Effect of GSK3640254 on the Pharmacokinetics of a Combination Oral Contraceptive
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: GSK3640254; Portia
Intervention description: GSK3640254 will be available as a 100 mg capsule. Subjects will be administered 200 mg GSK3640254 once daily via the oral route on Days 11 to 21.; Portia will be available in the form of tablets containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 23.0
Sex: Female
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GSK3640254; ethinyl estradiol; levonorgestrel; oral contraceptive; drug-drug interaction

Summary:

      This is an open-label, single-sequence, 1-way drug-drug interaction study to investigate the
      effect of GSK3640254 on the pharmacokinetics of a combination oral contraceptive containing
      ethinyl estradiol (EE) and levonorgestrel (LNG). Effective contraception for women infected
      with human immunodeficiency virus (HIV) is important in the prevention of unplanned
      pregnancies. The study will consist of a screening period of 28 days, check-in (Day -4), a
      run-in period and a treatment period. During the run-in period, subjects will be administered
      Portia® (0.03 milligrams [mg] EE/0.15 mg LNG) once daily on Days -3 to -1. Subjects will then
      be administered Portia once daily on Days 1 to 10 of treatment period A followed by
      administration of Portia once daily along with GSK3640254 200 mg on Days 11 to 21 of
      treatment period B. The duration of the study is approximately 8 weeks, including Screening
      and Run-in. Portia is a registered trademark of Teva Pharmaceuticals USA.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject must be 18 to 50 years of age inclusive, at the time of signing the informed
             consent.

          -  Subjects who are 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 (history and ECG).

          -  Body weight >=45.0 kilograms (kg) (99 pounds [lbs]) and body mass index (BMI) within
             the range 18.5 to 31.0 kilograms per meter square (kg/m^2) (inclusive).

          -  Contraceptive use should be consistent with local regulations regarding the methods of
             contraception for those participating in clinical studies.

          -  Female subjects will be included.

          -  Subject must not be pregnant or breastfeeding.

          -  Subject is a woman of childbearing potential (WOCBP) with intact ovarian function, as
             determined by medical history. Subjects must use Portia for the duration of the run-in
             and treatment periods.

          -  WOCBP must have been on an acceptable form of contraceptive for at least 28 days prior
             to start of study intervention. Acceptable forms of contraception prior to study
             intervention include the following: Intrauterine device or intrauterine system;
             Combined estrogen and progestogen oral contraceptive; Contraceptive vaginal ring;
             Percutaneous contraceptive patches (if used, the patch must be removed during study
             participation); Bilateral tubal occlusion; Male partner sterilization with
             documentation of azoospermia prior to the female subject's entry into the study, and
             this male is the sole partner for that subject. The documentation on male sterility
             can come from the site personnel's review of subject's medical records, medical
             examination and/or semen analysis, or medical history interview provided by her or her
             partner.; Sexual abstinence.

          -  Subjects who have been on a stable regimen of an oral contraceptive for at least 3
             consecutive months must be without evidence of breakthrough bleeding or spotting.

          -  Subjects who have been taking oral contraceptives should continue their current
             regimen until check-in to the clinic for the run-in period. Subjects not currently
             taking an oral contraceptive are eligible, provided all other eligibility criteria are
             met.

          -  Subjects may proceed to the treatment period provided the toxicity profile during the
             run-in period with Portia is acceptable in the opinion of the investigator.

          -  Subjects must agree to use an additional method of contraception from the following
             list of contraceptive methods for the run-in period, treatment period, and for 28 days
             after the last dose of study intervention: Non hormonal Intrauterine device; Bilateral
             tubal occlusion; Male partner sterilization with documentation of azoospermia prior to
             the female subject's entry into the study, and this male is the sole partner for that
             subject. The documentation on male sterility can come from the site personnel's review
             of subject's medical records, medical examination and/or semen analysis, or medical
             history interview provided by her or her partner.; Sexual abstinence. For the 28 days
             after study exit, women may resume oral contraceptives but double barrier methods (a
             combination of male condom with either cervical cap, diaphragm, or sponge with
             spermicide) must be used in addition.

          -  Women of childbearing potential must have a negative highly sensitive serum pregnancy
             test on Day -4 and Day -1.

          -  Additional requirements for pregnancy testing during and after study intervention as
             outlined in protocol.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form and protocol.

        Exclusion Criteria:

          -  History of jaundice associated with taking oral contraceptives or with pregnancy.

          -  History of clinically significant irregular bleeding while taking oral contraceptives.

