Title: Accuracy of calprotectin in evaluating sub- clinical inflammation in Ulcerative

Transcription

1 PROTOCOL ACERTIVE STUDY Title: Accuracy of calprotectin in evaluating sub- clinical inflammation in Ulcerative colitis (ACERTIVE) Sponsor: Portuguese IBD Study Group (Grupo de Estudos da Doença Inflamatória Intestinal GEDII) Principal Investigator: Fernando Magro Monitoring: A CRO will be contracted in order to elaborate the CRF and protocol to submit to local ethical committee. The monitoring will be performed by GEDII. Timelines: May 2012 Protocol Draft Fernando Magro June 2012 Final protocol January 2013 Submission to Local ethics committee March, 31st, 2013 Study Start July, 31st, 2014 Last patient included September 2014 Investigator Meeting December 2014 Paper submission Introduction and Rationale Ulcerative colitis is an inflammatory disorder characterized by rectal bleeding, persistent bloody diarrhea and abdominal cramping. An accurate monitoring of mucosal inflammation is important for an effective management of patients with inflammatory bowel disease. Intestinal inflammation can be detected by faecal calprotectin (FC) level. Page 1 of 11

2 Colonic mucosal involvement may present initially as vascular congestion, erythema, edema, and/or granularity. With increasing disease severity, mucosal friability, spontaneous bleeding, and small ulcers coalescing into large or linear ulcers may occur (1). Although endoscopic and histologic parameters tend to lag behind symptom improvement (2) these measures are particularly useful in confirming clinical improvement in ulcerative colitis and may be important tools for predicting long- term outcome (3). Residual acute inflammation after treatment in ulcerative colitis may suggest an increased risk of disease relapse. Mucosal healing has emerged as an important treatment goal in ulcerative colitis because evidence is accumulating that it can alter the course of the disease (4,5). Patients who have received conventional therapy to date and have achieved clinical response and/or remission may continue to experience subclinical inflammatory processes that leave them at risk of further disease relapses or the development of disease complications (6 8). A population- based cohort study confirmed that mucosal healing had a significant impact on disease outcome in patients with ulcerative colitis. In patients with ulcerative colitis, 3 of 178 patients (2%) with mucosal healing at 1 year underwent colectomy by 5 years as compared with 13 of 176 patients (7%) without mucosal healing at 1 year (P <.02) (4). Achievement of early mucosal healing (i.e., endoscopy sub scores of 0 or 1 at week 8) after treatment with infliximab may lead to better long- term clinical outcomes for patients with moderately to severely active ulcerative colitis. Early mucosal healing was associated with a lower risk of colectomy through 54 weeks of follow- up evaluation and better long- term outcomes related to symptomatic remission, corticosteroid- free symptomatic remission and corticosteroid use, and subsequent mucosal healing at weeks 30 and 54. With the exception of colectomy outcomes, an endoscopic sub score of 0 (i.e., complete healing) at week 8 was associated with a greater proportion of patients with long- term clinical benefit (9). Likewise, patients with healed mucosa also may have a lower risk of dysplasia and adenocarcinoma of the colon (10) because active inflammation (11, 12) increases the risk of colon cancer development in patients with active colitis. Page 2 of 11

3 Calprotectin is remarkably stable in stools for up to 7 days at room temperature, enabling sample collection at home even in cases of distant hospitals or reference centers. Fecal calprotectin (FC) is an excellent marker of intestinal inflammation, as it reflects the migration of neutrophils through the inflamed bowel wall to the mucosa (13). FC appears to have good diagnostic precision in distinguishing IBD from non- IBD patients. Moreover, FC concentrations correlate well with histological and endoscopic inflammation (14, 15). FC showed a high correlation (r=0.655) with the histologic grade of mucosal inflammation, similar to that observed for endoscopy (r=0.699), and it resulted the most accurate tool (sensitivity 94%, specificity 64%, positive predictive value 81%, negative predictive value 87%) to detect the presence of active mucosal inflammation when compared to clinical scores and common serum markers (16). For patients with quiescent IBD in predicting relapse the sroc curve showed an optimum joint sensitivity and specificity of 0.77, with AUC of 0.83 (meta- analyses) (17) The performance of clinical impression in recognizing disease activity, as determined by endoscopy, was relatively poor: sensitivity %, predictive value negative %, kappa coefficient Among the 369 patients, agreement between physician clinical impression of UC activity and endoscopic mucosal findings was only found in 56% of the patient. The clinical impression underestimated inflammatory activity in approximately one- third of UC patients and overestimated disease activity in 10%. (18). To our knowledge, there isn t any prospective study addressing the accuracy of FC in differencing patients without clinical symptoms but with persisting inflammation, turning FC a tool of reduction endoscopic procedures in UC. The aim of this study is to assess the accuracy of calprotectin in predicting endoscopic activity in UC patients without clinical activity. Page 3 of 11

