Evaluation of the Efficacy and Safety of Two Dosing Regimens of Olokizumab (OKZ), Compared to Placebo and Adalimumab, in Subjects With Rheumatoid Arthritis (RA) Who Are Taking Methotrexate But Have Active Disease

Phase 3

Completed

Conditions: Rheumatoid Arthritis

Interventions: Drug: Olokizumab 64mg q4w
Drug: Olokizumab 64mg q2w
Drug: Adalimumab 40mg q2w
Drug: Placebo q2w

Registration Number: NCT02760407

Lead Sponsor: R-Pharm International, LLC

Brief Summary: The purpose of this study was to determine how effective and safe the study drug Olokizumab was in patients with Rheumatoid Arthritis (RA) who had been already receiving but not fully responding to treatment with methotrexate (MTX).

The primary objective of this study was to evaluate the efficacy of OKZ 64 mg administered subcutaneously (SC) once every 2 weeks (q2w) or once every 4 weeks (q4w) relative to placebo in subjects with moderately to severely active RA inadequately controlled by MTX therapy.

The secondary objective was to evaluate the efficacy of OKZ relative to adalimumab in subjects with moderately to severely active RA inadequately controlled by MTX therapy.

Detailed Description: The goal of this Phase III study was to assess the efficacy, safety and tolerability of OKZ in subjects with moderately to severely active RA who had responded inadequately to MTX. The primary endpoint of the trial was at Week 12. Olokizumab was expected to reduce the disease activity and improve physical function. The study was expected to provide safety information in a large group of subjects over at least a 24 week period.

This study included a 4-week Screening Period, a double-blind Treatment Period from Week 0 to Week 24, and a Safety Follow-Up Period from Week 24 to Week 44. Subjects were assessed for eligibility to enter the study during the 4-week Screening Period. A total of 1575 subjects were planned to be randomly assigned to 1 of 4 treatment groups in a 2:2:2:1 ratio (450, 450, 450, and 225 subjects per group, respectively):

1. Olokizumab 64 mg q4w: SC injection of OKZ 64 mg q4w (alternating with SC injection of placebo q4w to maintain blinding) + MTX

2. Olokizumab 64 mg q2w: SC injection of OKZ 64 mg q2w + MTX

3. Adalimumab 40 mg q2w: SC injection of adalimumab 40 mg q2w + MTX

4. Placebo: SC injection of placebo q2w + MTX

Throughout the double-blind Treatment Period, all subjects were required to remain on a stable dose of background MTX with a stable route of administration. Concomitant treatment with folic acid was required for all subjects. The last dose of study treatment (OKZ, adalimumab, or placebo) was at Week 22 in all groups.

Following Visit 2 (randomization; Week 0), subjects returned to the study site at least every 2 weeks through Week 24 for response and safety assessments.

At Week 14, subjects who had not improved by at least 20% in both swollen and tender joint counts were classified as nonresponders and were administered sulfasalazine and/or hydroxychloroquine as rescue medication in addition to the assigned treatment.

After completion of the 24-week double-blind Treatment Period, subjects either rolled over into the long-term open-label extension (OLE) study or entered the Safety Follow-Up Period. During the Safety Follow-Up Period, subjects returned for visits +4, +8, and +22 weeks after the last dose of study treatment.

Subjects who had discontinued randomized treatment prematurely were required to come for the End of Treatment (EoT) Visit 2 weeks after the last study treatment administration and then continue with the scheduled study visits.

Adverse events (AEs) were assessed throughout the study (starting when the subject signed the informed consent form) and evaluated using the Common Terminology Criteria for Adverse Events Version 4.0. There was ongoing monitoring of safety events, including laboratory findings, by the Sponsor or the Sponsor's designee. In addition, safety was assessed throughout the study by an independent Data Safety Monitoring Board and potential major adverse cardiac events were evaluated by an independent Cardiovascular Adjudication Committee.

