Budesonide for the Induction and Maintenance of Remission in Crohn’s Disease: Systematic Review and Meta-Analysis for the Cochrane Collaboration

Budesonide for the Induction and Maintenance of Remission in Crohn’s Disease: Systematic Review... Background: Budesonide is an oral glucocorticoid designed for the treatment of inflammatory bowel disease (IBD) that may reduce systemic adverse events (AEs). This review examined the efficacy and safety of budesonide for the induction and maintenance of clinical remission in Crohn’s disease (CD). Methods: MEDLINE, EMBASE, other electronic databases, reference lists and conference pro- ceedings were searched to November 2017 to identify randomized controlled trials of budesonide. Outcomes were the induction and maintenance of remission at eight weeks and one year, respectively, as well as corticosteroid-related AEs and abnormal adrenocorticotropic hormone (ACTH) tests. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random effects models. Results: Thirteen induction and 10 maintenance trials were included. Budesonide 9  mg/day was more effective than placebo (RR 1.93; 95% CI, 1.37–2.73; GRADE: moderate) but less effective than conventional steroids (RR 0.85; 95% CI, 0.75–0.97; GRADE: moderate) to induce remission. Corticosteroid-related AEs occurred less often with induction doses of budesonide than steroids (RR 0.64; 95% CI, 0.54–0.76; GRADE: moderate); budesonide did not increase AEs relative to placebo (RR 0.97; 95% CI, 0.76–1.23; GRADE: moderate). Budesonide 6  mg/day was not different from placebo for maintaining remission (RR 1.13; 95% CI, 0.94–1.35; GRADE: moderate). Both induc - tion (GRADE: low for 3  mg/day, moderate for 9  mg/day) and maintenance budesonide treatment (GRADE: very low for 3  mg/day, low for 6  mg/day) increased the risk of an abnormal ACTH test compared with placebo, but less than conventional steroids (GRADE: very low for both induction and maintenance). Conclusion: For induction of clinical remission, budesonide was more effective than placebo, but less effective than conventional steroids. Budesonide was not effective for the maintenance of remission. © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 1 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 2 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Budesonide was safer than conventional steroids, but the long-term effects on the adrenal axis and bone health remain unknown. Keywords: Budesonide; Corticosteroids; Crohn’s disease; Induction and maintenance of remission; Meta-analysis Study identification and selection INTRODUCTION RCTs of oral budesonide therapy (CIR or pH-dependent Crohn’s disease (CD) is characterized by chronic transmural release formulations) for the induction or maintenance of inflammation of the gastrointestinal tract. Patients experience remission published in any language were included. Participants abdominal pain, diarrhea and fatigue. CD typically follows a were patients of any age with CD defined by conventional clin- relapsing and remitting disease course. Medications used in the ical, radiological and endoscopic criteria. Studies comparing management of CD suppress the inflammatory response. budesonide to placebo or another active agent were consid- Corticosteroids are a mainstay of treatment for acute flares of ered for inclusion in this review. Studies comparing different CD (1, 2). However, systemic corticosteroids are associated with doses of budesonide were excluded if they did not also include adverse effects such as moon facies, acne, infection (including an a non-budesonide comparison arm. Concomitant therapy was increased risk of abdominal and pelvic abscess in CD patients), permitted, provided it was balanced between treatment and ecchymoses, hypertension, diabetes mellitus, osteoporosis, cata- control groups. racts, glaucoma and growth failure in children (1). More impor- We searched PubMed, MEDLINE (2014-November tantly, the use of systemic corticosteroids has been independently 2017), EMBASE (2014-November 2017)  and the Cochrane associated with mortality in patients with CD (3). Central Register of Controlled Trials (to November 2017). Budesonide is a glucocorticoid with limited systemic bioavail- RCTs published before 2014 were identified from Cochrane ability, due to extensive (90%) first-pass hepatic metabolism by reviews on the efficacy of budesonide in Crohn’s disease by the cytochrome p-450 enzyme system. These properties limit sys - Kuenzig et  al. (maintenance, 2014)  (5) and Rezaie et  al. temic adverse effects. Budesonide is commercially available in two (induction, 2015)  (6). The search strategy is outlined in forms: an oral controlled ileal release (CIR) preparation designed Table  S1 of the supplementary materials. Ongoing and to deliver the drug to the distal small intestine (Entocort®, Astra unpublished trials were identified using clinicaltrials.gov. Zeneca, London, UK; Entocir®, Sofar S.p.A, Trezzano Rosa, Reference lists of trials and review articles were reviewed to Italy; Budecol®, AstraZeneca A&D, Lund, Sweden) and a pH-de- identify additional studies. Relevant pharmaceutical com- pendent release formulation (Budenofalk® or Budeson®, Dr Falk panies were contacted for ongoing studies. Abstracts were Pharma, Freiburg, Germany). The controlled ileal release med - screened for eligibility independently by two study authors ication is in the form of a gelatin capsule containing acid-stable (MEK and AR). Full-text articles were independently microgranules composed of an inner sugar core surrounded by a reviewed by two authors (MEK and AR). Disagreements layer of budesonide in ethylcellulose and an outer acrylic-based were resolved by consensus and consultation with resin coating (Eudragit L 100-55) that dissolves at a pH higher EIB and CHS. than 5.5. The pH-dependent release formulation is available as a capsule containing 400 pellets of budesonide coated with Outcomes Eudragit resistant to a pH of less than six (4). Induction of remission was defined by a Crohn’s Disease This systematic review and meta-analysis provides a sum- Activity Index (CDAI) <150 or a Pediatric Crohn’s Disease mary of the evidence from randomized controlled trials Activity Index (PCDAI) <10 by eight weeks of therapy. (RCTs) with regard to the safety and efficacy of budesonide Maintenance of remission was defined as the proportion for the induction and maintenance of remission in CD. This of patients in continued remission at 12 months, as defined systematic review and meta-analysis is based on two recent by each trial. If patients were followed beyond these prede- reviews published by the Cochrane collaboration (5, 6) and is termined time points, only eight-week and 12-month data updated to November 2017. were pooled for induction and maintenance trials, respec- tively. Inductions studies with less than eight weeks of fol- MATERIALS AND METHODS low-up and maintenance studies with less than 12  months This systematic review and meta-analysis was conducted based of follow-up were excluded. Corticosteroid-related adverse on a previously published protocol (5–10) and in accordance events (AEs) and abnormal ACTH stimulation tests were with the PRISMA guidelines (11). also assessed. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 3 the authors of this study did not define remission. Two main- Data extraction tenance studies that had been included in the last Cochrane Two authors (MEK and AR) independently extracted data review (5) were excluded. One did not have sufficient fol - from each eligible study, including the following elements: low-up, reporting relapse rates at 13 weeks (17), and the other study design and quality; formulation and dose of budesonide; did not include a nonbudesonide treatment group (18). This comparator; study inclusion/exclusion criteria; age of partici- left 13 induction and 10 maintenance trials for inclusion in the pants; trial duration; method used to induce remission (main- updated meta-analysis (Figure  1). There was 100% agreement tenance trials); and all study outcomes including definition of among reviewers regarding the eligibility of the included stud- remission (induction trials), definition of relapse (maintenance ies. The characteristics of included induction and maintenance trials), corticosteroid-related AEs and abnormal ACTH stim- studies are provided in Tables  1 and 2, respectively. Table  S2 ulation tests. Prespecified subgroup analyses were conducted (see supplementary materials) outlines the reasons for study based on the dose and formulation of budesonide (CIR versus exclusion. pH-dependent), disease location, the method used to induce remission (e.g., medical versus surgical induction, maintenance Risk of bias in included studies trials) and the age of trial participants (pediatric versus adult). Three induction trials had a high risk of bias ( Table  S3 of the supplementary materials) (19–21). Two failed to ensure appro- Risk of bias priate blinding (open label studies) (19, 20). One selectively The risk of bias of included studies was assessed independently reported study outcomes, failing to outline AEs for each study by two reviewers (MEK and AR) using the Cochrane group (21). Three maintenance studies had a high risk of bias Collaboration’s tool (http://methods.cochrane.org/bias/ (Table  S4 of the supplementary materials) due to failure to assessing-risk-bias-included-studies) (12). Disagreements blind participants (22, 23) and outcome assessors (24). In were resolved by consensus. The overall quality of evidence addition, allocation was not adequately concealed in one main- was assessed using the GRADE approach, incorporating risk of tenance trial (22). bias (methodological quality), indirectness of evidence, unex- plained heterogeneity, imprecision (sparse data) and publica- Budesonide to induce remission tion bias (12, 13). At eight weeks, 47% (115 of 246) of those receiving a daily dose of budesonide 9 mg/day entered remission compared with 22% Statistical analysis (29/133) of those receiving placebo (Figure 2). This difference Data were analyzed using Review Manager (RevMan 5.3.5, was statistically significant (pooled RR 1.93; 95% CI, 1.37– Copenhagen: The Nordic Cochrane Centre, The Cochrane 2.73, P = 0.00018; I  = 0%; three studies; 379 participants). The Collaboration, 2014). Data from individual studies were pooled 15 mg/day dose of budesonide was similarly superior to placebo for meta-analysis if the interventions, patient groups and out- (two studies), but there was no difference between budesonide comes were sufficiently similar (determined by consensus). 