First Time in Human (FTIH) Safety and Pharmacokinetics (PK) Study of GSK3036656 in Healthy Subjects
Condition: Tuberculosis
MeSH terms: Tuberculosis
Intervention: GSK3036656; Placebo
Intervention description: GSK3036656 is available as capsules (for oral administration) containing 5 mg, 25 mg or 100 mg of GSK3036656 as free base equivalent.; Placebo is a matching capsule containing Avicel PH (Suitable for Pharmaceutical Use) 102, for oral administration.
Intervention MeSH terms: GSK656
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Enrollment: 30.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: ascending dose; Pharmacokinetics; GSK3036656; FTIH; Safety

Summary:

      GSK3036656 is being developed by GSK for the treatment of tuberculosis (TB). This is the FTIH
      study for GSK3036656 to evaluate the safety, tolerability and PK of single ascending and
      repeat oral doses of GSK3036656 in healthy adult subjects. The results of this study are
      intended to be used to identify appropriate and well-tolerated doses of GSK3036656 to be used
      in further studies. A food effect assessment will also be undertaken to investigate the
      influence of food on the PK of GSK3036656. The study will be conducted in two parts: Part A
      (single dose) and Part B (repeat dose). Up to two cohorts will be included in Part A. 9
      healthy adult subjects will be included in each cohort. Each cohort will participate in up to
      4 treatment (dosing) periods including a food effect treatment period. During each treatment
      period, GSK3036656 will be administered to 6 subjects and placebo will be administered to 3
      subjects. The starting dose in Part A will be 5 milligrams (mg), and the maximum dose will be
      1500 mg. The two cohorts in Part A will be dosed sequentially (i.e., dosing in Cohort 2
      starts after dosing in Cohort 1 is completed). Initially, there will be a 14 day wash out
      period for individual subjects between each dose level. Study progression to Part B from Part
      A will be based on an acceptable safety, tolerability and PK profile in Part A. Part B will
      comprise up to 4 cohorts (Cohorts 3, 4, 5, and 6) each containing 10 (8 active: 2 placebo)
      healthy adult subjects to examine the safety, tolerability and PK of a repeated daily dose of
      GSK3036656 over a period of up to 14 days. Appropriate doses and dose regimens for Part B
      will be selected based on available safety, tolerability and PK data from Part A and/or any
      preceding repeat dose cohorts from Part B. Dividing the total daily dose into 2 or 3 smaller
      doses may be done in both Part A and Part B. Up to 18 subjects will be enrolled into Part A
      and up to 40 subjects will be enrolled into Part B. The total duration of the study for each
      subject recruited into Part A and Part B will be approximately 12 weeks and 8 weeks,
      respectively.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Between 18 and 55 years of age inclusive, at the time of signing the informed consent.

          -  Healthy as determined by the investigator or medically qualified designee based on a
             medical evaluation including medical history, physical examination, laboratory tests
             and cardiac monitoring.

          -  A subject with a clinical abnormality or laboratory parameter(s) which is/are not
             specifically listed in the inclusion or exclusion criteria, outside the reference
             range for the population being studied, may be included only if the investigator in
             consultation with the medical monitor, if required, agree and document that the
             finding is unlikely to introduce additional risk factors and will not interfere with
             the study procedures.

          -  Body weight >=60 kilograms (kg) and body mass index (BMI) within the range 19 to 29.9
             kg/meter^2 inclusive.

          -  Male

          -  Female subjects of non-child bearing potential are eligible to participate. Non-child
             bearing potential is 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 or documented bilateral salpingectomy; hysterectomy;
                  documented bilateral oophorectomy.

               -  Postmenopausal defined as 12 months of spontaneous amenorrhea. Post-menopausal
                  status will be confirmed by a simultaneous follicle stimulating hormone (FSH) and
                  estradiol levels test.

          -  Male subjects with female partners of child bearing potential must comply with the
             following contraception requirements from the time of first dose of study medication
             until 90 days after the last dose of study treatment (i.e. one sperm cycle).

               -  Vasectomy with documentation of azoospermia.

               -  Male condom plus partner use of one of the contraceptive options as follows:
                  contraceptive subdermal implant; intrauterine device or intrauterine system;
                  highly effective oral contraceptive, either combined or progestogen alone
                  (provided it is associated with inhibition of ovulation); injectable progestogen;
                  contraceptive vaginal ring; percutaneous contraceptive patches.

          -  These allowed methods of contraception are only effective when used consistently,
             correctly and in accordance with the product label. The investigator is responsible
             for ensuring that subjects understand how to properly use these methods of
             contraception.

          -  The subject is able to understand and comply with protocol requirements, instructions
             and protocol-stated restrictions.

        Exclusion criteria:

          -  Alanine aminotransferase (ALT) and bilirubin >1.5 times of upper limit of normal (ULN)
             (isolated bilirubin >1.5 times of ULN may be acceptable, after consultation with the
             GlaxoSmithKline (GSK) medical monitor, if bilirubin is fractionated and direct
             bilirubin <35 percent)

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  QTcF >450 milliseconds.

          -  Presence of moderate or severe valve disorder or any other clinically significant
             abnormality.

          -  Subjects with a history of photosensitivity.

          -  Females of non-childbearing potential who are susceptible to heavy periods or vaginal
             bleeding or spotting.

          -  Pregnant females. A human chorionic gonadotrophin (hCG) test will be performed on Day
             -1 of each treatment (dosing) period in Part A and Part B for women for whom
             post-menopausal status has not been confirmed by FSH/estradiol testing. No pregnancy
             tests will be required for female subjects confirmed as post-menopausal by
             FSH/estradiol testing.

          -  Lactating females.

          -  Use of prescription or non-prescription drugs, including high-dose vitamins, herbal
             and dietary supplements (including Saint John's Wort) within 7 days (or 14 days if the
             drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the
             first dose of study medication, unless in the opinion of the investigator and sponsor,
             the medication will not interfere with the study procedures or compromise subject
             safety. Paracetamol for mild analgesia will be permitted.

          -  Breath carbon monoxide test indicative of smoking or history of current use of
             tobacco- or nicotine-containing products.

          -  Current regular alcohol consumption defined as an average weekly intake of >21 units
             for males or >14 units for females. One unit is equivalent to 8 grams (g) of alcohol:
             a half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 ml) of wine or 1
             (25 ml) measure of spirits.

          -  Subjects must not sunbathe or use a tanning device whilst taking the study medication
             and until at least 2 weeks after their last dose. Subjects are to be advised that they
             should wear protective clothing (e.g. sun hat, long sleeves) and use a broad spectrum
             ultraviolet A/ ultraviolet B sunscreen (sun protection factor >=30) when outdoors.

          -  History of sensitivity to heparin or heparin-induced thrombocytopenia.

          -  History of sensitivity to any of the study medications, or components thereof or a
             history of drug or other allergy that, in the opinion of the investigator or medical
             monitor, contraindicates their participation.

          -  Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study treatment.

          -  A positive test for human immunodeficiency virus (HIV) antibody.

          -  A positive pre-study drug/alcohol screen.

          -  The subject has participated in a clinical trial and has received an investigational
             product within the following time period prior to the first dosing day in the current
             study: 3 months, 5 half-lives or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Exposure to more than four new chemical entities within 12 months prior to the first
             dosing day.