A Study of the Efficacy and Safety of Etrolizumab in Participants With Ulcerative Colitis Who Have Been Previously Exposed to Tumor Necrosis Factor (TNF) Inhibitors
- Conditions
- Ulcerative Colitis
- Interventions
- Drug: EtrozulimabDrug: Placebo
- Registration Number
- NCT02100696
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This Phase III, double-blind, placebo-controlled, multicenter study will investigate the efficacy and safety of etrolizumab during induction and maintenance of remission compared with placebo in the treatment of participants with moderately to severely active ulcerative colitis (UC) who have been previously exposed to TNF inhibitors.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 609
- Diagnosis of UC established at least 3 months prior to Day 1
- Moderately to severely active UC as determined by the Mayo Clinic Score (MCS) assessment
- Treatment within 5 years prior to screening with one or two induction regimens that contain TNF inhibitors (including TNF inhibitor biosimilars)
- Washout of anti-TNF therapy for at least 8 weeks preceding Day 1
- Background regimen for UC may include oral 5-aminosalicylic acid (5-ASA), oral corticosteroids, budesonide, probiotics, azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX) if doses have been stable during the screening period
- Use of highly effective contraception as defined by the protocol
- Must have received a colonoscopy within the past year or be willing to undergo a colonoscopy in lieu of a flexible sigmoidoscopy at screening
- A history of or current conditions and diseases affecting the digestive tract, such as indeterminate colitis, suspicion of ischemic colitis, radiation colitis, or microscopic colitis, Crohn's disease, fistulas or abdominal abscesses, colonic mucosal dysplasia, intestinal obstruction, toxic megacolon, or unremoved adenomatous colonic polyps
- Prior or planned surgery for UC
- Past or present ileostomy or colostomy
- Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, vedolizumab, and efalizumab)
- Any prior treatment with anti-adhesion molecules (e.g. anti-MAdCAM-1)
- Any prior treatment with rituximab
- Any treatment with tofacitinib during screening
- Congenital or acquired immune deficiency, chronic hepatitis B or C infection, human immunodeficiency virus (HIV) positive, or history of tuberculosis (active or latent)
- Evidence of or treatment for Clostridium difficile or clinically significant cytomegalovirus (CMV) colitis within 60 days prior to Day 1
- Evidence of or treatment for other intestinal pathogens within 30 days prior to Day 1
- History of recurrent opportunistic infections and/or severe disseminated viral infections
- History of organ transplant
- Any major episode of infection requiring treatment with intravenous (IV) antibiotics within 8 weeks prior to screening or oral antibiotics within 4 weeks prior to screening
- Received a live attenuated vaccine within 4 weeks prior to Day 1
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort 1: Etrolizumab (Open-Label Induction (OLI) Phase) Etrozulimab Participants assigned to this arm will receive treatment with open-label etrolizumab 105 milligrams (mg) subcutaneous (SC) injection once every 4 weeks (Q4W) for 14 weeks during the induction phase. Cohort 2: Etrolizumab (Double-Blind Induction Phase) Etrozulimab Participants randomized to this arm will receive treatment with double-blind etrolizumab 105 mg SC injection Q4W for 14 weeks during the induction phase. Etrolizumab Responders: Placebo (Maintenance Phase) Placebo Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive placebo SC injection Q4W from Week 16 up to Week 66. Placebo Responders: Placebo (Maintenance Phase) Placebo Participants who received placebo during the induction phase, Cohort 2: Placebo (Double-Blind Induction Phase), and achieve a clinical response with placebo at Week 14 will continue to receive blinded placebo from Week 16 up to Week 66 during the maintenance phase. Etrolizumab Responders: Etrolizumab (Maintenance Phase) Etrozulimab Participants who received etrolizumab during the induction phase, Cohort 1: Etrolizumab (Open-Label Induction Phase) and Cohort 2: Etrolizumab (Double-Blind Induction Phase), and achieved a clinical response at Week 14 will be re-randomized by Week 16 for the double-blind maintenance phase. Clinical responders re-randomized to this arm will receive etrolizumab 105 mg SC injection Q4W from Week 16 up to Week 66. Cohort 2: Placebo (Double-Blind Induction Phase) Placebo Participants randomized to this arm will receive treatment with double-blind placebo SC injection Q4W for 14 weeks during the induction phase.
