A Study of the Efficacy and Safety of Tocilizumab in Participants With Systemic Sclerosis (SSc)
- Registration Number
- NCT02453256
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This study will assess the efficacy and safety of tocilizumab compared with placebo in participants with SSc across approximately 120 planned global study sites. The study will consist of a 48-week, double-blind, placebo-controlled period followed by a 48-week open-label treatment period. Participants will be assigned, in a 1:1 ratio, to double-blind treatment with active tocilizumab or matching placebo. In the open-label period, eligible participants from either arm may receive active tocilizumab.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 212
- Diagnosis of SSc according to American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) criteria, meeting criteria for active disease and with total disease duration of less than or equal to (</=) 60 months
- mRSS of 10-35 units, inclusive
- Agreement to remain abstinent or use an effective contraceptive method among males and females with childbearing potential
- Pregnant or lactating females
- Major surgery within 8 weeks prior to screening
- Scleroderma limited to the face or areas distal to the elbows or knees
- Rheumatic autoimmune disease other than SSc
- Immunization with a live or attenuated vaccine within 4 weeks prior to Baseline
- Known hypersensitivity to human, humanized, or murine monoclonal antibodies
- Moderately severe nervous system, renal, endocrine, pulmonary, cardiovascular, or gastrointestinal (GI) disease not related to SSc, including diverticulitis or ulcerative lower GI disorders, or myocardial infarction (MI) within 6 months prior to screening
- Active or significant history of infection, including treatment with intravenous (IV) antibiotics within 4 weeks or oral antibiotics within 2 weeks prior to screening
- Significant history of tuberculosis (TB)
- Primary or secondary immunodeficiency
- Malignant disease, with the exception of excised/cured local basal or squamous cell carcinoma of the skin or carcinoma in situ of the uterine cervix
- History of drug or alcohol abuse
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Double-Blind Placebo Placebo Participants will receive double-blind matching placebo from Baseline to Week 47. Participants may then receive open-label tocilizumab from Weeks 48 to 96. Double-Blind Placebo Tocilizumab Participants will receive double-blind matching placebo from Baseline to Week 47. Participants may then receive open-label tocilizumab from Weeks 48 to 96. Double-Blind Tocilizumab Tocilizumab Participants will receive double-blind tocilizumab from Baseline to Week 47. Participants may then receive open-label tocilizumab from Weeks 48 to 96.
- Primary Outcome Measures
Name Time Method Change in Modified Rodnan Skin Score (mRSS) During Double-blind Period From baseline to week 48 The efficacy of TCZ vs placebo is evaluated in terms of in mean change in mRSS. Skin thickness will be assessed by palpation and rated using an mRSS that ranges from 0 (normal) to 3 (severe skin thickening) across 17 different body sites. The total score is the sum of the individual skin scores from all of these sites and ranges from 0 to 51 units.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Greater Than or Equal to (>/=) 20%, 40%, or 60% Improvement in mRSS During Double-blind Period From Baseline to Week 48 The proportion of participants with threshold improvements in mRSS at Week 48 relative to baseline.
Change From Baseline in Percent Predicted FVC (ppFVC) During Double-blind Period Baseline to week 48 FVC is pulmonary function test and will be conducted as per the study Pulmonary Function Manual, which is based on the American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement. FVC is the maximum amount of air exhaled from the lungs after taking the deepest breath possible. Patients perform three to eight exhalations into a spirometer with the highest value recorded.
Change in Forced Vital Capacity (FVC) During Double-blind Period From Baseline to Week 48 FVC is pulmonary function test and will be conducted as per the study Pulmonary Function Manual, which is based on the American Thoracic Society/European Respiratory Society (ATS/ERS) Consensus Statement. FVC is the maximum amount of air exhaled from the lungs after taking the deepest breath possible. Patients perform three to eight exhalations into a spirometer with the highest value recorded.
Change in Health Assessment Questionnaire Disability Index (HAQ-DI) Score During Double-blind Period From Baseline to Week 48 The Health Assessment Questionnaire Disability Index (HAQ-DI) consists of 20 questions referring to eight component sets consisting of dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities. Each item is scored on a 4-point scale from 0 to 3: 0 = Without any difficulty; 1 = With some difficulty; 2 = With much difficulty; 3 = Unable to do. Overall score was computed as the sum of component set scores and divided by the number of component sets answered. Total possible score range 0-3 where 0 = least difficulty and 3 = extreme difficulty. The total score indicates the patient's self-assessed level of disability. This outcome measure represents the change in mean score from baseline. A negative change from baseline indicates improvement.
