Pharmacokinetic Study of Cabotegravir Long-acting in Healthy Adult Volunteers
Condition: Infection, Human Immunodeficiency Virus; HIV Infections
MeSH terms: Infections; Communicable Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
Intervention: Cabotegravir tablet 30 mg once daily for 28 days.; Cabotegravir injection 3 mL (200 mg/mL) IM given once on Day 1.
Intervention description: GSK1265744B, lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate, Aquarius film-coating, white BP18237; Cabotegravir will be supplied as sterile suspension for injection 200 mg/mL vial. Each vial appears as sterile white to slightly colored suspension containing 200 mg/mL of CAB for administration by intramuscular (intragluteal) injection and will be administered as 1 × 3 mL Injections (3 mL [600 mg] total) IM given once on Day 1 of injection phase
Intervention MeSH terms: Cabotegravir
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 19.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Cabotegravir; Pharmacokinetic; Healthy Adult Volunteers; GSK1265744

Summary:

      Cabotegravir (CAB) long-acting (LA) is a promising candidate for human immunodeficiency virus
      (HIV) pre exposure prophylaxis (PrEP) due to its potent antiretroviral activity and
      infrequent dosing requirements. Currently, the CAB concentrations achieved in the anatomical
      sites associated with sexual HIV transmission following the proposed 600 milligram (mg)
      intramuscular (IM) PrEP dose are unknown. These data will enhance our understanding of CAB
      distribution to the anatomical mucosal tissue believed to be relevant to sexual HIV-1
      transmission and supplement the data to support future PrEP clinical trial development. The
      primary objective is to determine the PK concentrations of CAB following LA administration in
      plasma and in vaginal tissue (VT), cervical tissue (CT), and cervicovaginal fluid (CVF) in
      healthy women and in rectal tissue (RT) and rectal fluid (RF) in healthy men and women
      following a single 600 mg IM dose. This will be a Phase 1, open label study in healthy
      subjects to assess the pharmacokinetics of CAB LA in the plasma and mucosal locations
      associated with sexual HIV-1 transmission: VT, CT, CVF, RT and RF. The study will consist of
      a screening period, a 28-day oral lead-in phase at a dose of 30 mg per day followed by a
      14-42 day washout period, and a single dose of CAB LA 600 mg as an IM (intragluteal)
      injection with compartmental pharmacokinetic (PK) sampling for up to 12 weeks. Subjects will
      return for safety assessments and plasma PK sampling at Week 24 and Week 36 post-injection
      and undergo a follow-up/withdrawal visit at Week 52 post-injection.
    

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 agree and document that the finding is unlikely
             to introduce additional risk factors and will not interfere with the study procedures.
             A single repeat of a procedure or lab parameter is allowed to determine eligibility.

          -  Body weight >= 40 kilogram (kg) and body mass index (BMI) within the range 18.5 to 35
             kg /meter square (inclusive).

          -  Male or female

          -  A female subject is eligible to participate if she is pre-menopausal, has an intact
             uterus and cervix, AND is not pregnant (as confirmed by a negative human chorionic
             gonadotrophin [hCG] test), not lactating, and at least one of the following conditions
             applies: a) Non-reproductive potential 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, Documented
             Bilateral Oophorectomy. b)Reproductive potential and agrees to follow one of the
             options listed below in the GlaxoSmithKline (GSK) Modified List of Highly Effective
             Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements
             from 30 days prior to the first dose of study medication and until at least five
             terminal half-lives OR until any continuing pharmacologic effect has ended, whichever
             is longer (can be up to 66 weeks on study) after the last dose of study medication and
             completion of the follow-up visit. Female subjects desiring pregnancy or foresee that
             they might wish to become pregnant within 52 weeks of receiving a CAB LA injection
             must be excluded. All subjects participating in the study must be counseled on safe
             sexual practices including the use of effective barrier methods to minimize risk of
             HIV transmission.

          -  Capable of giving signed informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form and in this protocol.

        Exclusion Criteria:

          -  Liver Function: ALT or AST > upper limit of normal (ULN)

          -  Total bilirubin >ULN (isolated total bilirubin >ULN is acceptable if total bilirubin
             is fractionated and direct bilirubin <35%)

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Corrected QT (QTc) Interval: QTc > 450 milliseconds (msec):

        NOTES: The QTc is the QT interval corrected for heart rate according to Bazette's formula
        (QTcB), machine-read or manually over-read. QTcB will be used to determine eligibility for
        an individual subject. Exclusion criteria for screening electrocardiogram (ECG) (a single
        repeat is allowed for eligibility determination): Heart rate (<45 and >100 beats per minute
        (bpm) for males and <50 and >100 bpm for females; QRS duration: >120 msec; QTc interval:
        >450 msec for males and females

          -  The subject's systolic blood pressure is outside the range of 90-140 millimeter (mm)
             mercury (Hg), or diastolic blood pressure is outside the range of 45-90 mmHg.

