A Meta-Analysis of the Placebo Rates of Remission and Response in Clinical Trials of Active Ulcerative Colitis
2006; Elsevier BV; Volume: 132; Issue: 2 Linguagem: Inglês
10.1053/j.gastro.2006.12.037
ISSN1528-0012
AutoresChinyu Su, James D. Lewis, Brittany Goldberg, Colleen Brensinger, Gary R. Lichtenstein,
Tópico(s)Pharmacological Effects of Natural Compounds
ResumoBackground & Aims: Knowledge of the placebo outcomes and understanding specific study features that influence these outcomes is important for designing future clinical trials evaluating therapy of ulcerative colitis (UC). The aims of this study were to estimate the placebo rates of remission and response in placebo-controlled, randomized clinical trials for active UC and to identify factors influencing these rates. Methods: We performed a systematic review and meta-analysis of placebo-controlled, randomized clinical trials evaluating therapies for active UC identified from MEDLINE from 1966 through 2005. Results: Forty studies met the inclusion criteria. The pooled estimates of the placebo rates of remission and response were 13% (95% confidence interval, 9%–18%; range, 0%–40%; median, 12%) and 28% (95% confidence interval, 23%–33%; range, 0%–67%; median, 30%), respectively, both with significant heterogeneity. Studies that used more stringent definitions of outcomes had lower placebo rates of remission and response. Study duration, number of study visits, disease duration, baseline composite and rectal bleeding scores of the disease activity index, and inclusion of endoscopic mucosal healing as the remission definition all were associated with the placebo remission rate. Conclusions: Rates of remission in the placebo arm of UC clinical trials ranges from 0% to 40%. The placebo remission rates are influenced by the trial length, number of study visits, use of stricter remission definitions, and design features that enroll patients with more active disease. These factors should be considered when designing future placebo-controlled clinical trials in patients with active UC. Background & Aims: Knowledge of the placebo outcomes and understanding specific study features that influence these outcomes is important for designing future clinical trials evaluating therapy of ulcerative colitis (UC). The aims of this study were to estimate the placebo rates of remission and response in placebo-controlled, randomized clinical trials for active UC and to identify factors influencing these rates. Methods: We performed a systematic review and meta-analysis of placebo-controlled, randomized clinical trials evaluating therapies for active UC identified from MEDLINE from 1966 through 2005. Results: Forty studies met the inclusion criteria. The pooled estimates of the placebo rates of remission and response were 13% (95% confidence interval, 9%–18%; range, 0%–40%; median, 12%) and 28% (95% confidence interval, 23%–33%; range, 0%–67%; median, 30%), respectively, both with significant heterogeneity. Studies that used more stringent definitions of outcomes had lower placebo rates of remission and response. Study duration, number of study visits, disease duration, baseline composite and rectal bleeding scores of the disease activity index, and inclusion of endoscopic mucosal healing as the remission definition all were associated with the placebo remission rate. Conclusions: Rates of remission in the placebo arm of UC clinical trials ranges from 0% to 40%. The placebo remission rates are influenced by the trial length, number of study visits, use of stricter remission definitions, and design features that enroll patients with more active disease. These factors should be considered when designing future placebo-controlled clinical trials in patients with active UC. See Sparrow MP et al on page 209 and Yacyshyn B et al on page 215 in the February 2007 issue of CGH.Ulcerative colitis (UC) is an idiopathic inflammatory disorder of the colon that is characterized clinically by intermittent episodes of acute exacerbation alternating with quiescence. Patients with UC may experience spontaneous clinical improvement or even remission in the absence of any medical intervention. Thus, establishing efficacy of medical therapies for UC requires proof of superiority to placebo via placebo-controlled, randomized clinical trials (PC-RCTs). In this regard, understanding the outcomes of placebo-treated patients and factors influencing these outcomes in clinical trials of active UC is