A Two-part Study to Compare a Tablet and Capsule Formulation of GSK2838232 With and Without Food, and to Assess the Safety and Drug Levels of Repeated Once-daily Doses of GSK2838232 Without Ritonavir
Condition: Infection, Human Immunodeficiency Virus; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
Intervention: GSK2838232 100 mg tablet; GSK2838232 50 mg capsule; Ritonavir 100 mg tablets; Placebo for GSK2838232 tablets
Intervention description: It is a white to slightly colored tablet. It will be supplied as prefilled tablets in bulk for dispensing to subjects at the site according to the treatment code.; It is a pink unmarked capsule. It will be supplied as prefilled capsules in bulk for dispensing to subjects at the site according to the treatment code.; It is a white film-coated ovaloid tablets.; It is a white to slightly colored tablet. The placebo tablets supplied will not be identical to GSK2838232 tablets. It will be administered by site staff via an opaque card or paper tube.
Intervention MeSH terms: Ritonavir; GSK-2838232
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: The randomization number will determine the allocation of treatment sequences (ABC or BAC) for Part 1, and of treatment (GSK2838232 without RTV or placebo) for Part 2. Allocation to treatment for Part 1A or Part 1B (with Part 2 being fixed) will be according to a predetermined random order.
Masking: Double (Participant, Investigator)
Masking description: Part 1 of the study will be open label and thus not be blinded. Part 2 of the study will be single blinded because of the unavailability of matching placebo tablets. The Principal Investigator and the subject will be completely blinded to specific treatment assignment.
Enrollment: 26.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GSK2838232; safety; food effect; capsule; healthy; PK; tablet

Summary:

      This study will be conducted in two Parts to confirm the acceptability/selection of a tablet
      formulation for future clinical development of GSK2838232. Part 1 of the study will assess
      single ritonavir (RTV)-boosted doses of a new tablet formulation given with food (containing
      approximately 30% fat) against the reference capsule formulation also given with food and
      then will assess the impact of fasted conditions on the tablet performance. In Part 2,
      non-boosted GSK2838232 will be given as once-daily tablet doses for 11 days in a separate
      group of subjects, assuming the tablet performance is considered acceptable from Part 1.
      Approximately 16 healthy subjects will be enrolled to provide at least 12 evaluable subjects
      through the three study periods in Part 1. 10 healthy subjects will be enrolled to provide at
      least 8 evaluable subjects through the single study period in Part 2. The maximum duration of
      study participation will be approximately 9 to 10 weeks for Part 1; and 8 to 9 weeks for Part
      2.
    

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, and 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.

          -  A creatinine clearance (CLcr) > 80 milliliter per minute (mL/min) as determined by
             Cockcroft-Gault equation: CLcr = (140 minus age) multiplied by weight divided by (72
             multiplied by serum creatinine) (times 0.85 if female) where age is in years, weight
             in kilogram (kg), and serum creatinine is in units of milligram per deciliter (mg/dL).

          -  Body weight >=50.0 kg (110 pounds [lbs.]) for men and >=45.0 kg (99 lbs) for women and
             body mass index (BMI) within the range 18.5 to 31.0 kg/meter (m)^2 (inclusive).

          -  Males or females.

          -  A female subject is eligible to participate if she is not pregnant (as confirmed by a
             negative serum human chorionic gonadotrophin [hCG] test), not lactating, and of
             non-reproductive potential which is defined as:

        Reproductive potential:

        There is no definitive drug-drug interaction (DDI) information with GSK2838232 and an
        interaction with oral contraceptives is possible, so other (barrier, inter-uterine device
        etc.) methods of contraception will be required. Females of reproductive potential may only
        be enrolled if they are using two forms of complementary contraception, which must include
        at least one barrier method. They will be counseled on safer sex practices. Fertile
        females, who have an established, long-term lifestyle of sexual abstinence, or only same
        sex partners, require no other means of birth control.

        Non-reproductive potential:

          -  Pre-menopausal females with one of the following: Documented tubal ligation;
             documented hysteroscopic tubal occlusion procedure with follow-up confirmation of
             bilateral tubal occlusion; hysterectomy; documented Bilateral Oophorectomy.

