Regimen Switch to Dolutegravir/Lamivudine Fixed Dose Combination From Current Antiretroviral Regimen in HIV-1 Infected and Virologically Suppressed Adults (SALSA)
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: DTG/3TC FDC; CAR
Intervention description: DTG/3TC FDC will be available as white, oval, film-coated tablets at a unit dose strength of 50 mg/300 mg. Participants will take DTG/3TC once daily via oral route.; Participants who are randomized to the CAR arm will continue to take the current treatment until Week 52. CAR will include 2 NTRIs plus either an INI, NNRTI, or boosted PI or atazanavir unboosted.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a randomized study with parallel group assignment where participants will be randomized into one of the two treatment groups. Participants randomized to DTG/3TC FDC will receive DTG/3TC FDC up to Week 52. Participants randomized to CAR will continue to take their current regimen up to Week 52. Randomization will be stratified by Baseline third agent class (protease inhibitor [PI], integrase inhibitor [INI], or non-nucleoside reverse transcriptase inhibitor [NNRTI]).
Masking: None (Open Label)
Enrollment: 493.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Current antiretroviral regimen (CAR); HIV-1; Long-term antiviral activity; Dolutegravir/lamivudine; Fixed dose combination

Summary:

      The aim of this study is to determine if virologically suppressed Human Immunodeficiency
      Virus (HIV) Type 1 infected adults on a current antiretroviral regimen (CAR) (including 2
      nucleoside reverse transcriptase inhibitors [NRTIs] plus a third agent) remain suppressed
      upon switching to dolutegravir/lamivudine (DTG/3TC) fixed dose combination (FDC). The main
      objective of the study is to demonstrate the non-inferior antiviral activity of switching to
      DTG/3TC FDC once daily compared to continuation of CAR over 48 weeks in virologically
      suppressed adults living with HIV-1. The study will also evaluate information regarding the
      safety and health related quality of life. The study will include Screening Phase (up to 28
      days), a Randomization Phase (up to Week 52) and a Continuation Phase (post Week 52). The
      Continuation Phase is not applicable for participants in Sweden and Denmark. Approximately
      490 participants will be randomized in 1:1 ratio to receive DTG/3TC FDC once daily for up to
      52 weeks or continue their CAR for 52 weeks. Participants in the DTG/3TC FDC arm who
      successfully complete up to 52 weeks of treatment will have the opportunity to continue
      receiving DTG/3TC FDC once daily in Continuation Phase.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Eligible participants must be able to understand and comply with protocol
             requirements, instructions, and restrictions; participant must be likely to complete
             the study as planned; participants should be considered appropriate candidates for
             participation in an investigative clinical trial with oral medication (example given
             [e.g.] no active problematic substance abuse, acute major organ disease, or potential
             long-term work assignments out of the country).

          -  Participant should be aged 18 years or older (or older, if required by local
             regulatory agencies), at the time of signing the informed consent.

          -  Participants living with HIV.

          -  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.

          -  Participant must be on uninterrupted current regimen (either the initial or second
             Combination antiretroviral therapy [cART] regimen) for at least 3 months prior to
             Screening.

             i) 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 and must not have been done for
             suspected or established treatment failure. The following switches, if they are the
             only switches, would not be considered a change in regimen. a) A switch from a PI
             boosted with ritonavir (RTV) to the same PI boosted with cobicistat is allowed (and
             vice versa). b) A switch from 3TC to emtricitabine (FTC) (and vice versa). c) A switch
             from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) (and vice
             versa).

        ii) Acceptable stable cART regimens prior to Screening include 2 NRTIs plus a) INI (either
        the initial or second cART regimen) b) NNRTI (either the initial or second cART regimen) c)
        Boosted PI (or atazanavir [ATV] unboosted) (either the initial or second PI-based cART
        regimen).

          -  A male or female participant.

          -  A female participant is eligible to participate if she is not pregnant [as confirmed
             by a negative serum human chorionic gonadotrophin (hCG) test at screen and a negative
             urine hCG test at randomization (a local serum hCG test at randomization is allowed if
             it can be done, and results obtained, within 24 hours prior to randomization)], not
             breastfeeding, and at least one of the following conditions applies; not a woman of
             childbearing potential (WOCBP) or a WOCBP who agrees to follow the contraceptive
             guidance during the treatment period from 28 days prior to the first dose of study
             medication and for at least 2 weeks after the last dose of study medication. All
             participants 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; The investigator is responsible for
             review of medical history, menstrual history, and recent sexual activity to decrease
             the risk for inclusion of a woman with an early undetected pregnancy.

          -  Participant must be capable of giving signed informed consent.

          -  Participants enrolled in France must be affiliated to, or a beneficiary of, a social
             security category.