- Primary Outcome Measures
Name Time Method Induction Phase: Percentage of Participants With Remission at Week 14, as Determined by the Mayo Clinic Score (MCS) Week 14 The Mayo Clinic Score (MCS) ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0.
Maintenance Phase: Percentage of Participants With Remission at Week 66 Among Participants Who Had Achieved a Clinical Response at Week 14, as Determined by the MCS Week 66 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Clinical Response is MCS with ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1.
- Secondary Outcome Measures
Name Time Method Maintenance Phase: Change From Baseline to Week 66 in Health-Related Quality of Life, as Assessed by the Overall Score of the IBDQ Baseline and Week 66 The IBDQ is used to assess participant's health-related quality of life (QOL). The IBDQ score is a Total Score summed up from across all 32 questions on the questionnaire. The Total Score range is from 32 to 224 with higher scores representing a better quality of life.
Number of Participants With at Least One Adverse Event by Severity, According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) From Baseline up to Week 78 All Adverse Events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Grade 5 = death related to AE. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
Number of Participants With Adverse Events Leading to Study Drug Discontinuation From Baseline up to Week 78 Number of Participants With Serious Infection-Related Adverse Events From Baseline up to Week 78 Induction Phase: Percentage of Participants With Clinical Remission at Week 14, as Determined by the MCS Week 14 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Clinical Remission is MCS ≤2 with individual subscores ≤1.
Induction Phase: Percentage of Participants With Clinical Response at Week 14, as Determined by the MCS Week 14 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Clinical Response is MCS with ≥3-point decrease and 30% reduction from baseline as well as ≥1-point decrease in rectal bleeding subscore or an absolute rectal bleeding score of 0 or 1.
Induction Phase: Percentage of Participants With Improvement From Baseline in Endoscopic Appearance of the Mucosa at Week 14, as Determined by the MCS Endoscopic Subscore Baseline and Week 14 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Improvement in endoscopic appearance of the mucosa is Endoscopy subscore ≤1.
Induction Phase: Percentage of Participants With Endoscopic Remission at Week 14, as Determined by the MCS Endoscopic Subscore Week 14 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Endoscopic Remission is Endoscopy subscore = 0.
Induction Phase: Percentage of Participants With Histologic Remission at Week 14, as Determined by the Nancy Histological Index Week 14 Nancy Histological Index (NHI) is a 5-level classification ranging from grade 0 (No histologically significant disease) to grade 4 (severely active disease). Histologic remission is defined as a Nancy Histological Index of 0 or 1.
Induction Phase: Change From Baseline to Week 6 in MCS Rectal Bleed Subscore Baseline and Week 6 Rectal bleeding data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = no blood in the stool; 1 = streaks of blood with stool less than half the time; 2 = obvious blood with stool most of the time; 3 = blood alone passed. The Mayo Clinic Score (MCS) rectal bleeding subscore was calculated as the worst value of three days of daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline rectal bleeding (RB) subscore.
Induction Phase: Change From Baseline to Week 6 in MCS Stool Frequency Subscore Baseline and Week 6 Stool frequency data were collected via the participant's diaries and each day a participant provided a score from 0 to 3 according to the following definitions: 0 = normal number of stools; 1 = 1 to 2 more stools than normal; 2 = 3 to 4 more stools than normal; 3 = 5 or more stools than normal. The Mayo Clinic Score (MCS) stool frequency subscore was calculated as the average of three days daily diary scores closest to anchor dates at baseline and post-baseline. The data was considered non-parametric and was reported using RANK analysis of covariance (ANCOVA). Participants were stratified by concomitant treatment with corticosteroids or immunosuppressants at randomization and disease activity measured during screening (MCS ≤9/MCS ≥10); the model adjusted for these stratification factors along with the baseline stool frequency (SF) subscore.
