Oral Baricitinib (LY3009104)Treatment in Japanese Participants With Active Rheumatoid Arthritis on Background Methotrexate Therapy

Eli Lilly and Company145 enrolled

Overview

This is a Phase 2b, outpatient, randomized, double-blinded (with a single-blind extension), placebo-controlled, dose-ranging, parallel-group study of baricitinib (LY3009104) in Japanese participants with active rheumatoid arthritis (RA) on background methotrexate (MTX) therapy. Baricitinib will be orally administered once a day with background methotrexate \[6 to 16 milligrams (mg)/week\] therapy for 12 weeks in the double-blind treatment period (1, 2, 4 or 8 mg/day, or placebo), and for 52 weeks in the single-blind extension period (4 or 8 mg/day).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

145

Conditions

Arthritis, Rheumatoid

Interventions

Placebo

Eligibility

Sex: ALLMin age: 20 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Ambulatory males or females between the ages of 20 and 75 years, inclusive, at time of study entry * Diagnosis of adult-onset RA (of at least 6 months duration but not longer than 15 years prior to screening) according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Responder Index classification criteria for RA * Have active RA defined as at least 6 swollen and at least 6 tender joints based on the 66/68 joint count * Regular use of MTX for at least 12 weeks, and treatment at a stable dose of 6 to 16 mg/week (2 or 3 times a week) for at least 8 weeks prior to the treatment period. The dose of MTX should remain stable throughout the study, but may be adjusted for safety reasons. * For participants receiving corticosteroids, they must be on a dose not to exceed 10 mg of prednisone daily (or equivalent) and have been on the same dosing regimen for at least 6 weeks prior to the treatment period * Have C-Reactive Protein (CRP) measurement \> 0.5 milligrams/deciliter (mg/dL) or Erythrocyte Sedimentation Rate (ESR) \> 28 millimeters/hour (mm/hr). The CRP and ESR may be repeated once during the screening period at the discretion of the investigator, and the repeat results may be accepted for study eligibility purposes Exclusion Criteria: * Use of nonsteroidal anti-inflammatories (NSAIDs) for less than 4 weeks prior to the treatment period. If on NSAIDs, must be on a stable dose of the drug for at least 4 weeks prior to the treatment period and must remain on a stable dose throughout the study * Received prior treatment with an oral Janus Kinase (JAK) inhibitor regardless of when they received it * Have a diagnosis of Felty's syndrome * Evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV antibodies * Have hepatitis C virus (HCV; positive for anti-hepatitis C antibody with confirmed presence of HCV) * Positive for hepatitis B surface antigen (HBsAg+), OR negative for hepatitis B surface antigen (HBsAg-), but positive for hepatitis B core antibody (HBcAb+) and/or positive for hepatitis B surface antibody (HBsAb+) with positive Hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) \[≥2.1 Log copy/mL by Polymerase Chain Reaction (PCR) method\] detected in the serum * Have a positive result of the QuantiFERON®-tuberculosis (TB) Gold test (QFT-G) or a purified protein derivative (PPD) test * Have estimated Glomerular Filtration Rate (GFR) from serum creatinine using the Modification of Diet in Renal Disease (MDRD) method of \<50 milliliter/minute (mL/min)

Locations (14)

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Chiba, Japan

Fukuoka, Japan

Hiroshima, Japan

Hokkaido, Japan

Outcomes

Primary Outcomes

Percentage of Participants in the 4 mg and 8 mg Dose Groups Who Achieved an American College of Rheumatology 20 (ACR20) Responder Index Response Baseline Through Week 12 .

ACR20 responders are participants with at least 20% improvement from baseline for tender joint count (TJC), swollen joint count (SJC), and at least 3 of the 5 remaining core set measures: Health Assessment Questionnaire-Disability Index (HAQ-DI) which measured participants perceived degree of difficulty performing daily activities, C-reactive Protein (CRP) and erythrocyte sedimentation rate (ESR), Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS) , Patient's Global Assessment of Disease Activity-VAS (PtGADA-VAS), and Physician's Global Assessment of Disease Activity-VAS (PhGA-VAS). Missing values were imputed using Non-Responder Imputation (NRI), where non-responders were participants who discontinued the study prior to the completion of Part A. Percentage of participants achieving ACR20 response = (number of ACR20 responders) /(number of participants treated) \* 100.

Time frame: 12 weeks

Secondary Outcomes

Percentage of Participants Who Achieved an ACR20 Response at 64 Weeks

ACR20 responders are participants with at least 20% improvement from baseline for TJC, SJC, and at least 3 of the 5 remaining core set measures: HAQ-DI which measured participants perceived degree of difficulty performing daily activities, CRP and ESR, PAAP-VAS, PtGADA-VAS, or PhGA-VAS. Missing values were imputed using NRI, where non-responders were participants who discontinued the study prior to the completion of Part B. Percentage of participants achieving ACR20 response = (number of ACR20 responders) / (number of participants treated) \* 100.

Time frame: Baseline up to 64 weeks

Percentage of Participants Who Achieved an ACR70 Response at 12 Weeks (Part A)

ACR70 responders were participants with at least 70% improvement from baseline for TJC, SJC, and at least 3 of the 5 remaining core set measures: HAQ-DI, CRP, PAAP-VAS, PtGADA-VAS, or PhGA-VAS. Missing values were imputed using NRI, where non-responders were participants who discontinued the study prior to the completion of Part A. Percentage of participants achieving ACR70 response=(number of ACR70 responders / number of participants treated) \* 100.

Time frame: Baseline up to 12 weeks

Percentage of Participants Who Achieved an ACR70 Response at 64 Weeks (Part B)

ACR70 responders were participants with at least 70% improvement from baseline for TJC, SJC, and at least 3 of the 5 remaining core set measures: HAQ-DI, CRP, PAAP-VAS, PtGADA-VAS, or PhGA-VAS. Missing values were imputed using NRI, where non-responders were participants who discontinued the study prior to the completion of Part B. Percentage of participants achieving ACR70 response=(number of ACR70 responders) / (number of participants treated) \* 100.

Time frame: Baseline up to 64 weeks

Mean Change From Baseline to Week 12 in Disease Activity Score (DAS) Based on the 28 Diarthrodial Joint Count and CRP Level (DAS28-CRP)

DAS modified included the DAS28 that consisted of a composite score of the following variables: tender joint count out of 28 (TJC28), swollen joint count out of 28 (SJC28), CRP \[milligrams per liter (mg/L)\], and PtGADA on a 0 to 100 millimeter (mm) VAS (0mm=no arthritis activity to 100 mm= extremely active arthritis). DAS28 calculated as: DAS28-CRP = 0.56(square root of TJC28)+0.28(square root of SJC28)+0.36\[ln(CRP +1)\]+0.014(VAS)+0.96. A decrease in DAS28-CRP indicated an improvement in participant's condition.

Time frame: Baseline, 12 weeks

Mean Change From Baseline to Week 64 in DAS Based on the 28 Diarthrodial Joint Count and CRP Level (DAS28-CRP)

DAS modified included the 28 diarthroidal joint count (DAS28) that consisted of a composite score of the following variables: TJC28, SJC28, CRP (mg/L), and PtGADA on a 0 to 100 mm VAS (0mm=no arthritis activity to 100 mm= extremely active arthritis). DAS28 calculated as: DAS28-CRP = 0.56(square root of TJC28)+0.28(square root of SJC28)+0.36\[ln(CRP +1)\]+0.014(VAS)+0.96. A decrease in DAS28-CRP indicated an improvement in participant's condition.

Time frame: Baseline, 64 weeks

Percentage of Participants Who Achieved an European League Against Rheumatism Rating of 28-Joint Arthritic Condition (EULAR28) Response at 12 Weeks (Part A)

EULAR Responder Index based on 28 joint counts categorizes clinical response based on improvement from baseline in DAS28-CRP. DAS28-CRP scores range from 1.0-9.4, where lower scores indicated less disease activity. High disease activity: DAS28-CRP \>5.1, low disease activity: DAS28-CRP ≤3.2, and remission: DAS28-CRP \<2.6. Participants are categorized as EULAR responders or non-responders based on improvement of DAS28-CRP scores from baseline. EULAR DAS28-CRP responder index defines a good (absolute: ≤3.2 and \>1.2 improvement from baseline), moderate (absolute: \>3.2 and ≤5.1 and \>0.6 and ≤1.2 improvement from baseline), or no response (absolute: \>5.1 and ≤0.6 improvement from baseline). Percentage of participants calculated as = (number of good +moderate responders) / (number of participants treated) \* 100.

