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Crohn Disease: HELP
Articles from Austria
Based on 106 articles published since 2008
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These are the 106 published articles about Crohn Disease that originated from Austria during 2008-2019.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
1 Review Cannabinoids for treating inflammatory bowel diseases: where are we and where do we go? 2017

Hasenoehrl, Carina / Storr, Martin / Schicho, Rudolf. ·a Institute of Experimental and Clinical Pharmacology , Medical University of Graz , Graz , Austria. · b Department of Medicine , Ludwig-Maximilians University , Munich , Germany. · c Zentrum für Endoskopie , Starnberg , Germany. ·Expert Rev Gastroenterol Hepatol · Pubmed #28276820.

ABSTRACT: INTRODUCTION: Fifty years after the discovery of Δ

2 Review Diet therapy for inflammatory bowel diseases: The established and the new. 2016

Durchschein, Franziska / Petritsch, Wolfgang / Hammer, Heinz F. ·Franziska Durchschein, Wolfgang Petritsch, Heinz F Hammer, Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria. ·World J Gastroenterol · Pubmed #26900283.

ABSTRACT: Although patients with inflammatory bowel diseases (IBD) have a strong interest in dietary modifications as part of their therapeutic management, dietary advice plays only a minor part in published guidelines. The scientific literature shows that dietary factors might influence the risk of developing IBD, that dysbiosis induced by nutrition contributes to the pathogenesis of IBD, and that diet may serve as a symptomatic treatment for irritable bowel syndrome-like symptoms in IBD. The role of nutrition in IBD is underscored by the effect of various dietary therapies. In paediatric patients with Crohn's disease (CD) enteral nutrition (EN) reaches remission rates similar to steroids. In adult patients, however, EN is inferior to corticosteroids. EN is not effective in ulcerative colitis (UC). Total parenteral nutrition in IBD is not superior to steroids or EN. The use of specific probiotics in patients with IBD can be recommended only in special clinical situations. There is no evidence for efficacy of probiotics in CD. By contrast, studies in UC have shown a beneficial effect in selected patients. For patients with pouchitis, antibiotic treatment followed by probiotics, like VSL#3 or Lactobacillus GG, is effective. When probiotics are used, the risk of bacterial translocation and subsequent bacteremia has to be considered. More understanding of the normal intestinal microflora, and better characterization of probiotic strains at the phenotypic and genomic levels is needed as well as clarification of the mechanisms of action in different clinical settings. A FODMAP reduced diet may improve symptoms in IBD.

3 Review Surgical recurrence in Crohn's disease: Are we getting better? 2015

Kristo, Ivan / Stift, Anton / Bergmann, Michael / Riss, Stefan. ·Ivan Kristo, Anton Stift, Michael Bergmann, Stefan Riss, Department of Surgery, Medical University of Vienna, A-1090 Vienna, Austria. ·World J Gastroenterol · Pubmed #26034346.

ABSTRACT: Crohn's disease (CD) still remains a challenging chronic inflammatory disorder, both for colorectal surgeons and gastroenterologists. The need for recurrent surgery following primary intestinal resection is still considerable, though recent evidence suggested a declining rate of recurrence. Several conflicting surgical parameters have been identified that might impact on the postoperative outcome positively, such as access to the abdomen, anastomotic configuration or type of disease. Additionally, promising results have been achieved with the increased use of immunosuppressive medications in CD. Consequently, the question arises if we are getting better as a result of novel medical and surgical strategies.

4 Review Is laparoscopic ileocecal resection a safe option for Crohn's disease? Best evidence topic. 2014

Antoniou, Stavros A / Antoniou, George A / Koch, Oliver O / Pointner, Rudolph / Granderath, Frank A. ·Center for Minimally Invasive Surgery, Hospital Neuwerk, Dünner Str. 214-216, 41066 Mönchengladbach, Germany; Department of General Surgery, University General Hospital of Heraklion, Panepistimiou Ave., 71500 Heraklion, Crete, Greece. Electronic address: stavros.antoniou@hotmail.com. · Department of Vascular Surgery, Red Cross Hospital, Athanasaki 1 & Erythrou Stavrou, Ampelokipi, 11526 Athens, Greece. · Department of General and Visceral Surgery, Sisters of Charity Hospital, Seilerstätte 4, 4010 Linz, Austria. · Department of General and Visceral Surgery, Hospital Zell am See, Paracelsusstr. 8, 5700 Zell am See, Austria. · Center for Minimally Invasive Surgery, Hospital Neuwerk, Dünner Str. 214-216, 41066 Mönchengladbach, Germany. ·Int J Surg · Pubmed #24246171.

ABSTRACT: A best evidence topic was constructed according to a structured protocol. The question addressed was whether laparoscopic ileocecal resection for Crohn's disease is associated with higher morbidity rates in comparison to open surgery. From a total of 123 articles, 11 studies provided the best available evidence on this topic. Five observational studies, two randomized trials, three follow up studies and a meta-analysis were identified. The primary author, date and country of publication, study type, patient group characteristics, relevant outcome parameters and results of these papers were tabulated. Perioperative morbidity was either similar between the laparoscopic and the open group, or favored the laparoscopic approach. Convalescence was consistently reported to be shorter in the laparoscopic treatment arm, at cost of longer duration of surgery. Limited evidence suggests lower incidence of small bowel obstruction and disease recurrence for laparoscopy, although follow up data are of poor quality. It may be concluded that laparoscopic ileocecal resection is a safe alternative approach to open surgery for uncomplicated Crohn's disease, provided laparoscopic expertise is available.

5 Review Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I). 2014

Sebastian, Shaji / Hernández, Vincent / Myrelid, Pär / Kariv, Revital / Tsianos, Epameinondas / Toruner, Murat / Marti-Gallostra, Marc / Spinelli, Antonino / van der Meulen-de Jong, Andrea E / Yuksel, Elif Sarıtas / Gasche, Christoph / Ardizzone, Sandro / Danese, Silvio. ·Hull & East Yorkshire Hospitals NHS Trust, Hull York Medical School, Hull, United Kingdom. Electronic address: Shaji.Sebastian@hey.nhs.uk. · Gastroenterology Department, Complexo Hospitalario Universitario de Vigo, Vigo, Spain. · Division of Surgery, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, County Council of Östergötland, Linköping, Sweden. · Service for Gastrointestinal Malignancies, Department of Gastroenterology & Liver Disease, Tel Aviv Sourasky Medical Center, Israel. · University of Ioannina, 1st Division of Internal Medicine and Hepato-Gastroenterology Unit, Greece. · Ankara University Medical School, Ibni Sina Hospital, Division of Gastroenterology, Ankara, Turkey. · Department of Colorectal Surgery, University Hospital of Valle de Hebron, Barcelona, Spain. · Dipartimento e Cattedra di Chirurgia Generale, Istituto Clinico Humanitas IRCCS, Università degli Studi di Milano, Rozzano, Milano, Italy. · Leiden University Medical Center, Department of Gastroenterology, Leiden, The Netherlands. · Department of Gastroenterology, Katip Celebi University, Ataturk Research and Teaching Hospital, Izmir, Turkey. · Christian Doppler Laboratory on Molecular Cancer Chemoprevention, Division of Gastroenterology, Medical University of Vienna, Vienna, Austria. · Chair of Gastroenterology, "L. Sacco" University Hospital, Milan, Italy. · Department of Gastroenterology, Istituto Clinico Humanitas, Milan, Italy. Electronic address: sdanese@hotmail.com. ·J Crohns Colitis · Pubmed #23664897.