Induction Phase: Change From Baseline to Week 14 in UC Bowel Movement Signs and Symptoms, as Assessed by the Ulcerative Colitis Patient-Reported Outcome Signs and Symptoms (UC-PRO/SS) Questionnaire Baseline and Week 14 The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS). The bowel domain score ranges from 0-27, with a higher score indicating a worse disease state.
Induction Phase: Change From Baseline to Week 14 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire Baseline and Week 14 The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS). The functional (abdominal symptoms) domain score ranges from 0-12, with a higher score indicating a worse disease state.
Induction Phase: Change From Baseline to Week 14 in Health-Related Quality of Life, as Assessed by the Overall Score of the Inflammatory Bowel Disease Questionnaire (IBDQ) Baseline and Week 14 The IBDQ score is a Total Score summed up from across all 32 questions on the questionnaire. The Total Score range is from 32 to 224 with higher scores representing a better quality of life.
Maintenance Phase: Percentage of Participants With Clinical Remission at Week 66 Among Participants Who Had Achieved Clinical Remission at Week 14, as Determined by the MCS Week 66 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Clinical Remission is MCS ≤2 with individual subscores ≤1.
Maintenance Phase: Percentage of Participants With Clinical Remission at Week 66, as Determined by the MCS Week 66 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0. Clinical Remission is MCS ≤2 with individual subscores ≤1.
Maintenance Phase: Percentage of Participants With Remission at Week 66 Among Participants Who Had Achieved Remission at Week 14, as Determined by the MCS Week 66 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Remission was defined as MCS less than or equal to (≤)2 with individual subscores ≤1 and a rectal bleeding subscore of 0.
Maintenance Phase: Percentage of Participants With Improvement From Baseline in Endoscopic Appearance of the Mucosa at Week 66, as Determined by the MCS Endoscopic Subscore Baseline and Week 66 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Improvement in endoscopic appearance of the mucosa is Endoscopy subscore ≤1.
Maintenance Phase: Percentage of Participants With Histologic Remission at Week 66, as Determined by the Nancy Histological Index Week 66 Nancy Histological Index (NHI) is a 5-level classification ranging from grade 0 (No histologically significant disease) to grade 4 (severely active disease). Histologic remission is defined as a Nancy Histological Index of 0 or 1.
Maintenance Phase: Percentage of Participants With Endoscopic Remission at Week 66, as Determined by the MCS Endoscopic Subscore Week 66 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Endoscopic Remission is Endoscopy subscore = 0.
Maintenance Phase: Percentage of Participants With Corticosteroid-Free Clinical Remission at Week 66 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS Week 66 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Corticosteroid-Free analysis was conducted only on a subgroup of participants who were randomized into the maintenance phase and receiving Corticosteroids (CS) at baseline. Participants were defined as being off CS if they had no record of taking CS on the date that was 24 weeks prior to Week 66.
Maintenance Phase: Percentage of Participants With Corticosteroid-Free Remission at Week 66 Among Participants Who Were Receiving Corticosteroids at Baseline, as Determined by the MCS Week 66 The MCS ranges from 0 to 12 and is a composite of 4 assessments (each rated from 0-3): stool frequency, rectal bleeding, endoscopy, and physician's global assessment. Higher scores represent greater disease severity. Corticosteroid-Free analysis was conducted only on a subgroup of participants who were randomized into the maintenance phase and receiving Corticosteroids (CS) at baseline. Participants were defined as being off CS if they had no record of taking CS on the date that was 24 weeks prior to Week 66.
Maintenance Phase: Change From Baseline to Week 66 in UC Bowel Movement Signs and Symptoms, as Assessed by the UC-PRO/SS Questionnaire Baseline and Week 66 The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS). The bowel domain score ranges from 0-27, with a higher score indicating a worse disease state.