important for designing and interpreting results of open-label and randomized clinical trials. In addition, the disease course of placebo-treated patients in these studies may help clinicians in decision making by predicting the likelihood of achieving remission in patients without changing existing therapy.We have shown previously that the study duration, number of study visits, and baseline scores of a standardized disease activity index all were predictors of attaining placebo remission in clinical trials of active Crohn’s disease (CD).1Su C. Lichtenstein G.R. Krok K. Brensinger C.M. Lewis J.D. A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn’s disease.Gastroenterology. 2004; 126: 1257-1269Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar A prior systematic review of placebo-controlled trails for active UC only included studies before 1995 and reported a placebo clinical remission rate of 9.1% and a placebo benefit rate of 26.7%.2Ilnyckyj A. Shanahan F. Anton P.A. Cheang M. Bernstein C.N. Quantification of the placebo response in ulcerative colitis.Gastroenterology. 1997; 112: 1854-1858Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar That analysis suggested that studies with 3 or more follow-up visits tend to have higher rates of improvement in patients treated with placebo than studies with fewer than 3 study visits. However, heterogeneity in the definitions of outcomes among clinical trials of UC makes interpretation of those results difficult. In this study, we performed a systematic review and meta-analysis of PC-RCTs for active UC through 2005 to estimate the rates of remission and response among patients receiving placebo and to identify factors that influence these rates, including different outcome definitions.Materials and MethodsStudy Identification and InclusionPC-RCTs for the treatment of active UC were identified from the MEDLINE electronic database. We searched this database from January 1966 through May 2005 using the following medical subject headings: “ulcerative colitis” or “UC” or “colitis” or “inflammatory bowel disease,” AND “placebo” or “double-blind” or “clinical trial.” The search was limited to “human and English language” studies, and excluded “comment or editorial or letter or review.” The bibliographies of all the review articles were identified and all meta-analysis studies were searched manually to identify other potential studiesStudies that fulfilled all the following criteria were included for analysis: (1) the study was a placebo-controlled trial, (2) all patients in the study had active disease at entry unless the study was designed specifically with an induction and a maintenance therapy arm separately, (3) the study reported the methodology of defining clinical response or remission, and (4) the proportion of patients achieving response or remission was available. For studies in which results were reported for multiple time points, the results of the primary end point defined in the studies were recorded. However, if the primary end point was not defined, the results from the final time point were recorded. Studies reported solely as abstracts were not included in the meta-analysis.Data AbstractionData abstraction was conducted by 2 independent reviewers (C.S. and B.G.). The definition and the proportions of patients achieving the following outcomes were recorded: clinical remission, clinical response, endoscopic remission, and histologic remission. Unless otherwise specified, remission and response in the remainder of this article refer to clinical remission and clinical response, respectively. In addition, data on features of study design, patient characteristics, and study outcomes were abstracted. These included the publication year, the study location, the sample size, the inclusion criteria, the active treatment modalities and their route of administration, the duration of follow-up evaluation, the number and frequency of study visits, the duration and distribution of disease, prior and concurrent medical therapies, and, when applicable, the entry disease activity scores and the results on the individual components of the disease activity index. Outcomes were dichotomized into remission vs no remission, and response vs no response based on the outcome definition. In studies in which endoscopic data were reported but endoscopic remission was not defined, an endoscopic score of zero was chosen arbitrarily as the definition of remission.Statistical