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

A Phase 1, Placebo-Controlled, Randomized Study Evaluating the Safety and Pharmacokinetics of GS-4059 in Healthy Volunteers and Subjects With Rheumatoid Arthritis (RA)

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02626026

Enrollment

Registered

2015-12-10

Start date

2016-01-26

Completion date

2016-09-01

Last updated

2020-09-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Rheumatoid Arthritis

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).

Interventions

DRUGTirabrutinib

Capsules administered orally.

DRUGPlacebo

Capsules administered orally.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

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

Design outcomes

Primary

Measure	Time frame	Description
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.
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.
Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities	First dose date up to last dose (maximum: 7 days) plus 30 days	—
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.
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.
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.
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.
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).
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).
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.
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.
Part B: Percentage of Participants With 12-Lead ECG Abnormalities	First dose date up to last dose (maximum: 29 days) plus 30 days	—

Secondary

Measure	Time frame	Description
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).

Countries

United States

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 details

58 participants were screened and 42 participants were enrolled.

Participants by arm

Arm	Count
Cohort 1, Part A: Tirabrutinib 20 mg QD Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week.	8
Cohort 1, Part A: Placebo Placebo to match tirabrutinib capsules orally QD in the morning for 1 week.	2
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.	8
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.	2
Part B: Tirabrutinib 20 mg QD Tirabrutinib 20 mg capsules orally QD for 4 weeks.	16
Part B: Placebo Placebo to match tirabrutinib capsules orally QD for 4 weeks.	5
Total	41

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	Randomized but Never Treated	0	0	0	0	1	0

Baseline characteristics

Characteristic	Cohort 1, Part A: Placebo	Cohort 1, Part A: Tirabrutinib 20 mg QD	Cohort 2, Part A: Tirabrutinib 10 mg BID	Cohort 2, Part A: Placebo	Part B: Tirabrutinib 20 mg QD	Part B: Placebo	Total
Age, Continuous	37 years	38 years	34 years	38 years	55 years	52 years	45.5 years
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	8 Participants	8 Participants	2 Participants	2 Participants	2 Participants	24 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants	0 Participants	0 Participants	0 Participants	14 Participants	3 Participants	17 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Race Black	0 Participants	4 Participants	0 Participants	1 Participants	0 Participants	0 Participants	5 Participants
Race/Ethnicity, Customized Race White	2 Participants	4 Participants	8 Participants	1 Participants	16 Participants	5 Participants	36 Participants
Sex: Female, Male Female	1 Participants	4 Participants	2 Participants	0 Participants	13 Participants	4 Participants	24 Participants
Sex: Female, Male Male	1 Participants	4 Participants	6 Participants	2 Participants	3 Participants	1 Participants	17 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 8	0 / 8	0 / 16	0 / 9
other Total, other adverse events	2 / 8	3 / 8	6 / 16	3 / 9
serious Total, serious adverse events	0 / 8	0 / 8	0 / 16	0 / 9

Outcome results

Primary

Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib

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

Population: Participants in the PK Analysis Set were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib	Day 1	228.3 h*ng/mL	Standard Deviation 89.96
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib	Day 7	377.8 h*ng/mL	Standard Deviation 119.8
Cohort 1, Part A: Placebo	Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib	Day 1	107.1 h*ng/mL	Standard Deviation 27.54
Cohort 1, Part A: Placebo	Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib	Day 7	245.5 h*ng/mL	Standard Deviation 65.02

Primary

Part A: AUCtau: Area Under the Plasma Concentration (AUC) Versus Time Curve Over the Dosing Interval of Tirabrutinib

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

Population: Participants in the PK Analysis Set were analyzed.

Arm	Measure	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: AUCtau: Area Under the Plasma Concentration (AUC) Versus Time Curve Over the Dosing Interval of Tirabrutinib	360.5 hoursnanogram per milliliter (hng/mL)	Standard Deviation 97.49
Cohort 1, Part A: Placebo	Part A: AUCtau: Area Under the Plasma Concentration (AUC) Versus Time Curve Over the Dosing Interval of Tirabrutinib	195.2 hoursnanogram per milliliter (hng/mL)	Standard Deviation 44.43

Primary

Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib

Clast is the last observed concentration of drug in plasma.

