An Extension Study to Learn More About the Long-Term Safety of Litifilimab (BIIB059) Injections and Whether They Can Improve Symptoms of Adult Participants Who Have Systemic Lupus Erythematosus
- Conditions
- Systemic Lupus Erythematosus (SLE)
- Interventions
- Drug: Litifilimab-matching placebo
- Registration Number
- NCT05352919
- Lead Sponsor
- Biogen
- Brief Summary
In this study, researchers will learn more about a study drug called litifilimab (BIIB059) in participants with systemic lupus erythematosus (SLE). The study will focus on participants who have active disease and are already taking standard of care medications. These may include antimalarials, steroids, and immunosuppressants. This is an extension study of 230LE303 and 230LE304 (TOPAZ-1 and TOPAZ-2). It will enroll participants who completed the treatment periods of either one of the parent studies.
The main objective of the study is to learn more about the long-term safety of litifilimab. The main question researchers want to answer is:
- How many participants have adverse events and serious adverse events? Researchers will also learn about the effect litifilimab has on controlling symptoms of SLE and lowering its activity. They will measure symptoms of SLE over time using a variety of scoring tools. These include the SLE Responder Index (SRI), the Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K), and the British Isles Lupus Activity Group-2004 (BILAG-2004), among others.
Researchers will also study how participants' immune systems respond to litifilimab. Additionally, they will measure the effect litifilimab and SLE have on the quality of life of participants using a group of questionnaires.
The study will be done as follows:
* The Week 52 visit of studies 230LE303 and 230LE304 will be Day 1 of this study.
* Participants who were receiving either a high or low dose of litifilimab in the parent studies will continue receiving the same doses.
* Participants who were receiving placebo in the parent studies will be randomized to receive either a high or low dose of litifilimab.
* All participants will receive litifilimab as injections under the skin once every 4 weeks. The treatment period will last 156 weeks. Participants will continue to take their standard of care medications.
* Neither the researchers nor the participants will know which doses of litifilimab the participants are receiving.
* There will be a follow-up safety period that lasts up to 24 weeks.
* In total, participants will have up to 47 study visits. The total study duration for participants will be up to 180 weeks.
- Detailed Description
This is an extension study for all participants who completed study 230LE303 (NCT04895241) and 230LE304 (NCT04961567) (parent phase 3 studies) through Week 52 and did not discontinue litifilimab or placebo. Eligible participants from parent phase 3 studies will be followed for up to 180 weeks.
The primary objective of this study is to evaluate the long-term safety and tolerability of litifilimab in participants with active systemic lupus erythematosus (SLE).
The secondary objectives of this study are to evaluate the long-term effect of litifilimab on disease activity in participants with SLE, to evaluate the long-term effect of litifilimab in participants with SLE in maintaining low disease activity, to evaluate the effect of litifilimab in participants with active SLE in preventing irreversible organ damage, to assess long-term use of oral corticosteroid (OCS) with participants receiving litifilimab treatment, to assess the impact of litifilimab on participant-reported Health-Related Quality-of-Life Questionnaire (HRQoL), symptoms, and impacts of SLE, to evaluate long-term effect of litifilimab on laboratory parameters, and to evaluate immunogenicity of litifilimab.
