Budesonide for induction of remission in crohn's disease

Budesonide for induction of remission in Crohn's disease
Seow CH, Benchimol EI, Griffiths AM, Otley AR, Steinhart AH
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2009, Issue 4 Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
PLAIN LANGUAGE SUMMARY AUTHORS' CONCLUSIONS CHARACTERISTICS OF STUDIES Analysis 1.1. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 1 Induction of clinical remission (CDAI < = 150).
Analysis 1.2. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 2 Corticosteroid related adverse events.
Analysis 1.3. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 3 Withdrawal due to adverse events.
Analysis 1.4. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 4 Withdrawal due to disease worsening.
Analysis 1.5. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 5 Abnormal ACTH test.
Analysis 1.6. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 6 Change in IBDQ score. . . . .
Analysis 2.1. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 1 Induction of clinical remission (CDAI < = 150).
Analysis 2.2. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 2 Induction of clinical remission at 8 weeks (severe disease, CDAI > = 300).
Analysis 2.3. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 3 Induction of clinical remission at 8 weeks (Ileal or right sided ileocolonic disease). . . . . . . . . . . .
Analysis 2.4. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 4 Induction of clinical remission at 8 weeks (CIR formulation). . . . . . . . . . . . . . . .
Analysis 2.5. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 5 Induction of clinical remission at 8 weeks (pH dependent formulation).
Analysis 2.6. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 6 Change in CDAI.
Analysis 2.7. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 7 Corticosteroid related adverse events.
Analysis 2.8. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 8 Withdrawal due to adverse events.
Analysis 2.9. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 9 Withdrawal due to disease worsening.
Analysis 2.10. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 10 Abnormal ACTH test. .
Analysis 2.11. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 11 Plasma cortisol below normal range (150 nmol per liter).
Analysis 2.12. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 12 Decrease in osteocalcin levels.
Analysis 3.1. Comparison 3 Budesonide 9 mg vs. mesalamine, Outcome 1 Induction of clinical remission (CDAI < = Analysis 3.2. Comparison 3 Budesonide 9 mg vs. mesalamine, Outcome 2 Induction of clinical remission at 8 weeks (severe disease, CDAI > = 300).
Analysis 3.3. Comparison 3 Budesonide 9 mg vs. mesalamine, Outcome 3 Withdrawal due to adverse events. .
CONTRIBUTIONS OF AUTHORS Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Budesonide for induction of remission in Crohn's disease
Cynthia H Seow1, Eric I Benchimol2, Anne Marie Griffiths2, Anthony R Otley3, A Hillary Steinhart4 1Departments of Medicine & Community Health Sciences, University of Calgary, Calgary, Canada. 2Division of Gastroenterology,Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Canada. 3Head, Division of Gastroenterology, IWK Health Centre,Halifax, Canada. 4Department of Medicine, University of Toronto, Toronto, Canada Contact address: Cynthia H Seow, Departments of Medicine & Community Health Sciences, University of Calgary, TRW BuildingRm 6D18, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4Z6, Canada. Editorial group: Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group.
Publication status and date: Edited (no change to conclusions), published in Issue 4, 2009.
Review content assessed as up-to-date: 2 March 2008.
Citation: Seow CH, Benchimol EI, Griffiths AM, Otley AR, Steinhart AH. Budesonide for induction of remission in Crohn's disease.
Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD000296. DOI: 10.1002/14651858.CD000296.pub3.
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Corticosteroids play a key role in the induction of remission in Crohn's disease. However, corticosteroids can cause significant adverseevents. Budesonide is an alternate enteral glucocorticoid with limited systemic bioavailability.
The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in Crohn's disease.
The following electronic databases were searched: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, theCochrane IBD/FBD Group Specialised Trial Register, and ClinicalTrials.gov. Reference lists of articles, as well as conference proceedingswere manually searched. Pharmaceutical companies were also contacted.
Randomized controlled trials comparing budesonide to a control treatment were included. The study population included patients ofany age with active Crohn's disease (CDAI > 150). The primary outcome was induction of remission (CDAI < 150) by week 8 to 16 oftreatment. Secondary outcomes included: time to remission, mean change in CDAI, clinical, histological or endoscopic improvement,improvement in quality of life, adverse events and early withdrawal.
Data collection and analysis
Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality. A random effects model wasused and studies were weighted using the DerSimonian & Laird method. Meta-analysis was performed using RevMan 4.2.10 software.
Main results
Twelve studies were included: 9 compared budesonide with conventional corticosteroids, 2 were placebo-controlled, and 1 comparedbudesonide with mesalamine. After 8 weeks of treatment, budesonide was significantly more effective than placebo (RR 1.96, 95% CI1.19 to 3.23) or mesalamine (RR 1.63; 95% CI 1.23 to 2.16) for induction of remission. Budesonide was significantly less effective thanconventional steroids for induction of remission (RR 0.86, 95% CI 0.76 to 0.98), particularly among patients with severe disease (CDAI> 300) (RR 0.52, 95% CI 0.28 to 0.95). Fewer adverse events occurred in those treated with budesonide compared to conventional Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
steroids (RR 0.64, 95% CI 0.54 to 0.76) and budesonide was better able to preserve adrenal function (RR for abnormal ACTH test0.65, 95% CI 0.55 to 0.78).
Budesonide is more effective than placebo or mesalamine for induction of remission in Crohn's disease. Although short-term efficacywith budesonide is less than with conventional steroids, particularly in those with severe disease or more extensive colonic involvement,the likelihood of adverse events and adrenal suppression is lower.
Budesonide for treatment of active Crohn's disease
Traditional corticosteroids are often used as treatment for active Crohn's disease. Unfortunately, corticosteroids can cause side effects.
Budesonide is a newer corticosteroid drug which is quickly metabolized by the liver thereby reducing corticosteroid related side effects.
