Study of Treat to Target Versus Routine Care Maintenance Strategies in Crohn's Disease Patients Treated With Ustekinumab
- Registration Number
- NCT03107793
- Lead Sponsor
- Janssen-Cilag Ltd.
- Brief Summary
The purpose of this study is to evaluate the efficacy of a treat to target strategy coupled with early endoscopic assessment versus a clinically driven (routine care) approach in achieving endoscopic response.
- Detailed Description
Study investigates benefit of treat to target maintenance treatment strategy versus routine care to test hypothesis that 'treat to target' ustekinumab (UST) maintenance treatment strategy coupled with early endoscopic assessment will result in higher endoscopic response rate after 48 weeks of treatment, compared to pragmatic maintenance treatment strategy. It consists of screening (5 weeks); treatment period (Week 0 to 48); extension period (Weeks 48 to 104) and safety follow up visit (16 weeks after last dose). Participants will be given an option to enter ultrasound sub-study to assess intestinal ultrasound (IUS) parameters indicating transmural changes in response to treatment with UST in participants with Crohn's disease. Study treatment will be unaffected by participation in sub-study which is optional for participants of main study.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 500
Main Study:
- Have active, moderate to severe, ileal and/or colonic Crohn's disease, demonstrated by: baseline CDAI score of greater than or equal to (>=) 220 and less than equal to (<=) 450, and endoscopy with evidence of active Crohn's disease (defined as simple endoscopic score for Crohn's disease [SES-CD] score >=3 excluding the contribution of the narrowing component score) obtained within the 5 week screening period. A prior endoscopy may be used only if obtained within 3 months prior to baseline (Week 0), in which case the prior endoscopy must be centrally read again and SES-CD calculated based on this second, centralized read-out
- Has had an inadequate response with, lost response to, was intolerant to, or had medical contraindications to either conventional therapy, or one previous biologic therapy approved for the treatment of Crohn's disease in the countries in which the study is conducted
- Are eligible according to tuberculosis (TB) infection screening criteria
- Must sign an informed consent form (ICF) or their legally acceptable representative if applicable must sign) indicating that he or she understands the purpose of, and procedures required for, the study and is willing to participate in the study.
Sub-study:
- Be enrolled into the main study at a participating site
- Sign a separate ICF indicating that they understand the purpose of and procedures required for this sub-study and are willing to participate in the sub-study
- Satisfy all inclusion criteria and none of the exclusion criteria specified in the main study
Main Study:
- Has complications of Crohn's disease such as symptomatic strictures or stenoses, short gut syndrome, or any other manifestation that might be anticipated to require surgery, could preclude the use of the Crohn's Disease Activity Index (CDAI) to assess response to therapy, or would possibly confound the ability to assess the effect of treatment with ustekinumab
- Currently has or is suspected to have an abscess. Recent cutaneous and perianal abscesses are not exclusionary if drained and adequately treated at least 3 weeks prior to baseline, or 8 weeks prior to baseline for intra-abdominal abscesses, provided there is no anticipated need for any further surgery. Participants with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses identified
- Has had any kind of bowel resection within 6 months prior to baseline
- Has a draining (i.e, functioning) stoma or ostomy
- Has received more than one previous biologic therapy approved for the treatment of Crohn's disease in the countries in which the study is conducted
Sub-study:
- Obesity or other characteristics considered likely to preclude intestinal ultrasound (IUS) visualization of the affected bowel segment
- Normal bowel wall thickness (BWT) (that is, <=2.0 millimeter [mm] for the terminal ileum; <=3.0 mm for the colon) for all bowel segments at baseline (Week 0)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description All Participants Ustekinumab At Week (Wk) 0, all eligible participants will initiate intravenous (IV) induction treatment with ustekinumab (UST) on a weight-tiered basis at a dose of approximately 6 milligram per kilogram (mg/kg). At Week 8, all participants will receive a 90 milligram (mg) subcutaneous (SC) injection of ustekinumab. At Week 16, participants who do not achieve a Crohn's Disease Activity Index (CDAI) improvement of greater than or equal to (\>=) 70 points versus Week 0 (CDAI 70) will leave the study. Remaining participants will be randomized in a 1:1 ratio to either one of two arms for open label maintenance treatment up to Week 48: the treat