Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-248
Condition: Healthy
Intervention: GS-248; Placebo
Intervention description: GS-248 oral solution; Placebo oral solution with the same composition to match active drug
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Part I (SAD) Within each cohort, subjects will be randomised in a 3:1 ratio to receive either GS 248 (n=6) or placebo (n=2) in a blinded fashion.
Part II (MAD) Within each cohort, subjects will be randomised in a 3:1 ratio to receive GS-248 (n=6) or placebo (n=2) in a blinded fashion.
Masking: Double (Participant, Investigator)
Masking description: The study will be conducted in double-blind fashion and the allocation of treatments will not be disclosed until clean file has been declared and the database has been locked.
GS-248 and the placebo are identical in appearance, taste and smell.
Enrollment: 72.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This is a First in Human (FIH), double-blinded, parallel-group, randomised,
      placebo-controlled study designed to evaluate the safety, tolerability, PK and PD of single
      and multiple ascending oral doses of GS-248 in healthy subjects.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Willing and able to give written informed consent for participation in the study.

          2. Male and female healthy subjects aged 18-70 years inclusive (Part I [SAD]) and 40-75
             years inclusive (Part II [MAD])

          3. Women of child bearing potential must practice abstinence or must agree to use a
             highly effective method of contraception with a failure rate of < 1% to prevent
             pregnancy from at least 4 weeks prior to dose to 4 weeks after last dose. Their male
             partner must agree to use a condom during the same time frame. Women of
             non-childbearing potential are defined as pre-menopausal females who are sterilised or
             post-menopausal defined as 12 months of amenorrhea.

             Male subjects must be willing to use condom or be vasectomised or practice sexual
             abstinence. Their female partner of child-bearing potential must use contraceptive
             methods with a failure rate of < 1% to prevent pregnancy (see above).

          4. Body mass index (BMI) ≥ 19 and ≤ 30 kg/m2.

          5. Subjects must be in good health as determined by medical history, physical
             examination, vital signs, 12-lead ECG and clinical laboratory assessments at the time
             of screening, as judged by the Investigator.

        Exclusion Criteria:

          1. Known allergy to any components of the GS-248 formulation.

          2. Females who are breast feeding or plan to be pregnant.

          3. Positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent
             units of human chorionic gonadotropin [HCG]) at screening and within 24 h prior to the
             first administration of Investigational Medicinal Product (IMP).

          4. Use of corticosteroids (inhaled and systemic), NSAIDs (including e.g. coxibs and
             aspirin), antacids, Proton pump inhibitors (PPIs) or any medication that changes
             gastric pH within 2 weeks prior to the (first) administration of IMP.

          5. Regular use of any prescribed or non-prescribed medication including analgesics,
             herbal remedies, vitamins and minerals within 2 weeks prior to the (first)
             administration of IMP, except hormonal contraception and occasional intake of
             paracetamol (maximum 2000 mg/day; and not exceeding 3000 mg/week) and nasal
             decongestants without cortisone, antihistamine or anticholinergics for a maximum of 10
             days, at the discretion of the Investigator.

          6. Inherited or acquired disorders of platelet function, bleeding or coagulation.

          7. Presence of any clinically relevant acute or chronic disease that could interfere with
             the subject's safety during the clinical study or expose the subject to undue risk.

          8. After 10 minutes supine rest at the time of screening, any vital signs values outside
             the following ranges:

               -  Systolic blood pressure <90 or >140 mmHg, or

               -  Diastolic blood pressure <50 or >90 mmHg, or

               -  Pulse <40 or >90 bpm

          9. Any positive result on screening for serum hepatitis B surface antigen (HBsAg),
             hepatitis C virus antibodies (HCVAb) or human immunodeficiency virus (HIV) 1 and/or 2
             antibodies at screening.

         10. Presence or history of drug and/or alcohol abuse and/or excessive intake of alcohol
             and/or history, or current use, of anabolic steroids, as judged by the Investigator.

         11. Any positive result for drug abuse and/or alcohol at screening or on admission to the
             unit prior to administration of the IMP.

         12. Participation in another clinical study with an experimental drug within 3 months
             before the administration of IMP.

         13. Consumption of grapefruit or grapefruit juice within 14 days of study drug
             administration.

         14. Any clinically significant illness, medical/surgical procedure or trauma within 4
             weeks of the first administration of IMP.

         15. Malignancy within the past 5 years with the exception of in situ removal of basal cell
             carcinoma or resected benign colonic polyps.

         16. Any planned major surgery within the duration of the study.

         17. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant
             abnormalities in the resting ECG at the time of screening, as judged by the
             Investigator.

         18. Current smokers or users of nicotine products. Irregular use of nicotine (e.g.
             smoking, snuffing, chewing tobacco) less than 3 times per week is allowed before
             screening visit.

         19. Regular excessive caffeine consumption defined by a daily intake of >5 cups of
             caffeine containing beverages.

         20. Intake of xanthine and/or taurine containing energy drinks within 2 days prior to
             screening.

         21. Plasma donation within one month of screening or blood donation (or corresponding
             blood loss) during the three months prior to screening.

         22. Investigator considers the subject unlikely to comply with study procedures,
             restrictions and requirements.