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• W2018902013 abstract "Background & Aims: We performed a randomized, double-blind, placebo-controlled, multicenter trial to investigate the efficacy and safety of recombinant interferon-β-1a (rIFN-β-1a) in outpatients with active steroid-refractory ulcerative colitis. Methods: Ninety-one randomized patients subcutaneously received 3 MIU rIFN-β-1a (group A, n = 32), 1 MIU rIFN-β-1a (group B, n = 30), or placebo (group C, n = 29) 3 times a week over a period of 8 weeks in addition to standard therapy. An intention-to-treat analysis was performed to evaluate the efficacy and safety of treatment. Results: In all 3 groups, the median prestudy clinical activity index (CAI) was 10. In 18 of 32 patients (56%) in group A, in 11 of 30 patients (36%) in group B, and in 10 of 29 patients (34%) in group C, a reduction of the CAI of 6 points or greater (response) was achieved (differences were not statistically significant). Complete response (reduction of CAI to ≤4) was achieved in 56%, 30%, and 38% of patients in groups A, B, and C, respectively. Compared with baseline, the median endoscopic index had been reduced by 5, 3, and 4 points in groups A, B, and C, respectively. Steroid reduction was 12 mg in group A, 6 mg in group B, and 10 mg in group C. Identical side effects occurred in all 3 groups. Seven serious adverse events were reported (1 in group A and 6 in group C). All were unrelated to therapy as judged by the investigating physicians. Conclusions: rIFN-β-1a was safe but not significant, at the dosage and/or duration of treatment used, in steroid-refractory ulcerative colitis. Further studies are indicated. Background & Aims: We performed a randomized, double-blind, placebo-controlled, multicenter trial to investigate the efficacy and safety of recombinant interferon-β-1a (rIFN-β-1a) in outpatients with active steroid-refractory ulcerative colitis. Methods: Ninety-one randomized patients subcutaneously received 3 MIU rIFN-β-1a (group A, n = 32), 1 MIU rIFN-β-1a (group B, n = 30), or placebo (group C, n = 29) 3 times a week over a period of 8 weeks in addition to standard therapy. An intention-to-treat analysis was performed to evaluate the efficacy and safety of treatment. Results: In all 3 groups, the median prestudy clinical activity index (CAI) was 10. In 18 of 32 patients (56%) in group A, in 11 of 30 patients (36%) in group B, and in 10 of 29 patients (34%) in group C, a reduction of the CAI of 6 points or greater (response) was achieved (differences were not statistically significant). Complete response (reduction of CAI to ≤4) was achieved in 56%, 30%, and 38% of patients in groups A, B, and C, respectively. Compared with baseline, the median endoscopic index had been reduced by 5, 3, and 4 points in groups A, B, and C, respectively. Steroid reduction was 12 mg in group A, 6 mg in group B, and 10 mg in group C. Identical side effects occurred in all 3 groups. Seven serious adverse events were reported (1 in group A and 6 in group C). All were unrelated to therapy as judged by the investigating physicians. Conclusions: rIFN-β-1a was safe but not significant, at the dosage and/or duration of treatment used, in steroid-refractory ulcerative colitis. Further studies are indicated. Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease of unknown cause. Standard treatment of UC includes 5-aminosalicylates such as sulfasalazine and mesalamine combined with corticosteroids if necessary. This therapy has proven to be effective in the acute phase of the disease in approximately 60%–90% of patients.1Sutherland L.R. May G.R. Shaffer E.A. Sulfasalazine revisited a meta-analysis of 5-aminosalicylic acid in the treatment of ulcerative colitis.Ann Intern Med. 1993; 118: 540-549Crossref PubMed Scopus (243) Google Scholar, 2Kornbluth A.A. Salomon P. Sacks H.S. et al.Metaanalysis of the effectiveness of current drug therapy of ulcerative colitis.J Clin Gastroenterol. 