Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Investigation of GSK3335065 Intravenous (IV) Infusion in Healthy Adults
Condition: Pancreatitis, Acute Necrotizing
MeSH terms: Pancreatitis; Pancreatitis, Acute Necrotizing
Intervention: GSK3335065; Placebo
Intervention description: GSK3335065 is being developed as a treatment for acute pancreatitis with the intent of reducing 3-hydroxykynurenine (3HK) levels to the normal range (or lower) and maintaining them at this level. GSK3335065 is a solution and will be administered as intravenous injection and infusion with dose strength of 5 milligram (mg)/mL that may be diluted in 0.9% weight by volume (w/v) sodium chloride.; Placebo solution to match GSK3335065 will be given as intravenous injection and infusion.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: Double (Participant, Investigator)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: 3-hydroxykynurenine; Acute pancreatitis; Dose-escalation; Healthy subjects; GSK3335065

Summary:

      GSK3335065 is being developed as a treatment for acute pancreatitis with the intent of
      reducing 3-hydroxykynurenine (3HK) levels to the normal range (or lower) and maintaining them
      at this level throughout the treatment period. This study will utilize an adaptive design and
      is divided into 3 parts. Part A will consist of 8 cohorts (1-8) and is Single Ascending Dose
      (SAD) of GSK3335065 by IV bolus in males. Part B will be initiated after completion of dosing
      in Part A. It will involve ascending IV bolus doses of GSK3335065 followed by IV constant
      infusion for 7 days in males and will consist of four cohorts (9-12). Part C consists of a
      single dose of GSK3335065 by IV bolus (cohort 13), and a single dose followed by continuous
      infusion over 7 days (cohort 14) in females of non-child bearing potential (WONCBP). Total 64
      subjects will be evaluated in the study of which Part A will include 16 healthy male
      subjects, Part B will include 32 healthy male subjects and Part C will include 16 WONCBP. In
      Part A, cohorts 1 and 2 will last up to 19 weeks and cohorts 3 to 8 will last up to 7 weeks
      and Part B will last up to 13 weeks. In Part C cohort 7 will last up to 7 weeks and cohort 8
      will last for 13 weeks.
    

Eligibility criteria:

        Inclusion Criteria

          -  Subjects must be 18 to 50 years of age inclusive, at the time of signing the informed
             consent. In Part C (WONCBP) subjects must be between 18 and 60 years of age.

          -  Subjects who are overtly healthy as determined by 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 greater than 50 kilogram (kg) and body mass index (BMI) within the range
             18.5 - 32 kilogram per meter square (kg/m^2).

          -  Length of time required for abstinence or use of contraceptives should take into
             account the reproductive toxicity profile including genotoxicity and teratogenicity,
             the size of the molecule, and the number of doses. Male subjects must agree to use
             contraception during the treatment period and for at least 2 days after the last dose
             of study treatment and refrain from donating sperm during this period. Only female
             subjects of WONCBP are eligible to participate.

          -  Capable of giving signed informed consent.

        Exclusion Criteria

          -  ALT and bilirubin greater than 1.5 times upper limit of normal (ULN) (isolated
             bilirubin greater than 1.5 times ULN is acceptable if bilirubin is fractionated and
             direct bilirubin less than 35%).

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones)

          -  QTc corrected by Fridericia's formula(QTcF) greater than 450 millisecond (msec) from a
             mean of triplicate readings taken 5 mins apart

          -  Clinically significant abnormal echocardiogram

          -  The subject has a history or current evidence of depression, bipolar disorder,
             suicidal ideation and behavior, or a lifetime history of suicide attempt

          -  Cardiac troponin (cTn) or Brain natriuretic peptide (BNP) greater than ULN

          -  Use of prohibited medication

          -  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

          -  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. For
             potent immunosuppressive agents, subjects with presence of hepatitis B core antibody
             (HBcAb) should also be excluded.

          -  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 milliliter (mL) within 84 days.

          -  Poor or unsuitable venous access

          -  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 gram of alcohol: a
             half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.

          -  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.

          -  History of smoking within 6 months of the study.