Clincosm LogoSign in Get a demo

Study to Evaluate Safety and Pharmacokinetics of GS-4059 (Tirabrutinib) in Healthy Volunteers and Participants With Rheumatoid Arthritis (RA)

Sponsor
Gilead Sciences (Industry)
Overall Status
Completed
CT.gov ID
NCT02626026
Collaborator
Ono Pharmaceutical Co. Ltd (Industry)
42
Enrollment
9
Locations
6
Arms
7.2
Actual Duration (Months)
4.7
Patients Per Site
0.6
Patients Per Site Per Month

Study Details

Study Description

Brief 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).

Condition or Disease Intervention/Treatment Phase
Phase 1

Study Design

Study Type:
Interventional
Actual Enrollment :
42 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 1, Placebo-Controlled, Randomized Study Evaluating the Safety and Pharmacokinetics of GS-4059 in Healthy Volunteers and Subjects With Rheumatoid Arthritis (RA)
Actual Study Start Date :
Jan 26, 2016
Actual Primary Completion Date :
Sep 1, 2016
Actual Study Completion Date :
Sep 1, 2016

Arms and Interventions

Arm Intervention/Treatment
Experimental: Cohort 1, Part A: Tirabrutinib 20 mg QD

Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week.

Drug: Tirabrutinib
Capsules administered orally.
Other Names:
  • GS-4059

    		•
    Placebo Comparator: Cohort 1, Part A: Placebo

    Placebo to match tirabrutinib capsules orally QD in the morning for 1 week.

    Drug: Placebo
    Capsules administered orally.
    Experimental: Cohort 2, Part A: Tirabrutinib 10 mg BID

    Tirabrutinib 10 mg capsules orally twice daily (BID) (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.

    Drug: Tirabrutinib
    Capsules administered orally.
    Other Names:
  • GS-4059

    		•
    Placebo Comparator: Cohort 2, Part A: Placebo

    Placebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.

    Drug: Placebo
    Capsules administered orally.
    Experimental: Part B: Tirabrutinib 20 mg QD

    Tirabrutinib 20 mg capsules orally QD for 4 weeks.

    Drug: Tirabrutinib
    Capsules administered orally.
    Other Names:
  • GS-4059

    		•
    Placebo Comparator: Part B: Placebo

    Placebo to match tirabrutinib capsules orally QD for 4 weeks.

    Drug: Placebo
    Capsules administered orally.

    Outcome Measures

    Primary Outcome Measures

    1. Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) [First dose date up to last dose (maximum: 7 days) plus 30 days]

      An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment-emergent adverse events (TEAEs) were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or Any AEs leading to premature discontinuation of study drug.

    2. Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities [First dose date up to last dose (maximum: 7 days) plus 30 days]

      A treatment-emergent laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment after the first dose of study drug and within 30 days after last study drug administration. Laboratory abnormalities without clinical significance were not recorded as AEs or serious AEs. Treatment-emergent laboratory abnormalities were graded per Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 where 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life threatening.

    3. Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities [First dose date up to last dose (maximum: 7 days) plus 30 days]

    4. Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib [Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose]

      Cmax is maximum observed concentration of drug in plasma.

    5. Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib [Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose]

      Clast is the last observed concentration of drug in plasma.

    6. Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib [Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose]

      Tmax is the time observed for the Cmax of tirabrutinib.

    7. Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib [Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose]

      Tlast is the time observed for the Clast of tirabrutinib.

    8. Part A: AUCtau: Area Under the Plasma Concentration (AUC) Versus Time Curve Over the Dosing Interval of Tirabrutinib [Cohorts 1 and 2, Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose relative to the morning dose]

      AUC is concentration of drug over time (area under the plasma concentration versus time curve).

    9. Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib [Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose]

      AUC is concentration of drug over time (area under the plasma concentration versus time curve).

    10. Part B: Percentage of Participants Who Experienced TEAEs [First dose date up to last dose (maximum: 29 days) plus 30 days]

      An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or Any AEs leading to premature discontinuation of study drug.

    11. Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities [First dose date up to last dose (maximum: 29 days) plus 30 days]

      A treatment-emergent laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment after the first dose of study drug and within 30 days after last study drug administration. Laboratory abnormalities without clinical significance were not recorded as AEs or serious AEs. Treatment-emergent laboratory abnormalities were graded per CTCAE, version 4.03 where 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life threatening.

    12. Part B: Percentage of Participants With 12-Lead ECG Abnormalities [First dose date up to last dose (maximum: 29 days) plus 30 days]

    Secondary Outcome Measures

    1. Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7 [Days 1 and 7: Predose and 2, 6, 12, 24 hours postdose; Days 3 and 5: Predose and 2 hours postdose]

      The effect of tirabrutinib on biomarkers was assessed through the CD63 basophil activation test (BAT) FlowCast assay, which was used to measure the percentage of CD63+ basophils and percentage inhibition of CD63 induction relative to baseline. CD63+ % inhibition was calculated as 100 - CD63+ % baseline. Baseline defined as day 1 predose.

    2. Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7 [Day 1: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24 hours postdose; Days 3 and 5: Predose and 2 hours postdose; Day 7: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, 120 hours postdose]

      BTK occupancy was assessed with the BTK occupancy assay, which was used to measure undetectable free BTK, normalized free BTK, normalized free BTK adjusted to baseline, and percentage BTK occupancy adjusted to baseline. % BTK occupancy adjusted was calculated as 100 * (1 - normalized free BTK adjusted to baseline). Normalized free BTK was calculated as Free BTK / Total BTK. Baseline defined as day 1 predose.

