Systematic review/Meta-analysis An indirect comparison of infliximab versus adalimumab or golimumab for active ulcerative colitis Paweł Kawalec1, Andrzej Pilc2 1Drug Management Department, Institute of Public Health, Faculty of Health Corresponding author: Sciences, Jagiellonian University Medical College, Krakow, Poland Paweł Kawalec 2Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland Drug Management Department Submitted: 13 May 2015 Institute of Public Health Accepted: 19 October 2015 Faculty of Health Sciences Jagiellonian University Arch Med Sci 2016; 12, 5: 1097–1109 Medical College DOI: 10.5114/aoms.2016.58682 20 Grzegorzecka St Copyright © 2016 Termedia & Banach 31-531 Krakow, Poland Phone: +48 607 345 792 E-mail: Abstract [email protected] Introduction: The aim of the study was to compare adalimumab or golimum- ab with infliximab in patients with moderately-to-severely active ulcerative colitis (UC). Material and methods: This paper was prepared according to the PRISMA guidelines. The systematic literature search was performed in PubMed, Em- base, and Cochrane Library. No direct head-to-head comparisons for inflix- imab vs. adalimumab or golimumab were available so an indirect compar- ison according to the Bucher method was performed after a homogeneity evaluation of the included studies. Results: Six RCTs were included in the systematic review. An indirect com- parison was performed, which revealed that infliximab was more effective in inducing clinical response compared with both doses of adalimumab (160/80 mg or 80/40 mg; p < 0.05), and, in clinical remission, infliximab was more effective than adalimumab (only for a dosage regime of 80/40 mg; p < 0.05). No statistically significant differences in clinical response and clin- ical remission were observed between infliximab and golimumab in the in- duction phase. A significant (p < 0.05) advantage only of infliximab compared with adalimumab at doses of 80/40 mg and 80/160 mg was seen in terms of clinical response in the maintenance phase (up to 52–54 weeks). The indirect comparison revealed that serious adverse events were significantly more fre- quent among patients treated with a maintenance dose of 100 mg of golim- umab compared with those treated with infliximab (p < 0.05). Conclusions: No significant differences in efficacy in the maintenance phase between infliximab and golimumab or adalimumab were revealed. Infliximab proved to be more effective than adalimumab but of similar efficacy to that of golimumab in the induction phase. Key words: infliximab, adalimumab, golimumab, ulcerative colitis, biological therapy, systematic review, indirect comparison. Introduction Ulcerative colitis (UC) is a type of inflammatory bowel disease that af- fects the mucosa of the colon [1–3], usually diagnosed at the age of 20 to 30 years, and is always a chronic life-long condition [4]. The condition is more and more common worldwide, especially in highly developed soci- eties, and its prevalence varies by geographic region, ranging from 4.9 to 505 per 100 000 in Europe, 4.9 to 168.3 per 100 000 in Asia and the Mid- Paweł Kawalec, Andrzej Pilc dle East, and 37.5 to 248.6 per 100 000 in North efficacy. Therefore, we applied a valid, adjusted America [3, 4]. The fact that the highest incidence indirect comparison assessment according to the and prevalence of UC are in the populations of Eu- Bucher method, being one of the most suitable rope and North America is considered to be linked approaches for indirect treatment comparisons of to genetic factors, environment, and lifestyle, par- randomized controlled trials (RCTs). This method ticularly to a diet high in fat and sugar, alcohol, is based on the assumption that indirect evidence medication use, stress, and high socioeconomic is consistent with the direct comparison. It is also status [1, 3, 5–12]. The goal of therapy in UC is to based on a meta-analysis but compares the value induce and maintain remission, improve quality of of treatment effects in RCTs of the interventions life, and prevent colectomy [13–15]. in comparison with placebo or a control group. Conventional therapy of ulcerative colitis in- Supposing that treatments A and C are compared cludes corticosteroids and immunosuppressives in one RCT, and treatments B and C are compared (e.g. azathioprine, methotrexate); in the case of in another RCT, then the indirect comparison of lack of such therapy, biologic treatment should A and B is adjusted according to the results of be introduced; moreover, in some patients there their direct comparisons with a common inter- is no clinical improvement after pharmacothera- vention (comparator) – C [21, 22]. In our previous py, so surgery (colectomy) has to be performed. study, we analyzed the efficacy