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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02626026
Recruitment Status : Completed
First Posted : December 10, 2015
Results First Posted : September 9, 2020
Last Update Posted : September 9, 2020
Sponsor:
Collaborator:
Ono Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
Gilead Sciences

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

Condition or disease Intervention/treatment Phase
Rheumatoid Arthritis Drug: Tirabrutinib Drug: Placebo Phase 1

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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1, Part A: Tirabrutinib 20 mg QD
Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week.
Drug: Tirabrutinib
Capsules administered orally.
Other Name: GS-4059

Placebo Comparator: Cohort 1, Part A: Placebo
Placebo to match tirabrutinib capsules orally QD in the morning for 1 week.
Drug: Placebo
Capsules administered orally.

Experimental: Cohort 2, Part A: Tirabrutinib 10 mg BID
Tirabrutinib 10 mg capsules orally twice daily (BID) (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Drug: Tirabrutinib
Capsules administered orally.
Other Name: GS-4059

Placebo Comparator: Cohort 2, Part A: Placebo
Placebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered.
Drug: Placebo
Capsules administered orally.

Experimental: Part B: Tirabrutinib 20 mg QD
Tirabrutinib 20 mg capsules orally QD for 4 weeks.
Drug: Tirabrutinib
Capsules administered orally.
Other Name: GS-4059

Placebo Comparator: Part B: Placebo
Placebo to match tirabrutinib capsules orally QD for 4 weeks.
Drug: Placebo
Capsules administered orally.




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

  2. Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities [ Time Frame: First dose date up to last dose (maximum: 7 days) plus 30 days ]
    A treatment-emergent laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment after the first dose of study drug and within 30 days after last study drug administration. Laboratory abnormalities without clinical significance were not recorded as AEs or serious AEs. Treatment-emergent laboratory abnormalities were graded per Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 where 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life threatening.

  3. Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities [ Time Frame: First dose date up to last dose (maximum: 7 days) plus 30 days ]
  4. Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib [ Time Frame: Cohorts 1 and 2, Day 1: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 hours postdose; Day 7: 0 (predose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, and 120 hours postdose ]
    Cmax is maximum observed concentration of drug in plasma.

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

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

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

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

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

  10. Part B: Percentage of Participants Who Experienced TEAEs [ Time Frame: First dose date up to last dose (maximum: 29 days) plus 30 days ]
    An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as 1 or both of the following: Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or Any AEs leading to premature discontinuation of study drug.

  11. Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities [ Time Frame: First dose date up to last dose (maximum: 29 days) plus 30 days ]
    A treatment-emergent laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment after the first dose of study drug and within 30 days after last study drug administration. Laboratory abnormalities without clinical significance were not recorded as AEs or serious AEs. Treatment-emergent laboratory abnormalities were graded per CTCAE, version 4.03 where 0 = none, 1 = mild, 2 = moderate, 3 = severe, 4 = potentially life threatening.

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

Secondary Outcome Measures :
  1. Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7 [ Time Frame: Days 1 and 7: Predose and 2, 6, 12, 24 hours postdose; Days 3 and 5: Predose and 2 hours postdose ]
    The effect of tirabrutinib on biomarkers was assessed through the CD63 basophil activation test (BAT) FlowCast assay, which was used to measure the percentage of CD63+ basophils and percentage inhibition of CD63 induction relative to baseline. CD63+ % inhibition was calculated as 100 - CD63+ % baseline. Baseline defined as day 1 predose.

  2. Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7 [ Time Frame: Day 1: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24 hours postdose; Days 3 and 5: Predose and 2 hours postdose; Day 7: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 60, 72, 96, 120 hours postdose ]
    BTK occupancy was assessed with the BTK occupancy assay, which was used to measure undetectable free BTK, normalized free BTK, normalized free BTK adjusted to baseline, and percentage BTK occupancy adjusted to baseline. % BTK occupancy adjusted was calculated as 100 * (1 - normalized free BTK adjusted to baseline). Normalized free BTK was calculated as Free BTK / Total BTK. Baseline defined as day 1 predose.