Budesonide is more effective than placebo (fake medicine) or mesalamine for the treatment of active Crohn's disease. Traditionalcorticosteroids are more effective than budesonide for the treatment of active Crohn's disease, particularly in patients with severe disease.
However, budesonide is less likely than traditional corticosteroids to cause side effects.
B A C K G R O U N D
moon facies, hirsutism and acne; to more serious disturbances, Crohn's disease (CD) is characterized by transmural inflammation such as growth failure in children; to potentially life threatening that can affect any part of the gastrointestinal tract. It is a chronic complications such as infection, hypertension, diabetes mellitus, condition with a relapsing and remitting course for which there osteoporosis, and glaucoma ). Newer agents such currently is no cure. Medications are designed to suppress the in- as budesonide, a glucocorticoid with anti-inflammatory proper- flammatory response. A variety of therapeutic agents have been ties and limited systemic bioavailability due to extensive (90%) used to treat Crohn's disease, including corticosteroids, 5-aminos- first pass hepatic metabolism by cytochrome p-450 enzymes, may alicylic acid (5-ASA) products (e.g. sulfasalazine or mesalamine), limit adverse effects and may be a promising option if shown to and more recently biologic agents, such as antibodies against tu- be efficacious and safe.
mour necrosis factor alpha (anti-TNF-α) (). Cor-ticosteroids are widely used for the treatment of CD, and they have The use of an oral controlled release preparation of budesonide, been demonstrated to be more effective than placebo or 5-aminos- designed to deliver the drug to the distal small intestine, was first alicylic acid products ( described in pilot studies in the early 1990's (). There ; for treating acute flares of CD in adults are two formulations of budesonide used for the treatment of CD; and children. While the introduction of newer biologic agents in- controlled-ileal release (Entocort® - Astra Zeneca or Astra Draco, cluding infliximab, adalimumab and certolizumab ; Lund Sweden; Entocir®, Sofar S.p.A, Trezzano Rosa [MI], Italy) ; ) are starting to change treatment and pH-dependent release budesonide (Budenofalk® or Bude- paradigms, they are not as readily available and are far most costly son® - Dr. Falk Pharma). The controlled-ileal release formulation uses a gelatin capsule containing acid-stable microgranules com- Corticosteroids inhibit protein synthesis and transcription, and posed of an inner sugar core surrounded by a layer of budesonide ultimately downregulate the production of NF- B and inflam- in ethylcellulose and an outer acrylic-based resin coating (Eudragit matory cytokines such as interleukin (IL)-1, IL-6, and tumour L100-55) that dissolves at a pH of 5.5 or higher. Absorption of this necrosis factor (TNF)-alpha Unfortunately, sys- formulation in the ileocecal region is approximately 69 percent.
temically-administered corticosteroids are associated with multi- The pH-dependent release formulations are available as capsules ple adverse events ranging from cosmetic disturbances such as which contain 400 pellets with a diameter of 1 mm, coated with Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Eudragit resistant to a pH < 6.0 Van Hees Index ()) at the time ofrecruitment were included.
Importance of this review
Standard medical therapeutic options for CD vary in efficacy andtoxicity. Alternative treatments are continually being evaluated.
Types of interventions
There are a number of systematic reviews and metanalyses exam- Trials were considered for inclusion if patients in the active treat- ining the efficacy of budesonide for the induction of remission in ment arm received oral budesonide. Trials assessing budesonide CD ; ; ) . This review provides a versus placebo, or another active agent (including but not re- comprehensive update with an expanded search strategy, and in- stricted to conventional corticosteroids, 5-aminosalicylic acid or cludes a number of additional studies in which efficacy or safety sulfasalazine) were included. Trials comparing budesonide with were not listed as the primary outcome. Additional outcomes eval- various co-interventions were permitted when the co-interven- uated in this review include time to remission, mean change in tions were balanced between the study groups. There were no ex- the CDAI, clinical, histological or endoscopic improvement, im- clusions based on type, dose or duration of budesonide treatment.
provement in quality of life, and adverse events associated withbudesonide therapy. Adverse events include change in bone min-eral parameters, and patients withdrawals. Due to the widespread Types of outcome measures
use of traditional corticosteroids in CD and their significant ad- verse event profile, it is important to carefully examine the efficacy The primary outcome was induction of remission of CD. This and safety of budesonide in order to provide an evidence-based was defined by a CDAI < 150 by 8 to 16 weeks of therapy and approach to the risk/benefit profile of this class of medication.
was expressed as the percentage of patients randomised (intentionto treat analysis).
Secondary outcomes O B J E C T I V E S
The secondary outcomes that were documented included:1. Time to remission; The primary objectives of this review were to evaluate the efficacy 2. The mean change in the CDAI; and safety of oral budesonide for induction of remission in Crohn's 3. Clinical, histologic, or endoscopic improvement as defined by the authors;4. Improvement in quality of life as defined by a validated qualityof life tool; and 5. Adverse events associated with budesonide therapy for the treat-ment of CD.
The different outcome measures used to evaluate the safety of Criteria for considering studies for this review
budesonide included:a. The percentage of patients experiencing adverse events (includ-ing changes in adrenal function);b. The percentage of patients withdrawing from the study due to Types of studies
Randomised controlled trials reporting either the primary or sec- c. The percentage of patients undergoing surgery; and ondary objective and published in any language, with the follow- d. Mortality expressed as a percentage.
ing study designs: parallel arm placebo-controlled trials and trialscomparing budesonide with another active agent were consideredfor this review. Studies published in abstract form were only con- Search methods for identification of studies
sidered for inclusion when sufficient data were provided to assessthe validity of the study and reported outcomes.
See: Cochrane Inflammatory Bowel Disease and Functional BowelDisorders Group methods used in reviews.