1993; 16: 215-218Crossref PubMed Scopus (79) Google Scholar Steroid-refractory UC patients are treated with immunomodulators such as azathioprine, 6-mercaptopurine, or cyclosporine A.3Fraser A.G. Orchard T.R. Jewell D.P. The efficacy of azathioprine for the treatment of inflammatory bowel disease a 30 year review.Gut. 2002; 50: 485-489Crossref PubMed Scopus (542) Google Scholar, 4Lichtiger S. Present D.H. Kornbluth A. et al.Cyclosporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med. 1994; 330: 1841-1845Crossref PubMed Scopus (1497) Google Scholar However, there are many patients who fail to respond to immunosuppressive treatment or who cannot tolerate these treatment options. Therefore, other effective and safe compounds are needed.The chronic mucosal inflammation in UC may be caused by an inappropriate secretion of proinflammatory cytokines in response to initial stimulatory events and/or an impaired down-regulation of cytokine secretion. Some of these disturbances, such as a disturbed production of interleukin-1 receptor antagonist, seem to be determined genetically.5Mansfield J.C. Holden H. Tarlow J.K. et al.Novel genetic association between ulcerative colitis and the antiinflammatory cytokine interleukin-1 receptor antagonist.Gastroenterology. 1994; 106: 637-642PubMed Google Scholar, 6Andus T. Daig R. Vogl D. et al.Imbalance of the interleukin 1 system in colonic mucosa—association with intestinal inflammation and interleukin 1 receptor antagonist genotype 2.Gut. 1997; 41: 651-657Crossref PubMed Scopus (134) Google Scholar Correcting these imbalances between pro- and anti-inflammatory cytokines has been shown to be of therapeutic benefit in Crohn’s disease and UC.7Targan S.R. Hanauer S.B. van Deventer S.J. et al.A short-term study of chronic monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease Crohn’s Disease cA2 Study Group.N Engl J Med. 1997; 337: 1029-1035Crossref PubMed Scopus (3048) Google Scholar, 8Evans R.C. Clarke L. Heath P. et al.Treatment of ulcerative colitis with an engineered human anti-TNF alpha antibody CHP571.Aliment Pharmacol Ther. 1997; 11: 1031-1035Crossref PubMed Scopus (135) Google ScholarInterferon-β (IFN-β) has been used successfully in many experimental and therapeutic trials in patients with multiple sclerosis, which also is believed to be an immune-mediated disorder occurring in genetically susceptible people.9Noseworthy J.H. Luchinetti C. Rodriguez M. et al.Multiple sclerosis.N Engl J Med. 2000; 343: 938-952Crossref PubMed Scopus (2994) Google Scholar Several mechanisms of action of IFN-β in multiple sclerosis, such as the up-regulation of the anti-inflammatory cytokines interleukin-10 and interleukin-1 receptor antagonist, a down-regulation of the proinflammatory cytokines tumor necrosis factor and interleukin-2, and of the costimulatory molecules B7-1 and CD40 in lymphocytes, have been described.10Rudick R.A. Ransohoff R.M. Peppler R. et al.Interferon beta induces interleukin-10 expression relevance to multiple sclerosis.Ann Neurol. 1996; 40: 618-627Crossref PubMed Scopus (235) Google Scholar, 11Sciacca F.L. Canal N. Edoardo Grimaldi L.M. Induction of IL-1 receptor antagonist by interferon beta implication for the treatment of multiple sclerosis.J Neurovirol. 2000; 6: S33-S37PubMed Google Scholar, 12Liu Z. Pelfrey C.M. Cotleur A. et al.Immunomodulatory effects of interferon-β-1a in multiple sclerosis.J Neuroimmunol. 2001; 112: 153-162Abstract Full Text Full Text PDF PubMed Scopus (97) Google ScholarResults of treatment with IFN in Crohn’s disease have been rather inconsistent.13Hadzisemilovic F. Emmons L.R. Schaub U. Interferon-α-2a (Roferon) treatment of inflammatory bowel disease in children and adolescents.in: Hirschsprung F. Hadzisemilovic B. Pediatric gastroenterology inflammatory bowel diseases and morbus Crohn. Kluwer Academic Publishers, Dordrecht1992: 109-123Google Scholar, 14Gasche C. Reinisch W. Vogelsang H. et al.Prospective evaluation of interferon-a in treatment of chronic active Crohn’s disease.Dig Dis Sci. 1995; 40: 800-804Crossref PubMed Scopus (50) Google Scholar Several open-label, non–placebo-controlled series using IFN-alfa in patients with UC have delivered promising results15Sumer N. Palabiyikoglu M. Induction of remission by interferon-alpha in patients with chronic active ulcerative colitis.Eur J Gastroenterol Hepatol. 1995; 7: 597-602PubMed Google Scholar, 16Madsen S.M. Schlichting P. Davidsen B. et al.An open-labeled, randomized study comparing systemic interferon-alpha-2A and prednisolone enemas in the treatment of left-sided ulcerative colitis.Am J Gastroenterol. 