to target arm or the routine care arm. From Week 48, participants will continue ustekinumab treatment in the study extension period, up to Week 104. Dosing frequency will be adjusted in the extension period for the participants failing to meet the treatment target. Routine Care Arm Ustekinumab In the routine care arm, assessment visits will be scheduled according to the timing of maintenance treatment injections up to Week 48, which will be in compliance with the EU SmPC for ustekinumab for the treatment of Crohn's disease, in which dosing every 12 weeks is recommended. At Week 16, (that is, 8 weeks after the first SC dose) participants continuing in the study will have demonstrated a CDAI-70 response. Nonetheless, participants who have not shown adequate response based on the investigator's judgment may receive a second SC dose at Week 16. During the routine care maintenance treatment period, in case of clinical worsening reported by the participant, consistent with disease flare in the investigator's judgment, clinical assessments of disease flare will be performed at the investigator's discretion. Treat to Target (T2T) Arm Ustekinumab UST maintenance treatment assignment will be based on centrally-read colonoscopy (at Wk16). Participants with \<25% improvement in SES-CD score at Wk16 will be assigned to Q8 (8-weekly) treatment and will receive UST 90mg SC at Wk16. In contrast, participants with \>=25% improvement in SES-CD score at Wk16 will be assigned to Q12 treatment and will receive next UST dose (90 mg SC) at Wk20. At assessment visits (from Wk24 for participants assigned to the Q8 regimen or from Wk20 for the Q12 group) UST maintenance treatment (up to Wk 48) will be directed by T2T assessments. Participants meeting target will continue with same UST dosing frequency. The dosing frequency will be optimized for all participants failing to meet the target at assessment visit. Those previously on Q12 regimens will be adjusted to Q8 dosing; those previously on Q8 regimens will be adjusted to Q4 dosing. Participants subsequently failing to meet the target will not be able to adjust further and will leave the study. Exploratory Extension period: From Week 48 to Week 104 Ustekinumab At Week 48, dose de-escalation will be implemented for participants with both endoscopic remission (SES-CD score \<=2) and corticosteroid-free clinical remission of at least 16 weeks duration. Participants receiving 12 weekly dosing frequency (Q12) ustekinumab will maintain this dosing frequency. Participants with either clinical remission or endoscopic remission, but not both, at Week 48 will continue with same dosing frequency or de-escalate provided maintenance of corticosteroid-free clinical remission and biomarker remission at 2 consecutive visits. Participants with neither corticosteroid-free clinical remission nor endoscopic remission will escalate dose or leave study if already on 4 weekly dosing frequency (Q4) dose. If neither clinical remission nor biomarker remission is evident at the next visit, participant will leave study. Later in the extension period, only those who achieve corticosteroid-free clinical remission and biomarker remission will undergo dose de-escalation.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Endoscopic Response at Week 48 Week 48 Endoscopic response defined as showing a reduction from baseline in simple endoscopic score for Crohn's disease (SES-CD) of greater than or equal to (\>=) 50 percent (%). SES-CD is a validated instrument reflecting an endoscopist global appraisal of mucosal lesions in Crohn's disease. SES-CD grades lesions by location (5 bowel segments: ileum, right colon, transverse colon, left colon, and rectum) using 4 endoscopic variables: ulcer size, extent of ulcerated surface, extent of affected surface, and presence/type of narrowing. Total SES-CD is sum of 4 variables for all 5 bowel segments. Scores range from 0-60 with higher scores indicating more severe disease. Randomized participants who stopped treatment before reaching Week 48 due to any reason, or participants without endoscopic data at Week 48 were analyzed as nonresponders.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With Endoscopic Response at Week 48 (Premature Drop-outs Excluded) Week 48 Endoscopic response defined as showing a reduction from baseline in SES-CD (a validated instrument reflecting an endoscopist's global appraisal of mucosal lesions) score of \>=50%. SES-CD grades lesions by location (5 bowel segments: ileum, right colon, transverse colon, left colon, and rectum) using 4 endoscopic variables: ulcer size, extent of ulcerated surface, extent of affected surface, and presence/type of narrowing. Total SES-CD is calculated as sum of 4 variables for 5 bowel segments. Scores ranges 0-60. Higher scores indicates more severe disease. Randomized participants who stopped treatment before reaching Week 48 due to reasons other than lack/loss of efficacy were excluded from analysis.