3 mg/day and placebo (one study; Figure S1 of the supplemen- Relative risks (RR) and their corresponding 95% confidence tary materials). All studies comparing budesonide to placebo intervals (CI) were calculated using random-effects models to used the CIR formulation of budesonide and excluded individ- allow for expected clinical and statistical heterogeneity across uals with distal colonic disease. No study provided subgroup studies (14). Heterogeneity was assessed by calculating the analyses based on disease severity, and all studies were limited to I measure, interpreted as low heterogeneity (25%), moder- adult participants. As assessed with the GRADE approach, there ate heterogeneity (50%) and high heterogeneity (75%) (15). was moderate quality of evidence for budesonide 9  mg/day Cochran’s χ test for homogeneity (Q test) was also calculated, and 15 mg/day to induce remission and low quality of evidence with P  <  0.10 considered statistically significant. Publication for budesonide 3 mg/day. The 9 mg/day and 15 mg/day doses bias was assessed using a visual inspection of funnel plots. were downgraded due to sparse data, and the 3  mg/day dose was downgraded due to very spare data. No evidence of publi- RESULTS cation bias was detected upon visual assessment of studies com- Description of studies paring budesonide 9 mg/day with placebo (Figure S2). The published Cochrane reviews (5, 6) included 14 induction Two studies compared budesonide with mesalamine. and 12 maintenance trials. The updated literature search yielded However, these studies could not be pooled due to significant 243 new records; 181 remained aeft r removing duplicates. heterogeneity (P = 0.002, I  = 81%). Budesonide was superior None of these were eligible for inclusion; therefore, no addi- to mesalamine in the trial by Thomsen et  al. (27) (RR 1.63; tional studies were included in the updated systematic review 95% CI, 1.23–2.16) but there was no significant difference and meta-analysis. One induction study (16) that had been between the two medications in the trial by Tromm et al. (28) included in the last Cochrane review (6) was excluded because (RR 1.12; 95% CI, 0.95–1.32). A similar proportion of patients Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 4 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Figure 1. Study flow diagram depicting results of electronic database search from 2014–2017. Trials published before 2014 were identified from two previous Cochrane reviews on the efficacy of budesonide, published in 2014 and 2015 (5, 6). receiving budesonide entered clinical remission at eight weeks for adult patients (pooled RR 0.85; 95% CI, 0.74–0.97; in both studies (68% and 69% for Thomsen et  al. (27) and P = 0.02; I  = 0%; si x studies; 669 par ticipants) and patients Tromm et al. (28), respectively). However, a greater proportion with severe disease as defined by CDAI ≥300 (pooled RR of patients receiving mesalamine entered clinical remission in 0.52; 95% CI, 0.28–0.95; P  =  0.03; I   =  0%; two studies; the study by Tromm et  al. (28) (62%) as compared with the 64 participants). Conventional steroids were no longer study by Thomsen et al. (27) (42%). Subgroup analysis based superior to budesonide when limiting the analyses to the on disease severity failed to explain between-study heteroge- pediatric population (pooled RR 0.87; 95% CI, 0.58–1.31; 2 2 neity (I   =  88% for mild-to-moderate disease as defined by a P  =  0.5; I   =  0%; two studies; 81 participants), those CDAI  <300; I   =  68% for severe disease as defined by CDAI with mild-to-moderate disease as defined by CDAI  <300 ≥300). Children were not included in either study. Using the (pooled RR 1.00; 95% CI, 0.65–1.56; P  =  0.99; I   =  67%; GRADE approach, the quality of evidence from each study two studies; 175 participants) or those with ileal or right- was rated as moderate. Both studies were downgraded due to sided ileocolonic disease (pooled RR 0.86; 95% CI, 0.75– sparse data. 1.00, P  =  0.05; I   =  0%; six studies; 561 participants). Conventional steroids induced remission in 61% (210 of Conventional steroids were superior to the CIR formula- 344)  of patients, whereas budesonide 9  mg/day induced tion of budesonide, but not the pH-dependent formulation remission in 52% (211 of 406; Figure  3). Budesonide was for the induction of remission (Table  S5 of the supple- inferior to conventional steroids (pooled RR 0.85; 95% mentary materials). According to the GRADE approach, CI,  0.75–0.97; P  =  0.012; I   =  0%; eight studies; 750 par- the evidence comparing budesonide with conventional ticipants). Subgroup analyses yielded similar findings steroids was of moderate quality and was downgraded due Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 5 Th TT Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 1. Characteristics of included induction trials Study Country (number Years of Number Interventions (Number of Formulation Age of Participants Definition of Definition of Duration of Disease Duration of centres) recruitment of Patients patients in each arm, ITT) (mean*) Active Disease Remission erapy (mean*) (I) Bar-Meir Israel (14) Not 201 Budesonide 3 mg tid (n=100) pH-dependent Adults (both CDAI 150–350 CDAI ≤ 150 8 weeks Both † † 1998 reported Prednisone 40 mg od for two arms: 33 y ) arms: 5 y (35) weeks, then tapered (n=101) ‡ § ¶ Campieri Europe, New Zealand, Not 178 Budesonide 9 mg od (n=58) CIR Adults (37 y) CDAI ≥200 CDAI ≤ 150 12 weeks 7 y 1997 Australia (26) reported Budesonide 4.5 mg bid (n=61) (36) Prednisolone 40 mg od for two weeks, then tapered (n=58) § ¶ Escher Europe (36) 1998–2000 48 Budesonide 9 mg daily (n=22) CIR Pediatric (13 y) CDAI ≥200 CDAI ≤ 150 12 weeks 0.7 y 2004 Prednisolone 1 mg/kg daily (37) for four weeks, then tapered (n=26) Greenberg Canada (27) 1991–1992 258 Budesonide 3 mg daily (n=67) CIR Adults (32 y) CDAI >200 CDAI ≤ 150 8 weeks 6 y 1994 Budesonide 9 mg daily (n=61) (38) Budesonide 15 mg daily (n=64) Placebo (n=66) Gross Europe (16) Not 67 Budesonide 3 mg tid (n=34) pH-dependent Adults (31 y) CDAI >150 CDAI ≤ 150 or 8 weeks 68 months (6 y) 1996 reported Methylprednisolone 48 mg for decrease ≥60 (39) 1 week, then tapered (n=33) if baseline CDAI > 200 Levine Israel (13) Not 35 Budesonide 3 mg tid (n=20) pH-dependent Pediatric PCDAI 12.5–40 PCDAI ≤ 10 10 weeks Not reported 2003 reported Prednisone 40 mg daily, then (14 y) (19) tapered (n=15) § ¶ Rutgeerts Europe (11) Not 176 Budesonide 9 mg daily (n=88) CIR Adults (34 y) CDAI >200 CDAI ≤ 150 or 10 weeks 7 y 1994 reported Prednisolone 40 mg daily for decrease in (40) two weeks, then tapered (n=88) CDAI > 100 § ¶ Suzuki Japan (21) 2006–2008 77 Budesonide 9 mg daily (n=26) CIR Adults (37 y) CDAI > 200 CDAI ≤ 150 10 weeks <10 y: 63/77 (82%) 2013 Budesonide 15 mg daily (n=25) ≥10 y: 14/77 (18%) (41) Placebo (n=26) Thomsen Europe, South 1994–1996 182 Budesonide 9 mg daily (n=93) CIR Adults (Budesonide: CDAI 200–400 CDAI ≤ 150 16 weeks Budesonide: 6 y ; ‖ ‖ 1998 Africa, Australia Mesalamine 2 mg bid (n=89) 34 y ; Mesalamine: Mesalamine: 5 y (28) (25) 31 y ) Tremaine USA (24) 1995–1997 200 Budesonide 9 mg od (n=80) CIR Adults (39 y) CDAI 200–400 CDAI ≤ 150 10 weeks 11 y 2002 Budesonide 4.5 mg bid (n=79) (42) Placebo (n=41) 6 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Th TT ft Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 1. Continued Study Country (number Years of Number Interventions (Number of Formulation Age of Participants Definition of Definition of Duration of Disease Duration of centres) recruitment of Patients patients in each arm, ITT) (mean*) Active Disease Remission erapy (mean*) (I) Tromm Europe and 2004–2008 311 Budesonide 9 mg od (n=81) pH-dependent Adults (37 y) CDAI 200–400 CDAI ≤ 150 8 weeks 6 y 2011 Israel (46) Budesonide 3 mg tid (n=77) (29) Mesalamine 4.5 mg daily (n=153) Tursi 2006 Italy (multicentre; 2004 30 Budesonide 9 mg od (n=15) CIR Adults (36 y) CDAI CDAI ≤ 150 8 weeks Not reported (20) number of Beclomethasone 150–250 centres not dipropionate 10 mg reported) daily (n=15) § ** ¶ Van Ierssel Netherlands (1) Not 18 Budesonide 9 mg od (n=9) CIR Adults (35 y ) CDAI ≥200 CDAI ≤ 150 10 weeks Not reported 1995 reported Prednisolone 40 mg daily for (21) two weeks, then tapered (n=9) ABBREVIATIONS: od, once daily; bid, twice daily; tid, three times daily; CIR , controlled ileal release; CDAI, Crohn’s Disease Activity Index; y, years. *Weighted average of all study arms. Unclear if study reported mean or median age and disease duration of trial participants. Campieri 1997 did not provide intention-to-treat numbers for each treatment arm. One patient was randomized but did not receive treatment, but it is not known which treatment arm this patient was randomized to. Dose of budesonide was tapered aer eight weeks. W hen trials followed patients beyond the primary endpoint of eight weeks, only remission data at eight weeks were pooled. Median. ** Average age for the full cohort was reported in the study. Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 7 Th Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 2. Characteristics of included maintenance trials Study Country Years of Number Interventions Formulation Age of Method to Induce Definition of Duration of Disease Duration (number of recruitment of Patients Participants Remission Disease Relapse erapy (mean*) centres) (mean*) Ewe Germany 1992–1994 83 Budesonide 1 mg pH-dependent Adults Surgically Endoscopic 1 year Budesonide: 1999 (43) (3) tid (n=43) (Budesonide: recurrence or 100 months (8 y) Placebo (n=40) 35 y ; Placebo: increase in CDAI Placebo: 81 † † 33 y ) from 60 up to 200 months (7 y) from first follow-up or CDAI > 200 Ferguson Europe, Not reported 75 Budesonide 6 mg CIR Adults (36 y) Medically induced CDAI ≥ 150 1 year 7 y 1998 (44) Australia bid (n=22) (budesonide (20) Budesonide 3 mg clinical trial) od (n=26) Placebo Greenberg Canada (23) 1992–1994 105 Budesonide 6 mg od CIR Adults (35.6 y) Medically induced CDAI ≥ 150 1 year 8 y 1996 (45) (n=36) Budesonide (budesonide 3 mg od (n=33) clinical trial) Placebo (n=36) Gross 1998 Germany Not reported 179 Budesonide 1 mg pH-dependent Adults (32 y) Medically induced CDAI > 150 for >2 1 year 63 months (5 y) (46) (multicentre; tid (n=84) (corticosteroids) subsequent weeks number of Placebo (n=95) or CDAI > 150 at centres not last visit reported) Hanauer United Not reported 110 Budesonide 6 mg od CIR Adults (40 y) Medically induced CDAI ≥ 150 1 year Not reported 2005 (47) States (22) (n=55) (budesonide Placebo (n=55) clinical trial) Hellers Europe (13) 1992–1993 130 Budesonide 6 mg od CIR Adults (35 y) Surgically CDAI ≥ 150 1 year Not reported 1999 (48) (n=63) Placebo (n=67) Lofberg Europe (11) Not reported 90 Budesonide 6 mg CIR Adults (30 y) Medically induced CDAI ≥ 150 1 year 7 y 1996 (49) od (n=32) (budesonide Budesonide 3 mg clinical trial) od (n=31) Placebo (n=27) Mantzaris Greece (1) 1994–1998 57 Budesonide 6 mg daily CIR Adults (33 y) Medically induced CDAI ≥ 150 and 1 year 3 y 2003 (23) (n=29)pH-dependent (steroid-dependent) increase of ≥100 mesalamine points from (Salofalk) 1 g tid (n=28) baseline 8 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Th Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 2. Continued Study Country Years of Number Interventions Formulation Age of Method to Induce Definition of Duration of Disease Duration (number of recruitment of Patients Participants Remission Disease Relapse erapy (mean*) centres) (mean*) Mantzaris Greece (1) 1998–2001 77 Budesonide 6–9 mg od CIR Adults Medically (steroid- Increase in 1 year 2 y 2009 (22) (n=39)Azathioprine 2.0– (budesonide: 35 dependent) CDAI ≥ 100 2.5 mg/kg daily (n=38) y ; azathioprine: points from 34 y ) baseline and CDAI ≥ 150 Schoon 2005 Europe (34) 1996–1999 90 Budesonide 9 mg daily with CIR Adults (39 y) Medically CDAI ≥ 200 2 years 7 y (24) tapering prednisolone (corticosteroid-free or prednisone and corticosteroid- (n=46)Continuation of dependent) pre-existing prednisolone (n=44) ABBREVIATIONS: od, once daily; bid, twice daily; tid, three times daily; CIR , controlled ileal release; CDAI, Crohn’s Disease Activity Index; y, years. *Weighted average of all study arms, unless otherwise specified. Unclear if study reported mean or medina age and disase duration of trial participants. Median. Efficacy data were only available for study participants who were steroid-dependent. Thus, only the steroid-dependent patients were included in the review. Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 9 Figure 2. Budesonide 9 mg versus placebo: induction of clinical remission. Figure 3. Budesonide versus conventional steroids: induction of clinical remission. to the inclusion of studies at a high risk of bias. No evi- Budesonide to maintain remission dence of publication bias was detected on the funnel plot Neither the 3 mg/day nor the 6 mg/day doses of budesonide (Figure S3 of the supplementar y materials). were more effective than placebo to maintain remission at Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 10 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 12  months (Figure  4). Fifty-five percent (114 of 208)  of due to a single-blinded design and a lack of allocation conceal- those receiving budesonide 6  mg/day remained in remission ment). There was low-quality evidence comparing budesonide compared with 48% (101 of 212)  of those receiving placebo with conventional steroids (sparse data; high risk of bias due to (pooled RR 1.13; 95% CI, 0.94–1.35; P  =  0.19; I   =  0%; five lack of blinding). studies; 420 participants). Among those receiving budesonide 3  mg/day, 42% (92 of 217)  remained in remission compared Safety of budesonide Corticosteroid-related adverse events. with 40% (90 of 225) of participants receiving placebo (pooled Induction treatment with budesonide did not increase either the RR 1.08; 95% CI, 0.87–1.34; P  =  0.48; I   =  0%; five studies; risk of corticosteroid-related adverse events relative to placebo 442 participants). Based on the GRADE approach, there (3  mg/day: pooled RR 0.58; 95% CI, 0.29–1.17; P  =  0.13; 1 was evidence for both the 3  mg/day and 6  mg/day doses of study; 27 participants) (9 mg/day: RR 0.97; 95% CI, 0.76–1.13; budesonide compared with placebo was moderate. Both were P = 0.80; I  = 0%; three studies; 384 participants) (15 mg/day: downgraded due to sparse data. Of the five studies comparing pooled RR 1.40; 95% CI, 0.84–2.34; P = 0.19; I  = 0%; two stud- budesonide 3  mg/day with placebo, three used the CIR for- ies; 181 participants) (Figure 5). Using a GRADE approach, the mulation and two used the pH-dependent formulation: there quality of evidence was moderate when comparing budesonide were no significant differences between budesonide and pla - 9 mg/day and 15 mg/day with placebo, with both being down- cebo with either formulation (Table  S5 of the supplementary graded due to sparse data. There was low quality of evidence for materials). All studies with the 6  mg/day dose used the CIR the comparison of budesonide 3 mg/day versus placebo due to formulation. Two studies evaluated the efficacy of budesonide very sparse data. to prevent postoperative recurrence (one with a dose of 3 mg/ Likewise, there were no differences between budesonide and day and the other with a dose of 6 mg/day); the remainder of placebo in terms of corticosteroid-related adverse events follow- studies induced remission medically either with budesonide ing maintenance treatment (3  mg/day: pooled RR 1.19; 95% or conventional steroids. Budesonide was not significantly dif - CI, 0.63–2.24; P = 0.59; I  = 50%; five studies; 440 participants) ferent from placebo with either mode of remission (Table  S6 (6  mg/day: pooled RR 1.51; 95% CI, 0.90–2.52; P  =  0.12; of the supplementary materials). Budesonide was superior to I   =  34%; five studies; 419 participants; Figure  6). Using the mesalamine, but was not significantly different from either con- GRADE approach, there was moderate-quality evidence when ventional steroids or azathioprine (Table S7 of the supplemen- comparing budesonide 3  mg/day and 6  mg/day with placebo tary materials). No evidence of publication bias was detected due to sparse data in both cases. Findings remained consistent upon visual inspection of the funnel plot (Figure  S4 of the when pooling across doses of budesonide for both induction supplementary materials). Based on the GRADE approach, and maintenance treatment (Figure  S5 of the supplementary there was very low quality of evidence comparing budesonide materials). Using the GRADE approach, the quality of evidence to mesalamine (very sparse data, high risk of bias due to lack for the pooled doses of budesonide compared with placebo was of blinding) and azathioprine (sparse data; high risk of bias Figure 4. Budesonide versus placebo: maintenance of clinical remission. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 11 Figure 5. Corticosteroid-related adverse events ae ft r induction treatment with budesonide compared with placebo and conventional corticosteroids. moderate for induction and maintenance treatment. Both were comparing budesonide to conventional steroids, mesalamine downgraded due to sparse data. and azathioprine. Budesonide decreased the risk of corticosteroid-related adverse events compared with conventional steroids when Abnormal ACTH stimulation tests. used to induce remission (pooled RR 0.64; 95% CI, 0.54–0.76; An induction dose of budesonide 9 mg/day increased the risk P < 0.00001; I   =  15%; Figure  5). Using a GRADE approach, of an abnormal ACTH test relative to placebo (pooled RR there was high-quality evidence. This decreased risk of cor - 2.15; 95% CI, 1.41–3.29; P = 0.00040; I  = 24%; three studies; ticosteroid-related adverse events was seen in both children 356 participants; Figure  S5 of the supplementary materials). (pooled RR 0.58; 95% CI, 0.39–0.86; P  =  0.007; I   =  0%) However, abnormal ACTH tests were less common for those and adults (pooled RR 0.65; 95% CI, 0.52–0.80; P  =  0.19; receiving budesonide 9  mg/day than conventional steroids 2 2 I   =  37%). The risk of corticosteroid-related adverse events (pooled RR 0.65; 95% CI, 0.55–0.78; P  <  0.0001; I   =  0%; was not assessed in induction trials comparing budesonide three studies; 244 participants) and remained consistent when with mesalamine; this was also the case for maintenance trials limiting to studies including adult patients (RR 0.65; 95% CI, Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 12 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Figure 6. Corticosteroid-related adverse events ae ft r maintenance treatment with budesonide compared with placebo. 0.53–0.79; 1 study; 177 participants), but not pediatric patients There was low quality evidence when comparing budesonide (pooled RR 0.69; 95% CI, 0.46–1.04; P  =  0.49; I   =  0%; two 6 mg/day with placebo (due to sparse data and selective out- studies; 67 participants). There was no difference in the risk of come reporting). an abnormal ACTH test when comparing budesonide 3 mg/day with placebo (RR 1.29; 95% CI, 0.68–2.44; P  =  0.44; one DISCUSSION study; 133 participants). Using a GRADE approach, the qual - ity of evidence was low when comparing 3  mg/day with pla- Oral budesonide is a corticosteroid designed for release in the cebo (due to very sparse data) and moderate when comparing small intestine with high first-pass hepatic metabolism, limiting 9  mg/day with placebo (due to sparse data). There was very the systemic adverse events caused by conventional corticoste- low-quality evidence when comparing budesonide to con- roids. This review summarizes available controlled clinical trials ventional steroids due to selective outcome reporting, sparse for the efficacy and safety of budesonide, compared with other data and one study being at high risk of bias due to a lack of active agents, for both the induction and maintenance of remis- blinding. Comparisons between budesonide 15  mg/day with sion in CD. placebo and budesonide 9 mg/day with mesalamine could not Budesonide was more effective than placebo, but was less be made due to significant heterogeneity; I values were 79% effective than conventional steroids for the induction of remis - and 85%, respectively. sion. Remission rates were 15% higher among those receiv- Maintenance doses of budesonide 6 mg/day also increased ing conventional steroids as compared with those receiving the likelihood of an abnormal ACTH test relative to placebo budesonide. These results are in agreement with previous (pooled RR 2.72; 95% CI, 1.62–4.58; P  =  0.0002; I   =  0%; meta-analyses (6, 8, 9, 25–27). Subgroup analyses suggest the four studies; 297 participants; Figure  S7 of the supplemen- superiority of conventional steroids over budesonide to induce tary materials). However, abnormal ACTH tests were not remission is specific to adults. However, the proportion of chil - more common among participants receiving maintenance dren achieving remission was almost 10% higher among those doses of budesonide 3  mg/ day as compared with placebo receiving conventional steroids than budesonide. We were (pooled RR 1.89; 95% CI, 0.76–4.69; P  =  0.17; I   =  27%; underpowered to detect a difference between these two med - three studies; 165 participants). Budesonide resulted in sig- ications, as only two studies (81 patients) compared these two nificantly fewer abnormal ACTH tests than conventional medications in children (19, 37). steroids (RR 0.60; 95% CI, 0.36–1.00; P  =  0.048; 1 study; Current data do not allow for a firm conclusion on the relative 69 participants). Using a GRADE approach, there was very efficacy of budesonide in comparison to mesalamine. Although low-quality evidence when comparing budesonide 3 mg/day the study by Thomsen et al. (28) suggested that budesonide was with placebo (due to very sparse data and selective outcome superior to mesalamine. Another study by Tromm et  al. (29) reporting) and budesonide to conventional steroids (due to found no difference in the proportion of patients entering clin- ver y sparse data and high risk of bias due to lack of blinding). ical remission at eight weeks. An editorial (30) accompanying Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 13 Tromm et  al. (29) highlighted that the remission rate in the and placebo. Considering the finding that adrenocortical axis mesalamine arm of that trial was higher than other RCTs of suppression was more prominent in those treated with both mesalamine: 62% compared with 42% in the Thomsen et  al. induction and maintenance doses of budesonide, compared (28) RCT. Methodological criticisms of that trial included its with placebo, bone health deterioration may be of significant switch from superiority to noninferiority design, inclusion of concern in patients taking budesonide—particularly for long individuals with low levels of inflammatory markers (i.e., eryth- periods of time. rocyte sedimentation rate and C-reactive protein) and a lack Our systematic review was limited by the availability and of power to detect noninferiority between the two treatments. quality of data evaluating the efficacy of budesonide to induce Unlike previous traditional meta-analyses (9, 25), our updated and maintain remission. Three of the eight studies comparing analysis included the RCT by Tromm et al. (29) Additionally, budesonide with conventional steroids to induce remission two recent network meta-analyses, which included the Tromm were at high risk of bias, while studies comparing budesonide et  al. study (29), are contradictory regarding the efficacy of to mesalamine were highly heterogeneous and do not allow for budesonide relative to mesalamine: one found budesonide to a firm conclusion as to the relative efficacy of these two med - be superior to mesalamine, while the other found no differ - ications. Further, comparisons of budesonide to both mesala- ence between the two treatments (31, 32). Further, prior sys- mine and azathioprine were limited to single studies, both of tematic reviews and meta-analyses have concluded that 5-ASA which were at a high risk of bias. W hile the safety of budesonide agents are not more effective than placebo in the induction of precludes its usefulness as a maintenance agent in CD, further remission in CD (33). Overall, our systematic review high- research is needed to evaluate the roles of budesonide and lights uncertainty in the evidence comparing budesonide to mesalamine to induce remission with a focus on the specific mesalamine. phenotype each medication is designed to target (i.e., disease In contrast, budesonide was not more effective than placebo in the terminal ileum and proximal colon for budesonide and for maintaining remission in patients with CD. Similarly, nei- left-sided colonic disease with mesalamine). ther weaning doses of conventional steroids nor azathioprine In conclusion, budesonide is more effective than placebo were found to be significantly different than budesonide for the for the induction of remission in active ileocecal CD. A  dose maintenance of remission. Subgroup analyses of drug formu- of 9  mg daily for eight weeks, followed by weaning the dose lations (CIR and pH-dependent), varying doses and method to discontinuation, is considered the optimal dosing regimen. used to induce remission consistently demonstrated lack of Budesonide was less effective than conventional steroids, par - superiority for budesonide in maintaining remission. Subgroup ticularly in patients with severe disease or those with extensive analyses need to be interpreted with caution as several of the colonic involvement. However, the likelihood of adverse events comparisons were made in a single RCT with a small number of with budesonide was significantly lower than with conventional patients, and several RCTs were associated with high risk of bias steroids and was no higher than in patients receiving placebo. due to lack of blinding and allocation concealment. Overall, Budesonide was not found to be effective for maintenance current evidence does not support the use of budesonide in of remission at 12  months in CD. While budesonide did not maintenance of remission in CD. increase the risk of corticosteroid-related adverse events, the Corticosteroid-related AEs were not elevated among patients long-term implications of budesonide on bone metabolism and receiving budesonide as compared with placebo, either when adrenal axis suppression remain uncertain (34). Thus, given the budesonide was used in the short-term to induce remission or weak efficacy and the potential for long-term consequences, the in the long-term to maintain remission. As expected, conven- use of budesonide for maintenance of remission in CD is diffi - tional steroids were associated with statistically and clinically cult to justify. more corticosteroid-related AEs including moon face, acne, mood changes and muscle weakness. SUPPLEMENTARY DATA Prolonged exposure to steroids is known to have detrimen- Supplementary data are available at Journal of the Canadian tal effects on bone metabolism, leading to diminished growth, Association of Gastroenterology online. osteopenia or osteoporosis. The maintenance trial compar - ing budesonide with conventional steroids was specifically designed to compare bone mineral density among the two ACKNOWLEDGEMENTS treatment groups (24). Among corticosteroid-naïve patients, The authors would like to thank John MacDonald, the managing editor decreases in bone mineral density were less pronounced ae ft r at the Cochrane Inflammatory Bowel Disease and Functional Bowel treatment with budesonide than prednisolone. However, this Disorders Group for his assistance with the cited Cochrane reviews. differential reduction in bone mineral density has not been con- Funding for the IBD/FBD Review Group (September 1, 2010–August sistently observed (34). No randomized clinical trial has com- 31, 2015) was provided by the following: Canadian Institutes of Health pared changes in bone mineral density between budesonide Research (CIHR) Knowledge Translation Branch (CON-105529), the Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 14 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX CIHR Institutes of Nutrition, Metabolism and Diabetes (INMD) and References Infection and Immunity (III), and the Ontario Ministry of Health and 1. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: Long-Term Care (HLTC3968FL-2010-2235). Eric Benchimol was Clinical aspects and established and evolving therapies. Lancet. supported by a New Investigator Award from the Canadian Institutes 2007;369(9573):1641–57. of Health Research, Canadian Association of Gastroenterology and 2. Hyams JS. Inflammatory bowel disease. Pediatr Rev. Crohn’s and Colitis Canada. He was also supported by a career devel- 2005;26(9):314–20. opment award from the Canadian Child Health Clinician Scientist 3. Lewis JD, Gelfand JM, Troxel AB, et  al. Immunosuppressant Program. Ellen Kuenzig was supported by a postdoctoral fellowship medications and mortality in inflammatory bowel disease. Am J from the CIHR, Canadian Association of Gastroenterology and Gastroenterol. 2008;103(6):1428–35. Crohn’s and Colitis Canada. Author contributions: MEK wrote the 4. Fedorak RN, Bistritz L. Targeted delivery, safety, and efficacy of manuscript. MEK and AR performed the research, collected, analyzed oral enteric-coated formulations of budesonide. Advanced Drug and interpreted the data. GGK, EIB and CHS designed the study and Delivery Reviews. 2005;57(2):303–16. reviewed the analysis and interpretation of the data. ARO, AHS and 5. Kuenzig ME, Rezaie A, Seow CH, et  al. 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Budesonide for induction of remis- for Board membership; fee(s) from Janssen, Abbvie and Ferring for sion in Crohn’s disease. Cochrane Database Syst Rev. consultancy; grants or grants pending from Johnson and Johnson and 2005;(4):CD000296. Abbvie; lecture fee(s) from Abbvie and Merck and payment for devel- 9. Seow CH, Benchimol EI, Griffiths AM, et  al. Budesonide for opment of educational presentations from Ferring. All of these activi- induction of remission in Crohn’s disease (Review). Cochrane ties are outside the current work. Database Syst Rev. 2008;(3):CD000296. ARO’s centre was a participating site in an AstraZeneca-funded, 10. Benchimol EI, Seow CH, Otley AR, et  al. Budesonide for main- FDA-approved induction and maintenance clinical trial studying tenance of remission in Crohn’s disease (Review). Cochrane Entocort safety in pediatric Crohn’s disease. 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Budesonide for the Induction and Maintenance of Remission in Crohn’s Disease: Systematic Review and Meta-Analysis for the Cochrane Collaboration

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© The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.