    3. Part B: Change From Baseline in Disease Activity Score for 28 Joint Counts (DAS28) Using C-Reactive Protein (CRP) at Weeks 2, 4 and Posttreatment Week 4 [Baseline; Weeks 2, 4 and Posttreatment Week 4]

      DAS28 score was used to measure the participant's disease activity or assessments of rheumatoid arthritis (RA) calculated using the tender joint counts (TJC) (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (PtGA) (visual analog scale: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

    4. Part B: Change From Baseline in Individual American College of Rheumatology (ACR) Component: Tender Joint Count (TJC) Based on 68 Joints (TJC68) at Weeks 2, 4 and Posttreatment Week 4 [Baseline; Weeks 2, 4 and Posttreatment Week 4]

      ACR TJC was an assessment of 68 joints. At each study visit, a joint evaluator assessed whether a particular joint was "tender" where presence of tenderness was scored as "1" and the absence of tenderness was scored as "0," provided the joint was not replaced or could not be assessed due to other reasons. It was derived as the sum of all tender joints. The range for TJC68 was 0 to 68, with a higher score indicating a greater degree of tenderness. A negative change from baseline indicates improvement.

    5. Part B: Change From Baseline in Individual ACR Component: Swollen Joint Count (SJC) Based on 66 Joints (SJC66) at Weeks 2, 4 and Posttreatment Week 4 [Baseline; Weeks 2, 4 and Posttreatment Week]

      ACR SJC was an assessment of 66 joints. At each study visit, a joint evaluator assessed whether a particular joint was swollen where presence of swelling was scored as "1" and the absence of swelling was scored as "0," provided the joint was not replaced or could not be assessed due to other reasons. It was derived as the sum of all swollen joints. The range for SJC66 was 0 to 66, with a higher score indicating a greater degree of swelling. A negative change from baseline indicates improvement.

    6. Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4 [Baseline; Weeks 2, 4 and Posttreatment Week 4]

      SDAI is a composite measure that sums the TJC based on 28 joints (TJC28), SJC based on 28 joints (SJC28), PtGA, Physician's Global Assessment of Disease Activity (PhGA), and the CRP (in mg/dL). PtGA and PhGA assessed using Visual Analogue Scale (VAS) on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.

    7. Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4 [Baseline; Weeks 2, 4 and Posttreatment Week 4]

      CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.

    8. Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Disease Activity (PtGA) at Weeks 2, 4 and Posttreatment Week 4 [Baseline; Weeks 2, 4 and Posttreatment Week 4]

      PtGA was assessed by the participant using a VAS on a scale of 0 (no disease activity) to 100 (maximum disease activity). A horizontal visual analog scale was used to provide the patient's overall assessment of how the arthritis is doing. A mark was placed on the horizontal line to assess the current arthritis disease activity. The lowest mark indicated 'no arthritis activity', and the highest mark indicated 'extremely active arthritis'. A negative change from baseline indicates improvement.

    9. Part B: Change From Baseline in Individual ACR Component: Physician's Global Assessment of Disease Activity (PhGA) at Weeks 2, 4 and Posttreatment Week 4 [Baseline; Weeks 2, 4 and Posttreatment Week 4]

      PhGA was assessed by the physician using a VAS on a scale of 0 (no disease activity) to 100 (maximum disease activity). A horizontal visual analog scale was used to measure the physician's assessment of the patient's current disease activity. A mark was placed on the horizontal line to assess the disease activity (independent of the participant's self-assessment). The lowest mark indicated 'no disease activity', and the highest mark indicated 'maximum disease activity'. A negative change from baseline indicates improvement.

    10. Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4 [Baseline; Weeks 2, 4 and Posttreatment Week 4]

      The participant assessed their pain severity using a VAS on a scale of 0 (no pain) to 100 (severe pain). A horizontal visual analog scale was used to assess the patient's current level of pain. A mark was placed on the horizontal line to assess the severity of pain. The lowest mark indicated 'no pain', and the highest mark indicated 'unbearable pain'. A negative change from baseline indicates improvement.

    11. Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4 [Baseline; Weeks 2, 4 and Posttreatment Week 4]

      The HAQ-DI score is defined as the average of the scores of eight functional categories (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities), usually administered by the participant. Responses in each functional category were collected as 0-3 [0 (without any difficulty) to 3 (unable to do a task in that area), with or without aids or devices. A negative change from baseline indicates improvement.

    12. Part B: Percentage of Participants Who Achieved an American College of Rheumatology (ACR) 20% Improvement (ACR20) Response at Weeks 2, 4 and Posttreatment Week 4 [Weeks 2, 4 and Posttreatment Week 4]

      ACR20 response is achieved when the participant has: ≥ 20% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PhGA and PtGA assessed using VAS on a scale of 0-100 (0 and 100 indicating no disease activity and maximum disease activity); patient's pain assessment using VAS on a scale of 0-100 (0 indicating no pain and 100 indicating unbearable pain); HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities and scored on a scale of 0-3 (0 and 3 indicating without difficulty and unable to do); high-sensitivity CRP (hsCRP).

    13. Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4 [Weeks 2, 4 and Posttreatment Week 4]

      ACR70 response is achieved when the participant has: ≥ 70% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PhGA and PtGA assessed using VAS on a scale of 0-100 [0 and 100 indicating no disease activity and maximum disease activity]; patient's pain assessment using VAS on a scale of 0-100 [0 indicating no pain and 100 indicating unbearable pain]; HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities and scored on a scale of 0-3 [0 and 3 indicating without difficulty and unable to do]; hsCRP.

    14. Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4 [Weeks 2, 4 and Posttreatment Week 4]

      Hybrid ACR evaluates the improvement in active RA by combining elements of the ACR20, ACR50, and ACR70 with a continuous score of the mean change in core set measures. The percentage improvement from baseline was computed in each of the components of the ACR. The average percent improvement was calculated and used with the participant's ACR20, ACR50, and ACR70 status to compute the hybrid ACR response, with a positive change indicating improvement.

    15. Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4 [Weeks 2, 4 and Posttreatment Week 4]

      Clinical remission is defined as DAS28-CRP < 2.6. DAS28 score was used to measure the participant's disease activity or assessments of RA calculated using the TJC28, SJC28, PtGA (VAS: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

    16. Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4 [Weeks 2, 4 and Posttreatment Week 4]

      Low disease activity is defined as DAS28-CRP ≤ 3.2. DAS28 score was used to measure the participant's disease activity or assessments of RA calculated using the TJC28, SJC28, PtGA (VAS: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

    17. Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4 [Weeks 2, 4 and Posttreatment Week 4]

      Clinical remission is defined as CDAI ≤ 2.8. CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.