Recruitment & Eligibility
- Status
- ENROLLING_BY_INVITATION
- Sex
- All
- Target Recruitment
- 864
- Participants who completed 1 of the 52-week of the double-blind placebo-controlled, parent Phase 3 studies (230LE303 (NCT04895241) and 230LE304 (NCT04961567)) on study treatments with either litifilimab or placebo to Week 48 and attended the last study assessment visit at Week 52
Key
- Early parent Phase 3 studies treatment terminators (participants who discontinued study treatment before Week 52)
- Early parent Phase 3 studies terminators (participants who withdrew from study participation and did not complete the 52-week treatment period)
- Participants who developed moderate-to-severe worsening of organ-specific lupus manifestations that would require a change in antimalarials and/or immunosuppressive therapy (initiation of new treatment or increase in dose above the allowed maximum dose)
- Use of other investigational drugs or off-label drugs used to treat SLE, cutaneous lupus, or lupus nephritis during the parent Phase 3 studies
NOTE: Other inclusion/exclusion criteria may apply.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Litifilimab Low Dose Litifilimab-matching placebo Participants who are receiving background nonbiologic lupus standard of care (SOC) therapy and received litifilimab low dose, subcutaneously (SC), every 4 weeks (Q4W) during the parent Phase 3 studies (i.e. studies 230LE303 \[NCT04895241\] or 230LE304 \[NCT04961567\]) will continue to receive litifilimab low dose, SC, Q4W from Day 1 up to 152 weeks with an additional dose of litifilimab-matching placebo at Week 2. Participants who are receiving background nonbiologic lupus SOC therapy and received litifilimab-matching placebo in the parent Phase 3 studies (i.e. studies 230LE303 \[NCT04895241\] or 230LE304 \[NCT04961567\]) will be randomized to receive litifilimab low dose, SC, Q4W from Day 1 up to 152 weeks with an additional dose at Week 2. Litifilimab High Dose Litifilimab-matching placebo Participants who are receiving background nonbiologic lupus SOC therapy and received litifilimab high dose, SC, Q4W during the parent Phase 3 studies (i.e. studies 230LE303 \[NCT04895241\] or 230LE304 \[NCT04961567\]) will continue to receive litifilimab high dose, SC, Q4W from Day 1 up to 152 weeks with an additional dose of litifilimab-matching placebo at Week 2. Participants who are receiving background nonbiologic lupus SOC therapy and received litifilimab-matching placebo in the parent Phase 3 studies (i.e. studies 230LE303 \[NCT04895241\] or 230LE304 \[NCT04961567\]) will be randomized to receive litifilimab high dose, SC, Q4W from Day 1 up to 152 weeks with an additional dose at Week 2. Litifilimab Low Dose Litifilimab Participants who are receiving background nonbiologic lupus standard of care (SOC) therapy and received litifilimab low dose, subcutaneously (SC), every 4 weeks (Q4W) during the parent Phase 3 studies (i.e. studies 230LE303 \[NCT04895241\] or 230LE304 \[NCT04961567\]) will continue to receive litifilimab low dose, SC, Q4W from Day 1 up to 152 weeks with an additional dose of litifilimab-matching placebo at Week 2. Participants who are receiving background nonbiologic lupus SOC therapy and received litifilimab-matching placebo in the parent Phase 3 studies (i.e. studies 230LE303 \[NCT04895241\] or 230LE304 \[NCT04961567\]) will be randomized to receive litifilimab low dose, SC, Q4W from Day 1 up to 152 weeks with an additional dose at Week 2. Litifilimab High Dose Litifilimab Participants who are receiving background nonbiologic lupus SOC therapy and received litifilimab high dose, SC, Q4W during the parent Phase 3 studies (i.e. studies 230LE303 \[NCT04895241\] or 230LE304 \[NCT04961567\]) will continue to receive litifilimab high dose, SC, Q4W from Day 1 up to 152 weeks with an additional dose of litifilimab-matching placebo at Week 2. Participants who are receiving background nonbiologic lupus SOC therapy and received litifilimab-matching placebo in the parent Phase 3 studies (i.e. studies 230LE303 \[NCT04895241\] or 230LE304 \[NCT04961567\]) will be randomized to receive litifilimab high dose, SC, Q4W from Day 1 up to 152 weeks with an additional dose at Week 2.
- Primary Outcome Measures
Name Time Method Number of Participants with Serious Adverse Events (SAEs) Up to Week 180 An SAE is any untoward medical occurrence that at any dose results in death, in the view of the Investigator, places the participant at immediate risk of death (a life threatening event), requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, and is a medically important event.
Number of Participants with Treatment Emergent Adverse Events (TEAEs) Up to Week 180 An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A TEAE is an AE that started or worsened in severity after the first dose of study treatment through 28 days after the last dose of study treatment or end of study (EOS) date, whichever comes earlier.