Change in Patient Global Assessment Score During Double-blind Period From Baseline to Week 48 The Patient's Global Assessment represents the patient's overall assessment of current SSc status on a 100-mm horizontal visual analogue scale (VAS), ranging from 0 on the extreme left end of the scale indicating "has no effect at all" (symptom free), and 100 on the extreme right end indicating "worst possible effect."
Change in Physician Global Assessment Score During Double-blind Period From Baseline to Week 48 The Physician's Global Assessment is to be completed on the basis of examination and overall assessment of the patient. The physician's assessment of the patient's SSc status will be scored on a 100-mm horizontal visual analogue scale (VAS), ranging from 0 on the extreme left end of the scale indicating "has no effect at all" (symptom free), and 100 on the extreme right end indicating "worst possible effect."
Time to Treatment Failure According to mRSS, FVC, or Protocol-Specified Event During Double-blind Period From Baseline to Week 48 Time to treatment failure is defined as the time from randomization to the time of death, decline in percent-predicted FVC \> 10% relative to baseline, \> 20% increase in mRSS and an increase in mRSS of equal to or more than 5 points, or occurrence of a predefined SSc-related complication as adjudicated by the Clinical Adjudication Committee (whichever occurs first) during the 48-week double-blind treatment period. The median TTF was not estimable and is not presented for either treatment arm because of the low number of patients with events at Week 48.
Summary of Adverse Events During Double-blind Period From Baseline until Week 48 Summary of key safety results including Adverse Events of Special Interest (AESI). All adverse events categorized according to MedDRA version 20.1. NMSC = Non-Melanoma Skin Cancer
Incidence and Severity of Adverse Events During Double-blind Period From Baseline until Week 48 Adverse events listed according to MedDRA version 20.1 preferred terms and severity grade.
Number of Participants With Adverse Events Leading to Death During Double-blind Period From Baseline up to Week 48 Reason of death is coded using MedDRA 20.1
Frequency of Serious Systemic Sclerosis (SSC) Related Complications During Double-blind Period From Baseline up to Week 48 Adverse event terms coded using MedDRA 20.1. Includes only those serious events adjudicated as SSC-related complications by an independent external committee.
Incidence of Haematology and Hepatic Laboratory Parameters During Double-blind Period From Baseline up to Week 48 A laboratory event occurred if the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade for a post-baseline laboratory measurement increased from baseline.
Percentage of Participants With Change in Digital Ulcer Count During Double-blind Period From Baseline to Week 48 A digital ulcer is defined as an ulcer at or distal to the MCP joint on either the dorsal or volar surface, with loss of surface epithelialization. This does not include fissures, cracks, or calcium extrusions from calcinosis cutis. The number of fingers (0-10) with digital ulcers and the number of digital (or finger) ulcers will be counted and recorded by the investigator.
Percentage of Participants With Positive Anti-Tocilizumab Assay Result at Baseline Baseline Incidence of anti-Tocilizumab at baseline
Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline up to Week 48 Double-blind period (up to Week 48) Incidence of anti-Tocilizumab antibodies during the study relative to the prevalence of anti-Tocilizumab antibodies at baseline. Samples that are positive for anti-TCZ in the screening assay will be further analyzed by a confirmation assay to confirm specificity. If the confirmation assay is positive, two additional tests will be performed: a neutralizing assay for the ability to inhibit the activity of TCZ and a test for anti -TCZ of the IgE isotype.
Correlation Between Anti-Tocilizumab Antibody Status and Outcome Measures Pertaining to the Efficacy, Safety, and Pharmacokinetics of Tocilizumab Baseline; during Weeks 8, 16, 24, 36, 48, 96, and/or at treatment discontinuation (up to 96 weeks); and 8 weeks after treatment discontinuation (up to 104 weeks overall) Pre-specified analysis of the relationship between Anti-Tocilizumab Antibody status and safety, efficacy, and PK endpoints were not analyzed via subgroup analyses as there was only 1 patient with ADA-positive status.
Erythrocyte Sedimentation Rate (ESR), Mean, From Baseline to Week 48 From Predose up to Week 48 Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.