The original search strategy (was updated. Signifi- Types of participants
cant changes were made to the electronic search strategy to ensure CD is diagnosed using a combination of clinical, radiologic, en- comprehensiveness. In addition, EMBASE, the Cochrane Central doscopic and histologic criteria. Patients (both paediatric and Register of Controlled Trials, the Cochrane Inflammatory Bowel adult) with active CD, defined by a Crohn's Disease Activity In- Disease and Functional Bowel Disorders (IBD/FBD) Group Spe- dex (CDAI) score of >150 Paediatric Crohn's Disease cialised Trial Register, and ClinicalTrials.gov were searched.
Activity Index (PCDAI) >15 ), or a validated sever- ity scale indicating active disease (e.g. Harvey-Bradshaw Index ( Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A. Electronic searching The EMBASE search strategy included all disease terms (enteri- 1. MEDLINE (1950 - March 2008) tis/or ileitis/ or colon crohn disease/ or crohn disease/ or (in- 2. EMBASE (1980 - March 2008) flammatory adj5 bowel).ti,ab.) and all drug terms (Budesonide/ 3. Cochrane Central Register of Controlled Trials or 51333-22-3.rn. or Budesonide.mp.). This base set was com- 4. Cochrane Inflammatory Bowel Disease and Functional Bowel bined with 1) EMBASE and textword terms for RCTs and CCTs Disorders (IBD/FBD) Group Specialised Trial Register (controlled study/ or case control study/ or randomized controlled 5. Ongoing trials were identified from the registry link http:// trial/ or (random: or rct or rcts or cct or ccts).mp. or (control: adj5 trial:).mp.); 2) EMBASE clinical trial subheading as a floating B. Hand searching using reference lists of trials and review articles subheading; 3) disease terms (enteritis/or ileitis/ or colon crohn identified by means of the computer-assisted search.
disease/ or crohn disease/ or (inflammatory adj5 bowel).ti,ab.) and C. Proceedings from major gastroenterology meetings drug term Budesonide/ct with the subheading. All 3 sets were (American Gastroenterology Association, British Society of Gas- combined to make the final review set.
troenterology, United European Gastroenterology Week) weremanually searched from 2002 onwards.
D. Pharmaceutical and personal contacts Data collection and analysis
Contact with the relevant pharmaceutical companies that have been involved in the development of budesonide.
All the article abstracts identified by the above search strategies Search terms
were reviewed for eligibility. The full text articles of potentially relevant studies were reviewed independently by CHS and EIB 1 Crohn Disease/ or Inflammatory Bowel Diseases/ for inclusion in the review. Review articles were also retrieved 2 Budesonide/or Budesonide (nm) or Budesonide.mp. or gluco- and reference lists were manually searched. Disagreements were corticoid, synthetic/or (synthetic: adj5 glucocorticoid:).mp resolved by consensus with AHS and ARO. Trials published in abstract form were only included if full details of the protocol and 4 limit 3 to (controlled clinical trial or randomized controlled results could be obtained from the authors.
5 (rct or rcts or random: or (control: adj5 trial:)).mp. or controlled The eligible articles were independently reviewed by two authors clinical trials/ or randomized controlled trials/ (CHS, EIB) and the results of the trials were abstracted onto spe- cially designed data extraction forms. The following information The MEDLINE search strategy included all disease terms (Crohn 1. General article information (study title, first author, and year Disease/ or Inflammatory Bowel Diseases/) and all drug terms (Budesonide/or Budesonide (nm) or Budesonide.mp. or gluco- 2. Study design (randomisation process, allocation concealment, corticoid, synthetic/or (synthetic: adj5 glucocorticoid:).mp.). This set was combined with MeSH and textword terms for RCTs and 3. Patient cohort (countries in which the study was performed, CCTs ((rct or rcts or random: or (control: adj5 trial:)).mp. or con- years patients were entered into the study, total number of pa- trolled clinical trials/ or randomized controlled trials/) and lim- tients screened and randomised, inclusion/exclusion criteria, base- ited to publication types (controlled clinical trial or randomized line characteristics including demographics, disease extent, disease controlled trial). The sets were combined to make the final review 4. Intervention (budesonide formulation, route of administration, dose and dosing schedule); 1 enteritis/or ileitis/ or colon crohn disease/ or crohn disease/ or 5. Control (placebo, or details of co-intervention); (inflammatory adj5 bowel).ti,ab.
6. Primary outcome (proportion of patients achieving remission 2 Budesonide/or 51333-22-3.rn. or Budesonide.mp.
defined as CDAI < 150 by 8 to 16 weeks of therapy in the inter- vention and control groups; and 4 Budesonide/ct [Clinical Trial] 7. Secondary outcomes (time to remission; mean change in the 5 controlled study/ or case control study/ or randomized controlled disease activity index score; clinical, histologic or endoscopic im- trial/ or (random: or rct or rcts or cct or ccts).mp. or (control: adj5 provement; improvement in quality of life; adverse events and withdrawal of participants from either the intervention or control Assessment of methodological quality of included studies
The scale which assesses randomisation, blinding and withdrawals/dropouts was used to assess the quality of eligible Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
studies. The five point ordinal scale was independently completed form only. A separate sensitivity analysis for abstract studies was by CHS and EIB; and any disagreement was resolved by consensus not required.
with AHS and ARO. Articles with a Jadad score of 0-2 (poor qual- Analyses were performed using Review Manager software ity) were considered for sensitivity analysis of study quality. Since (RevMan 4.2.10, Copenhagen: The Nordic Cochrane Centre, The reliability of the Jadad scale is not high ), Cochrane Collaboration, 2006).
the final score was used only as a general guideline and decisionon eligibility was accomplished by the mutual agreement of theauthors based on the adequacy of concealment, blinding of in-tervention and outcome, and completeness of follow-up ( ; Studies were classified as "low risk of bias" (i.e.