    18. Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4 [Weeks 2, 4 and Posttreatment Week 4]

      Low disease activity is defined as CDAI ≤ 10. CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.

    19. Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4 [Weeks 2, 4 and Posttreatment Week 4]

      Clinical remission is defined as SDAI ≤ 3.3. SDAI is a composite measure that sums the TJC28, SJC28, PtGA, PhGA, and the CRP (in mg/dL). PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.

    20. Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4 [Weeks 2, 4 and Posttreatment Week 4]

      Low disease activity is defined as SDAI ≤ 11. SDAI is a composite measure that sums the TJC28, SJC28, PtGA, PhGA, and the CRP (in mg/dL). PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 65 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    Yes

    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UC Davis Lawrence J. Ellison Sacramento California United States 95817
    2 SeaView Research, Inc. Miami Florida United States 33126
    3 Omega Research Consultants, LLC Orlando Florida United States 32804
    4 Lovelace Scientific Resources, Inc. Venice Florida United States 34292
    5 Center for Arthritis & Osteoporosis Elizabethtown Kentucky United States 42701
    6 Justus J. Fiechtner, M.D., P.C. Lansing Michigan United States 48910
    7 Altoona Center for Clinical Research Duncansville Pennsylvania United States 16635
    8 Clinical Research Center of Reading, LLC Wyomissing Pennsylvania United States 19610
    9 Arthritis & Osteoporosis Center of South Texas San Antonio Texas United States 78232

    Sponsors and Collaborators

    • Gilead Sciences
    • Ono Pharmaceutical Co. Ltd

    Investigators

    • Study Director: Gilead Study Director, Gilead Sciences

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Gilead Sciences
    ClinicalTrials.gov Identifier:
    NCT02626026
    Other Study ID Numbers:
    • GS-US-407-1833
    • 2015-003240-40
    First Posted:
    Dec 10, 2015
    Last Update Posted:
    Sep 9, 2020
    Last Verified:
    Aug 1, 2020
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:
    Arthritis
    Arthritis, Rheumatoid

    Study Results

    Participant Flow

    Recruitment Details Participants were enrolled at 11 study sites in the United States. The first participant was screened on 26 January 2016. The last study visit occurred on 01 September 2016.
    Pre-assignment Detail 58 participants were screened and 42 participants were enrolled.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 1, Part A: Placebo Cohort 2, Part A: Tirabrutinib 10 mg BID Cohort 2, Part A: Placebo Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week. Placebo to match tirabrutinib capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally twice daily (BID) (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Placebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Period Title: Overall Study
    STARTED 8 2 8 2 17 5
    COMPLETED 8 2 8 2 16 5
    NOT COMPLETED 0 0 0 0 1 0

    Baseline Characteristics

    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 1, Part A: Placebo Cohort 2, Part A: Tirabrutinib 10 mg BID Cohort 2, Part A: Placebo Part B: Tirabrutinib 20 mg QD Part B: Placebo Total
    Arm/Group Description Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week. Placebo to match tirabrutinib capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally twice daily (BID) (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Placebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks. Total of all reporting groups
    Overall Participants 8 2 8 2 16 5 41
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    38
    37
    34
    38
    55
    52
    45.5
    Sex: Female, Male (Count of Participants)
    Female
    4
    50%
    1
    50%
    2
    25%
    0
    0%
    13
    81.3%
    4
    80%
    24
    58.5%
    Male
    4
    50%
    1
    50%
    6
    75%
    2
    100%
    3
    18.8%
    1
    20%
    17
    41.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    8
    100%
    2
    100%
    8
    100%
    2
    100%
    2
    12.5%
    2
    40%
    24
    58.5%
    Not Hispanic or Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    14
    87.5%
    3
    60%
    17
    41.5%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    Black
    4
    50%
    0
    0%
    0
    0%
    1
    50%
    0
    0%
    0
    0%
    5
    12.2%
    White
    4
    50%
    2
    100%
    8
    100%
    1
    50%
    16
    100%
    5
    100%
    36
    87.8%

    Outcome Measures

    1. Primary Outcome
    Title Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)
    Description An adverse event (AE) is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Treatment-emergent adverse events (TEAEs) were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or Any AEs leading to premature discontinuation of study drug.
    Time Frame First dose date up to last dose (maximum: 7 days) plus 30 days

    Outcome Measure Data

    Analysis Population Description
    The Safety Analysis Set included all participants who received at least 1 dose of study drug.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 1, Part A: Placebo Cohort 2, Part A: Tirabrutinib 10 mg BID Cohort 2, Part A: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week. Placebo to match tirabrutinib capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally twice daily (BID) (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 8 2 8 2
    Number [percentage of participants]
    25.0
    312.5%
    50.0
    2500%
    37.5
    468.8%
    0
    0%
    2. Primary Outcome
    Title Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities
    Description A treatment-emergent laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment after the first dose of study drug and within 30 days after last study drug administration. Laboratory abnormalities without clinical significance were not recorded as AEs or serious AEs. Treatment-emergent laboratory abnormalities were graded per Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 where 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life threatening.
    Time Frame First dose date up to last dose (maximum: 7 days) plus 30 days

    Outcome Measure Data

    Analysis Population Description
    Participants in the Safety Analysis Set were analyzed.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 1, Part A: Placebo Cohort 2, Part A: Tirabrutinib 10 mg BID Cohort 2, Part A: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Placebo to match tirabrutinib capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Placebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 8 2 8 2
    Hemoglobin Decreased
    25.0
    312.5%
    0
    0%
    37.5
    468.8%
    50.0
    2500%
    Neutrophils Decreased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    White Blood Cells Decreased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Alanine Aminotransferase (ALT) Increased
    25.0
    312.5%
    0
    0%
    25.0
    312.5%
    0
    0%
    Aspartate Aminotransferase (AST) Increased
    12.5
    156.3%
    0
    0%
    25.0
    312.5%
    0
    0%
    Alkaline Phosphatase Increased
    0
    0%
    0
    0%
    12.5
    156.3%
    0
    0%
    Amylase
    12.5
    156.3%
    0
    0%
    0
    0%
    0
    0%
    Calcium Increased
    12.5
    156.3%
    0
    0%
    0
    0%
    0
    0%
    Fasting Glucose Increased
    12.5
    156.3%
    0
    0%
    0
    0%
    0
    0%
    Gamma-glutamyl Transferase (GGT) Increased
    25.0
    312.5%
    0
    0%
    0
    0%
    0
    0%
    Glucose Increased
    12.5
    156.3%
    0
    0%
    0
    0%
    0
    0%
    Phosphorus Decreased
    12.5
    156.3%
    0
    0%
    0
    0%
    0
    0%
    Sodium Decreased
    0
    0%
    50.0
    2500%
    0
    0%
    0
    0%
    Total Cholesterol Increased
    25.0
    312.5%
    0
    0%
    12.5
    156.3%
    100.0
    5000%
    Triglycerides Increased
    25.0
    312.5%
    0
    0%
    37.5
    468.8%
    50.0
    2500%
    Magnesium Increased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Potassium Decreased
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    3. Primary Outcome
    Title Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities
    Description
    Time Frame First dose date up to last dose (maximum: 7 days) plus 30 days