4 General study objective To characterize the accuracy of FC in asymptomatic UC patients. Primary Endpoints: a. Ability of gastroenterologists to recognize endoscopic and activity based on clinical assessment of the patient. b. Sensitivity, specificity, predictive value positive, predictive value negative and Kappa (Overall measure of degree of non- random agreement, i.e., beyond chance, between endoscopy and FC/clinical evaluation). Secondary Endpoints: a. Endoscopic evidence of disease in the absence of clinical evidence; b. FC evidence of disease in the absence of clinical evidence; c. Endoscopic and FC evidence of disease in the absence of clinical evidence. Population The number of expected patients to be enrolled in this study is 400. Every participating physician will be asked to include 50 patients with UC. Data will be collected by application of 3 questionnaires, two to be filled by the physician during the patient s visit. The severity of mucosal inflammation will be assessed using specific endoscopic scores - Mayo Clinic score and the ulcerative Colitis Endoscopic Index of Severity (UCEIS). The Inclusion criteria for the study of patients with a diagnosis of UC, confirmed by endoscopy and histopathology, were: - Patients ( 18 years old) of both sexes. Page 4 of 11

5 - Mayo score modified of 0-1, and asymptomatic on Montreal classification, which attend to practice office of the gastroenterologists involved in the study - Patients must have at least rectum and sigmoid involved, so patients with only proctitis are not allowed - Subjects willing to participate voluntarily in the study by providing written informed consent. Investigator selection criteria: The study will be set- up in hospitals with a clinical practice in IBD and gastroenterologists. The hospitals and gastroenterologists to be included will be representative of the patterns of treatment for this disease in Portugal. Ethical Considerations: The study protocol will be submitted to the National Data Protection Committee (Comissão Nacional de Protecção de Dados), to the local Ethics Committees of the involved hospitals and to the administration review board of each site. Written informed consent will be obtained from all patients. The study will be conducted in compliance with the protocol, the ethical principals of the 6 th revision of the Helsinki Declaration, and with all local regulatory requirements. Study Publication: The results will be presented by the Principal investigator in national and international meetings and published in international papers. The publication of the study results may only be performed after the end of the clinical investigation, the complete analysis of the data and upon the agreement of the scientific study board. The publication should include the results of all centers which have participated in the clinical investigation, once the clinical investigation was performed as a multi- center investigation. The publication should be made in Page 5 of 11

6 accordance with all participating clinical investigators and in strictly adherence to the Declaration of Helsinki Statistic details: Categorical variables will be described as absolute frequencies (n) and relative frequencies (%). Median and percentiles or mean and standard deviation were used for continuous when appropriated. When testing a hypothesis about continuous variables, nonparametric tests (Mann Whitney or Kruskall Walis) or parametric test (T test for independent or ANOVA) will be used as appropriate, taking into account normality assumptions and the number of groups compared. When testing a hypothesis about categorical variables a chi- square test and Fisher s exact test will be used, as appropriate. To evaluate the strength of association between FC/clinical evaluation and endoscopic were used the Pearson or Spearmen correlation. To measure the concordance between endoscopy and concurrent FC/clinical evaluation, Kappa weight /and 95% intervals confidence) or intraclass correlation (with 95 % intervals confidence) will be used as appropriated. The significance level used will be 0.05 and, for a correlation high than 0.5, with an sample size of 400 patients, the statistical power expected will be are 99%. Statistical analysis will be performed using the software Statistical Package for the Social Sciences v Measure Sensitivity, Specificity, Predictive value positive, Predictive value negative, Kappa Page 6 of 11

7 Interpretation Sensitivity: Probability that a patient with endoscopic evidence of disease (UC) will be identified through FC as having active disease. Specificity: Probability that a patient without endoscopic evidence of disease (UC) will be correctly identified through FC as not having active disease. Predictive value positive: Probability that a patient with FC of disease (UC) will show endoscopic evidence of disease (i.e., true positive). Predictive value positive: Probability that a patient without FC will show an absence of disease from endoscopy (i.e., true negative). Kappa: Overall measure of degree of non- random agreement (i.e., beyond chance) between endoscopy and FC/clinical evaluation. Visit assessments Assessments Informed consent 1 Eligibility confirmation 2 Visit Screening/ Baseline Wk - 0 Page 7 of 11

