A Moderate to Severe Rheumatoid Arthritis Study

Eli Lilly and Company527 enrolled

Overview

The purpose of this study is to determine whether baricitinib 4 milligram (mg) once daily is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had an inadequate response to a tumor necrosis factor (TNF) inhibitor, despite ongoing treatment with conventional disease-modifying antirheumatic drugs (cDMARDs).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

527

Conditions

Rheumatoid Arthritis

Interventions

PlaceboDRUG

Administered orally

BaricitinibDRUG

Administered orally

cDMARDDRUG

Participants will continue to take background cDMARD therapy throughout study.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Have a diagnosis of adult-onset Rheumatoid Arthritis (RA) as defined by the American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) 2010 Criteria for the Classification of RA * 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 ≥ (greater than or equal to) 1 times the upper limit of normal (ULN) * Have been treated at approved doses with at least 1 biologic tumor necrosis factor (TNF)- alpha inhibitor for at least 3 months and either: * experienced insufficient efficacy or loss of efficacy * experienced intolerance of such treatment * Have had regular use of at least 1 conventional disease-modifying antirheumatic drugs (cDMARD) for at least the 12 weeks prior to study entry with a continuous, nonchanging dose for at least 8 weeks prior to study entry Exclusion Criteria: * Have received a biologic treatment for RA within 28 days of planned randomization; have received rituximab within 6 months of planned randomization * Are currently receiving corticosteroids at doses \> (greater than) 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 * Are currently receiving concomitant treatment with methotrexate (MTX), hydroxychloroquine, and sulfasalazine or combination of any 3 cDMARDs * 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 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 have 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 \< (less than) 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 (e.g. Fridericia's corrected QT interval \>500 millisecond \[msec\]) * Have symptomatic herpes simplex at the time of study enrollment * Have evidence of active or latent tuberculosis (TB)

Locations (103)

Outcomes

Primary Outcomes

Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response - Placebo Versus Baricitinib 4 mg

ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. 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 discontinue study or drug or are rescued before analysis timepoint are deemed non-responders.

Time frame: Week 12

Secondary Outcomes

Change From Baseline in HAQ-DI Score - Placebo Versus Baricitinib 4 mg

The HAQ-DI questionnaire 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 were averaged to calculate the HAQ-DI score, which ranged from 0 (no disability) to 3 (worst disability). A decrease in HAQ-DI score indicated an improvement in the participant's condition.

Time frame: Baseline, Week 12

Change From Baseline in the Disease Activity Score Based on a 28-Joint Count (DAS-28) High Sensitivity C-Reactive Protein (hsCRP) - Placebo Versus Baricitinib 4 mg

DAS-28 consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), high sensitivity C-reactive protein (hsCRP) (milligrams per liter), and Patient's Global Assessment of Disease Activity. DAS28 was calculated using following formula: DAS28-hsCRP=0.56\*square root (sqrt)(TJC28)+0.28\*sqrt(SJC28)+0.36\*natural log(CRP+1)+0.014\*Patient's Global VAS+0.96. Total scores ranged from 1.0-9.4, where lower scores indicated less disease activity.

Time frame: Baseline, Week 12

Data from ClinicalTrials.gov

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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.

Glendale, Arizona, United States

Phoenix, Arizona, United States

Tucson, Arizona, United States

Palo Alto, California, United States

Upland, California, United States

Danbury, Connecticut, United States

Trumbull, Connecticut, United States

Lewes, Delaware, United States

Boynton Beach, Florida, United States

Orlando, Florida, United States

...and 93 more locations

Percentage of Participants Achieving American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Remission - Simplified Disease Activity Index (SDAI) ≤3.3 - Placebo Versus Baricitinib 4 mg

The ACR/EULAR definitions of rheumatoid arthritis (RA) remission includes an index-based definition. The index-based definition of remission occurs with a SDAI score ≤3.3. The SDAI is a tool for measurement of disease activity in RA that integrates TJC28 (0 to 28), SJC28 (0 to 28), acute phase response using C-reactive protein (0.1 to 10.0 mg/dL), Patient's Global Assessment of Disease Activity using VAS (0 to 10.0 cm), and Physician's Global Assessment of Disease Activity using VAS (0 to 10.0 cm). Lower scores indicated less disease activity.

Time frame: Week 12

Percentage of Participants Achieving ACR20 Response - Placebo Versus Baricitinib 2 mg

ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. 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 using VAS, Patient's Global Assessment of Disease Activity using VAS, HAQ-DI, pain due to arthritis, and hsCRP. Participants with missing responses and participants who discontinue study or drug or are rescued before analysis time point are deemed non-responders.

Time frame: Week 12

Change From Baseline in HAQ-DI Score - Placebo Versus Baricitinib 2 mg

The HAQ-DI questionnaire 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 were averaged to calculate the HAQ-DI score. Total scores ranged from 0 (no disability) to 3 (worst disability). A decrease in HAQ-DI score indicated an improvement in the participant's condition.