    Outcome Measure Data

    Analysis Population Description
    Participants in the Safety Analysis Set were analyzed.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 1, Part A: Placebo Cohort 2, Part A: Tirabrutinib 10 mg BID Cohort 2, Part A: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Placebo to match tirabrutinib capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Placebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 8 2 8 2
    Number [percentage of participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    4. Primary Outcome
    Title Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib
    Description Cmax is maximum observed concentration of drug in plasma.
    Time Frame Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose

    Outcome Measure Data

    Analysis Population Description
    The Pharmacokinetics (PK) Analysis Set included all randomized participants who received at least 1 dose of tirabrutinib and had at least 1 non-missing PK concentration data reported by the PK lab for each respective analyte.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 8 8
    Day 1
    33.8
    (7.94)
    16.2
    (4.66)
    Day 7
    56.4
    (11.19)
    32.3
    (8.59)
    5. Primary Outcome
    Title Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib
    Description Clast is the last observed concentration of drug in plasma.
    Time Frame Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose

    Outcome Measure Data

    Analysis Population Description
    Participants in the PK Analysis Set were analyzed.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 8 8
    Day 1
    2.58
    (1.366)
    5.22
    (1.729)
    Day 7
    1.50
    (0.551)
    2.03
    (0.756)
    6. Primary Outcome
    Title Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib
    Description Tmax is the time observed for the Cmax of tirabrutinib.
    Time Frame Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose

    Outcome Measure Data

    Analysis Population Description
    Participants in the PK Analysis Set were analyzed.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 8 8
    Day 1
    2.00
    3.00
    Day 7
    2.00
    2.00
    7. Primary Outcome
    Title Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib
    Description Tlast is the time observed for the Clast of tirabrutinib.
    Time Frame Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose

    Outcome Measure Data

    Analysis Population Description
    Participants in the PK Analysis Set were analyzed.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 8 8
    Day 1
    23.92
    11.92
    Day 7
    30.00
    24.00
    8. Primary Outcome
    Title Part A: AUCtau: Area Under the Plasma Concentration (AUC) Versus Time Curve Over the Dosing Interval of Tirabrutinib
    Description AUC is concentration of drug over time (area under the plasma concentration versus time curve).
    Time Frame Cohorts 1 and 2, Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose relative to the morning dose

    Outcome Measure Data

    Analysis Population Description
    Participants in the PK Analysis Set were analyzed.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 8 8
    Mean (Standard Deviation) [hours*nanogram per milliliter (h*ng/mL)]
    360.5
    (97.49)
    195.2
    (44.43)
    9. Primary Outcome
    Title Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib
    Description AUC is concentration of drug over time (area under the plasma concentration versus time curve).
    Time Frame Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose

    Outcome Measure Data

    Analysis Population Description
    Participants in the PK Analysis Set were analyzed.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 8 8
    Day 1
    228.3
    (89.96)
    107.1
    (27.54)
    Day 7
    377.8
    (119.80)
    245.5
    (65.02)
    10. Primary Outcome
    Title Part B: Percentage of Participants Who Experienced TEAEs
    Description An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or Any AEs leading to premature discontinuation of study drug.
    Time Frame First dose date up to last dose (maximum: 29 days) plus 30 days

    Outcome Measure Data

    Analysis Population Description
    Participants in the Safety Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Number [percentage of participants]
    37.5
    468.8%
    40.0
    2000%
    11. Primary Outcome
    Title Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities
    Description A treatment-emergent laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment after the first dose of study drug and within 30 days after last study drug administration. Laboratory abnormalities without clinical significance were not recorded as AEs or serious AEs. Treatment-emergent laboratory abnormalities were graded per CTCAE, version 4.03 where 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life threatening.
    Time Frame First dose date up to last dose (maximum: 29 days) plus 30 days

    Outcome Measure Data

    Analysis Population Description
    Participants in the Safety Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Hemoglobin Decreased
    6.3
    78.8%
    0
    0%
    Neutrophils Decreased
    6.3
    78.8%
    0
    0%
    White Blood Cells Decreased
    6.3
    78.8%
    0
    0%
    Alanine Aminotransferase (ALT) Increased
    12.5
    156.3%
    20.0
    1000%
    Fasting Glucose Increased
    12.5
    156.3%
    20.0
    1000%
    Glucose Increased
    12.5
    156.3%
    20.0
    1000%
    Magnesium Increased
    18.8
    235%
    0
    0%
    Potassium Decreased
    12.5
    156.3%
    0
    0%
    12. Primary Outcome
    Title Part B: Percentage of Participants With 12-Lead ECG Abnormalities
    Description
    Time Frame First dose date up to last dose (maximum: 29 days) plus 30 days

    Outcome Measure Data

    Analysis Population Description
    Participants in the Safety Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Number [percentage of participants]
    0
    0%
    0
    0%
    13. Secondary Outcome
    Title Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7
    Description The effect of tirabrutinib on biomarkers was assessed through the CD63 basophil activation test (BAT) FlowCast assay, which was used to measure the percentage of CD63+ basophils and percentage inhibition of CD63 induction relative to baseline. CD63+ % inhibition was calculated as 100 - CD63+ % baseline. Baseline defined as day 1 predose.
    Time Frame Days 1 and 7: Predose and 2, 6, 12, 24 hours postdose; Days 3 and 5: Predose and 2 hours postdose