- Secondary Outcome Measures
Name Time Method Percentage of Participants who Achieved an Systemic Lupus Erythematosus Responder Index (SRI)-4 Response Up to Week 180 SRI-4 is a composite endpoint defined as the following:
* A reduction from baseline of ≥4 points in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI-2K) score.
* No new organ system affected, as defined by no new British Isles Lupus Activity Group-2004 (BILAG-2004 grade A) and no more than 1 new BILAG 2004 grade B versus previous visit.
* No worsening from baseline in lupus disease activity as defined by \<0.3-point increase on 3-point Physician's Global Assessment (PGA) visual analog scale (VAS).
* No violation of protocol-specified medication rulesPercentage of Participants With at Least 4 Joints (Both Swollen and Tender) at Baseline who Achieved a Joint-50 Response Up to Week 180 Joint-50 response is a 50% reduction in total active joint count from baseline. An active joint is defined as a joint with pain and signs of inflammation (e.g., tenderness, swelling or effusion). A 28-joint assessment will be performed to determine the active joint count, which is defined as the sum of tender and swollen joint counts.
Percentage of Participants With a Cutaneous Lupus Erythematosus Disease Area and Severity Index - Activity (CLASI-A) Score ≥10 at Baseline who Achieved a CLASI-50, CLASI-70, and CLASI-90 Response Up to Week 180 CLASI score is used to evaluate lupus skin manifestations. The activity scale (CLASI-A) includes measurements of erythema, scale and hypertrophy, and mucous membrane disease. Each part of the body is listed separately, from the scalp to the feet, in addition to sections focusing on mucous membrane involvement and alopecia. Points are given for the presence of erythema, scale, mucous membrane lesions, recent hair loss, and inflammatory alopecia. Scores for each area are assigned based on the most severe lesion within the area of interest. CLASI-A scores of 0 to 9, 10 to 20, and 21 to 70 represent disease severity of mild, moderate, and severe, respectively. CLASI-50, CLASI-70, and CLASI-90 responders are defined as ≥ 50%, ≥ 70%, and ≥ 90% improvement in CLASI-A score from baseline at the specified timepoint.
Percentage of Participants who Achieved a British Isles Lupus Assessment Group based Composite Lupus Assessment (BICLA) Response Up to Week 180 BICLA is a composite endpoint defined as the following:
* BILAG-2004 improvement, defined as all of BILAG-2004 Grade A at baseline improved to B, C, or D and all of BILAG-2004 Grade B at baseline improved to C or D.
* No BILAG-2004 worsening in other BILAG-2004 organ systems such that there are no new BILAG-2004 Grade A or greater than 1 new BILAG-2004 Grade B.
* No worsening in the SLEDAI-2K total score compared to baseline.
* No worsening from baseline in lupus disease activity as defined by \<0.3-point increase on 3-point PGA VAS.
* No violation of protocol-specified medication rules.Annualized Severe Safety of Estrogens in Systemic Lupus Erythematosus National Assessment - Systemic Lupus Erythematosus Disease Activity Index Flare Index (SFI) Flare Rate Up to Week 156 A severe flare is defined as any of the following:
* Change in SLEDAI instrument score to \>12
* New or worse: central nervous system SLE; vasculitis; nephritis; myositis; platelets \<60,000/mL, or hemolytic anemia with hemoglobin \<7 grams per deciliter (g/dL) or decrease in hemoglobin \>3 g/dL and requiring: doubling prednisone dose, increase to \>0.5 milligrams per kilograms per day (mg/kg/day) or hospitalization
* Increase in prednisone dose to \>0.5 mg/kg/day
* New requirement for cyclophosphamide, azathioprine, methotrexate, or mycophenolate for SLE activity
* Hospitalization for SLE activity
* Increase in PGA score to \>2.5Percentage of Time Spent in Lupus Low Disease Activity State (LLDAS) Up to Week 180 LLDAS is a composite endpoint defined as the following:
i. SLEDAI-2K score ≤ 4, with no activity in a major organ system (renal, central nervous system, cardiopulmonary, vasculitis, fever); and ii. No new features of lupus disease activity compared with the previous assessment; and iii. SELENA-SLEDAI PGA ≤ 1; and iv. Current prednisone (or equivalent) dose ≤ 7.5 mg/day; and v. Standard maintenance doses of immunosuppressive drugs and approved biological agents.
