A Phase 1, Placebo-Controlled, Randomized Study Evaluating the Safety and Pharmacokinetics of GS-4059 in Healthy Volunteers and Subjects With Rheumatoid Arthritis (RA)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 42
- 试验地点
- 9
- 主要终点
- Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Part B: Tirabrutinib 20 mg QD
Tirabrutinib 20 mg capsules orally QD for 4 weeks.
干预措施: Tirabrutinib (Drug)
Part B: Placebo
Placebo to match tirabrutinib capsules orally QD for 4 weeks.
干预措施: Placebo (Drug)
Cohort 1, Part A: Tirabrutinib 20 mg QD
Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week.
干预措施: Tirabrutinib (Drug)
Cohort 1, Part A: Placebo
Placebo to match tirabrutinib capsules orally QD in the morning for 1 week.
干预措施: Placebo (Drug)
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.
干预措施: Tirabrutinib (Drug)
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.
干预措施: Placebo (Drug)
结局指标
主要结局
Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities
时间窗: First dose date up to last dose (maximum: 7 days) plus 30 days
Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib
时间窗: 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 With Treatment-Emergent Laboratory Abnormalities
时间窗: 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 A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities
时间窗: 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 Who Experienced Treatment-Emergent Adverse Events (TEAEs)
时间窗: 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: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib
时间窗: 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
时间窗: 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
时间窗: 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: AUCtau: Area Under the Plasma Concentration (AUC) Versus Time Curve Over the Dosing Interval of Tirabrutinib
时间窗: 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 B: Percentage of Participants Who Experienced TEAEs
时间窗: 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 12-Lead ECG Abnormalities
时间窗: First dose date up to last dose (maximum: 29 days) plus 30 days
Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4(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(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(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(Baseline; 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(Baseline; 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(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(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(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(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(Baseline; 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(Weeks 2, 4 and Posttreatment Week 4)