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

NCT02626026 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: GS-US-407-18332015-003240-40
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 9

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).

Conditions

Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (12)

• Part A: Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs)

  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.

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

• Part A: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities

  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.

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

• Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities

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

• Part A: Cmax: Maximum Observed Plasma Concentration of Tirabrutinib

  Cmax is maximum observed concentration of drug in plasma.

  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: Clast: Last Observed Quantifiable Plasma Concentration of Tirabrutinib

  Clast is the last observed concentration of drug in plasma.

  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: Tmax: Time (Observed Time Point) of Cmax of Tirabrutinib

  Tmax is the time observed for the Cmax of tirabrutinib.

  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

  Tlast is the time observed for the Clast of tirabrutinib.

  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: AUCtau: Area Under the Plasma Concentration (AUC) Versus Time Curve Over the Dosing Interval of Tirabrutinib

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

  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: AUClast: AUC Versus Time Curve From Time Zero to the Last Quantifiable Concentration of Tirabrutinib

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

  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 Who Experienced TEAEs

  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.

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

• Part B: Percentage of Participants With Treatment-Emergent Laboratory Abnormalities

  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.

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

• Part B: Percentage of Participants With 12-Lead ECG Abnormalities

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

Secondary Outcomes (20)

• 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 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 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 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 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

Study Arms (6)

Cohort 1, Part A: Tirabrutinib 20 mg QD

EXPERIMENTAL

Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week.

Drug: Tirabrutinib

Cohort 1, Part A: Placebo

PLACEBO COMPARATOR

Placebo to match tirabrutinib capsules orally QD in the morning for 1 week.

Drug: Placebo

Cohort 2, Part A: Tirabrutinib 10 mg BID

EXPERIMENTAL

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

Cohort 2, Part A: Placebo

PLACEBO COMPARATOR

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

Part B: Tirabrutinib 20 mg QD

EXPERIMENTAL

Tirabrutinib 20 mg capsules orally QD for 4 weeks.

Drug: Tirabrutinib

Part B: Placebo

PLACEBO COMPARATOR

Placebo to match tirabrutinib capsules orally QD for 4 weeks.

Drug: Placebo

Interventions

Tirabrutinib DRUG

Capsules administered orally.

Also known as: GS-4059

Cohort 1, Part A: Tirabrutinib 20 mg QD; Cohort 2, Part A: Tirabrutinib 10 mg BID; Part B: Tirabrutinib 20 mg QD

Placebo DRUG

Capsules administered orally.

Cohort 1, Part A: Placebo; Cohort 2, Part A: Placebo; Part B: Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)
• 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

Sponsors & Collaborators

• Gilead Sciences: lead
• Ono Pharmaceutical Co. Ltd: collaborator

Study Sites (9)

UC Davis Lawrence J. Ellison

Sacramento, California, 95817, United States

Location

SeaView Research, Inc.

Miami, Florida, 33126, United States

Location

Omega Research Consultants, LLC

Orlando, Florida, 32804, United States

Location

Lovelace Scientific Resources, Inc.

Venice, Florida, 34292, United States

Location

Center for Arthritis & Osteoporosis

Elizabethtown, Kentucky, 42701, United States

Location

Justus J. Fiechtner, M.D., P.C.

Lansing, Michigan, 48910, United States

Location

Altoona Center for Clinical Research

Duncansville, Pennsylvania, 16635, United States

Location

Clinical Research Center of Reading, LLC

Wyomissing, Pennsylvania, 19610, United States

Location

Arthritis & Osteoporosis Center of South Texas

San Antonio, Texas, 78232, United States

Location

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

tirabrutinib

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Results Point of Contact

• Title: Gilead Clinical Study Information Center
• Organization: Gilead Sciences

GileadClinicalTrials@gilead.com

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

Study Officials

• Gilead Study Director

  Gilead Sciences

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 3, 2015
• First Posted: December 10, 2015
• Study Start: January 26, 2016
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2016
• Last Updated: September 9, 2020
• Results First Posted: September 9, 2020

Record last verified: 2020-08

Locations

US (9)