Evaluation of the Safety, Tolerability and Pharmacokinetics (PK) of GSK3732394 First-Time-in-Human (FTIH) Study
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: GSK3732394; Placebo
Intervention description: It is composed of an anti-CD4 adnectin, an anti-N17 adnectin, and a peptide inhibitor. This will be provided as a solution for injection in 1 (milliliter) mL glass vials with the unit dose strength of 100 mg/mL; Placebo will comprise of 0.9% weight per volume (w/v) sodium chloride.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In Part 1 of the study each of the subjects in the SAD cohorts (SAD Cohorts 1-5; SAD Cohort 6 is a possible expansion cohort that will be added as needed) will receive a single dose of blinded GSK3732394 or blinded PBO (GSK3732394: PBO = 6:2), per their randomization assignment. Part 2 will consist of up to three ascending repeat-dose cohorts (MAD Cohorts 1, 2, and 3), each with 8 subjects (blinded GSK3732394: blinded PBO = 6:2) will receive four weekly doses of GSK3732394 or PBO on Days 1, 8, 15, and 22.
Masking: Double (Participant, Investigator)
Masking description: This is double-blind (sponsor-unblinded) study with subjects and the site staff blinded, except for an unblinded pharmacist at the site who will prepare the blinded drug product. The blind may be broken if, in the opinion of the investigator, it is in the subject's best interest for the investigator to know the study treatment assignment.
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: DAIDS, FTIH, HIV-1, MAD, SAD

Summary:

      This is a phase 1, 2-part, double-blind (sponsor-unblinded), randomized, placebo-controlled,
      FTIH study, that includes both single-ascending and multiple-ascending dose phase to assess
      the safety, tolerability, and pharmacokinetic (PK)/pharmacodynamic (PD) attributes of
      GSK3732394 in healthy subjects. The data gathered in this study will further enable clinical
      development of GSK3732394 in HIV-infected subjects. Approximately 72 healthy subjects will be
      randomized in the FTIH study. Part 1 will be the single ascending dose (SAD) phase and Part 2
      will be the multiple ascending dose (MAD) phase. Each subject in the SAD cohort will receive
      a single dose of blinded GSK3732394 or blinded placebo (PBO) in 6:2 ratio. Part 1 will
      consist of five ascending single-dose cohorts with an additional expansion cohort included as
      needed. Part 2 will consist of up to three ascending repeat-dose cohorts (MAD Cohorts 1, 2,
      and 3), randomized to four weekly doses of blinded GSK3732394 or blinded PBO in 6:2 ratio to
      be administered on Days 1, 8, 15, and 22.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must be 18 to 50 years of age inclusive, at the time of signing the informed
             consent.

          -  Subjects who are overtly healthy as determined by medical evaluation including medical
             history, physical examination, laboratory tests, and cardiac monitoring.

          -  Subjects who are able to understand and comply with protocol requirements and
             timetables, instructions, and protocol-stated restrictions

          -  Body mass index within the range 19 to 30 kilogram per meter square (kg/m2) inclusive,
             in addition to a weight range of 50kg to 100kg.

          -  Male and female healthy volunteers.

          -  All male subjects must agree to use contraception during the treatment period and for
             at least 100 days after the last dose of study treatment and refrain from donating
             sperm during this period.

          -  A female subject is eligible to participate if she is not pregnant, not breastfeeding,
             and at least one of the following conditions applies; Not a woman of childbearing
             potential (WOCBP), A WOCBP who agrees to follow the contraceptive guidance during the
             treatment period and for at least 28 days prior to first dose, and 40 days after, the
             last dose of study treatment.

          -  Capable of giving signed informed consent.

          -  A signed and dated written informed consent must be completed prior to the subject's
             entry into the study.

        Exclusion Criteria:

          -  Subject has a history or presence of cardiovascular, dermatological, respiratory,
             hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders
             capable of significantly altering the absorption, metabolism, or elimination of drugs;
             constituting a risk when taking the study intervention; or interfering with the
             interpretation of data.