ABSTRACT: Epidemiological studies demonstrate an increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). A detailed literature review was conducted on epidemiology, risk factors, pathophysiology, chemoprevention and outcomes of colorectal cancer (CRC) in IBD as part of the 3rd ECCO scientific pathogenesis workshop.

6 Review Health determining concepts important to people with Crohn's disease and their coverage by patient-reported outcomes of health and wellbeing. 2014

Dür, Mona / Sadloňová, Martina / Haider, Stefanie / Binder, Alexa / Stoffer, Michaela / Coenen, Michaela / Smolen, Josef / Dejaco, Clemens / Kautzky-Willer, Alexandra / Fialka-Moser, Veronika / Moser, Gabriele / Stamm, Tanja Alexandra. ·Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Electronic address: mona.duer@meduniwien.ac.at. · Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Electronic address: martina.sadlonova@meduniwien.ac.at. · Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Electronic address: stefanie.haider@meduniwien.ac.at. · Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Electronic address: alexa.binder@meduniwien.ac.at. · Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Electronic address: michaela.stoffer@meduniwien.ac.at. · Institute for Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany. Electronic address: michaela.coenen@med.uni-muenchen.de. · Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Electronic address: josef.smolen@wienkav.at. · Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria. Electronic address: clemens.dejaco@meduniwien.ac.at. · Department of Internal Medicine III, Division of Diabetology, Medical University of Vienna, Austria. Electronic address: alexandra.kautzky-willer@meduniwien.ac.at. · Department of Physical Medicine and Rehabilitation, Medical University of Vienna, Austria. Electronic address: pmr-office@meduniwien.ac.at. · Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria. Electronic address: gabriele.moser@meduniwien.ac.at. · Department of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Austria. Electronic address: Tanja.stamm@meduniwien.ac.at. ·J Crohns Colitis · Pubmed #23375212.

ABSTRACT: BACKGROUND AND AIMS: Busy clinical settings often restrict the possibility to focus on concepts that determine health in a positive way, commonly assessed by using patient-reported outcomes (PROs). We aimed to explore which determinants of health (DHs) are important to people with Crohn's disease (CD), to understand possible gender differences and to analyze whether these DHs are covered by PROs used in CD. METHODS: Two systematic literature reviews were done to identify relevant DHs and clinically relevant PROs. We conducted a qualitative narrative biographical study and mapped the patients' experiences to concepts that determine health in a positive way. Experiences, DHs and the items of the PROs were compared by the WHO International Classification of Functioning, Disability and Health (ICF) as a common framework. RESULTS: 15 people with CD with a median age of 46 years (IQR 34-60) and median disease duration of 15 years (IQR 8-30) participated. Self-efficacy, social support, job satisfaction and occupational balance were mentioned most frequently. While participation appeared to have greater meaning to men, appreciation and resilience seemed to be more important for women. Of 18 PROs the Perceived Stress Questionnaire (PSQ), the Inflammatory Bowel disease - Self-efficacy scale (IBD-SES), the Life Orientation Test - Revised (LOT-R) and the Patient Activation Measure 13 (PAM-13) cover most DHs. CONCLUSIONS: This is the first study elaborating the coverage of patient's perspective by commonly used PROs in CD. The findings could support health professionals to focus on DHs in people with CD in clinical practice and research.

7 Review Optimising monitoring in the management of Crohn's disease: a physician's perspective. 2013

Papay, Pavol / Ignjatovic, Ana / Karmiris, Konstantinos / Amarante, Heda / Milheller, Pal / Feagan, Brian / D'Haens, Geert / Marteau, Philippe / Reinisch, Walter / Sturm, Andreas / Steinwurz, Flavio / Egan, Laurence / Panés, Julián / Louis, Edouard / Colombel, Jean-Frédéric / Panaccione, Remo. ·Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University Vienna, Vienna, Austria. ·J Crohns Colitis · Pubmed #23562672.

ABSTRACT: Management of Crohn's disease has traditionally placed high value on subjective symptom assessment; however, it is increasingly appreciated that patient symptoms and objective parameters of inflammation can be disconnected. Therefore, strategies that objectively monitor inflammatory activity should be utilised throughout the disease course to optimise patient management. Initially, a thorough assessment of the severity, location and extent of disease is needed to ensure a correct diagnosis, identify any complications, help assess prognosis and select appropriate therapy. During follow-up, clinical decision-making should be driven by disease activity monitoring, with the aim of optimising treatment for tight disease control. However, few data exist to guide the choice of monitoring tools and the frequency of their use. Furthermore, adaption of monitoring strategies for symptomatic, asymptomatic and post-operative patients has not been well defined. The Annual excHangE on the ADvances in Inflammatory Bowel Disease (IBD Ahead) 2011 educational programme, which included approximately 600 gastroenterologists from 36 countries, has developed practice recommendations for the optimal monitoring of Crohn's disease based on evidence and/or expert opinion. These recommendations address the need to incorporate different modalities of disease assessment (symptom and endoscopic assessment, measurement of biomarkers of inflammatory activity and cross-sectional imaging) into robust monitoring. Furthermore, the importance of measuring and recording parameters in a standardised fashion to enable longitudinal evaluation of disease activity is highlighted.

8 Review Enterolithiasis-associated ileus in Crohn's disease. 2012

Perathoner, Alexander / Kogler, Pamela / Denecke, Christian / Pratschke, Johann / Kafka-Ritsch, Reinhold / Zitt, Matthias. ·Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, Medical University of Innsbruck, 6020 Innsbruck, Austria. alexander.perathoner@uki.at ·World J Gastroenterol · Pubmed #23155347.

ABSTRACT: Stasis of the flow of the intestinal contents, ingested material and unfavorable composition of the chylus can lead to the formation of enteroliths inside the bowel. Enterolithiasis represents a rare disorder of the gastrointestinal tract that can be associated with intermittent abdominal pain or more serious complications such as bleeding or obstruction. Enterolithiasis in Crohn's disease represents an extremely rare condition and usually occurs only in patients with a long symptomatic history of Crohn's disease. We report an unusual case of enterolithiasis-related intestinal obstruction in a young male patient with Crohn's disease (A2L3B1 Montreal Classification for Crohn's disease 2005) undergoing emergency laparotomy and ileocoecal resection. In addition, we present an overview of the relevant characteristics of enterolithiasis on the basis of the corresponding literature.

9 Review Aminosalicylates. 2011

Campregher, Christoph / Gasche, Christoph. ·Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Waehringer Guertel 18-20, Vienna, Austria. ·Best Pract Res Clin Gastroenterol · Pubmed #22122769.