    Outcome Measure Data

    Analysis Population Description
    The Biomarker Analysis Set included all randomized participants who received at least 1 dose of study drug and for whom biomarker data were available.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 1, Part A: Placebo Cohort 2, Part A: Tirabrutinib 10 mg BID Cohort 2, Part A: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Placebo to match tirabrutinib capsules orally QD in the morning for 1 week. Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Placebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
    Measure Participants 7 2 8 2
    Day 1, Predose
    0
    (0)
    0
    (0)
    0
    (0)
    0
    (0)
    Day 1, 2 Hours Postdose
    17.189
    (6.8306)
    0.272
    (2.3326)
    19.557
    (11.0479)
    3.568
    (1.4734)
    Day 1, 6 Hours Postdose
    34.966
    (15.6436)
    8.779
    (9.9101)
    27.506
    (16.0744)
    1.782
    (6.3117)
    Day 1, 12 Hours Postdose
    35.008
    (24.1663)
    -2.688
    (16.7688)
    Day 1, 24 Hours Postdose
    33.305
    (14.9248)
    5.604
    (1.2275)
    Day 3, Predose
    47.416
    (17.0470)
    0.917
    (11.4281)
    83.832
    (10.1042)
    -11.354
    (16.5029)
    Day 3, 2 Hours Postdose
    73.972
    (15.1658)
    -0.842
    (4.6395)
    90.187
    (5.6699)
    -13.641
    (13.0667)
    Day 5, Predose
    55.680
    (21.5018)
    2.779
    (3.7023)
    83.380
    (10.3976)
    -2.271
    (0.2060)
    Day 5, 2 Hours Postdose
    80.271
    (16.8806)
    -0.043
    (2.3069)
    91.159
    (7.4740)
    -15.923
    (11.5733)
    Day 7, Predose
    56.986
    (20.3972)
    5.234
    (0.8757)
    80.024
    (11.0371)
    6.271
    (7.9790)
    Day 7, 2 Hours Postdose
    79.910
    (15.3155)
    -2.831
    (0.7358)
    88.032
    (7.8750)
    -0.978
    (9.9380)
    Day 7, 6 Hours Postdose
    88.102
    (11.6072)
    -1.320
    (8.1776)
    89.681
    (7.0909)
    -2.645
    (6.3382)
    Day 7, 12 Hours Postdose
    80.640
    (10.0574)
    -10.062
    (13.2554)
    Day 7, 24 Hours Postdose
    52.017
    (17.5829)
    -0.046
    (0.6432)
    14. Secondary Outcome
    Title Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7
    Description BTK occupancy was assessed with the BTK occupancy assay, which was used to measure undetectable free BTK, normalized free BTK, normalized free BTK adjusted to baseline, and percentage BTK occupancy adjusted to baseline. % BTK occupancy adjusted was calculated as 100 * (1 - normalized free BTK adjusted to baseline). Normalized free BTK was calculated as Free BTK / Total BTK. Baseline defined as day 1 predose.
    Time Frame Day 1: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24 hours postdose; Days 3 and 5: Predose and 2 hours postdose; Day 7: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, 120 hours postdose

