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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02626026
• Date of registration: 03/12/2015
• Prospective Registration: Yes
• Primary sponsor: Gilead Sciences
• Public title: Study to Evaluate Safety and Pharmacokinetics of GS-4059 (Tirabrutinib) in Healthy Volunteers and Participants With Rheumatoid Arthritis (RA)
• Scientific 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)
• Date of first enrolment: January 26, 2016
• Target sample size: 42
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02626026
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 1

Countries of recruitment

United States

Contacts

• Name: Gilead Study Director
• Affiliation: Gilead Sciences

Key inclusion & exclusion 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



Age minimum: 18 Years
Age maximum: 65 Years
Gender: All

Health Condition(s) or Problem(s) studied

Rheumatoid Arthritis

Intervention(s)

Drug: Placebo

Drug: Tirabrutinib

Primary Outcome(s)

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]

Part B: Percentage of Participants Who Experienced TEAEs [Time Frame: First dose date up to last dose (maximum: 29 days) plus 30 days]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Secondary Outcome(s)

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Part B: Hybrid ACR Improvement Response at Weeks 2, 4 and Posttreatment Week 4 [Time Frame: 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 [Time Frame: Weeks 2, 4 and Posttreatment Week 4]

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

Secondary ID(s)

GS-US-407-1833

2015-003240-40

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Ono Pharmaceutical Co. Ltd

Results

• Results available: Yes
• Date Posted: 09/09/2020
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02626026