Trial Outcomes & Findings for Study to Evaluate Safety and Pharmacokinetics of GS-4059 (Tirabrutinib) in Healthy Volunteers and Participants With Rheumatoid Arthritis (RA) (NCT NCT02626026)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

42 participants

Primary outcome timeframe

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

Results posted on

2020-09-09

Participant Flow

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.

58 participants were screened and 42 participants were enrolled.

Participant milestones

Participant milestones
Measure	Cohort 1, Part A: Tirabrutinib 20 mg QD Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week.	Cohort 1, Part A: Placebo Placebo to match tirabrutinib capsules orally QD in the morning for 1 week.	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.	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.	Part B: Tirabrutinib 20 mg QD Tirabrutinib 20 mg capsules orally QD for 4 weeks.	Part B: Placebo Placebo to match tirabrutinib capsules orally QD for 4 weeks.
Overall Study STARTED	8	2	8	2	17	5
Overall Study COMPLETED	8	2	8	2	16	5
Overall Study NOT COMPLETED	0	0	0	0	1	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1, Part A: Tirabrutinib 20 mg QD Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week.	Cohort 1, Part A: Placebo Placebo to match tirabrutinib capsules orally QD in the morning for 1 week.	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.	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.	Part B: Tirabrutinib 20 mg QD Tirabrutinib 20 mg capsules orally QD for 4 weeks.	Part B: Placebo Placebo to match tirabrutinib capsules orally QD for 4 weeks.
Overall Study Randomized but Never Treated	0	0	0	0	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week.	Cohort 1, Part A: Placebo n=2 Participants Placebo to match tirabrutinib capsules orally QD in the morning for 1 week.	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants 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.	Cohort 2, Part A: Placebo n=2 Participants Placebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Part B: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD for 4 weeks.	Part B: Placebo n=5 Participants Placebo to match tirabrutinib capsules orally QD for 4 weeks.	Total n=41 Participants Total of all reporting groups
Age, Continuous	38 years n=5 Participants	37 years n=7 Participants	34 years n=5 Participants	38 years n=4 Participants	55 years n=21 Participants	52 years n=10 Participants	45.5 years n=115 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants	0 Participants n=4 Participants	13 Participants n=21 Participants	4 Participants n=10 Participants	24 Participants n=115 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	1 Participants n=7 Participants	6 Participants n=5 Participants	2 Participants n=4 Participants	3 Participants n=21 Participants	1 Participants n=10 Participants	17 Participants n=115 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants	2 Participants n=4 Participants	2 Participants n=21 Participants	2 Participants n=10 Participants	24 Participants n=115 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	14 Participants n=21 Participants	3 Participants n=10 Participants	17 Participants n=115 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	0 Participants n=115 Participants
Race/Ethnicity, Customized Race · Black	4 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants	5 Participants n=115 Participants
Race/Ethnicity, Customized Race · White	4 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants	1 Participants n=4 Participants	16 Participants n=21 Participants	5 Participants n=10 Participants	36 Participants n=115 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=2 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants 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.	Cohort 2, Part A: Placebo n=2 Participants Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)	50.0 percentage of participants	25.0 percentage of participants	37.5 percentage of participants	0 percentage of participants

PRIMARY outcome

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

Population: Participants in the Safety Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=2 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants 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.	Cohort 2, Part A: Placebo n=2 Participants Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Hemoglobin Decreased	0 percentage of participants	25.0 percentage of participants	37.5 percentage of participants	50.0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Neutrophils Decreased	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities White Blood Cells Decreased	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Alanine Aminotransferase (ALT) Increased	0 percentage of participants	25.0 percentage of participants	25.0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Aspartate Aminotransferase (AST) Increased	0 percentage of participants	12.5 percentage of participants	25.0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Alkaline Phosphatase Increased	0 percentage of participants	0 percentage of participants	12.5 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Amylase	0 percentage of participants	12.5 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Calcium Increased	0 percentage of participants	12.5 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Fasting Glucose Increased	0 percentage of participants	12.5 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Gamma-glutamyl Transferase (GGT) Increased	0 percentage of participants	25.0 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Glucose Increased	0 percentage of participants	12.5 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Phosphorus Decreased	0 percentage of participants	12.5 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Sodium Decreased	50.0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Total Cholesterol Increased	0 percentage of participants	25.0 percentage of participants	12.5 percentage of participants	100.0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Triglycerides Increased	0 percentage of participants	25.0 percentage of participants	37.5 percentage of participants	50.0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Magnesium Increased	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants
Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Potassium Decreased	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants

PRIMARY outcome

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

Population: Participants in the Safety Analysis Set were analyzed.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=2 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants 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.	Cohort 2, Part A: Placebo n=2 Participants Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities	0 percentage of participants	0 percentage of participants	0 percentage of participants	0 percentage of participants

PRIMARY outcome

Timeframe: 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: 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.