The study was conducted at 208 sites across 18 countries globally (in US, European Union (EU),United Kingdom (UK), Russian Federation, Asia, Latin America).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1648

Inclusion Criteria

Subjects willing and able to sign informed consent
Subjects must have a diagnosis of adult onset RA classified by ACR/EULAR 2010 revised classification criteria for RA for at least 12 weeks prior to Screening. (If the subject was diagnosed according to ACR 1987 criteria previously, the Investigator may classify the subject per ACR 2010 retrospectively, using available source data)
Inadequate response to treatment with oral, SC, or intramuscular MTX (defined as a subject with at least 12 weeks of exposure prior to Screening and with either absence of any documented clinically significant response, or documented initial clinical response with subsequent loss of that response or partial response) for at least 12 weeks prior to Screening at a dose of 15 to 25 mg/week (or ≥10 mg/week if intolerant to higher doses). The dose and route of administering MTX had to have been stable for at least 6 weeks prior to Screening. A lower dose of MTX (≥7.5 mg/week) was permitted for subjects enrolled in the Republic of Korea, consistent with local clinical practice.
Subjects must be willing to take folic acid or equivalent throughout the study.
Subjects must have moderately to severely active RA disease as defined by all of the following:
- ≥6 tender joints (68 joint count) at Screening and baseline; and
- ≥6 swollen joints (66 joint count) at Screening and baseline; and
- CRP above the normal range (ULN) at Screening based on the central laboratory results.

Exclusion Criteria

Diagnosis of any other inflammatory arthritis or systemic rheumatic disease (eg, gout, psoriatic or reactive arthritis, Crohn's disease, Lyme disease, juvenile idiopathic arthritis, or systemic lupus erythematosus). However, subjects could have secondary Sjogren's syndrome or hypothyroidism.
Subjects who are Steinbrocker class IV functional capacity (incapacitated, largely or wholly bed-ridden or confined to a wheelchair, with little or no self-care)
Prior exposure to any licensed or investigational compound directly or indirectly targeting IL 6 or IL 6R (including tofacitinib or other Janus kinases and spleen tyrosine kinase [SYK] inhibitors)
Prior treatment with cell depleting therapies including anti CD20 or investigational agents (e.g., CAMPATH, anti CD4, anti CD5, anti CD3, and anti CD19)
Prior use of bDMARDs
Use of parenteral and/or intra-articular glucocorticoids within 4 weeks prior to baseline
Use of oral glucocorticoids greater than 10 mg/day prednisone (or equivalent) or change in dosage within 2 weeks prior to baseline
Prior documented history of no response to hydroxychloroquine and sulfasalazine
Prior use of cDMARDs (other than MTX) within the following windows prior to baseline (cDMARDs should not be discontinued to facilitate a subject's participation in the study, but should instead have been previously discontinued as part of a subject's medical management of RA):
1. 4 weeks for sulfasalazine, azathioprine, cyclosporine, hydroxychloroquine, chloroquine, gold, penicillamine, minocycline, or doxycycline
2. 12 weeks for leflunomide unless the subject has completed the following elimination procedure at least 4 weeks prior to baseline: Cholestyramine at a dosage of 8 grams 3 times daily for at least 24 hours, or activated charcoal at a dosage of 50 grams 4 times daily for at least 24 hours
3. 24 weeks for cyclophosphamide
Vaccination with live vaccines in the 6 weeks prior to baseline or planned vaccination with live vaccines during the study
Participation in any other investigational drug study within 30 days or 5 times the terminal half-life of the investigational drug, whichever is longer, prior to baseline
Other treatments for RA (e.g., Prosorba Device/Column) within 6 months prior to baseline
Use of intra-articular hyaluronic acid injections within 4 weeks prior to baseline
Use of non-steroidal anti-inflammatory drugs (NSAIDs) on unstable dose or switching of NSAIDs within 2 weeks prior to baseline
Previous participation in this study (randomized) or another study of OKZ