Change From Baseline in European Quality Of Life 5 Dimensions 5 Level (EQ-5D-5L) Visual Analog Scale (VAS) Score Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) EQ-5D-5L, validated quality-of-life instrument completed by participants. It consists of EQ-5D-5L descriptive system and EQ-VAS. EQ-5D-5L descriptive system comprises 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) describes participants current health state. Each dimension scores where 1 indicates no problems and 5 indicates extreme problems. EQ-5D-5L VAS records the respondent's self-rated, visual analogue scale score on a scale of 0-100, where 0 labelled as 'the worst health you can imagine and 100 labelled 'the best health you can imagine.' LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint defined as last available postbaseline result within main analysis period (i.e., first 48 weeks).
Percentage of Participants With Endoscopic Response at Week 48 (Last Observation Carried Forward [LOCF]) Week 48 (LOCF) Endoscopic response defined as a reduction from baseline in SES-CD score of \>= 50%. SES-CD is a validated instrument reflecting an endoscopist global appraisal of mucosal lesions in Crohn's disease. SES-CD grades lesions by location (5 bowel segments: ileum, right colon, transverse colon, left colon, and rectum) using 4 endoscopic variables: ulcer size, extent of ulcerated surface, extent of affected surface, and presence/type of narrowing. The total SES-CD was calculated as the sum of the 4 variables for the 5 bowel segments. Scores range from 0 to 60, with higher scores indicating more severe disease. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward.
Percentage of Participants With Clinical Response at Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Clinical response defined as a \>=100-point reduction from the baseline in Crohn's Disease Activity Index (CDAI) score, or a CDAI score of \<150. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A decrease in CDAI over time indicates improvement in disease activity. In general, CDAI score ranges from 0 to approximately 600Íž higher score indicates higher disease activities. Participants with missing data were considered as non-responder. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Percentage of Participants With Clinical Remission at Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Clinical Remission defined as a CDAI score of \<150 points. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A decrease in CDAI over time indicates improvement in disease activity. In general, CDAI score ranges from 0 to approximately 600Íž higher score indicates higher disease activities. Participants with missing data were considered as non-remitter. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Percentage of Participants With Endoscopic Remission at Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Percentage of participants with Endoscopic remission defined as SES-CD score \<=2 at Weeks 16, 48, and Endpoint (Week 48 \[LOCF\]) were reported. SES-CD is a validated instrument reflecting an endoscopist global appraisal of mucosal lesions in Crohn's disease. SES-CD grades lesions by location (5 bowel segments: ileum, right colon, transverse colon, left colon, and rectum) using 4 endoscopic variables: ulcer size, extent of ulcerated surface, extent of affected surface, and presence/type of narrowing. Total SES-CD is sum of 4 variables for all 5 bowel segments. Scores range from 0-60 with higher scores indicating more severe disease. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Percentage of Participants With Mucosal Healing at Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Mucosal healing is defined as the complete absence of mucosal ulcerations in any ileocolonic segment. SES-CD grades lesions by location (5 bowel segments: ileum, right colon, transverse colon, left colon, and rectum) using 4 endoscopic variables: ulcer size, extent of ulcerated surface, extent of affected surface, and presence/type of narrowing. Total SES-CD is sum of 4 variables for all 5 bowel segments. Scores range from 0-60 with higher scores indicating more severe disease. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (i.e. first 48 weeks of the study).