Population: Participants in the PK Analysis Set were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib	Day 1	2.58 ng/mL	Standard Deviation 1.366
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib	Day 7	1.50 ng/mL	Standard Deviation 0.551
Cohort 1, Part A: Placebo	Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib	Day 1	5.22 ng/mL	Standard Deviation 1.729
Cohort 1, Part A: Placebo	Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib	Day 7	2.03 ng/mL	Standard Deviation 0.756

Primary

Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib

Cmax is maximum observed concentration of drug in plasma.

Population: 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	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib	Day 1	33.8 nanogram per milliliter (ng/mL)	Standard Deviation 7.94
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib	Day 7	56.4 nanogram per milliliter (ng/mL)	Standard Deviation 11.19
Cohort 1, Part A: Placebo	Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib	Day 1	16.2 nanogram per milliliter (ng/mL)	Standard Deviation 4.66
Cohort 1, Part A: Placebo	Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib	Day 7	32.3 nanogram per milliliter (ng/mL)	Standard Deviation 8.59

Primary

Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)

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

Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.

Arm	Measure	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)	25.0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)	50.0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)	37.5 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)	0 percentage of participants

Primary

Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities

Time frame: First dose date up to last dose (maximum: 7 days) plus 30 days

Population: Participants in the Safety Analysis Set were analyzed.

Arm	Measure	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities	0 percentage of participants

Primary

Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities

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

Population: Participants in the Safety Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Glucose Increased	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Gamma-glutamyl Transferase (GGT) Increased	25.0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alkaline Phosphatase Increased	0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Calcium Increased	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Fasting Glucose Increased	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Amylase	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Magnesium Increased	0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	White Blood Cells Decreased	0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Potassium Decreased	0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Triglycerides Increased	25.0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Total Cholesterol Increased	25.0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alanine Aminotransferase (ALT) Increased	25.0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Neutrophils Decreased	0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Sodium Decreased	0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Phosphorus Decreased	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Aspartate Aminotransferase (AST) Increased	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Hemoglobin Decreased	25.0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Aspartate Aminotransferase (AST) Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Hemoglobin Decreased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Neutrophils Decreased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	White Blood Cells Decreased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alanine Aminotransferase (ALT) Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alkaline Phosphatase Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Calcium Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Fasting Glucose Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Gamma-glutamyl Transferase (GGT) Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Glucose Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Phosphorus Decreased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Sodium Decreased	50.0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Total Cholesterol Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Potassium Decreased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Amylase	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Triglycerides Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Magnesium Increased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Aspartate Aminotransferase (AST) Increased	25.0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	White Blood Cells Decreased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Triglycerides Increased	37.5 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alanine Aminotransferase (ALT) Increased	25.0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Neutrophils Decreased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Magnesium Increased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Potassium Decreased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Amylase	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Sodium Decreased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Calcium Increased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Glucose Increased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alkaline Phosphatase Increased	12.5 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Phosphorus Decreased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Fasting Glucose Increased	0 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Hemoglobin Decreased	37.5 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Total Cholesterol Increased	12.5 percentage of participants
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Gamma-glutamyl Transferase (GGT) Increased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Amylase	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Gamma-glutamyl Transferase (GGT) Increased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Glucose Increased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alanine Aminotransferase (ALT) Increased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Potassium Decreased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Phosphorus Decreased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Neutrophils Decreased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Sodium Decreased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	White Blood Cells Decreased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Total Cholesterol Increased	100.0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Triglycerides Increased	50.0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alkaline Phosphatase Increased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Magnesium Increased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Calcium Increased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Hemoglobin Decreased	50.0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Fasting Glucose Increased	0 percentage of participants
Cohort 2, Part A: Placebo	Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Aspartate Aminotransferase (AST) Increased	0 percentage of participants

Primary

Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib

Tlast is the time observed for the Clast of tirabrutinib.

Population: Participants in the PK Analysis Set were analyzed.

Arm	Measure	Group	Value (MEDIAN)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib	Day 7	30.00 hours
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib	Day 1	23.92 hours
Cohort 1, Part A: Placebo	Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib	Day 1	11.92 hours
Cohort 1, Part A: Placebo	Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib	Day 7	24.00 hours

Primary

Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib

Tmax is the time observed for the Cmax of tirabrutinib.