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Abstract

Background: Budesonide is an oral glucocorticoid designed for the treatment of inflammatory bowel disease (IBD) that may reduce systemic adverse events (AEs). This review examined the efficacy and safety of budesonide for the induction and maintenance of clinical remission in Crohn’s disease (CD). Methods: MEDLINE, EMBASE, other electronic databases, reference lists and conference pro- ceedings were searched to November 2017 to identify randomized controlled trials of budesonide. Outcomes were the induction and maintenance of remission at eight weeks and one year, respectively, as well as corticosteroid-related AEs and abnormal adrenocorticotropic hormone (ACTH) tests. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated using random effects models. Results: Thirteen induction and 10 maintenance trials were included. Budesonide 9  mg/day was more effective than placebo (RR 1.93; 95% CI, 1.37–2.73; GRADE: moderate) but less effective than conventional steroids (RR 0.85; 95% CI, 0.75–0.97; GRADE: moderate) to induce remission. Corticosteroid-related AEs occurred less often with induction doses of budesonide than steroids (RR 0.64; 95% CI, 0.54–0.76; GRADE: moderate); budesonide did not increase AEs relative to placebo (RR 0.97; 95% CI, 0.76–1.23; GRADE: moderate). Budesonide 6  mg/day was not different from placebo for maintaining remission (RR 1.13; 95% CI, 0.94–1.35; GRADE: moderate). Both induc - tion (GRADE: low for 3  mg/day, moderate for 9  mg/day) and maintenance budesonide treatment (GRADE: very low for 3  mg/day, low for 6  mg/day) increased the risk of an abnormal ACTH test compared with placebo, but less than conventional steroids (GRADE: very low for both induction and maintenance). Conclusion: For induction of clinical remission, budesonide was more effective than placebo, but less effective than conventional steroids. Budesonide was not effective for the maintenance of remission. © The Author(s) 2018. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology. 1 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 2 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Budesonide was safer than conventional steroids, but the long-term effects on the adrenal axis and bone health remain unknown. Keywords: Budesonide; Corticosteroids; Crohn’s disease; Induction and maintenance of remission; Meta-analysis Study identification and selection INTRODUCTION RCTs of oral budesonide therapy (CIR or pH-dependent Crohn’s disease (CD) is characterized by chronic transmural release formulations) for the induction or maintenance of inflammation of the gastrointestinal tract. Patients experience remission published in any language were included. Participants abdominal pain, diarrhea and fatigue. CD typically follows a were patients of any age with CD defined by conventional clin- relapsing and remitting disease course. Medications used in the ical, radiological and endoscopic criteria. Studies comparing management of CD suppress the inflammatory response. budesonide to placebo or another active agent were consid- Corticosteroids are a mainstay of treatment for acute flares of ered for inclusion in this review. Studies comparing different CD (1, 2). However, systemic corticosteroids are associated with doses of budesonide were excluded if they did not also include adverse effects such as moon facies, acne, infection (including an a non-budesonide comparison arm. Concomitant therapy was increased risk of abdominal and pelvic abscess in CD patients), permitted, provided it was balanced between treatment and ecchymoses, hypertension, diabetes mellitus, osteoporosis, cata- control groups. racts, glaucoma and growth failure in children (1). More impor- We searched PubMed, MEDLINE (2014-November tantly, the use of systemic corticosteroids has been independently 2017), EMBASE (2014-November 2017)  and the Cochrane associated with mortality in patients with CD (3). Central Register of Controlled Trials (to November 2017). Budesonide is a glucocorticoid with limited systemic bioavail- RCTs published before 2014 were identified from Cochrane ability, due to extensive (90%) first-pass hepatic metabolism by reviews on the efficacy of budesonide in Crohn’s disease by the cytochrome p-450 enzyme system. These properties limit sys - Kuenzig et  al. (maintenance, 2014)  (5) and Rezaie et  al. temic adverse effects. Budesonide is commercially available in two (induction, 2015)  (6). The search strategy is outlined in forms: an oral controlled ileal release (CIR) preparation designed Table  S1 of the supplementary materials. Ongoing and to deliver the drug to the distal small intestine (Entocort®, Astra unpublished trials were identified using clinicaltrials.gov. Zeneca, London, UK; Entocir®, Sofar S.p.A, Trezzano Rosa, Reference lists of trials and review articles were reviewed to Italy; Budecol®, AstraZeneca A&D, Lund, Sweden) and a pH-de- identify additional studies. Relevant pharmaceutical com- pendent release formulation (Budenofalk® or Budeson®, Dr Falk panies were contacted for ongoing studies. Abstracts were Pharma, Freiburg, Germany). The controlled ileal release med - screened for eligibility independently by two study authors ication is in the form of a gelatin capsule containing acid-stable (MEK and AR). Full-text articles were independently microgranules composed of an inner sugar core surrounded by a reviewed by two authors (MEK and AR). Disagreements layer of budesonide in ethylcellulose and an outer acrylic-based were resolved by consensus and consultation with resin coating (Eudragit L 100-55) that dissolves at a pH higher EIB and CHS. than 5.5. The pH-dependent release formulation is available as a capsule containing 400 pellets of budesonide coated with Outcomes Eudragit resistant to a pH of less than six (4). Induction of remission was defined by a Crohn’s Disease This systematic review and meta-analysis provides a sum- Activity Index (CDAI) <150 or a Pediatric Crohn’s Disease mary of the evidence from randomized controlled trials Activity Index (PCDAI) <10 by eight weeks of therapy. (RCTs) with regard to the safety and efficacy of budesonide Maintenance of remission was defined as the proportion for the induction and maintenance of remission in CD. This of patients in continued remission at 12 months, as defined systematic review and meta-analysis is based on two recent by each trial. If patients were followed beyond these prede- reviews published by the Cochrane collaboration (5, 6) and is termined time points, only eight-week and 12-month data updated to November 2017. were pooled for induction and maintenance trials, respec- tively. Inductions studies with less than eight weeks of fol- MATERIALS AND METHODS low-up and maintenance studies with less than 12  months This systematic review and meta-analysis was conducted based of follow-up were excluded. Corticosteroid-related adverse on a previously published protocol (5–10) and in accordance events (AEs) and abnormal ACTH stimulation tests were with the PRISMA guidelines (11). also assessed. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 3 the authors of this study did not define remission. Two main- Data extraction tenance studies that had been included in the last Cochrane Two authors (MEK and AR) independently extracted data review (5) were excluded. One did not have sufficient fol - from each eligible study, including the following elements: low-up, reporting relapse rates at 13 weeks (17), and the other study design and quality; formulation and dose of budesonide; did not include a nonbudesonide treatment group (18). This comparator; study inclusion/exclusion criteria; age of partici- left 13 induction and 10 maintenance trials for inclusion in the pants; trial duration; method used to induce remission (main- updated meta-analysis (Figure  1). There was 100% agreement tenance trials); and all study outcomes including definition of among reviewers regarding the eligibility of the included stud- remission (induction trials), definition of relapse (maintenance ies. The characteristics of included induction and maintenance trials), corticosteroid-related AEs and abnormal ACTH stim- studies are provided in Tables  1 and 2, respectively. Table  S2 ulation tests. Prespecified subgroup analyses were conducted (see supplementary materials) outlines the reasons for study based on the dose and formulation of budesonide (CIR versus exclusion. pH-dependent), disease location, the method used to induce remission (e.g., medical versus surgical induction, maintenance Risk of bias in included studies trials) and the age of trial participants (pediatric versus adult). Three induction trials had a high risk of bias ( Table  S3 of the supplementary materials) (19–21). Two failed to ensure appro- Risk of bias priate blinding (open label studies) (19, 20). One selectively The risk of bias of included studies was assessed independently reported study outcomes, failing to outline AEs for each study by two reviewers (MEK and AR) using the Cochrane group (21). Three maintenance studies had a high risk of bias Collaboration’s tool (http://methods.cochrane.org/bias/ (Table  S4 of the supplementary materials) due to failure to assessing-risk-bias-included-studies) (12). Disagreements blind participants (22, 23) and outcome assessors (24). In were resolved by consensus. The overall quality of evidence addition, allocation was not adequately concealed in one main- was assessed using the GRADE approach, incorporating risk of tenance trial (22). bias (methodological quality), indirectness of evidence, unex- plained heterogeneity, imprecision (sparse data) and publica- Budesonide to induce remission tion bias (12, 13). At eight weeks, 47% (115 of 246) of those receiving a daily dose of budesonide 9 mg/day entered remission compared with 22% Statistical analysis (29/133) of those receiving placebo (Figure 2). This difference Data were analyzed using Review Manager (RevMan 5.3.5, was statistically significant (pooled RR 1.93; 95% CI, 1.37– Copenhagen: The Nordic Cochrane Centre, The Cochrane 2.73, P = 0.00018; I  = 0%; three studies; 379 participants). The Collaboration, 2014). Data from individual studies were pooled 15 mg/day dose of budesonide was similarly superior to placebo for meta-analysis if the interventions, patient groups and out- (two studies), but there was no difference between budesonide comes were sufficiently similar (determined by consensus). 