Percentage of Participants With Corticosteroid-free Endoscopic Response at Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Corticosteroid-free endoscopic response defined as a reduction from baseline in SES-CD score of \>=50% and not taking any corticosteroids for at least 30 days prior to Weeks 16, 48 and endpoint (Week 48 \[LOCF\]). SES-CD grades lesions by location (5 bowel segments: ileum, right colon, transverse colon, left colon, and rectum) using 4 endoscopic variables: ulcer size, extent of ulcerated surface, extent of affected surface, and presence/type of narrowing. Total score is sum of 4 variables. Scores range 0-60. Higher scores means severe disease. Participants with missing data were analyzed as No SES-CD Improvement. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint defined as last available postbaseline result within main analysis period (i.e., first 48 weeks).
Change From Baseline in Fecal Calprotectin (FC) Baseline, Weeks 16, 48 and Endpoint (Week 48 [LOCF]) Change from baseline in FC were reported. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Percentage of Participants With Corticosteroid-free Clinical Remission at Week 48 and Endpoint (Week 48 [LOCF]) Week 48 and Endpoint (Week 48 [LOCF]) Corticosteroid-free Clinical Remission at Week 48 and Endpoint (Week 48 \[LOCF\]) is defined as a CDAI score \<150 and not taking any corticosteroids for at least 30 days prior to Week 48 and Endpoint assessment. The CDAI score is used to quantify the symptoms of participants with Crohn's Disease. A decrease in CDAI over time indicates improvement in disease activity. In general, CDAI score ranges from 0 to approximately 600Íž higher score indicates higher disease activities. Participants with missing data were analyzed as non-remitter. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Change From Baseline in Serum C-reactive Protein (CRP) Baseline, Weeks 16, 48 and Endpoint (Week 48 [LOCF] Change from baseline in serum CRP were reported. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Score Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) The HADS Score is a validated 14-item scale with 7 of the items relating to anxiety and 7 relating to depression. Each item is scored from 0 to 3, with higher scores indicating greater likelihood of depression or anxiety. Cases of anxiety or depression are each defined by subscale scores of 8 or greater and categorized as normal (score of 0 to 7), mild (score of 8 to 10), moderate (score of 11 to 14), and severe (score of 15 to 21). LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Percentage of Participants With 7-point Change From Baseline in Work Productivity and Activity Impairment (WPAI) Scores for Each Domain Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Percentage of participants with 7-point change from baseline in WPAI scores for each domain were reported. WPAI is 6-item (7-day recall period) well-validated questionnaire to measure impairments in work and activities that produces 4 types of domains: absenteeism (work time missed), presenteeism (impairment at work/reduced on-the-job effectiveness), work productivity loss (overall work impairment/absenteeism plus presenteeism), activity impairment. Participants who answered first question of the questionnaire 'Are you currently employed' as 'Yes' were included in absenteeism, presenteeism, and work productivity. In activity impairment all participants were included. Each score range: 0-100, higher scores=greater impairment and less productivity. LOCF: Participants who had missing value at Week 48 or stopped treatment before reaching Week 48 had last non-missing value carried forward. Endpoint: last available postbaseline result in main analysis period (first 48 weeks).
Change From Baseline in IBDQ Score Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) The IBDQ is 32-item questionnaire used to evaluate disease-specific health-related quality of life. Each item score ranged from 1 (worst possible response) to 7 (best possible response). Items were grouped into 4 domains: bowel function, emotional status, systemic symptoms and social function with scored as follows: 10 to 70 (bowel symptoms); 5 to 35 (systemic symptoms); 12 to 84 (emotional function); and 5 to 35 (social function). Higher score, better quality of life. Total score is sum of each item score and ranges from 32 to 224. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint defined as last available postbaseline result within main analysis period (that is, first 48 weeks of the study). Only participants with non-missing baseline value and at least one non-missing post-baseline value during main treatment period were included in analysis.