Population: Participants in the PK Analysis Set were analyzed.

Arm	Measure	Group	Value (MEDIAN)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib	Day 1	2.00 hours
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib	Day 7	2.00 hours
Cohort 1, Part A: Placebo	Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib	Day 1	3.00 hours
Cohort 1, Part A: Placebo	Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib	Day 7	2.00 hours

Primary

Part B: Percentage of Participants Who Experienced TEAEs

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

Population: Participants in the Safety Analysis Set were analyzed.

Arm	Measure	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Experienced TEAEs	37.5 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Experienced TEAEs	40.0 percentage of participants

Primary

Part B: Percentage of Participants With 12-Lead ECG Abnormalities

Time frame: First dose date up to last dose (maximum: 29 days) plus 30 days

Population: Participants in the Safety Analysis Set were analyzed.

Arm	Measure	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants With 12-Lead ECG Abnormalities	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants With 12-Lead ECG Abnormalities	0 percentage of participants

Primary

Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities

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

Population: Participants in the Safety Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Hemoglobin Decreased	6.3 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Neutrophils Decreased	6.3 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	White Blood Cells Decreased	6.3 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alanine Aminotransferase (ALT) Increased	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Fasting Glucose Increased	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Glucose Increased	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Magnesium Increased	18.8 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Potassium Decreased	12.5 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Potassium Decreased	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Hemoglobin Decreased	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Fasting Glucose Increased	20.0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Neutrophils Decreased	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Magnesium Increased	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	White Blood Cells Decreased	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Glucose Increased	20.0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities	Alanine Aminotransferase (ALT) Increased	20.0 percentage of participants