ABSTRACT: Aminosalicylates are the most common drugs for the primary treatment of inflammatory bowel disease. Various pro-drugs and formulations were developed in order to improve pharmacological profiles, optimize bioavailability and to gain highest efficacy in the treatment of ulcerative colitis (UC) and Crohn's disease. In vitro studies have greatly contributed to the understanding of the molecular actions in vivo and clinical studies have proven aminosalicylates to be effective and safe. This review summarizes the current knowledge on the molecular, pharmacological and clinical properties of aminosalicylates with respect to chemoprevention for UC-associated colorectal cancer.

10 Review Safety of anti-tumour necrosis factor agents in patients with chronic hepatitis C infection: a systematic review. 2011

Brunasso, Alexandra M G / Puntoni, Matteo / Gulia, Andrea / Massone, Cesare. ·Department of Environmental Dermatology and Venereology, Medical University of Graz, Auenbruggerplatz 8, A-8036 Graz, Austria. giovanna.brunasso@gmail.com ·Rheumatology (Oxford) · Pubmed #21690185.

ABSTRACT: OBJECTIVES: To identify all of the patients affected by chronic hepatitis C infection treated with TNF-α blockers (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab) in order to evaluate the safety profile. METHODS: A systematic review of the literature from January 1990 to October 2010. RESULTS: In total, 37 publications with data on 153 patients who were treated with anti-TNF-α agents in the setting of HCV infection were found. The mean anti-TNF-α treatment duration was 11.9 months. Ninety-one patients had RA, 22 had psoriasis, 6 had Crohn's disease and 14 patients had other chronic inflammatory diseases. To date, etanercept is the biological agent that has been most extensively used in the patients with HCV infection, with only one definitely confirmed case of HCV hepatitis worsening and five suspected cases (elevation of transaminases not associated with an increase in the HCV viral load and vice versa) in 110 treated patients. Treatment with this agent resulted in stable levels of liver transaminases and a stable viral load in 74 patients, with an improvement in HCV chronic liver disease in combination with IFN-ribavirin therapy in 29 patients. CONCLUSIONS: The safety profile of anti-TNF-α agents in the setting of HCV infection seems to be acceptable, even if differences in the hepatotoxic profile are apparent between different agents. In the absence of long-term and large, controlled clinical trials a definitive statement on the safety of anti-TNF-α therapies in the setting of chronic HCV infection cannot be made.

11 Review Crohn's disease: NOD2, autophagy and ER stress converge. 2011

Fritz, Teresa / Niederreiter, Lukas / Adolph, Timon / Blumberg, Richard S / Kaser, Arthur. ·Department of Medicine II, Anichstr 35, A-6020 Innsbruck, Austria. ·Gut · Pubmed #21252204.

ABSTRACT: Polymorphisms in NOD2, encoding an intracellular pattern recognition receptor, contribute the largest fraction of genetic risk for Crohn's disease among the >40 risk loci identified so far. Autophagy plays a prominent role in the innate immune response towards intracellular bacteria. The discovery of the autophagy genes ATG16L1 and IRGM as risk factors for Crohn's disease turned autophagy into the spotlight in inflammatory bowel disease (IBD). Remarkably, NOD2 has recently been identified as a potent autophagy inducer. A physical interaction of NOD2 and ATG16L1 appears to be required for autophagic clearance of intracellular pathogens. Moreover, Crohn's disease-associated NOD2 and ATG16L1 variants exhibit a defect in the induction of an autophagic response and hence predict autophagy as a key converging mechanism that leads to Crohn's disease. Another pathway that is closely intertwined with autophagy and mutually cross-regulated is the unfolded protein response (UPR), which is induced by endoplasmic reticulum (ER) stress. Genes involved in the UPR (XBP1, ORMDL3) have also been genetically associated with Crohn's disease and ulcerative colitis. Moreover, the intestinal epithelium at the interface between host and microbe appears particularly affected by IBD-associated hypomorphic function of autophagy and the UPR. The functional convergence of main genetic risk factors for IBD on these innate immune pathways has hence important implications for the host's interaction with the microbiota. Moreover, the genetic convergence on these molecular mechanisms may open novel therapeutic options for IBD that deserve further exploration.

12 Review [Conventional colonoscopy]. 2008

Häfner, M. ·Klinische Abteilung für Gastroenterologie und Hepatologie, Universitätsklinik für Innere Medizin III, Währinger Gürtel 18-20, A-1090, Wien, Osterreich. michael.haefner@meduniwien.ac.at ·Radiologe · Pubmed #18210059.

ABSTRACT: In the last 40 years colonoscopy has been the gold standard in diagnosis of conditions affecting the large intestine. We see its main disadvantages in the necessity for intestinal preparation and in the pain not infrequently experienced by patients who are not sedated. Widespread use of sedation has made it possible to improve patient acceptance in recent years. Complications of colonoscopy are rare, and even the removal of large polyps is regarded as a safe procedure. One of the main problems of colonoscopy is that a large number of far from trivial polyps--up to 20% in the literature--are overlooked. New developments, such as higher resolution videochips and chromoendoscopy, lead to a better diagnostic yield, especially of flat lesions. The rapidly developing sector of interventional colonoscopy in particular will ensure that colonoscopy continues to have an important place in the management of illnesses affecting the large intestine.

13 Clinical Trial Long-term Efficacy and Safety of Stem Cell Therapy (Cx601) for Complex Perianal Fistulas in Patients With Crohn's Disease. 2018

Panés, Julián / García-Olmo, Damián / Van Assche, Gert / Colombel, Jean Frederic / Reinisch, Walter / Baumgart, Daniel C / Dignass, Axel / Nachury, Maria / Ferrante, Marc / Kazemi-Shirazi, Lili / Grimaud, Jean C / de la Portilla, Fernando / Goldin, Eran / Richard, Marie Paule / Diez, Mary Carmen / Tagarro, Ignacio / Leselbaum, Anne / Danese, Silvio / Anonymous5150931. ·Department of Gastroenterology, Hospital Clínic, IDIBAPS, CIBERehd, Barcelona, Spain. Electronic address: jpanes@clinic.cat. · Department of Surgery, Hospital U. Fundación Jiménez Díaz, Madrid, Spain. · Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. · Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York. · Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; McMaster University, Hamilton, Ontario, Canada. · Department of Gastroenterology and Hepatology, Charité Medical School - Humboldt-University of Berlin, Berlin, Germany. · Department of Medicine I, Agaplesion Markus Hospital, Frankfurt, Germany. · Department of Gastroenterology and Hepatology, CHU Lille, Lille, France. · Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria. · Department of Hepato-Gastroenterology, Hôpital Nord, Marseille, France. · Department of Surgery, Unit of Coloproctology, University Virgen del Rocio Hospital/IBiS/CSIC/University of Seville, Seville, Spain. · Digestive Diseases Institute, Sharee Zedek MC, Jerusalem, Israel. · TiGenix, Parque Tecnológico de Madrid, Madrid, Spain. · TiGenix, Parque Tecnológico de Madrid, Madrid, Spain; CDD-Clinical Drug Development, S.L., Barcelona, Spain. · Department of Gastroenterology, Istituto Clinico Humanitas IRCCS, Milano, Italy. ·Gastroenterology · Pubmed #29277560.

