Study to Evaluate Safety and Pharmacokinetics of GS-4059 (Tirabrutinib) in Healthy Volunteers and Participants With Rheumatoid Arthritis (RA)
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: Tirabrutinib; Placebo
Intervention description: Capsules administered orally.; Capsules administered orally.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This study will consist of two parts: Part A will evaluate the safety, tolerability,
      pharmacokinetics (PK), and pharmacodynamics (PD) of tirabrutinib in healthy participants.
      Part B will evaluate the safety, tolerability, and the effect of tirabrutinib on
      disease-specific clinical markers and outcomes in participants with rheumatoid arthritis
      (RA).
    

Eligibility criteria:

        Inclusion Criteria

        Part A

          -  Be a nonsmoker

          -  Have a calculated body mass index (BMI) from 19 to 30 kg/m^2, inclusive, at screening

          -  Have a creatinine clearance (CrCl) ≥ 90 mL/min (using the Cockcroft-Gault method based
             on serum creatinine and actual body weight as measured at screening

          -  Females of childbearing potential must have a negative serum pregnancy test at
             screening and clinic admission.

          -  Male and female individuals of childbearing potential who engage in heterosexual
             intercourse must agree to use protocol specified method(s) of contraception

          -  Must, in the opinion of the investigator, be in good health based upon medical history
             and physical examination, including vital signs

          -  Screening laboratory evaluations (hematology including reticulocytes, fasting lipids,
             chemistry, and urinalysis) must fall within the normal range of the local laboratory's
             reference ranges unless the results have been determined by the investigator to have
             no clinical significance

          -  Have either a normal 12-lead ECG or one with abnormalities that are considered
             clinically insignificant by the investigator in consultation with the Sponsor

        Part B

          -  Diagnosis of RA (according to the 1987 American College of Rheumatology (ACR)
             classification criteria OR a score of ≥ 6 as defined by the ACR/European League
             Against Rheumatism Classification and Diagnostic Criteria for RA)

          -  Individuals must have taken methotrexate (MTX) 7.5 to 25 mg/week continuously for at
             least 12 weeks, with at least 6 weeks of stable dose prior to first study drug dose
             and throughout study duration.

          -  Individuals must be receiving folic or folinic acid supplementation at a stable dose
             for at least 6 weeks prior to Day 1 dosing and throughout study duration

          -  Individuals are allowed to remain on anti-malarial therapy, with at least 8 weeks of
             stable dose prior to first study drug dose

          -  Use of oral corticosteroids of no more than 10 mg prednisone or its equivalent per day
             is allowed if dose is stable for at least 28 days prior to first study drug dose

          -  Nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics (including aspirin ≤
             100 mg daily) are allowed if doses are stable for at least 14 days prior to the first
             dose of study drug

          -  Estimated creatinine clearance (CLCr) ≥ 60 mL/min (using the Cockcroft-Gault method)
             based on serum creatinine and actual body weight as measured at the screening
             evaluation

          -  White blood cells (WBC), neutrophil count, lymphocyte count, and platelet count ≥ 0.75
             x lower limit of normal (LLN)

          -  A negative serum pregnancy test at screening and a negative pregnancy test on the Day
             1 visit prior to the first dose of study drug for female individual of child bearing
             potential.

          -  Male and female individuals of childbearing potential who engage in heterosexual
             intercourse must agree to use protocol specified method(s) of contraception

        Exclusion Criteria

        Part A

          -  Pregnant or lactating individuals

          -  Have any serious or active medical or psychiatric illness (including depression)
             which, in the opinion of the Investigator, would interfere with individual's
             treatment, assessment, or compliance with the protocol. This would include renal,
             cardiac, hematological, hepatic, pulmonary (including chronic asthma), endocrine
             (including diabetes), central nervous, gastrointestinal (including an ulcer),
             vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders,
             active infection, or malignancy that are clinically significant or requiring treatment

          -  Positive test for drugs of abuse, including alcohol at screening or on Day -1/check-in

          -  A positive test result for human immunodeficiency virus (HIV-1) antibody, hepatitis B
             (HBV) surface antigen or hepatitis C (HCV) antibody

          -  Have poor venous access that limits phlebotomy

          -  Have taken any prescription medications or over-the-counter medications, including
             herbal products, within 28 days prior to start of study drug dosing, with the
             exception of vitamins and/or acetaminophen and/or hormonal contraceptive medications

          -  Have been treated with systemic steroids, immunosuppressant therapies, or
             chemotherapeutic agents within 3 months prior to Screening or expected to receive
             these agents during the study (eg, corticosteroids, immunoglobulins, and other immune-
             or cytokine-based therapies)

          -  Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)

          -  Medical or surgical treatment that permanently alters gastric absorption (eg, gastric
             or intestinal surgery); a history of cholecystectomy is not exclusionary

        Part B

          -  Known hypersensitivity to formulation excipient.

          -  Pregnant or lactating females

          -  Previous treatment with B-cell depleting agents (eg, rituximab) within 12 months of
             treatment

          -  Prior treatment with any commercially available or investigational Bruton's tyrosine
             kinase (BTK) inhibitor

          -  Diagnosis of diabetes, history of impaired glucose tolerance test, history of abnormal
             glycated haemoglobin (HbA1c), or history of impaired fasting glucose

          -  Current treatment with any other disease modifying anti-rheumatic drug (DMARD) other
             than MTX and hydroxychloroquine, unless appropriate wash out

          -  Current treatment with any biologic agent, unless appropriate wash out

          -  Any laboratory abnormality or condition that, in the investigator's opinion, could
             adversely affect the safety of the individual or impair the assessment of study
             results

          -  History of or current inflammatory joint disease, other than RA

          -  Active significant systemic involvement secondary to RA such as vasculitis, pulmonary
             fibrosis or Felty's syndrome

          -  History of or current autoimmune or rheumatic disorders, other than RA

          -  RA functional class 4 or other uncontrolled medical conditions

          -  History of ongoing, chronic or recurrent infections or recent serious or
             life-threatening infection

          -  Presence of any condition that could, in the opinion of the investigator, compromise
             the individual's ability to participate in the study, such as history of substance
             abuse, alcoholism, or a psychiatric condition