Secondary

Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7

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

Population: 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	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 2 Hours Postdose	55.250 percentage of BTK occupancy	Standard Deviation 10.023
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 0.5 Hour Postdose	-2.765 percentage of BTK occupancy	Standard Deviation 14.6036
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 1 Hour Postdose	11.635 percentage of BTK occupancy	Standard Deviation 17.8025
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 3 Hours Postdose	62.719 percentage of BTK occupancy	Standard Deviation 7.706
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 4 Hours Postdose	66.790 percentage of BTK occupancy	Standard Deviation 7.9494
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 6 Hours Postdose	71.936 percentage of BTK occupancy	Standard Deviation 8.3606
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 12 Hours Postdose	77.411 percentage of BTK occupancy	Standard Deviation 8.6928
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 18 Hours Postdose	81.187 percentage of BTK occupancy	Standard Deviation 8.8687
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 24 Hours Postdose	72.691 percentage of BTK occupancy	Standard Deviation 10.8289
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 3, Predose	84.010 percentage of BTK occupancy	Standard Deviation 8.4919
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 3, 2 Hours Postdose	90.606 percentage of BTK occupancy	Standard Deviation 6.1066
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 5, Predose	70.841 percentage of BTK occupancy	Standard Deviation 43.0596
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 5, 2 Hours Postdose	93.128 percentage of BTK occupancy	Standard Deviation 4.0582
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, Predose	86.936 percentage of BTK occupancy	Standard Deviation 6.4745
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 0.5 Hours Postdose	87.013 percentage of BTK occupancy	Standard Deviation 5.2426
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 1 Hour Postdose	86.274 percentage of BTK occupancy	Standard Deviation 6.072
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 2 Hours Postdose	92.651 percentage of BTK occupancy	Standard Deviation 3.4603
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 3 Hours Postdose	92.983 percentage of BTK occupancy	Standard Deviation 2.1906
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 4 Hours Postdose	90.070 percentage of BTK occupancy	Standard Deviation 7.4086
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 12 Hours Postdose	91.251 percentage of BTK occupancy	Standard Deviation 6.03
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 18 Hours Postdose	85.209 percentage of BTK occupancy	Standard Deviation 5.0694
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 24 Hours Postdose	86.256 percentage of BTK occupancy	Standard Deviation 6.5648
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 96 Hours Postdose	24.922 percentage of BTK occupancy	Standard Deviation 6.87
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 120 Hours Postdose	15.285 percentage of BTK occupancy	Standard Deviation 9.414
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, Predose	0 percentage of BTK occupancy	Standard Deviation 0
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 8 Hours Postdose	75.350 percentage of BTK occupancy	Standard Deviation 11.5216
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 6 Hours Postdose	91.591 percentage of BTK occupancy	Standard Deviation 7.7733
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 8 Hours Postdose	92.789 percentage of BTK occupancy	Standard Deviation 3.2221
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 36 Hours Postdose	71.963 percentage of BTK occupancy	Standard Deviation 10.555
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 48 Hours Postdose	64.763 percentage of BTK occupancy	Standard Deviation 14.3072
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 60 Hours Postdose	57.431 percentage of BTK occupancy	Standard Deviation 9.0638
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 72 Hours Postdose	46.218 percentage of BTK occupancy	Standard Deviation 14.3155
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 96 Hours Postdose	-41.721 percentage of BTK occupancy	Standard Deviation 32.0255
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, Predose	0 percentage of BTK occupancy	Standard Deviation 0
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 2 Hours Postdose	-34.573 percentage of BTK occupancy	Standard Deviation 17.962
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 0.5 Hour Postdose	-4.686 percentage of BTK occupancy	Standard Deviation 1.8358
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 8 Hours Postdose	-16.584 percentage of BTK occupancy	Standard Deviation 17.8202
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 1 Hour Postdose	-11.927 percentage of BTK occupancy	Standard Deviation 8.4893
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 2 Hours Postdose	-8.959 percentage of BTK occupancy	Standard Deviation 16.7122
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 3 Hours Postdose	-32.920 percentage of BTK occupancy	Standard Deviation 20.1029
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 3 Hours Postdose	-9.810 percentage of BTK occupancy	Standard Deviation 18.8212
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 0.5 Hours Postdose	-23.284 percentage of BTK occupancy	Standard Deviation 9.9539
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 4 Hours Postdose	-16.597 percentage of BTK occupancy	Standard Deviation 25.0492
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 8 Hours Postdose	-31.144 percentage of BTK occupancy	Standard Deviation 20.1974
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 6 Hours Postdose	-6.014 percentage of BTK occupancy	Standard Deviation 19.5348
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 4 Hours Postdose	-37.253 percentage of BTK occupancy	Standard Deviation 16.2208
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 12 Hours Postdose	6.170 percentage of BTK occupancy	Standard Deviation 12.7312
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 12 Hours Postdose	-33.947 percentage of BTK occupancy	Standard Deviation 16.3475
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 18 Hours Postdose	-2.261 percentage of BTK occupancy	Standard Deviation 27.3338
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 48 Hours Postdose	-46.249 percentage of BTK occupancy	Standard Deviation 24.2785
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 1, 24 Hours Postdose	-28.029 percentage of BTK occupancy	Standard Deviation 10.1821
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 18 Hours Postdose	-34.408 percentage of BTK occupancy	Standard Deviation 12.5471
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 3, Predose	-19.564 percentage of BTK occupancy	Standard Deviation 20.3282
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 6 Hours Postdose	-39.632 percentage of BTK occupancy	Standard Deviation 13.1749
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 3, 2 Hours Postdose	-35.206 percentage of BTK occupancy	Standard Deviation 25.2258
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 24 Hours Postdose	-42.577 percentage of BTK occupancy	Standard Deviation 17.2138
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 5, Predose	25.095 percentage of BTK occupancy	Standard Deviation 99.0827
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 72 Hours Postdose	-49.093 percentage of BTK occupancy	Standard Deviation 21.4447
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 5, 2 Hours Postdose	-25.646 percentage of BTK occupancy	Standard Deviation 17.6912
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 60 Hours Postdose	-15.465 percentage of BTK occupancy	Standard Deviation 9.4556
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, Predose	-22.662 percentage of BTK occupancy	Standard Deviation 23.6252
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 120 Hours Postdose	-48.863 percentage of BTK occupancy	Standard Deviation 20.7533
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 36 Hours Postdose	-43.574 percentage of BTK occupancy	Standard Deviation 8.4952
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7	Day 7, 1 Hour Postdose	-12.230 percentage of BTK occupancy	Standard Deviation 6.6727

