Switch Study to Evaluate Dolutegravir Plus Lamivudine in Virologically Suppressed Human Immunodeficiency Virus Type 1 Positive Adults (TANGO)
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: DTG + 3TC; TAF based regimen (TBR)
Intervention description: DTG+3TC is supplied as white, oval, film-coated, fixed dose combination tablet. The tablets will be available in packed high density polyethylene (HDPE) bottles with induction seals and child-resistant closures.; Participants will continue to receive their TBR.
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 will receive DTG + 3TC up to Week 200. Participants randomized to TBR will continue to take their current regimen up to Week 148, at which time and if HIV-1 RNA <50 c/mL at Week 144, these participants will switch to DTG + 3TC up to Week 200. 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)
Masking description: This will be an open-label study and therefore no blinding is required. No summaries of the study data according to actual randomized treatment groups will be available to sponsor staff prior to the planned Week 24 preliminary analysis.
Enrollment: 743.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Switch study; Non-inferiority; Human immunodeficiency virus type 1; Tenofovir alafenamide; Dolutegravir; Lamivudine

Summary:

      The aim of the study is to establish if human immunodeficiency virus type 1 (HIV-1) infected
      adult participants with current virologic suppression on a >=3-drug tenofovir alafenamide
      (TAF) based regimen (TBR) remain suppressed upon switching to a two-drug regimen of
      dolutegravir (DTG) 50 milligram (mg) + lamivudine (3TC) 300 mg. This study will also provide
      important information regarding the safety and participant satisfaction with this two-drug
      regimen. The primary objective of this trial is to demonstrate the non-inferior antiviral
      activity of switching to DTG + 3TC once daily compared to continuation of TBR over 48 weeks
      in HIV-1 infected, antiretroviral therapy (ART)-experienced, virologically suppressed
      participants. This study also will characterize the long-term antiviral activity,
      tolerability and safety of DTG + 3TC compared to TBR through Week 144 and characterize the
      long-term antiviral activity, tolerability and safety of DTG + 3TC through Week 200.

      This will be a 200-week, Phase III, randomized, open-label, active-controlled, multicenter,
      parallel- group study. The study will include a screening phase (up to 28 days), a randomized
      early switch phase (Day 1 up to Week 148), a randomized late switch phase (Week 148 up to
      Week 200), and a continuation phase (post Week 200). HIV-1 infected adults on stable TBR will
      be randomized 1:1 to switch to DTG + 3TC once daily for up to 200 weeks, or to continue their
      TBR for 148 weeks, at which time and if HIV-1 ribonucleic acid (RNA) <50 copies per
      milliliter (c/mL) at Week 144, these participants will switch to DTG + 3TC up to Week 200.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participant must be able to understand and comply with protocol requirements,
             instructions, and restrictions;

          -  Participant must be likely to complete the study as planned;

          -  Participant must be considered an appropriate candidate for participation in an
             investigative clinical trial with medication (example no active substance abuse, acute
             major organ disease, or planned long-term work assignments out of the country).

          -  Aged 18 years or older (or older where required by local regulatory agencies), at the
             time of signing the informed consent.

          -  HIV-1 infected men or women.

          -  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.

          -  Must be on uninterrupted ART for at least 6 months prior to screening. Only the
             following regimens are allowed:

               -  Participant on a TAF-based regimen for at least 6 months as the initial regimen,
                  or

               -  Participants who switched from a tenofovir disoproxil fumarate (TDF)
                  first-regimen TAF, without any changes to the other drugs in their regimen, and
                  have been on the TAF-based regimen for at least 3 months immediately prior to
                  Screening i.e., the only switch made is from TDF to TAF. This switch must have
                  occurred due to tolerability/safety, access to medications, or
                  convenience/simplification, and must NOT have been done for suspected or
                  established treatment failure. A switch from a PI boosted with ritonavir to the
                  same PI boosted with cobicistat is allowed (and vice versa).

          -  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
             lactating, and at least one of the following conditions applies:

             a. Non-reproductive potential defined as:

          -  Pre-menopausal females with one of the following:

               -  Documented tubal ligation

               -  Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of
                  bilateral tubal occlusion

               -  Hysterectomy

               -  Documented bilateral oophorectomy

          -  Post-menopausal 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 [refer to laboratory reference ranges for
             confirmatory levels]). 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 enrolment.

             b. 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
             and for at least 2 weeks after the last dose of study medication.

          -  The investigator is responsible for ensuring that participants understand how to
             properly use these methods of contraception. 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.

          -  Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form and the protocol. Eligible
             participants or their legal guardians must sign a written informed consent form before
             any protocol-specified assessments are conducted.

        Participants enrolled in France must be affiliated to, or a beneficiary of, a social
        security category.

        Exclusion Criteria:

          -  Women who are 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/millimeter (mm)^3 are NOT exclusionary.

          -  Participants with severe hepatic impairment (Class C) as determined by Child-Pugh
             classification.

          -  Unstable liver disease (as defined by the presence of ascites, encephalopathy,
             coagulopathy, hypoalbuminaemia, 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), 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.

          -  Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of
             the study, or anticipated need for HCV therapy based on interferon or for any drugs
             that have a potential for adverse drug-drug interactions with study treatment
             throughout the entire study period.

          -  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.

          -  History or presence of allergy or intolerance 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, anal or penile
             intraepithelial neoplasia.

          -  Participants who in the investigator's judgment, poses a significant suicidality risk.

          -  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 systemic immune suppressant.

          -  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).

          -  Use of any regimen consisting of single or dual ART.

          -  Any evidence of major nucleoside reverse transcriptase inhibitor (NRTI) mutation or
             presence of any major INSTI resistance-associated mutation in any available prior
             resistance genotype assay test result, if known, must be provided to ViiV after
             screening and before randomization for review by ViiV Virology.

          -  Any verified Grade 4 laboratory abnormality.

          -  Alanine aminotransferase (ALT) >=5 times (*) the upper limit of normal (ULN) or ALT
             >=3 * ULN and bilirubin >=1.5 * ULN (with >35 percent [%] direct bilirubin).

          -  Creatinine clearance of <50 milliliter (mL)/minute/1.73 meter^2 via Chronic Kidney
             Disease Epidemiology Collaboration (CKD-EPI) method.

          -  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.

          -  Within 6 months prior to Screening and after confirmed suppression to <50 c/mL on
             current ART regimen, any plasma HIV-1 RNA measurement >=50 c/mL.

          -  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.

          -  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 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.