An Efficacy, Safety, and Tolerability Study Comparing Dolutegravir (DTG) Plus Lamivudine (3TC) With Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Participants (Gemini 2)
Condition: Infection, Human Immunodeficiency Virus; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
Intervention: Dolutegravir (DTG); Lamivudine (3TC); Tenofovir disoproxil fumarate/Emtricitabine (TDF/FTC FDC)
Intervention description: DTG is available as 50 mg white, round, biconvex, film coated tablet debossed on one side with 'SV 572' and on the other side with '50'. The tablets are packaged into high density polyethylene (HDPE) bottles with induction seals and child resistant closures. Each 45 ml bottle contains 30 tablets and a desiccant. DTG 50 mg tablet will be orally administered once daily with or without food upto 148 weeks.; Lamivudine is available as swedish orange, 'AA' sized elongated double blind HPMC capsules containing 300 mg lamivudine to visually match overencapsulated TDF/FTC FDC tablet. The capsules are packaged into HDPE bottles with induction seals and child resistant closures. Each 150 mL bottle contains 30 capsules and a desiccant. Overencapsulated 3TC 300 mg tablet will be orally administered once daily with or without food upto 96 weeks. From Week 96 to Week 148, lamivudine will be dispensed as 300 mg white, diamond shaped, scored, film coated tablets debossed with 'GX CJ7' on both sides, packed in over labelled HDPE bottles with child-resistant closures each containing 30 tablets.; Tenofovir disoproxil fumarate and Emtricitabine are available as swedish orange, 'AA' sized elongated double blind HPMC capsules containing 300 mg TDF and 200 mg FTC to visually match overencapsulated 3TC tablet. The capsules are packaged into HDPE bottles with induction seals and child resistant closures. Each 150 mL bottle contains 30 capsules and a desiccant. Overencapsulated tenofovir disoproxil fumarate/emtricitabine tablet will be orally administered once daily with or without food upto 96 weeks. From Week 96 to Week 148, tenofovir disoproxil fumarate/emtricitabine will be dispensed as 300/200 mg white, blue, capsule shaped, film coated tablets debossed with 'GILEAD' on one side and '701' on another side, packed in overlabelled HDPE bottles with polypropylene childresistant closures each containing 30 tablets and a desiccant.
Intervention MeSH terms: Tenofovir; Lamivudine; Emtricitabine; Dolutegravir
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 722.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: tolerability; HIV 1; efficacy; treatment naïve; two-drug regimen; safety; non inferiority

Summary:

      This study will compare safety, efficacy, and tolerability of a two drug regimen of
      dolutegravir (DTG) plus (+) lamivudine (3TC) administered once daily with DTG plus two
      nucleoside reverse transcriptase inhibitors (tenofovir disoproxil fumarate
      [TDF]/emtricitabine [FTC] fixed dose combination [FDC]) administered once daily in human
      immunodeficiency virus (HIV) 1 infected adult participants that have not previously received
      antiretroviral therapy. The study is designed to demonstrate the non inferior antiviral
      activity of DTG + 3TC regimen to that of DTG + TDF/FTC FDC and will characterise the long
      term antiviral activity, tolerability and safety of DTG plus 3TC through Week 148.
      Approximately, 700 participants will be randomised 1:1 to receive DTG + 3TC or DTG + TDF/FTC
      FDC. Participants will be stratified by screening HIV 1 ribonucleotide nucleic acid (RNA)
      levels and by screening CD4+ (cluster of differentiation 4) cell count.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Must be an HIV 1 infected adult >=18 years of age (or older, if required by local
             regulations) at the time of signing the informed consent

          -  An eligible female participant should not be pregnant (as confirmed by a negative
             serum human chorionic gonadotrophin (hCG) test at Screening and negative urine test at
             Baseline), not lactating, and at least one of the following conditions applies

               -  Non reproductive premenopausal women are those that have undergone documented
                  tubal ligation or documented hysteroscopic tubal occlusion procedure with follow
                  up confirmation of bilateral tubal occlusion or documented bilateral oophorectomy
                  or hysterectomy

               -  Non reproductive premenopausal women are those with 12 months of spontaneous
                  amenorrhea and >=45 years of age

               -  Women with reproductive potential agree to follow one of the protocol-defined
                  methods for avoiding pregnancy

          -  Should have screening plasma HIV 1 RNA levels of 1000 c/mL to <=100,000 c/mL. If an
             independent review of accumulated data from other clinical trials investigating the
             DTG plus 3TC dual regimen is supportive of the DTG plus 3TC treatment regimen,
             enrolment will be opened to participants with Screening plasma HIV 1 RNA of 1000 c/mL
             to <=500,000 c/mL

          -  Participant should be antiretroviral naïve (defined as <=10 days of prior therapy with
             any antiretroviral agent following a diagnosis of HIV 1 infection). Participants who
             received HIV post exposure prophylaxis (PEP) or pre exposure prophylaxis (PrEP) in the
             past are allowed as long as the last PEP/PrEP dose was >1 year from HIV diagnosis or
             there is documented HIV seronegativity between the last prophylactic dose and the date
             of HIV diagnosis

          -  Participants or the participants legal representative capable of giving signed
             informed consent which includes compliance with the requirements and restrictions
             listed in the consent form and the protocol

          -  Participants enrolled in France: a participant will be eligible for inclusion in this
             study only if either 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 (CDC, 2014), except cutaneous Kaposi's sarcoma not requiring systemic therapy
             and historical or current CD4 cell counts less than 200 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 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 or HBV surface antibody (anti-HBs or
             HBsAb) based on:

        Participants positive for HBV surface antigen (HBsAg) at screening will be excluded
        Participants negative for HBV core antibody (anti HBs) but positive for anti HBc (negative
        HBsAg status) and positive for HBV deoxyribose nucleic acid (DNA) will be excluded;
        however, participants positive for anti HBc (negative HBsAg status) and positive for anti
        HBs (past and/or current evidence) are immune to HBV and will not be excluded

          -  Anticipated need for any hepatitis C virus (HCV) therapy during the first 48 weeks of
             the study and for HCV therapy based on interferon or any drugs that have a potential
             for adverse drug:drug interactions with study treatment throughout the entire study
             period

          -  Untreated syphilis infection positive RPR at Screening without clear documentation of
             treatment. Participants who are at least 14 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; other localised malignancies require agreement between the
             investigator and the Study Medical Monitor for inclusion of the participant

          -  Participants who in the Investigator's judgment, poses a significant suicidality risk.
             Recent history of suicidal behaviour and/or suicidal ideation may be considered as
             evidence of serious suicide 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

          -  Treatment with any agent, except recognised ART as allowed above, with documented
             activity against HIV 1 in vitro within 28 days of first dose of study treatment

          -  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 study treatment

          -  Participants enrolled in France: the participant has participated in any study using
             an investigational drug 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 the participant will participate
             simultaneously in another clinical study

          -  Any evidence of pre existing viral resistance based on the presence of any major
             resistance associated mutation in the Screening result or, if known, in any historical
             resistance test result

          -  Any verified Grade 4 laboratory abnormality. 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 participants participation in the study of an
             investigational compound

          -  Alanine aminotransferase (ALT) >=5 times the upper limit of normal (ULN) or ALT
             >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin)

          -  Creatinine clearance of <50 mL/min per 1.73 m^2 via the chronic kidney disease
             epidemiology collaboration (CKD EPI) method