A Study to Evaluate Efficacy and Safety of Cabotegravir (CAB) Long Acting (LA) Plus (+) Rilpivirine (RPV) LA Versus BIKTARVY® (BIK) in Participants With Human Immunodeficiency Virus (HIV)-1 Who Are Virologically Suppressed
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: Cabotegravir Tablets; Cabotegravir Injectable Suspension (CAB LA); Rilpivirine Tablets; Rilpivirine Injectable Suspension (RPV LA); BIKTARVY Tablets (BIK)
Intervention description: CAB tablets will be available as film coated tablets for oral administration.; CAB LA will be available as sterile suspension for injection in GSK1265744 for administration as IM injection.; RPV will be administered as tablets for oral administration.; RPV LA will be available as a sterile suspension of RPV to be administered as an IM injection.; BIK will be a three-drug fixed dose combination product BIC, FTC, and TAF for oral administration.
Intervention MeSH terms: Rilpivirine; Cabotegravir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 687.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HIV; Cabotegravir; Rilpivirine; BIKTARVY; Antiretroviral therapy

Summary:

      This study is designed to assess the antiviral activity and safety of a two-drug regimen of
      CAB LA + RPV LA compared with maintenance of BIK. BIKTARVY is a registered trademark of
      Gilead Sciences.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants aged 18 years or older (or >=19 where required by local regulatory
             agencies), at the time of signing the informed consent.

          -  A female participant is eligible to participate if she is not pregnant (as confirmed
             by a negative serum human chorionic gonadotropin (hCG) test at screen and a negative
             urine hCG test at Randomization), not lactating, and at least one of the following
             conditions applies.

               1. Non-reproductive potential defined as:

                    -  Pre-menopausal females with one of the following:

                         1. Documented tubal ligation.

                         2. Documented hysteroscopic tubal occlusion procedure with follow-up
                            confirmation of bilateral tubal occlusion.

                         3. Hysterectomy.

                         4. Documented Bilateral Oophorectomy

                    -  Postmenopausal defined as 12 months of spontaneous amenorrhea (in
                       questionable cases a blood sample with simultaneous follicle stimulating
                       hormone [FSH] and estradiol levels consistent with menopause). Females on
                       hormone replacement therapy (HRT) and whose menopausal status is in doubt
                       will be required to use one of the highly effective contraception methods if
                       they wish to continue their HRT during the study. Otherwise, they must
                       discontinue HRT to allow confirmation of post-menopausal status prior to
                       study enrollment.

               2. Reproductive potential and agrees to follow one of the options listed in the
                  Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of
                  Reproductive Potential (FRP) from 30 days prior to the first dose of study
                  medication, throughout the study, for at least 30 days after discontinuation of
                  all oral study medications, and for at least 52 weeks after discontinuation of
                  CAB LA and RPV LA.

          -  Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.
             Eligible participants or their legal guardians (and next of kin when locally
             required), must sign a written Informed Consent Form before any protocol-specified
             assessments are conducted. Enrollment of participants who are unable to provide direct
             informed consent is optional and will be based on local legal/regulatory requirements
             and site feasibility to conduct protocol procedures.

          -  Participants enrolled in France must be affiliated to, or a beneficiary of, a social
             security category.

          -  Must be on the uninterrupted current regimen of BIK for at least 6 months prior to
             Screening with an undetectable HIV-1 viral load for at least 6 months prior to
             Screening. BIK must be the participant's first or second regimen. If BIK is the second
             regimen, the first regimen must be an integrase inhibitor (INI) regimen. Only a single
             prior Integrase inhibitor (INI) regimen is allowed if BIK is a second line regimen >=6
             months prior to screening. Any history of non-integrase strand transfer inhibitor
             regimens (that is. non-nucleoside reverse transcriptase inhibitor, protease inhibitor,
             C-C chemokine receptor 5 and other entry inhibitors) are not permitted. Any prior
             change in regimen, defined as a change of a single drug or multiple drugs
             simultaneously, must have occurred due to tolerability/safety, access to medications,
             or convenience/simplification, and must not have been done for treatment failure
             (HIV-1 RNA >=400 c/mL).

        The following are limited exceptions:

          -  A change from Tenofovir disoproxil fumarate (TDF) to TAF will not be considered a
             regimen change.

          -  Historical perinatal use of Nucleoside reverse transcriptase inhibitor (NRTI) when
             given in addition to an ongoing Highly active antiretroviral therapy (HAART) will not
             be considered a change in ART therapy regimen.

          -  The past use of ARVs in the context of Post Exposure Prophylaxis (PEP) or Pre-Exposure
             Prophylaxis (PrEP) while the participant was HIV negative will be allowed. Such cases
             will be evaluated on a case by case basis with the Medical Monitor, and may require
             documentation of HIV negative serology during time of PEP or PrEP.

          -  A change in dosing scheme of the same drug from twice daily to once daily will not be
             considered a change in ART regimen if data support similar exposures and efficacy.

          -  A change in formulation from multiple class regimens to single treatment regimens (of
             the same medications) would not be considered a change in ART regimen.

               -  Documented evidence of plasma HIV-1 RNA measurements <50 c/mL in the 6 months
                  prior to Screening.

               -  Plasma HIV-1 RNA <50 c/mL at Screening.

        Exclusion Criteria:

          -  Within 6 months prior to Screening, any plasma HIV-1 RNA measurement >=50 c/mL.

          -  Within the 6 to 12-month window prior to Screening, documented evidence of any plasma
             HIV-1 RNA measurement greater than (>)200 c/mL, or 2 or more plasma HIV-1 RNA
             measurements >=50 c/mL.

          -  History of prior treatment failure to any Department of Health and Human Services
             (DHHS) recommended ART regimen.

          -  History of drug holiday >1 month for any reason prior to Screening visit, except where
             all ART was stopped due to tolerability and/or safety concerns.

          -  Any change to a second line regimen, defined as change of a single drug or multiple
             drugs simultaneously, due to virologic failure to therapy (defined as a confirmed
             plasma HIV 1 RNA measurement >=200 c/mL after initial suppression to <50 c/mL while on
             first line HIV therapy regimen).

          -  Participants who are currently participating in or anticipate being selected for any
             other interventional study.

          -  Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during
             the study.

          -  Any evidence of a current Center for Disease Control and Prevention (CDC) Stage 3
             disease except cutaneous Kaposi's sarcoma not requiring systemic therapy, and CD4+
             counts <200 cells/microliter are not exclusionary.

          -  Participants with moderate to severe hepatic impairment.

          -  Any pre-existing physical or mental condition (including substance use disorder)
             which, in the opinion of the Investigator, may interfere with the participant's
             ability to comply with the dosing schedule and/or protocol evaluations or which may
             compromise the safety of the participant.

          -  Participants determined by the Investigator to have a high risk of seizures, including
             participants with an unstable or poorly controlled seizure disorder. A participant
             with a prior history of seizure may be considered for enrollment if the Investigator
             believes the risk of seizure recurrence is low. All cases of prior seizure history
             should be discussed with the Medical Monitor prior to enrollment.

          -  All participants will be screened for syphilis.

               -  Participants with untreated secondary (late latent) or tertiary syphilis
                  infection, defined as a positive rapid plasma reagin (RPR) and a positive
                  treponemal test without clear documentation of treatment, are excluded.

               -  Participants with a false positive RPR (with negative treponemal test) or
                  serofast RPR result (persistence of a reactive nontreponemal syphilis test
                  despite history of adequate therapy and no evidence of re-exposure) may enroll
                  after consultation with the Medical Monitor.

               -  Participants with primary syphilis or early latent secondary syphilis (acquired
                  within the preceding year) who have a positive RPR test and have not been treated
                  may be treated during the screening period and if completion of antibiotic
                  treatment occurs during the screening period, may be allowed entry after
                  consultation with the Medical Monitor. If antibiotic treatment cannot be
                  completed before the screening window ends, participants may be rescreened once
                  following completion of antibiotic therapy for primary or early latent secondary
                  syphilis.

          -  Participants who, in the investigator's judgment, pose a significant suicide risk.
             Participant's recent history of suicidal behavior and/or suicidal ideation should be
             considered when evaluating for suicide risk.

          -  The participant has a tattoo, gluteal implant/enhancements or other dermatological
             condition overlying the gluteus region which may interfere with interpretation of
             injection site reactions.

          -  Evidence of Hepatitis B virus (HBV) infection based on the results of testing at
             Screening for Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody
             (anti-HBc), Hepatitis B surface antibody (anti-HBs) and HBV deoxyribonucleic acid
             (DNA) as follows:

               1. Participants positive for HBsAg are excluded.

               2. Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg
                  status), whether negative or positive for HBV DNA, are excluded.