2001; 6: 1807-1811Google Scholar as well as our own noncontrolled pilot trial with IFN-β,17Musch E. Andus T. Malek M. Induction and maintenance of clinical remission by interferon-beta is safe and successful in patients with steroid-refractory active ulcerative colitis—an open long-term pilot trial.Aliment Pharmacol Ther. 2002; 16: 1233-1239Crossref PubMed Scopus (54) Google Scholar which was the basis for planning 2 dose levels of 1 MIU and 3 MIU recombinant interferon-β-1a (rIFN-β-1a) in our randomized, double-blind, placebo-controlled, multicenter trial. The decision to use IFN-β instead of IFN-alfa for treatment refers to in vitro studies in which IFN-β, in contrast to IFN-alfa, did not interfere with the arachidonic or the leukotriene B4 pathway.18Hoffmann T. Lizzio E.F. Marshall L.A. et al.Release of arachidonic acid metabolite by human monocytes or lymphocytes effect of treatment with interferon on stimulation by phorbol ester or calcium ionophore.Clin Immunol Immunopathol. 1987; 44: 82-92Crossref PubMed Scopus (19) Google Scholar, 19Ito M. Ishida E. Tanabe F. et al.Interferon-alpha enhances the production of leukotriene B4 in murine peritoneal macrophages stimulated by opsonized zymosan.Immunology. 1987; 60: 617-619PubMed Google Scholar Therefore, this type of interferon reduces the risk for promoting proinflammatory chemical mediators.Materials and MethodsStudy DesignThe study was a European, double-blind, placebo-controlled, multicenter trial of 3 parallel treatment groups of outpatients with steroid-refractory UC and was approved by the ethics committee of the Westphalian Wilhelms University, Münster, Germany, the Westphalian-Lippe General Medical Council, and by the respective ethics committees and General Medical Councils of all participating study centers. It was performed in accordance with the Second Helsinki Declaration and later amendments. Informed written consent was obtained from all participants. Supervision was performed by a steering committee of investigators who were blinded from the results throughout the trial. The steering committee reviewed the prospectively scheduled interim analysis of safety and efficacy performed after half of the patients had been enrolled.Patients and TreatmentPatients eligible for randomization were at least 18 years of age and had an established diagnosis of active UC defined by clinical, histologic, and/or endoscopic findings. The extension had to be more than 15 cm from the anus with acute lesions to be identified by rectosigmoidoscopy. The clinical activity index (CAI) as published by Rachmilewitz20Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis a randomised trial.BMJ. 1989; 298: 82-86Crossref PubMed Scopus (962) Google Scholar had to be at least 8 points. A steroid-refractory situation was assumed when the reduction of the CAI during a 4-week prestudy treatment phase with mesalamine of 3 g/day or greater (orally plus the optional topical administration) including a cumulative corticosteroid dose of 450 mg or greater was less than 5 points and did not decrease below the absolute limit of 8 points. From the beginning of the study, the dose as well as the mode of application of the conventional therapy had to remain constant. A tapering off of the steroid dose according to the procedure suggested by the European Cooperation Crohn’s Disease Study (ECCDS) was not permitted until the patient’s CAI had decreased below the limit of 4 points or less. Immunosuppressive or immunomodulatory treatment and putative treatments for UC were not permitted within the 4 weeks before entry and throughout the study. The use of nonsteroidal anti-inflammatory medication including ibuprofen was allowed.Patients were assigned to either 3 or 1 MIU rIFN-β-1a (group A or B, respectively), or to placebo (group C) by a central randomization schedule. According to the study protocol, access to the code was limited strictly. The patients had to inject rIFN-β-1a or placebo subcutaneously 3 times a week over a period of 8 weeks. Regular visits were scheduled for days 1, 3, and 5 from weeks 2–8, during which patients underwent regular assessments unless they withdrew consent. Treatment had to be discontinued in case of intolerable adverse events, clinically relevant laboratory deviations, pregnancy, or progression of disease (ie, increase of ≥6 points at 2 consecutive visits).Efficacy ParametersThe primary end point was the evaluation of the response rate at the end of treatment. Response was defined as reduction of 6 or more CAI points at week 8 compared with baseline. Secondary efficacy parameters were (1) number of patients with complete response (CR) = reduction of CAI to 4 score points or less after 8 weeks of treatment, (2) time until response, (3) reduction of CAI after 4 and 8 weeks, (4) reduction of the endoscopic index after 8 weeks, (5) number of patients receiving colectomy, and (6) reduction of steroid dose.Statistical AnalysisData management and statistical analyses were performed by an external institution (nQuery Advisor, by J. D. Elashoff, Los Angeles, CA; BZT GmbH, München, Germany). The sample size estimation was based on a comparison of response rates. Thirty-five percent was determined as the relevant clinical difference (effect size) between the placebo group and the active drug groups. To show a difference of 35% between the treatment groups with a significance level of P = .05 and a power of 1 − β = .80, 35 patients were scheduled to be included in each treatment group. The scheduled total sample size was 105 patients, including a calculated drop-out rate of 10%.Confirmatory analysis was performed in 3 steps by using the χ2 and Fisher exact test (2-sided). Because a closed test procedure was applied, no adjustment of the significance level was required. Because 1 interim and 1 final analysis were performed, the significance level was adjusted according to group-sequential testing procedures of O’Brien/Fleming.21Koepcke W. Hasford J. Weber-Falkensammer H. et al.Rheumatology trials selection of adequate response variables and their evaluation.Rev Epidemiol Sante Publique. 1984; 32: 237-242PubMed Google Scholar The α level was .05 for the interim analysis and .0482 for the final analysis.Missing values in the CAI were imputed by a last-value-carried-forward procedure if at least 1 efficacy parameter was available and at least 1 application of the study medication was received by the patient. This missing value imputation procedure was performed for weeks 2–24. If a CAI value was available for any week during therapy but missing for baseline, the first available CAI value of the therapy was used as the baseline value.ResultsPatient CharacteristicsBetween February 1998 and January 2001, 98 patients (37 women, 54 men) were screened for the study. After 3 years of recruitment the study was terminated prematurely by the sponsor before the intended 105 patients could be included because of slow recruitment. Ninety-one of the 98 randomized patients received 3 MIU rIFN-β-1a (group A, n = 32), 1 MIU rIFN-β-1a (group B, n = 30), or placebo (group C, n = 29). Seven of the 98 patients were not treated because they failed to fulfill the criteria for the intention-to-treat analysis. The baseline demographic characteristics for the 91 randomized patients are shown in Table 1. Patient characteristics did not differ significantly among treatment groups.Table 1Patient Characteristics at Inclusion (Intention-To-Treat Population)Characteristics3-MIU group1-MIU groupPlacebo groupTotal patients (n)323029Age (median)38.034.538.0Sex Male (n)211815 Female (n)111214Ethnic group (Caucasian/African American)32/030/028/1Median duration of disease (y)7.56.73.2Median duration of last attacks (days)11610Bacteriology (positive/negative/not defined)0/31/10/30/00/28/1Median endoscopic index1099Median CAI101010Time in response (mean/median; days)32.1/29.034.3/27.536.2/39.0Extent of disease (n) Proctitis203 Protosigmoiditis8118 Left-sided UC998 Extended colitis224 Pancolitis185Extraintestinal manifestation (n) Iritis112 Erythema nodosum001 Arthritis1699 Other110 Open table in a new tab Figure 1 shows the flow chart describing the progress of patients through the 3 different treatment arms reaching study evaluation. Of the 91 patients, 16 patients dropped out until week 8 (at 17.5%, this was higher than expected). Reasons for the discontinuation were withdrawal of informed consent (n = 7), uncooperative patients (n = 3), worsening of health (n = 2), protocol violation (n = 1), participation in other studies (n = 1), intolerable adverse events (n = 1), and unspecified