all above criteria met), "moderate risk of bias" (i.e. one or morecriteria partly met) and "high risk of bias" (i.e. one or more crite-ria not met). The latter group was to be considered for subgroup Description of studies
analysis of low-quality studies. When insufficient information was provided to determine the methodological quality, study authors were contacted to provide further details on the above criteria. Any A total of 77 studies from MEDLINE and a further 531 studies disagreement between authors (EIB and CHS) was to be resolved from EMBASE were identified as being potentially eligible for in- by consensus with content experts (AHS and ARO).
clusion in the review. These papers were obtained in full, and of these studies, twelve studies of patients with CD involving ileum Measures of treatment effect and/or the right colon were eligible for inclusion. A further two Data were extracted from the original studies and converted into studies (; were secondary analyses of individual 2 x 2 tables (e.g. remission versus no remission x budes- previously included studies (re- onide versus control) for each study. The proportion of patients spectively) but provided some additional data (See Table of In- who entered remission was calculated and reported as a relative cluded Studies, Table of Excluded Studies, and Table of Ongoing risk (RR) and 95% confidence interval (95% CI). For continuous Studies). Agreement among reviewers regarding the eligibility of variables, the results were presented as the weighted mean differ- the included studies was 100%. Nine studies compared budes- ence (WMD) and 95% CI or the standardised mean difference onide with traditional corticosteroids (prednisone/prednisolone/ (SMD) when the outcomes were not comparable. Where avail- 6-methylprednisolone; ; able, individual 2 x 2 tables for strata within studies were also ab- ; ). Two studies compared budesonide with placebo and one study The 2 x 2 tables were synthesised into a summary test statistic using compared budesonide with 5-aminosalicylic acid (mesalamine; a more conservative random effects model. Studies were weighted ). Ten studies were conducted in adult patients, using the DerSimonian & Laird method.
and two trials included paediatric patients (; Assessment of heterogeneity Nine studies used a controlled-ileal release (CIR) formula- The studies were independently assessed for clinical or method- tion of budesonide ; ological heterogeneity. The I2 measure was calculated to quan- tify inconsistency and aided in the decision of whether to pool ; ) and three studies used a pH-depen- studies. This measure describes the percentage of total variation dent formulation (; Ac- across studies due to heterogeneity rather than chance, and was tive disease was defined by a CDAI of 150 or greater (most studies interpreted as follows: low heterogeneity (25%), moderate het- used a minimum value of 200). A single study used erogeneity (50%), high heterogeneity (75%) (). The the PCDAI (minimum value 12.5) for defining active disease in Cochran chi-square test (Q test) was also calculated. Being a rel- paediatric patients. Two studies ; atively insensitive test for the presence of heterogeneity, a P-value specified a maximum allowable CDAI of 400 and 450 respectively.
of < 0.10 was considered to be statistically significant.
All studies using CIR formulation included patients with Crohn's Subgroup analysis disease limited to the ileum and or the ascending colon. The three A priori subgroup analyses were planned for the different doses, studies utilizing the pH-dependent formulation of budesonide in- different durations of treatment, disease severity, disease location cluded patients with more extensive colonic involvement. The use and age of the study subjects (paediatric versus adult).
of concomitant therapies such as 5-aminosalicylic acid prepara- Sensitivity analysis tions, non-steroidal anti-inflammatory agents, antibiotics, or total A sensitivity analysis was performed excluding poor quality studies.
enteral/parenteral nutrition were permitted in one study ( There were no included studies that were published in abstract In this study, participants were eligible if the dose of 5-ASA Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
or antibiotics was stable for more than 30 days before study entry the 3 mg budesonide group (33% P = 0.03). Patients treated with and for the duration of the study.
9 mg budesonide achieved a significantly larger decrease in CDAIwhen compared to those receiving 3 mg budesonide or placebo Adverse events were recorded for all studies. However, there was (P < 0.001). Improved health related quality of life (HRQOL), as lack of uniformity in the definitions of corticosteroid-related ad- measured by the IBDQ, was demonstrated in those receiving 9 mg verse events. While tests of adrenal suppression were employed, or 15 mg of budesonide versus placebo (P < 0.001 and P = 0.012 re- some studies measured raw cortisol values, whilst others mea- spectively). More detailed information on HRQOL is provided in sured ACTH stimulated values. Five studies included quality of the secondary analysis paper by Patients treated with life assessments as a secondary outcome measure. The Inflam- 9 mg of budesonide had significantly better bowel, systemic, social matory Bowel Disease Questionnaire (IBDQ) was used in four and emotional subscores. Furthermore, improved HRQOL scores correlated well with decreased CDAI scores. Adrenal suppression ). The SF-36 instrument was also used by and (as measured by plasma cortisol levels and the corticotropin stim- The Psychological Well-Being Index was utilised ulation test) was more pronounced in the 9 and 15 mg budesonide groups compared to baseline values and placebo (P < 0.001). The BUDESONIDE VERSUS PLACEBO
authors concluded that the 9 mg dose of budesonide was the low- There were two large multi-centre, randomized, double-blind, est effective dose for inducing remission in patients with active controlled trials comparing budesonide to placebo Crohn's disease.