3 mg/day and placebo (one study; Figure S1 of the supplemen- Relative risks (RR) and their corresponding 95% confidence tary materials). All studies comparing budesonide to placebo intervals (CI) were calculated using random-effects models to used the CIR formulation of budesonide and excluded individ- allow for expected clinical and statistical heterogeneity across uals with distal colonic disease. No study provided subgroup studies (14). Heterogeneity was assessed by calculating the analyses based on disease severity, and all studies were limited to I measure, interpreted as low heterogeneity (25%), moder- adult participants. As assessed with the GRADE approach, there ate heterogeneity (50%) and high heterogeneity (75%) (15). was moderate quality of evidence for budesonide 9  mg/day Cochran’s χ test for homogeneity (Q test) was also calculated, and 15 mg/day to induce remission and low quality of evidence with P  <  0.10 considered statistically significant. Publication for budesonide 3 mg/day. The 9 mg/day and 15 mg/day doses bias was assessed using a visual inspection of funnel plots. were downgraded due to sparse data, and the 3  mg/day dose was downgraded due to very spare data. No evidence of publi- RESULTS cation bias was detected upon visual assessment of studies com- Description of studies paring budesonide 9 mg/day with placebo (Figure S2). The published Cochrane reviews (5, 6) included 14 induction Two studies compared budesonide with mesalamine. and 12 maintenance trials. The updated literature search yielded However, these studies could not be pooled due to significant 243 new records; 181 remained aeft r removing duplicates. heterogeneity (P = 0.002, I  = 81%). Budesonide was superior None of these were eligible for inclusion; therefore, no addi- to mesalamine in the trial by Thomsen et  al. (27) (RR 1.63; tional studies were included in the updated systematic review 95% CI, 1.23–2.16) but there was no significant difference and meta-analysis. One induction study (16) that had been between the two medications in the trial by Tromm et al. (28) included in the last Cochrane review (6) was excluded because (RR 1.12; 95% CI, 0.95–1.32). A similar proportion of patients Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 4 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Figure 1. Study flow diagram depicting results of electronic database search from 2014–2017. Trials published before 2014 were identified from two previous Cochrane reviews on the efficacy of budesonide, published in 2014 and 2015 (5, 6). receiving budesonide entered clinical remission at eight weeks for adult patients (pooled RR 0.85; 95% CI, 0.74–0.97; in both studies (68% and 69% for Thomsen et  al. (27) and P = 0.02; I  = 0%; si x studies; 669 par ticipants) and patients Tromm et al. (28), respectively). However, a greater proportion with severe disease as defined by CDAI ≥300 (pooled RR of patients receiving mesalamine entered clinical remission in 0.52; 95% CI, 0.28–0.95; P  =  0.03; I   =  0%; two studies; the study by Tromm et  al. (28) (62%) as compared with the 64 participants). Conventional steroids were no longer study by Thomsen et al. (27) (42%). Subgroup analysis based superior to budesonide when limiting the analyses to the on disease severity failed to explain between-study heteroge- pediatric population (pooled RR 0.87; 95% CI, 0.58–1.31; 2 2 neity (I   =  88% for mild-to-moderate disease as defined by a P  =  0.5; I   =  0%; two studies; 81 participants), those CDAI  <300; I   =  68% for severe disease as defined by CDAI with mild-to-moderate disease as defined by CDAI  <300 ≥300). Children were not included in either study. Using the (pooled RR 1.00; 95% CI, 0.65–1.56; P  =  0.99; I   =  67%; GRADE approach, the quality of evidence from each study two studies; 175 participants) or those with ileal or right- was rated as moderate. Both studies were downgraded due to sided ileocolonic disease (pooled RR 0.86; 95% CI, 0.75– sparse data. 1.00, P  =  0.05; I   =  0%; six studies; 561 participants). Conventional steroids induced remission in 61% (210 of Conventional steroids were superior to the CIR formula- 344)  of patients, whereas budesonide 9  mg/day induced tion of budesonide, but not the pH-dependent formulation remission in 52% (211 of 406; Figure  3). Budesonide was for the induction of remission (Table  S5 of the supple- inferior to conventional steroids (pooled RR 0.85; 95% mentary materials). According to the GRADE approach, CI,  0.75–0.97; P  =  0.012; I   =  0%; eight studies; 750 par- the evidence comparing budesonide with conventional ticipants). Subgroup analyses yielded similar findings steroids was of moderate quality and was downgraded due Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 5 Th TT Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 1. Characteristics of included induction trials Study Country (number Years of Number Interventions (Number of Formulation Age of Participants Definition of Definition of Duration of Disease Duration of centres) recruitment of Patients patients in each arm, ITT) (mean*) Active Disease Remission erapy (mean*) (I) Bar-Meir Israel (14) Not 201 Budesonide 3 mg tid (n=100) pH-dependent Adults (both CDAI 150–350 CDAI ≤ 150 8 weeks Both † † 1998 reported Prednisone 40 mg od for two arms: 33 y ) arms: 5 y (35) weeks, then tapered (n=101) ‡ § ¶ Campieri Europe, New Zealand, Not 178 Budesonide 9 mg od (n=58) CIR Adults (37 y) CDAI ≥200 CDAI ≤ 150 12 weeks 7 y 1997 Australia (26) reported Budesonide 4.5 mg bid (n=61) (36) Prednisolone 40 mg od for two weeks, then tapered (n=58) § ¶ Escher Europe (36) 1998–2000 48 Budesonide 9 mg daily (n=22) CIR Pediatric (13 y) CDAI ≥200 CDAI ≤ 150 12 weeks 0.7 y 2004 Prednisolone 1 mg/kg daily (37) for four weeks, then tapered (n=26) Greenberg Canada (27) 1991–1992 258 Budesonide 3 mg daily (n=67) CIR Adults (32 y) CDAI >200 CDAI ≤ 150 8 weeks 6 y 1994 Budesonide 9 mg daily (n=61) (38) Budesonide 15 mg daily (n=64) Placebo (n=66) Gross Europe (16) Not 67 Budesonide 3 mg tid (n=34) pH-dependent Adults (31 y) CDAI >150 CDAI ≤ 150 or 8 weeks 68 months (6 y) 1996 reported Methylprednisolone 48 mg for decrease ≥60 (39) 1 week, then tapered (n=33) if baseline CDAI > 200 Levine Israel (13) Not 35 Budesonide 3 mg tid (n=20) pH-dependent Pediatric PCDAI 12.5–40 PCDAI ≤ 10 10 weeks Not reported 2003 reported Prednisone 40 mg daily, then (14 y) (19) tapered (n=15) § ¶ Rutgeerts Europe (11) Not 176 Budesonide 9 mg daily (n=88) CIR Adults (34 y) CDAI >200 CDAI ≤ 150 or 10 weeks 7 y 1994 reported Prednisolone 40 mg daily for decrease in (40) two weeks, then tapered (n=88) CDAI > 100 § ¶ Suzuki Japan (21) 2006–2008 77 Budesonide 9 mg daily (n=26) CIR Adults (37 y) CDAI > 200 CDAI ≤ 150 10 weeks <10 y: 63/77 (82%) 2013 Budesonide 15 mg daily (n=25) ≥10 y: 14/77 (18%) (41) Placebo (n=26) Thomsen Europe, South 1994–1996 182 Budesonide 9 mg daily (n=93) CIR Adults (Budesonide: CDAI 200–400 CDAI ≤ 150 16 weeks Budesonide: 6 y ; ‖ ‖ 1998 Africa, Australia Mesalamine 2 mg bid (n=89) 34 y ; Mesalamine: Mesalamine: 5 y (28) (25) 31 y ) Tremaine USA (24) 1995–1997 200 Budesonide 9 mg od (n=80) CIR Adults (39 y) CDAI 200–400 CDAI ≤ 150 10 weeks 11 y 2002 Budesonide 4.5 mg bid (n=79) (42) Placebo (n=41) 6 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Th TT ft Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 1. Continued Study Country (number Years of Number Interventions (Number of Formulation Age of Participants Definition of Definition of Duration of Disease Duration of centres) recruitment of Patients patients in each arm, ITT) (mean*) Active Disease Remission erapy (mean*) (I) Tromm Europe and 2004–2008 311 Budesonide 9 mg od (n=81) pH-dependent Adults (37 y) CDAI 200–400 CDAI ≤ 150 8 weeks 6 y 2011 Israel (46) Budesonide 3 mg tid (n=77) (29) Mesalamine 4.5 mg daily (n=153) Tursi 2006 Italy (multicentre; 2004 30 Budesonide 9 mg od (n=15) CIR Adults (36 y) CDAI CDAI ≤ 150 8 weeks Not reported (20) number of Beclomethasone 150–250 centres not dipropionate 10 mg reported) daily (n=15) § ** ¶ Van Ierssel Netherlands (1) Not 18 Budesonide 9 mg od (n=9) CIR Adults (35 y ) CDAI ≥200 CDAI ≤ 150 10 weeks Not reported 1995 reported Prednisolone 40 mg daily for (21) two weeks, then tapered (n=9) ABBREVIATIONS: od, once daily; bid, twice daily; tid, three times daily; CIR , controlled ileal release; CDAI, Crohn’s Disease Activity Index; y, years. *Weighted average of all study arms. Unclear if study reported mean or median age and disease duration of trial participants. Campieri 1997 did not provide intention-to-treat numbers for each treatment arm. One patient was randomized but did not receive treatment, but it is not known which treatment arm this patient was randomized to. Dose of budesonide was tapered aer eight weeks. W hen trials followed patients beyond the primary endpoint of eight weeks, only remission data at eight weeks were pooled. Median. ** Average age for the full cohort was reported in the study. Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 7 Th Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 2. Characteristics of included maintenance trials Study Country Years of Number Interventions Formulation Age of Method to Induce Definition of Duration of Disease Duration (number of recruitment of Patients Participants Remission Disease Relapse erapy (mean*) centres) (mean*) Ewe Germany 1992–1994 83 Budesonide 1 mg pH-dependent Adults Surgically Endoscopic 1 year Budesonide: 1999 (43) (3) tid (n=43) (Budesonide: recurrence or 100 months (8 y) Placebo (n=40) 35 y ; Placebo: increase in CDAI Placebo: 81 † † 33 y ) from 60 up to 200 months (7 y) from first follow-up or CDAI > 200 Ferguson Europe, Not reported 75 Budesonide 6 mg CIR Adults (36 y) Medically induced CDAI ≥ 150 1 year 7 y 1998 (44) Australia bid (n=22) (budesonide (20) Budesonide 3 mg clinical trial) od (n=26) Placebo Greenberg Canada (23) 1992–1994 105 Budesonide 6 mg od CIR Adults (35.6 y) Medically induced CDAI ≥ 150 1 year 8 y 1996 (45) (n=36) Budesonide (budesonide 3 mg od (n=33) clinical trial) Placebo (n=36) Gross 1998 Germany Not reported 179 Budesonide 1 mg pH-dependent Adults (32 y) Medically induced CDAI > 150 for >2 1 year 63 months (5 y) (46) (multicentre; tid (n=84) (corticosteroids) subsequent weeks number of Placebo (n=95) or CDAI > 150 at centres not last visit reported) Hanauer United Not reported 110 Budesonide 6 mg od CIR Adults (40 y) Medically induced CDAI ≥ 150 1 year Not reported 2005 (47) States (22) (n=55) (budesonide Placebo (n=55) clinical trial) Hellers Europe (13) 1992–1993 130 Budesonide 6 mg od CIR Adults (35 y) Surgically CDAI ≥ 150 1 year Not reported 1999 (48) (n=63) Placebo (n=67) Lofberg Europe (11) Not reported 90 Budesonide 6 mg CIR Adults (30 y) Medically induced CDAI ≥ 150 1 year 7 y 1996 (49) od (n=32) (budesonide Budesonide 3 mg clinical trial) od (n=31) Placebo (n=27) Mantzaris Greece (1) 1994–1998 57 Budesonide 6 mg daily CIR Adults (33 y) Medically induced CDAI ≥ 150 and 1 year 3 y 2003 (23) (n=29)pH-dependent (steroid-dependent) increase of ≥100 mesalamine points from (Salofalk) 1 g tid (n=28) baseline 8 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Th Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Table 2. Continued Study Country Years of Number Interventions Formulation Age of Method to Induce Definition of Duration of Disease Duration (number of recruitment of Patients Participants Remission Disease Relapse erapy (mean*) centres) (mean*) Mantzaris Greece (1) 1998–2001 77 Budesonide 6–9 mg od CIR Adults Medically (steroid- Increase in 1 year 2 y 2009 (22) (n=39)Azathioprine 2.0– (budesonide: 35 dependent) CDAI ≥ 100 2.5 mg/kg daily (n=38) y ; azathioprine: points from 34 y ) baseline and CDAI ≥ 150 Schoon 2005 Europe (34) 1996–1999 90 Budesonide 9 mg daily with CIR Adults (39 y) Medically CDAI ≥ 200 2 years 7 y (24) tapering prednisolone (corticosteroid-free or prednisone and corticosteroid- (n=46)Continuation of dependent) pre-existing prednisolone (n=44) ABBREVIATIONS: od, once daily; bid, twice daily; tid, three times daily; CIR , controlled ileal release; CDAI, Crohn’s Disease Activity Index; y, years. *Weighted average of all study arms, unless otherwise specified. Unclear if study reported mean or medina age and disase duration of trial participants. Median. Efficacy data were only available for study participants who were steroid-dependent. Thus, only the steroid-dependent patients were included in the review. Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 9 Figure 2. Budesonide 9 mg versus placebo: induction of clinical remission. Figure 3. Budesonide versus conventional steroids: induction of clinical remission. to the inclusion of studies at a high risk of bias. No evi- Budesonide to maintain remission dence of publication bias was detected on the funnel plot Neither the 3 mg/day nor the 6 mg/day doses of budesonide (Figure S3 of the supplementar y materials). were more effective than placebo to maintain remission at Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 10 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 12  months (Figure  4). Fifty-five percent (114 of 208)  of due to a single-blinded design and a lack of allocation conceal- those receiving budesonide 6  mg/day remained in remission ment). There was low-quality evidence comparing budesonide compared with 48% (101 of 212)  of those receiving placebo with conventional steroids (sparse data; high risk of bias due to (pooled RR 1.13; 95% CI, 0.94–1.35; P  =  0.19; I   =  0%; five lack of blinding). studies; 420 participants). Among those receiving budesonide 3  mg/day, 42% (92 of 217)  remained in remission compared Safety of budesonide Corticosteroid-related adverse events. with 40% (90 of 225) of participants receiving placebo (pooled Induction treatment with budesonide did not increase either the RR 1.08; 95% CI, 0.87–1.34; P  =  0.48; I   =  0%; five studies; risk of corticosteroid-related adverse events relative to placebo 442 participants). Based on the GRADE approach, there (3  mg/day: pooled RR 0.58; 95% CI, 0.29–1.17; P  =  0.13; 1 was evidence for both the 3  mg/day and 6  mg/day doses of study; 27 participants) (9 mg/day: RR 0.97; 95% CI, 0.76–1.13; budesonide compared with placebo was moderate. Both were P = 0.80; I  = 0%; three studies; 384 participants) (15 mg/day: downgraded due to sparse data. Of the five studies comparing pooled RR 1.40; 95% CI, 0.84–2.34; P = 0.19; I  = 0%; two stud- budesonide 3  mg/day with placebo, three used the CIR for- ies; 181 participants) (Figure 5). Using a GRADE approach, the mulation and two used the pH-dependent formulation: there quality of evidence was moderate when comparing budesonide were no significant differences between budesonide and pla - 9 mg/day and 15 mg/day with placebo, with both being down- cebo with either formulation (Table  S5 of the supplementary graded due to sparse data. There was low quality of evidence for materials). All studies with the 6  mg/day dose used the CIR the comparison of budesonide 3 mg/day versus placebo due to formulation. Two studies evaluated the efficacy of budesonide very sparse data. to prevent postoperative recurrence (one with a dose of 3 mg/ Likewise, there were no differences between budesonide and day and the other with a dose of 6 mg/day); the remainder of placebo in terms of corticosteroid-related adverse events follow- studies induced remission medically either with budesonide ing maintenance treatment (3  mg/day: pooled RR 1.19; 95% or conventional steroids. Budesonide was not significantly dif - CI, 0.63–2.24; P = 0.59; I  = 50%; five studies; 440 participants) ferent from placebo with either mode of remission (Table  S6 (6  mg/day: pooled RR 1.51; 95% CI, 0.90–2.52; P  =  0.12; of the supplementary materials). Budesonide was superior to I   =  34%; five studies; 419 participants; Figure  6). Using the mesalamine, but was not significantly different from either con- GRADE approach, there was moderate-quality evidence when ventional steroids or azathioprine (Table S7 of the supplemen- comparing budesonide 3  mg/day and 6  mg/day with placebo tary materials). No evidence of publication bias was detected due to sparse data in both cases. Findings remained consistent upon visual inspection of the funnel plot (Figure  S4 of the when pooling across doses of budesonide for both induction supplementary materials). Based on the GRADE approach, and maintenance treatment (Figure  S5 of the supplementary there was very low quality of evidence comparing budesonide materials). Using the GRADE approach, the quality of evidence to mesalamine (very sparse data, high risk of bias due to lack for the pooled doses of budesonide compared with placebo was of blinding) and azathioprine (sparse data; high risk of bias Figure 4. Budesonide versus placebo: maintenance of clinical remission. Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 11 Figure 5. Corticosteroid-related adverse events ae ft r induction treatment with budesonide compared with placebo and conventional corticosteroids. moderate for induction and maintenance treatment. Both were comparing budesonide to conventional steroids, mesalamine downgraded due to sparse data. and azathioprine. Budesonide decreased the risk of corticosteroid-related adverse events compared with conventional steroids when Abnormal ACTH stimulation tests. used to induce remission (pooled RR 0.64; 95% CI, 0.54–0.76; An induction dose of budesonide 9 mg/day increased the risk P < 0.00001; I   =  15%; Figure  5). Using a GRADE approach, of an abnormal ACTH test relative to placebo (pooled RR there was high-quality evidence. This decreased risk of cor - 2.15; 95% CI, 1.41–3.29; P = 0.00040; I  = 24%; three studies; ticosteroid-related adverse events was seen in both children 356 participants; Figure  S5 of the supplementary materials). (pooled RR 0.58; 95% CI, 0.39–0.86; P  =  0.007; I   =  0%) However, abnormal ACTH tests were less common for those and adults (pooled RR 0.65; 95% CI, 0.52–0.80; P  =  0.19; receiving budesonide 9  mg/day than conventional steroids 2 2 I   =  37%). The risk of corticosteroid-related adverse events (pooled RR 0.65; 95% CI, 0.55–0.78; P  <  0.0001; I   =  0%; was not assessed in induction trials comparing budesonide three studies; 244 participants) and remained consistent when with mesalamine; this was also the case for maintenance trials limiting to studies including adult patients (RR 0.65; 95% CI, Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 12 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX Figure 6. Corticosteroid-related adverse events ae ft r maintenance treatment with budesonide compared with placebo. 