other reasons (n = 1).Intention-to-Treat AnalysisPrimary efficacy parametersThe main efficacy parameter was the response rate at the end of the treatment, defined by a reduction of 6 or more CAI points after the 8-week treatment period. This response was achieved by 18 of 32 patients (56%), 11 of 30 patients (36%), and by 10 of 29 patients (34%) in groups A, B, and C, respectively. The median course of the CAI up to the end of treatment is shown in Figure 2. In all groups, the median CAI at baseline (before onset of therapy) was 10, and at the end of treatment it decreased to 4 score points in group A, to 7 points in group B, and to 6 points in group C. The differences between groups A, B, and C were not statistically significant in both cases.Figure 2Median values of CAI from baseline to week 8 for the different treatment groups.View Large Image Figure ViewerDownload (PPT)Secondary efficacy parametersThe secondary efficacy parameters were as follows: (1) the highest percentage of patients with CR (reduction of CAI to ≤4 points after 8 weeks of treatment) was seen in the 3 MIU group with 56% (18 of 32), compared with the placebo group with 38% (11 of 29) and the 1 MIU group with 30% (9 of 30). The difference between the 3 MIU and the 1 MIU group was statistically significant (P = .04), but not significant when compared with placebo. Differences between groups A, B, and C were not statistically significant in all other cases of secondary efficacy parameters. (2) The mean time from the first application of medication to response was 32.1 ± 17.9 days (median, 29.0 days; range, 4–60 days) in group A, 34.3 ± 20.0 days (median, 27.5 days; range, 0–62 days) in group B, and 36.2 ± 16.4 days (median, 39.0 days; range, 4–57 days) in group C. (3) From baseline to week 4 and week 8, patients in group A showed the most pronounced reduction of CAI with a median of 5 score points at week 4, and 6 points at week 8, compared with group B with a median reduction of 3 and 3 points, respectively. (4) The reduction of the endoscopic index was calculated as the difference between points at baseline and week 8. Group A exhibited the best result with a mean reduction of 4.4 ± 3.4 points (median, 5.0 points; range, 5–9 points), followed by group C with 3.6 ± 3.4 points (median, 4.0 points; range 4–10 points), and by group B with 3.3 ± 4.1 points (median, 3.0 points; range, 3–9 points). (5) Two colectomies were performed in this study: in 1 patient from the placebo group after 3 weeks, and in 1 patient from the 1-MIU group after 8 weeks. No colectomy was performed for any patients in the 3-MIU group. (6) There was a mean reduction of prednisolone equivalents of 11.7 ± 18.5 mg in group A, 5.5 ± 20.5 mg in group B, and 9.5 ± 14.1 mg in group C. Overall, in patients obtaining 3 MIU per application, steroids could be reduced most effectively.SafetyThroughout the study, 68% (62 of 91) of patients experienced 618 adverse events. The most frequent occurrences were headache, arthralgia, myalgia, abdominal pain, fatigue, back pain, nausea, application site reactions, rigors, fever, and vomiting. Adverse events obviously associated with rIFN-β-1a treatment were fatigue, back pain, application site reaction, and rigors. There were no deaths in the study. Overall, 7 serious adverse events were reported in 5 patients: chest pain, aggravated condition, pharyngitis, malaise, infection, respiratory disorder, and anemia. The relationship to the study medication generally was estimated as none or unlikely. Apart from chest pain (3-MIU group), all other serious adverse events were seen in patients from the placebo group.The tolerance of treatment was assessed independently by the patient and the investigator on a weekly basis, and was judged as very good, good, moderate, poor, or very poor. During week 1, the majority of the investigators rated the treatment tolerance as very good or good in the 3-MIU group (very good, 28.1%; good, 56.3%; moderate, 12.5%; very poor, 3.1%), as well as in the 1-MIU group (very good, 33.3%; good, 56.7%; moderate, 10.0%), and the placebo group (very good, 34.5%; good, 55.2%; moderate, 10.3%). There were only minor changes throughout the remaining study period, and there were no noticeable differences between the 3 groups.DiscussionThe present