          -  Postmenopausal defined as 12 months of spontaneous amenorrhea in questionable cases a
             blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels
             consistent with menopause. Females on hormone replacement therapy (HRT) must
             discontinue HRT to allow confirmation of post-menopausal status prior to study
             enrolment.

               -  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 one week after the last dose of study medication.

          -  Vasectomy with documentation of azoospermia.

          -  Male condom plus partner use of one of the contraceptive options below: Contraceptive
             subdermal implant with a <1 percent rate of failure per year; intrauterine device or
             intrauterine system with a <1 percent rate of failure per year; oral contraceptive,
             either combined or progestogen alone or injectable progestogen; contraceptive vaginal
             ring; percutaneous contraceptive patches.

               -  Capable of giving signed informed consent.

        Exclusion Criteria:

          -  ALT >1.5 times upper limit of normal (ULN)

          -  Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin
             is fractionated and direct bilirubin <35 percent).

          -  Current or chronic history of liver disease, or known hepatic or biliary
             abnormalities.

          -  Subjects who have asthma or a history of asthma.

          -  Medical history of cardiac arrhythmias or cardiac disease or a family or personal
             history of long QT syndrome.

          -  Unable to refrain from the use of prescription or non-prescription drugs, including
             vitamins, herbal and dietary supplements (including St 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 GlaxoSmithKline medical monitor, the medication will not interfere
             with the study procedures or compromise participant safety.

          -  History of regular alcohol consumption (within 6 months prior to screening or unable
             to refrain from alcohol use from 5 days prior to admission through the last blood
             sample collected) defined as:

             • For United States sites: an average weekly intake of >14 drinks for males or >7
             drinks for females. One drink is equivalent to 12 gram of alcohol: 12 ounces (360 mL)
             of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled
             spirits.

          -  Regular use of tobacco- or nicotine- containing products within 6 months prior to
             screening. Unable to refrain from smoking from the Screening Visit through the last
             blood sample collected. As confirmed by a urine cotinine test.

          -  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), or positive hepatitis C virus (HCV)
             test result at screening or within 3 months prior to first dose of study treatment.

          -  Screening or Baseline cardiac troponin I greater than the 99 percent cutoff (>0.045
             nanogram [ng]/mL by the Dimension Vista cTnI assay) for a given assay.

          -  A positive pre-study drug/alcohol screen.

          -  A positive test for human immunodeficiency virus (HIV) antibody.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within 56 days.

          -  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: 30 days, 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.

          -  Exclusion Criteria for 24-hour Screening Holter:

               -  Any symptomatic arrhythmia (except isolated extra systoles).

               -  Sustained cardiac arrhythmias (such as atrial fibrillation or flutter,
                  supraventricular tachycardia (>= 10 consecutive beats), complete heart block).

               -  Non-sustained or sustained ventricular tachycardia (defined as >=3 consecutive
                  ventricular ectopic beats).

               -  Any conduction abnormality (including but not specific to left or right
                  incomplete or complete bundle branch block, atrioventricular (AV) block [2nd
                  degree or higher], Wolff Parkinson White (WPW) syndrome etc.).

               -  Sinus Pauses >3 seconds.

               -  300 or more supraventricular ectopic beats in 24 hours.

               -  250 or more ventricular ectopic beats in 24 hours.

          -  Any clinically significant abnormal echocardiogram finding.

          -  Exclusion criteria for screening ECG (a single repeat is allowed for eligibility
             determination):

               -  Heart rate <45 or >100 beats per minute (bpm) for males; <50 or >100 bpm for
                  females

               -  PR interval <120 or >220 milliseconds (msec)

               -  QRS duration <70 or >120 msec

               -  QTc interval (Fridericia's) >450 msec

               -  Evidence of previous myocardial infarction (does not include ST segment changes
                  associated with re-polarization).

               -  Any conduction abnormality (including but not specific to left or right complete
                  bundle branch block, AV block [2nd degree or higher], WPW syndrome).

               -  Sinus Pauses >3 seconds.

               -  Any significant arrhythmia which, in the opinion of the Investigator or GSK
                  medical monitor, will interfere with the safety for the individual subject.

               -  Non-sustained or sustained ventricular tachycardia (>=3 consecutive ventricular
                  ectopic beats).