Secondary

Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7

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

Population: 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	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 5, Predose	55.680 percentage of Inhibition	Standard Deviation 21.5018
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 2 Hours Postdose	79.910 percentage of Inhibition	Standard Deviation 15.3155
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 5, 2 Hours Postdose	80.271 percentage of Inhibition	Standard Deviation 16.8806
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, Predose	56.986 percentage of Inhibition	Standard Deviation 20.3972
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 6 Hours Postdose	34.966 percentage of Inhibition	Standard Deviation 15.6436
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, Predose	0 percentage of Inhibition	Standard Deviation 0
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 24 Hours Postdose	52.017 percentage of Inhibition	Standard Deviation 17.5829
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 2 Hours Postdose	17.189 percentage of Inhibition	Standard Deviation 6.8306
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 24 Hours Postdose	33.305 percentage of Inhibition	Standard Deviation 14.9248
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 3, Predose	47.416 percentage of Inhibition	Standard Deviation 17.047
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 6 Hours Postdose	88.102 percentage of Inhibition	Standard Deviation 11.6072
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 3, 2 Hours Postdose	73.972 percentage of Inhibition	Standard Deviation 15.1658
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, Predose	0 percentage of Inhibition	Standard Deviation 0
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 5, Predose	2.779 percentage of Inhibition	Standard Deviation 3.7023
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 24 Hours Postdose	-0.046 percentage of Inhibition	Standard Deviation 0.6432
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 6 Hours Postdose	-1.320 percentage of Inhibition	Standard Deviation 8.1776
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 2 Hours Postdose	-2.831 percentage of Inhibition	Standard Deviation 0.7358
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 5, 2 Hours Postdose	-0.043 percentage of Inhibition	Standard Deviation 2.3069
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, Predose	5.234 percentage of Inhibition	Standard Deviation 0.8757
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 24 Hours Postdose	5.604 percentage of Inhibition	Standard Deviation 1.2275
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 3, 2 Hours Postdose	-0.842 percentage of Inhibition	Standard Deviation 4.6395
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 6 Hours Postdose	8.779 percentage of Inhibition	Standard Deviation 9.9101
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 3, Predose	0.917 percentage of Inhibition	Standard Deviation 11.4281
Cohort 1, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 2 Hours Postdose	0.272 percentage of Inhibition	Standard Deviation 2.3326
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 5, 2 Hours Postdose	91.159 percentage of Inhibition	Standard Deviation 7.474
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, Predose	0 percentage of Inhibition	Standard Deviation 0
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 2 Hours Postdose	19.557 percentage of Inhibition	Standard Deviation 11.0479
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 6 Hours Postdose	27.506 percentage of Inhibition	Standard Deviation 16.0744
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 12 Hours Postdose	35.008 percentage of Inhibition	Standard Deviation 24.1663
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 3, Predose	83.832 percentage of Inhibition	Standard Deviation 10.1042
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 3, 2 Hours Postdose	90.187 percentage of Inhibition	Standard Deviation 5.6699
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 5, Predose	83.380 percentage of Inhibition	Standard Deviation 10.3976
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, Predose	80.024 percentage of Inhibition	Standard Deviation 11.0371
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 2 Hours Postdose	88.032 percentage of Inhibition	Standard Deviation 7.875
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 6 Hours Postdose	89.681 percentage of Inhibition	Standard Deviation 7.0909
Cohort 2, Part A: Tirabrutinib 10 mg BID	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 12 Hours Postdose	80.640 percentage of Inhibition	Standard Deviation 10.0574
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 3, 2 Hours Postdose	-13.641 percentage of Inhibition	Standard Deviation 13.0667
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 6 Hours Postdose	1.782 percentage of Inhibition	Standard Deviation 6.3117
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 2 Hours Postdose	-0.978 percentage of Inhibition	Standard Deviation 9.938
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 3, Predose	-11.354 percentage of Inhibition	Standard Deviation 16.5029
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 12 Hours Postdose	-2.688 percentage of Inhibition	Standard Deviation 16.7688
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, 2 Hours Postdose	3.568 percentage of Inhibition	Standard Deviation 1.4734
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 6 Hours Postdose	-2.645 percentage of Inhibition	Standard Deviation 6.3382
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 1, Predose	0 percentage of Inhibition	Standard Deviation 0
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 5, 2 Hours Postdose	-15.923 percentage of Inhibition	Standard Deviation 11.5733
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, 12 Hours Postdose	-10.062 percentage of Inhibition	Standard Deviation 13.2554
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 7, Predose	6.271 percentage of Inhibition	Standard Deviation 7.979
Cohort 2, Part A: Placebo	Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7	Day 5, Predose	-2.271 percentage of Inhibition	Standard Deviation 0.206

Secondary

Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at 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.