          -  History of clinically significant cardiovascular disease including:

        Evidence of previous myocardial infarction (pathologic Q waves, S-T segment changes (except
        early repolarization); History/evidence of symptomatic arrhythmia, angina/ischemia,
        coronary artery bypass grafting (CABG) surgery or percutaneous transluminal coronary
        angioplasty (PCTA) or any clinically significant cardiac disease; Any conduction
        abnormality (including but not specific to left or right complete bundle branch block, AV
        block (2nd degree [type II] or higher), Wolf Parkinson White [WPW] syndrome); Sinus pauses
        > 3 seconds.

          -  Any significant arrhythmia which, in the opinion of the principal Investigator and GSK
             Medical Monitor, will interfere with the safety for the individual subject.
             Non-sustained (>=3 consecutive ventricular ectopic beats) or sustained ventricular
             tachycardia.

          -  History of ongoing or clinically relevant seizure disorder within the previous 2
             years, including subjects who have required treatment for seizures within this time
             period. A prior history of seizure, with a seizure free period of at least 2 years,
             off anti-epileptics, may be considered for enrolment if the investigator believes the
             risk of seizure recurrence is low. All cases of prior seizure history should be
             discussed with the medical monitor prior to enrolment

          -  Use of any concurrent prohibited medications as outlined in protocol

          -  History of regular alcohol consumption within 6 months of the study defined as: An
             average weekly intake of >14 drinks for males or >7 drinks for females. One drink is
             equivalent to 12 gram (g) of alcohol: 12 ounces (360 milliliter [mL]) of beer, 5
             ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

          -  Inability or unwillingness to comply with lifestyle and/or dietary restrictions
             outlined in protocol.

          -  High-risk behavior for HIV infection which includes, but is not limited to, one of the
             following risk factors within six months before entering the study (Day 1 of the oral
             lead-in): Unprotected vaginal or anal sex with a known HIV infected person or a casual
             partner, engaged in sex work for money or drugs, acquired a sexually transmitted
             disease, high risk partner currently or in the previous six months or intravenous drug
             use.

          -  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.

          -  For subjects participating in magnetic resonance imaging (MRI) imaging:
             Contraindication for MRI scanning (as assessed by local MRI safety questionnaire),
             which includes but is not limited to: a) Intracranial aneurysm clips (except Sugita)
             or other non-MRI compatible metallic objects; b) Intra- orbital metal fragments that
             have not been removed by a medical professional; c) Pacemakers or other implanted
             cardiac rhythm management devices and non-MRI compatible heart valves, d) Inner ear
             implants, e) History of claustrophobia

          -  Positive hepatitis B surface antigen or positive hepatitis B core antibody with
             negative hepatitis B surface antibody test result at screening or within 3 months
             prior to first dose of study treatment.

          -  Positive hepatitis C antibody test result at screening or within 3 months prior to
             first dose of study treatment

          -  A positive pre-study drug/alcohol screen. A positive drug screen is permitted if due
             to a prescribed medication, provided that medication is not on the list of prohibited
             medications and approved by the investigator and medical monitor.

          -  A positive test for HIV antibody.

          -  A positive pre-study screen for sexually transmitted diseases including Neisseria
             gonorrhea or Chlamydia trachomatis, Trichomonas, syphilis, or an active Herpes simplex
             virus (HSV) genital lesion.

          -  Presence of a tattoo or other dermatological condition overlying the buttocks which in
             the opinion of the investigator may interfere with the interpretation of injection
             site reactions.

          -  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.

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 mL within a 56 day period.

          -  Unwillingness or inability to follow the procedures outlined in the protocol.

          -  Subject is mentally or legally incapacitated.

        Additional Criteria for Female Subjects Only:

          -  Any current medical conditions that in the opinion of the investigator may compromise
             the conduct or analysis of the genital tract sampling (e.g., active genital tract
             infection or lesions).

          -  Inability to abstain from the use of intravaginal products (e.g. tampons, spermicides,
             lubricants, vaginal hygiene products, diaphragms) for 72 hours prior to the genital
             tract sample collection visits and for up to 72 hours after.

          -  Inability to abstain from any sexual activity (e.g., vaginal intercourse,
             masturbation, and penetration of the vagina by penises, fingers, tampons, sex toys)
             for 72 hours prior to the genital tract sample collection visits and for up to 72
             hours after.

        Additional Criteria for Male Subjects and Female Subjects who consent to rectal PK
        sampling:

          -  Any current medical conditions that in the opinion of the investigator may compromise
             the conduct or analysis of the rectal compartment sampling (e.g., active rectal
             compartment infection, lesions or disease).

          -  Inability to abstain from the use of intrarectal products (e.g., suppositories,
             lubricants) for 72 hours prior to the rectal compartment sample collection visits and
             for up to 72 hours after.

          -  Inability to abstain from any receptive anal sexual activity (e.g., anal receptive
             intercourse and penetration of the rectum by fingers, sex toys or other) for 72 hours
             prior to the rectal compartment sample collection visit and for up to 72 hours after.