0.53–0.79; 1 study; 177 participants), but not pediatric patients There was low quality evidence when comparing budesonide (pooled RR 0.69; 95% CI, 0.46–1.04; P  =  0.49; I   =  0%; two 6 mg/day with placebo (due to sparse data and selective out- studies; 67 participants). There was no difference in the risk of come reporting). an abnormal ACTH test when comparing budesonide 3 mg/day with placebo (RR 1.29; 95% CI, 0.68–2.44; P  =  0.44; one DISCUSSION study; 133 participants). Using a GRADE approach, the qual - ity of evidence was low when comparing 3  mg/day with pla- Oral budesonide is a corticosteroid designed for release in the cebo (due to very sparse data) and moderate when comparing small intestine with high first-pass hepatic metabolism, limiting 9  mg/day with placebo (due to sparse data). There was very the systemic adverse events caused by conventional corticoste- low-quality evidence when comparing budesonide to con- roids. This review summarizes available controlled clinical trials ventional steroids due to selective outcome reporting, sparse for the efficacy and safety of budesonide, compared with other data and one study being at high risk of bias due to a lack of active agents, for both the induction and maintenance of remis- blinding. Comparisons between budesonide 15  mg/day with sion in CD. placebo and budesonide 9 mg/day with mesalamine could not Budesonide was more effective than placebo, but was less be made due to significant heterogeneity; I values were 79% effective than conventional steroids for the induction of remis - and 85%, respectively. sion. Remission rates were 15% higher among those receiv- Maintenance doses of budesonide 6 mg/day also increased ing conventional steroids as compared with those receiving the likelihood of an abnormal ACTH test relative to placebo budesonide. These results are in agreement with previous (pooled RR 2.72; 95% CI, 1.62–4.58; P  =  0.0002; I   =  0%; meta-analyses (6, 8, 9, 25–27). Subgroup analyses suggest the four studies; 297 participants; Figure  S7 of the supplemen- superiority of conventional steroids over budesonide to induce tary materials). However, abnormal ACTH tests were not remission is specific to adults. However, the proportion of chil - more common among participants receiving maintenance dren achieving remission was almost 10% higher among those doses of budesonide 3  mg/ day as compared with placebo receiving conventional steroids than budesonide. We were (pooled RR 1.89; 95% CI, 0.76–4.69; P  =  0.17; I   =  27%; underpowered to detect a difference between these two med - three studies; 165 participants). Budesonide resulted in sig- ications, as only two studies (81 patients) compared these two nificantly fewer abnormal ACTH tests than conventional medications in children (19, 37). steroids (RR 0.60; 95% CI, 0.36–1.00; P  =  0.048; 1 study; Current data do not allow for a firm conclusion on the relative 69 participants). Using a GRADE approach, there was very efficacy of budesonide in comparison to mesalamine. Although low-quality evidence when comparing budesonide 3 mg/day the study by Thomsen et al. (28) suggested that budesonide was with placebo (due to very sparse data and selective outcome superior to mesalamine. Another study by Tromm et  al. (29) reporting) and budesonide to conventional steroids (due to found no difference in the proportion of patients entering clin- ver y sparse data and high risk of bias due to lack of blinding). ical remission at eight weeks. An editorial (30) accompanying Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX 13 Tromm et  al. (29) highlighted that the remission rate in the and placebo. Considering the finding that adrenocortical axis mesalamine arm of that trial was higher than other RCTs of suppression was more prominent in those treated with both mesalamine: 62% compared with 42% in the Thomsen et  al. induction and maintenance doses of budesonide, compared (28) RCT. Methodological criticisms of that trial included its with placebo, bone health deterioration may be of significant switch from superiority to noninferiority design, inclusion of concern in patients taking budesonide—particularly for long individuals with low levels of inflammatory markers (i.e., eryth- periods of time. rocyte sedimentation rate and C-reactive protein) and a lack Our systematic review was limited by the availability and of power to detect noninferiority between the two treatments. quality of data evaluating the efficacy of budesonide to induce Unlike previous traditional meta-analyses (9, 25), our updated and maintain remission. Three of the eight studies comparing analysis included the RCT by Tromm et al. (29) Additionally, budesonide with conventional steroids to induce remission two recent network meta-analyses, which included the Tromm were at high risk of bias, while studies comparing budesonide et  al. study (29), are contradictory regarding the efficacy of to mesalamine were highly heterogeneous and do not allow for budesonide relative to mesalamine: one found budesonide to a firm conclusion as to the relative efficacy of these two med - be superior to mesalamine, while the other found no differ - ications. Further, comparisons of budesonide to both mesala- ence between the two treatments (31, 32). Further, prior sys- mine and azathioprine were limited to single studies, both of tematic reviews and meta-analyses have concluded that 5-ASA which were at a high risk of bias. W hile the safety of budesonide agents are not more effective than placebo in the induction of precludes its usefulness as a maintenance agent in CD, further remission in CD (33). Overall, our systematic review high- research is needed to evaluate the roles of budesonide and lights uncertainty in the evidence comparing budesonide to mesalamine to induce remission with a focus on the specific mesalamine. phenotype each medication is designed to target (i.e., disease In contrast, budesonide was not more effective than placebo in the terminal ileum and proximal colon for budesonide and for maintaining remission in patients with CD. Similarly, nei- left-sided colonic disease with mesalamine). ther weaning doses of conventional steroids nor azathioprine In conclusion, budesonide is more effective than placebo were found to be significantly different than budesonide for the for the induction of remission in active ileocecal CD. A  dose maintenance of remission. Subgroup analyses of drug formu- of 9  mg daily for eight weeks, followed by weaning the dose lations (CIR and pH-dependent), varying doses and method to discontinuation, is considered the optimal dosing regimen. used to induce remission consistently demonstrated lack of Budesonide was less effective than conventional steroids, par - superiority for budesonide in maintaining remission. Subgroup ticularly in patients with severe disease or those with extensive analyses need to be interpreted with caution as several of the colonic involvement. However, the likelihood of adverse events comparisons were made in a single RCT with a small number of with budesonide was significantly lower than with conventional patients, and several RCTs were associated with high risk of bias steroids and was no higher than in patients receiving placebo. due to lack of blinding and allocation concealment. Overall, Budesonide was not found to be effective for maintenance current evidence does not support the use of budesonide in of remission at 12  months in CD. While budesonide did not maintenance of remission in CD. increase the risk of corticosteroid-related adverse events, the Corticosteroid-related AEs were not elevated among patients long-term implications of budesonide on bone metabolism and receiving budesonide as compared with placebo, either when adrenal axis suppression remain uncertain (34). Thus, given the budesonide was used in the short-term to induce remission or weak efficacy and the potential for long-term consequences, the in the long-term to maintain remission. As expected, conven- use of budesonide for maintenance of remission in CD is diffi - tional steroids were associated with statistically and clinically cult to justify. more corticosteroid-related AEs including moon face, acne, mood changes and muscle weakness. SUPPLEMENTARY DATA Prolonged exposure to steroids is known to have detrimen- Supplementary data are available at Journal of the Canadian tal effects on bone metabolism, leading to diminished growth, Association of Gastroenterology online. osteopenia or osteoporosis. The maintenance trial compar - ing budesonide with conventional steroids was specifically designed to compare bone mineral density among the two ACKNOWLEDGEMENTS treatment groups (24). Among corticosteroid-naïve patients, The authors would like to thank John MacDonald, the managing editor decreases in bone mineral density were less pronounced ae ft r at the Cochrane Inflammatory Bowel Disease and Functional Bowel treatment with budesonide than prednisolone. However, this Disorders Group for his assistance with the cited Cochrane reviews. differential reduction in bone mineral density has not been con- Funding for the IBD/FBD Review Group (September 1, 2010–August sistently observed (34). No randomized clinical trial has com- 31, 2015) was provided by the following: Canadian Institutes of Health pared changes in bone mineral density between budesonide Research (CIHR) Knowledge Translation Branch (CON-105529), the Downloaded from https://academic.oup.com/jcag/advance-article-abstract/doi/10.1093/jcag/gwy018/5002120 by Ed 'DeepDyve' Gillespie user on 07 June 2018 14 Journal of the Canadian Association of Gastroenterology, 2018, Vol. XX, No. XX CIHR Institutes of Nutrition, Metabolism and Diabetes (INMD) and References Infection and Immunity (III), and the Ontario Ministry of Health and 1. Baumgart DC, Sandborn WJ. Inflammatory bowel disease: Long-Term Care (HLTC3968FL-2010-2235). Eric Benchimol was Clinical aspects and established and evolving therapies. Lancet. supported by a New Investigator Award from the Canadian Institutes 2007;369(9573):1641–57. of Health Research, Canadian Association of Gastroenterology and 2. Hyams JS. Inflammatory bowel disease. Pediatr Rev. 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