Cmax is maximum observed concentration of drug in plasma.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib Day 1	16.2 nanogram per milliliter (ng/mL) Standard Deviation 4.66	33.8 nanogram per milliliter (ng/mL) Standard Deviation 7.94	—	—
Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib Day 7	32.3 nanogram per milliliter (ng/mL) Standard Deviation 8.59	56.4 nanogram per milliliter (ng/mL) Standard Deviation 11.19	—	—

PRIMARY outcome

Timeframe: 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.

Clast is the last observed concentration of drug in plasma.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib Day 1	5.22 ng/mL Standard Deviation 1.729	2.58 ng/mL Standard Deviation 1.366	—	—
Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib Day 7	2.03 ng/mL Standard Deviation 0.756	1.50 ng/mL Standard Deviation 0.551	—	—

PRIMARY outcome

Timeframe: 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.

Tmax is the time observed for the Cmax of tirabrutinib.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib Day 1	3.00 hours Interval 1.5 to 4.0	2.00 hours Interval 1.5 to 4.0	—	—
Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib Day 7	2.00 hours Interval 1.5 to 4.0	2.00 hours Interval 1.5 to 3.0	—	—

PRIMARY outcome

Timeframe: 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.

Tlast is the time observed for the Clast of tirabrutinib.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib Day 1	11.92 hours Interval 11.92 to 12.0	23.92 hours Interval 12.0 to 23.92	—	—
Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib Day 7	24.00 hours Interval 18.0 to 36.0	30.00 hours Interval 24.0 to 48.0	—	—

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	360.5 hoursnanogram per milliliter (hng/mL) Standard Deviation 97.49	—	—

PRIMARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=8 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	228.3 h*ng/mL Standard Deviation 89.96	—	—
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	377.8 h*ng/mL Standard Deviation 119.80	—	—

PRIMARY outcome

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

Population: Participants in the Safety Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part B: Percentage of Participants Who Experienced TEAEs	40.0 percentage of participants	37.5 percentage of participants	—	—

PRIMARY outcome

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

Population: Participants in the Safety Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Hemoglobin Decreased	0 percentage of participants	6.3 percentage of participants	—	—
Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Neutrophils Decreased	0 percentage of participants	6.3 percentage of participants	—	—
Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities White Blood Cells Decreased	0 percentage of participants	6.3 percentage of participants	—	—
Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Alanine Aminotransferase (ALT) Increased	20.0 percentage of participants	12.5 percentage of participants	—	—
Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Fasting Glucose Increased	20.0 percentage of participants	12.5 percentage of participants	—	—
Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Glucose Increased	20.0 percentage of participants	12.5 percentage of participants	—	—
Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Magnesium Increased	0 percentage of participants	18.8 percentage of participants	—	—
Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities Potassium Decreased	0 percentage of participants	12.5 percentage of participants	—	—

PRIMARY outcome

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

Population: Participants in the Safety Analysis Set were analyzed.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part B: Percentage of Participants With 12-Lead ECG Abnormalities	0 percentage of participants	0 percentage of participants	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=2 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=7 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	Cohort 2, Part A: Tirabrutinib 10 mg BID n=8 Participants 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.	Cohort 2, Part A: Placebo n=2 Participants Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	0 percentage of Inhibition Standard Deviation 0	0 percentage of Inhibition Standard Deviation 0	0 percentage of Inhibition Standard Deviation 0
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	17.189 percentage of Inhibition Standard Deviation 6.8306	19.557 percentage of Inhibition Standard Deviation 11.0479	3.568 percentage of Inhibition Standard Deviation 1.4734
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	34.966 percentage of Inhibition Standard Deviation 15.6436	27.506 percentage of Inhibition Standard Deviation 16.0744	1.782 percentage of Inhibition Standard Deviation 6.3117
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	-2.688 percentage of Inhibition Standard Deviation 16.7688
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	33.305 percentage of Inhibition Standard Deviation 14.9248	—	—
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	47.416 percentage of Inhibition Standard Deviation 17.0470	83.832 percentage of Inhibition Standard Deviation 10.1042	-11.354 percentage of Inhibition Standard Deviation 16.5029
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	73.972 percentage of Inhibition Standard Deviation 15.1658	90.187 percentage of Inhibition Standard Deviation 5.6699	-13.641 percentage of Inhibition Standard Deviation 13.0667
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	55.680 percentage of Inhibition Standard Deviation 21.5018	83.380 percentage of Inhibition Standard Deviation 10.3976	-2.271 percentage of Inhibition Standard Deviation 0.2060
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	80.271 percentage of Inhibition Standard Deviation 16.8806	91.159 percentage of Inhibition Standard Deviation 7.4740	-15.923 percentage of Inhibition Standard Deviation 11.5733
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	56.986 percentage of Inhibition Standard Deviation 20.3972	80.024 percentage of Inhibition Standard Deviation 11.0371	6.271 percentage of Inhibition Standard Deviation 7.9790
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	79.910 percentage of Inhibition Standard Deviation 15.3155	88.032 percentage of Inhibition Standard Deviation 7.8750	-0.978 percentage of Inhibition Standard Deviation 9.9380
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	88.102 percentage of Inhibition Standard Deviation 11.6072	89.681 percentage of Inhibition Standard Deviation 7.0909	-2.645 percentage of Inhibition Standard Deviation 6.3382
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	-10.062 percentage of Inhibition Standard Deviation 13.2554
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	52.017 percentage of Inhibition Standard Deviation 17.5829	—	—