Maintenance Phase: Change From Baseline to Week 66 in UC Functional Symptoms, as Assessed by the UC-PRO/SS Questionnaire Baseline and Week 66 The UC-PRO questionnaire is collected in the e-diary and completed by participants for at least 9-12 consecutive days prior to a study visit. The UC-PRO is being reported in three domains; two domains are key endpoints and reported as UC-PRO Signs and Symptoms (UC-PRO/SS). The functional (abdominal symptoms) domain score ranges from 0-12, with a higher score indicating a worse disease state.
Number of Participants With Infection-Related Adverse Events From Baseline up to Week 78 All Adverse Events (AEs) were graded for severity using the NCI-CTCAE v4.0. Any AE not specifically listed was assessed per the following 5 grades: Grade 1 = mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or intervention not indicated. Grade 2 = moderate; minimal, local, or non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living. Grade 3 = severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living. Grade 4 = life-threatening consequences or urgent intervention indicated. Not all grades are appropriate for all AEs; some AEs have fewer than 5 options. The terms "severe" and "serious" are not synonymous and are independently assessed for each AE. Multiple occurrences of AEs were counted only once per participant at the highest (worst) grade.
Number of Participants With Injection-Site Reaction-Related Adverse Events From Baseline up to Week 78 Number of Participants With Hypersensitivity Reaction-Related Adverse Events From Baseline up to Week 78 Number of Participants With Malignancies From Baseline up to Week 78 Number of Participants With Anti-Therapeutic Antibodies to Etrolizumab at Baseline and During the Study Pre-dose at Baseline, Weeks 4, 14, 24, 44, and 66, and Early Termination/End of Safety Follow-Up (up to Week 78) A tiered strategy was used to detect and characterize etrolizumab antibodies within this clinical study. When determining post baseline incidence, participants were considered to be ADA positive if they were ADA negative or had missing data at baseline but developed an ADA response following etrolizumab drug exposure (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post baseline samples was at least 0.60 titer unit greater than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be ADA negative if they were ADA negative or had missing data at baseline and all post baseline samples were negative, or if they were ADA positive at baseline but did not have any post baseline samples with a titer that was at least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected).
Etrolizumab Serum Trough Concentration (for Arms/Timepoints Above LLOQ) Pre-dose (0 hour) at Baseline and Weeks 14, 24, 44 and 66 As per Protocol, the timepoints for each arm where more than a third of the samples were above the lower limit of quantification (LLOQ), full summary statistics (Mean and Standard Deviation) were reported. For timepoints below the LLOQ, only the Median and Max were reported as a separate outcome measure below.
Etrolizumab Serum Trough Concentration (for Arms/Timepoints Below LLOQ) Weeks 44 and 66 As per Protocol, the timepoints for each arm where more than a third of the samples were below the LLOQ only the Median and Max were reported.
Trial Locations
- Locations (184)
Louisiana Research Center, LLC
🇺🇸Shreveport, Louisiana, United States
CHU de Liège; Tour de Pathologie
🇧🇪Liège, Belgium
Gastroenterology Center of the Midsouth, P.C.