          -  History of past deep venous thrombosis, pulmonary embolism, stroke, transient ischemic
             attack, phlebitis, or migraine headaches with prolonged aura.

          -  History of cerebrovascular or coronary artery disease.

          -  History of retinal vascular lesions.

          -  History of carcinoma of the breast, endometrium, or other known estrogen-dependent
             neoplasia.

          -  Current or chronic history of liver disease or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  A pre-existing condition interfering with normal gastrointestinal (GI) anatomy or
             motility (e.g., gastroesophageal reflux disease, gastric ulcers, gastritis), hepatic
             and/or renal function, that could interfere with the absorption, metabolism, and/or
             excretion of the study drugs or render the subject unable to take oral study
             intervention.

          -  Any history of significant underlying psychiatric disorder, including, but not limited
             to, schizophrenia, bipolar disorder with or without psychotic symptoms, other
             psychotic disorders, or schizotypal (personality) disorder.

          -  Any history of major depressive disorder with or without suicidal features, or anxiety
             disorders that required medical intervention (pharmacologic or not) such as
             hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient
             treatment. Subjects with other conditions such as adjustment disorder or dysthymia
             that have required shorter term medical therapy (<6 months) without inpatient
             treatment and are currently well-controlled clinically or resolved may be considered
             for entry after discussion and agreement with the ViiV Healthcare/GlaxoSmithKline
             (GSK) Medical Monitor.

          -  Any pre-existing physical or other psychiatric condition (including alcohol or drug
             abuse), which, in the opinion of the investigator (with or without psychiatric
             evaluation), could interfere with the subject's ability to comply with the dosing
             schedule and protocol evaluations or which might compromise the safety of the subject.

          -  Medical history of cardiac arrhythmias, prior myocardial infarction in the past 3
             months, or cardiac disease or a family or personal history of long QT syndrome.

          -  Presence of hepatitis B surface antigen at Screening or within 3 months prior to
             starting study intervention.

          -  Positive hepatitis C antibody test result at Screening or within 3 months prior to
             starting study intervention AND positive on reflex to hepatitis C ribonucleic acid
             (RNA).

          -  Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.

          -  ALT >1.5 times upper limit of normal (ULN). A single repeat of ALT is allowed within a
             single screening period to determine eligibility.

          -  Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin
             is fractionated and direct bilirubin <35%).

          -  Any acute laboratory abnormality at Screening which, in the opinion of the
             investigator, should preclude participation in the study of an investigational
             compound.

          -  Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of creatine
             phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides,
             etc), and ALT (described above), will exclude a subject from the study unless the
             investigator can provide a compelling explanation for the laboratory result(s) and has
             the assent of the sponsor. A single repeat of any laboratory abnormality is allowed
             within a single screening period to determine eligibility.

          -  A positive test result for drugs of abuse (including marijuana), alcohol, or cotinine
             (indicating active current smoking) at Screening or before the first dose of study
             intervention.

          -  Unable to refrain from the use of prescription or nonprescription 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 intervention and for the duration of the
             study (acetaminophen/paracetamol at doses of <=2 grams/day and hydrocortisone cream 1%
             are permitted for use any time during the study).

          -  Treatment with any vaccine within 30 days prior to receiving study intervention.

          -  Unwillingness to abstain from excessive consumption of any food or drink containing
             grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos or their
             fruit juices within 7 days prior to the first dose of study intervention(s) until the
             end of the study.

          -  Participation in another concurrent clinical study or prior clinical study (with the
             exception of imaging trials) 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).

          -  Where participation in the study would result in donation of blood or blood products
             in excess of 500 milliliters (mL) within 56 days.

          -  Any positive (abnormal) response confirmed by the investigator on a screening
             clinician- or qualified designee-administered Columbia Suicide Severity Rating Scale
             (C-SSRS).

          -  Any significant arrhythmia or ECG finding (e.g., symptomatic bradycardia,
             non-sustained or sustained atrial arrhythmias, non-sustained or sustained ventricular
             tachycardia, second-degree atrioventricular block Mobitz Type II, or third-degree
             atrioventricular block) which, in the opinion of the investigator or ViiV
             Healthcare/GSK Medical Monitor, will interfere with the safety for the individual
             subject.

          -  Exclusion criteria for screening ECG (a single repeat is allowed for eligibility
             determination): heart rate-<50 or >100 beats per minute and QTcF->450 milliseconds.

          -  History of regular alcohol consumption within 6 months of the study defined as: an
             average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a
             half-pint (equivalent to 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL)
             measure of spirits.

          -  Unable to refrain from tobacco- or nicotine-containing within 3 months prior to
             Screening.

          -  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.