  3. Part B: Change From Baseline in Disease Activity Score for 28 Joint Counts (DAS28) Using C-Reactive Protein (CRP) at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Baseline; Weeks 2, 4 and Posttreatment Week 4 ]
    DAS28 score was used to measure the participant's disease activity or assessments of rheumatoid arthritis (RA) calculated using the tender joint counts (TJC) (28 joints), swollen joint counts (28 joints), Patient's Global Assessment of Disease Activity (PtGA) (visual analog scale: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

  4. Part B: Change From Baseline in Individual American College of Rheumatology (ACR) Component: Tender Joint Count (TJC) Based on 68 Joints (TJC68) at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Baseline; Weeks 2, 4 and Posttreatment Week 4 ]
    ACR TJC was an assessment of 68 joints. At each study visit, a joint evaluator assessed whether a particular joint was "tender" where presence of tenderness was scored as "1" and the absence of tenderness was scored as "0," provided the joint was not replaced or could not be assessed due to other reasons. It was derived as the sum of all tender joints. The range for TJC68 was 0 to 68, with a higher score indicating a greater degree of tenderness. A negative change from baseline indicates improvement.

  5. Part B: Change From Baseline in Individual ACR Component: Swollen Joint Count (SJC) Based on 66 Joints (SJC66) at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Baseline; Weeks 2, 4 and Posttreatment Week ]
    ACR SJC was an assessment of 66 joints. At each study visit, a joint evaluator assessed whether a particular joint was swollen where presence of swelling was scored as "1" and the absence of swelling was scored as "0," provided the joint was not replaced or could not be assessed due to other reasons. It was derived as the sum of all swollen joints. The range for SJC66 was 0 to 66, with a higher score indicating a greater degree of swelling. A negative change from baseline indicates improvement.

  6. Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Baseline; Weeks 2, 4 and Posttreatment Week 4 ]
    SDAI is a composite measure that sums the TJC based on 28 joints (TJC28), SJC based on 28 joints (SJC28), PtGA, Physician's Global Assessment of Disease Activity (PhGA), and the CRP (in mg/dL). PtGA and PhGA assessed using Visual Analogue Scale (VAS) on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.

  7. Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Baseline; Weeks 2, 4 and Posttreatment Week 4 ]
    CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.

  8. Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Disease Activity (PtGA) at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Baseline; Weeks 2, 4 and Posttreatment Week 4 ]
    PtGA was assessed by the participant using a VAS on a scale of 0 (no disease activity) to 100 (maximum disease activity). A horizontal visual analog scale was used to provide the patient's overall assessment of how the arthritis is doing. A mark was placed on the horizontal line to assess the current arthritis disease activity. The lowest mark indicated 'no arthritis activity', and the highest mark indicated 'extremely active arthritis'. A negative change from baseline indicates improvement.

  9. Part B: Change From Baseline in Individual ACR Component: Physician's Global Assessment of Disease Activity (PhGA) at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Baseline; Weeks 2, 4 and Posttreatment Week 4 ]
    PhGA was assessed by the physician using a VAS on a scale of 0 (no disease activity) to 100 (maximum disease activity). A horizontal visual analog scale was used to measure the physician's assessment of the patient's current disease activity. A mark was placed on the horizontal line to assess the disease activity (independent of the participant's self-assessment). The lowest mark indicated 'no disease activity', and the highest mark indicated 'maximum disease activity'. A negative change from baseline indicates improvement.

  10. Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Baseline; Weeks 2, 4 and Posttreatment Week 4 ]
    The participant assessed their pain severity using a VAS on a scale of 0 (no pain) to 100 (severe pain). A horizontal visual analog scale was used to assess the patient's current level of pain. A mark was placed on the horizontal line to assess the severity of pain. The lowest mark indicated 'no pain', and the highest mark indicated 'unbearable pain'. A negative change from baseline indicates improvement.

  11. Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Baseline; Weeks 2, 4 and Posttreatment Week 4 ]
    The HAQ-DI score is defined as the average of the scores of eight functional categories (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other activities), usually administered by the participant. Responses in each functional category were collected as 0-3 [0 (without any difficulty) to 3 (unable to do a task in that area), with or without aids or devices. A negative change from baseline indicates improvement.

  12. Part B: Percentage of Participants Who Achieved an American College of Rheumatology (ACR) 20% Improvement (ACR20) Response at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Weeks 2, 4 and Posttreatment Week 4 ]
    ACR20 response is achieved when the participant has: ≥ 20% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PhGA and PtGA assessed using VAS on a scale of 0-100 (0 and 100 indicating no disease activity and maximum disease activity); patient's pain assessment using VAS on a scale of 0-100 (0 indicating no pain and 100 indicating unbearable pain); HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities and scored on a scale of 0-3 (0 and 3 indicating without difficulty and unable to do); high-sensitivity CRP (hsCRP).