AnalysesPooled estimates of the placebo remission and response rates and stratum-specific rates for different categories of study designs were calculated using random-effects logistic regression analysis, after applying sample weights according to the placebo sample size, as implemented using STATA’s (STATA Corp, College Station, TX) xtlogit command. Heterogeneity among studies was assessed with the Pearson χ2 test. In addition, the medians and ranges of the placebo rates were reported to complement interpretation of the pooled estimates. The effect of study design on the placebo remission rate was estimated using univariate logistic regression models with a random study effect. Analyses also were performed to limit studies to those using the same definition of outcomes. Multivariate models could not be performed because of the limited number of studies using the same definitions for remission or response and colinearity of several variables.The most commonly used disease activity indices among all the trials in this study were the Mayo Score3Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Scopus (2023) Google Scholar or the Sutherland Index4Sutherland L.R. Martin F. Greer S. Robinson M. Greenberger N. Saibil F. Martin T. Sparr J. Prokipchuk E. Borgen L. 5-Aminosalicylic acid enema in treatment of distal ulcerative colitis, proctosigmoiditis and proctitis.Gastroenterology. 1987; 92: 1894-1898Abstract PubMed Google Scholar (Appendix). Both instruments use a 12-point scale incorporating 4 components of disease activity: stool frequency, rectal bleeding, mucosal appearance on sigmoidoscopy, and physician’s global assessment. Although the precise definitions of these 2 metrics differ slightly, they are sufficiently similar for the purpose of this study and thus were considered one scale, Ulcerative Colitis Disease Activity Index (UCDAI), in our analyses.The correlation between placebo rates of outcomes based on different definitions was assessed with the Spearman correlation coefficient. For all the analyses, a P value of less than .05 was considered statistically significant. All analyses were completed using STATA version 9.0 (STATA Corp) and SAS version 9.1 (SAS Institute, Cary, NC).ResultsDescription of the StudiesOur search strategy identified 480 potentially relevant articles. Reviewing their titles and abstracts allowed us to exclude 377 articles that were not clinical trials of active UC. Of the 102 articles selected for full article review, 39 fulfilled the inclusion criteria.3Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Scopus (2023) Google Scholar, 4Sutherland L.R. Martin F. Greer S. Robinson M. Greenberger N. Saibil F. Martin T. Sparr J. Prokipchuk E. Borgen L. 5-Aminosalicylic acid enema in treatment of distal ulcerative colitis, proctosigmoiditis and proctitis.Gastroenterology. 1987; 92: 1894-1898Abstract PubMed Google Scholar, 5Palmer K.R. Goepel J.R. Holdsworth C.D. Sulphasalazine retention enemas in ulcerative colitis: a double-blind trial.BMJ. 1981; 282: 1571-1573Crossref PubMed Scopus (24) Google Scholar, 6Selby W.S. Barr G.D. Ireland A. Mason C.H. Jewell D.P. Olsalazine in active ulcerative colitis.BMJ. 1985; 291: 1373-1375Crossref PubMed Scopus (91) Google Scholar, 7Meyers S. Sachar D.B. Present D.H. Janowitz H.D. Olsalazine sodium in the treatment of ulcerative colitis among patients intolerant of sulfasalazine A prospective, randomized, placebo-controlled, double-blind, dose-ranging clinical trial.Gastroenterology. 1987; 93: 1255-1262PubMed Google Scholar, 8Sutherland L.R. Martin F. 5-Aminosalicylic acid enema in treatment of distal ulcerative colitis and proctitis in Canada.Dig Dis Sci. 1987; 32: 64S-66SCrossref PubMed Scopus (41) Google Scholar, 9Williams C.N. Haber G. Aquino J.A. Double-blind, placebo-controlled evaluation of 5-ASA suppositories in active distal proctitis and measurement of extent of spread using 99mTc-labeled 5-ASA suppositories.Dig Dis Sci. 1987; 32: 71S-75SCrossref PubMed Scopus (96) Google Scholar, 10Ginsberg A.L. Beck L.S. McIntosh T.M. Nochomovitz L.E. 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A placebo-controlled trial of cyclosporine enemas for mildly to moderately active left-sided ulcerative colitis.Gastroenterology. 