🇺🇸Memphis, Tennessee, United States
Pacific Gastroenterology Associates
🇨🇦Vancouver, British Columbia, Canada
AZ Delta (Stedelijk Ziekenhuis)
🇧🇪Roeselare, Belgium
St Vincent's Hospital Melbourne
🇦🇺Fitzroy, Victoria, Australia
Hospital Provincial del Centenario
🇦🇷Rosario, Argentina
Hotel Dieu de Levis
🇨🇦Levis, Quebec, Canada
St Frances Xavier Cabrini Hospital
🇦🇺Malvern, Victoria, Australia
LKH - Universitätsklinikum der PMU Salzburg
🇦🇹Salzburg, Austria
Medizinische Universität Wien
🇦🇹Wien, Austria
UZ Brussel
🇧🇪Brussel, Belgium
Hôpital Maisonneuve - Rosemont
🇨🇦Montreal, Quebec, Canada
Bekes Megyei Kozponti Korhaz Dr. Rethy Pal Tagkorhaza
🇭🇺Bekescsaba, Hungary
Pannonia Maganorvosi Centrum
🇭🇺Budapest, Hungary
Queen Elizabeth II Health Sciences Centre; Gastroenterology Research
🇨🇦Halifax, Nova Scotia, Canada
Pecsi Tudomanyegyetem
🇭🇺Pecs, Hungary
Rabin Medical Center-Beilinson Campus; Gaucher Clinic, Genetics Institute
🇮🇱Petach Tiqwa, Israel
Anticancer Hospital of Thessaliniki " Theagenio"
🇬🇷Thessaloniki, Greece
Markhot Ferenc Oktato Korhaz es Rendelointezet
🇭🇺Eger, Hungary
Petz Aladar Megyei Oktato Korhaz
🇭🇺Gyor, Hungary
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹Roma, Lazio, Italy
Centrum Zdrowia MDM
🇵🇱Warszawa, Poland
SC Euroclinic Hospital SA
🇷🇴Bucuresti, Romania
Inselspital-Universitaetsspital Bern; Institut fuer Spitalpharmazie
🇨🇭Bern, Switzerland
Cliniques Universitaires Saint-Luc; Nephrology
🇨🇭Bern, Switzerland
Crohn-Colitis Zentrum Bern - Gemeinschaftspraxis Balsiger, Seibold und Partner
🇨🇭Bern, Switzerland
Southwest Gastroenterology
🇺🇸Oak Lawn, Illinois, United States
Clinical Applications Laboratories, Inc.
🇺🇸San Diego, California, United States
Internal Medicine Specialists
🇺🇸Orlando, Florida, United States
FQL Research, LLC
🇺🇸Miramar, Florida, United States
Shafran Gastroenterology Center
🇺🇸Winter Park, Florida, United States
Henry Ford Health System
🇺🇸Detroit, Michigan, United States
Clinica Peruano Americana S.A.
🇺🇸Great Neck, New York, United States
UC Health, LLC.
🇺🇸Cincinnati, Ohio, United States
AZ Sint Elisabeth Herentals
🇧🇪Herentals, Belgium
Centro Digestivo de Curitiba
🇧🇷Curitiba, PR, Brazil
Zeidler Ledcor Centre - University of Alberta; Division of Gasroenterology
🇨🇦Edmonton, Alberta, Canada
University of Calgary; Heritage Medical Research Clinic
🇨🇦Calgary, Alberta, Canada
Klinikum der Johann Wolfgang Goethe-Universitaet
🇩🇪Frankfurt, Germany
Universitaetsklinikum Erlangen
🇩🇪Erlangen, Germany
Gastroenterologie Eppendorfer Baum
🇩🇪Hamburg, Germany
Universitaetsklinikum Schleswig-Holstein, Campus Kiel
🇩🇪Kiel, Germany
Universitaetsklinikum Ulm
🇩🇪Ulm, Germany
Obudai Egeszsegugyi Centrum Kft.