; ). The trial was conducted over 27 Canadian centres, while the study recruited Criteria for withdrawal from the study included: worsening dis- across 24 American centres. The studies differed in treatment al- ease defined by an increase in the CDAI of greater than 100 points location. In the study a total of 258 participants above baseline or a CDAI exceeding 450; symptoms requiring were randomized into four study groups; three groups were as- additional medications, hospitalization or surgery; or noncom- signed budesonide at differing doses, 3 mg (n = 67), 9 mg (n = pliance. This trial used an unbalanced randomization schedule 61) and 15 mg (n = 64) in two divided doses, and a fourth group of 2:2:1 (budesonide once daily; budesonide twice daily; versus received placebo (n = 66). In the Tremaine study, 200 participants placebo). The withdrawal rate was 20% (39/200), and 15 partici- were randomized into three study groups. Two budesonide groups pants withdrew because of worsening disease. There was no statis- received a daily dose of 9 mg budesonide, as either 9 mg once tically significant difference in the number of patients withdraw- daily (n = 80) or 4.5 mg twice daily (n = 79), the third group ing from the three study groups. An intention to treat analysis at received placebo (n = 41). A central computer-generated random- 8 weeks showed no statistically significant difference in the pro- ization schedule was utilised in both studies. In the portion achieving remission in the placebo group (31.7%, 13/41) study, participants were stratified by treatment centre and compared to once daily (46.2%, 37/80) or twice daily budesonide whether they had received corticosteroid treatment for longer than (51.9%, 41/79). Post hoc analysis revealed a statistically significant two weeks in the preceding year. No stratification was specified difference in the median time to remission between the placebo in the study. The primary outcome measure was (66 days) and budesonide (27 days) groups. There were no sta- assessed at 8 weeks, at which point the study medications were tistically significant differences in HRQOL (budesonide versus tapered. The total treatment duration was 10 weeks.
placebo, P = 0.13). Placebo treated patients were more likely to maintain normal adrenal function (83%) compared to those re- Criteria for withdrawal included the need for additional therapy ceiving budesonide (53%; P <0.01). There was no difference in (excluding antidiarrheal agents), disease worsening, or lack of im- the ability to respond to adrenal stimulation between the groups.
provement. This was defined as a CDAI ≥ 400, an increase from There was no difference in the proportion of participants experi- baseline by 100 points at week 2, or a CDAI ≥ 300 which had encing adverse events.
not decreased by 100 points by week 4 or thereafter. A total of 119 of 258 patients (46%) withdrew prematurely, with 96 (81%) withdrawing as a result of insufficient therapeutic effect. More premature withdrawals occurred in the 3 mg budesonide (45%) This randomized, double-blind, double dummy study compared and placebo (48%) groups compared with the 9 mg (26%) and budesonide (CIR formulation) 9 mg once daily to mesalamine 15 mg (28%) budesonide groups. The incidence of adverse events 2 g twice daily for the induction of remission in active Crohn's leading to study withdrawal was no greater in patients receiving disease. A total of 182 patients from Europe and Australia were budesonide compared to placebo (5.2% versus 4.5%). At 8 weeks, randomized in permuted blocks of four at each of the 25 cen- the proportion achieving remission with 9 mg budesonide (51%) tres. This study was conducted over a 16 week period. No other and budesonide 15 mg (43%) was significantly higher than that in medications, apart from antidiarrheals, were allowed during the the placebo group (20%; P < 0.001 and P = 0.009 respectively) or study period. Criteria for withdrawal were not defined. The study Budesonide for induction of remission in Crohn's disease (Review)
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groups were well matched with respect to baseline characteristics.
ment (P = 0.07). At this point the prednisolone dose was 5 mg, A larger proportion of the mesalamine group withdrew from the while the budesonide dose was 6 mg. At all time points, there were study prematurely (44%) compared to the budesonide (17%; P a greater proportion of patients with lower unstimulated cortisol < 0.001). At 8 weeks, a significantly greater proportion of pa- levels in the prednisolone versus the budesonide groups.
tients in the budesonide group (69%) achieved remission com- pared to the mesalamine group (45%; P = 0.001). This differ- This randomized, double-blind, double dummy, multicentre trial ence remained at 16 weeks (62% and 36% in the budesonide and compared a pH-modified release formulation of budesonide with mesalamine groups respectively; P < 0.001). Patients achieved re- prednisone over an 8 week study period. Falk Pharma provided de- mission more quickly in the budesonide group (28 days) compared tails on the randomisation process (computer generated sequences, to mesalamine (58 days; P = 0.12). Remission rates were lower 1:1 ratio, permuted blocks of 4). Budesonide treated patients re- in those with more severe disease (CDAI > 300) or in those with ceived 3 mg budesonide three times a day while those randomized colonic involvement. There was a significantly greater improve- to prednisone received 40 mg of prednisone once daily for two ment in HRQOL in the budesonide compared to mesalamine weeks, 30 mg of prednisone daily in the third week, then begin- (Psychological General Well Being index; P = 0.05). The incidence ning in the fourth week the prednisone dose was decreased by 5 of adverse reactions did not differ between the two groups. Patients mg per week until the end of the study. No concurrent Crohn's dis- treated with mesalamine were more likely to have a normal incre- ease therapy was allowed, apart from antidiarrheals. A total of 201 ment in cortisol in response to cosyntropin (100% versus 90% in patients were enrolled in the study. Thirty patients were excluded the mesalamine and budesonide groups respectively).