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	4.54 score on a scale Standard Deviation 1.728	—	—
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	-0.35 score on a scale Standard Deviation 0.821	—	—
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	-0.45 score on a scale Standard Deviation 1.097	—	—
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	-0.41 score on a scale Standard Deviation 1.208	—	—

SECONDARY outcome

Timeframe: Baseline; Weeks 2, 4 and Posttreatment Week 4

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

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	18.20 tender joint count Standard Deviation 14.454	—	—
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 7.980	-2.57 tender joint count Standard Deviation 6.666	—	—
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	-6.69 tender joint count Standard Deviation 8.432	—	—
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	-3.13 tender joint count Standard Deviation 9.968	—	—

SECONDARY outcome

Timeframe: Baseline; Weeks 2, 4 and Posttreatment Week

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

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	12.70 swollen joint count Standard Deviation 10.944	—	—
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 9.910	-4.13 swollen joint count Standard Deviation 6.446	—	—
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	-4.82 swollen joint count Standard Deviation 7.586	—	—
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	-3.07 swollen joint count Standard Deviation 5.272	—	—

SECONDARY outcome

Timeframe: Baseline; Weeks 2, 4 and Posttreatment Week 4

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

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	30.19 score on a scale Standard Deviation 20.283	—	—
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	-4.49 score on a scale Standard Deviation 11.786	—	—
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	-6.84 score on a scale Standard Deviation 14.016	—	—
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	-4.82 score on a scale Standard Deviation 14.349	—	—

SECONDARY outcome

Timeframe: Baseline; Weeks 2, 4 and Posttreatment Week 4

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

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	29.63 score on a scale Standard Deviation 19.994	—	—
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	-4.44 score on a scale Standard Deviation 11.748	—	—
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	-6.80 score on a scale Standard Deviation 13.925	—	—
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	-4.73 score on a scale Standard Deviation 14.180	—	—

SECONDARY outcome

Timeframe: Baseline; Weeks 2, 4 and Posttreatment Week 4

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

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	42 score on a scale Standard Deviation 27.4	—	—
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 Change from Baseline at Week 2	-6 score on a scale Standard Deviation 17.6	-10 score on a scale Standard Deviation 20.7	—	—
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	-10 score on a scale Standard Deviation 22.1	—	—
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	-4 score on a scale Standard Deviation 22.2	—	—

SECONDARY outcome

Timeframe: Baseline; Weeks 2, 4 and Posttreatment Week 4

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

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	39 score on a scale Standard Deviation 27.4	—	—
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 Change from Baseline at Week 2	-16 score on a scale Standard Deviation 13.4	-3 score on a scale Standard Deviation 23.5	—	—
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	-8 score on a scale Standard Deviation 20.3	—	—
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	-4 score on a scale Standard Deviation 22.7	—	—

SECONDARY outcome

Timeframe: Baseline; Weeks 2, 4 and Posttreatment Week 4

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

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	39 score on a scale Standard Deviation 28.6	—	—
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	-5 score on a scale Standard Deviation 26.2	—	—
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	-9 score on a scale Standard Deviation 24.6	—	—
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	-2 score on a scale Standard Deviation 22.9	—	—

SECONDARY outcome

Timeframe: Baseline; Weeks 2, 4 and Posttreatment Week 4

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

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	1.063 score on a scale Standard Deviation 0.7130	—	—
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	-0.203 score on a scale Standard Deviation 0.5242	—	—
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	-0.234 score on a scale Standard Deviation 0.4492	—	—
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	-0.156 score on a scale Standard Deviation 0.3550	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

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).