Percentage of Participants With Inflammatory Bowel Disease Questionnaire (IBDQ) Response Weeks 16, 48, and Endpoint (Week 48 [LOCF]) IBDQ response was defined as \>= 16-point improvement in IBDQ total score from baseline. The IBDQ is 32-item questionnaire for participants with IBD used to evaluate disease-specific health-related quality of life. Each item score ranged from 1 (worst possible response) to 7 (best possible response). Each items were grouped into 4 domains: bowel function, emotional status, systemic symptoms and social function. The 4 domains were scored as: 10 to 70 (bowel symptoms); 5 to 35 (systemic symptoms); 12 to 84 (emotional function); 5 to 35 (social function). For each domain, higher score indicated better quality of life. Total score is sum of each item score and ranges from 32 to 224 with higher score indicating better quality of life. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint defined as last available postbaseline result within main analysis period (i.e, first 48 weeks).
Change From Baseline in WPAI Score Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) The WPAI questionnaire is a well-validated instrument to measure impairments in work and activities. It is a 6-item questionnaire with a 7-day recall period. The WPAI questionnaire produces 4 types of scores: absenteeism (work time missed), presenteesism (impairment at work/reduced on-the-job effectiveness), work productivity loss (overall work impairment/absenteeism plus presenteeism), and activity impairment. Each score ranges from 0 to 100 with higher scores indicating greater impairment and less productivity. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Change From Baseline in Time Lost From Work Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Time lost from work was collected by asking the participants a single question, "How many days did you miss from work due to your Crohn's disease in the last 4 weeks?" LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Number of Participants With Adverse Events (AEs) That Occurred in Participants Administered With Ustekinumab up to Week 48 Up to Week 48 An adverse event is any untoward medical event that occurs in participants administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.
Changes From Baseline in Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F) Scale Score Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) The FACIT-F scale is a 13-item fatigue scale with a 7-day recall period. It measures the level of fatigue during the usual daily activities. The level of fatigue is measured on a 4-point Likert scale (0=very much fatigue to 4=not at all fatigue). The sum of all responses resulted in the FACIT-Fatigue score for a total possible score of 0 (worst score) to 52 (best score). LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Change From Baseline in Body Weight Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Change from baseline in body weight were reported. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Change From Baseline in Body Mass Index (BMI) Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Change from baseline in BMI were reported. BMI is a person's weight (in kilograms) divided by the square of height (in meters).LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (that is, first 48 weeks of the study).
Change From Baseline in Blood Pressure Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Change from baseline in Blood Pressure (Systolic Blood Pressure \[SPB\] and Diastolic Blood Pressure \[DBP\]) were reported. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (i.e. first 48 weeks of the study).
Change From Baseline in Pulse Rate Baseline, Weeks 16, 48, and Endpoint (Week 48 [LOCF]) Change from baseline in pulse rate were reported. LOCF: Participants who had a missing value at Week 48 or who stopped treatment before reaching Week 48 had their last non-missing value carried forward. Endpoint is defined as the last available postbaseline result within the main analysis period (i.e. first 48 weeks of the study).
Trial Locations
- Locations (107)
Hospices Civils de Lyon HCL
đŤđˇPierre BĂŠnite, France
CHU Rangueil
đŤđˇToulouse, France
GZA Ziekenhuizen
đ§đŞAntwerpen, Belgium
UZ Brussel
đ§đŞBrussel, Belgium
Imelda Ziekenhuis
đ§đŞBonheiden, Belgium
Cliniques Universitaires Saint Luc
đ§đŞBruxelles, Belgium
Universitair Ziekenhuis Antwerpen
đ§đŞEdegem, Belgium
AZ Maria Middelares
đ§đŞGent, Belgium
UZ Gent
đ§đŞGent, Belgium
CHU de Liege
đ§đŞLiège, Belgium
Az Groeninge
đ§đŞKortrijk, Belgium
UZ Leuven
đ§đŞLeuven, Belgium
CHC MontLegia
đ§đŞLiège, Belgium
Fakultni nemocnice Hradec Kralove
đ¨đżHradec Kralove, Czechia
EGK s.r.o. - Sanatorium sv. Anny
đ¨đżPrague, Czechia
Algemeen Ziekenhuis Jan Palfijn Merksem
đ§đŞMerksem, Belgium
AZ Damiaan
đ§đŞOostende, Belgium
Hepato-gastroenterologie HK, s.r.o.