Erythrocyte Sedimentation Rate (ESR), Median, From Baseline to Week 48 From Baseline to Week 48 Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 48 From Baseline to Week 48 Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Interleukin (IL)-6 Level, Median, From Baseline to Week 48 From Baseline to Week 48 Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Interleukin (IL)-6 Level, Mean Change From Baseline to Week 48 From Baseline to Week 48 Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Interleukin (IL)-6 Level, Median Change From Baseline to Week 48 From Baseline to Week 48 Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, From Baseline to Week 48 From Baseline to Week 48 Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Soluble Interleukin (IL)-6 Receptor Level, Median, From Baseline to Week 48 From Baseline to Week 48 Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Soluble Interleukin (IL)-6 Receptor Level, Mean Change From Baseline to Week 48 From Baseline to Week 48 Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Soluble Interleukin (IL)-6 Receptor Level, Median Change From Baseline to Week 48 From Baseline to Week 48 Serum soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Serum C-Reactive Protein (CRP) Level, Mean, From Baseline to Week 48 From Baseline up to Week 48 Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.
Serum C-Reactive Protein (CRP) Level, Median, From Baseline to Week 48 From Baseline up to Week 48 Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Tocilizumab Concentration, Mean, From Baseline to Week 48 From Baseline to Week 48 Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter
Serum Tocilizumab Concentration, Median, From Baseline to Week 48 From Baseline to Week 48 Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter
Correlation Between Low Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Correlation Between Low Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Correlation Between Medium Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Correlation Between Medium Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Correlation Between High Serum Tocilizumab Exposure and Mean Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Correlation Between High Serum Tocilizumab Exposure and Median Modified Rodnan Skin Score (mRSS) From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Change in Mean Modified Rodnan Skin Score (mRSS) at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Change in Median Modified Rodnan Skin Score (mRSS), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, mRSS scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Incidence and Severity of Adverse Events Up to Week 96 Up to Week 96 Adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) severity grade: 1 = mild, 2 = moderate, 3 = severe and/or requiring medical intervention but not life-threatening, 4 = life-threatening consequences, and 5 = death.
Change in Mean Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, ppFVC scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Serum Soluble Interleukin (IL)-6 Receptor Level, Mean, Up to Week 96 Up to Week 96 Serum Soluble Interleukin (IL)-6 receptor levels predose at baseline and at subsequent time points after initiation of study drug.
Change in Median Percent Predicted Forced Vital Capacity (ppFVC), at Low, Medium and High Serum Tocilizumab Exposure From Baseline to Week 48 From Baseline to Week 48 In order to characterize exposure-efficacy relationships, ppFVC scores are summarized based on TCZ exposure tertiles (high, medium, and low exposures) in the active treatment group and compared to placebo patients. Low Exposure = 0-\<41 ug/ml, Medium = 41-\<=61.1 ug/ml, High = 61.1-\<=145 ug/ml.
Serum Interleukin (IL)-6 Level, Mean, From Baseline to Week 96 Up to Week 96 Serum Interleukin (IL)-6 levels predose at baseline and at subsequent time points after initiation of study drug.
Summary of Adverse Events Up to Week 96 Up to Week 96 Summary of key safety results including Adverse Events of Special Interest (AESI). All adverse events categorized according to MedDRA version 21.1. NMSC = Non-Melanoma Skin Cancer
Number of Participants With Adverse Events Leading to Death Up to Week 96 Up to Week 96 Percentage of Participants With Change in Digital Ulcer Count at Week 96 From Baseline to Week 96 A digital ulcer is defined as an ulcer at or distal to the MCP joint on either the dorsal or volar surface, with loss of surface epithelialization. This does not include fissures, cracks, or calcium extrusions from calcinosis cutis. The number of fingers (0-10) with digital ulcers and the number of digital (or finger) ulcers will be counted and recorded by the investigator.
Percentage of Participants With Positive Anti-Tocilizumab Assay Post-Baseline From Week 48 to 96 Open-label period from Week 48 to 96 Reported were the percentage of participants with post-baseline treatment-induced anti-TCZ antibodies. Positive samples underwent additional analyses: a neutralizing assay for the ability to inhibit the activity of TCZ and a test for anti -TCZ of the IgE isotype.
Erythrocyte Sedimentation Rate (ESR) Up to Week 96 Up to Week 96 Erythrocyte Sedimentation Rate (ESR) levels predose at baseline and at subsequent time points after initiation of study drug.
Serum C-Reactive Protein (CRP) Level, Mean, Up to Week 96 From Baseline up to Week 96 Serum C-Reactive Protein (CRP) levels predose at baseline and at subsequent time points after initiation of study drug.