  13. Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Weeks 2, 4 and Posttreatment Week 4 ]
    ACR70 response is achieved when the participant has: ≥ 70% improvement (reduction) from baseline in TJC68, SJC66 and in at least 3 of the following 5 items: PhGA and PtGA assessed using VAS on a scale of 0-100 [0 and 100 indicating no disease activity and maximum disease activity]; patient's pain assessment using VAS on a scale of 0-100 [0 indicating no pain and 100 indicating unbearable pain]; HAQ-DI score contains 20 questions, 8 components: dressing/grooming, arising, eating, walking, hygiene, reach, grip and activities and scored on a scale of 0-3 [0 and 3 indicating without difficulty and unable to do]; hsCRP.

  14. Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Weeks 2, 4 and Posttreatment Week 4 ]
    Hybrid ACR evaluates the improvement in active RA by combining elements of the ACR20, ACR50, and ACR70 with a continuous score of the mean change in core set measures. The percentage improvement from baseline was computed in each of the components of the ACR. The average percent improvement was calculated and used with the participant's ACR20, ACR50, and ACR70 status to compute the hybrid ACR response, with a positive change indicating improvement.

  15. Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Weeks 2, 4 and Posttreatment Week 4 ]
    Clinical remission is defined as DAS28-CRP < 2.6. DAS28 score was used to measure the participant's disease activity or assessments of RA calculated using the TJC28, SJC28, PtGA (VAS: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

  16. Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Weeks 2, 4 and Posttreatment Week 4 ]
    Low disease activity is defined as DAS28-CRP ≤ 3.2. DAS28 score was used to measure the participant's disease activity or assessments of RA calculated using the TJC28, SJC28, PtGA (VAS: 0 = no disease activity to 100 = maximum disease activity) and CRP for a total possible score of 2 to 10. Higher values indicate higher disease activity. A negative change from baseline indicates improvement.

  17. Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Weeks 2, 4 and Posttreatment Week 4 ]
    Clinical remission is defined as CDAI ≤ 2.8. CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.

  18. Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Weeks 2, 4 and Posttreatment Week 4 ]
    Low disease activity is defined as CDAI ≤ 10. CDAI is a composite measure that sums the TJC28, SJC28, PtGA, and PhGA. PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. CDAI total score range: 0 to 76. CDAI <= 2.8 indicates disease remission, > 2.8 to 10 = low disease activity, > 10 to 22 = moderate disease activity, and > 22 = high disease activity. A negative change from baseline indicates improvement.

  19. Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Weeks 2, 4 and Posttreatment Week 4 ]
    Clinical remission is defined as SDAI ≤ 3.3. SDAI is a composite measure that sums the TJC28, SJC28, PtGA, PhGA, and the CRP (in mg/dL). PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.

  20. Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4 [ Time Frame: Weeks 2, 4 and Posttreatment Week 4 ]
    Low disease activity is defined as SDAI ≤ 11. SDAI is a composite measure that sums the TJC28, SJC28, PtGA, PhGA, and the CRP (in mg/dL). PtGA and PhGA assessed using VAS on a scale of 0-100 [0 indicating no disease activity and 100 indicating maximum disease activity]. SDAI total score range: 0 to 86. SDAI <= 3.3 indicates disease remission and SDAI > 26 = high disease activity. A negative change from baseline indicates improvement.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria

Part A

  • Be a nonsmoker
  • Have a calculated body mass index (BMI) from 19 to 30 kg/m^2, inclusive, at screening
  • Have a creatinine clearance (CrCl) ≥ 90 mL/min (using the Cockcroft-Gault method based on serum creatinine and actual body weight as measured at screening
  • Females of childbearing potential must have a negative serum pregnancy test at screening and clinic admission.
  • Male and female individuals of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
  • Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs
  • Screening laboratory evaluations (hematology including reticulocytes, fasting lipids, chemistry, and urinalysis) must fall within the normal range of the local laboratory's reference ranges unless the results have been determined by the investigator to have no clinical significance
  • Have either a normal 12-lead ECG or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the Sponsor

Part B

  • Diagnosis of RA (according to the 1987 American College of Rheumatology (ACR) classification criteria OR a score of ≥ 6 as defined by the ACR/European League Against Rheumatism Classification and Diagnostic Criteria for RA)
  • Individuals must have taken methotrexate (MTX) 7.5 to 25 mg/week continuously for at least 12 weeks, with at least 6 weeks of stable dose prior to first study drug dose and throughout study duration.
  • Individuals must be receiving folic or folinic acid supplementation at a stable dose for at least 6 weeks prior to Day 1 dosing and throughout study duration
  • Individuals are allowed to remain on anti-malarial therapy, with at least 8 weeks of stable dose prior to first study drug dose
  • Use of oral corticosteroids of no more than 10 mg prednisone or its equivalent per day is allowed if dose is stable for at least 28 days prior to first study drug dose
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) or other analgesics (including aspirin ≤ 100 mg daily) are allowed if doses are stable for at least 14 days prior to the first dose of study drug
  • Estimated creatinine clearance (CLCr) ≥ 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at the screening evaluation
  • White blood cells (WBC), neutrophil count, lymphocyte count, and platelet count ≥ 0.75 x lower limit of normal (LLN)
  • A negative serum pregnancy test at screening and a negative pregnancy test on the Day 1 visit prior to the first dose of study drug for female individual of child bearing potential.
  • Male and female individuals of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception

Exclusion Criteria

Part A

  • Pregnant or lactating individuals
  • Have any serious or active medical or psychiatric illness (including depression) which, in the opinion of the Investigator, would interfere with individual's treatment, assessment, or compliance with the protocol. This would include renal, cardiac, hematological, hepatic, pulmonary (including chronic asthma), endocrine (including diabetes), central nervous, gastrointestinal (including an ulcer), vascular, metabolic (thyroid disorders, adrenal disease), immunodeficiency disorders, active infection, or malignancy that are clinically significant or requiring treatment
  • Positive test for drugs of abuse, including alcohol at screening or on Day -1/check-in
  • A positive test result for human immunodeficiency virus (HIV-1) antibody, hepatitis B (HBV) surface antigen or hepatitis C (HCV) antibody
  • Have poor venous access that limits phlebotomy
  • Have taken any prescription medications or over-the-counter medications, including herbal products, within 28 days prior to start of study drug dosing, with the exception of vitamins and/or acetaminophen and/or hormonal contraceptive medications
  • Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to Screening or expected to receive these agents during the study (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
  • Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity)
  • Medical or surgical treatment that permanently alters gastric absorption (eg, gastric or intestinal surgery); a history of cholecystectomy is not exclusionary

Part B

  • Known hypersensitivity to formulation excipient.
  • Pregnant or lactating females
  • Previous treatment with B-cell depleting agents (eg, rituximab) within 12 months of treatment
  • Prior treatment with any commercially available or investigational Bruton's tyrosine kinase (BTK) inhibitor
  • Diagnosis of diabetes, history of impaired glucose tolerance test, history of abnormal glycated haemoglobin (HbA1c), or history of impaired fasting glucose
  • Current treatment with any other disease modifying anti-rheumatic drug (DMARD) other than MTX and hydroxychloroquine, unless appropriate wash out
  • Current treatment with any biologic agent, unless appropriate wash out
  • Any laboratory abnormality or condition that, in the investigator's opinion, could adversely affect the safety of the individual or impair the assessment of study results
  • History of or current inflammatory joint disease, other than RA
  • Active significant systemic involvement secondary to RA such as vasculitis, pulmonary fibrosis or Felty's syndrome
  • History of or current autoimmune or rheumatic disorders, other than RA
  • RA functional class 4 or other uncontrolled medical conditions
  • History of ongoing, chronic or recurrent infections or recent serious or life-threatening infection
  • Presence of any condition that could, in the opinion of the investigator, compromise the individual's ability to participate in the study, such as history of substance abuse, alcoholism, or a psychiatric condition

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02626026


Locations
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United States, California
UC Davis Lawrence J. Ellison
Sacramento, California, United States, 95817
United States, Florida
SeaView Research, Inc.
Miami, Florida, United States, 33126
Omega Research Consultants, LLC
Orlando, Florida, United States, 32804
Lovelace Scientific Resources, Inc.
Venice, Florida, United States, 34292
United States, Kentucky
Center for Arthritis & Osteoporosis
Elizabethtown, Kentucky, United States, 42701
United States, Michigan
Justus J. Fiechtner, M.D., P.C.
Lansing, Michigan, United States, 48910
United States, Pennsylvania
Altoona Center for Clinical Research
Duncansville, Pennsylvania, United States, 16635
Clinical Research Center of Reading, LLC
Wyomissing, Pennsylvania, United States, 19610
United States, Texas
Arthritis & Osteoporosis Center of South Texas
San Antonio, Texas, United States, 78232
Sponsors and Collaborators
Gilead Sciences
Ono Pharmaceutical Co. Ltd
Investigators
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Study Director: Gilead Study Director Gilead Sciences
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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02626026    
Other Study ID Numbers: GS-US-407-1833
2015-003240-40 ( EudraCT Number )
First Posted: December 10, 2015    Key Record Dates
Results First Posted: September 9, 2020
Last Update Posted: September 9, 2020
Last Verified: August 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Arthritis
Arthritis, Rheumatoid
Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases