A Study in Participants With Moderate to Severe Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to determine whether baricitinib therapy alone is noninferior to methotrexate (MTX) therapy alone in the treatment of moderate to severe active rheumatoid arthritis (RA) in those who have had limited or no treatment with MTX and are naive to other conventional or biologic disease-modifying antirheumatic drugs (DMARDs).

Official Title
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A Randomized, Double-Blind, Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Baricitinib (LY3009104) in Patients With Moderately to Severely Active Rheumatoid Arthritis Who Have Had Limited or No Treatment With Disease-Modifying Antirheumatic Drugs

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Baricitinib
* Drug: Methotrexate
* Drug: Baricitinib Placebo
* Drug: MTX Placebo
* Drug: Folic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a diagnosis of adult-onset rheumatoid arthritis (RA) as defined by American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) 2010 Criteria for the Classification of RA Have documented history of positive rheumatoid factor and/or cyclic citrullinated peptide (CCP) antibody test Have moderately to severely active RA defined as the presence of at least 6/68 tender joints and at least 6/66 swollen joints Have a C-reactive protein (CRP) or high-sensitivity C-reactive protein (hsCRP) measurement ≥1.2 times the upper limit of normal (ULN) Have had limited or no treatment with methotrexate (MTX) Exclusion Criteria: Have received conventional disease-modifying antirheumatic drugs (DMARDs) other than MTX (eg, gold salts, cyclosporine, leflunomide, azathioprine, hydroxychloroquine, sulfasalazine or any other immunosuppressives) Are currently receiving corticosteroids at doses >10 mg per day of prednisone (or equivalent) or have been receiving an unstable dosing regimen of corticosteroids within 2 weeks of study entry or within 6 weeks of planned randomization Have started treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or have been receiving an unstable dosing regimen of NSAIDs within 2 weeks of study entry or within 6 weeks of planned randomization Have started a new physiotherapy treatment for RA in the 2 weeks prior to study entry Have ever received any biologic DMARD Have received interferon therapy within 4 weeks prior to study entry or are anticipated to require interferon therapy during the study Have received any parenteral corticosteroid administered by intramuscular or intravenous (IV) injection within 2 weeks prior to study entry or within 6 weeks prior to planned randomization or are anticipated to require a parenteral injection of corticosteroids during the study Have had 3 or more joints injected with intraarticular corticosteroids or hyaluronic acid within 2 weeks prior to study entry or within 6 weeks prior to planned randomization Have active fibromyalgia that, in the investigator's opinion, would make it difficult to appropriately assess RA activity for the purposes of this study Have a diagnosis of any systemic inflammatory condition other than RA, such as, but not limited to, juvenile chronic arthritis, spondyloarthropathy, Crohn's disease, ulcerative colitis, psoriatic arthritis, active vasculitis, or gout (Participants with secondary Sjogren's syndrome are not excluded.) Have a diagnosis of Felty's syndrome Have had any major surgery within 8 weeks of study entry or will require major surgery during the study that, in the opinion of the investigator in consultation with Lilly or its designee, would pose an unacceptable risk to the participant Have experienced any of the following within 12 weeks of study entry: myocardial infarction, unstable ischemic heart disease, stroke, or New York Heart Association Stage IV heart failure Have a history or presence of cardiovascular, respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric disorders or any other serious and/or unstable illness that, in the opinion of the investigator, could constitute a risk when taking investigational product or could interfere with the interpretation of data Are largely or wholly incapacitated permitting little or no self care, such as, being bedridden or confined to a wheelchair Have an estimated Glomerular Filtration Rate (eGFR) based on the most recent available serum creatinine using the Modification of Diet in Renal Disease (MDRD) method of <40 milliliter per minute per 1.73 m^2 (mL/min/1.73 m^2) Have a history of chronic liver disease with the most recent available aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times the ULN or the most recent available total bilirubin ≥1.5 times the ULN Have a history of, lymphoproliferative disease; or have signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly; or have active primary or recurrent malignant disease; or have been in remission from clinically significant malignancy for <5 years Have been exposed to a live vaccine within 12 weeks prior to planned randomization or are expected to need/receive a live vaccine during the course of the study (with the exception of herpes zoster vaccination) Have a current or recent clinically serious viral, bacterial, fungal, or parasitic infection Have had symptomatic herpes zoster infection within 12 weeks prior to study entry Have a history of disseminated/complicated herpes zoster (eg, multidermatomal involvement, ophthalmic zoster, central nervous system involvement, postherpetic neuralgia) Are immunocompromised and, in the opinion of the investigator, are at an unacceptable risk for participating in the study Have a history of active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) Have screening laboratory test values, including thyroid-stimulating hormone (TSH), outside the reference range for the population or investigative site that, in the opinion of the investigator, pose an unacceptable risk for the participant's participation in the study Have screening electrocardiogram (ECG) abnormalities that, in the opinion of the investigator or the sponsor, are clinically significant and indicate an unacceptable risk for the participant's participation in the study Have symptomatic herpes simplex at the time of study enrollment Have evidence of active or latent tuberculosis (TB)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Baricitinib + MTX<br>Baricitinib 4 milligram (mg) administered orally once daily through Week 52. Participants received methotrexate (MTX) orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly. | Drug: Baricitinib<br>* Administered orally<br>* Other names: LY3009104;Drug: Methotrexate<br>* Administered orally<br>Drug: Folic Acid<br>* Administered orally every day<br>|
| Experimental: Baricitinib<br>Baricitinib 4 mg administered orally once daily through Week 52. Participants received MTX placebo orally once weekly through Week 52. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly. | Drug: Baricitinib<br>* Administered orally<br>* Other names: LY3009104;Drug: MTX Placebo<br>* MTX placebo administered orally once weekly.<br>Drug: Folic Acid<br>* Administered orally every day<br>|
| Active Comparator: MTX<br>MTX administered orally once weekly with dose ranging from 10 to 20 mg per week through Week 52. Participants also received baricitinib placebo orally once daily. Starting at Week 24, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily and MTX orally once weekly. | Drug: Methotrexate<br>* Administered orally<br>Drug: Baricitinib Placebo<br>* Baricitinib placebo administered orally once daily.<br>Drug: Folic Acid<br>* Administered orally every day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20) | ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis (RA). ACR20 Responder is a participant who has at least 20% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity using visual analog scale (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI), pain due to arthritis, and high-sensitivity C-reactive protein (hsCRP). Participants with missing responses and participants who discontinued study or drug or were rescued before analysis time point were deemed non-responders. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20) | ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis (RA). ACR20 Responder is a participant who has at least 20% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity using visual analog scale (VAS), Health Assessment Questionnaire-Disability Index (HAQ-DI), pain due to arthritis, and high-sensitivity C-reactive protein (hsCRP). Participants with missing responses and participants who discontinued study or drug or were rescued before analysis time point were deemed non-responders. | Week 52 | 
| Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score | HAQ-DI assesses the participant's self-perception on the degree of difficulty [0 (without any difficulty), 1 (with some difficulty), 2 (with much difficulty), and 3 (unable to do)] when dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and performing other daily activities. Scores for each functional area are averaged to calculate the HAQ-DI score, which ranges from 0 (no disability) to 3 (worst disability). A decrease in HAQ-DI score indicates an improvement in the participant's condition. | Baseline, Week 24 | 
| Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and High-sensitivity C-reactive Protein (DAS28-hsCRP) | Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of a composite score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), C-reactive protein (CRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity. DAS28 was calculated using the following formula: DAS28-CRP=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.36*natural log(CRP+1)+0.014*Patient's Global VAS+0.96. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. | Baseline, Week 24 | 
| Change From Baseline in the Modified Total Sharp Score (mTSS) | X-rays of the hands/wrists and feet were scored for structural progression as measured using the mTSS (van der Heijde 2000). This methodology quantified the extent of bone erosions and joint space narrowing for 44 and 42 joints, with higher scores representing greater damage. The mTSS at a time point is the sum of the erosion (range from 0 to 280) and JSN (range from 0 to 168) scores, for a maximum score of 448. | Baseline, Week 24 | 
| Percentage of Participants Who Achieved a Simplified Disease Activity Index (SDAI) Score ≤3.3 | SDAI is a tool for measurement of disease activity in RA that integrates TJC28, SJC28, acute phase response using C-reactive protein (milligrams per liter), Patient's Global Assessment of Disease Activity using VAS centimeters (cm), and Physician's Global Assessment of Disease Activity using VAS (cm). The SDAI is calculated by summing the values of the 5 components. Lower scores indicated less disease activity. An index-based definition of remission occurs with an SDAI score ≤3.3. | Week 24 | 
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response | ACR50 Responder Index is composite of clinical, laboratory, and functional measures in RA. ACR50 Responder is a participant who has at least 50% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, HAQ-DI, pain due to arthritis, and hsCRP. Participants with missing responses and participants who discontinued study or drug or were rescued before analysis time point were deemed non-responders. | Week 12, Week 24, Week 52 | 
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response | ACR70 Responder Index is composite of clinical, laboratory, and functional measures in RA. ACR70 Responder is a participant who has at least 70% improvement in both tender and swollen joint counts and in at least 3 of the following 5 criteria: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, HAQ-DI, pain due to arthritis, and hsCRP. Participants with missing responses and participants who discontinued study or drug or were rescued before analysis timepoint were deemed non-responders. | Week 12, Week 24, Week 52 | 
| Change From Baseline in Clinical Disease Activity Index (CDAI) Score | The CDAI is a tool for measurement of disease activity in RA that does not require a laboratory component and was scored by the investigative site. It integrates TJC28 (scored 0-28 with higher scores indicating higher disease activity), SJC28 (scored 0-28 with higher scores indicating higher disease activity), Patient's Global Assessment of Disease Activity (scored on a visual analogue scale from 0-10 cm with higher scores indicating higher disease activity), and Physician's Global Assessment of Disease Activity (scored on a visual analogue scale from 0-10 cm with higher scores indicating higher disease activity). The CDAI is calculated by summing the values of the 4 components. CDAI scores range from 0 to 76; lower scores indicated lower disease activity. A negative change from baseline indicates improvement in condition. | Baseline, Week 24; Baseline, Week 52 | 
| Change From Baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) | DAS28 consisted of a composite score of the following variables: tender joint count (TJC28), swollen joint count (SJC28), erythrocyte sedimentation rate (ESR) (millimeters per hour), and Patient's Global Assessment of Disease Activity. DAS28 was calculated using the following formula: DAS28-ESR=0.56*square root (sqrt)(TJC28)+0.28*sqrt(SJC28)+0.70*natural log(ESR)+0.014*Patient's Global VAS. Scores ranged 1.0-9.4, where lower scores indicated less disease activity. | Baseline, Week 24; Baseline, Week 52 | 
| Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Remission | The ACR/EULAR definitions of RA remission include a Boolean-based definition. The Boolean-based definition of remission occurs when all 4 of the following criteria are met at the same visit: TJC28 ≤1, SJC28 ≤1, acute phase response using C-reactive protein (milligrams per deciliter) ≤1, Patient's Global Assessment of Disease Activity using VAS (cm) ≤1. | Week 12, Week 24, Week 52 | 
| Change From Baseline in Joint Space Narrowing and Bone Erosion Scores | X-rays of the hands/wrists and feet were assessed for joint space narrowing (JSN) and bone erosions. Assessment of JSN for each hand (15 joints per hand) and foot (6 joints per foot), including subluxation, is scored from 0 to 4, with 0 indicating no (normal) JSN and 4 indicating complete loss of joint space, bony ankylosis or luxation. JSN scores ranged from 0-168. A score of 0 would indicate no change and higher scores represent a worsening of joint space narrowing. The bone erosion score is a summary of erosion severity in 32 joints of the hands and 12 joints of the feet. Each joint is scored according to the surface area involved from 0 to 5 for hand joints and 0 to 10 for the foot joints, with 0 indicating no erosion and the highest score (5 for the hand and 10 for the foot) indicating extensive loss of bone from more than one half of the articulating bone. Erosion scores ranged from 0 (no erosion) to 280 (high erosion). | Baseline, Week 24; Baseline, Week 52 | 
| Change From Baseline in Duration of Morning Joint Stiffness | Participants reported the duration of their morning joint stiffness (MJS) in hours and minutes. The participants were asked about their duration of morning joint stiffness on the day prior to the study visit to capture actual symptoms, since the participant may have had an atypical morning routine on the day of the study visit. If morning joint stiffness duration was longer than 12 hours (720 minutes), it was truncated to 720 minutes for statistical presentations and analyses. A decrease in duration of morning joint stiffness indicated an improvement in the participant's condition. | Baseline, Week 52 | 
| Change From Baseline in Worst Tiredness Numeric Rating Scale (NRS) | Participants rated their tiredness by selecting a number from 0 to 10 that best described their worst tiredness during the last 24 hours, where 0 represents no tiredness and 10 represents as bad as you can imagine. | Baseline, Week 24; Baseline Week 52 | 
| Change From Baseline in Worst Joint Pain Numeric Rating Scale (NRS) | Participants rated their joint pain by selecting a number from 0 to 10 that best described their worst joint pain during the last 24 hours, where 0 represents no pain and 10 represents pain as bad as you can imagine. | Baseline, Week 24; Baseline Week 52 | 
| Change From Baseline in Mental Component Score (MCS) and Physical Component Score (PCS) of the Medical Outcomes Study 36-Item Short Form Health Survey Version 2 Acute (SF-36v2 Acute) | The SF-36 is a health-related survey that assesses participant's quality of life and consists of 36 questions covering 8 health domains: physical functioning, bodily pain, role limitations due to physical problems and emotional problems, general health, mental health, social functioning, vitality, and 2 component scores (MCS and PCS). MCS consisted of social functioning, vitality, mental health, and role-emotional scales. PCS consisted of physical functioning, bodily pain, role-physical, and general health scales. Each domain is scored by summing the individual items and transforming the scores into a 0 to 100 scale with higher scores indicating better health status or functioning. | Baseline, Week 24; Baseline Week 52 | 
| Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores | European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) is a standardized measure of health status of the participant. One component consists of a descriptive system of the respondent's health comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using the United Kingdom (UK) algorithm, with scores ranging from -0.594 to 1, and the United States (US) algorithm, with scores ranging from -0.109 to 1. A higher score indicates better health state. | Baseline, Week 24; Baseline Week 52 | 
| Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health) | A second component of the EQ-5D-5L is a self-perceived health score which is assessed using a VAS that ranges from 0 to 100 millimeter (mm), where 0 indicates the worst health you can imagine and 100 indicates the best health you can imagine. | Baseline, Week 24; Baseline Week 52 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scores | The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale is a13-item, symptom-specific questionnaire that specifically assesses the participant's self-reported severity of fatigue and its impact upon daily activities and functioning. The FACIT-F uses a numeric rating scale of 0 (Not at all) to 4 (Very much) for each item to assess fatigue and its impact in the past 7 days. Total scores range from 0 to 52, with higher scores indicating less fatigue. | Baseline, Week 24; Baseline Week 52 | 
| Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores | The Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) questionnaire was developed to measure the effect of general health and symptom severity on work productivity and regular activities in the 7 days prior to the visit. It contains 6 items covering overall work productivity (health), overall work productivity (symptom), impairment of regular activities (health), and impairment of regular activities (symptom). Scores are calculated as impairment percentages. The WPAI-RA yields four types of scores: Absenteeism (work time missed), Presenteeism (impairment at work), Work productivity loss (overall work impairment), and Activity impairment. | Baseline, Week 24; Baseline Week 52 | 
| Population Pharmacokinetics (PK): Peak Concentration at Steady State (Cmax,ss) of Baricitinib |  | Week 0: 15 and 60 minutes postdose; Week 4: 2 to 4 hours post-dose; Week 8: 4 to 6 hours post-dose; Week 12; Week 24; Week 32; Pre-dose | 
| Population PK: Area Under the Concentration Versus Time Curve at a Dosing Interval at Steady State (AUCtau,ss) of Baricitinib |  | Week 0: 15 and 60 minutes postdose; Week 4: 2 to 4 hours post-dose; Week 8: 4 to 6 hours post-dose; Week 12; Week 24; Week 32; Pre-dose |