A First in Human Study to Evaluate the Safety, Tolerability and PK of GB1211 in Healthy Subjects
Condition: Safety and Tolerability
Intervention: GB1211; Placebo
Intervention description: Hard capsules for oral use; Hard capsules for oral use
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: Part A: 56 subjects will be studied in 7 cohorts (Cohorts A1 to A7) Part B: 22 subjects will be studied in 2 cohorts (Cohorts B1 to B2)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 78.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: GB1211; Phase 1; First Time in Human; Safety; Tolerability; Pharmacokinetics; Single Ascending Dose (SAD); Multiple Ascending Dose (MAD); Healthy Volunteers; Nonalcoholic Steatohepatitis (NASH); Liver Fibrosis

Summary:

      This was a Phase 1, randomized, double-blind, placebo-controlled, first-in-human study in
      which the safety, tolerability, and pharmacokinetics of orally administered GB1211 will be
      evaluated in healthy adult subjects and adult subjects with indication of suspected
      Nonalcoholic steatohepatitis (NASH) and liver fibrosis.
    

Eligibility criteria:

        Inclusion Criteria:

        Subjects for Parts A and B must satisfy all of the following criteria at the Screening
        visit unless otherwise stated:

          1. Males or females, of any race, between 18 and 55 years of age (60 years for Part B),
             inclusive.

          2. Body mass index (BMI) of 18.0 to 32.0 kg/m^2 (inclusive) with a minimum body weight of
             50 kg.

          3. In good health, determined by no clinically significant findings from medical history,
             physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory
             evaluations

          4. Females will not be pregnant or lactating, and females of childbearing potential and
             males will agree to use contraception as detailed further in the protocol.

          5. Male subjects must agree to refrain from sperm donation and females should refrain
             from ova donation from the date of Check-in (Day -1) until 90 days after the Follow-up
             visit.

          6. Able to comprehend and willing to sign an ICF and to abide by the study restrictions.

        Subjects for Parts C must satisfy all of the following criteria at the Screening visit
        unless otherwise stated:

          1. Males or females, of any race, between 18 and 60 years of age, inclusive.

          2. Body mass index (BMI) of ≥ 25.0 and ≤ 38.0 kg/m^2.

          3. Documented history of fatty liver within the last 24 weeks by one of the following:
             magnetic resonance imaging (MRI) suggesting liver fat ≥ 8%, ultrasound (US) indicating
             fatty liver, or Fibroscan Controlled Attenuation Parameter (CAP) > 270 dB/m. In
             subjects without a documented history of fatty liver, a Fibroscan CAP or US can be
             performed at Screening. Subjects with Fibroscan CAP > 270 dB/m or US indicating fatty
             liver are eligible.

          4. Metabolic syndrome (Adult Treatment Panel III definition) or T2DM (defined as stable
             diabetes with glycosylated haemoglobin [HbA1c] ≤ 9.5%).

          5. Alanine aminotransferase (ALT) ≥ 20 U/L for females and ≥ 30 U/L for males at
             Screening.

          6. Fibroscan ≥ 7 KPa and < 13 KPa, or Fibrosis-4 (FIB-4) index ≥ 1.1 and <3.25.

          7. Females of nonchildbearing potential defined as permanently sterile (ie, due to
             hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) or
             postmenopausal (defined as at least 12 months postcessation of menses without an
             alternative medical cause and follicle-stimulating hormone [FSH] level ≥ 40 mIU/mL).
             Males will agree to use contraception as detailed in protocol.

          8. Male subjects must agree to refrain from sperm donation and females should refrain
             from ova donation from the date of Check-in (Day -1) until 90 days after the Follow-up
             visit.

          9. Able to comprehend and willing to sign an ICF and to abide by the study restrictions.

        Exclusion Criteria:

        Subjects from Part A & B will be excluded from the study if they satisfy any of the
        following criteria at the Screening visit unless otherwise stated:

          1. Significant history or clinical manifestation of any metabolic, allergic,
             dermatological, hepatic, renal, haematological, pulmonary, cardiovascular,
             gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as
             determined by the Investigator (or designee).