          -  Subject has abnormal blood pressure (as determined by the investigator).

          -  Subject had symptomatic herpes zoster within 3 months prior to screening.

          -  Evidence of active or latent tuberculosis (TB) as documented by medical history and
             examination, TB testing that includes a positive tuberculin skin test [TST]; defined
             as a skin induration greater than 5 millimeter [mm] at 48 to 72 hours,and regardless
             of Bacillus Calmette-Guerin [BCG] or other vaccination history) or a positive (not
             indeterminate) QuantiFERON-TB Gold test.

          -  Subjects with lymphoma, leukemia, or any malignancy within the past 5 years except for
             basal cell or squamous epithelial carcinomas of the skin that have been resected with
             no evidence of metastatic disease for 3 years.

          -  Subjects who had breast cancer within the past 10 years.

          -  Subjects who had history of severe injection site reaction (i.e., required emergency
             care or hospitalization) following any prior injection, including reaction to
             vaccines.

          -  Subjects with history of clinically significant allergy or prior hypersensitivity
             including those with a documented yeast allergy.

          -  Subjects with history of, or current concern for, a chronic immune deficiency disorder
             including, but not limited to: diabetes, sickle cell anemia, and malnutrition.

          -  Subjects having alanine transaminase (ALT) greater than 1.1 x upper limit of normal
             (ULN).

          -  Subjects with Hemoglobin levels below the normal range.

          -  Subjects with Platelet count <130,000 per cubic millimeters.

          -  Subjects with Creatinine clearance (CrCL) <90 milliliters per minute.

          -  Subjects with bilirubin greater than 1.1xULN (isolated bilirubin greater than 1.1xULN
             is acceptable if bilirubin is fractionated and direct bilirubin greater than 35%).

          -  Subjects who has current or chronic history of liver disease, or known hepatic or
             biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic
             gallstones).

          -  Subjects having Fridericia QT correction formula (QTcF) greater than 450 milliseconds
             (msec).

          -  Subjects who had intended use of over-the-counter or prescription medication within 7
             days prior to dosing.

          -  Subjects who had live vaccine(s) within 1 month prior to screening, or plans to
             receive such vaccines during the study.

          -  Subjects who had treatment with biologic agents (such as monoclonal antibodies
             including marketed drugs) within 3 months or 5 half-lives (whichever is longer) prior
             to dosing.

          -  Subjects who had exposure to immune-modulating medications (including corticosteroids)
             within 30-days of Screening.

          -  Subjects whose participation in the study would result in loss of blood or blood
             products in excess of 500 (milliliter) mL within 56 days.

          -  Subjects who had Exposure to more than four new chemical entities within 12 months
             prior to the first dosing day.

          -  Subjects with current enrollment or past participation within the last 30 days before
             signing of consent in this or any other clinical study involving an investigational
             study intervention or any other type of medical research.

          -  Absolute CD4+ T-cell count and CD4 percent (CD4%) outside of the normal range for the
             reference laboratory (to be confirmed at baseline, e.g., Day -1).

          -  Subjects who had presence of Hepatitis B surface antigen (HBsAg) at screening.

          -  Subjects with positive Hepatitis C antibody test result at screening.

          -  Subjects with positive Hepatitis C RNA test result at screening or within 3 months
             prior to first dose of study intervention.

          -  Subjects with positive pre-study drug/alcohol screen.

          -  Subjects with positive human immunodeficiency virus (HIV) antibody test.

          -  Subjects with history of regular alcohol consumption within 6 months of the study
             defined as: an average weekly intake of greater than 14 units. One unit is equivalent
             to 8 grams (g) of alcohol: a half pint (~240 mL) of beer, 1 glass (125 mL) of wine or
             1 (25 mL) measure of spirits.

          -  Subjects with urinary cotinine levels indicative of smoking or history or regular use
             of tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing
             devices) within 6 months prior to screening.

          -  Subjects who has sensitivity to any of the study interventions, or components thereof,
             or drug or other allergy that, in the opinion of the investigator or medical monitor,
             contraindicates participation in the study.