randomized, double-blind, placebo-controlled trial with rIFN-β-1a showed that rIFN-β-1a was safe and without major side effects in steroid-refractory UC. Even the side effects typical for rIFN-β-1a did not significantly increase compared with placebo.The analysis of the primary end point (response = reduction of CAI ≥6 points after a treatment period of 8 weeks) with 56%, 36%, and 34% of patients in the 3-MIU, 1-MIU, and placebo group, respectively, showed no significant efficacy of rIFN-β-1a compared with placebo. Even with most of the secondary parameters, including the endoscopic results, suggesting a trend of efficacy and the difference of the CR (reduction of CAI to ≤4 points) between the 3-MIU and 1-MIU group reaching a significance level of .04, there was no statistically significant difference between rIFN-β-1a and placebo.We know of 6 other, mostly open labeled and successful, trials that used IFN-alfa or IFN-β in patients with UC. Sumer and Palabiyikoglu15Sumer N. Palabiyikoglu M. Induction of remission by interferon-alpha in patients with chronic active ulcerative colitis.Eur J Gastroenterol Hepatol. 1995; 7: 597-602PubMed Google Scholar described how 23 of their 28 steroid-refractory patients (82%) responded to high-dose rIFN-alfa-2a therapy (starting dose of 9 MIU three times/wk) with rapid improvement within 15 days. The investigators showed CR and endoscopic response after 6 months of maintenance therapy with 3 MIU. Treatment of UC patients with high-dose rIFN-alfa-2a (9 MIU during the first week, 6 MIU during the second week, 3 MIU during weeks 3–12, 3 times a week) performed by Madsen et al16Madsen S.M. Schlichting P. Davidsen B. et al.An open-labeled, randomized study comparing systemic interferon-alpha-2A and prednisolone enemas in the treatment of left-sided ulcerative colitis.Am J Gastroenterol. 2001; 6: 1807-1811Google Scholar resulted in significant depression of the disease activity as reflected by the Powell–Tuck Index, Inflammatory Bowel Disease Questionnaire score, and histologic disease activity scoring. Ruther et al22Ruther U. Nunnensiek C. Muller H.A. et al.Interferon alpha (IFN alpha 2a) therapy for herpes virus-associated inflammatory bowel disease (ulcerative colitis and Crohn’s disease).Hepatogastroenterology. 1998; 45: 691-699PubMed Google Scholar treated only 4 steroid-refractory patients with rIFN-alfa-2a, thus, no meaningful statistics can be calculated. Tilg et al23Tilg H. Vogelsang H. Ludwiczek O. et al.A randomised placebo controlled trial of pegylated interferon alpha in active ulcerative colitis.Gut. 2003; 52: 1728-1733Crossref PubMed Scopus (87) Google Scholar failed to show an efficacy of pegylated IFN-alfa with dosages of .5 or 1.0 μg/kg body weight compared with placebo once a week over a period of 12 weeks in patients with active UC. In their randomized, placebo-controlled trial with 60 patients they observed 47%, 33%, and 35% CR, respectively, without significant differences. The investigators conclude that higher doses probably would have been more effective.In our open-labeled, non–placebo-controlled trial in steroid-refractory patients (n = 25) with .5-MIU natural IFN-β or 1.0-MIU rIFN-β-1a once a day, respectively, we could show that 22 of 25 patients (88%) achieved a CR in a mean time of 3 weeks.17Musch E. Andus T. Malek M. Induction and maintenance of clinical remission by interferon-beta is safe and successful in patients with steroid-refractory active ulcerative colitis—an open long-term pilot trial.Aliment Pharmacol Ther. 2002; 16: 1233-1239Crossref PubMed Scopus (54) Google Scholar A randomized, placebo-controlled, dose-escalating study with rIFN-β-1a was published recently. The investigators showed that 18 patients with moderately active UC who were treated with rIFN-β-1a or placebo (22 μg for weeks 1–2, 44 μg for weeks 3–4, and if no response was observed from weeks 4–8 then 88 μg 3 times/wk over a maximum treatment period of 8 weeks) achieved a response in 50% and 14%, respectively. The difference was statistically significant. Thus, an efficacy of rIFN-β-1a could be shown.24Nikolaus S. Rutgeerts P. Fedorak R. et al.Interferon beta-1a in ulcerative colitis a placebo controlled, randomised, dose escalating study.Gut. 2003; 52: 1286-1290Crossref PubMed Scopus (94) Google ScholarOne