Serum Tocilizumab Concentration, Mean, Up to Week 96 Up to Week 96 Predose observed serum TCZ concentration at baseline and at specified timepoints thereafter
Trial Locations
- Locations (83)
UZ Leuven Gasthuisberg
🇧🇪Leuven, Belgium
Hopital Claude Huriez; Internal Medicine
🇫🇷Lille, France
Joint & Muscle Research Institute
🇺🇸Charlotte, North Carolina, United States
West Michigan Rheumatology, PLLC
🇺🇸Grand Rapids, Michigan, United States
Georgetown Uni. Hosp.; Rheumatology, Immunology and Allergy Dept.
🇺🇸Washington, District of Columbia, United States
Clinical Research Center of Reading
🇺🇸Wyomissing, Pennsylvania, United States
Hospital Britanico; Haematology
🇦🇷Buenos Aires, Argentina
MHAT Kaspela; Rheumatology
🇧🇬Plovdiv, Bulgaria
Sanatorio Parque S.A.
🇦🇷Rosario, Santa FE, Argentina
Aarhus Universitetshospital Skejby, Hud- og Kønssygdomme
🇩🇰Aarhus N, Denmark
Millenium Research
🇺🇸Ormond Beach, Florida, United States
MHAT Sv.Ivan Rilski; Clinic of Rheumatology
🇧🇬Sofia, Bulgaria
UZ Gent
🇧🇪Gent, Belgium
TriWest Research Associates, LLC
🇺🇸El Cajon, California, United States
Organizacion Medica de Investigacion
🇦🇷Buenos Aires, Argentina
Centro de Investigaciones Reumatologicas Tucuman
🇦🇷Tucuman, Argentina
MHAT-Plovdiv AD; Reumatology Department
🇧🇬Plovdiv, Bulgaria
Szpital Uniwersytecki; nr 2 im. Dr J. Biziela; Klinika Reumatologii i Ukladowych Chorob
🇵🇱Bydgoszcz, Poland
Uniwersyteckie Centrum Kliniczne; Klinika Chorob Wewnetrznych, Chorob Tkanki Łacznej i Geriatrii
🇵🇱Gdansk, Poland
Gornoslaskie Centrum Medyczne
🇵🇱Katowice, Poland
Szpital Specjalistyczny im Jozefa Dietla; Centrum Reumatologii, Immunologii i Rehabilitacji, I Oddzi
🇵🇱Krakow, Poland
National Institute of Rheumatology and Physiology
🇭🇺Budapest, Hungary
Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji im. Prof. Eleonory Reicher
🇵🇱Warszawa, Poland
Pécsi Tudományegyetem Klinikai Központ: Immunológiai és Reumatológiai Klinika
🇭🇺Pécs, Hungary
Ospedale Maggiore Policlinico; Unità Operativa Complessa di Allergologia e Immunologia Clinica
🇮🇹Milano, Lombardia, Italy
Kanazawa University Hospital
🇯🇵Ishikawa, Japan
Bispebjerg Hospital, Dermatologisk afdeling
🇩🇰København NV, Denmark
Uni ' Cattolica Del Sacro Cuore; Facoltà Di Medicina E Chirurgia A.Gemelli-Clinica Reumatologica
🇮🇹Roma, Lazio, Italy
Vilnius University Hospital Santariskiu Clinic Public Insti
🇱🇹Vilnius, Lithuania
Universitätsspital Zürich; Klinik für Rheumatologie
🇨🇭Zürich, Switzerland
Spitalul Judetean Cluj; Sectia de Reumatologie
🇷🇴Cluj-napoca, Romania
Instituto Nacional de Ciencias Médicas Y de La Nutricion Zubirán
🇲🇽Mexico City, Mexico
Unidad De Enfermedades; Cronico Degenerativas, SC.
🇲🇽Mexico, Mexico
Hospital Prof. Dr. Fernando Fonseca; Medicina IV
🇵🇹Amadora, Portugal
Queen Elizabeth Hospital; Rheumatology Dept.