"No new features" is defined as any new SLEDAI-2K component that was not present at the previous assessment. The SELENA-SLEDAI PGA Scale ranges from 0-3, where 0 is no disease activity and 3 is maximum disease activity. "Standard maintenance doses" include drugs limited to those allowed per protocol.Percentage of Participants With Sustained LLDAS Up to Week 180 LLDAS is a composite endpoint defined as the following:
i. SLEDAI-2K score ≤ 4, with no activity in a major organ system (renal, central nervous system, cardiopulmonary, vasculitis, fever); and ii. No new features of lupus disease activity compared with the previous assessment; and iii. SELENA-SLEDAI PGA ≤ 1; and iv. Current prednisone (or equivalent) dose ≤ 7.5 mg/day; and v. Standard maintenance doses of immunosuppressive drugs and approved biological agents.
"No new features" is defined as any new SLEDAI-2K component that was not present at the previous assessment. The SELENA-SLEDAI PGA Scale ranges from 0-3, where 0 is no disease activity and 3 is maximum disease activity. "Standard maintenance doses" include drugs limited to those allowed per protocol.Duration of Sustained LLDAS as Defined by the Number of Visits in LLDAS Up to Week 180 LLDAS is a composite endpoint defined as the following:
i. SLEDAI-2K score ≤ 4, with no activity in a major organ system (renal, central nervous system, cardiopulmonary, vasculitis, fever); and ii. No new features of lupus disease activity compared with the previous assessment; and iii. SELENA-SLEDAI PGA ≤ 1; and iv. Current prednisone (or equivalent) dose ≤ 7.5 mg/day; and v. Standard maintenance doses of immunosuppressive drugs and approved biological agents.
"No new features" is defined as any new SLEDAI-2K component that was not present at the previous assessment. The SELENA-SLEDAI PGA Scale ranges from 0-3, where 0 is no disease activity and 3 is maximum disease activity. "Standard maintenance doses" include drugs limited to those allowed per protocol.Annual Change From Baseline Value From the Parent Phase 3 Studies in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) Score Up to Week 156 SDI score is used to assess the accumulated damage in participants with SLE. It assess 12 organ systems and records damage in participants with lupus, regardless of its cause. Damage could be due to previous disease activity, medication, or intercurrent illness (such as surgery or cancer). To distinguish between active inflammation and damage, an item must be present for at least 6 months. It is assumed that persistent inflammation (for at least 6 months) would result in tissue injury and hence damage. SDI is evaluated on a scale 0-47 with higher score indicating higher damage.
Cumulative Exposure to OCS Over Time Up to Week 156 Percentage of Participants With OCS ≤7.5 mg Up to Week 156 Percentage of Participants With OCS ≤5 mg Up to Week 156 Change From Baseline in Lupus-Specific Health-Related Quality-Of-Life (LupusQoL) Score Up to Week 156 The LupusQoL is a participant-reported, lupus-specific, HRQoL questionnaire consisting of 34 items grouped in 8 domains: physical health, pain, planning, intimate relationships, burden to others, emotional health, body image and fatigue. Participants indicate their responses on a 5-point Likert response format, where 4 = never, 3 = occasionally, 2 = a good bit of the time, 1 = most of the time, and 0 = all the time. A LupusQoL score for each domain will be reported on a 0 to 100 scale, with greater values indicating better HRQoL.
Change From Baseline in Short Form Health Survey-36 (SF-36) (Acute Version) Score Up to Week 156 The SF-36 is a 36-item scale which assesses HRQoL in 8 domains: limitations in physical activities due to health problems, limitations in social activities due to physical or emotional problems, limitations in usual role activities due to physical health problems, bodily pain, general mental health (psychological distress and well-being), limitations in usual role activities due to emotional problems, vitality (energy and fatigue), general health perceptions. The SF-36 (Acute Version) form asks for participants to reply to questions (items) according to how they have felt over a specifically defined period of time. Items 1-4 primarily contribute to the physical component summary (PCS) score of the SF-36. Items 5-8 primarily contribute to the mental component summary (MCS) score of the SF-36 where higher scores indicate best health. Scores on each item are summed and averaged (range: 0=worse health to 100=best possible health).