🇭🇺Budapest, Hungary
Semmelweis Egyetem
🇭🇺Budapest, Hungary
Magyar Honvedseg Egeszsegugyi Kozpont; Fázis I-es Klinikai Farmakológiai Vizsgálóhely
🇭🇺Budapest, Hungary
Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktato Korhaz; II. Belgyogyaszat
🇭🇺Miskolc, Hungary
Kaplan Medical Center
🇮🇱Rehovot, Israel
Assaf Harofeh
🇮🇱Rishon Lezion, Israel
Fejer Megyei Szent Gyorgy Egyetemi Oktato Korhaz
🇭🇺Székesfehérvár, Hungary
Hadassah University Hospital - Ein Kerem; Neurosurgery
🇮🇱Jerusalem, Israel
Azienda Ospedaliera S. Orsola-Malpighi
🇮🇹Bologna, Emilia-Romagna, Italy
A.O.U. Policlinico di Modena
🇮🇹Modena, Emilia-Romagna, Italy
Azienda Ospedaliera San Camillo Forlanini
🇮🇹Roma, Lazio, Italy
Istituto Clinico Humanitas
🇮🇹Rozzano (MI), Lombardia, Italy
Azienda Ospedaliera Universitaria Policlinico Tor Vergata
🇮🇹Roma, Lazio, Italy
Azienda Ospedaliera Di Padova
🇮🇹Padova, Veneto, Italy
I.R.C.C.S Policlinico San Donato
🇮🇹San Donato Milanese (MI), Lombardia, Italy
Kyungpook National University Hospital; Opthalmology
🇰🇷Daegu, Korea, Republic of
Seoul National University Bundang Hospital
🇰🇷Seongnam-si, Korea, Republic of
Severance Hospital, Yonsei University
🇰🇷Seoul, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Asan Medical Center.
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
The Catholic University of Korea St. Vincent's Hospital
🇰🇷Suwon-si,, Korea, Republic of
Hospital of Lithuanian University of Health. Sciences Kaunas Clinics
🇱🇹Kaunas, Lithuania
EuroMediCare Szpital Specjalistyczny z Przychodnią we Wrocławiu
🇵🇱Wroclaw, Poland
Hospital Universitario de Fuenlabrada
🇪🇸Madrid, Spain
St Thomas Hospital
🇬🇧London, United Kingdom
King's College London
🇬🇧London, United Kingdom
Fairfield General Hospital
🇬🇧Manchester, United Kingdom
Southampton General Hospital
🇬🇧Southampton, United Kingdom
Fiona Stanley Hospital
🇦🇺Murdoch, Western Australia, Australia
Shaare Zedek Medical Center
🇮🇱Jerusalem, Israel
CHU de Toulouse - Hôpital Rangueil
🇫🇷Toulouse Cedex 09, France
Hôpital de Brabois Adultes
🇫🇷Vandoeuvre-les-nancy, France
Gastroenterology Associates of Central Georgia
🇺🇸Macon, Georgia, United States
Precision Research Institute, LLC
🇺🇸San Diego, California, United States
Center For Digestive Health
🇺🇸Orlando, Florida, United States
Northwestern University Feinberg School Of Medicine
🇺🇸Chicago, Illinois, United States
Cotton-O'Neil Clinical Research Center, Digestive Health
🇺🇸Topeka, Kansas, United States
University of Michigan; Michigan Institute for Clinical and Health Research (MICHR)
🇺🇸Ann Arbor, Michigan, United States
Gastroenterology Associates, LLC
🇺🇸Baton Rouge, Louisiana, United States
Gastrointestinal Specialists of Georgia, PC
🇺🇸Marietta, Georgia, United States
Hamburgisches Forschungsinstitut fuer CED
🇩🇪Hamburg, Germany
Universitaetsklinikum Halle (Saale)
🇩🇪Halle, Germany
Center for Digestive Health
🇺🇸Troy, Michigan, United States
University of North Carolina at Chapel Hill
🇺🇸Chapel Hill, North Carolina, United States
Massachusetts General Hospital; Crohn's & Colitis Center
🇺🇸Boston, Massachusetts, United States
Weill Cornell Medical College-New York Presbyterian Hospital
🇺🇸New York, New York, United States
Kansas City Research Institute, LLC
🇺🇸Kansas City, Missouri, United States
Consultants for Clinical Research Inc.