          -  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; participants who require or qualify for immediate HCV treatment
             are excluded for those co-infected participants who post entry into Switch Onto Long
             Acting Regimen (SOLAR) decide treatment for HCV infection is warranted or desired
             either by the participant or by the treating physician.

        Participants with HCV co-infection will be allowed entry into this study if:

          1. Liver enzymes meet entry criteria

          2. HCV Disease has undergone appropriate work-up, and is not advanced, and will not
             require treatment prior to the Month 14 visit. Additional information (where
             available) on participants with HCV co-infection at screening should include results
             from any liver biopsy, Fibroscan, ultrasound, or other fibrosis evaluation, history of
             cirrhosis or other decompensated liver disease, prior treatment, and timing/plan for
             HCV treatment.

          3. In the event that recent biopsy or imaging data is not available or inconclusive, the
             fibrosis (Fib)-4 score will be used to verify eligibility

        i. Fib-4 score >3.25 is exclusionary ii. Fib-4 scores 1.45-3.25 requires Medical Monitor
        consultation Fibrosis 4 Score Formula: d. Age x aspartate aminotransferase (AST)/ Platelets
        x (square [Alanine aminotransferase {ALT}]).

          -  Unstable liver disease (as defined by any of the following: presence of ascites,
             encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or
             persistent jaundice or cirrhosis, or decompensated cirrhosis [for example {e.g.}
             ascites, encephalopathy, or variceal bleeding]), known biliary abnormalities (with the
             exception of Gilbert's syndrome or asymptomatic gallstones or otherwise stable chronic
             liver disease per investigator assessment).

          -  History of liver cirrhosis with or without hepatitis viral co-infection.

          -  Ongoing or clinically relevant pancreatitis

          -  Clinically significant cardiovascular disease, as defined by history/evidence of
             congestive heart failure, symptomatic arrhythmia, angina/ischemia, coronary artery
             bypass grafting (CABG) surgery or percutaneous transluminal coronary angioplasty
             (PTCA) or any clinically significant cardiac disease.

          -  Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or
             resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial
             neoplasia; other localized malignancies require agreement between the investigator and
             the Study medical monitor for inclusion of the participant prior to randomization.

          -  Any condition which, in the opinion of the Investigator, may interfere with the
             absorption, distribution, metabolism or excretion of the study drugs or render the
             participant 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 pharmacokinetic (PK)
             sampling, participants with a history of sensitivity to heparin or heparin-induced
             thrombocytopenia must not be enrolled.

          -  Current or anticipated need for chronic anti-coagulation with the exception of the use
             of low dose acetylsalicylic acid (less than or equal to [<=]325 milligram) or
             hereditary coagulation and platelet disorders such as hemophilia or Von Willebrand
             Disease.

          -  Corrected QT interval (QTc [Bazett]) >450 milliseconds (msec) or QTc (Bazett) >480
             msec for participants with bundle branch block.

          -  Known or suspected active Coronavirus Disease-2019 (COVID-19) infection or has had
             contact with an individual with known COVID-19, within 14 days of study enrollment.

          -  Known or suspected presence of resistance mutations as defined by the International
             Antiviral Society-United States of America (IAS-USA) resistance guidelines to the
             individual components of BIK (BIC, FTC, TAF), RPV, and CAB by any historical
             resistance test result.

          -  Any verified Grade 4 laboratory abnormality. A single repeat test is allowed during
             the Screening phase to verify a result.

          -  Any acute laboratory abnormality at Screening, which, in the opinion of the
             investigator, would preclude the participant's participation in the study of an
             investigational compound.

          -  Participant has estimated creatine clearance <30mL/minute per 1.73 meter square (m^2)
             via Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) Method.

          -  ALT >=3 times upper limit of normal (ULN).

          -  Exposure to an experimental drug or experimental vaccine within either 30 days, 5
             half-lives of the test agent, or twice the duration of the biological effect of the
             test agent, whichever is longer, prior to Day 1 of this study.

          -  Treatment with any of the following agents within 28 days of Screening:

               -  radiation therapy;

               -  cytotoxic chemotherapeutic agents;

               -  tuberculosis therapy with the exception of isoniazid (isonicotinylhydrazid/INH);

               -  anti-coagulation agents;

               -  Immunomodulators that alter immune responses such as chronic 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 study Day 1. Treatment with
             acyclovir/valacyclovir is permitted.

          -  Use of medications which are associated with Torsade de Pointes.

          -  Participants receiving any prohibited medication and who are unwilling or unable to
             switch to an alternate medication.