Time frame: Baseline up to 12 weeks

Percentage of Participants Who Achieved an EULAR28 Response at 64 Weeks (Part B)

EULAR Responder Index based on 28 joint counts categorizes clinical response based on improvement from baseline in DAS28-CRP. DAS28-CRP scores range from 1.0-9.4, where lower scores indicated less disease activity. High disease activity: DAS28-CRP \>5.1, low disease activity: DAS28-CRP \<3.2, and remission: DAS28-CRP \<2.6. Participants are categorized as EULAR responders or non-responders based on improvement of DAS28-CRP scores from baseline. EULAR DAS28-CRP Responder Index defines a good (absolute: ≤3.2 and \>1.2 improvement from baseline), moderate (absolute: \>3.2 and ≤5.1 and \>0.6 and ≤1.2 improvement from baseline), or no response (absolute: \>5.1 and ≤0.6 improvement from baseline). Percentage of participants calculated as = (number of good +moderate responders) / (number of participants treated) \* 100.

Time frame: Baseline up to 64 weeks

Mean Change in Simplified Disease Activity Index (SDAI) Responses up to 12 Weeks (Part A)

The SDAI is the numerical sum of 5 outcome parameters: TJC28, SJC28, patient and physician global assessment of disease activity and CRP. The equation used to calculate the SDAI:SDAI=SJC28+TJC28+PtGADA-VAS+PhGA-VAS+CRP where PtGADA-VAS=PtGADA-VAS / 10 and PhGA-VAS=PhGA-VAS / 10, with lower values indicating fewer symptoms.

Time frame: Baseline up to 12 weeks

Mean Change in SDAI Responses up to 64 Weeks (Part B)

The SDAI is the numerical sum of 5 outcome parameters: TJC28, SJC28, PtGADA, PhGA, and CRP. The equation used to calculate the SDAI: SDAI=SJC28+TJC28+PtGADA-VAS+PhGA-VAS+CRP where PtGADA-VAS=PtGADA -VAS/ 10 and PhGA-VAS=PhGA-VAS/ 10, with lower values indicating fewer symptoms.

Time frame: Baseline, 64 weeks

Mean Change in Health Assessment Questionnaire - Disability Index (HAQ-DI) Responses up to 12 Weeks (Part A)

HAQ-DI was a participant-reported questionnaire that consisted of 24 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the week using response categories: without any difficulty (0), with some difficulty (1), with much difficulty (2), and unable to do (3). The highest score for any question in a category was the score of that category unless special aids or devices or help from another person was required. Answers for at least 6 of the 8 domains were required. Otherwise, HAQ-DI score was considered missing. The HAQ-DI score was the sum of the category scores divided by the number of categories scored, with a possible scores range from 0 to 3, 0 being without any difficulty and 3 being unable to do.

Time frame: Baseline, 12 weeks

Mean Change in HAQ-DI Responses up to 64 Weeks (Part B)

HAQ-DI was a participant-reported questionnaire that consisted of 24 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the week using response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). The highest score for any question in a category was the score of that category unless special aids or devices or help from another person was required. Answers for at least 6 of the 8 domains were required. Otherwise, HAQ-DI score was considered missing. The HAQ-DI score was the sum of the category scores divided by the number of categories scored, with a possible scores range from 0 to 3, 0 being without any difficulty and 3 being unable to do.

Time frame: Baseline, 64 weeks

Mean Value of ACR-N Response (Part A)

The ACR-N Response Index is a continuous measure of clinical, laboratory, and functional measures in RA to characterize the percentage of improvement from baseline in RA disease activity. This index is defined as the lowest of either: a) percent change in TJC, b) percent change in SJC, or c) median percent change of the remaining 5 ACR core criteria (HAQ-DI, CRP, PAAP-VAS, PtGADA-VAS, or PhGA-VAS). A participant with an ACR-N of "X" has improvement of at least "X%" in tender and swollen joints and a median improvement of at least "X%" in the 5 remaining ACR core criteria. Since ACR-N is a continuous measure, the mean values are reported instead of the originally registered percentage of participants.