(16 in the budesonide group, 14 in the prednisone group) as a re- BUDESONIDE VERSUS TRADITIONAL CORTICOS-
sult of protocol violations leaving 171 patients for the per-protocol analysis. Response was defined as a reduction of the CDAI below150 with a reduction of > 60 points for patients with a baseline CDAI of ≤210 points. Remission was defined as a reduction of the This randomized, double-blind, double dummy study compared CDAI to ≤ 150 irrespective of the baseline CDAI (Personal com- budesonide CIR formulation with prednisolone for the induction munication with Falk Pharma). There were no statistically signif- of remission in ileal or ileocaecal Crohn's disease. One hundred icant differences in baseline characteristics between the treatment and seventy six patients at 11 centres in 6 European countries groups. The study was terminated in 46 patients, 23 in each group participated in the study. Patients were randomized in permuted due to lack of efficacy, adverse effects, and noncompliance. Inten- blocks of four at each centre. The intervention was delivered over tion-to-treat analysis showed a 51% overall response rate in the 10 weeks. Patients receiving budesonide were provided 9 mg once budesonide group compared to 52.5% in the prednisone group daily for 8 weeks, then 6 mg daily for the last two weeks. Those (per-protocol analysis 56% and 55% respectively). Remission was randomized to prednisolone received 40 mg daily for two weeks, achieved in 51% of the budesonide group compared to 55.4% of 30 mg for two weeks, and 25 mg for two weeks. The daily dose of the prednisone group. Subgroup analysis showed similar efficacy prednisolone was then decreased by 5 mg each week for the last of budesonide or prednisone for treating disease localized to the four weeks. No other Crohn's disease therapy was allowed, except terminal ileum, cecum or ascending colon. However, when the for antidiarrheals. There were no statistically significant differences disease involved the distal colon and rectum, budesonide was less in the baseline characteristics between the two groups. effective than prednisone (44% vs. 62.5%). In a small group of reported 16 withdrawals from the budesonide group, com- patients (n=27) with exclusive colonic involvement, 58.8% in the pared to 15 in the prednisolone group. However, there were an prednisone group responded compared to 20% of the budesonide additional 2 patients in each group who withdrew before week group. In patients with more severe disease (CDAI ≥ 300), 44.8% 2 and these patients were not included in the efficacy analysis.
of budesonide patients responded compared to 42.4% of pred- At 8 weeks, the authors reported per-protocol remission rates of nisone patients. The authors concluded that both drugs were less 52% and 65% for the budesonide and prednisolone groups re- effective in patients with more active disease. There was a simi- spectively (P = 0.12). An intention-to-treat analysis showed re- lar decrease in CDAI in patients treated with budesonide (127.3 mission rates of 51% and 64% respectively. A rapid therapeutic points) or prednisone (129.5 points). Improvement in HRQOL effect was noted, with a substantial decrease in CDAI scores after was observed in both treatment groups as measured by generic (SF- two weeks of treatment. There was a greater decrease in the mean 36) and disease-specific (IBDQ) tools. concluded CDAI value over the 10 week study in the prednisolone group that budesonide was as effective as prednisone for the treatment compared with the budesonide group. Glucocorticosteroid-asso- of active Crohn's disease involving the right colon and terminal ciated adverse events were greater in the prednisolone group (55%) ileum, with significantly fewer steroid-related adverse events.
compared with budesonide (33%; P = 0.003). The plasma corti-sol levels were significantly suppressed in the prednisolone treated group at all measured time points except the final, 10 week assess- This European multicentre, randomized, double-blind, double Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
dummy study compared an oral pH-modified release formula- at 4.0 months in the budesonide once daily group compared to tion of budesonide with 6-methylprednisolone over an eight week 7.6 months in the budesonide twice daily group. Thirty-six pa- study period. One group received budesonide 9 mg once daily (3 tients withdrew from the study. Worsening disease was the main X 3 mg) while the control group received a tapering dose schedule reason for withdrawal (15%). At the 8-week comparison point, of methylprednisolone (48 mg methylprednisolone during week the remission rates in the budesonide once daily and prednisolone 1, 32 mg during week 2, 24 mg during week 3, 20 mg during groups were both 60%, compared to 42% in the budesonide twice week 4, 16 mg during week 5, 12 mg during week 6, and 8 mg daily group (P = 0.062). Remission rates were lower in patients in week 7 and 8). The primary outcome was the 'response' rate at with greater disease severity, (i.e. a CDAI ≥ 300 compared to a 8 weeks. Response was defined by a CDAI of <150 points and a CDAI < 300; P = 0.0007). However, the number of patients in minimum CDAI decrease of 60 points in patients with a baseline each group were relatively small; 13, 18 and 13 respectively. There CDAI of < 210 points. Of 69 patients randomized, 67 patients were no statistically significant differences in glucocorticosteroid- who had a CDAI >150 points at study entry received at least one associated adverse events which occurred in 50% of the budes- daily dose of the study medication were included in the analysis onide once daily group compared to 44% of the budesonide twice (n = 67). Although the authors stated that the groups were com- daily group, and 59% of the prednisolone group. There was evi- parable at baseline, a few differences are apparent. Women made dence of reduced adrenal function in all three groups at the con- up 71% of the budesonide study group compared to 45% of the clusion of the study, with the maximum reduction occurring in the 6-methylprednisolone group. At study entry the mean duration prednisolone group. The investigators concluded that once daily of Crohn's disease exacerbation in patients treated with budes- budesonide at a dose of 9 mg was equally effective as prednisolone onide was twice that of 6-methylprednisolone group (104±302 for inducing remission, with budesonide providing the extra ad- days vs. 50±49 days, respectively). There were no significant dif- vantage of fewer glucocorticosteroid-associated adverse events.
ferences between the budesonide response rate (55.9%) and that of the 6-methylprednisolone group (72.7%) (P = 0.24) at eight This randomized, double-blind, double dummy study assessed the weeks. found comparable response rates for budes- efficacy of budesonide and prednisolone in children with Crohn's onide and 6-methylprednisolone on subgroup analysis of disease disease. This trial was conducted at 36 European centres, with a location. The response rate for patients with disease distal to the planned sample size of 120 patients. The study was terminated transverse colon was not different between the budesonide and 6- prematurely due to low enrolment numbers, with 56 patients en- methylprednisolone groups (15/25, 60% versus 14/20, 70%, re- rolled at 22 centres. Participants were randomized by country and spectively). Corticosteroid-related adverse events were more com- stratified by pubertal stage to receive 9 mg of budesonide daily mon in the 6-methylprednisolone group (23 of 33, 69.7%) than for eight weeks, followed by 6 mg for 4 weeks or to receive a in the budesonide group (10 of 34, 28.6%, P = 0.0015). Most weight adjusted dose of prednisolone (1 mg/kg for 4 weeks, then of these corticosteroid-related adverse events were dermatological, tapering over 8 weeks to a dose of 2.5 mg/day). The duration such as moon faces and acne. The authors concluded that budes- of treatment was 12 weeks. The primary outcome measure was onide is effective for the treatment of acute ileocolonic Crohn's clinical remission after eight weeks of treatment. The CDAI was minimally modified for use in pediatric patients: hematocrit cut- off was set at 41%, and standard weight was replaced by ideal This 26 centre, multinational, randomized, double-blind, dou- (50% percentile) weight for actual height as determined from stan- ble-dummy study compared budesonide (CIR formulation) with dard growth charts. Disease activity was assessed using both the prednisolone over a 12 week study period. A total of 178 partici- CDAI and PCDAI. The patients were well matched at baseline.
