Clinical trial NCT02626026: Study to Evaluate Safety and Pharmacokinetics of GS-4059 (Tirabrutinib) in Healthy Volunteers and Participants With Rheumatoid Arthritis (RA)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Rheumatoid Arthritis
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
Collaborators: name: Ono Pharmaceutical Co. Ltd
First posted: 2015-12-10
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility 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

Primary outcomes:
measure: Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)
timeFrame: First dose date up to last dose (maximum: 7 days) plus 30 days
measure: Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities
timeFrame: First dose date up to last dose (maximum: 7 days) plus 30 days
measure: Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities
timeFrame: First dose date up to last dose (maximum: 7 days) plus 30 days
measure: Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib
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
measure: Part A: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib
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
measure: Part A: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib
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
measure: Part A: Tlast: Time (Observed Time Point) of Clast of Tirabrutinib
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
measure: Part A: AUCtau: Area Under the Plasma Concentration (AUC) Versus Time Curve Over the Dosing Interval of Tirabrutinib
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
measure: Part A: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib
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
measure: Part B: Percentage of Participants Who Experienced TEAEs
timeFrame: First dose date up to last dose (maximum: 29 days) plus 30 days
measure: Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities
timeFrame: First dose date up to last dose (maximum: 29 days) plus 30 days
measure: Part B: Percentage of Participants With 12-Lead ECG Abnormalities
timeFrame: First dose date up to last dose (maximum: 29 days) plus 30 days
Secondary outcomes:
measure: Part A: Change From Baseline in Percent Inhibition of CD63 Basophils at Days 1, 3, 5 and 7
timeFrame: Days 1 and 7: Predose and 2, 6, 12, 24 hours postdose; Days 3 and 5: Predose and 2 hours postdose
measure: Part A: Change From Baseline in Percent Bruton's Tyrosine Kinase (BTK) Occupancy at Days 1, 3, 5 and 7
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
measure: 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
timeFrame: Baseline; Weeks 2, 4 and Posttreatment Week 4
measure: 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
timeFrame: Baseline; Weeks 2, 4 and Posttreatment Week 4
measure: 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
timeFrame: Baseline; Weeks 2, 4 and Posttreatment Week
measure: Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Baseline; Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Change From Baseline in Clinical Disease Activity Index (CDAI) at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Baseline; Weeks 2, 4 and Posttreatment Week 4
measure: 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
timeFrame: Baseline; Weeks 2, 4 and Posttreatment Week 4
measure: 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
timeFrame: Baseline; Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Change From Baseline in Individual ACR Component: Patient's Global Assessment of Pain at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Baseline; Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Change From Baseline in the Health Assessment Questionnaire Disability Subscales (HAQ-DI) Score at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Baseline; Weeks 2, 4 and Posttreatment Week 4
measure: 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
timeFrame: Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Percentage of Participants Who Achieved ACR 70% Improvement (ACR70) Response at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Percentage of Participants Who Achieved Remission as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by DAS28-CRP at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Percentage of Participants Who Achieved Remission as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by CDAI at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Percentage of Participants Who Achieved Remission as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Weeks 2, 4 and Posttreatment Week 4
measure: Part B: Percentage of Participants Who Achieved Low Disease Activity Response as Measured by SDAI at Weeks 2, 4 and Posttreatment Week 4
timeFrame: Weeks 2, 4 and Posttreatment Week 4
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: UC Davis Lawrence J. Ellison
state: California
city: Miami
country: United States
facility: SeaView Research, Inc.
state: Florida
city: Orlando
country: United States
facility: Omega Research Consultants, LLC
state: Florida
city: Venice
country: United States
facility: Lovelace Scientific Resources, Inc.
state: Florida
city: Elizabethtown
country: United States
facility: Center for Arthritis & Osteoporosis
state: Kentucky
city: Lansing
country: United States
facility: Justus J. Fiechtner, M.D., P.C.
state: Michigan
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Wyomissing
country: United States
facility: Clinical Research Center of Reading, LLC
state: Pennsylvania
city: San Antonio
country: United States
facility: Arthritis & Osteoporosis Center of South Texas
state: Texas
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References: