Regimen Switch to Dolutegravir + Rilpivirine From Current Antiretroviral Regimen in Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults (SWORD-2)
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: DTG 50 mg; RPV 25 mg; CAR
Intervention description: Participants will take one oral tablet of 50 mg DTG daily administered concomitantly with RPV. Each DTG tablet will contain 52.62 mg dolutegravir sodium salt, which is equivalent to 50 mg dolutegravir free acid.; Participants will take one oral tablet of 25 mg RPV daily administered concomitantly with DTG along with a meal. Each RPV tablet will contain 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of RPV.; CAR will include following combinations: 2 NRTIs + 1 INI, 2 NRTIs + 1 NNRTI, or 2 NRTIs + 1 PI.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 518.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HIV; NNRTI-sparing; two-drug regimen; nucleoside reverse transcriptase inhibitors; protease inhibitor; integrase inhibitor; non-nucleoside reverse transcriptase inhibitor; dolutegravir plus rilpivirine; virologically-suppressed

Summary:

      The aim of this study is to determine if virologically suppressed, human immunodeficiency
      virus type 1 (HIV-1) infected adults on an antiretroviral regimen (including 2 nucleoside
      reverse transcriptase inhibitors [NRTIs] plus a third agent) remain suppressed upon switching
      to a two-drug regimen with dolutegravir (DTG) + rilpivirine (RPV). The study will primarily
      assess the non-inferiority antiviral activity of switching to DTG + RPV once daily compared
      to continuation of current antiretroviral regimen (CAR) up to Week 48 with a switch visit for
      eligible subjects in the CAR group to initiate DTG + RPV therapy at Week 52. CAR will include
      2 NRTIs plus 1 HIV-1 integrase inhibitor (INI), or 1 non-nucleoside reverse transcriptase
      inhibitor (NNRTI), or 1 protease inhibitor (PI). The study will include a 148-week open-label
      treatment phase, comprising of an Early Switch Phase (Day 1 to Week 52) and a Late Switch
      Phase (Week 52 to Week 148). The participants fulfilling the study eligibility criteria will
      participate in the Early Switch Phase where they will either switch from their CAR to DTG +
      RPV, or continue taking their CAR, until Week 52. At the end of Early Switch Phase, eligible
      participants will proceed to the Late Switch Phase where all participants in both DTG + RPV
      and CAR treatment groups will receive DTG + RPV therapy until Week 148. After Week 148,
      subjects may be eligible to continue to receive DTG +RPV in the Continuation Phase. The study
      is planned to be conducted in approximately 476 participants.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must be able to understand and comply with protocol requirements,
             instructions, and restrictions.

          -  Participants must be likely to complete the study as planned.

          -  Participants must be considered appropriate candidates for participation in an
             investigative clinical trial with oral medication (e.g., no active substance abuse,
             acute major organ disease, or planned long-term work assignments out of the country,
             etc.).

          -  HIV-1 infected men or women of >=18 years of age.

          -  Must be on uninterrupted current regimen (either the initial or second combination
             antiretroviral therapy [cART] regimen) for at least 6 months prior to screening; Any
             prior switch, defined as a change of a single drug or multiple drugs simultaneously,
             must have occurred due to tolerability and/or safety concerns or access to
             medications, or convenience/simplification. Acceptable stable cART regimens prior to
             screening include 2 NRTIs plus; INI (either the initial or second cART regimen), or an
             NNRTI (either the initial or second cART regimen), or a Boosted PI (or atazanavir
             unboosted) ( either the initial or second PI-based cART regimen).

          -  Documented evidence of at least two plasma HIV-1 RNA measurements <50 c/mL in the 12
             months prior to Screening: one within the 6 to 12 month window, and one within 6
             months prior to Screening;

          -  Plasma HIV-1 RNA <50 c/mL at Screening;

          -  A female may be eligible to enter and participate in the study if she is of :
             Non-child-bearing potential either defined as 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
             child-bearing potential with a negative pregnancy test at both Screening and Day 1 and
             agrees to use one of the following methods of contraception to avoid pregnancy:
             Complete abstinence from intercourse from 2 weeks prior to administration of study
             drug, throughout the study, and for at least 2 weeks after discontinuation of all
             study medications and completion of the Follow-up visit; Any intrauterine device (IUD)
             with published data showing that the expected failure rate is <1% per year (not all
             IUDs meet this criterion); Male partner sterilization with documentation of
             azoospermia prior to the female participant's entry into the study and this male is
             the sole partner for that participant. The documentation on male sterility can come
             from the site personnel's review of participant's medical records, medical
             examination, and/or semen analysis, or medical history interview provided by her or
             her partner; Approved hormonal contraception for participants randomly assigned to DTG
             + RPV arm (and for participants randomly assigned to CAR following switch to DTG + RPV
             at Week 52) or approved hormonal contraception plus a barrier method for participants
             assigned to CAR through Week 52. Approved hormonal contraception includes: Combined
             estrogen and progestogen oral contraceptive, Contraceptive subdermal implant,
             Injectable progestogen, Contraceptive vaginal ring, Percutaneous contraceptive
             patches; Any other method with published data showing that the expected failure rate
             is <1% per year. Any contraception method must be used consistently, in accordance
             with the approved product label during treatment with study drug and for at least 2
             weeks after discontinuation of study drug and completion of the Follow-Up Visit. The
             investigator is responsible for ensuring that participants understand how to properly
             use these methods of contraception. Periodic abstinence (e.g. calendar, ovulation,
             symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
             contraception. Note: these contraceptive requirements do not apply to females of
             reproductive potential with same sex partners only, when this is their preferred and
             usual lifestyle. All participants participating in the study should be counseled on
             safer sexual practices including the use and benefit/risk of effective barrier methods
             (e.g., male condom) and on the risk of HIV transmission to an uninfected partner.