Time frame: Baseline up to 12 weeks

Mean Value of ACR-N Response (Part B)

Time frame: Baseline up to 64 weeks

Percentage of Participants Who Achieved a DAS28 Remission at 12 Weeks (Part A)

DAS modified included the DAS28 that consisted of a composite score of the following variables: TJC28, SJC28, CRP (mg/L), and PtGADA on a 0 to 100 mm VAS: 0 mm (no arthritis activity) to 100 mm (extremely active arthritis). DAS28 calculated as: DAS28-CRP = 0.56(square root of TJC28)+0.28(square root of SJC28)+0.36\[ln(CRP +1)\]+0.014(VAS)+0.96. For remission, DAS28 is \<2.6. Percentage of participants = (number of participants with DAS28 remission) / (number of participants treated) \* 100.

Time frame: Baseline up to 12 weeks

Percentage of Participants Who Achieved a DAS28 Remission at 64 Weeks (Part B)

DAS modified included the DAS28 that consisted of a composite score of the following variables: TJC28, SJC28, CRP (mg/L), and PtGADA-VAS on a 0 to 100 mm VAS: 0 mm (no arthritis activity) to 100 mm (extremely active arthritis). DAS28 calculated as: DAS28-CRP = 0.56(sqrt of TJC28)+0.28(sqrt of SJC28)+0.36\[ln(CRP +1)\]+0.014(VAS)+0.96. For remission, DAS28 is \<2.6. Percentage of participants = (number of participants with DAS 28 remission) / (number of participants treated) \* 100.

Time frame: Baseline up to 64 weeks

Percentage of Participants Who Achieved an SDAI Remission at 12 Weeks (Part A)

The SDAI is the numerical sum of 5 outcome parameters: TJC28, SJC28, PtGADA, PhGA and CRP. The equation used to calculate the SDAI: SDAI=SJC28+TJC28+PtGADA-VAS+PhGA-VAS+CRP where PtGADA-VAS=PtGADA -VAS/ 10 and PhGA-VAS=PhGA-VAS / 10. Definition of remission is SDAI ≤ 3.3. Percentage of participants = (number of responders) / (number of participants treated) \* 100

Time frame: Baseline up to 12 weeks

Percentage of Participants Who Achieved an SDAI Remission at 64 Weeks (Part B)

The SDAI is the numerical sum of 5 outcome parameters: TJC28, SJC28, PtGADA, PhGA, and CRP. The equation used to calculate the SDAI: SDAI=SJC28+TJC28+PtGADA-VAS+PhGA-VAS+CRP where PtGADA-VAS=PtGADA-VAS / 10 and PhGA-VAS=PhGA-VAS / 10. Definition of remission is SDAI ≤ 3.3. Percentage of participants = (number of responders) / (number of participants treated) \* 100

Time frame: Baseline up to 64 weeks

Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve at a Dosing Interval at Steady State (AUCtau,ss) of LY3009104

Steady state is achieved when the rate of drug input is equal to the rate of drug elimination. The AUC(tau,ss) at 1 dosing interval is the average concentration of the drug at steady state multiplied by the time of the dosing interval.

Time frame: Weeks (Wks) 0, 8, 12, or 20: Predose, 15 to 30 minutes and 1 to 3 hours postdose; Wks 2 or 4 and 15 or 16: Predose; Wks 28, 40, 52, or 64: random single sample.

PK: Maximum Concentration at Steady State of Dosing (Cmax,ss) of LY3009104

Time frame: Wks 0, 8, 12, or 20: Predose, 15 to 30 minutes and 1 to 3 hours postdose; Wks 2 or 4 and 15 or 16: Predose; Wks 28, 40, 52, or 64: random single sample.

Hyōgo, Japan

Ibaraki, Japan

Kagoshima, Japan

Kanagawa, Japan

Nagasaki, Japan

Okayama, Japan