First Time in Human (FTIH) Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single and Repeat Doses of GSK3439171A in Healthy Subjects and to Assess Food Effect
Condition: Muscular Dystrophies
MeSH terms: Muscular Dystrophies
Intervention: GSK3439171A; Placebo
Intervention description: Oral solution with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards; Placebo oral solution to match with doses 0.5 mg up to 4.5 mg and capsule for doses 5 mg and upwards
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Part A is a Crossover group single ascending dose study with 2 arms per cohort that is subject and investigator blinded. Part B is a Parallel group repeat dose study with 2 arms per cohort that is subject and investigator blinded. Part C is a Crossover group food effect study with 2 arms per cohort that is not-masked."
Masking: Double (Participant, Investigator)
Enrollment: 66.0
Sex: Male
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Dose proportionality; Food effect; Pharmacokinetics; FTIH; Pharmacodynamics; Dose Escalation

Summary:

      The FTIH study with GSK3439171A will evaluate the safety of GSK3439171A in healthy subjects
      in order to avoid confounding factors due to the disease or concomitant drugs in patients.
      The study design is based on pre-clinical findings for GSK3439171A, contributing to the
      frequency, type and duration of safety assessment and monitoring during treatment periods in
      each cohort. The single dose assessments in Part A will be conducted to determine safety,
      tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of the study intervention in
      individuals before progressing to doses explored further in other parts of the study and will
      allow for any adjustments needed based on emerging safety, tolerability, and PK information.
      Part A will also serve to identify a dose for use in examining the effect of food on
      GSK3439171A exposure in Part C. In Part B, a single dose safety, tolerability and PK will be
      collected followed by progression of these subjects to the repeat dose portion of the study.
      The up to 14-day dosing was chosen as it is thought to provide sufficient safety and
      tolerability data to bridge to longer duration studies. The dosing period can be adjusted
      depending on PK and PD data collected in Part A of the study. Part B will involve more
      detailed PK/PD/metabolite assessments to better understand the impact of GSK3439171A on
      target engagement and metabolism in humans. Approximately 150 subjects will be screened to
      achieve 75 randomly assigned to study intervention. Duration for Part A, B and C will be
      approximately 10 weeks, 9 weeks and 8 weeks respectively.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject must be 18 to 65 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. A subject
             with a clinical abnormality or laboratory parameter(s) not specifically listed in the
             exclusion or exclusion criteria that is 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.

          -  Subjects with Body weight >=50.0 kilograms (Kg) (110 lbs.) and body mass index (BMI)
             within the range 18.5 to 31.0 kilograms per square meter (inclusive).

          -  Only male subjects are eligible for this study. Contraceptive use should be consistent
             with local regulations regarding the methods of contraception for those participating
             in clinical studies.

          -  Male subjects are eligible to participate if they agree to the following during the
             their entire enrolment in the study plus an additional 5 days or 5 terminal half-lives
             (whichever is longer): Refrain from donating sperm plus either be abstinent from
             sexual intercourse as their preferred and usual lifestyle (abstinent on a long term
             and persistent basis) and agree to remain abstinent or must agree to use
             contraception/barrier (female partner to use an additional highly effective
             contraceptive method with a failure rate of <1% per year)

          -  Subjects must be capable of giving signed informed consent

        Exclusion Criteria:

          -  Subjects are excluded from the study if they have history or presence of
             cardiovascular, 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.

          -  Subjects are excluded from the study if they have any clinically significant abnormal
             vital signs

          -  Subjects are excluded from the study if they have 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 are excluded from the study if they have ALT >1.5 times upper limit of normal
             (ULN)

          -  Subjects are excluded from the study if Bilirubin >1.5 times ULN (isolated bilirubin
             >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)

          -  Subjects are excluded from the study if they have current or chronic history of liver
             disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's
             syndrome or asymptomatic gallstones)

          -  Subjects are excluded from the study if they have QTc >450 milliseconds

          -  Subjects who are unable to refrain from the use of prescription or non-prescription
             drugs, including aspirin, Non-steroidal Anti-inflammatory Drugs (NSAIDs), vitamins,
             herbal and dietary supplements (including St John's Wort) within 10 days prior to the
             first dose of study medication.

          -  In cases, where participation in the study would result in loss of blood or blood
             products in excess of 500 milliliter (mL) within 56 days

          -  Subjects with exposure to more than 4 new chemical entities within 12 months prior to
             the first dosing day.

          -  Subjects with current enrolment 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.

          -  Subjects with presence of Hepatitis B surface antigen (HBsAg) at screening.

          -  Subjects with Positive Hepatitis C antibody test result at screening. Subjects with
             positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a
             confirmatory negative Hepatitis C ribonucleic acid (RNA) test is obtained.

          -  Subjects with Positive Hepatitis C Ribonucleic acid (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 regular use of known drugs of abuse or positive urine drug test at
             screening or each in-house admission to the clinical research unit

          -  Subjects with regular alcohol consumption within 6 months prior to screening and 5
             days prior to admission defined as: An average weekly intake of > 14 units for males.
             One unit is equivalent to 8 gram of alcohol: a half-pint (Approximately 240 mL) of
             beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of 80 proof distilled spirits

          -  Subjects with positive urinary cotinine test indicative of smoking history at
             screening or each in-house admission to the clinical research unit or regular use of
             tobacco- or nicotine-containing products (e.g. nicotine patches or vaporizing devices)
             within 6 months prior to screening

          -  Subjects with 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.