Time frame: Baseline; Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4	Baseline	29.63 score on a scale	Standard Deviation 19.994
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 2	-4.44 score on a scale	Standard Deviation 11.748
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 4	-6.80 score on a scale	Standard Deviation 13.925
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Posttreatment Week 4	-4.73 score on a scale	Standard Deviation 14.18
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Posttreatment Week 4	-1.74 score on a scale	Standard Deviation 11.562
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4	Baseline	31.96 score on a scale	Standard Deviation 18.622
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 4	-2.02 score on a scale	Standard Deviation 5.206
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 2	-5.32 score on a scale	Standard Deviation 13.264

Secondary

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

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

Population: 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	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	4.54 score on a scale	Standard Deviation 1.728
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Week 2	-0.35 score on a scale	Standard Deviation 0.821
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Week 4	-0.45 score on a scale	Standard Deviation 1.097
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Posttreatment Week 4	-0.41 score on a scale	Standard Deviation 1.208
Cohort 1, Part A: Placebo	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	Change from Baseline at Posttreatment Week 4	-0.05 score on a scale	Standard Deviation 0.782
Cohort 1, Part A: Placebo	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	5.12 score on a scale	Standard Deviation 1.576
Cohort 1, Part A: Placebo	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	Change from Baseline at Week 4	-0.11 score on a scale	Standard Deviation 0.612
Cohort 1, Part A: Placebo	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	Change from Baseline at Week 2	-0.28 score on a scale	Standard Deviation 0.977

Secondary

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

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

Population: Participants in the Full Analysis Set with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	42 score on a scale	Standard Deviation 27.4
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Week 2	-10 score on a scale	Standard Deviation 20.7
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Week 4	-10 score on a scale	Standard Deviation 22.1
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Posttreatment Week 4	-4 score on a scale	Standard Deviation 22.2
Cohort 1, Part A: Placebo	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	Change from Baseline at Posttreatment Week 4	-9 score on a scale	Standard Deviation 17.8
Cohort 1, Part A: Placebo	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	63 score on a scale	Standard Deviation 30.5
Cohort 1, Part A: Placebo	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	Change from Baseline at Week 4	-10 score on a scale	Standard Deviation 16.7
Cohort 1, Part A: Placebo	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	Change from Baseline at Week 2	-6 score on a scale	Standard Deviation 17.6

Secondary

Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at 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.

Time frame: Baseline; Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 4	-9 score on a scale	Standard Deviation 24.6
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4	Baseline	39 score on a scale	Standard Deviation 28.6
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Posttreatment Week 4	-2 score on a scale	Standard Deviation 22.9
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 2	-5 score on a scale	Standard Deviation 26.2
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 2	-6 score on a scale	Standard Deviation 15.7
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 4	-13 score on a scale	Standard Deviation 16.2
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Posttreatment Week 4	-11 score on a scale	Standard Deviation 24.9
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4	Baseline	59 score on a scale	Standard Deviation 28.9

Secondary

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

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

Population: Participants in the Full Analysis Set with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	39 score on a scale	Standard Deviation 27.4
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Week 2	-3 score on a scale	Standard Deviation 23.5
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Week 4	-8 score on a scale	Standard Deviation 20.3
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Posttreatment Week 4	-4 score on a scale	Standard Deviation 22.7
Cohort 1, Part A: Placebo	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	Change from Baseline at Posttreatment Week 4	-3 score on a scale	Standard Deviation 17.7
Cohort 1, Part A: Placebo	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	49 score on a scale	Standard Deviation 15.5
Cohort 1, Part A: Placebo	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	Change from Baseline at Week 4	5 score on a scale	Standard Deviation 14.9
Cohort 1, Part A: Placebo	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	Change from Baseline at Week 2	-16 score on a scale	Standard Deviation 13.4