Subjects with concurrent acute or chronic viral hepatitis B or C infection as detected by blood tests at Screening(e.g., positive for hepatitis B surface antigen [HBsAg], total hepatitis B core antibody [anti-HBc], or hepatitis C virus antibody [HCV Ab]). Subjects who are are positive for hepatitis B surface antibodies (anti-HBs), but negative for HBsAg and anti-HBc, will be eligible
Subjects with human immunodeficiency virus (HIV) infection
Subjects with:
1. Suspected or confirmed current active TB disease or a history of active TB disease
2. Close contact (i.e., sharing the same household or other enclosed environment, such as a social gathering place, workplace, or facility, for extended periods during the day) with an individual with active TB within 1.5 years prior to Screening
Concurrent malignancy or a history of malignancy within the last 5 years (with the exception of successfully treated carcinoma of the cervix in situ and successfully treated basal cell carcinoma and squamous cell carcinoma not less than 1 year prior to Screening [and no more than 3 excised skin cancers within the last 5 years prior to Screening])
Subjects with any infection requiring oral antibiotic or antiviral therapy in the 2 weeks prior to Screening or at baseline, injectable anti-infective therapy in the last 4 weeks prior to baseline, or serious or recurrent infection with history of hospitalization in the 6 months prior to baseline
Subjects with evidence of disseminated herpes zoster infection, zoster encephalitis, meningitis, or other non-self-limited herpes zoster infections in the 6 months prior to baseline
Subjects with planned surgery during the study or surgery ≤ 4 weeks prior to Screening and from which the subject has not fully recovered, as judged by the Investigator
Subjects with diverticulitis or other symptomatic GI conditions that might predispose the subject to perforations, including subjects with history of such predisposing conditions (e.g., diverticulitis, GI perforation, or ulcerative colitis)
Pre-existing central nervous system demyelinating disorders (e.g., multiple sclerosis and optic neuritis)
History of chronic alcohol or drug abuse as judged by the Investigator
Female subjects who are pregnant, currently lactating, have lactated within the last 12 weeks, or who are planning to become pregnant during the study or within 6 months of last dose of study treatment
Female subjects of childbearing potential (unless permanent cessation of menstrual periods, determined retrospectively after a woman has experienced 12 months of natural amenorrhea as defined by the amenorrhea with underlying status (e.g., correlative age) or 6 months of natural amenorrhea with documented serum follicle-stimulating hormone levels >40 mIU/mL and estradiol <20 pg/mL) who are not willing to use a highly effective method of contraception during the study and for at least 6 months after the last administration of study treatment OR Male subjects with partners of childbearing potential not willing to use a highly effective method of contraception during the study and for at least 3 months after the last administration of study treatment.
Subjects with a known hypersensitivity to any component of the OKZ drug product, adalimumab, or placebo
Subjects with a known hypersensitivity or contraindication to any component of the rescue medication
History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1: Olokizumab q4w	Olokizumab 64mg q4w	Olokizumab 64 mg subcutaneous q4w +placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)
Arm 2: Olokizumab q2w	Olokizumab 64mg q2w	Olokizumab 64mg subcutaneous q2w + Methotrexate 64 mg Olokizumab administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)
Arm 1: Olokizumab q4w	Placebo q2w	Olokizumab 64 mg subcutaneous q4w +placebo+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular) in order to maintain the blind, subjects randomized to receive OKZ q4w received placebo injections at the alternate q4w interval (e.g., Week 2, Week 6, etc.)
Arm 3: Adalimumab q2w	Adalimumab 40mg q2w	Adalimumab 40mg q2w subcutaneous + Methotrexate Subjects were administered adalimumab 40 mg q2w via SC injection as an active comparator+ concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)
Arm 4: Placebo q2w	Placebo q2w	Placebo q2w subcutaneous + Methotrexate Placebo administered subcutaneously once every 2 weeks + concomitant background therapy (Methotrexate) at a stable dose with a stable route of administration (oral, subcutaneous, or intramuscular)