possible explanation as to why the present study failed to show a significant result of the primary end point could be the fact that the study was stopped prematurely before the calculated number of patients had been enrolled (91 treated patients instead of 105 patients). Furthermore, we observed a considerably high placebo response rate (34%; CR, 38%) comparable with the findings of the controlled trial of Tilg et al23Tilg H. Vogelsang H. Ludwiczek O. et al.A randomised placebo controlled trial of pegylated interferon alpha in active ulcerative colitis.Gut. 2003; 52: 1728-1733Crossref PubMed Scopus (87) Google Scholar (35% CR using the same response criteria as in our study). These results are much higher than described by Ilnyckyj et al,25Ilnyckyj A. Shanahan F. Anton P.A. et al.Quantification of the placebo response in ulcerative colitis.Gastroenterology. 1997; 112: 1854-1858Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar who quantified the placebo effect in 38 controlled trials of active UC (9.1%; confidence interval, 6.6–11.6). On the other hand, they suggested that the placebo response was greater in trials with more frequent study visits (>3). Thus, our high placebo response rate may be owing to the fact that we had a high frequency of study visits (3 times/wk over the total treatment period). Additionally, it is possible that a subcutaneous injection has a higher placebo rate than oral administration.Another reason as to why our study failed to show an efficacy of rIFN-β-1a may be the considerably high drop-out rate (17.5% was higher than calculated), mainly owing to withdrawal of consent and uncooperative patients. Interestingly, in the controlled trial of Tilg et al,23Tilg H. Vogelsang H. Ludwiczek O. et al.A randomised placebo controlled trial of pegylated interferon alpha in active ulcerative colitis.Gut. 2003; 52: 1728-1733Crossref PubMed Scopus (87) Google Scholar early withdrawal from the study was observed in all treatment groups, with a total of 45%. Thus, a high drop-out rate for patients with active UC seems likely. This observation is confirmed by Madsen et al16Madsen S.M. Schlichting P. Davidsen B. et al.An open-labeled, randomized study comparing systemic interferon-alpha-2A and prednisolone enemas in the treatment of left-sided ulcerative colitis.Am J Gastroenterol. 2001; 6: 1807-1811Google Scholar (drop-out rate of 18.8%).Additionally, high remission rates were obtained with rIFN-alfa-2a using high doses and a long duration of treatment, for up to 6 months.15Sumer N. Palabiyikoglu M. Induction of remission by interferon-alpha in patients with chronic active ulcerative colitis.Eur J Gastroenterol Hepatol. 1995; 7: 597-602PubMed Google Scholar, 16Madsen S.M. Schlichting P. Davidsen B. et al.An open-labeled, randomized study comparing systemic interferon-alpha-2A and prednisolone enemas in the treatment of left-sided ulcerative colitis.Am J Gastroenterol. 2001; 6: 1807-1811Google Scholar Thus, the present study might have been more successful with a higher dose and/or a longer duration of treatment.Our data suggest that rIFN-β-1a therapy, at the low doses used and with a short treatment period, was safe but not effective in steroid-refractory UC. In conclusion, rIFN-β-1a therapy in steroid-refractory UC, at the low doses used and with a short treatment period, results in a reduction of the CAI score, however, not at a significant level when compared with placebo. The therapy was safe. Further clinical trials should investigate higher doses and the duration of initial treatment. It may be of interest to test whether safe low doses of rIFN-β-1a can maintain remission in this chronic relapsing disorder. Ulcerative colitis (UC) is a chronic relapsing inflammatory bowel disease of unknown cause. Standard treatment of UC includes 5-aminosalicylates such as sulfasalazine and mesalamine combined with corticosteroi" @default.
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• W2018902013 title "Interferon-β-1a for the Treatment of Steroid-Refractory Ulcerative Colitis: A Randomized, Double-Blind, Placebo-Controlled Trial" @default.
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• W2018902013 doi "https://doi.org/10.1016/s1542-3565(05)00208-9" @default.
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