    Outcome Measure Data

    Analysis Population Description
    Participants in the Biomarker Analysis Set were analyzed. All of the baseline samples collected for BTK occupancy assay in Part A Cohort 2 were compromised and therefore not evaluable.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 1, Part A: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD in the morning for 1 week. Placebo to match tirabrutinib capsules orally QD in the morning for 1 week.
    Measure Participants 7 2
    Day 1, Predose
    0
    (0)
    0
    (0)
    Day 1, 0.5 Hour Postdose
    -2.765
    (14.6036)
    -4.686
    (1.8358)
    Day 1, 1 Hour Postdose
    11.635
    (17.8025)
    -11.927
    (8.4893)
    Day 1, 2 Hours Postdose
    55.250
    (10.0230)
    -8.959
    (16.7122)
    Day 1, 3 Hours Postdose
    62.719
    (7.7060)
    -9.810
    (18.8212)
    Day 1, 4 Hours Postdose
    66.790
    (7.9494)
    -16.597
    (25.0492)
    Day 1, 6 Hours Postdose
    71.936
    (8.3606)
    -6.014
    (19.5348)
    Day 1, 8 Hours Postdose
    75.350
    (11.5216)
    -16.584
    (17.8202)
    Day 1, 12 Hours Postdose
    77.411
    (8.6928)
    6.170
    (12.7312)
    Day 1, 18 Hours Postdose
    81.187
    (8.8687)
    -2.261
    (27.3338)
    Day 1, 24 Hours Postdose
    72.691
    (10.8289)
    -28.029
    (10.1821)
    Day 3, Predose
    84.010
    (8.4919)
    -19.564
    (20.3282)
    Day 3, 2 Hours Postdose
    90.606
    (6.1066)
    -35.206
    (25.2258)
    Day 5, Predose
    70.841
    (43.0596)
    25.095
    (99.0827)
    Day 5, 2 Hours Postdose
    93.128
    (4.0582)
    -25.646
    (17.6912)
    Day 7, Predose
    86.936
    (6.4745)
    -22.662
    (23.6252)
    Day 7, 0.5 Hours Postdose
    87.013
    (5.2426)
    -23.284
    (9.9539)
    Day 7, 1 Hour Postdose
    86.274
    (6.0720)
    -12.230
    (6.6727)
    Day 7, 2 Hours Postdose
    92.651
    (3.4603)
    -34.573
    (17.9620)
    Day 7, 3 Hours Postdose
    92.983
    (2.1906)
    -32.920
    (20.1029)
    Day 7, 4 Hours Postdose
    90.070
    (7.4086)
    -37.253
    (16.2208)
    Day 7, 6 Hours Postdose
    91.591
    (7.7733)
    -39.632
    (13.1749)
    Day 7, 8 Hours Postdose
    92.789
    (3.2221)
    -31.144
    (20.1974)
    Day 7, 12 Hours Postdose
    91.251
    (6.0300)
    -33.947
    (16.3475)
    Day 7, 18 Hours Postdose
    85.209
    (5.0694)
    -34.408
    (12.5471)
    Day 7, 24 Hours Postdose
    86.256
    (6.5648)
    -42.577
    (17.2138)
    Day 7, 36 Hours Postdose
    71.963
    (10.5550)
    -43.574
    (8.4952)
    Day 7, 48 Hours Postdose
    64.763
    (14.3072)
    -46.249
    (24.2785)
    Day 7, 60 Hours Postdose
    57.431
    (9.0638)
    -15.465
    (9.4556)
    Day 7, 72 Hours Postdose
    46.218
    (14.3155)
    -49.093
    (21.4447)
    Day 7, 96 Hours Postdose
    24.922
    (6.8700)
    -41.721
    (32.0255)
    Day 7, 120 Hours Postdose
    15.285
    (9.4140)
    -48.863
    (20.7533)
    15. Secondary Outcome
    Title Part B: Change From Baseline in Disease Activity Score for 28 Joint Counts (DAS28) Using C-Reactive Protein (CRP) at Weeks 2, 4 and Posttreatment Week 4
    Description DAS28 score was used to measure the participant's disease activity or assessments of rheumatoid arthritis (RA) calculated using the tender joint counts (TJC) (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (PtGA) (visual analog scale: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.
    Time Frame Baseline; Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set (who were randomized into the study and received at least 1 dose of study drug) with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Baseline
    4.54
    (1.728)
    5.12
    (1.576)
    Change from Baseline at Week 2
    -0.35
    (0.821)
    -0.28
    (0.977)
    Change from Baseline at Week 4
    -0.45
    (1.097)
    -0.11
    (0.612)
    Change from Baseline at Posttreatment Week 4
    -0.41
    (1.208)
    -0.05
    (0.782)
    16. Secondary Outcome
    Title Part B: Change From Baseline in Individual American College of Rheumatology (ACR) Component: Tender Joint Count (TJC) Based on 68 Joints (TJC68) at Weeks 2, 4 and Posttreatment Week 4
    Description ACR TJC was an assessment of 68 joints. At each study visit, a joint evaluator assessed whether a particular joint was "tender" where presence of tenderness was scored as "1" and the absence of tenderness was scored as "0," provided the joint was not replaced or could not be assessed due to other reasons. It was derived as the sum of all tender joints. The range for TJC68 was 0 to 68, with a higher score indicating a greater degree of tenderness. A negative change from baseline indicates improvement.
    Time Frame Baseline; Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Baseline
    18.20
    (14.454)
    21.70
    (12.656)
    Change from Baselline at Week 2
    -2.57
    (6.666)
    -1.17
    (7.980)
    Change from Baselline at Week 4
    -6.69
    (8.432)
    0.01
    (0.829)
    Change from Baselline at Posttreatment Week 4
    -3.13
    (9.968)
    1.11
    (12.638)
    17. Secondary Outcome
    Title Part B: Change From Baseline in Individual ACR Component: Swollen Joint Count (SJC) Based on 66 Joints (SJC66) at Weeks 2, 4 and Posttreatment Week 4
    Description ACR SJC was an assessment of 66 joints. At each study visit, a joint evaluator assessed whether a particular joint was swollen where presence of swelling was scored as "1" and the absence of swelling was scored as "0," provided the joint was not replaced or could not be assessed due to other reasons. It was derived as the sum of all swollen joints. The range for SJC66 was 0 to 66, with a higher score indicating a greater degree of swelling. A negative change from baseline indicates improvement.
    Time Frame Baseline; Weeks 2, 4 and Posttreatment Week