Change From Baseline in European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L) Up to Week 156 The EQ-5D is a standardized generic measure of health status developed by the European Quality of Life Group. This study uses the EQ-5D-3L version of the instrument. This instrument consists of 2 sections. The first section comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. All dimensions are measured on a 3-point scale, 1: No problems; 2: Some problems; 3: Extreme problems. The second section comprises the Visual Analogue Scale, which records the respondent's self-rated health on a vertical scale ranging from 0 to 100, lower scores indicate the worst possible health state.
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Score Up to Week 156 The FACIT-Fatigue is a participant-administered HRQoL questionnaire that evaluates participant's fatigue in 5 broad categories: physical well-being, social/family well-being, emotional well-being, functional well-being and additional concerns. The level of fatigue is measured by questions assessed on a 5-point scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). The responses for each item are added to obtain a total score which ranges from 0 to 52, with a higher score indicating less fatigue.
Change From Baseline in Patient Health Questionnaire-9 (PHQ-9) Score Up to Week 156 The PHQ-9 is a participant-administered HRQoL questionnaire to screen for the presence and severity of depression. The PHQ-9 is a participant-reported outcome (PRO) that is used to measure depression in adults. It contains 9 questions, with a 2 week recall period. The PHQ-9 yields an overall severity score that can range from 0 to 27 with the following severity scores: 0-4 = none; 5-9 = mild; 10-14 = moderate; 15-19 = moderate-to-severe; and 20-27 = severe.
Change From Baseline in Work Productivity and Activity Impairment (WPAI):Lupus Score Up to Week 156 WPAI questionnaire is a validated instrument to measure impairments in work and activities. The WPAI yields four types of scores: 1. Absenteeism (work time missed) 2. Presenteesism (impairment at work / reduced on-the-job effectiveness) 3. Work productivity loss (overall work impairment / absenteeism plus presenteeism) 4. Activity Impairment. Each score ranges from 0 to 100, with higher numbers indicating greater impairment and less productivity.
Change from Baseline in Patient Global Assessment (PtGA) Score Up to Week 156 The PtGA is participant-administered, single-item question evaluating the impact of health and illness, with responses ranging from very poor to very well on a 100 mm VAS. The participant will consider the previous week when addressing this question.
Number of Participants with Clinically Relevant Abnormalities in Standard Laboratory Parameters Up to Week 180 Standard laboratory parameters will include hematology, blood chemistry, urinalysis, and coagulation.
Number of Participants with Clinically Relevant Abnormalities in Electrocardiogram (ECG) Results Up to Week 156 Number of Participants with Antibodies to Litifilimab Up to Week 180
Trial Locations
- Locations (141)
Arizona Arthritis & Rheumatology Associates, P.C.
🇺🇸Phoenix, Arizona, United States
Wallace Rheumatic Study Center
🇺🇸Beverly Hills, California, United States
Care Access Research - Huntington Beach
🇺🇸Huntington Beach, California, United States
Providence Facey Medical Foundation
🇺🇸Mission Hills, California, United States
Inland Rheumatology Clinical Trials, Inc.