pants were randomized to one of three treatment groups: budes- Per-protocol results were presented in the paper. An intention-to- onide 9 mg once daily, budesonide 4.5 mg twice daily or pred- treat analysis showed that 17 of 26 patients in the prednisolone nisolone 40 mg once daily. The study used a dose tapering regi- group (65.4%) achieved remission compared to 12 of 22 (54.5%) men, with budesonide decreased to 6 mg after eight weeks and to 3 in the budesonide group. The mean CDAI values were higher at mg after a further two weeks. Prednisolone was decreased to 30 mg all time points in patients treated with budesonide compared to after two weeks and then was continually tapered to a final dose of the prednisolone group. Half of the patients receiving budesonide 5 mg at week nine. This 5 mg dose was sustained until the study compared to 76.9% of those receiving prednisolone experienced conclusion at week 12. The study authors described the groups as at least one glucocorticosteroid-related adverse event (P = 0.03).
well-matched with respect to baseline demographic characteristics Seven patients treated with prednisolone withdrew due to serious and disease history. However, the duration of disease appeared to adverse events compared to one patient in the budesonide group.
differ between groups, with patients in the prednisolone group One patient in the prednisolone group withdrew due to disease having a mean disease duration of 6.7 years, whilst those in the worsening compared with three patients in the budesonide group.
budesonide once daily group had a longer mean duration of 8.3 Prednisolone had a greater detrimental effect on adrenal suppres- years. The mean duration of the current exacerbation was shorter sion than budesonide, with 29% in the prednisolone group and Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
58% in the budesonide group demonstrating a normal cortisol dipropionate 10 mg a day for 8 weeks. On intention to treat anal- level at 8 weeks (P = 0.052). Eleven per cent of prednisolone pa- ysis, 66.7% of patients achieved symptomatic remission based on tients had a normal ACTH test result compared with 38% of the a clinical evaluation and a reduction in CDAI to ≤150 compared budesonide group (P = 0.07). The authors concluded that while to 53.3% treated with beclomethasone dipropionate (P < 0.001).
there was a trend for prednisolone to be more effective for induc- Clinical response was defined by an improvement in symptoms ing remission in children with active Crohn's disease, the remis- and a decrease in the CDAI by at least 50 points, and was obtained sion rates were not significantly different between the two groups.
in 86.7% in the budesonide group and 66.7% in the beclometha- However there were significantly fewer adverse effects in those sone dipropionate group (P < 0.001). The study demonstrated treated with budesonide.
there was no statistically significant difference in the time taken to achieve symptomatic remission. There was a greater improve- This small randomized, double-blind, double-dummy, single cen- ment in HRQOL as measured by the IBDQ in the budesonide tre trial performed in the Netherlands compared a controlled ileal group compared to the beclomethasone dipropionate group (P < release (CIR) formulation of budesonide to a tapering course of 0.05). Adverse effects were encountered in 13% of the budesonide prednisolone. No information was provided on the method used treated patients, and 20% of the beclomethasone treated patients.
to generate the randomisation sequence, the method of double The authors concluded that budesonide was more effective than blinding or a description of withdrawals and dropouts. A total beclomethasone dipropionate for the treatment of mild-to-mod- of 18 adult patients (9 in each group) ranging in age from 20 to erate Crohn's disease.
60 years with active Crohn's disease as defined by CDAI ≥ 200, affecting the ileocaecal region were eligible for this 10 week study.
This randomized, single-centre trial compared budesonide and Patients in the budesonide group received 9 mg once a day for the methylprednisolone. The method of randomisation was not re- first 8 weeks, then 6 mg a day for the subsequent 2 weeks. The dose ported. The study recruited 29 patients (both male and female) of prednisolone was 40 mg/day in the first 2 weeks, 30 mg/day in with active Crohn's disease of the ileum and/or right colon with weeks 3 and 4, 25 mg/day in weeks 5 and 6, 20 mg/day in week a CDAI > 200. Patients were assigned to budesonide CIR 9 mg 7, 15 mg/day in week 8, 10 mg/day in week 9 and 5 mg/day in once a day or a tapering regimen of methylprednisolone for 10 the last week of the study. No concurrent therapy was permitted weeks. The methylprednisolone dosage was 32 mg for 3 weeks, during the 2 weeks prior to, or during the study. The primary tapered by 4 mg per week. Methylprednisolone 32 mg is equiva- outcome was the effect on peripheral blood natural killer (NK) lent to 40 mg of prednisone. The primary outcome variables were cell activity. Data on remission (defined as a CDAI ≤ 150) were parameters of osteoblast and osteoclast function. Response and also provided. At 10 weeks, 56% of patients in the budesonide remission were not rigidly defined. It appears that response was study achieved remission, compared to 89% in the prednisolone defined by those who continued treatment and were not in the 'in- group. The mean CDAI and standard error of the mean (SEM) sufficient improvement or worsening symptoms' categories, since were provided at multiple time points. Patients in the budesonide "patients who did not respond at 4 weeks, or in whom the disease group entered the study with a lower CDAI (243 ± 18; CDAI, worsened, dropped out from the study" and were considered to be SEM) compared to patients in the prednisolone group (264 ± 21), 'non-responders'. Given the ambiguity over the definition, these and completed the study with a higher CDAI (139 ± 25 versus data were not metanalysed. Thirty-one per cent of the budesonide 100 ± 21 in the prednisolone group). These values were estimated group and 38% of the methylprednisolone group dropped out of from a bar histogram (; Figure 4). The authors the study. There was a greater reduction in CDAI in the methyl- stated that while the prednisolone treated group showed a lower prednisolone group, with a baseline of 238 ± 33 (CDAI ± SEM), CDAI score after treatment compared to budesonide, this result and a value of 107 ± 30 at 10 weeks; compared to 231 ± 17 and was not statistically significant.