Primary Outcome Measures

Name	Time	Method
Percentage of Subjects Achieving American College of Rheumatology 20% (ACR20) Response	at Week 12	The difference between OKZ and placebo in the percentage of subjects achieving an ACR20 response and remaining on randomized treatment and in the study at Week 12. (where a responder was defined as any subject satisfying ACR20 criteria and remaining on randomized treatment and in the study at Week 12) This endpoint served to demonstrate that the efficacy of OKZ was superior to placebo. American College of Rheumatology 20 % response is a composite defined as a ≥ 20% improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥20% improvement from baseline in at least 3 of the 5 remaining core set measures: * Patient Global Assessment of Disease Activity (VAS) * Patient Assessment of Pain (VAS) * HAQ-DI * Physician Global Assessment (VAS) * Level of acute phase reactant (CRP)

Secondary Outcome Measures

Name	Time	Method
Percentage of Subjects Achieving Low Disease Activity	at Week 12	Defined as Disease Activity Score 28-joint count (DAS28) C-reactive protein (CRP) \<3.2, and remaining on randomized treatment and in the study at Week 12
Percentage of Subjects Achieving ACR20 Response: Olokizumab Comparison With Adalimumab	at Week 12	A responder was defined as any subject satisfying ACR20 criteria and remaining on randomized treatment and in the study at Week 12.This endpoint served to demonstrate that the efficacy of OKZ was non-inferior to adalimumab, provided that superiority of adalimumab to placebo (assay sensitivity) was demonstrated concurrently based on the same endpoint. American College of Rheumatology 20 % response is a composite defined as a ≥ 20% improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥20% improvement from baseline in at least 3 of the 5 remaining core set measures: * Patient Global Assessment of Disease Activity (VAS) * Patient Assessment of Pain (VAS) * HAQ-DI * Physician Global Assessment (VAS) * Level of acute phase reactant (CRP)
Improvement of Physical Ability From Baseline to Week 12, as Measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI)	Baseline to Week 12	Change of physical ability from baseline (the last available assessment prior to the first dose of the study treatment) to week 12, as measured by HAQ-DI. The HAQ-DI assesses the degree of difficulty experienced in 8 domains of daily living activities using 20 questions.The domains are dressing and grooming, arising, eating, walking, hygiene, reach, grip and common daily activities, and each domain consists of 2 or 3 items. For each question, the level of difficulty is scored from 0 to 3 where 0 = without any difficulty (the best outcome), 1 = with some difficulty, 2 = much difficulty, and 3 = unable to do (the worst outcome). Each category is given a score by taking the maximum score of each question. A decrease from baseline indicates improvement for HAQ-DI.The HAQ-DI was calculated by dividing the sum of the category scores by the number of categories with at least 1 question answered. The HAQ-DI total score ranges from 0 (the best outcome) to 3 (the worst outcome).
Percentage of Subjects Achieving Low Disease Activity: Olokizumab Comparison With Adalimumab	at Week 12	Percentage of subjects achieving low disease activity, defined as DAS28 (CRP) \<3.2, and remaining on randomized treatment and in the study at Week 12; served to demonstrate that the efficacy of OKZ was noninferior to adalimumab, provided that superiority of adalimumab to placebo (assay sensitivity) was demonstrated concurrently based on the same endpoint
Percentage of Subjects Achieving American College of Rheumatology 50% (ACR50) Response	at Week 24	Difference between OKZ and placebo in the percentage of subjects achieving an ACR50 response and remaining on randomized treatment and in the study at Week 24 American College of Rheumatology 50% Response is a composite defined as ≥50%, improvement from baseline in the swollen joint counts assessed in 66 joints and in the tender joint count assessed in 68 joints; and a ≥50%, improvement from baseline in at least 3 of the 5 remaining core set measures: * Patient Global Assessment of Disease Activity (VAS) * Patient Assessment of Pain (VAS) * HAQ-DI * Physician Global Assessment (VAS) * Level of acute phase reactant (CRP)
Percentage of Subjects With Clinical Disease Activity Index (CDAI) ≤ 2.8 (Remission)	at Week 24	Difference between OKZ and placebo in the percentage of subjects with Clinical Disease Activity Index (CDAI) ≤2.8 (remission) and remaining on randomized treatment and in the study at Week 24