🇺🇸Upland, California, United States
University of Colorado Denver
🇺🇸Aurora, Colorado, United States
Georgetown University Hospital-Medstar
🇺🇸Washington, District of Columbia, United States
Arthritis & Rheumatic Disease Specialties
🇺🇸Aventura, Florida, United States
Clinical Research of West Florida - Corporate
🇺🇸Clearwater, Florida, United States
Omega Research Consultants
🇺🇸DeBary, Florida, United States
Life Clinical Trials
🇺🇸Margate, Florida, United States
AdventHealth Medical Group
🇺🇸Tampa, Florida, United States
Arthritis Center of North Georgia
🇺🇸Gainesville, Georgia, United States
University of Massachusetts Chan Medical School
🇺🇸Worcester, Massachusetts, United States
AA MRC LLC Ahmed Arif Medical Research Center
🇺🇸Flint, Michigan, United States
Saint Louis Rheumatology
🇺🇸Saint Louis, Missouri, United States
NYU Langone Brooklyn
🇺🇸Brooklyn, New York, United States
DJL Clinical Research, PLLC
🇺🇸Charlotte, North Carolina, United States
University of Cincinnati
🇺🇸Cincinnati, Ohio, United States
Paramount Medical Research & Consulting, LLC
🇺🇸Middleburg Heights, Ohio, United States
West Tennessee Research Institute
🇺🇸Jackson, Tennessee, United States
Ramesh C Gupta, MD
🇺🇸Memphis, Tennessee, United States
Precision Comprehensive Clinical Research Solution
🇺🇸Colleyville, Texas, United States
Precision Comprehensive Clinical Research Solutions
🇺🇸Colleyville, Texas, United States
Accurate Clinical Research, Inc.
🇺🇸Humble, Texas, United States
Sun Research Institute, LLC
🇺🇸San Antonio, Texas, United States
Accurate Clinical Research
🇺🇸Stafford, Texas, United States
Advanced Rheumatology of Houston
🇺🇸The Woodlands, Texas, United States
Swedish Medical Center
🇺🇸Seattle, Washington, United States
CER San Juan Centro Polivalente de Asistencia e Inv. Clinica
🇦🇷San Juan, Argentina
Centro de Investigaciones Medicas Mar del Plata
🇦🇷Mar del Plata, Buenos Aires, Argentina
Centro Dermatologico Schejtman
🇦🇷San Miguel, Buenos Aires, Argentina
Centro Medico Barrio Parque
🇦🇷Ciudad Autonoma de Buenos Aires, Ciudad Autonoma Buenos Aires, Argentina
Instituto CAICI
🇦🇷Rosario, Santa Fe, Argentina
Centro de Investigaciones Medicas Tucuman
🇦🇷San Miguel de Tucuman, Tucuman, Argentina
Investigaciones Clinicas Tucuman
🇦🇷San Miguel de Tucuman, Tucuman, Argentina
Hospital Italiano de La Plata
🇦🇷Buenos Aires, Argentina
Instituto de Investigaciones Clinicas Quilmes
🇦🇷Buenos Aires, Argentina
Centro Medico Dra Laura Maffei Investigacion Clinica Aplicada
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
STAT Research S.A.
🇦🇷Ciudad Autonoma Buenos Aires, Argentina
Instituto de Reumatologia
🇦🇷Mendoza, Argentina
Centre Hospitalier Universitaire de Liege
🇧🇪Liège, Belgium
Clínica SER da Bahia
🇧🇷Salvador, Bahia, Brazil
HUWC - UFC - Hospital Universitário Walter Cantídio - Universidade Federal do Ceará
🇧🇷Fortaleza, Ceara, Brazil
L2IP - Instituto de Pesquisas Clínicas Ltda.
🇧🇷Brasilia, Distrito Federal, Brazil
IPC MT Instituto de Pesquisas Clinicas do Mato Grosso
🇧🇷Santo Ângelo, Mato Grosso, Brazil
Santa Casa de Misericordia de Belo Horizonte
🇧🇷Belo Horizonte, Minas Gerais, Brazil
CMiP - Centro Mineiro de Pesquisa
🇧🇷Juiz de Fora, Minas Gerais, Brazil
CETI - Centro de Estudos em Terapias Inovadoras Ltda.