🇺🇸Cincinnati, Ohio, United States
Great Lakes Gastroenterology Research, LLC
🇺🇸Mentor, Ohio, United States
Ericksen Research and Development
🇺🇸Clinton, Utah, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
McGuire Research Institute; Gastroenterology
🇺🇸Richmond, Virginia, United States
Royal Brisbane and Women's Hospital
🇦🇺Herston, Queensland, Australia
Klinikum Klagenfurt am Wörtersee; Acute geriatric care
🇦🇹Klagenfurt, Austria
Footscray Hospital; Gastroenterology
🇦🇺Footscray, Victoria, Australia
Imeldaziekenhuis
🇧🇪Bonheiden, Belgium
Mater Adult Hospital
🇦🇺South Brisbane, Queensland, Australia
Launceston General Hospital; Gastroenterology Research
🇦🇺Launceston, Tasmania, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Toronto Liver Centre
🇨🇦Toronto, Ontario, Canada
CHU St Pierre (St Pierre)
🇧🇪Brussels, Belgium
Hospital de Clínicas de Porto Alegre X
🇧🇷Porto Alegre, RS, Brazil
Hospital Estadual Mario Covas
🇧🇷Santo Andre, SP, Brazil
UZ Gent
🇧🇪Gent, Belgium
UZ Leuven; Neurology
🇧🇪Leuven, Belgium
Instituto Goiano de Gastroenterologia e Endoscopia Digestiva Ltda
🇧🇷Goiânia, GO, Brazil
Hospital Felicio Rocho
🇧🇷Belo Horizonte, MG, Brazil
UNESP - Faculdade de Medicina da Universidade Estadual Paulista - Campus Botucatu
🇧🇷Botucatu, SP, Brazil
Hospital Moinhos de Vento
🇧🇷Porto Alegre, RS, Brazil
Hospital Universitario Clementino Fraga Filho - UFRJ
🇧🇷Rio de Janeiro, RJ, Brazil
CAEP - Centro Avancado de Estudos e Pesquisas Ltda.
🇧🇷Campinas, SP, Brazil
Mount Sinai Hospital
🇨🇦Toronto, Ontario, Canada
Taunton Health Centre
🇨🇦Oshawa, Ontario, Canada
Toronto Digestive Disease Associates
🇨🇦Vaughan, Ontario, Canada
Fakultni nemocnice Brno; Interni kardiologicka klinika
🇨🇿Brno, Czechia
Hepato-Gastroenterologie HK, s.r.o.
🇨🇿Hradec Kralove, Czechia
Pardubicka krajska nemocnice, a.s.
🇨🇿Pardubice, Czechia
Rigshospitalet; Medicinsk gastroenterologisk klinik
🇩🇰København Ø, Denmark
Ålborg Universitets Hospital; Gastromedicinsk
🇩🇰Ålborg, Denmark
ISCARE a.s.
🇨🇿Praha 7, Czechia
Krajska zdravotni, a.s. - Masarykova nemocnice v Usti nad Labem, o.z., Ocni oddeleni
🇨🇿Usti Nad Labem, Czechia
Hopital Claude Huriez - CHU Lille
🇫🇷Lille, France
CHU Amiens - Hopital Sud; Pharmacie - Secteur des Essais cliniques
🇫🇷Amiens Cedex01, France
Hôpital Beaujon
🇫🇷Clichy cedex, France
Universitätsklinikum Freiburg; Innere Medizin I; Hämatologie, Onkologie und Stammzelltransplantation
🇩🇪Freiburg, Germany
Debreceni Egyetem
🇭🇺Debrecen, Hungary
Hôpital Nord - CHU Marseille; Gastroenterology and Hepatology
🇫🇷Marseille cedex 20, France
CHU Nice - Hopital de l'Archet 2
🇫🇷Nice, France
Hôpital Saint-Louis
🇫🇷Paris, France
Charite Universitaetsmedizin Berlin - Campus Charite Mitte
🇩🇪Berlin, Germany
Groupe Hospitalier Sud - Hôpital Haut-Lévêque - USN
🇫🇷Pessac, France
DRK Kliniken Berlin Westend
🇩🇪Berlin, Germany
CHU Saint Etienne - Hôpital Nord
🇫🇷Saint Etienne, France
Höpital Hautepierre; Pediatrie1
🇫🇷Strasbourg, France
Medizinische Hochschule Hannover; Klinik für Gastroenterologie, Hepatologie und Endokrinologie
🇩🇪Hannover, Germany
Universitätsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Universitaetsklinikum Muenster
🇩🇪Muenster, Germany
Klinikum Mannheim GmbH Universitätsklinikum
🇩🇪Mannheim, Germany
Eszak-Kozep-budai Centrum, Uj Szent Janos Korhaz es Szakrendelo
🇭🇺Budapest, Hungary
Azienda Socio Sanitaria Territoriale Fatebenefratelli (Presidio Ospedale Sacco)
🇮🇹Milano, Lombardia, Italy
Ospedale di Circolo; Neuropsichiatria Infantile
🇮🇹Rho, Lombardia, Italy
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Toscana, Italy
Vilnius University Hospital Santariskiu Clinic Public Insti
🇱🇹Vilnius, Lithuania
Centro Regiomontano de Estudios Clínicos Roma S.C.
