Open-label Study of Dolutegravir (DTG) or Efavirenz (EFV) for Human Immunodeficiency Virus (HIV) - Tuberculosis (TB) Co-infection
Condition: Infection, Human Immunodeficiency Virus; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Tuberculosis; Acquired Immunodeficiency Syndrome; Coinfection; Immunologic Deficiency Syndromes
Intervention: DTG 50 mg; EFV 600 mg
Intervention description: DTG is available as 50 mg film-coated tablet. DTG may be administered with or without food; EFV is supplied as film-coated capsule-shaped oral tablet containing 600 mg of EFV and must be administered without food
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 113.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: integrase inhibitor; Mycobacterium tuberculosis; rifampicin-sensitive; dolutegravir; antiretroviral therapy-naïve; HIV-1 infection; efavirenz; co-infection

Summary:

      HIV/Tuberculosis (TB) co-infection have profound effects on the host's immune system. TB is
      the most common cause of death in patients with HIV worldwide. Rifamycins (such as rifampicin
      [RIF]) are an important component of TB therapy because of their unique activity. The problem
      is that most protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors
      (NNRTI) used to treat HIV have significant drug-drug interactions with RIF that can lead to
      reduced concentrations of these agents with risk of treatment failure or resistance. The
      non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV) does not present the
      same significant drug interactions with RIF. EFV-based HIV treatment was tested in patients
      concomitantly treated with RIF-containing TB therapy, demonstrating that their
      co-administration can be used safely and effectively. However, the side effect profile of EFV
      overlaps with the RIF-containing TB regimens and makes the management of treatment toxicities
      very complex. Integrase inhibitors (INI), such as dolutegravir (DTG), may offer an important
      alternative to EFV-based therapy in TB coinfected patients. A Phase I drug-drug interaction
      study was conducted in healthy, HIV-seronegative subjects, and showed that DTG at 50 mg twice
      daily given together with RIF was well-tolerated and resulted in DTG concentrations similar
      to those of DTG 50 mg given once daily alone, which is the recommended dose for INI-naive
      patients. Therefore, ART regimens using DTG 50 mg twice daily may represent a new treatment
      option for TB-infected patients who require concurrent treatment for HIV infection. This is a
      Phase III b, randomized, open-label study describing the efficacy and safety of DTG and
      EFV-containing ART regimens in HIV/TB co-infected patients. This study is designed to assess
      the antiviral activity of DTG or efavirenz (EFV) ART-containing regimens through 48 weeks. A
      total of approximately 115 +/-5% subjects will be randomly assigned in a 3:2 ratio to DTG
      (approximately 69 subjects) and EFV (approximately 46 subjects), respectively. This study
      will include a Screening Period, a Randomized Phase (Day 1 to 48 weeks plus a 4-week
      extension), and a DTG Open-label extension (OLE). During the DTG OLE, subjects will be
      supplied with DTG until it is locally approved and commercially available, the subject no
      longer derives clinical benefit, or the subject meets a protocol-defined reason for
      discontinuation, which ever comes first.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject or the subject's legal representative is willing and able to understand and
             provide signed and dated written informed consent prior to Screening

          -  Adult subject (at least 18 years of age) with plasma HIV-1 RNA>=1000 copies/
             milliliter (mL) at Screening

          -  CD4+ cell count is >= 50 cells/ cubic millimetre (mm^3) at Screening

          -  HIV-1-infected, ART-naïve; (<=10 days of prior therapy with any antiretroviral drug
             following a diagnosis of HIV-1 infection)

          -  A female subject may be eligible to enter and participate in the study if she: is of
             non-childbearing potential defined as either postmenopausal (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, 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 IP,
             throughout the study, and for at least 2 weeks after discontinuation of all study
             medications

          -  Double-barrier method (male condom/spermicide, male condom/diaphragm,
             diaphragm/spermicide)

          -  Approved hormonal contraception plus a barrier method while receiving Rifampicin
             (RIF)-containing TB treatment for subjects randomly assigned to the DTG arm or
             approved hormonal contraception plus a barrier method for subjects randomly assigned
             to the EFV arm (regardless of RIF-containing TB treatment)

          -  Any intrauterine device 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

          -  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 counseled on safer sexual practices
             including the use of effective barrier methods

          -  New diagnosis of pulmonary, pleural, or Lymph node (LN) TB based on identification of
             Mycobacterium tuberculosis using culture methods or validated nucleic acid
             amplification test on sputum or on samples collected by needle aspirate of pleural
             fluid or an affected LN

          -  RIF sensitivity of Mycobacterium tuberculosis either by culture or validated nucleic
             acid amplification test

          -  RIF-containing first-line TB treatment or an alternate RIF-containing TB treatment
             started up to a maximum of 8 weeks before randomization and no later than the
             screening date

          -  Karnofsky score >=70% before randomization

        Exclusion Criteria:

          -  Any previous TB treatment (not including treatment for latent disease)

          -  Evidence of RIF resistance of Mycobacterium tuberculosis either by culture or
             validated nucleic acid amplification test

          -  Expected requirement for TB treatment >9 months

          -  Concomitant disorders or conditions for which isoniazid, RIF, pyrazinamide, or
             ethambutol are contraindicated

          -  Central nervous system, miliary, or pericardial TB

          -  Women who are pregnant or breastfeeding

          -  Any evidence of an active Acquired immunodeficiency syndrome (AIDS)-defining disease
             (Centers for Disease Control and Prevention, Category C). Exceptions include TB,
             cutaneous Kaposi's sarcoma not requiring systemic therapy, and historic CD4+ cell
             counts of <200 cells/mm^3

          -  Subjects with moderate to severe hepatic impairment (Class B or C) as determined by
             Child-Pugh classification unstable liver disease (as defined by the presence of
             ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices,
             or persistent jaundice), cirrhosis, or known biliary abnormalities (with the exception
             of Gilbert's syndrome or asymptomatic gallstones)

          -  Subjects positive for hepatitis B surface antigen (HBsAg) at screening

          -  Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase of
             the study

          -  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,
             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

          -  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
             response

          -  Treatment with any agent, other than licensed ART as allowed above with documented
             activity against HIV-1 in vitro/vivo within 28 days of first dose of IP

          -  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 IP

          -  Any evidence of primary viral resistance to Nucleoside reverse transcriptase inhibitor
             (NRTIs), Non-nucleoside reverse transcriptase inhibitor (NNRTIs), or Protease
             inhibitor (PIs) based on the presence of any major resistance-associated mutation
             (according to the International AIDS Society Update of the Drug Resistant Mutations in
             HIV-1 ) in the Screening result or, if known, any historical resistance test result.
             Note: Retests of Screening genotypes are not allowed

          -  Any verified Grade 4 laboratory abnormality

          -  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 >=2 × upper limit of normal

          -  Hemoglobin <=7.4 grams per deciliter;

          -  Platelet count <50000/mm^3