ABSTRACT: BACKGROUND & AIMS: Therapies for perianal fistulas in patients with Crohn's disease are often ineffective in producing long-term healing. We performed a randomized placebo-controlled trial to determine the long-term efficacy and safety of a single local administration of allogeneic expanded adipose-derived stem cells (Cx601) in patients with Crohn's disease and perianal fistulas. METHODS: We performed a double-blind study at 49 hospitals in Europe and Israel, comprising 212 patients with Crohn's disease and treatment-refractory, draining, complex perianal fistulas. Patients were randomly assigned (1:1) to groups given a single local injection of 120 million Cx601 cells or placebo (control), in addition to the standard of care. Efficacy endpoints evaluated in the modified intention-to-treat population (randomly assigned, treated, and with 1 or more post-baseline efficacy assessment) at week 52 included combined remission (closure of all treated external openings draining at baseline with absence of collections >2 cm, confirmed by magnetic resonance imaging) and clinical remission (absence of draining fistulas). RESULTS: The study's primary endpoint, at week 24, was previously reported (combined remission in 51.5% of patients given Cx601 vs 35.6% of controls, for a difference of 15.8 percentage points; 97.5% confidence interval [CI] 0.5-31.2; P = .021). At week 52, a significantly greater proportion of patients given Cx601 achieved combined remission (56.3%) vs controls (38.6%) (a difference of 17.7 percentage points; 95% CI 4.2-31.2; P = .010), and clinical remission (59.2% vs 41.6% of controls, for a difference of 17.6 percentage points; 95% CI 4.1-31.1; P = .013). Safety was maintained throughout week 52; adverse events occurred in 76.7% of patients in the Cx601 group and 72.5% of patients in the control group. CONCLUSION: In a phase 3 trial of patients with Crohn's disease and treatment-refractory complex perianal fistulas, we found Cx601 to be safe and effective in closing external openings, compared with placebo, after 1 year. ClinicalTrials.gov no: NCT01541579.

14 Clinical Trial Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial. 2018

Colombel, Jean-Frederic / Panaccione, Remo / Bossuyt, Peter / Lukas, Milan / Baert, Filip / Vaňásek, Tomas / Danalioglu, Ahmet / Novacek, Gottfried / Armuzzi, Alessandro / Hébuterne, Xavier / Travis, Simon / Danese, Silvio / Reinisch, Walter / Sandborn, William J / Rutgeerts, Paul / Hommes, Daniel / Schreiber, Stefan / Neimark, Ezequiel / Huang, Bidan / Zhou, Qian / Mendez, Paloma / Petersson, Joel / Wallace, Kori / Robinson, Anne M / Thakkar, Roopal B / D'Haens, Geert. ·Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: jean-frederic.colombel@mssm.edu. · Inflammatory Bowel Disease Unit, Department of Medicine, University of Calgary, Calgary, AB, Canada. · Imelda General Hospital, Bonheiden, Belgium. · Clinical and Research Centre for Inflammatory Bowel Disease, ISCARE Clinical Centre, Prague, Czech Republic; First Medical Faculty, Charles University, Prague, Czech Republic. · AZ Delta, Roeselare-Menen, Belgium. · Hepato-Gastroenterologie HK, sro, Hradec Králové, Czech Republic. · Department of Gastroenterology, Bezmialem Vakif University, Istanbul, Turkey. · Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Presidio Columbus, Fondazione Policlinico Gemelli Università Cattolica, Rome, Italy. · Service de Gastro-entérologie et Nutrition Clinique, Nice, France; Université de Nice-Sophia-Antipolis, Nice, France. · Oxford University Hospitals, Oxford, UK. · Department of Biomedical Sciences, Humanitas University, Milan, Italy; Humanitas Clinical and Research Centre, Milan, Italy. · Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA, USA. · Department of Gastroenterology, University of Leuven, Leuven, Belgium. · Department of Medicine, University of California, Los Angeles, CA, USA. · Department of Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany. · AbbVie Inc, North Chicago, IL, USA. · AbbVie Spain SLU, Madrid, Spain. · Academic Medical Center, Amsterdam, Netherlands. ·Lancet · Pubmed #29096949.

ABSTRACT: BACKGROUND: Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. METHODS: CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. FINDINGS: Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9-28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. INTERPRETATION: CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. FUNDING: AbbVie.

15 Clinical Trial Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study. 2018

Sandborn, William J / Lee, Scott D / Tarabar, Dino / Louis, Edouard / Klopocka, Maria / Klaus, Jochen / Reinisch, Walter / Hébuterne, Xavier / Park, Dong-Il / Schreiber, Stefan / Nayak, Satyaprakash / Ahmad, Alaa / Banerjee, Anindita / Brown, Lisa S / Cataldi, Fabio / Gorelick, Kenneth J / Cheng, John B / Hassan-Zahraee, Mina / Clare, Robert / D'Haens, Geert R. ·Department of Medicine, Division of Gastroenterology, University of California San Diego, La Jolla, California, USA. · Department of Medicine, Division of Gastroenterology, University of Washington, Seattle, Washington, USA. · Clinic of Gastroenterology and Hepatology, Military Medical Academy, Belgrade, Serbia. · Department of Gastroenterology, University Hospital CHU of Liege, Liège, Belgium. · Department of Vascular Diseases and Internal Medicine, Nicolaus Copernicus University, Toruń, Collegium Medicum in Bydgoszcz, Poland. · Department of Medicine, Universitatsklinikum Ulm, Ulm, Germany. · Department of Medicine, Division of Gastroenterology, Medical University of Vienna, Vienna, Austria. · Division of Gastroenterology, Department of Medicine, McMaster University, Hamilton, Canada. · Department of Medicine, Université de Nice Sophia Antipolis, Hôpital de l'Archet, Nice, France. · Department of Internal Medicine, Division of Gastroenterology, Kangbuk Samsung Hospital, Sungkyunkwan University, Seoul, South Korea. · Department of Medicine, University of Kiel, Kiel, Germany. · Department of Gastroenterology, Pfizer, Cambridge, Massachusetts, USA. · IBD Unit, Academic Medical Center, Amsterdam, The Netherlands. ·Gut · Pubmed #28982740.

ABSTRACT: OBJECTIVE: This phase II, randomised, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of PF-00547659, a fully human monoclonal antibody that binds to human mucosal addressin cell adhesion molecule (MAdCAM) to selectively reduce lymphocyte homing to the intestinal tract, in patients with moderate-to-severe Crohn's disease (CD). DESIGN: Eligible adults were aged 18-75 years, with active moderate-to-severe CD (Crohn's Disease Activity Index (CDAI) 220-450), a history of failure or intolerance to antitumour necrosis factor and/or immunosuppressive agents, high-sensitivity C reactive protein >3.0 mg/L and ulcers on colonoscopy. Patients were randomised to PF-00547659 22.5 mg, 75 mg or 225 mg or placebo. The primary endpoint was CDAI 70-point decrease from baseline (CDAI-70) at week 8 or 12. RESULTS: In all, 265 patients were eligible for study entry. Although CDAI-70 response was not significantly different with placebo versus PF-00547659 treatment at weeks 8 or 12, remission rate was greater in patients with higher baseline C reactive protein (>5 mg/L vs >18.8 mg/L, respectively). Soluble MAdCAM decreased significantly from baseline to week 2 in a dose-related manner and remained low during the study in PF-00547659-treated patients. Circulating β CONCLUSIONS: Clinical endpoint differences between PF-00547659 and placebo did not reach statistical significance in patients with moderate-to-severe CD. PF-00547659 was pharmacologically active, as shown by a sustained dose-related decrease in soluble MAdCAM and a dose-related increase in circulating β TRIAL REGISTRATION NUMBER: NCT01276509; Results.