and safety of bi- Immunosuppressives have limited efficacy due to ologic drugs in comparison with placebo for the inadequate control of the disease, especially in treatment of active UC [3]. Currently, we would patients with more advanced disease, and this is like to perform further research to investigate the often associated with the risk of intolerance or re- difference between biologics with the best meth- sistance to concurrent treatment [3, 13]. Because od available – an indirect comparison. of that and the increasing prevalence of UC [5], identification of an alternative and more effec- Material and methods tive treatment is crucial to increase the number of Search strategy and study selection available therapeutic options and to improve clini- cal outcomes [3]. In a number of patients a biolog- As described in detail previously [3] the sys- ic therapy is used with tumor necrosis factor (TNF) tematic review was conducted and reported ac- antagonists; among them infliximab is the most cording to the methods and recommendations commonly used; other potentially useful mono- from the Preferred Reporting Items for Systematic clonal antibodies for UC include adalimumab and Reviews and Meta-Analysis (PRISMA) Statement golimumab [3]. Infliximab, adalimumab and goli- [23] and the Cochrane Handbook [24]. The sys- mumab have been approved for the treatment of tematic literature review was conducted using the UC by the U.S. Food and Drug Administration (FDA) main electronic databases, Medline via PubMed, and the European Medicines Agency (EMA) [16, Embase, and the Cochrane Central Register of 17]; infliximab was the first biologic agent autho- Controlled Trials, until 27 November 2014. The key rized in the therapy of UC; currently it is very often words ulcerative colitis (population) and inflix- used for this indication, usually in the first stage imab or adalimumab or golimumab (intervention) of biologic therapy; adalimumab and golimumab were used to find relevant citations. Only English, are newer alternatives; the most recent, golimum- French, and German publications were includ- ab, was introduced in the European Union for this ed. The search strategy was presented with the indication in 2013. Infliximab, adalimumab, and QUOROM diagram (Figure 1). Two reviewers inde- golimumab are antagonists of the TNF. All of them pendently conducted the search and selection of bind soluble and transmembrane TNF, neutralizing studies on the basis of the previously established TNF activity and inhibiting binding to TNF recep- inclusion criteria. The decision for inclusion was tors. In addition, infliximab and adalimumab are made by consensus to reach the final decision. responsible for the induction of activated T cells The Clinical Trials Register (www.clinicaltrials.gov) and macrophage apoptosis; adalimumab also ly- was searched for unpublished or ongoing trials. ses TNF-expressing cells by complement-depen- Compared datasets included data only from dent cytotoxicity [3, 18–20]. randomized, double-blind, placebo-controlled, and Therefore, the aim of this systematic review parallel trials of phase II/III studies. Results from was to evaluate the clinical efficacy and safety of nonrandomized or uncontrolled open-label stud- newer biologic drugs (adalimumab and golimum- ies were not incorporated into the dataset [25]. ab) in comparison with infliximab in patients with The population of interest comprised adults with moderately-to-severely active UC. Owing to the moderately-to-severely active UC (confirmed by lack of evidence from head-to-head studies com- biopsy and defined as a Mayo score ranging from paring different biologics, an indirect method may 6 to 12 points with an endoscopy subscore of at provide useful information about their relative least 2) despite concurrent treatment with stable 1098 Arch Med Sci 5, October / 2016 An indirect comparison of infliximab versus adalimumab or golimumab for active ulcerative colitis Records identified through main database searching Additional records identified (PubMed 321; Embase 599; through other sources 128 Cochrane 443) Records screened after duplicates removed: 766 Records excluded on basis of title and abstract: 659 Full-text articles assessed for eligibility: 107 Full-text articles excluded, with reasons: N = 64 – retrospective analysis of included studies (no predefined endpoints) N = 8 – pooled analysis of two or more trials Articles from hand searching of reference lists: 1 N = 5 – efavirenz included in every treatment arm N = 1 – previously treated patients Studies included in qualitative synthesis: 34 RCTs described in 44 references Studies included in quantitative synthesis (meta-analysis): 26 RCTs Figure 1. Study flow diagram showing the results of the search