Trial Locations

Locations (200): Reliable Clinical Research, LLC
🇺🇸
Hialeah, Florida, United States
Valerius Medical Group
🇺🇸
Los Alamitos, California, United States
Physician Resrch Collaboration
🇺🇸
Lincoln, Nebraska, United States
AA MRC LLC Ahmed Arif Medical Research Center
🇺🇸
Grand Blanc, Michigan, United States
Arthritis Research
🇺🇸
Palm Harbor, Florida, United States
Lovelace Scientific Resources, Inc.
🇺🇸
Venice, Florida, United States
Low Country Rheumatology, PA
🇺🇸
Summerville, South Carolina, United States
Amarillo Center for Clinical Research
🇺🇸
Amarillo, Texas, United States
Inland Rheumatology Clinical Trials
🇺🇸
Upland, California, United States
APRILLUS Asistencia e Investigacion
🇦🇷
Ciudad Autonoma Buenos aires, Argentina
University of Kansas Hospital
🇺🇸
Kansas City, Kansas, United States
Instituto DAMIC Fundacion Rusculleda
🇦🇷
Cordoba, Argentina
Altoona Center for Clinical Research, P.C.
🇺🇸
Duncansville, Pennsylvania, United States
MHAT - Ruse, AD
🇧🇬
Ruse, Bulgaria
UMHAT Pulmed OOD
🇧🇬
Plovdiv, Bulgaria
Graves Gilbert Clinic
🇺🇸
Bowling Green, Kentucky, United States
Sanatorio San Martin
🇦🇷
Venado Tuerto, Santa Fe, Argentina
Instituto de Investigaciones Clinicas-Mar del Plata
🇦🇷
Mar del Plata, Buenos Aires, Argentina
Javed Rheumatology Associates
🇺🇸
Newark, Delaware, United States
CCBR Brasil Centro de Pesquisas e Análises Clínicas Ltda.
🇧🇷
Rio de Janeiro, Brazil
NYU Langone ambulatory care
🇺🇸
Brooklyn, New York, United States
STAT Research, Inc.
🇺🇸
Dayton, Ohio, United States
CCR Pardubice
🇨🇿
Pardubice, Czechia
Accurate Clinical Management LLC
🇺🇸
Baytown, Texas, United States
Accurate Clinical Research, Inc.
🇺🇸
League City, Texas, United States
Endocrinology, Internal Medicine
🇺🇸
Lubbock, Texas, United States
Clinica de Higado y Aparato Digestivo
🇦🇷
Rosario, Santa Fe, Argentina
Medizinski Zentar-1-Sevlievo EOOD
🇧🇬
Sevlievo, Bulgaria
Hospital Abreu Sodré - AACD
🇧🇷
São Paulo, Brazil
Arthritis Northwest, PLLC
🇺🇸
Spokane, Washington, United States
Centro de Investigaciones Medicas Mar del Plata
🇦🇷
Mar del Plata, Buenos Aires, Argentina
Institute Investigaciones Clinc Quilme
🇦🇷
Buenos Aires, Argentina
CPCLIN - Centro de Pesquisas Clínicas Ltda.
🇧🇷
São Paulo, Brazil
MHAT "Lyulin", EAD
🇧🇬
Sofia, Bulgaria
MHAT - Shumen, AD
🇧🇬
Shumen, Bulgaria
Revmatologie s.r.o.
🇨🇿
Brno, Czechia
Hospital Privado Centro Medico de Cordoba S.A
🇦🇷
Cordoba, Argentina
CCBR - Lodz - PL
🇵🇱
Skierniewice, Poland
Clinica de Artritis Temprana S.A.
🇨🇴
Cali, Colombia
Clínica de Neoplasias Litoral
🇧🇷
Santa Catarina, Brazil
Clinilive - Clínica do Idoso e Pesquisa Clínica
🇧🇷
Maringá, Paraná, Brazil
Instituto Centenario
🇦🇷
Ciudad Autonoma Buenos Aires, Argentina
NMTH "Tsar Boris III"
🇧🇬
Sofia, Bulgaria
Organizacion Medica de Investigacion (OMI)
🇦🇷
Ciudad Autonoma Buenos Aires, Argentina
ETYKA Osrodek Badan Klinicznych
🇵🇱
Olsztyn, Poland
Centrum Medyczne AMED
🇵🇱
Lodz, Poland
Vesalion s.r.o.
🇨🇿
Ostrava, Czechia
Medycyna Kliniczna
🇵🇱
Warszawa, Poland
KO-MED Centra Kliniczne Zamosc
🇵🇱
Zamosc, Poland
Rheumapraxis Dr. med. Reiner Kurthen
🇩🇪
Aachen, Westfalen, Germany
Institute n a Nasonova
🇷🇺
Moscow, Russian Federation
SPb SBHI "Clinical Rheumatological Hospital #25", Fourth Rheumatology Unit
🇷🇺
Saint Petersburg, Leningradskaya Oblast, Russian Federation
Szpital Wojewodzki im. Prymasa Kardynala Stefana Wyszynskiego
🇵🇱
Sieradz, Poland
Samodzielny Publiczny ZOZ Tomaszow Lubelski