Time frame: Baseline, Week 12

Change From Baseline in the DAS28 - hsCRP - Placebo Versus Baricitinib 2 mg

DAS28 consisted of composite score of following variables: TJC28, SJC28, hsCRP (mg/mL), and Patient's Global Assessment of Disease Activity. DAS28 was calculated using 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. Total scores ranged from 1.0-9.4, where lower scores indicated less disease activity.

Time frame: Baseline, Week 12

Percentage of Participants Achieving ACR/EULAR Remission - SDAI ≤3.3 - Placebo Versus Baricitinib 2 mg

Time frame: Week 12

Percentage of Participants Achieving ACR20 Response

ACR20 Responder Index is a composite of clinical, laboratory, and functional measures in rheumatoid arthritis. 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 using VAS, Patient's Global Assessment of Disease Activity using VAS, HAQ-DI, pain due to arthritis, and hsCRP. Participants with missing responses and participants who discontinue study or drug or are rescued before analysis time point are deemed non-responders.

Time frame: Week 24

Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response

ACR50 Responder Index is a 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 discontinue study or drug or are rescued before analysis time point are deemed non-responders.

Time frame: Week 12 and Week 24

Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response

ACR70 Responder Index is a 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 discontinue study or drug or are rescued before analysis time point are deemed non-responders.

Time frame: Week 12 and Week 24

Change From Baseline in DAS28 - Erythrocyte Sedimentation Rate (ESR)

DAS28 consisted of composite score of following variables: tender joint count (TJC28), swollen joint count (SJC28), ESR (millimeters per hour), and Patient's Global Assessment of Disease Activity. DAS28 was calculated using 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. Total scores ranged from 1.0-9.4, where lower scores indicated less disease activity.

Time frame: Baseline, Week 12

Change From Baseline in Clinical Disease Activity Index 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.

Time frame: Baseline, Week 24

Change From Baseline in Measures of SDAI Score

The 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 visual analog scale (cm), and Physician's Global Assessment of Disease Activity using visual analog scale (cm). The SDAI is calculated by summing the values of the 5 components. Lower scores indicated less disease activity. The SDAI is expressed as a score on a scale with the minimum score=0 (best) to maximum score=86 (worst). A negative change from baseline indicates an improvement.

Time frame: Baseline, Week 24

Percentage of Participants Achieving ACR/EULAR Remission - Boolean Remission

The ACR/EULAR definitions of RA remission includes 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.

Time frame: Week 24

Change From Baseline in Duration of Participant Reported Outcome - 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 that day. 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.

Time frame: Baseline, Week 24

Change From Baseline in Worst Tiredness Numeric Rating Scale (NRS)

A participant-administered, single-item, 11-point horizontal scale anchored at 0 and 10, with 0 representing (no tiredness) and 10 representing (as bad as you can imagine). Participants rate their tiredness by selecting the one number that describes their worst level of tiredness during the past 24 hours. Total scores ranged from 0-10.

Time frame: Baseline, Week 24

Change From Baseline in Worst Joint Pain NRS

Participant-administered, single-item, 11-point horizontal scale anchored at 0 and 10, with 0 representing (no joint pain) and 10 representing (pain as bad as you can imagine). Participants rate their joint pain by selecting the one number that describes their worst level of joint pain during the past 24 hours. Total scores ranged from 0-10.

Time frame: Baseline, Week 24

Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale Scores

The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale is a brief 13-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.

Time frame: Baseline, Week 12, Week 24

Change From Baseline in Mental Component Score (MCS), 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 (mental \[MCS\] and physical \[PCS\]). 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.

Time frame: Baseline, Week 12, Week 24

Change From Baseline in European Quality of Life-5 Dimensions-5 Level Scores

European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) is a standardized measure of health status of the participant. The first component is 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. The second component is a self-perceived health score which is assessed using a VAS that ranged from 0 to 100 millimeter (mm), where 0 mm indicated the worst health you can imagine and 100 mm indicated the best health you can imagine.

Time frame: Baseline, Week 12, Week 24

Percentage Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores

The WPAI-RA participant 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. Using 6 questions, it yields four types of scores: absenteeism (work time missed), presenteeism (impairment at work), work productivity loss (overall work impairment), and activity impairment, with outcomes expressed as impairment percentages. Percentage work time missed absenteeism: Q2/(Q2+Q4)\*100, Percentage impairment while working presenteeism: Q5/10\*100; Percentage overall work impairment work productivity loss: Q2/(Q2+Q4)+\[(1-Q2/(Q2+Q4))x(Q5/10)\]\*100; Percentage activity impairment activity impairment: Q6/10\*100. Higher numbers indicate greater impairment and less productivity, that is, worse outcomes.

Time frame: Baseline, Week 12, Week 24

Population Pharmacokinetics (PK): Maximum Concentration at Steady State of Dosing (Cmax,ss) of Baricitinib

Time frame: Week 0 (Baseline): 15 min. post-dose, 1 hour post-dose. Week 4 (Day 28 ±2 days): 2 to 4 hours post-dose. Week 8 (Day 56 ±3 days): 4 to 6 hours post-dose. Week 12 (Day 84 ±3 days): Pre-dose. Week 24 (Day 168 ±5 days): Pre-dose.

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