          2. History of febrile illness within 7 days prior to the first dose of study drug or
             subjects with evidence of active infection.

        3 (Part A). Any of the following: a. QTcF > 450 msec confirmed by repeat measurement. b.
        QRS duration > 110 msec confirmed by repeat measurement. c. PR interval > 220 msec
        confirmed by repeat measurement. d. findings which would make QTc measurements difficult or
        QTc data uninterpretable. e. history of additional risk factors for torsades de pointes
        (eg, heart failure, hypokalaemia, family history of long QT syndrome).

        3 (Part B). Clinically significant ECG abnormalities or QTcF greater than 450 msec for
        males and 470 msec for females at either Screening or Day 1 predose, or any prior history
        of QT abnormality.

        4. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in.

        5. Positive hepatitis panel and/or positive human immunodeficiency virus (HIV) test.

        6. Participation in a clinical study involving administration of an investigational agent
        or vaccine (new chemical entity) or having received a biological product in the past 90
        days prior to dosing.

        7. Use or intend to use any medications/products known to alter drug absorption,
        metabolism, or elimination processes, including St. John's wort, within 30 days prior to
        dosing, unless deemed acceptable by the Investigator (or designee).

        8. Use or intend to use any prescription medications/products other than hormone
        replacement therapy, oral, implantable, transdermal, injectable, or intrauterine
        contraceptives within 14 days prior to dosing, unless deemed acceptable by the Investigator
        (or designee).

        9. Use of tobacco- or nicotine-containing products within 3 months prior to Check-in, or
        positive cotinine at Screening or Check-in.

        10. Receipt of blood products within 2 months prior to Check-in and donation of blood from
        3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6
        weeks prior to Screening.

        11. Subject who, in the opinion of the Investigator (or designee), should not participate
        in this study.

        Subjects from Part C will be excluded from the study if they satisfy any of the following
        criteria at the Screening visit unless otherwise stated:

          1. If diabetic and diabetes is other than T2DM.

          2. Subjects, who have had bariatric surgery of any kind or, in the opinion of the
             Investigator, have experienced a clinically significant change in body weight within
             the 3 months prior to Screening.

          3. History of any known serious disease (such as cancer, except skin basocellular
             carcinomas, major infection, clinically significant gastrointestinal disorder, major
             autoimmune disease) or other disease which in the Investigator's opinion would exclude
             the patient from the study.

          4. The following clinical laboratory results at Screening: -Total Bilirubin > 2 × ULN,
             ALT > 155 U/L for females and > 185 U/L for males, AST > 155 U/L for females and > 200
             U/L for males

          5. Other abnormal clinical laboratory values that are considered clinically significant
             for this population.

          6. Clinically significant ECG abnormalities or QTcF greater than 450 msec for males and
             470 msec for females at either Screening or Day 1 predose, or any prior history of QT
             abnormality.

          7. History of alcoholism or drug/chemical abuse within 1 year prior to Check-in.

          8. Alcohol consumption of > 14 units per week for males and for females. One unit of
             alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill
             (25 mL) of spirits.

          9. Positive alcohol breath test result or positive urine drug screen (confirmed by
             repeat) at Screening or Check-in.

         10. Positive hepatitis panel and/or positive HIV test .

         11. A creatinine clearance of less than 50 mL/min (as calculated by Cockcroft-Gault
             equation) or estimated glomerular filtration rate (eGFR) < 60 mL/[min*1.73 m²] at
             Screening.

         12. Subject taking any antidiabetic medications, with the exception of metformin,
             sulfonylureas, gliptins, and sodium/glucose co-transporter 2 inhibitors, within 3
             months prior to Screening.

         13. Use of any of the following non-permitted medication within 6 months prior to
             Screening: amiodarone, bile salt chelators, methotrexate, pharmacological doses of
             systemic corticosteroids for at least 2 consecutive weeks, or any other medications
             known to affect liver function.

         14. Have previously completed or withdrawn from this study investigating GB1211, and have
             previously received the investigational product.

         15. Subject who, in the opinion of the Investigator (or designee), should not participate
             in this study.