16 Clinical Trial Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study. 2017

Feagan, Brian G / Sandborn, William J / D'Haens, Geert / Panés, Julián / Kaser, Arthur / Ferrante, Marc / Louis, Edouard / Franchimont, Denis / Dewit, Olivier / Seidler, Ursula / Kim, Kyung-Jo / Neurath, Markus F / Schreiber, Stefan / Scholl, Paul / Pamulapati, Chandrasena / Lalovic, Bojan / Visvanathan, Sudha / Padula, Steven J / Herichova, Ivona / Soaita, Adina / Hall, David B / Böcher, Wulf O. ·Western University, Robarts Clinical Trials, London, ON, Canada. Electronic address: brian.feagan@robartsinc.com. · IBD Center, University of California San Diego and UC San Diego Health System, San Diego, CA, USA. · Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands. · Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. · University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. · University Hospitals Leuven, Leuven, Belgium. · University Hospital CHU Liège, Liège, Belgium. · Erasme University Hospital, Brussels, Belgium. · Cliniques Universitaires Saint-Luc, Brussels, Belgium. · Hannover Medical School, Hannover, Germany. · Asan Medical Center, Seoul, South Korea. · University of Erlangen-Nürnberg, Erlangen, Germany. · Christian-Albrechts-University Kiel, Kiel, Germany. · Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA. · Boehringer Ingelheim Pharma GmbH, Ingelheim, Germany. · Boehringer Ingelheim RCV GmbH, Vienna, Austria. ·Lancet · Pubmed #28411872.

ABSTRACT: BACKGROUND: The interleukin-23 pathway is implicated genetically and biologically in the pathogenesis of Crohn's disease. We aimed to assess the efficacy and safety of risankizumab (BI 655066, Boehringer Ingelheim, Ingelheim, Germany), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23, in patients with moderately-to-severely active Crohn's disease. METHODS: In this randomised, double-blind, placebo-controlled phase 2 study, we enrolled patients at 36 referral sites in North America, Europe, and southeast Asia. Eligible patients were aged 18-75 years, with a diagnosis of Crohn's disease for at least 3 months, assessed as moderate-to-severe Crohn's disease at screening, defined as a Crohn's Disease Activity Index (CDAI) of 220-450, with mucosal ulcers in the ileum or colon, or both, and a Crohn's Disease Endoscopic Index of Severity (CDEIS) of at least 7 (≥4 for patients with isolated ileitis) on ileocolonoscopy scored by a masked central reader. Patients were randomised 1:1:1 using an interactive response system to a double-blind investigational product, and stratified by previous exposure to TNF antagonists (yes vs no). Patients received intravenous 200 mg risankizumab, 600 mg risankizumab, or placebo, at weeks 0, 4, and 8. The primary outcome was clinical remission (CDAI <150) at week 12 (intention-to-treat population). Safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02031276. FINDINGS: Between March, 2014, and September, 2015, 213 patients were screened, and 121 patients randomised. At baseline, 113 patients (93%) had been previously treated with at least one tumour necrosis factor (TNF) antagonist (which had failed in 96 [79%]). At week 12, 25 (31%) of 82 risankizumab patients (pooled 41 patients in 200 mg and 41 patients in 600 mg arms) had clinical remission versus six (15%) of 39 placebo patients (difference vs placebo 15·0%, 95% CI 0·1 to 30·1; p=0·0489). Ten (24%) of 41 patients who received 200 mg risankizumab had clinical remission (9·0%, -8·3 to 26·2; p=0·31) and 15 (37%) of 41 who received the 600 mg dose (20·9%, 2·6 to 39·2; p=0·0252). 95 (79%) patients had adverse events (32 in the placebo group, 32 randomised to 200 mg risankizumab, 31 randomised to 600 mg risankizumab); 18 had severe adverse events (nine, six, three); 12 discontinued (six, five, one); 24 had serious adverse events (12, nine, three). The most common adverse event was nausea and most common serious adverse event was worsening of underlying Crohn's disease. No deaths occurred. INTERPRETATION: In this short-term study, risankizumab was more effective than placebo for inducing clinical remission in patients with active Crohn's disease. Therefore, selective blockade of interleukin-23 via inhibition of p19 might be a viable therapeutic approach in Crohn's disease. FUNDING: Boehringer Ingelheim.

17 Clinical Trial A Randomised, Double-blind, Placebo-controlled Trial of Trichuris suis ova in Active Crohn's Disease. 2017

Schölmerich, Jürgen / Fellermann, Klaus / Seibold, Frank W / Rogler, Gerhard / Langhorst, Jost / Howaldt, Stefanie / Novacek, Gottfried / Petersen, Andreas Munk / Bachmann, Oliver / Matthes, Harald / Hesselbarth, Norbert / Teich, Niels / Wehkamp, Jan / Klaus, Jochen / Ott, Claudia / Dilger, Karin / Greinwald, Roland / Mueller, Ralph / Anonymous9870883. ·Klinikum der Johann Wolfgang Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany. · UK-SH Campus Lübeck, Abt. Gastroenterologie, Lübeck, Germany. · Spital Netz Bern Tiefenau, Abt. Gastroenterologie, Bern, Switzerland. · University of Zurich, Division of Gastroenterology and Hepatology, Zurich, Switzerland. · Kliniken Essen-Mitte, University of Duisburg-Essen, Integrative Gastroenterologie, Essen, Germany. · Hamburgisches Forschungsinstitut für CED, HaFCED GmbH&Co.KG, Hamburg, Germany. · Medizinische Universität Wien, Universitätsklinik für Innere Medizin III, Vienna, Austria. · Hvidovre University Hospital, Department of Gastroenterology and Department of Clinical Microbiology, Hvidovre, Denmark. · Medizinische Hochschule Hannover, Hannover, Germany. · Gemeinschaftskrankenhaus Havelhöhe, Abt. Gastroenterologie, Berlin, Germany. · Ärztehaus am Klinikum, Schwalmstadt, Germany. · Internistische Gemeinschaftspraxis für Verdauungs- und Stoffwechselkrankheiten Leipzig & Schkeuditz, Leipzig, Germany. · Robert-Bosch-Krankenhaus, Abt. Innere Medizin I, Stuttgart, Germany. · Universitätsklinikum Ulm, Klinik für Innere Medizin I, Ulm, Germany. · University Hospital of Regensburg, Dept. of Internal Medicine I, Regensburg, Germany. · Dr Falk Pharma GmbH, Freiburg, Germany. ·J Crohns Colitis · Pubmed #27707789.