🇬🇧Birmingham, United Kingdom
Freeman Hospital; Musculoskeletal Unit
🇬🇧Newcastle Upon Tyne, United Kingdom
Hokkaido University Hospital
🇯🇵Hokkaido, Japan
St. Marianna University School of Medicine Hospital
🇯🇵Kanagawa, Japan
Hospital de la Santa Creu i Sant Pau; Servicio de Medicina Interna/Reumatologia
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Marañon; Servicio de Reumatología
🇪🇸Madrid, Spain
West Tennessee Research Institute
🇺🇸Jackson, Tennessee, United States
MHAT St.Ivan Rilski; Rheumtology Department
🇧🇬Sofia, Bulgaria
St. Paul's Hospital University of British Colambia Division of Hematology
🇨🇦Vancouver, British Columbia, Canada
Asklepios Kllinikum Bad Abbach; Klinik für Rheumatologie und Klinische Immunologie
🇩🇪Bad Abbach, Germany
Kerckhoff-Klinik; Rheumatologie&klin.Immunologie
🇩🇪Bad Nauheim, Germany
Klinikum der Universitat Munchen; Bereich Pettenkoferstr; Rheumaeinheit der medizinischen Klinik IV
🇩🇪München, Germany
Universitätsklinikum Dresden; Technische Universität Dresden; Rheumatologie, Innere Medizin III
🇩🇪Dresden, Germany
Universitätsklinikum Tübingen Medizinische UNI-Klinik und Poliklinik Abt. Innere Medizin II
🇩🇪Tübingen, Germany
Laiko General Hospital; Dept. of Pathophysiology-Uni of Athens
🇬🇷Athens, Greece
University Hospital of Patras; Rheumatology
🇬🇷Patras, Greece
Gunma University Hospital
🇯🇵Gunma, Japan
Ospedale Careggi Villa Monnatessa ; Sezione Di Reumatologia
🇮🇹Firenze, Toscana, Italy
Sapporo Medical University Hospital
🇯🇵Hokkaido, Japan
Kumamoto University Hospital
🇯🇵Kumamoto, Japan
Hospital of the University of Occupational and Environmental Health,Japan
🇯🇵Kitakyushu-shi, Japan
Nippon Medical School Hospital
🇯🇵Tokyo, Japan
Tohoku University Hospital
🇯🇵Miyagi, Japan
Osaka University Hospital
🇯🇵Osaka, Japan
The University of Tokyo Hospital
🇯🇵Tokyo, Japan
Klaipeda University Hospital; Department of Rheumatology
🇱🇹Klaipeda, Lithuania
Cliditer SA de CV
🇲🇽Miexico City, Mexico
Academisch Ziekenhuis Leiden; Dept of Rheumatology
🇳🇱Leiden, Netherlands
SPSK NR 4; Reumatologii i Ukladowych Chorob Tkanki
🇵🇱Lublin, Poland
Hospital Garcia de Orta; Servico de Reumatologia
🇵🇹Almada, Portugal
Puerto Rico Clinical & Translational Research Consortium
🇵🇷San Juan, Puerto Rico
Cantacuzino Hospital; Department of Internal Medicine and Rheumatology
🇷🇴Bucharest, Romania
Hospital Universitario Vall d'Hebron; Servicio de Medicina Interna
🇪🇸Barcelona, Spain
Universitätsspital Basel; Rheumatologische Poliklinik
🇨🇭Basel, Switzerland
Western General Hospital
🇬🇧Edinburgh, United Kingdom
Chapel Allerton Hospital; Leeds Institution of Rheumatology Medicine
🇬🇧Leeds, United Kingdom
Royal Free Hospital; Department of Rheumatology
🇬🇧London, United Kingdom
Uni Hospital Aintree; Academic Rheumatology Unit
🇬🇧Liverpool, United Kingdom
St. Joseph's Heritage Healthcare
🇺🇸Fullerton, California, United States
Univ of Calif., Los Angeles; Rheumatology
🇺🇸Los Angeles, California, United States
Arthritis Associates of Southern California
🇺🇸Los Angeles, California, United States
Rheumatology Assoc. of S. Florida - Clinical Research Center
🇺🇸Boca Raton, Florida, United States
Boston Univ Med Center - AC
🇺🇸Boston, Massachusetts, United States
Arthritis and Rheumatology; Center of Oklahoma PLLC
🇺🇸Oklahoma City, Oklahoma, United States
Thomas Jefferson Uni ; Division of Rheumatology
🇺🇸Philadelphia, Pennsylvania, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Metroplex Clinical Research
🇺🇸Dallas, Texas, United States
Mount Sinai Hospital; Rebecca Macdonald Centre For Arthritis & Autoimmune Disease
🇨🇦Toronto, Ontario, Canada
Policlinico Universitario-II Università di Napoli; Reumatologia
🇮🇹Napoli, Campania, Italy