        Exclusion Criteria:

          -  Women who are pregnant or breastfeeding or plan to become pregnant or breastfeed
             during the study.

          -  Any evidence of an active Centers for Disease Control and Prevention (CDC) Stage 3
             disease except cutaneous Kaposi's sarcoma not requiring systemic therapy. Historical
             or current CD4 cell counts less than 200 cells per cubic millimeter (mm^3) are not
             exclusionary.

          -  Participants with severe hepatic impairment (Class C) as determined by Child-Pugh
             classification.

          -  Participants with unstable liver disease (as defined by the presence of ascites,
             encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or
             persistent jaundice), cirrhosis, known biliary abnormalities (with the exception of
             Gilbert's syndrome or asymptomatic gallstones).

          -  Participants with the 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 antigen antibody (anti-HBs) and HBV
             deoxyribonucleic acid (DNA) as follows: Participants positive for HBsAg are excluded;
             Participants negative for anti-HBs but positive for anti-HBc (negative HBsAg status)
             and positive for HBV DNA are excluded. Participant's positive for anti-HBc (negative
             HBsAg status) and positive for anti-HBs (past and/or current evidence) are immune to
             HBV and are not excluded. Anti-HBc must be either total anti-HBc or anti-HBc
             immunoglobulin G (IgG), and not anti-HBc Immunoglobulin M (IgM). Participants with a
             documented history of chronic HBV and current undetectable HBV DNA while on a TAF/TDF
             regimen are excluded.

          -  Participants with anticipated need for any hepatitis C virus (HCV) therapy during the
             randomized phase of the study, or anticipated need for HCV therapy with a potential
             for adverse drug-drug interactions with DTG or 3TC.

          -  Participants with untreated syphilis infection (positive rapid plasma reagin [RPR] at
             Screening without clear documentation of treatment). Participants who are at least 7
             days post completed treatment are eligible.

          -  Participants with history or presence of allergy intolerance to the study
             interventions or their components or drugs of their class.

          -  Participants with ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell
             carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical,
             anal or penile intraepithelial neoplasia.

          -  Participants who in the investigator's judgment, poses a significant suicidality risk.

          -  Participants with 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 interventions or render
             the participant unable to take oral medication.

          -  Use of any regimen consisting of single or dual ART (peri-partum treatment with single
             dose nevirapine is allowed).

          -  Participants with current use of stavudine, didanosine, or nelfinavir.

          -  Participants receiving any prohibited medication and who are unwilling or unable to
             switch to an alternate medication.

          -  Participants receiving treatment with an HIV-1 immunotherapeutic vaccine within 90
             days of Screening.

          -  Participants receiving treatment with any of the following agents within 28 days of
             Screening like radiation therapy; cytotoxic chemotherapeutic agents; any systemic
             immune suppressant.

          -  Participants with 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 the first dose of
             investigational product (IP).

          -  Any evidence of major NRTI mutation or presence of any DTG resistance-associated
             mutation in any available prior resistance genotype assay test result, if known.

          -  Participants with 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.

          -  Participants with alanine aminotransferase (ALT) >= 5 times the upper limit of normal
             (ULN) or ALT >= 3 times ULN and bilirubin >= 1.5 times ULN (with >35 percent direct
             bilirubin).

          -  Participants with creatinine clearance of <30 mL/min/1.73m^2 via Chronic Kidney
             Disease Epidemiology Collaboration (CKD-EPI) method. Participants with creatinine
             clearance between 30 to 49 mL/min/1.73 m^2 are eligible after the medical monitor has
             provided approval after reviewing participant's current ART regimen.

          -  Participants with any acute laboratory abnormality at Screening, which, in the opinion
             of the investigator, would preclude the participant'sparticipation in the study of an
             investigational compound.

          -  Participants within the 12 month window prior to Screening and after confirmed
             suppression to <50 c/mL, any plasma HIV-1 RNA measurement >200 c/mL.

          -  Participants within the 12 month window prior to Screening and after confirmed
             suppression to <50 c/mL, 2 or more consecutive plasma HIV-1 RNA measurements >=50
             c/mL. A single plasma HIV-1 RNA measurement >50 c/mL but less than 200 c/mL, with
             confirmation of return to <50 c/mL is allowed.

          -  Any history of switch to another 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 >=400 c/mL).

          -  Participants with any drug holiday during the 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.

          -  Participants who are currently participating in or anticipate to be selected for any
             other interventional study after randomization.

          -  Participants enrolled in France (or in other countries as required by local
             regulations or Ethics Committee/Institutional Review Board [IRB]) who participated in
             any study using an investigational drug or vaccine during the previous 60 days or 5
             half-lives, or twice the duration of the biological effect of the experimental drug or
             vaccine, whichever is longer, prior to screening for the study, or participate
             simultaneously in another clinical study.