8 Lab analysis 3 Sigmoidoscopy 4 Disease activity 5 (Montreal classif.+ Mayo score) Calproctein in stools 6 1 Patients must provide signed informed consent voluntarily before any trial related procedure takes place. 2 Patients must have documented diagnosis of ulcerative colitis according to ECCO Consensus- See Supplement Hematology and biochemistry analysis should follow local practice. Ultrasensitive CRP should be performed. Stools collection for faecal calprotectin and lactoferrin assessments (by ELISA method) should be performed at every study visit. 4 Sigmoidoscopies will be performed at baseline and the Mayo Score and UCEIS will be determined. 5 Ulcerative colitis clinical activity will be assessed by Mayo score and Montreal classification. 6 Calprotectin will be done by Quantum Blue in São João Hospital. All samples results will be shipped to São João Hospital by mail. The quantum Blue to be used will be to cover a calprotectin level of 30 to 300 ug/g. References 1. Fefferman DS, Farrell RJ. Endoscopy in inflammatory bowel disease: indications, surveillance, and use in clinical practice. Clin Gastroenterol Hepatol 2005;3: Riley SA, Mani V, Goodman MJ, et al. Microscopic activity in ulcerative colitis: what does it mean? Gut 1991;32: Page 8 of 11

9 3. Bitton A, Peppercorn MA, Antonioli DA, et al. Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis. Gastroenterology 2001;120: Frøslie KF, Jahnsen J, Moum BA, et al. Mucosal healing in inflam- matory bowel disease: results from a Norwegian population- based cohort. Gastroenterology 2007;133: Solberg IC, Lygren I, Jøhnsen J, et al. Mucosal healing after initial treatment may be a prognostic marker for long- term outcome in inflammatory bowel disease. Gut 2008;57(Suppl 2):A Louis E, Collard A, Oger AF, et al. Behaviour of Crohn s disease according to the Vienna classification: changing pattern over the course of the disease. Gut 2001;49: Freeman HJ. Natural history and clinical behavior of Crohn s dis- ease extending beyond two decades. J Clin Gastroenterol 2003; 37: Cosnes J, Cattan S, Blain A, et al. Long- term evolution of disease behavior of Crohn s disease. Inflamm Bowel Dis 2002;8: Colombel JF,Rutgeerts P, Reibisch W, Esser D, Wang Y, Lang Y, Collen W, Strauss R, Oddens B, Feagan B, Hanauer S, Lichtenstein G, Present D, Sands B, and Sandborn W. Early Mucosal Healing With Infliximab Is Associated With Improved Long- term Clinical Outcomes in Ulcerative Colitis. Gastroenterology 2011;141: Rutter MD, Saunders BP, Wilkinson KH, et al. Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 2004;53: Rutter M, Saunders B, Wilkinson K, et al. Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 2004;126: Itzkowitz SH, Yio. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Page 9 of 11

10 Liver Physiol 2004;287:G7 G Van Assche G, Dignass A, Panes J, et al. The second European evi- dence- based consensus on the diagnosis and management of Crohn s disease: definitions and diagnosis. J Crohns Colitis. 2010;4: von Roon AC, Karamountzos L, Purkayastha S, et al. Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colo- rectal malignancy. Am J Gastroenterol. 2007;102: Sipponen T, Savilahti E, Kolho KL, et al. Crohn s disease activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn s disease activity index and endoscopic findings. Inflamm Bowel Dis. 2008;14: Canani R Berni, Terrin G, Rapacciuolo L, Miele E, Siani M C, Puzone C, Cosenza L, Staiano A, Troncone R. Digestive and liver disease. Jul 2008, 40 (7) p Ren Mao, Ying- lian ia, iang Gao, Bai- li Chen, Yao He, Li Yang, Pin- jin Hu, and Min- hu Chen. Fecal Calprotectin in Predicting Relapse of Inflammatory Bowel Diseases: A Meta- analysis of Prospective Studies. Inflamm Bowel Dis Miguel Regueiro, Joseph Rodemann, Kevin E. Kip, Melissa Saul, MS, Jason Swoger, Leonard Baidoo, Marc Schwartz, MD, Arthur Barrie, and David Binion. Physician Assessment of Ulcerative Colitis Activity Correlates Poorly with Endoscopic Disease Activity. Inflamm Bowel Dis 2011;17: Page 10 of 11

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