ABSTRACT: Background and Aims: To investigate the efficacy and safety of three different dosages of embryonated, viable eggs of Trichuris suis [TSO] versus placebo for induction of remission in mildly-to-moderately active ileocolonic, uncomplicated Crohn's disease [CD]. Methods: Adults with active CD [n = 252] randomly received six fortnightly doses of 250, 2500, or 7500 TSO/15 ml suspension/day [TSO 250, TSO 2500, TSO 7500], or 15 ml placebo solution/day, in a double-blind fashion, with 4 weeks' follow-up. Primary endpoint was the rate of clinical remission [Crohn's Disease Activity Index [CDAI] < 150] at end of treatment, ie at Week 12 or withdrawal. Secondary endpoints included the course of clinical remission, rate of clinical response, change in CDAI, change in markers of inflammation, mucosal healing, and Physician's Global Assessment. Results: Clinical remission at Week 12 occurred in 38.5%, 35.2%, and 47.2% of TSO 250, TSO 2500, and TSO 7500 patients, respectively, and in 42.9% of placebo recipients. TSO induced a dose-dependent immunological response. There was no response regarding laboratory markers of inflammation. Other secondary efficacy variables also showed no advantage of TSO over placebo for treatment of active CD. Administration of TSO did not result in any serious adverse drug reaction. Review of non-serious suspected adverse drug reactions following TSO did not reveal any safety concerns. Conclusions: Administration of 250-7500 TSO fortnightly over 12 weeks was safe and showed a dose-dependent immunological response, but no TSO dose showed a clinically relevant effect over placebo for induction of clinical remission or response in mildly-to-moderately active, ileocolonic CD.

18 Clinical Trial Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial. 2016

Panés, Julián / García-Olmo, Damián / Van Assche, Gert / Colombel, Jean Frederic / Reinisch, Walter / Baumgart, Daniel C / Dignass, Axel / Nachury, Maria / Ferrante, Marc / Kazemi-Shirazi, Lili / Grimaud, Jean C / de la Portilla, Fernando / Goldin, Eran / Richard, Marie Paule / Leselbaum, Anne / Danese, Silvio / Anonymous8640876. ·Department of Gastroenterology, Hospital Clínic, IDIBAPS, Centro Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas, Barcelona, Spain. Electronic address: jpanes@clinic.ub.es. · Department of Surgery, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain. · Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium. · Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. · Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; Department of Internal Medicine, Division of Gastroenterology and Hepatology, McMaster University, Hamilton, ON, Canada. · Department of Gastroenterology and Hepatology, Charité Medical School-Humboldt-University of Berlin, Berlin, Germany. · Department of Medicine Klinik I, Agaplesion Markus Krankenhaus, Frankfurt, Germany. · Department of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Lille, Lille, France. · Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria. · Department of Hepato-Gastroenterology, Hôpital Nord, Marseille, France. · Department of Surgery, Unit of Coloproctology, University Virgen del Rocio Hospital, Centro Superior de Investigaciones, University of Seville, Seville, Spain. · Digestive Diseases Institute, Shaare Zedek Medical Center, Jerusalem, Israel. · TiGenix, Parque Tecnológico de Madrid, Madrid, Spain. · Humanitas University, IBD Center, Department of Gastroenterology, Instituto Clinico Humanitas, Rozzano, Milan, Italy. ·Lancet · Pubmed #27477896.

ABSTRACT: BACKGROUND: Complex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease. METHODS: We did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (≥18 years) with Crohn's disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1:1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579. FINDINGS: 212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15·2%, 97·5% CI 0·2-30·3; p=0·024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15·8%, 0·5-31·2; p=0·021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine). INTERPRETATION: Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both. FUNDING: TiGenix.

19 Clinical Trial High-resolution Quantitative Computed Tomography Demonstrates Structural Defects in Cortical and Trabecular Bone in IBD Patients. 2016

Haschka, Judith / Hirschmann, Simon / Kleyer, Arnd / Englbrecht, Matthias / Faustini, Francesca / Simon, David / Figueiredo, Camille P / Schuster, Louis / Muschitz, Christian / Kocijan, Roland / Resch, Heinrich / Atreya, Raja / Rech, Jürgen / Neurath, Markus F / Schett, Georg. ·Department of Internal Medicine 3, St Vincent Hospital, VINFORCE Study Group, Medical University of Vienna, Vienna, Austria. · Department of Internal Medicine 1, University of Erlangen-Nuremberg, Erlangen, Germany. · Department of Internal Medicine 3. · Department of Internal Medicine 3, Division of Rheumatology, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. · St Vincent Hospital, VINFORCE Study Group, Medical University of Vienna, Vienna, Austria. · Department of Internal Medicine 3, georg.schett@uk-erlangen.de. ·J Crohns Colitis · Pubmed #26818661.

ABSTRACT: BACKGROUND AND AIMS: To investigate the macro- and microstructural changes of bone in patients with inflammatory bowel disease [IBD] and to define the factors associated with bone loss in IBD. METHODS: A total of 148 subjects, 59 with Crohn's disease [CD], 39 with ulcerative colitis [UC], and 50 healthy controls were assessed for the geometric, volumetric and microstructural properties of bone using high-resolution peripheral quantitative computed tomography. In addition, demographic and disease-specific characteristics of IBD patients were recorded. RESULTS: IBD patients and controls were comparable in age, sex, and body mass index. Total [p = 0.001], cortical [p < 0.001], and trabecular volumetric bone mineral density [BMD] [p = 0.03] were significantly reduced in IBD patients compared with healthy controls. Geometric and microstructural analysis revealed significantly lower cortical area [p = 0.001] and cortical thickness [p < 0.001] without differences in cortical porosity, pore volume, or pore diameter. CD showed a more severe bone phenotype than UC: cortical bone loss was observed in both diseases, but CD additionally showed profound trabecular bone loss with reduced trabecular BMD [p = 0.008], bone volume [p = 0.008], and trabecular thickness [p = 0.009]. Multivariate regression models identified the diagnosis of CD, female sex, lower body mass index, and the lack of remission as factors independently associated with bone loss in IBD. CONCLUSION: IBD patients develop significant cortical bone loss, impairing bone strength. Trabecular bone loss is limited to CD patients, who exhibit a more severe bone phenotype compared with UC patients.

20 Clinical Trial Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohn's Disease: A Randomized Placebo-controlled, Double-blind, Phase IIa Study. 2015

Eser, Alexander / Colombel, Jean-Frederic / Rutgeerts, Paul / Vermeire, Severine / Vogelsang, Harald / Braddock, Martin / Persson, Tore / Reinisch, Walter. ·*Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; †Icahn School of Medicine at Mount Sinai, New York, New York; ‡Department of Gastroenterology, Catholic University of Leuven, Leuven, Belgium; §Respiratory Projects, Global Medicines Development, AstraZeneca R&D, Alderley Park, United Kingdom; and ‖AstraZeneca R&D Mölndal, Biometrics & Information Sciences, Mölndal, Sweden. ·Inflamm Bowel Dis · Pubmed #26197451.