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Baseline
    12.70
    (10.944)
    12.04
    (12.488)
    Change from Baseline at Week 2
    -4.13
    (6.446)
    -2.58
    (9.910)
    Change from Baseline at Week 4
    -4.82
    (7.586)
    -2.23
    (6.048)
    Change from Baseline at Posttreatment Week 4
    -3.07
    (5.272)
    1.53
    (3.035)
    18. Secondary Outcome
    Title Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4
    Description SDAI is a composite measure that sums the TJC based on 28 joints (TJC28), SJC based on 28 joints (SJC28), PtGA, Physician's Global Assessment of Disease Activity (PhGA), and the CRP (in mg/dL). PtGA and PhGA assessed using Visual Analogue Scale (VAS) on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.
    Time Frame Baseline; Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Baseline
    30.19
    (20.283)
    33.20
    (19.061)
    Change from Baseline at Week 2
    -4.49
    (11.786)
    -5.20
    (14.035)
    Change from Baseline at Week 4
    -6.84
    (14.016)
    -1.69
    (5.439)
    Change from Baseline at Posttreatment Week 4
    -4.82
    (14.349)
    -1.16
    (12.293)
    19. Secondary Outcome
    Title Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4
    Description CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.
    Time Frame Baseline; Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Baseline
    29.63
    (19.994)
    31.96
    (18.622)
    Change from Baseline at Week 2
    -4.44
    (11.748)
    -5.32
    (13.264)
    Change from Baseline at Week 4
    -6.80
    (13.925)
    -2.02
    (5.206)
    Change from Baseline at Posttreatment Week 4
    -4.73
    (14.180)
    -1.74
    (11.562)
    20. Secondary Outcome
    Title Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Disease Activity (PtGA) at Weeks 2, 4 and Posttreatment Week 4
    Description PtGA was assessed by the participant using a VAS on a scale of 0 (no disease activity) to 100 (maximum disease activity). A horizontal visual analog scale was used to provide the patient's overall assessment of how the arthritis is doing. A mark was placed on the horizontal line to assess the current arthritis disease activity. The lowest mark indicated 'no arthritis activity', and the highest mark indicated 'extremely active arthritis'. A negative change from baseline indicates improvement.
    Time Frame Baseline; Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Baseline
    42
    (27.4)
    63
    (30.5)
    Change from Baseline at Week 2
    -10
    (20.7)
    -6
    (17.6)
    Change from Baseline at Week 4
    -10
    (22.1)
    -10
    (16.7)
    Change from Baseline at Posttreatment Week 4
    -4
    (22.2)
    -9
    (17.8)
    21. Secondary Outcome
    Title Part B: Change From Baseline in Individual ACR Component: Physician's Global Assessment of Disease Activity (PhGA) at Weeks 2, 4 and Posttreatment Week 4
    Description PhGA was assessed by the physician using a VAS on a scale of 0 (no disease activity) to 100 (maximum disease activity). A horizontal visual analog scale was used to measure the physician's assessment of the patient's current disease activity. A mark was placed on the horizontal line to assess the disease activity (independent of the participant's self-assessment). The lowest mark indicated 'no disease activity', and the highest mark indicated 'maximum disease activity'. A negative change from baseline indicates improvement.
    Time Frame Baseline; Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Baseline
    39
    (27.4)
    49
    (15.5)
    Change from Baseline at Week 2
    -3
    (23.5)
    -16
    (13.4)
    Change from Baseline at Week 4
    -8
    (20.3)
    5
    (14.9)
    Change from Baseline at Posttreatment Week 4
    -4
    (22.7)
    -3
    (17.7)
    22. Secondary Outcome
    Title Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4
    Description The participant assessed their pain severity using a VAS on a scale of 0 (no pain) to 100 (severe pain). A horizontal visual analog scale was used to assess the patient's current level of pain. A mark was placed on the horizontal line to assess the severity of pain. The lowest mark indicated 'no pain', and the highest mark indicated 'unbearable pain'. A negative change from baseline indicates improvement.
    Time Frame Baseline; Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Baseline
    39
    (28.6)
    59
    (28.9)
    Change from Baseline at Week 2
    -5
    (26.2)
    -6
    (15.7)
    Change from Baseline at Week 4
    -9
    (24.6)
    -13
    (16.2)
    Change from Baseline at Posttreatment Week 4
    -2
    (22.9)
    -11
    (24.9)
    23. Secondary Outcome
    Title Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4
    Description The HAQ-DI score is defined as the average of the scores of eight functional categories (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities), usually administered by the participant. Responses in each functional category were collected as 0-3 [0 (without any difficulty) to 3 (unable to do a task in that area), with or without aids or devices. A negative change from baseline indicates improvement.
    Time Frame Baseline; Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Baseline
    1.063
    (0.7130)
    1.650
    (0.7776)
    Change from Baseline at Week 2
    -0.203
    (0.5242)
    -0.150
    (0.2054)
    Change from Baseline at Week 4
    -0.234
    (0.4492)
    -0.100
    (0.3687)
    Change from Baseline at Posttreatment Week 4
    -0.156
    (0.3550)
    0.094
    (0.1197)
    24. Secondary Outcome
    Title Part B: Percentage of Participants Who Achieved an American College of Rheumatology (ACR) 20% Improvement (ACR20) Response at Weeks 2, 4 and Posttreatment Week 4
    Description ACR20 response is achieved when the participant has: ≥ 20% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PhGA and PtGA assessed using VAS on a scale of 0-100 (0 and 100 indicating no disease activity and maximum disease activity); patient's pain assessment using VAS on a scale of 0-100 (0 indicating no pain and 100 indicating unbearable pain); HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities and scored on a scale of 0-3 (0 and 3 indicating without difficulty and unable to do); high-sensitivity CRP (hsCRP).
    Time Frame Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Week 2
    6.3
    78.8%
    20.0
    1000%
    Week 4
    18.8
    235%
    0
    0%
    Posttreatment Week 4
    12.5
    156.3%
    0
    0%
    25. Secondary Outcome
    Title Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4
    Description ACR70 response is achieved when the participant has: ≥ 70% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PhGA and PtGA assessed using VAS on a scale of 0-100 [0 and 100 indicating no disease activity and maximum disease activity]; patient's pain assessment using VAS on a scale of 0-100 [0 indicating no pain and 100 indicating unbearable pain]; HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities and scored on a scale of 0-3 [0 and 3 indicating without difficulty and unable to do]; hsCRP.
    Time Frame Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    At Week 2
    0
    0%
    0
    0%
    At Week 4
    6.3
    78.8%
    0
    0%
    At Posttreatment Week 4
    0
    0%
    0
    0%
    26. Secondary Outcome
    Title Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4
    Description Hybrid ACR evaluates the improvement in active RA by combining elements of the ACR20, ACR50, and ACR70 with a continuous score of the mean change in core set measures. The percentage improvement from baseline was computed in each of the components of the ACR. The average percent improvement was calculated and used with the participant's ACR20, ACR50, and ACR70 status to compute the hybrid ACR response, with a positive change indicating improvement.
    Time Frame Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set with available data were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    At Week 2
    1.51
    (30.687)
    4.41
    (25.410)
    At Week 4
    3.29
    (36.098)
    -4.06
    (14.459)
    At Posttreatment Week 4
    0.44
    (34.589)
    -7.65
    (20.606)
    27. Secondary Outcome
    Title Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4
    Description Clinical remission is defined as DAS28-CRP < 2.6. DAS28 score was used to measure the participant's disease activity or assessments of RA calculated using the TJC28, SJC28, PtGA (VAS: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.
    Time Frame Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Week 2: Remission based on DAS28-CRP (< 2.6)
    12.5
    156.3%
    0
    0%
    Week 4: Remission based on DAS28-CRP (< 2.6)
    12.5
    156.3%
    0
    0%
    Post Week 4: Remission based on DAS28-CRP (< 2.6)
    25.0
    312.5%
    0
    0%
    28. Secondary Outcome
    Title Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4
    Description Low disease activity is defined as DAS28-CRP ≤ 3.2. DAS28 score was used to measure the participant's disease activity or assessments of RA calculated using the TJC28, SJC28, PtGA (VAS: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.
    Time Frame Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Week 2: Low Disease Activity on DAS28-CRP (<= 3.2)
    18.8
    235%
    20.0
    1000%
    Week 4: Low Disease Activity on DAS28-CRP (<= 3.2)
    12.5
    156.3%
    20.0
    1000%
    Post Week4: Low Disease Activity DAS28-CRP (<=3.2)
    37.5
    468.8%
    0
    0%
    29. Secondary Outcome
    Title Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4
    Description Clinical remission is defined as CDAI ≤ 2.8. CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.
    Time Frame Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Week 2: Remission based on CDAI (<= 2.8)
    12.5
    156.3%
    0
    0%
    Week 4: Remission based on CDAI (<= 2.8)
    6.3
    78.8%
    0
    0%
    Post Week 4: Remission based on CDAI (<= 2.8)
    6.3
    78.8%
    0
    0%
    30. Secondary Outcome
    Title Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4
    Description Low disease activity is defined as CDAI ≤ 10. CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.
    Time Frame Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Week 2: Low Disease Activity based on CDAI (<= 10)
    18.8
    235%
    20.0
    1000%
    Week 4: Low Disease Activity based on CDAI (<= 10)
    18.8
    235%
    20.0
    1000%
    Post Week 4: Low Disease Activity on CDAI (<= 10)
    31.3
    391.3%
    20.0
    1000%
    31. Secondary Outcome
    Title Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4
    Description Clinical remission is defined as SDAI ≤ 3.3. SDAI is a composite measure that sums the TJC28, SJC28, PtGA, PhGA, and the CRP (in mg/dL). PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.
    Time Frame Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Week 2: Remission based on SDAI (<= 3.3)
    12.5
    156.3%
    0
    0%
    Week 4: Remission based on SDAI (<= 3.3)
    6.3
    78.8%
    0
    0%
    Post Week 4: Remission based on SDAI (<= 3.3)
    6.3
    78.8%
    0
    0%
    32. Secondary Outcome
    Title Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4
    Description Low disease activity is defined as SDAI ≤ 11. SDAI is a composite measure that sums the TJC28, SJC28, PtGA, PhGA, and the CRP (in mg/dL). PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.
    Time Frame Weeks 2, 4 and Posttreatment Week 4