🇵🇱
Tomaszow Lubelski, Poland
CHA Bundang Medical Center
🇰🇷
Gyeonggi-do, Korea, Republic of
FSBEI HE "FMSMU n.a. I.M. Sechenov of MoH of RF", University Hospital #2, Departament of New Drugs Introduction
🇷🇺
Moscow, Moscovskaya Oblast, Russian Federation
State Budgetary Healthcare Institution "City Clinical Hospital # 15 n.a O.M. Filatov" of Moscow Healtheare Department
🇷🇺
Moscow, Moscow Region, Russian Federation
SBHI of Nizhny Novgorod Region "Nizhny Novgorod Regional Clinical Hospital n.a.Semashko"
🇷🇺
Nizhniy Novgorod, Nizhegorodskaya Oblast, Russian Federation
Royal Free Hospital
🇬🇧
London, Greater London, United Kingdom
Alytаus Regional S. Kudirkos Hospital, Public Institution
🇱🇹
Alytus, Lithuania
Non-govarnmental Healtheare Institution "Regional Clinical Hospital at Smolensk station of OJSC "Russian Railways"
🇷🇺
Smolensk, Smolenskaya Oblast, Russian Federation
Rheuma Medicus Zaklad Opieki Zdrowotnej
🇵🇱
Warszawa, Poland
Hospital n a Kuvatov
🇷🇺
Ufa, Republic Of Bashkortostan, Russian Federation
Santa Familia Centrum Badan, Profilaktyki i Leczenia
🇵🇱
Zgierz, Poland
Basingstoke and North Hampshire Hospital
🇬🇧
Basingstoke, Hampshire, United Kingdom
KO-MED Centra Kliniczne Staszow
🇵🇱
Staszow, Poland
McM Polimedica
🇵🇱
Warszawa, Poland
Torbay Hospital
🇬🇧
Torquay, Devon, United Kingdom
New England Research Associates LLC
🇺🇸
Bridgeport, Connecticut, United States
Marietta Rheumatology Associates, PC
🇺🇸
Marietta, Georgia, United States
RASF - Clinical Research Center
🇺🇸
Boca Raton, Florida, United States
Family Clinical Trials, LLC.
🇺🇸
Pembroke Pines, Florida, United States
Medication Management, LLC
🇺🇸
Greensboro, North Carolina, United States
Institute of Arthritis Research
🇺🇸
Idaho Falls, Idaho, United States
Klein and Associates, M.D., P.A.
🇺🇸
Hagerstown, Maryland, United States
North MS Medical Clinics, Inc.
🇺🇸
Tupelo, Mississippi, United States
DM Clinical Research
🇺🇸
Tomball, Texas, United States
Accelerium S. de R.L. de C.V.
🇲🇽
Monterrey, Nuevo León, Mexico
Universidad Autonoma de Nuevo Leon, Hospital Universitario Dr. Jose Eleuterio Gonzalez
🇲🇽
Monterrey, Nuevo León, Mexico
CEDOES - Diagnóstico e Pesquisa
🇧🇷
Vitória, Espírito Santo, Brazil
CMiP - Centro Mineiro de Pesquisa
🇧🇷
Juiz de Fora, Minas Gerais, Brazil
LMK Serviços Médicos S/S Ltda
🇧🇷
Porto Alegre, Rio Grande Do Sul, Brazil
Maidstone Hospital
🇬🇧
Maidstone, Kent, United Kingdom
Hospital Bruno Born
🇧🇷
Lajeado, Rio Grande Do Sul, Brazil
SBEI HPE "Ural State Medical University" of MoH of RF based MBI "Central City Clinical Hospital #6"
🇷🇺
Ekaterinburg, Sverdlovskaya Oblast, Russian Federation
SBHI of Republic of Karelia "Republican Hospital named after V.A.Baranov"
🇷🇺
Petrozavodsk, Republic Of Karelia, Russian Federation
Medical Center "Excelsior", OOD
🇧🇬
Sofia, Bulgaria
UMHAT Sv. Ivan Rilski EAD
🇧🇬
Sofia, Bulgaria
Centro de Investigaciones Reumatológicas
🇦🇷
San Miguel de Tucuman, Tucuman, Argentina
Atencion Integral en Reumatologia (AIR)
🇦🇷
Ciudad Autonoma Buenos Aires, Argentina
CER San Juan Centro Polivalente de Asistencia e Inv. Clinica
🇦🇷
San Juan, Argentina
Medita Kliinik OÜ
🇪🇪
Tartu, Estonia
Principal SMO Kft.
🇭🇺
Baja, Hungary
Arizona Arthritis & Rheumatology Research, PLLC
🇺🇸
Sun City, Arizona, United States
Medvin Clinical Research
🇺🇸
Whittier, California, United States
MD Med Corp.
🇺🇸
Hemet, California, United States
TriWest Research Associates
🇺🇸
