; TMC278; therapy-naive

Summary:

      This study is a Phase IIb, randomized, multicentre, parallel group, open-label, study having
      an overall objective to evaluate the antiviral activity, tolerability, and safety of two
      intramuscular (IM) dosing regimens of GSK744 LA plus TMC278 LA, relative to GSK744 30
      milligram (mg) plus Abacavir/Lamivudine (ABC/3TC) given orally once daily (QD), in HIV-1
      infected antiretroviral-naïve subjects. GSK744 is the oral formulation of GSK1265744
      (cabotegravir), GSK744 LA is the long acting injectable formulation of GSK1265744 and TMC278
      LA is the long acting injectable formulation of TMC278.

      The study will consist of three parts: an Induction Period, Maintenance Period and Extension
      Period. There is also a Long-Term Follow Up Period for subjects who withdraw from the study
      and have received at least one dose of GSK744 LA and / or TMC278 LA. In the Induction Period,
      eligible subjects will receive a combination of an oral regimen of 30 mg of GSK744 and
      600/300 mg of ABC/3TC, once daily for 20 weeks. In the Maintenance Period, eligible subjects
      will be randomized 2:2:1 at Day 1 to receive an IM regimen of GSK744 LA 400 mg + TMC278 LA
      600 mg every 4 weeks for 96 weeks (Q4W), an IM regimen of GSK744 LA 600 mg + TMC278 LA 900 mg
      every 8 weeks for 96 weeks (Q8W), or to continue on the oral Induction Period regimen of
      GSK744 30 mg + ABC/3TC once daily for 96 weeks (or 104 weeks if continuing on to the
      Extension Period). The Extension Period will allow for a collection of longer term efficacy
      and safety and tolerability data from subjects receiving GSK744 LA and TMC278 LA.

      The study will involve sufficient subjects at screening in order to ensure a total of
      approximately 265 subjects at the beginning of the Induction Period and approximately 225
      subjects randomized into the Maintenance Period.
    

Eligibility criteria:

        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.