Secondary

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

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

Population: Participants in the Full Analysis Set with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	12.70 swollen joint count	Standard Deviation 10.944
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Week 2	-4.13 swollen joint count	Standard Deviation 6.446
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Week 4	-4.82 swollen joint count	Standard Deviation 7.586
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baseline at Posttreatment Week 4	-3.07 swollen joint count	Standard Deviation 5.272
Cohort 1, Part A: Placebo	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	Change from Baseline at Posttreatment Week 4	1.53 swollen joint count	Standard Deviation 3.035
Cohort 1, Part A: Placebo	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	12.04 swollen joint count	Standard Deviation 12.488
Cohort 1, Part A: Placebo	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	Change from Baseline at Week 4	-2.23 swollen joint count	Standard Deviation 6.048
Cohort 1, Part A: Placebo	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	Change from Baseline at Week 2	-2.58 swollen joint count	Standard Deviation 9.91

Secondary

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

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

Population: Participants in the Full Analysis Set with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	18.20 tender joint count	Standard Deviation 14.454
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baselline at Week 2	-2.57 tender joint count	Standard Deviation 6.666
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baselline at Week 4	-6.69 tender joint count	Standard Deviation 8.432
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Change from Baselline at Posttreatment Week 4	-3.13 tender joint count	Standard Deviation 9.968
Cohort 1, Part A: Placebo	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	Change from Baselline at Posttreatment Week 4	1.11 tender joint count	Standard Deviation 12.638
Cohort 1, Part A: Placebo	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	21.70 tender joint count	Standard Deviation 12.656
Cohort 1, Part A: Placebo	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	Change from Baselline at Week 4	0.01 tender joint count	Standard Deviation 0.829
Cohort 1, Part A: Placebo	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	Change from Baselline at Week 2	-1.17 tender joint count	Standard Deviation 7.98

Secondary

Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at 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.

Time frame: Baseline; Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4	Baseline	30.19 score on a scale	Standard Deviation 20.283
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 2	-4.49 score on a scale	Standard Deviation 11.786
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 4	-6.84 score on a scale	Standard Deviation 14.016
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Posttreatment Week 4	-4.82 score on a scale	Standard Deviation 14.349
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Posttreatment Week 4	-1.16 score on a scale	Standard Deviation 12.293
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4	Baseline	33.20 score on a scale	Standard Deviation 19.061
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 4	-1.69 score on a scale	Standard Deviation 5.439
Cohort 1, Part A: Placebo	Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 2	-5.20 score on a scale	Standard Deviation 14.035

Secondary

Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at 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.

Time frame: Baseline; Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4	Baseline	1.063 score on a scale	Standard Deviation 0.713
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 2	-0.203 score on a scale	Standard Deviation 0.5242
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 4	-0.234 score on a scale	Standard Deviation 0.4492
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Posttreatment Week 4	-0.156 score on a scale	Standard Deviation 0.355
Cohort 1, Part A: Placebo	Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Posttreatment Week 4	0.094 score on a scale	Standard Deviation 0.1197
Cohort 1, Part A: Placebo	Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4	Baseline	1.650 score on a scale	Standard Deviation 0.7776
Cohort 1, Part A: Placebo	Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 4	-0.100 score on a scale	Standard Deviation 0.3687
Cohort 1, Part A: Placebo	Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4	Change from Baseline at Week 2	-0.150 score on a scale	Standard Deviation 0.2054

Secondary

Part B: Hybrid ACR Improvement Response at 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.

Time frame: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set with available data were analyzed.

Arm	Measure	Group	Value (MEAN)	Dispersion
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4	At Week 2	1.51 percent improvement	Standard Deviation 30.687
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4	At Week 4	3.29 percent improvement	Standard Deviation 36.098
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4	At Posttreatment Week 4	0.44 percent improvement	Standard Deviation 34.589
Cohort 1, Part A: Placebo	Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4	At Week 2	4.41 percent improvement	Standard Deviation 25.41
Cohort 1, Part A: Placebo	Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4	At Week 4	-4.06 percent improvement	Standard Deviation 14.459
Cohort 1, Part A: Placebo	Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4	At Posttreatment Week 4	-7.65 percent improvement	Standard Deviation 20.606

Secondary

Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at 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.