El Cajon, California, United States
Center for Rheumatology Research
🇺🇸
West Hills, California, United States
Medical Research Center of Miami
🇺🇸
Miami, Florida, United States
Arthritis Center of North Georgia
🇺🇸
Gainesville, Georgia, United States
Springfield Clinic, LLP
🇺🇸
Springfield, Illinois, United States
The Center for Rheumatology and Bone Research
🇺🇸
Wheaton, Maryland, United States
The Arthritis & Diabetes Clinic, Inc.
🇺🇸
Monroe, Louisiana, United States
Cape Fear Arthritis Care
🇺🇸
Leland, North Carolina, United States
Glacier View Research Instutute-Rheumatology
🇺🇸
Kalispell, Montana, United States
Arthritis & Osteoporosis Associates, PA
🇺🇸
Freehold, New Jersey, United States
Trinity Medical Group
🇺🇸
Minot, North Dakota, United States
Clinical Research Source, Inc.
🇺🇸
Toledo, Ohio, United States
Pioneer Research Solutions, Inc.
🇺🇸
Beaumont, Texas, United States
Precision Comprehensive Clinical Research Solutions
🇺🇸
Grapevine, Texas, United States
Instituto Medico CER
🇦🇷
Quilmes, Buenos Aires, Argentina
Centro Medico Privado de Reumatologia
🇦🇷
San Miguel de Tucuman, Tucuman, Argentina
Faculdade de Medicina do ABC
🇧🇷
Santo André, Sao Paulo, Brazil
HUWC - UFC - Hospital Universitário Walter Cantídio - Universidade Federal do Ceará
🇧🇷
Fortaleza, Ceará, Brazil
Centro Multidisciplinar de Estudos Clínicos - CEMEC
🇧🇷
Sao Bernardo Do Campo, Sao Paulo, Brazil
MC Synexus - Sofia EOOD
🇧🇬
Sofia, Bulgaria
Centro de Investigacion en Reumatologia y Especialidades Medicas SAS. CIREEM
🇨🇴
Bogotá, Colombia
MDHAT 'Dr. Stefan Cherkezov', AD
🇧🇬
Veliko Tarnovo, Bulgaria
Centro de Investigacion Medico
🇨🇴
Barranquilla, Atlantico, Colombia
Medicity S.A.S.
🇨🇴
Bucaramanga, Colombia
CCR Brno s.r.o
🇨🇿
Brno, Czechia
Nemocnice Jihlava p.o
🇨🇿
Jihlava, Czechia
CTCenter MaVe s.r.o.
🇨🇿
Olomouc, Czechia
Artroscan s.r.o.
🇨🇿
Ostrava - Trebovice, Czechia
Clintrial, s.r.o.
🇨🇿
Praha 10, Czechia
ARTHROHELP s.r.o.
🇨🇿
Pardubice, Czechia
MUDR. Zuzana Urbanova Revmatologie
🇨🇿
Praha 4, Czechia
MUDR. Zuzana URBANOVA Revmatologie
🇨🇿
Praha 4 Nusle, Czechia
CCR Prague s.r.o.
🇨🇿
Praha 3, Czechia
Fakultni nemocnice v Motole
🇨🇿
Praha 5, Czechia
MEDICAL PLUS s.r.o.
🇨🇿
Uherske Hradiste, Czechia
Revmatologicky ustav
🇨🇿
Praha, Czechia
Affidea Praha, s.r.o.
🇨🇿
Praha, Czechia
PV Medical Services s.r.o.
🇨🇿
Zlin, Czechia
East Tallinn Central Hospital
🇪🇪
Tallinn, Estonia
SMO.MD GmbH
🇩🇪
Magdeburg, Sachsen Anhalt, Germany
Klinische Forschung Berlin-Mitte GmbH
🇩🇪
Berlin, Germany
Studienambulanz Dr. Wassenberg
🇩🇪
Northeim, Germany
HRF Hamburger Rheuma Forschungszentrum
🇩🇪
Hamburg, Germany
DRC Gyogyszervizsgalo Kozpont Kft.
🇭🇺
Balatonfured, Hungary
Obudai Egeszsegugyi Centrum
🇭🇺
Budapest, Hungary
Kiskunhalasi Semmelweis Korhaz
🇭🇺
Kiskunhalas, Hungary
Clinexpert Egeszsegugyi Szolg. es Ker. Kft.
🇭🇺
Budapest, Hungary
DRC Szekesfehervar
🇭🇺
Szekesfehervar, Hungary
MAV Korhaz és Rendelointezet
🇭🇺
Szolnok, Hungary
Vital Medical Center
🇭🇺
Veszprem, Hungary
Eulji University Hospital
🇰🇷
Daejeon, Korea, Republic of
Chonnam National University Hospital
🇰🇷
Gwangju, Korea, Republic of
Severance Hospital, Yonsei University
🇰🇷
Seoul, Korea, Republic of
Dr.Saulite-Kandevica Private Practice
🇱🇻
Liepaja, Latvia
Jeju National University Hospital
🇰🇷
Jeju, Korea, Republic of
The Catholic University of Korea, Seoul St. Mary's Hospital
🇰🇷
Seoul, Korea, Republic of
Klaipeda University Hospital, Public Institution
🇱🇹
Klaipeda, Lithuania