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	6.3 percentage of participants	—	—
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	18.8 percentage of participants	—	—
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	12.5 percentage of participants	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	0 percentage of participants	—	—
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	6.3 percentage of participants	—	—
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	0 percentage of participants	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4 and Posttreatment Week 4

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

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4 At Week 2	4.41 percent improvement Standard Deviation 25.410	1.51 percent improvement Standard Deviation 30.687	—	—
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	3.29 percent improvement Standard Deviation 36.098	—	—
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	0.44 percent improvement Standard Deviation 34.589	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	12.5 percentage of participants	—	—
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	12.5 percentage of participants	—	—
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	25.0 percentage of participants	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	18.8 percentage of participants	—	—
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	12.5 percentage of participants	—	—
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	37.5 percentage of participants	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	12.5 percentage of participants	—	—
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	6.3 percentage of participants	—	—
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	6.3 percentage of participants	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	18.8 percentage of participants	—	—
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	18.8 percentage of participants	—	—
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	31.3 percentage of participants	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	12.5 percentage of participants	—	—
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	6.3 percentage of participants	—	—
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	6.3 percentage of participants	—	—

SECONDARY outcome

Timeframe: Weeks 2, 4 and Posttreatment Week 4

Population: Participants in the Full Analysis Set were analyzed.

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.

Outcome measures

Outcome measures
Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=5 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=16 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	25.0 percentage of participants	—	—
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	18.8 percentage of participants	—	—
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	37.5 percentage of participants	—	—

Adverse Events

Cohort 1, Part A: Tirabrutinib 20 mg QD

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Cohort 2, Part A: Tirabrutinib 10 mg BID

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Part B: Tirabrutinib 20 mg QD

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

All Placebo

Serious events: 0 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Gilead Clinical Study Information Center

Gilead Sciences

Phone: 1-833-445-3230 (GILEAD-0)

Email: [email protected]

Results disclosure agreements

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

Restriction type: OTHER

Measure	Cohort 2, Part A: Tirabrutinib 10 mg BID n=2 Participants Tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.	Cohort 1, Part A: Tirabrutinib 20 mg QD n=7 Participants Tirabrutinib 20 mg capsules orally QD in the morning for 1 week.	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.	Cohort 2, Part A: Placebo Placebo to match tirabrutinib 10 mg capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
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	0 percentage of BTK occupancy Standard Deviation 0	—	—
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	-2.765 percentage of BTK occupancy Standard Deviation 14.6036	—	—
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	11.635 percentage of BTK occupancy Standard Deviation 17.8025	—	—
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	55.250 percentage of BTK occupancy Standard Deviation 10.0230	—	—
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	62.719 percentage of BTK occupancy Standard Deviation 7.7060	—	—
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	66.790 percentage of BTK occupancy Standard Deviation 7.9494	—	—
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	71.936 percentage of BTK occupancy Standard Deviation 8.3606	—	—
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	75.350 percentage of BTK occupancy Standard Deviation 11.5216	—	—
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	77.411 percentage of BTK occupancy Standard Deviation 8.6928	—	—
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	81.187 percentage of BTK occupancy Standard Deviation 8.8687	—	—
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	72.691 percentage of BTK occupancy Standard Deviation 10.8289	—	—
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	84.010 percentage of BTK occupancy Standard Deviation 8.4919	—	—
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	90.606 percentage of BTK occupancy Standard Deviation 6.1066	—	—
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	70.841 percentage of BTK occupancy Standard Deviation 43.0596	—	—
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	93.128 percentage of BTK occupancy Standard Deviation 4.0582	—	—
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	86.936 percentage of BTK occupancy Standard Deviation 6.4745	—	—
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	87.013 percentage of BTK occupancy Standard Deviation 5.2426	—	—
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	86.274 percentage of BTK occupancy Standard Deviation 6.0720	—	—
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 17.9620	92.651 percentage of BTK occupancy Standard Deviation 3.4603	—	—
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	92.983 percentage of BTK occupancy Standard Deviation 2.1906	—	—
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	90.070 percentage of BTK occupancy Standard Deviation 7.4086	—	—
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	91.591 percentage of BTK occupancy Standard Deviation 7.7733	—	—
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	92.789 percentage of BTK occupancy Standard Deviation 3.2221	—	—
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	91.251 percentage of BTK occupancy Standard Deviation 6.0300	—	—
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	85.209 percentage of BTK occupancy Standard Deviation 5.0694	—	—
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	86.256 percentage of BTK occupancy Standard Deviation 6.5648	—	—
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	71.963 percentage of BTK occupancy Standard Deviation 10.5550	—	—
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	64.763 percentage of BTK occupancy Standard Deviation 14.3072	—	—
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	57.431 percentage of BTK occupancy Standard Deviation 9.0638	—	—
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	46.218 percentage of BTK occupancy Standard Deviation 14.3155	—	—
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	24.922 percentage of BTK occupancy Standard Deviation 6.8700	—	—
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	15.285 percentage of BTK occupancy Standard Deviation 9.4140	—	—