🇲🇽Monterrey, Nuevo LEON, Mexico
Amsterdam UMC, Locatie VUMC; Neurology
🇳🇱Amsterdam, Netherlands
Amsterdam UMC Location AMC
🇳🇱Amsterdam, Netherlands
Rijnstate; Internal Medicine Department
🇳🇱Arnhem, Netherlands
Nasz Lekarz Osrodek Badan Klinicznych
🇵🇱Bydgoszcz, Poland
Radboudumc
🇳🇱NL -nijmegen, Netherlands
Nzoz All-Medicus
🇵🇱Katowice, Poland
Gabinet Lekarski, Bartosz Korczowski
🇵🇱Rzeszów, Poland
Niepubliczny Zaklad Opieki Zdrowotnej SONOMED
🇵🇱Szczecin, Poland
Nzoz Vivamed
🇵🇱Warszawa, Poland
Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy
🇵🇱Warszawa, Poland
LexMedica Osrodek Badan Klinicznych
🇵🇱Wroclaw, Poland
PlanetMed
🇵🇱Wrocław, Poland
Fundacion Hospital de Alcorcon; Servicio de Digestivo
🇪🇸Alcorcon, Madrid, Spain
Hospital Universitario de la Princesa
🇪🇸Madrid, Spain
The Royal London Hospital
🇬🇧London, United Kingdom
Addenbrooke's Hospital
🇬🇧Cambridge, United Kingdom
Hospital Universitario Miguel Servet
🇪🇸Zaragoza, Spain
University College London Hospital
🇬🇧London, United Kingdom
Royal Devon and Exeter Hospital (Wonford)
🇬🇧Exeter, United Kingdom
Royal Victoria Infirmary
🇬🇧Newcastle upon Tyne, United Kingdom
Nottingham University Hospitals; QMC Campus
🇬🇧Nottingham, United Kingdom
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Hospital Universitari de Girona Dr Josep Trueta
🇪🇸Girona, Spain
Hospital Universitari i Politecnic La Fe
🇪🇸Valencia, Spain
Korea University Ansan Hospital
🇰🇷Gyeonggi-do, Korea, Republic of
University of Utah School of Medicine
🇺🇸Salt Lake City, Utah, United States
Nemocnice Na Bulovce
🇨🇿Prague, Czechia
Rocky Mountain Gastroenterology Associates
🇺🇸Denver, Colorado, United States
University of California San Diego Medical Center
🇺🇸La Jolla, California, United States
University of California at San Francisco
🇺🇸San Francisco, California, United States
Atlanta Gastroenterology Specialists, PC
🇺🇸Suwanee, Georgia, United States
Tyler Research Institute, LLC
🇺🇸Tyler, Texas, United States
Rocky Mountain Gastroenterology Associates, P.L.L.C.; Gastroenterology
🇺🇸Lakewood, Colorado, United States
Washington Gastroenterology
🇺🇸Bellevue, Washington, United States
Digestive and Liver Disease Specialists, Ltd.
🇺🇸Norfolk, Virginia, United States