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
Condition: Infection, Human Immunodeficiency Virus
MeSH terms: Acquired Immunodeficiency Syndrome; HIV Infections
Intervention: ABC/DTG/3TC FDC; Ongoing cART regimen
Intervention description: Purple, oval, biconvex tablets containing 702 mg Abacavir sulphate which is equivalent to 600 mg ABC, 52.62 mg Dolutegravir sodium which is equivalent to 50 mg Dolutegravir free acid and 300 mg 3TC; Stable cART regimens including boosted PI (or ATV unboosted) + 2 NRTIs; NNRTI + 2 NRTIs, or INI (RAL or EVG)+ 2 NRTIs
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 555.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Abacavir/dolutegravir/lamivudine; Fixed-dose combination; Once daily; Trii; Single-tablet regimen

Summary:

      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).
    

Eligibility criteria:

        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.