Time frame: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4	At Week 2	0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4	At Week 4	6.3 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4	At Posttreatment Week 4	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4	At Week 2	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4	At Week 4	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4	At Posttreatment Week 4	0 percentage of participants

Secondary

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

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

Population: Participants in the Full Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Week 4	18.8 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Week 2	6.3 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	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	Posttreatment Week 4	12.5 percentage of participants
Cohort 1, Part A: Placebo	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	Week 4	0 percentage of participants
Cohort 1, Part A: Placebo	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	Posttreatment Week 4	0 percentage of participants
Cohort 1, Part A: Placebo	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	Week 2	20.0 percentage of participants

Secondary

Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at 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.

Time frame: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Week 2: Low Disease Activity based on CDAI (<= 10)	18.8 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Week 4: Low Disease Activity based on CDAI (<= 10)	18.8 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Low Disease Activity on CDAI (<= 10)	31.3 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Week 2: Low Disease Activity based on CDAI (<= 10)	20.0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Week 4: Low Disease Activity based on CDAI (<= 10)	20.0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Low Disease Activity on CDAI (<= 10)	20.0 percentage of participants

Secondary

Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at 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.

Time frame: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Week 2: Low Disease Activity on DAS28-CRP (<= 3.2)	18.8 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Week 4: Low Disease Activity on DAS28-CRP (<= 3.2)	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Post Week4: Low Disease Activity DAS28-CRP (<=3.2)	37.5 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Week 2: Low Disease Activity on DAS28-CRP (<= 3.2)	20.0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Week 4: Low Disease Activity on DAS28-CRP (<= 3.2)	20.0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Post Week4: Low Disease Activity DAS28-CRP (<=3.2)	0 percentage of participants

Secondary

Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at 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.

Time frame: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Week 2: Low Disease Activity based on SDAI (<= 11)	25.0 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Week 4: Low Disease Activity based on SDAI (<= 11)	18.8 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Low Disease Activity on SDAI (<= 11)	37.5 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Week 2: Low Disease Activity based on SDAI (<= 11)	20.0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Week 4: Low Disease Activity based on SDAI (<= 11)	20.0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Low Disease Activity on SDAI (<= 11)	20.0 percentage of participants

Secondary

Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at 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.

Time frame: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Week 2: Remission based on CDAI (<= 2.8)	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Week 4: Remission based on CDAI (<= 2.8)	6.3 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Remission based on CDAI (<= 2.8)	6.3 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Week 2: Remission based on CDAI (<= 2.8)	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Week 4: Remission based on CDAI (<= 2.8)	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Remission based on CDAI (<= 2.8)	0 percentage of participants

Secondary

Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at 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.

Time frame: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Week 2: Remission based on DAS28-CRP (< 2.6)	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Week 4: Remission based on DAS28-CRP (< 2.6)	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Remission based on DAS28-CRP (< 2.6)	25.0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Week 2: Remission based on DAS28-CRP (< 2.6)	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Week 4: Remission based on DAS28-CRP (< 2.6)	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Remission based on DAS28-CRP (< 2.6)	0 percentage of participants

Secondary

Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at 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.

Time frame: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

Arm	Measure	Group	Value (NUMBER)
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Week 2: Remission based on SDAI (<= 3.3)	12.5 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Week 4: Remission based on SDAI (<= 3.3)	6.3 percentage of participants
Cohort 1, Part A: Tirabrutinib 20 mg QD	Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Remission based on SDAI (<= 3.3)	6.3 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Week 2: Remission based on SDAI (<= 3.3)	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Week 4: Remission based on SDAI (<= 3.3)	0 percentage of participants
Cohort 1, Part A: Placebo	Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4	Post Week 4: Remission based on SDAI (<= 3.3)	0 percentage of participants

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

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

Conditions

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib

Part A: AUCtau: Area Under the Plasma Concentration (AUC) Versus Time Curve Over the Dosing Interval of Tirabrutinib

Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib

Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib

Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)

Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities

Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities

Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib

Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib

Part B: Percentage of Participants Who Experienced TEAEs

Part B: Percentage of Participants With 12-Lead ECG Abnormalities

Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities

Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7

Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7

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

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

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

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

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

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

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

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

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

Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4

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

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

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

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

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

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

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

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