Republican Kaunas Hospital, Public Institution
🇱🇹
Kaunas, Lithuania
Center Outpatient Clinic, Public Institution
🇱🇹
Vilnius, Lithuania
Centro de Investigacion Clínica GRAMEL S.C
🇲🇽
Mexico, DisMexicotrito Federal, Mexico
Vilnius University Hospital Santariskiu Clinic, Public Institution
🇱🇹
Vilnius, Lithuania
Clinicos Asociados BOCM S.C.
🇲🇽
Mexico, Distrito Federal, Mexico
Clinical Research Institute S.C.
🇲🇽
Mexico City, Estado De Mexico, Mexico
Cryptex Investigacion Clinica S.C
🇲🇽
Mexico, Distrito Federal, Mexico
Clinica de Investigacion en Reumatologia y Obesidad S.C.
🇲🇽
Guadalajara, Jalisco, Mexico
Investigacion y Biomedicina de Chihuahua, S.C.
🇲🇽
Chihuahua, Mexico
Szpital Uniwersytecki nr 2 im.dr J. Biziela
🇵🇱
Bydgoszcz, Poland
Centro de Alta Especialidad en Reumatología e Investigación del Potosí, S.C.
🇲🇽
San Luis Potosi, Mexico
Polimedica Centrum Badań, Profilaktyki I Leczenia
🇵🇱
Kielce, Poland
State Budgetary Healthcare Institution of Sverdlovsk Region "Sverdlovsk Regional Clinical Hospital #1"
🇷🇺
Ekaterinburg, Sverdlovskaya Oblast, Russian Federation
Arrowe Park Hospital
🇬🇧
Wirral, Merseyside, United Kingdom
Kerckhoff-Klinik gGmbH
🇩🇪
Bad Nauheim, Hessen, Germany
MUDr. Gabriela Simkova ordinace lekare specialisty interna revmatologie
🇨🇿
Kladno, Czechia
Pacific Arthritis Center Medical Grpoup
🇺🇸
Santa Maria, California, United States
Whipps Cross University Hospital
🇬🇧
London, Greater London, United Kingdom
Fundacion Instituto de Reumatologia Fernando Chalem
🇨🇴
Bogota, Colombia
MCBK Iwona Czajkowska Anna PodrażkaSzczepaniak S.C.
🇵🇱
Grodzisk Mazowiecki, Poland
NZOZ ZDROWIE Osteo-Medic
🇵🇱
Bialystok, Poland
RCMed
🇵🇱
Sochaczew, Poland
Niepubliczny Zaklad Opieki Zdrowotnej "Nasz Lekarz" Praktyka Grupowa Lekarzy Rodzinnych z
🇵🇱
Torun, Poland
Siauliai Republican Hospital, Public Institution
🇱🇹
Siauliai, Lithuania
Clinstile, S.A. de C.V.
🇲🇽
Mexico, Distrito Federal, Mexico
Clinmed Research
🇵🇱
Skierniewice, Poland
Chi Mei Medical Center
🇨🇳
Tainan, Taiwan
CETI - Centro de Estudos em Terapias Inovadoras Ltda.
🇧🇷
Curitiba, Paraná, Brazil
Spitalul Clinic Judetean de Urgenta "Sf. Apostol Andrei" Constanta
🇷🇴
Constanta, Romania
Chang Gung Memorial Hospital, Linkou
🇨🇳
Taoyuan, Taiwan
Centro de Estudios de Investigacion Basica y Clinica SC
🇲🇽
Guadalajara, Jalisco, Mexico
Arizona Arthritis & Rheumatology Associates, P.C.
🇺🇸
Phoenix, Arizona, United States
Rheumatology Center of San Diego
🇺🇸
San Diego, California, United States
East Bay Rheumatology Medical Group, Inc.
🇺🇸
San Leandro, California, United States
Denver Arthritis Clinic
🇺🇸
Denver, Colorado, United States
Pharmax Research Clinic, Inc.
🇺🇸
Miami, Florida, United States
Accurate Clinical Research
🇺🇸
Houston, Texas, United States
Accurate Clinical Mangemnt LLC
🇺🇸
Houston, Texas, United States
Dr. Alex De Jesus Rheumatology, P.A.
🇺🇸
San Antonio, Texas, United States
Omega Research Consultants
🇺🇸
Orlando, Florida, United States
AdventHealth Medical Group, PA
🇺🇸
Tampa, Florida, United States
Health Research of Oklahoma, PLLC
🇺🇸
Oklahoma City, Oklahoma, United States
Lynn Health Science Institute
🇺🇸
Oklahoma City, Oklahoma, United States
Austin Regional Clinic, P.A.
🇺🇸
Austin, Texas, United States
Rheumatology Clinic of Houston, P.A.
🇺🇸
Houston, Texas, United States
Advanced Rheumatology of Houston
🇺🇸
Houston, Texas, United States
CIP - Centro Internacional de Pesquisa
🇧🇷
Goiânia, Goiás, Brazil