Rheumatoid ArthritisPhase 1NCT02626026
Study to Evaluate Safety and Pharmacokinetics of GS-4059 (Tirabrutinib) in Healthy Volunteers and Participants With Rheumatoid Arthritis (RA)
A Phase 1 study testing Tirabrutinib in people with Rheumatoid Arthritis, run by Gilead Sciences at 9 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Rheumatoid Arthritis
- What is being tested?
- Tirabrutinib
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 42 participants
- Where
- 9 sitesUnited States
- Study dates
- 26 Jan 2016to 1 Sep 2016
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
United States9 sites
Altoona Center for Clinical Research
Duncansville, Pennsylvania, 16635
Center for Arthritis & Osteoporosis
Elizabethtown, Kentucky, 42701
Justus J. Fiechtner, M.D., P.C.
Lansing, Michigan, 48910
SeaView Research, Inc.
Miami, Florida, 33126
Omega Research Consultants, LLC
Orlando, Florida, 32804
UC Davis Lawrence J. Ellison
Sacramento, California, 95817
Arthritis & Osteoporosis Center of South Texas
San Antonio, Texas, 78232
Lovelace Scientific Resources, Inc.
Venice, Florida, 34292
Clinical Research Center of Reading, LLC
Wyomissing, Pennsylvania, 19610
About this study
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)
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
- Being tested
- Tirabrutinib, Placebo
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TirabrutinibDrug
Also called GS-4059
Capsules administered orally.
PlaceboDrug
Capsules administered orally.
| Study group | Role | What they receive |
|---|---|---|
| Cohort 1, Part A: Tirabrutinib 20 mg QD | Experimental | Tirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week. Receives: Drug: Tirabrutinib |
| Cohort 1, Part A: Placebo | Placebo comparator | Placebo to match tirabrutinib capsules orally QD in the morning for 1 week. Receives: 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. Receives: 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. Receives: Drug: Placebo |
| Part B: Tirabrutinib 20 mg QD | Experimental | Tirabrutinib 20 mg capsules orally QD for 4 weeks. Receives: Drug: Tirabrutinib |
| Part B: Placebo | Placebo comparator | Placebo to match tirabrutinib capsules orally QD for 4 weeks. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: First dose date up to last dose (maximum: 7 days) plus 30 days
Part A: Percentage of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: First dose date up to last dose (maximum: 29 days) plus 30 days
Part B: Percentage of Participants With 12-Lead ECG Abnormalities
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: Baseline; Weeks 2, 4 and Posttreatment Week
Part B: Change From Baseline in Simplified Disease Activity Index (SDAI) at 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.
Measured: 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
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.
Measured: Baseline; 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: Baseline; 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
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).
Measured: 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
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.
Measured: Weeks 2, 4 and Posttreatment Week 4
Part B: Hybrid ACR Improvement Response at 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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: 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
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.
Measured: Weeks 2, 4 and Posttreatment Week 4
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Dec 2015 (estimated)
- Study start26 Jan 2016
- Primary completion1 Sep 2016
- Study completion1 Sep 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- More trials run by Gilead SciencesThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 42 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gilead Sciences
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Ono Pharmaceutical Co., Ltd.
- Responsible party
- Sponsor
- Investigators
- Gilead Study Director, Study director, Gilead Sciences
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02626026
- Sponsor's protocol ID
- GS-US-407-1833
- Other IDs
- 2015-003240-40, 2015
- Status last verified
- Aug 2020
- First submitted
- 3 Dec 2015
- Last updated
- 9 Sep 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 9 Sep 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT02626026
- Acronym / sponsor ID
- GS-US-407-1833
- Conditions
- Rheumatoid Arthritis
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 42 participants (actual)
- Lead sponsor
- Gilead SciencesIndustry (pharma, biotech, devices)
- Collaborators
- Ono Pharmaceutical Co., Ltd.
- Study start
- 26 Jan 2016 (actual)
- Primary completion
- 1 Sep 2016 (actual)
- Study completion
- 1 Sep 2016 (actual)
- First posted
- 10 Dec 2015 (estimated)
- Results
- Posted 9 Sep 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 6
| Arm | Type | Receives |
|---|---|---|
| Cohort 1, Part A: Tirabrutinib 20 mg QD | Experimental | Drug: TirabrutinibTirabrutinib 20 mg capsules orally once daily (QD) in the morning for 1 week. |
| Cohort 1, Part A: Placebo | Placebo comparator | Drug: PlaceboPlacebo to match tirabrutinib capsules orally QD in the morning for 1 week. |
| Cohort 2, Part A: Tirabrutinib 10 mg BID | Experimental | Drug: TirabrutinibTirabrutinib 10 mg capsules orally twice daily (BID) (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. |
| Cohort 2, Part A: Placebo | Placebo comparator | Drug: PlaceboPlacebo to match tirabrutinib capsules orally BID (morning and approximately 12 hours later) for 7 days. On Day 7, only morning dose was administered. |
| Part B: Tirabrutinib 20 mg QD | Experimental | Drug: TirabrutinibTirabrutinib 20 mg capsules orally QD for 4 weeks. |
| Part B: Placebo | Placebo comparator | Drug: PlaceboPlacebo to match tirabrutinib capsules orally QD for 4 weeks. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 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.
Key exclusion criteria (25 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TirabrutinibAlso: GS-4059Capsules administered orally. | Drug | Cohort 1, Part A: Tirabrutinib 20 mg QD, Cohort 2, Part A: Tirabrutinib 10 mg BID, Part B: Tirabrutinib 20 mg QD |
| PlaceboCapsules administered orally. | Drug | Cohort 1, Part A: Placebo, Cohort 2, Part A: Placebo, Part B: Placebo |
Primary outcome
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.
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.
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: 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.
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.
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.
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.
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).
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).
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.
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.
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
20 secondary outcomes
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 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 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 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 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: 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: 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 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: 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: 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 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 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 ACR 70% Improvement (ACR70) Response 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 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: 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: 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
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 SDAI 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 SDAI at Weeks 2, 4 and Posttreatment Week 4
Time frame: Weeks 2, 4 and Posttreatment Week 4
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Sep 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Gilead Study Director study director
Gilead Sciences
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Tirabrutinib in people with Rheumatoid Arthritis, run by Gilead Sciences at 9 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 9 Sep 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 12 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2020.