1994; 106: 1429-1435PubMed Google Scholar, 22Scheppach W. Treatment of distal ulcerative colitis with short-chain fatty acid enemas A placebo-controlled trial.Dig Dis Sci. 1996; 41: 2254-2259Crossref PubMed Scopus (169) Google Scholar, 23Steinhart A.H. Hiruki T. Brzezinski A. Baker J.P. Treatment of left-sided ulcerative colitis with butyrate enemas: a controlled trial.Aliment Pharmacol Ther. 1996; 10: 729-736Crossref PubMed Scopus (171) Google Scholar, 24Beeken W. Howard D. Bigelow J. Trainer T. Roy M. Thayer W. Wild G. Controlled trial of 4-ASA in ulcerative colitis.Dig Dis Sci. 1997; 42: 354-358Crossref PubMed Scopus (23) Google Scholar, 25Breuer R.I. Soergel K.H. Lashner B.A. Christ M.L. Hanauer S.B. Vanagunas A. Harig J.M. Keshavarzian A. Robinson M. Sellin J.H. Weinberg D. Vidican D.E. Flemal K.L. Rademaker A.W. Short chain fatty acid rectal irrigation for left-sided ulcerative colitis: a randomised, placebo controlled trial.Gut. 1997; 40: 485-491PubMed Google Scholar, 26Roberts W.G. Simon T.J. Berlin R.G. Haggitt R.C. Snyder E.S. Stenson W.F. Hanauer S.B. Reagan J.E. Cagliola A. Tanaka W.K. Simon S. Berger M.L. Leukotrienes in ulcerative colitis: results of a multicenter trial of leukotriene biosynthesis inhibitor, MK-591.Gastroenterology. 1997; 112: 725-732Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 27Sandborn W.J. Tremaine W.J. Offord K.P. Lawson G.M. Petersen B.T. Batts K.P. Croghan I.T. Dale L.C. Schroeder D.R. Hurt R.D. Transdermal nicotine for mildly to moderate active ulcerative colitis A randomized, double-blind, placebo-controlled trial.Ann Intern Med. 1997; 126: 364-371Crossref PubMed Scopus (247) Google Scholar, 28Hanauer S.B. Robinson M. Pruitt R. Lazenby A.J. Persson T. Nilsson L.G. Walton-Bowen K. Haskell L.P. Levine J.G. 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Olsalazine in active ulcerative colitis.BMJ. 1985; 291: 1373-1375Crossref PubMed Scopus (91) Google Scholar Of the 63 excluded articles, 30 studies did not clearly define clinical response or remission and/or report placebo rates of clinical outcomes, and 21 studies did not contain a placebo arm. Other reasons for exclusion included lack of clinical data (6 studies), inclusion of both patients with active and inactive disease (5 studies), cross-over study design precluding abstraction of relevant data (2 studies), and duplication of results reported in another article (2 studies). Some studies fulfilled multiple exclusion criteria.Among the 40 studies that fulfilled the inclusion criteria, 27 studies reported data on placebo remission rates (Table 1).3Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis A randomized study.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Scopus (2023) Google Scholar, 9Williams C.N. Haber G. Aquino J.A. Double-blind, placebo-controlled evaluation of 5-ASA suppositories in active distal proctitis and measurement of extent of spread using 99mTc-labeled 5-ASA suppositories.Dig Dis Sci. 1987; 32: 71S-75SCrossref PubMed Scopus (96) Google Scholar, 12Campieri M. Gionchetti P. Belluzzi A. Brignola C. Tampieri M. Iannone P. Brunetti G. Miglioli M. Barbara L. Topical treatment with 5-aminosalicylic in distal ulcerative colitis by using a new suppository preparation A double-blind placebo controlled trial.Int J Colorectal Dis. 1990; 5: 79-81Crossref PubMed Scopus (42) Google Scholar, 13Campieri M. De Franchis R. Bianchi Porro G. Ranzi T. Brunetti G. Barbara L. Mesalazine (5-aminosalicylic acid) suppositories in the treatment of ulcerative proctitis or distal proctosigmoiditis A randomized controlled trial.Scand J Gastroenterol. 1990; 25: 663-668Crossref PubMed Scopus (79) Google Scholar, 14Campieri M. Gionchetti P. Belluzzi A. Brignola C. Tampieri M. Iannone P. Miglioli M. Barbara L. Optimum dosage of 5-aminosalicylic acid as rectal enemas in patients with active ulcerative colitis.Gut. 1991; 32: 929-931Crossref PubMed Scopus (109) Google Scholar, 15Sninsky C.A. Cort D.H. Shanahan F. Powers B.J. Sessions J.T. Pruitt R.E. Jacobs W.H. Lo S.K. Targan S.R. Cerda J.J. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis A multicenter study.Ann Intern Med. 1991; 115: 350-355Crossref PubMed Scopus (216) Google Scholar, 16Angus P. Snook J.A. Reid M. Jewell D.P. Oral fluticasone propionate in active distal ulcerative colitis.Gut. 1992; 33: 711-714Crossref PubMed Scopus (42) Google Scholar, 18Hanauer S. Schwartz J. Robinson M. Roufail W. Arora S. Cello J. Safdi M. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled trial.Am J Gastroenterol. 