đ¨đżHradec Kralove, Czechia
AXON Clinical s.r.o.
đ¨đżPrague, Czechia
MEDIENDO s.r.o.
đ¨đżPrague, Czechia
ISCARE a.s.
đ¨đżPraha 9, Czechia
Aalborg University Hospital
đŠđ°Aalborg, Denmark
Aarhus Kommunehospital
đŠđ°Aarhus C., Denmark
Abdominalcenter K
đŠđ°København NV, Denmark
Odense Universitetshospital
đŠđ°Odense, Denmark
Silkeborg Hospital
đŠđ°Silkeborg, Denmark
Vejle Sygehus
đŠđ°Vejle, Denmark
Hopital Beaujon
đŤđˇClichy, France
CHU Grenoble
đŤđˇLa Tronche, France
Hopital de Bicetre
đŤđˇLe Kremlin BicĂŞtre, France
CHU Saint Eloi
đŤđˇMontpellier, France
CHU de Nice Hopital de l Archet
đŤđˇNice, France
Hopital Claude Huriez
đŤđˇLille, France
CHU Saint Etienne
đŤđˇSaint Priest en jarez, France
Hopital Saint Louis
đŤđˇParis, France
CHU Bordeaux
đŤđˇPessac, France
CHU-Nancy
đŤđˇVandoeuvre les Nancy, France
Medizinische Hochschule Hannover
đŠđŞHannover, Germany
Charite Universitatsmedizin Berlin Campus Virchow Klinikum
đŠđŞBerlin, Germany
Staedtisches Klinikum Lueneburg
đŠđŞLueneburg, Germany
Agaplesion Frankfurter Diakonie Kliniken GmbH, Markus Krankenhaus
đŠđŞFrankfurt, Germany
ASST Fatebenefratelli Sacco
đŽđšMilano, Italy
Azienda Ospedaliera San Camillo - Roma
đŽđšRoma, Italy
Universitaetsklinikum Mannheim
đŠđŞMannheim, Germany
MVZ Portal10
đŠđŞMuenster, Germany
Policlinico Sant'Orsola Malpighi
đŽđšBologna, Italy
Policlinico di Bari Ospedale Giovanni XXIII
đŽđšBari, Italy
Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
đŽđšMilano, Italy
Ospedale Classificato Equiparato Sacro Cuore Don Calabria di Negrar
đŽđšNegrar (VR), Italy
Azienda Ospedaliera G.Salvini Ospedale di Rho
đŽđšRHO, Italy
Ospedale Villa Sofia-Cervello
đŽđšPalermo, Italy
AO Ordine Mauriziano
đŽđšTorino, Italy
Erasmus MC
đłđąRotterdam, Netherlands
Fondazione Policlinico Gemelli UniversitĂ Cattolica
đŽđšRoma, Italy
Meander Medisch Centrum
đłđąAmersfoort, Netherlands
Istituto Clinico Humanitas
đŽđšRozzano, Italy
Albert Schweitzer Ziekenhuis
đłđąDordrecht, Netherlands
UMCG
đłđąGroningen, Netherlands
IRCCS Policlinico San Donato
đŽđšSan Donato Milanese, Italy
Azienda Sanitaria Universitaria Integrata di Udine
đŽđšUdine, Italy
AMC
đłđąAmsterdam, Netherlands
Rivas Zorggroep, Beatrixziekenhuis
đłđąGorinchem, Netherlands
Centro Hospitalar e UniversitĂĄrio do Algarve
đľđšFaro, Portugal
Centro Hospitalar Lisboa Norte EPE Hosp. Santa Maria
đľđšLisboa, Portugal
Centro Hospitalar de Tondela Viseu, EPE
đľđšViseu, Portugal
Centro Hospitalar e UniversitĂĄrio de Coimbra, EPE
đľđšCoimbra, Portugal
Centro Hospitalar Lisboa Central, EPE - Hospital Santo Antonio dos Capuchos
đľđšLisboa, Portugal
Centro Hospitalar do Porto, EPE
đľđšPorto, Portugal
GASTRO I. s.r.o.