🇧🇷Curitiba, Paraná, Brazil
LMK Serviços Médicos S/S Ltda
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto
🇧🇷Sao Jose Rio Preto, Sao Paulo, Brazil
Centro Multidisciplinar de Estudos Clínicos - CEMEC
🇧🇷São Bernardo do Campo, Sao Paulo, Brazil
CEPIC - Centro Paulista de Investigação Clínica e Serviços Médicos
🇧🇷São Paulo, Sao Paulo, Brazil
MC Artmed OOD
🇧🇬Plovdiv, Bulgaria
UMHAT "Pulmed" OOD
🇧🇬Plovdiv, Bulgaria
UMHAT-Plovdiv AD
🇧🇬Plovdiv, Bulgaria
DCC 1 - Ruse, EOOD
🇧🇬Ruse, Bulgaria
DCC 'Alexandrovska', EOOD
🇧🇬Sofia, Bulgaria
DCC Focus 5 - MEOH OOD
🇧🇬Sofia, Bulgaria
Military Medical Academy - MHAT - Sofia
🇧🇬Sofia, Bulgaria
Centro Medico Prosalud
🇨🇱Santiago, Chile
CTR Estudios
🇨🇱Santiago, Chile
Enroll Spa
🇨🇱Santiago, Chile
BioMedica Research Group
🇨🇱Santiago, Chile
Xuanwu Hospital Capital Medical University
🇨🇳Beijing, Beijing, China
Nanfang Hospital of Southern Medical University
🇨🇳Guangzhou, Guangdong, China
Shenzhen People's Hospital
🇨🇳Shenzhen, Guangdong, China
Xiangya Hospital, Central South University
🇨🇳Changsha, Hunan, China
ZhuZhou Central Hospital
🇨🇳ZhuZhou, Hunan, China
Jiujiang No.1 People's Hospital
🇨🇳Jiujiang, Jiangxi, China
Pingxiang People's Hospital
🇨🇳Pingxiang, Jiangxi, China
The First Affiliated Hospital of Ningbo University
🇨🇳Ningbo, Zhejiang, China
The First Hospital of Jilin University
🇨🇳Changchun, China
IPS Centro Medico Julian Coronel S.A.
🇨🇴Cali, Valle Del Cauca, Colombia
Centro de Investigacion Medico Asistencial S.A.S
🇨🇴Barranquilla, Colombia
Clínica de la Costa S.A.S
🇨🇴Barranquilla, Colombia
Centro de Investigacion en Reumatologia y Especialidades Medicas CIREEM S.A.S.
🇨🇴Bogotá, Colombia
Servimed S.A.S.
🇨🇴Bucaramanga, Colombia
Preventive Care Ltda
🇨🇴Chia, Colombia
Healthy Medical Center
🇨🇴Zipaquirá, Colombia
Revmatologie s.r.o.
🇨🇿Brno, Czechia
Fakultni nemocnice Olomouc
🇨🇿Olomouc, Czechia
CHU Clermont Ferrand - Hopital Gabriel Montpied
🇫🇷Clermont-Ferrand cedex 1, Drôme, France
NNA Hospital
🇬🇷Athens, Attica, Greece
Vita Verum Medical Egeszsegugyi Szolgaltato Bt.
🇭🇺Szekesfehervar, Fejer, Hungary
Del-pesti Centrumkorhaz - Orszagos Hematologiai es Infektologiai Intezet
🇭🇺Budapest, Hungary
Bekes Varmegyei Kozponti Korhaz
🇭🇺Gyula, Hungary
Vital Medical Center
🇭🇺Veszprem, Hungary
Rambam Health Care Campus
🇮🇱Haifa, Israel
Meir Medical Center
🇮🇱Kfar- Saba, Israel
Tel Aviv Sourasky Medical Center Pt
🇮🇱Tel Aviv, Israel
JCHO Chukyo Hospital
🇯🇵Nagoya-shi, Aichi-Ken, Japan
NHO Chibahigashi National Hospital
🇯🇵Chiba-shi, Chiba-Ken, Japan
NHO Kyushu Medical Center
🇯🇵Fukuoka-shi, Fukuoka-Ken, Japan
Hiroshima University Hospital
🇯🇵Hiroshima-shi, Hiroshima-Ken, Japan
Tonan Hospital
🇯🇵Sapporo-shi, Hokkaido, Japan
Japanese Red Cross Society Himeji Hospital
🇯🇵Himeji-shi, Hyogo-Ken, Japan
Kagawa University Hospital
🇯🇵Kita-gun, Kagawa-Ken, Japan
NHO Yokohama Medical Center
🇯🇵Yokohama-shi, Kanagawa-Ken, Japan
Japanese Red Cross Kumamoto Hospital
🇯🇵Kumamoto-shi, Kumamoto-Ken, Japan
Kindai University Hospital
🇯🇵Osakasayama-shi, Osaka-Fu, Japan
Nihon University Itabashi Hospital
🇯🇵Itabashi-ku, Tokyo-To, Japan
Toho University Ohashi Medical Center
🇯🇵Meguro-ku, Tokyo-To, Japan
Center Hospital of the National Center for Global Health and Medicine
🇯🇵Shinjuku-ku, Tokyo-To, Japan
Ajou University Hospital
🇰🇷Suwon, Gyeonggi-do, Korea, Republic of
Hanyang University Seoul Hospital
🇰🇷Seoul, Korea, Republic of
Clinstile, S.A. de C.V.