1993; 88: 1188-1197PubMed Google Scholar, 20Pullan R.D. Rhodes J. Ganesh S. Mani V. Morris J.S. Williams G.T. Newcombe R.G. Russell M.A. Feyerabend C. Thomas G.A. Transdermal nicotine for active ulcerative colitis.N Engl J Med. 1994; 330: 811-815Crossref PubMed Scopus (446) Google Scholar, 21Sandborn W.J. Tremaine W.J. Schroeder K.W. Batts K.P. Lawson G.M. Steiner B.L. Harrison J.M. Zinsmeister A.R. A placebo-controlled trial of cyclosporine enemas for mildly to moderately active left-sided ulcerative colitis.Gastroenterology. 1994; 106: 1429-1435PubMed Google Scholar, 22Scheppach W. Treatment of distal ulcerative colitis with short-chain fatty acid enemas A placebo-controlled trial.Dig Dis Sci. 1996; 41: 2254-2259Crossref PubMed Scopus (169) Google Scholar, 23Steinhart A.H. Hiruki T. Brzezinski A. Baker J.P. Treatment of left-sided ulcerative colitis with butyrate enemas: a controlled trial.Aliment Pharmacol Ther. 1996; 10: 729-736Crossref PubMed Scopus (171) Google Scholar, 26Roberts W.G. Simon T.J. Berlin R.G. Haggitt R.C. Snyder E.S. Stenson W.F. Hanauer S.B. Reagan J.E. Cagliola A. Tanaka W.K. Simon S. Berger M.L. Leukotrienes in ulcerative colitis: results of a multicenter trial of leukotriene biosynthesis inhibitor, MK-591.Gastroenterology. 1997; 112: 725-732Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 27Sandborn W.J. Tremaine W.J. Offord K.P. Lawson G.M. Petersen B.T. Batts K.P. Croghan I.T. Dale L.C. Schroeder D.R. Hurt R.D. Transdermal nicotine for mildly to moderate active ulcerative colitis A randomized, double-blind, placebo-controlled trial.Ann Intern Med. 1997; 126: 364-371Crossref PubMed Scopus (247) Google Scholar, 28Hanauer S.B. Robinson M. Pruitt R. Lazenby A.J. Persson T. Nilsson L.G. Walton-Bowen K. Haskell L.P. Levine J.G. Budesonide enema for the treatment of active, distal ulcerative colitis and proctitis: a dose-ranging study.Gastroenterology. 1998; 115: 525-532Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar, 29Hanauer S.B. Dose-ranging study of mesalamine (PENTASA) enemas in the treatment of acute ulcerative protosigmoiditis: results of a multicentered placebo-controlled trial.Inflamm Bowel Dis. 1998; 4: 79-83Crossref PubMed Scopus (95) Google Scholar, 30Pokrotnieks J. Marlicz K. Paradowski L. Margus B. Zaborowski P. Greinwald R. Efficacy and tolerability of mesalazine foam enema (Salofalk foam) for distal ulcerative colitis: a double-blind, randomized, placebo-controlled study.Aliment Pharmacol Ther. 2000; 14: 1191-1198Crossref PubMed Scopus (48) Google Scholar, 31Vernia P. Monteleone G. Grandinetti G. Villotti G. Di Giulio E. Frieri G. Marcheggiano A. Pallone F. Caprilli R. Torsoli A. Combined oral sodium butyrate and mesalazine treatment compared to oral mesalazine alone in ulcerative colitis: randomized, double-blind, placebo-controlled pilot study.Dig Dis Sci. 2000; 45: 976-981Crossref PubMed Scopus (93) Google Scholar, 33Tytgat G.N. Van Nueten L. Van De Velde I. Joslyn A. Hanauer S.B. Efficacy and safety of oral ridogrel in the treatment of ulcerative colitis: two multicentre, randomized, double-blind studies.Aliment Pharmacol Ther. 2002; 16: 87-99Crossref PubMed Scopus (24) Google Scholar, 34Nikolaus S. Rutgeerts P. Fedorak R. Steinhart A.H. Wild G.E. Theuer D. Mohrle J. Schreiber S. Interferon beta-la in ulcerative colitis: a placebo controlled, randomised, dose escalating study.Gut. 2003; 52: 1286-1290Crossref PubMed Scopus (94) Google Scholar, 35Probert C.S. Hearing S.D. Schreiber S. Kuhbacher T. Ghosh S. Arnott I.D. Forbes A. Infliximab in moderately severe glucocorticoid resistant ulcerative colitis: a randomised controlled trial.Gut. 2003; 52: 998-1002Crossref PubMed Scopus (329) Google Scholar, 36Sandborn W.J. Sands B.E. Wolf D.C. Valentine J.F. Safdi M. Katz S. Isaacs K.L. Wruble L.D. Katz J. Present D.H. Loftus Jr, E.V. Graeme-Cook F. Odenheimer D.J. Hanauer S.B. Repifermin (keratinocyte growth factor-2) for the treatment of active ulcerative colitis: a randomized, double-blind, placebo-controlled, dose-escalation trial.Aliment Pharmacol Ther. 2003; 17: 1355-1364Crossref PubMed Scopus (98) Google Scholar, 37Tilg H. Vogelsang H. Ludwiczek O. Lochs H. Kaser A. Colombel J.F. Ulmer H. Rutgeerts P. Kruger S. Cortot A. D’Haens G. Harrer M. Gasche C. Wrba F. Kuhn I. Reinisch W. A randomised placebo controlled trial of pegylated interferon alpha in active ulcerative colitis.Gut. 2003; 52: 1728-1733Crossref PubMed Scopus (87) Google Scholar, 38Vernia P. Annese V. Bresci G. d’Albasio G. D’Inca R. Giaccari S. Ingrosso M. Mansi C. Riegler G. Valpiani D. Caprilli R. Grupp
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