ABSTRACT: BACKGROUND: AZD9056 is a selective orally active inhibitor of the purinergic receptor P2X7, which is a key player in the generation and secretion of several proinflammatory cytokines involved in the pathogenesis of Crohn's disease (CD). The aim of this phase IIa study was to assess the efficacy and safety of AZD9056 for the treatment of moderately to severely active CD. METHODS: We conducted a placebo-controlled, multicenter, double-blind phase IIa study in patients with moderately to severely active CD as defined by a CD Activity Index (CDAI) of at least 220. Patients were randomized in a 2:1 mode either to 200 mg of AZD9056 administered orally as a tablet once daily for 28 days or matching placebo. Primary endpoint was the change in CDAI from baseline at day 28, and secondary endpoints included clinical remission (CDAI < 150) and CDAI 70 response and improvement in the quality of life measures Short Form 36 and Inflammatory Bowel Disease Questionnaire. Changes in serum C-reactive protein and fecal calprotectin were assessed. RESULTS: In total, 34 patients were enrolled, 24 to AZD9056 and 10 to placebo. The CDAI dropped in AZD9056-treated subjects from a baseline mean of 311 to 242 and from 262 to 239 in placebo-treated subjects (P = 0.049). Remission and response rates were numerically higher with AZD9056 versus placebo, (n = 5, 24% versus n = 1, 11%, P = 0.43 and n = 11, 52% versus n = 2, 22%, P = 0.13, respectively). Marked decrease in disease activity was observed for the CDAI subcomponents, pain and general well-being. Apart from a statistically significant improvement in the Mental Component Score of Short Form 36 for AZD9056 versus placebo (P = 0.017), no other differences in measurements of quality of life could be observed. There was no decrease in concentrations of serum C-reactive protein and fecal calprotectin during treatment. AZD9056 was well-tolerated, and no serious adverse events were reported. CONCLUSIONS: Our data suggest that the purinergic receptor P2X7 antagonist AZD9056 has the potential to improve symptoms in patients with moderate-to-severe CD combined with a beneficial risk profile. Although the lack in change of inflammatory biomarkers questions its anti-inflammatory potential, the results obtained in this study rather suggest P2X7 antagonism for the treatment of chronic abdominal pain.

21 Clinical Trial Population pharmacokinetics-pharmacodynamics of vedolizumab in patients with ulcerative colitis and Crohn's disease. 2015

Rosario, M / Dirks, N L / Gastonguay, M R / Fasanmade, A A / Wyant, T / Parikh, A / Sandborn, W J / Feagan, B G / Reinisch, W / Fox, I. ·Takeda Pharmaceuticals International Co., Cambridge, MA, USA. · Metrum Research Group LLC, Tariffville, CT, USA. · Takeda Pharmaceuticals International, Inc., Deerfield, IL, USA. · Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Robarts Research Institute, University of Western Ontario, London, ON, Canada. · Department Internal Medicine III, Medical University of Vienna, Vienna, Austria. · Department of Internal Medicine, McMaster University, Hamilton, ON, Canada. ·Aliment Pharmacol Ther · Pubmed #25996351.

ABSTRACT: BACKGROUND: Vedolizumab, an anti-α(4)β(7) integrin monoclonal antibody (mAb), is indicated for treating patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD). As higher therapeutic mAb concentrations have been associated with greater efficacy in inflammatory bowel disease, understanding determinants of vedolizumab clearance may help to optimise dosing. AIMS: To characterise vedolizumab pharmacokinetics in patients with UC and CD, to identify clinically relevant determinants of vedolizumab clearance, and to describe the pharmacokinetic-pharmacodynamic relationship using population modelling. METHODS: Data from a phase 1 healthy volunteer study, a phase 2 UC study, and 3 phase 3 UC/CD studies were included. Population pharmacokinetic analysis for repeated measures was conducted using nonlinear mixed effects modelling. Results from the base model, developed using extensive phase 1 and 2 data, were used to develop the full covariate model, which was fit to sparse phase 3 data. RESULTS: Vedolizumab pharmacokinetics was described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half-life of vedolizumab was 25.5 days; linear clearance (CL(L)) was 0.159 L/day for UC and 0.155 L/day for CD; central compartment volume of distribution (V(c)) was 3.19 L; and peripheral compartment volume of distribution was 1.66 L. Interindividual variabilities (%CV) were 35% for CLL and 19% for V(c); residual variance was 24%. Only extreme albumin and body weight values were identified as potential clinically important predictors of CL(L). CONCLUSIONS: Population pharmacokinetic parameters were similar in patients with moderately to severely active UC and CD. This analysis supports use of vedolizumab fixed dosing in these patients. Clinicaltrials.gov Identifiers: NCT01177228; NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2); NCT01224171 (GEMINI 3).

22 Clinical Trial Ferric maltol is effective in correcting iron deficiency anemia in patients with inflammatory bowel disease: results from a phase-3 clinical trial program. 2015

Gasche, Christoph / Ahmad, Tariq / Tulassay, Zsolt / Baumgart, Daniel C / Bokemeyer, Bernd / Büning, Carsten / Howaldt, Stefanie / Stallmach, Andreas / Anonymous3060816. ·*Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria; †University of Exeter Medical School, Exeter, United Kingdom; ‡Department of Medicine, Semmelweis University of Medicine, Budapest, Hungary; §Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt-University of Berlin, Germany; ‖Gastroenterology Practice, Minden, Germany; ¶Department of Hepatology and Gastroenterology, Charite, University of Medicine, Berlin, Germany; **Division of Inflammatory Bowel Disease, Hamburg Institute of Research, Hamburg, Germany; and ††Department of Internal Medicine IV (Gastroenterology, Hepatology and Infectious Diseases), Jena University Hospital, Jena, Germany. ·Inflamm Bowel Dis · Pubmed #25545376.

ABSTRACT: BACKGROUND: Iron deficiency anemia (IDA) is frequently seen in inflammatory bowel disease. Traditionally, oral iron supplementation is linked to extensive gastrointestinal side effects and possible disease exacerbation. This multicenter phase-3 study tested the efficacy and safety of ferric maltol, a complex of ferric (Fe) iron with maltol (3-hydroxy-2-methyl-4-pyrone), as a novel oral iron therapy for IDA. METHODS: Adult patients with quiescent or mild-to-moderate ulcerative colitis or Crohn's disease, mild-to-moderate IDA (9.5-12.0 g/dL and 9.5-13.0 g/dL in females and males, respectively), and documented failure on previous oral ferrous products received oral ferric maltol capsules (30 mg twice a day) or identical placebo for 12 weeks according to a randomized, double-blind, placebo-controlled study design. The primary efficacy endpoint was change in hemoglobin (Hb) from baseline to week 12. Safety and tolerability were assessed. RESULTS: Of 329 patients screened, 128 received randomized therapy (64 ferric maltol-treated and 64 placebo-treated patients) and comprised the intent-to-treat efficacy analysis: 55 ferric maltol patients (86%) and 53 placebo patients (83%) completed the trial. Significant improvements in Hb were observed with ferric maltol versus placebo at weeks 4, 8, and 12: mean (SE) 1.04 (0.11) g/dL, 1.76 (0.15) g/dL, and 2.25 (0.19) g/dL, respectively (P < 0.0001 at all time-points; analysis of covariance). Hb was normalized in two-thirds of patients by week 12. The safety profile of ferric maltol was comparable with placebo, with no impact on inflammatory bowel disease severity. CONCLUSIONS: Ferric maltol provided rapid clinically meaningful improvements in Hb and showed a favorable safety profile, suggesting its possible use as an alternative to intravenous iron in IDA inflammatory bowel disease.

