A Phase IIIb Study of the Safety, Efficacy, and Tolerability of Switching to a Fixed-dose Combination of Abacavir/Dolutegravir/ Lamivudine From Current Antiretroviral Regimen

201147: a Phase IIIb, Randomized, Open-label Study of the Safety, Efficacy, and Tolerability of Switching to a Fixed-dose Combination of Abacavir/Dolutegravir/ Lamivudine From Current Antiretroviral Regimen Compared With Continuation of the Current Antiretroviral Regimen in HIV-1 Infected Adults Who Are Virologically Suppressed, The STRIIVING Study.

This study is a 48-week, Phase IIIb, randomly assigned, open-label, active-controlled, multicenter, parallel group, non-inferiority study. This study is designed to demonstrate the non-inferior antiviral activity of switching to the Abacavir (ABC) 600 milligrams (mg)/Dolutegravir(DTG) 50 mg/Lamivudine (3TC) 300 mg fixed-dose combination (FDC) compared with continuing the subject's current suppressive regimen through 24 weeks. The study will be conducted in approximately 538 Human Immunodeficiency Virus -1 (HIV-1) infected individuals who are on stable suppressive combination antiretroviral therapy (cART) with 2 Nucleoside reverse transcriptase inhibitors (NRTIs) plus either a protease inhibitor (PI), an non-nucleoside reverse transcriptase inhibitor (NNRTI), or an integrase inhibitor (INI). Eligible subjects will be randomly assigned 1:1 to continue their current regimen (approximately 269 subjects) or be switched to ABC/DTG/3TC FDC (approximately 269 subjects) once daily for 24 weeks. At Week 24, individuals originally randomly assigned to continue their current regimen will switch to ABC/DTG/3TC FDC and be followed for an additional 24 weeks. Individuals initially randomly assigned to ABC/DTG/3TC FDC will continue on that treatment arm for an additional 24 weeks. A pharmacokinetic (PK) substudy will be conducted at a small number of sites (approximately 10) to evaluate predose DTG concentrations as well as residual drug concentrations of efavirenz (EFV), nevaripine (NVP), amprenavir (APV) and tipranavir (TPV) in a subgroup of subjects who switch from EFV, NVP, fosamprenavir/ritonavir (FPV/r) or tipranavir/ritonavir (TPV/r).

Inclusion Criteria:

• Be able to understand and comply with protocol requirements, instructions, and restrictions;
• Be likely to complete the study as planned;
• 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.).
• Signed and dated written informed consent is obtained from the subject or the subject's legal representative prior to screening
• HIV-1 infected men or women >=18 years of age;
• A female may be eligible to enter and participate in the study if she: a. Is of non-childbearing 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,
• A female may be eligible to enter and participate in the study if she: b. Is of childbearing 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 drugs; Double barrier method (e.g., male condom/spermicide, male condom/diaphragm, diaphragm/spermicide); Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year ; Male partner sterilization prior to the female subject's entry into the study and this male is the sole partner for that subject; Approved hormonal contraception for subjects randomly assigned to the ABC/DTG/3TC arm or approved hormonal contraception plus a barrier method for subjects assigned to continued antiretroviral therapy arm; 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 and for at least 2 weeks after discontinuation of study drug. A childbearing potential female subject who starts the study using complete abstinence as her contraceptive method and decides to become sexually active must use the double barrier method either as a bridge to an approved hormonal contraception (if possible) or as a method of choice to be maintained from that moment onwards.
• All subjects participating in the study should be counselled on safer sexual practices including the use of effective barrier methods (e.g., male condom/spermicide).
• Within the last year, 2 consecutive plasma HIV-1 Ribonucleic acid (RNA) measurements <50 copies/millilitres (c/mL) and plasma HIV-1 RNA<50 c/mL at Screening (<75 b Deoxyribonucleic acid [bDNA] is considered equal to <50 c/mL); Subjects who present at initial screening with a viral load between 50 to 200 c/mL can be retested once within the screening period.
• Must be on current regimen (whether first or second line Combination antiretroviral therapy [cART]) for at least 6 months prior to Screening;
• Acceptable stable cART regimens prior to Screening include: • Boosted PI (or Atazanavir [ATV]) unboosted) + 2 NRTIs, NNRTI + 2 NRTIs, • INI + 2 NRTIs. For subjects on an INI, their INI at Screening must be RAL or Elvitegravir (EVG)
• Any switch to a second line regimen, defined as change of a single drug or multiple drugs simultaneously, must have occurred due to tolerability and/or safety concerns.
• Subject must have achieved plasma HIV-1 RNA level <50 c/mL within 6 months of start of initial cART regimen with no plasma HIV-1 RNA level >200 c/mL following initial suppression;
• Documentation that the subject is negative for the human leukocyte antigen (HLA) B*5701 allele;

Exclusion Criteria:

Exclusionary Medical Conditions

• Women who are breastfeeding;
• Any evidence of an active (Centers for Disease Control and Prevention [CDC] Category C) disease. Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy and historic CD4+ cell counts of <200 cells/cubic millimeter (mm).
• Subjects with any degree of hepatic impairment;
• Subjects positive for hepatitis B virus surface antigen (+HBsAg) at Screening or with an anticipated need for hepatitis C virus (HCV) therapy during the study;
• 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 subject;
• Subjects who, in the investigator's judgment, pose a significant suicidality risk. Recent history of suicidal behavior and/or suicidal ideation may be considered as evidence of serious suicide risk;

Exclusionary Treatments Prior to Screening or Day 1

• 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 the first dose of study drug;
• A history of use of only mono or dual NRTI therapy prior to starting cART;
• Use of etravirine at time of switch;
• Use of DTG at time of switch;
• Subjects receiving any prohibited medication listed in the protocol and who are unwilling or unable to switch to an alternate medication

Exclusionary Laboratory Values or Clinical Assessments at Screening

• Evidence of primary viral resistance based on the presence of any resistance-associated major PI or any NRTI, NNRTI, or INI mutation in any prior resistance genotype assay result;
• Any verified Grade 4 laboratory abnormality, with the exception of Grade 4 triglyceride 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 subject's participation in the study of an investigational compound;
• Alanine aminotransferase (ALT) >=5 times the upper limit of normal (ULN), or ALT >=3 × ULN and bilirubin >=1.5 × ULN (with >35% direct bilirubin);
• Subject has CrCl of <50 mL/min using Modification of Diet in Renal Disease (MDRD);
• QTc (Bazett) >=450 msec or QTc (Bazett) >=480 msec for subjects with bundle branch block. The QTc is the QT interval corrected for heart rate according to Bazett's formula (QTcB). The QTc should be based on a single QTc value electrocardiogram (ECG) obtained.
• Eligibility of subjects for study participation will be decided by the investigators after taking into consideration various country specific guidelines, and notwithstanding the above mentioned minimum inclusion and exclusion criteria.