A Study in Moderate to Severe Rheumatoid Arthritis

Phase 3

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: Adalimumab
Drug: Methotrexate
Drug: Baricitinib
Drug: Adalimumab Placebo
Drug: Baricitinib Placebo

Registration Number: NCT01710358

Lead Sponsor: Eli Lilly and Company

Brief Summary: The purpose of this study is to determine whether baricitinib is superior to placebo in the treatment of participants with moderately to severely active Rheumatoid Arthritis (RA) who have had an inadequate response to methotrexate (MTX) treatment.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1307

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 ≥6 milligram per Liter (mg/L)
Have had regular use of methotrexate (MTX) for at least the 12 weeks prior to study entry at a dose that is considered acceptable to adequately assess clinical response.
Have at least 1 joint erosion in hand, wrist, or foot joints based on radiographic interpretation by the central reader and be rheumatoid factor or anticyclic citrullinated peptide (anti-CCP) antibody positive; or have at least 3 joint erosions in hand, wrist, or foot joints based on radiographic interpretation by the central reader regardless of rheumatoid factor or anti-CCP antibody status

Exclusion Criteria

Are currently receiving corticosteroids at doses >10 mg of prednisone per day (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 MTX, hydroxychloroquine, and sulfasalazine or combination of any 3 conventional disease-modifying antirheumatic drugs (cDMARDs)
Are currently receiving or have received cDMARDs (eg, gold salts, cyclosporine, azathioprine, or any other immunosuppressives) other than MTX, hydroxychloroquine (up to 400 mg/day), or sulfasalazine (up to 3000 mg/day) within 4 weeks prior to study entry
Have received leflunomide in the 12 weeks prior to study entry
Have started a new physiotherapy treatment for RA in the 2 weeks prior to study entry
Have ever received any biologic disease-modifying antirheumatic drugs (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 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 any condition or contraindication for adalimumab that would preclude the participant from participating in this protocol
Have active fibromyalgia that 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 Sjögren's syndrome are not excluded)
Have a diagnosis of Felty's syndrome
Have had any major surgery within 8 weeks prior to 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 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, or 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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Adalimumab	Adalimumab	Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Adalimumab	Baricitinib Placebo	Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Placebo	Adalimumab Placebo	Placebo administered orally once daily through Week 24 and placebo administered by subcutaneous (SC) injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Placebo	Baricitinib Placebo	Placebo administered orally once daily through Week 24 and placebo administered by subcutaneous (SC) injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Baricitinib	Adalimumab Placebo	Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Placebo	Methotrexate	Placebo administered orally once daily through Week 24 and placebo administered by subcutaneous (SC) injection every 2 weeks through Week 50. At Week 24, participants were given baricitinib 4 milligram (mg) orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Baricitinib	Baricitinib	Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Baricitinib	Methotrexate	Baricitinib 4 mg administered orally once daily through Week 52 and an adalimumab placebo SC injection every 2 weeks through Week 50. Starting at Week 16, nonresponder participants originally randomized to baricitinib continued to receive baricitinib 4 mg administered orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.
Adalimumab	Methotrexate	Adalimumab 40 mg administered by SC injection every 2 weeks through Week 50 and baricitinib placebo orally once daily through Week 52. Starting at Week 16, participants who were nonresponders were rescued with baricitinib 4 mg orally once daily through Week 52. Participants continued to take background methotrexate (MTX) therapy throughout study.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Achieving American College of Rheumatology 20% Improvement (ACR20)	Week 12	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 timepoint were deemed non-responders.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in the Modified Total Sharp Score (mTSS)	Baseline, Week 24	X-rays of the hands/wrists and feet were scored for structural progression as measured using the mTSS. 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.
Change From Baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) Score	Baseline, Week 12	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.
Change From Baseline in the Disease Activity Score Based on a 28-Joint Count and High-sensitivity C-reactive Protein (DAS28-hsCRP)	Baseline, Week 12	Disease Activity Score (DAS) modified to include 28 joint count (DAS28) consisted of composite score of 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 using visual analog scale (VAS) (participant global VAS). 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. Scores ranged 1.0-9.4, where lower scores indicated less disease activity.
Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) and 70% (ACR70) Response	Week 12, Week 24, Week 52	ACR50 and ACR70 Responder Index is a composite of clinical, laboratory, and functional measures in RA. ACR50 and ACR70 Responder is a participant who has at least 50% or 70% improvement, respectively, 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.
Change From Baseline in Clinical Disease Activity Index (CDAI) Score	Baseline, Week 12, Week 24, Week 52	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.
Percentage of Participants Achieving Simplified Disease Activity Index (SDAI) Score ≤3.3	Week 12, Week 24, Week 52	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.
Percentage of Participants Achieving American College of Rheumatology European League Against Rheumatism (ACR/EULAR) Remission - Boolean Remission	Week 12, Week 24, Week 52	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.
Median of Individual Participant Mean Duration of Morning Joint Stiffness in the Prior 7 Days as Collected in Electronic Diaries	Week 12	Participants recorded the duration of their morning joint stiffness (MJS) in hours and minutes into electronic diaries daily. If morning joint stiffness duration was longer than 12 hours (720 minutes), it was truncated to 720 minutes for statistical presentations and analyses. The average value across the 7 days preceding each visit was calculated. A decrease in duration of morning joint stiffness indicated an improvement in the participant's condition.
Mean Severity of Morning Joint Stiffness Numeric Rating Scale (NRS) in the Prior 7 Days as Collected in Electronic Diaries	Week 12	Participants rated the severity of their morning joint stiffness by selecting a number from 0 to 10 that best described their overall level of morning joint stiffness from the time they woke up, where 0 represents "no joint stiffness" and 10 represents "joint stiffness as bad as you can imagine". Participants reported their severity daily in electronic diaries. The average value across the 7 days preceding each visit was calculated.
Mean Worst Tiredness Numeric Rating Scale (NRS) in the Prior 7 Days as Collected in Electronic Diaries	Week 12	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". Participants reported their worst tiredness in electronic diaries. The average value across the 7 days preceding each visit is calculated.
Mean Worst Joint Pain NRS in the Prior 7 Days as Collected in Electronic Diaries	Week 12	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". Participants reported their worst joint pain in daily electronic diaries. The average value across the 7 days preceding each visit was calculated.
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale Scores	Baseline, Week 12, Week 24, Week 52	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.
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)	Baseline, Week 12, Week 24, Week 52	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 or functioning.
Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores	Baseline, Week 12, Week 24, Week 52	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.
Change From Baseline in European Quality of Life-5 Dimensions-5 Level (EQ-5D-5L) Scores (Self-Perceived Health)	Baseline, Week 12, Week 24, Week 52	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.
Change From Baseline in Work Productivity and Activity Impairment-Rheumatoid Arthritis (WPAI-RA) Scores	Baseline, Week 12, Week 24, Week 52	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.
Change From Baseline in Joint Space Narrowing (JSN) and Bone Erosion Scores	Baseline, Week 24, Week 52	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).
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 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 12; Week 24; Week 32: Pre-dose