    Outcome Measure Data

    Analysis Population Description
    Participants in the Full Analysis Set were analyzed.
    Arm/Group Title Part B: Tirabrutinib 20 mg QD Part B: Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally QD for 4 weeks. Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    Measure Participants 16 5
    Week 2: Low Disease Activity based on SDAI (<= 11)
    25.0
    312.5%
    20.0
    1000%
    Week 4: Low Disease Activity based on SDAI (<= 11)
    18.8
    235%
    20.0
    1000%
    Post Week 4: Low Disease Activity on SDAI (<= 11)
    37.5
    468.8%
    20.0
    1000%

    Adverse Events

    Time Frame Adverse Events: Part A: First dose date up to last dose (maximum: 7 days) plus 30 days; Part B: First dose date up to last dose (maximum: 29 days) plus 30 days; All-Cause Mortality: First dose date up to approximately 7 months
    Adverse Event Reporting Description Participants in the Safety Analysis Set were analyzed.
    Arm/Group Title Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID Part B: Tirabrutinib 20 mg QD All Placebo
    Arm/Group Description Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week. Tirabrutinib 10 mg capsules orally twice daily (BID) (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Tirabrutinib 20 mg capsules orally QD for 4 weeks. Cohort 1, Part A: Placebo to match tirabrutinib capsules orally QD in the morning for 1 week; Cohort 2, Part A: Placebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. Part B, Placebo to match tirabrutinib capsules orally QD for 4 weeks.
    All Cause Mortality
    Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID Part B: Tirabrutinib 20 mg QD All Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/8 (0%) 0/8 (0%) 0/16 (0%) 0/9 (0%)
    Serious Adverse Events
    Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID Part B: Tirabrutinib 20 mg QD All Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/8 (0%) 0/8 (0%) 0/16 (0%) 0/9 (0%)
    Other (Not Including Serious) Adverse Events
    Cohort 1, Part A: Tirabrutinib 20 mg QD Cohort 2, Part A: Tirabrutinib 10 mg BID Part B: Tirabrutinib 20 mg QD All Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/8 (25%) 3/8 (37.5%) 6/16 (37.5%) 3/9 (33.3%)
    Blood and lymphatic system disorders
    Iron deficiency anaemia 1/8 (12.5%) 0/8 (0%) 0/16 (0%) 1/9 (11.1%)
    Endocrine disorders
    Thyroid mass 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 0/9 (0%)
    Gastrointestinal disorders
    Abdominal tenderness 0/8 (0%) 0/8 (0%) 0/16 (0%) 1/9 (11.1%)
    Nausea 0/8 (0%) 1/8 (12.5%) 0/16 (0%) 0/9 (0%)
    General disorders
    Extravasation 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 0/9 (0%)
    Infections and infestations
    Urinary tract infection 0/8 (0%) 0/8 (0%) 0/16 (0%) 1/9 (11.1%)
    Injury, poisoning and procedural complications
    Contusion 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 0/9 (0%)
    Muscle strain 0/8 (0%) 1/8 (12.5%) 0/16 (0%) 0/9 (0%)
    Tooth fracture 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 0/9 (0%)
    Metabolism and nutrition disorders
    Hypokalaemia 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 0/9 (0%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 0/9 (0%)
    Back pain 1/8 (12.5%) 2/8 (25%) 0/16 (0%) 0/9 (0%)
    Periarthritis 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 0/9 (0%)
    Rheumatoid arthritis 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 1/9 (11.1%)
    Nervous system disorders
    Headache 0/8 (0%) 1/8 (12.5%) 1/16 (6.3%) 0/9 (0%)
    Psychiatric disorders
    Insomnia 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 0/9 (0%)
    Skin and subcutaneous tissue disorders
    Ecchymosis 0/8 (0%) 0/8 (0%) 1/16 (6.3%) 0/9 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years

    Results Point of Contact

    Name/Title Gilead Clinical Study Information Center
    Organization Gilead Sciences
    Phone 1-833-445-3230 (GILEAD-0)
    Email GileadClinicalTrials@gilead.com
    Responsible Party:
    Gilead Sciences
    ClinicalTrials.gov Identifier:
    NCT02626026
    Other Study ID Numbers:
    • GS-US-407-1833
    • 2015-003240-40
    First Posted:
    Dec 10, 2015
    Last Update Posted:
    Sep 9, 2020
    Last Verified:
    Aug 1, 2020