23 Clinical Trial AST-120 (spherical carbon adsorbent) in the treatment of perianal fistulae in mild-to-moderate Crohn's disease: FHAST-1, a phase 3, multicenter, placebo-controlled study. 2014

Reinisch, Walter / Travis, Simon / Hanauer, Stephen / Wang, Hong / Shara, Nawar / Harris, M Scott. ·*Medical University of Vienna, Vienna, Austria; †Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; ‡Northwestern University Feinberg School of Medicine, Chicago, Illinois; §Medstar Health Research Institute, Hyattsville, Maryland; ‖Georgetown University School of Medicine, Washington, District of Columbia; and ¶Ocera Therapeutics, San Diego, California. ·Inflamm Bowel Dis · Pubmed #24694794.

ABSTRACT: BACKGROUND: AST-120 (spherical carbon adsorbent) was previously reported to be effective for perianal fistula healing in Japanese patients with mild-to-moderate Crohn's disease. METHODS: To evaluate the efficacy and safety of AST-120 in a Western population, a phase 3, multicenter, randomized, double-blind, placebo-controlled, study (FHAST-1) was conducted in adult patients with at least 1 draining perianal fistula and a Crohn's disease activity index <400. Patients received either AST-120 or matching placebo at a dose of 2 g 3 times daily for 8 weeks. The primary endpoint was the proportion of patients with treatment success, defined as a 50% reduction in the number of draining fistulae, at both weeks 4 and 8. A multivariate model was generated to assess covariates for treatment success among baseline variables. RESULTS: Two hundred forty-nine patients were randomized (AST-120; n = 122; placebo, n = 127). The proportions of patients achieving the primary endpoint were no different between treatment groups (13.9% versus 16.5%, P = 0.6). No differences in fistula response were noted at week 4 (23.0% versus 25.2%, P = 0.77) or week 8 (27.0 versus 34.6%, P = 0.22). Serum C-reactive protein concentrations >0.6 mg/dL and Crohn's disease activity index scores >151 at baseline were associated with a reduced likelihood of treatment success (odds ratio, 0.40; confidence interval, 0.19-0.87; P = 0.02; and odds ratio, 0.45; confidence interval, 0.21-0.97; P = 0.04, respectively). CONCLUSIONS: In this largest placebo-controlled trial to date to evaluate the impact of a therapeutic agent on perianal fistulae in Crohn's disease, the efficacy of AST-120 could not be confirmed. An inverse relationship was observed between both inflammatory and clinical disease activity and fistula response.

24 Clinical Trial Extracorporeal photopheresis (ECP) in patients with steroid-dependent Crohn's disease: an open-label, multicenter, prospective trial. 2013

Reinisch, Walter / Knobler, Robert / Rutgeerts, Paul J / Ochsenkühn, Thomas / Anderson, Frank / von Tirpitz, Christian / Kaatz, Martin / Janneke van der Woude, C / Parenti, Dennis / Mannon, Peter J. ·Medical University of Vienna, Vienna, Austria. walter.reinisch@meduniwien.ac.at ·Inflamm Bowel Dis · Pubmed #22573600.

ABSTRACT: BACKGROUND: Extracorporeal photopheresis (ECP) involves ex vivo leukocyte treatment with methoxsalen and UVA light to generate a tolerogenic response. A previous trial demonstrated that ECP permits corticosteroid withdrawal in steroid-dependent Crohn's disease (CD) patients who were in clinical remission. We studied the effect of ECP on steroid withdrawal in steroid-dependent CD. METHODS: Patients with CD for ≥ 6 months, in remission at baseline while on steroids, but who had failed at ≥ 1 steroid withdrawal were included. Patients received two ECP treatments every 2 weeks for the 24-week steroid tapering period and underwent steroid-tapering. Patients completing steroid tapering could receive maintenance ECP (two treatments/week) every month for 24 weeks. RESULTS: Thirty-one patients (Crohn's Disease Activity Index [CDAI] score 91; Inflammatory Bowel Disease Questionnaire [IBDQ] 172.5) were enrolled (baseline corticosteroid dose, 20 mg/day); 65% were refractory to/intolerant of anti-tumor necrosis factor (TNF) agents or immunosuppressants. After 24 weeks of ECP, 7 of 31 (22.6%) patients discontinued steroids while maintaining a CDAI of <150. At week 24, the steroid dose for the remaining patients on corticosteroids was 10 mg (P < 0.003 vs. baseline) with a CDAI of 110 and an IBDQ of 179. Following maintenance treatment, three patients remained in steroid-free remission. The 10 patients in the study and receiving ECP at week 48 had a steroid dose of 3.5 mg with a CDAI of 40 and an IBDQ of 188. CONCLUSIONS: ECP permitted discontinuation or reduction of steroids in a population of refractory steroid-dependent CD patients. ECP may be useful in permitting steroid withdrawal in selected steroid-dependent CD patients. Ideally, these results need to be confirmed in a "sham-controlled clinical trial.

25 Clinical Trial Endoscopy and MR enteroclysis: equivalent tools in predicting clinical recurrence in patients with Crohn's disease after ileocolic resection. 2010

Koilakou, Stavroula / Sailer, Johannes / Peloschek, Philipp / Ferlitsch, Arnulf / Vogelsang, Harald / Miehsler, Wolfgang / Fletcher, Joel / Turetschek, Karl / Schima, Wolfgang / Reinisch, Walter. ·Department of Internal Medicine III, Division of Gastroenterology, Medical University of Vienna, Austria. ·Inflamm Bowel Dis · Pubmed #19504611.

ABSTRACT: BACKGROUND: Ileocolonoscopy poses the gold standard in the evaluation of postoperative recurrence of Crohn's disease (CD) at the site of ileocolonic anastomosis. Magnetic resonance enteroclysis (MRE) on the other hand is a promising technique for small bowel imaging. The aim was to compare MRE and ileocolonoscopy for predicting clinical recurrence in CD patients who have undergone ileocolonic resection. METHODS: We included 29 patients in the study. The median time since index operation was 35 months and between ileocolonoscopy and MRE was 3 days. Patients were followed up for a maximum of 2 years unless clinical recurrence occurred earlier. Endoscopic findings were evaluated on a 5-grade scale (i0-i4), whereas MRE findings on the neoterminal ileum and anastomosis were assessed according to a previously validated 4-grade scale MR score (MR0-MR3). RESULTS: By classifying patients into subgroups of endoscopic severity of postoperative recurrence using as a threshold an endoscopic score of i3, we found that 10% of patients in the i0 to i2 group had a clinical recurrence during the 2-year follow-up period as compared to 52.6% of subjects with i3 to i4 (P = 0.043). The corresponding clinical exacerbation rates in the subgroups based on MRE severity assessment were 12.5% for MR0 to MR1 and 50% for MR2 to MR3 (P = 0.09). CONCLUSIONS: Our data suggest that colonoscopy and MR enteroclysis are of similar value to predict the risk of clinical recurrence in postoperative patients with Crohn's disease.

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