Regimen Switch to Dolutegravir/Lamivudine Fixed Dose Combination From Current Antiretroviral Regimen in HIV-1 Infected and Virologically Suppressed Adults (SALSA)

A Phase III, Randomized, Multicenter, Open-label, Non-inferiority Study Evaluating the Efficacy, Safety and Tolerability of Switching to Dolutegravir/Lamivudine Fixed Dose Combination in HIV-1 Infected Adults Who Are Virologically Suppressed

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.

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.