🇲🇽Ciudad de México, Distrito Federal, Mexico
Centro de Investigacion Clínica GRAMEL S.C
🇲🇽Mexico, Distrito Federal, Mexico
Clinica de Investigacion en Reumatologia y Obesidad S.C.
🇲🇽Guadalajara, Jalisco, Mexico
Centro de investigacion medica y reumatologia
🇲🇽Guadalajara, Jalisco, Mexico
Consultorio Privado Dr. Miguel Cortes Hernandez
🇲🇽Cuernavaca, Morelos, Mexico
Centro Peninsular de Investigacion Clinica, SCP
🇲🇽Merida, Yucatán, Mexico
Medical Care & Research SA de CV
🇲🇽Merida, Yucatán, Mexico
Investigacion y Biomedicina de Chihuahua, S.C.
🇲🇽Chihuahua, Mexico
Centro de Investigacion y Atencion Integral Durango CIAID
🇲🇽Durango, Mexico
HMA - Hospital Maria Auxiliadora
🇵🇪Lima, Peru
Mary Mediatrix Medical Center
🇵🇭Lipa City, Batangas, Philippines
Davao Doctors Hospital
🇵🇭Davao City, Davao, Philippines
University of the Philippines Manila - Philippine General Hospital
🇵🇭Manila, Metro Manila, Philippines
Far Eastern University - Dr. Nicanor Reyes Medical Foundation
🇵🇭Quezon City, Metro Manila, Philippines
Medical Center Manila
🇵🇭Manila, Philippines
Nova Reuma Domysławska i Rusiłowicz, Spółka Partnerska Lekarza Reumatologa i Fizjoterapeuty
🇵🇱Bialystok, Poland
Szpital Uniwersytecki nr 2 im.dr J. Biziela
🇵🇱Bydgoszcz, Poland
Nzoz Bif-Med
🇵🇱Bytom, Poland
Pratia MCM Krakow
🇵🇱Krakow, Poland
Centrum Badawcze Panaceum Agnieszka Brzezicka, Magdalena Lenkiewicz Sp. z o.o.
🇵🇱Malbork, Poland
MICS Centrum Medyczne Warszawa
🇵🇱Warszawa, Poland
Centro Reumatologico
🇵🇷Caguas, Puerto Rico
S.C Centrul Medical de Diagnostic si Tratament Ambulator Neomed S.R.L
🇷🇴Brasov, Romania
S C Delta Health Care SRL
🇷🇴Bucuresti, Romania
Spitalul Clinic Judetean de Urgenta Cluj Napoca
🇷🇴Cluj-Napoca, Romania
S.C.Centrul Medical Unirea SRL
🇷🇴Iasi, Romania
Institute of Rheumatology
🇷🇸Belgrade, Serbia
University Clinical Center of Serbia
🇷🇸Belgrade, Serbia
Clinical Center "Bezanijska Kosa "
🇷🇸Belgrade, Serbia
Hospital Universitario Marques de Valdecilla
🇪🇸Santander, Castellón, Spain
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Quironsalud Infanta Luisa
🇪🇸Sevilla, Spain
Kaohsiung Chang Gung Memorial Hospital
🇨🇳Kaohsiung, Taiwan
Guy's Hospital
🇬🇧London, Greater London, United Kingdom
Doncaster Royal Infirmary
🇬🇧Doncaster, South Yorkshire, United Kingdom