Trial Locations

Locations (48): Metroplex Clinical Research Center
🇺🇸
Dallas, Texas, United States
The Seattle Arthritis Clinic
🇺🇸
Seattle, Washington, United States
Valley Arthritis Care, LLC
🇺🇸
Phoenix, Arizona, United States
Diagnostic Rheumatology and Research
🇺🇸
Indianapolis, Indiana, United States
Dr. George Timothy Kelly
🇺🇸
Las Vegas, Nevada, United States
Health Research Institute
🇺🇸
Oklahoma City, Oklahoma, United States
Pioneer Research Solutions
🇺🇸
Houston, Texas, United States
Valley Endocrine, Fresno
🇺🇸
Fresno, California, United States
Arizona Arthritis & Rheumatology Research
🇺🇸
Glendale, Arizona, United States
Desert Medical Advances
🇺🇸
Palm Desert, California, United States
New England Research Associates
🇺🇸
Trumbull, Connecticut, United States
Vancouver Clinic
🇺🇸
Vancouver, Washington, United States
Asheville Rheumatology & Osteoporosis Research Assoc, PA
🇺🇸
Asheville, North Carolina, United States
Healthcare Research Consultant
🇺🇸
Tulsa, Oklahoma, United States
East Penn Rheumatology
🇺🇸
Bethlehem, Pennsylvania, United States
Indiana University Health
🇺🇸
Indianapolis, Indiana, United States
Accurate Clinical Research
🇺🇸
Webster, Texas, United States
Delaware Arthritis
🇺🇸
Lewes, Delaware, United States
Mindful Medical Research
🇵🇷
San Juan, Puerto Rico
Orthopedic Research Institute
🇺🇸
Boynton Beach, Florida, United States
Bio Behavioral Health
🇺🇸
Toms River, New Jersey, United States
Drug Trials of America
🇺🇸
Hartsdale, New York, United States
Center for Arthritis and Rheumatic Diseases, PC
🇺🇸
Chesapeake, Virginia, United States
Arthritis & Osteoporosis Associates LLP
🇺🇸
Lubbock, Texas, United States
University of Boards Regent
🇺🇸
Tucson, Arizona, United States
Boulder Medical Center
🇺🇸
Boulder, Colorado, United States
Sun Valley Arthritis Center, LTD
🇺🇸
Peoria, Arizona, United States
Pacific Arthritis Center
🇺🇸
Santa Maria, California, United States
Sun Coast Clinical Research, Inc
🇺🇸
New Port Richey, Florida, United States
Integral Rheumatology & Immunology Specialists
🇺🇸
Plantation, Florida, United States
West Michigan Rheumatology
🇺🇸
Grand Rapids, Michigan, United States
(AOA) Arthritis & Osteoporosis Associates
🇺🇸
Freehold, New Jersey, United States
Paramount Medical Research
🇺🇸
Middleburg Heights, Ohio, United States
Carolina Rheumatology and Neurology Associates
🇺🇸
Myrtle Beach, South Carolina, United States
Rheumatology and Immunotherapy Center
🇺🇸
Franklin, Wisconsin, United States
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.
🇬🇧
Bradford, West Yorkshire, United Kingdom
Office of Dr. Ramon Toro
🇵🇷
San German, Puerto Rico
Clinical Research Center of Reading, LLP
🇺🇸
Wyomissing, Pennsylvania, United States
Inlande Rheumatology Clinical Trials
🇺🇸
Upland, California, United States
Clinical Research Center of CT/NY
🇺🇸
Danbury, Connecticut, United States
Jeffrey Alper, M.D.
🇺🇸
Naples, Florida, United States
Goldpoint Clinical Research LLC
🇺🇸
Indianapolis, Indiana, United States
University of Missouri
🇺🇸
Columbia, Missouri, United States
Latin Clinical Trial Center
🇵🇷
Santurce, Puerto Rico
Ramon L. Ortega Colon
🇵🇷
Carolina, Puerto Rico
Rheumatology Associates of Central Florida
🇺🇸
Orlando, Florida, United States
McIlwain Medical Group
🇺🇸
Tampa, Florida, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States