đ¸đ°Presov, Slovakia
Centro Hospitalar de Sao Joao Epe
đľđšPorto, Portugal
FNsP F.D.R. Banska Bystrica
đ¸đ°Banska Bystrica, Slovakia
Gastroenterology Center ASSIDUO
đ¸đ°Bratislava, Slovakia
Gastroenterology Department GASTROMART s.r.o.
đ¸đ°Bardejov, Slovakia
University Hospital in Bratislava, St. Cyril and Method Hospital
đ¸đ°Bratislava, Slovakia
KM Management spol. s r.o.
đ¸đ°Nitra, Slovakia
Gastroenterology Department ENDOMED, s.r.o.
đ¸đ°Vranov nad Toplou, Slovakia
Hosp. Gral. Univ. de Alicante
đŞđ¸Alicante, Spain
Hosp. Univ. Germans Trias I Pujol
đŞđ¸Badalona, Spain
Hosp Clinic de Barcelona
đŞđ¸Barcelona, Spain
Hosp Reina Sofia
đŞđ¸CĂłrdoba, Spain
Hosp. Arquitecto Marcide
đŞđ¸El Ferrol, Spain
Hosp. Univ. de Bellvitge
đŞđ¸L'Hospitalet de Llobregat, Spain
Hosp. Univ. La Paz
đŞđ¸Madrid, Spain
Hosp. Univ. de La Princesa
đŞđ¸Madrid, Spain
Hosp. Gral. Univ. Gregorio Maranon
đŞđ¸Madrid, Spain
Hosp. de Manises
đŞđ¸Manises, Spain
Hosp. Virgen Del Rocio
đŞđ¸Sevilla, Spain
Hosp. Univ. Son Espases
đŞđ¸Palma de Mallorca, Spain
Hosp. Clinico Univ. de Valencia
đŞđ¸Valencia, Spain
Hosp. Univ. I Politecni La Fe
đŞđ¸Valencia, Spain
Medicinkliniken
đ¸đŞStockholm, Sweden
Hosp. Clinico Univ. Lozano Blesa
đŞđ¸Zaragoza, Spain
Skane University Hospital
đ¸đŞLund, Sweden
Karolinska University Hospital
đ¸đŞSolna, Sweden
Glasgow Royal Infirmary
đŹđ§Glasgow, United Kingdom
Royal London Hospital
đŹđ§London, United Kingdom
Danderyd Hospital
đ¸đŞStockholm, Sweden
Royal Victoria Hospital
đŹđ§Belfast, United Kingdom
County Durham and Darlington NHS Foundation Trust
đŹđ§Darlington, United Kingdom
St George's University Hospital NHS Foundation Trust
đŹđ§London, United Kingdom
Whiston Hospital
đŹđ§Prescot, United Kingdom
Ninewells Hospital
đŹđ§Dundee, United Kingdom
Guys St Thomas Hospital
đŹđ§London, United Kingdom
Kings College Hospital NHS Trust
đŹđ§London, United Kingdom
Salford Royal NHS Foundation Trust
đŹđ§Salford, United Kingdom
Southampton University Hospital
đŹđ§Southampton, United Kingdom
Musgrove Park Hospital
đŹđ§Taunton, United Kingdom