          -  Participants who are willing and able to understand requirements of study
             participation and provide signed and dated written informed consent prior to
             screening.

          -  For participants enrolled in France: participants will be eligible for inclusion in
             this study only if either affiliated to or a beneficiary of a social security
             category.

        Exclusion Criteria:

        Exclusionary Criteria prior to screening or Day 1:

          -  Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on
             current Antiretroviral therapy (ART regimen), any plasma HIV-1 RNA measurement >=50
             c/mL.

          -  Within the 6 to 12 month window prior to screening and after confirmed suppression to
             <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL.

          -  Within the 6 to 12 month window prior to screening and after confirmed suppression to
             <50 c/mL, 2 or more plasma HIV-1 RNA measurements >=50 c/mL.

          -  Any drug holiday during the window between initiating first HIV ART and 6 months prior
             to screening, except for brief periods (less than 1 month) where all ART was stopped
             due to tolerability and/or safety concerns.

          -  Any switch 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 >=400 c/mL after initial suppression to <50 c/mL while on
             first line HIV therapy regimen).

        Exclusionary medical conditions:

          -  Women who are pregnant, breastfeeding or plan to become pregnant or breastfeed during
             the study.

          -  Any evidence of an active Centers for Disease Control and Prevention Category C
             disease. Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy
             and historic CD4+ lymphocyte counts of <200 cells per cubic millimeter (cells/mm^3).

          -  Participants with severe hepatic impairment (Class C) as determined by Child-Pugh
             Classification.

          -  Unstable liver disease (as defined by the presence of any of the following: ascites,
             encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or
             persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of
             Gilbert's syndrome or asymptomatic gallstones).

          -  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), and Hepatitis B surface antibody (HBsAb) as follows: participants positive
             for HBsAg are excluded; participants positive for anti-HBc (negative HBsAg status) and
             negative for HBsAb are excluded. Note: Participants positive for anti-HBc (negative
             HBsAg status) and positive for HBsAb are immune to HBV and are not excluded.

          -  Participants with an anticipated need for any Hepatitis C virus (HCV) therapy during
             the Early Switch Phase and for interferon-based therapy for HCV throughout the entire
             study period.

          -  History or presence of allergy to the study drugs or their components or drugs of
             their class;

          -  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;

          -  Participants who in the investigator's judgment pose a significant suicidality risk.
             Participant's history of suicidal behavior and/or suicidal ideation should be
             considered when evaluating for suicide risk;

          -  Any pre-existing physical or mental condition 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;

          -  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 take oral medication;

        Exclusionary Treatments prior to Screening or Day 1:

          -  Use of medications which are associated with Torsades de Pointes.

          -  Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.

          -  Treatment with any of the following agents within 28 days of Screening: radiation
             therapy; cytotoxic chemotherapeutic agents; any immunomodulators that alter immune
             responses.

          -  Exposure to an experimental drug or experimental vaccine within either 28 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.

          -  Participants who are currently participating, or are anticipated to be selected to
             participate in any other interventional study, with the exception of the DEXA
             sub-study 202094, after randomization (NOTE: Participants who are already enrolled
             into another interventional study at time of screening may be eligible after
             consultation with the GlaxoSmithKline study team prior to randomization.
             Considerations include participant's ability to attend all visits on schedule, and
             possible drug and study procedure compatibility).

          -  A history of use of any regimen consisting of only single NNRTI therapy (even if only
             for peri-partum treatment), or only single or dual NRTI therapy prior to starting
             cART.

          -  Current or prior history of etravirine (ETR) use.

          -  Current use of tipranavir/ritonavir or fosamprenavir/ritonavir.

          -  Participants receiving any prohibited medication and who are unwilling or unable to
             switch to an alternate medication. Note: Any prohibited medications that decrease DTG
             or RPV concentrations should be discontinued for a minimum of four weeks or a minimum
             of three half-lives (whichever is longer) prior to the first dose and any other
             prohibited medications should be discontinued for a minimum of two weeks or a minimum
             of three half-lives (whichever is longer) prior to the first dose.

        Exclusionary Laboratory Values or Clinical Assessments at Screening:

          -  Evidence of viral resistance based on the presence of any resistance associated major
             PI, INI, NRTI, or NNRTI mutation and integrase (IN) resistance associated substitution
             R263K in any available prior resistance genotype assay results. Note: Any prior
             genotypic resistance testing is not required but if available it must be provided to
             GlaxoSmithKline, after screening and before randomization, to provide direct evidence
             of no pre-existing exclusionary resistance mutations. You must wait for the study
             virologists to confirm the lack of exclusionary resistance mutations, which will be
             provided before the screening window closes.

          -  Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 lipid
             abnormalities. A single repeat test is allowed during the Screening period 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.

          -  Alanine aminotransferase (ALT) >=5 × upper limit of normal (ULN), or ALT >=3 × ULN and
             bilirubin >=1.5 × ULN (with >35% direct bilirubin).

          -  Corrected QT interval (QTc [Bazett]) >450 milliseconds or QTc (Bazett) >480
             milliseconds for participants with bundle branch block. The QTc is the QT interval
             corrected for heart rate according to Bazett's formula (QTcB).