157 ± 22 in the budesonide group. The authors did not make any conclusions regarding the efficacy of methylprednisolone or This randomized, non-blinded, multi-centre trial was conducted budesonide for the treatment of Crohn's disease. in Italy and compared budesonide to beclomethasone dipropi- concluded that budesonide did not result in a significant depres- onate. The method of randomisation was not reported. Thirty sion of bone formation unlike methylprednisolone.
adult patients who had newly diagnosed mild-to-moderately ac- tive, non-fistulizing, non-obstructive Crohn's disease (CDAI 150 This randomized, open label trial compared a pH modified re- to 250) with disease of the terminal ileum and/or the caecum, as- lease formulation to prednisone in 13 paediatric gastroenterology cending or transverse colon were recruited. There were 15 patients clinics in Israel. The method of random number generation was allocated to each treatment. Four patients in the beclomethasone not provided. This study enrolled a total of 35 patients with active group and 3 patients in the budesonide group had colonic disease.
Crohn's disease defined by a PCDAI between 12.5 and 40 points.
Budesonide (pH dependent formulation) was provided at 9 mg a One patient from each group was excluded due to inclusion or day for 8 weeks while the control group received beclomethasone exclusion criteria violations. The study was terminated early due Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
to difficulties with subject enrolment. Patients were allocated to 5/5; 5/5; 4/5; 5/5; budesonide 3 mg three times daily or tapering doses of prednisone 5/5; 5/5. The remaining studies for 10 weeks. Prednisone patients received 40 mg/d for 2 weeks, were given Jadad scores of 2/5; these were ; 30 mg/d during week 3, 25 mg/d during week 4, 20 mg/d during ; . Further details are provided week 5, 15 mg/d during week 5, 10 mg/d during weeks 7 and 8, in the 'Table of Included Studies'.
and 10 mg on alternate days for weeks 9 and 10. Disease remis-sion was defined by a PCDAI ≤ 10 points after twelve weeks. Onintention-to-treat analysis, the proportion of patients achieving Effects of interventions
remission in the prednisone group was 46.7% (7/15), compared to 45.0% (9/20) in the budesonide group. There was a slightly a. REMISSION (CDAI < 1 50)
larger decrease in PCDAI in the prednisone compared to thosetreated with budesonide (-13.4 ± 10.6 versus -9.3 ± 14.8; PCDAI BUDESONIDE VERSUS PLACEBO ± SD). In the final two weeks prior to outcome assessment (weeks11 and 12), neither corticosteroid was prescribed, and instead pa- Two trials ; ) with a combined to- tients received 3 to 4 g/d of mesalamine alone. Adverse events were tal of 327 patients compared the efficacy of budesonide to placebo.
more prevalent in the prednisone group at 71.4% compared to Comparisons were made at three time points; 2 weeks, 4 weeks 31.6% in the budesonide group (P < 0.05). The authors felt these and 8 weeks. It was not necessary to perform subgroup analy- adverse events were related to the study medications. The authors ses because the trials were clinically and statistically homogenous.
concluded that remission rates with budesonide and prednisone Equivalent doses were compared for this pooled analysis, hence were similar in pediatric patients with Crohn's disease and those only the 9 mg per day budesonide group () was treated with budesonide experienced significantly fewer adverse used for comparison with the study cohort.
At all three time points, budesonide was shown to be significantly superior to placebo for induction of remission in active Crohn's Three ongoing studies were identified from the registry link http:/ disease. At two weeks, the pooled relative risk was 2.97 (95% CI, /ClinicalTrials.gov (details are provided in the Table of ongoing 1.67 to 5.29) in favour of budesonide; at four weeks, the relative risk was 1.67 (95% CI, 1.12 to 2.47); and at 8 weeks the relative 1. Astra Zeneca: Efficacy and safety study of D9421-C 9 mg and risk was 1.96 (95% CI, 1.19 to 3.23). A more conservative random 15 mg versus placebo in Japanese patients with active Crohn's effects model was used for all 3 comparisons. The use of a fixed effects model did not significantly alter the point estimate.
2. Belgian IBD Research Group: The ideal management of Crohn's BUDESONIDE VERSUS CONVENTIONAL CORTICOS- disease: Top down versus step up strategies. A prospective con- trolled trial in the Benelux; and3. Falk Pharma GmbH: Oral budesonide versus oral mesalazine There were 9 trials which compared budesonide to traditional in active CD (BUC-52/CDA).
corticosteroids. reported the reduction in CDAI Personal communication with Falk Pharma GmbH alerted the scores. Eight trials ; authors to another budesonide study (BUC-47/CDA) that will require future review. It appears that the study design is dose- used a 'remission' endpoint, and were metanalysed. The data finding as budesonide is used in both arms of the study. The title of were statistically homogenous for the comparison of budesonide the trial is "A double-blind, randomized, active-controlled, parallel versus conventional corticosteroids at 2,4,8, and 12 weeks. Of the group, multi-centre phase IIb study to assess efficacy and safety of 8 trials, 3 trials made comparisons at 2 weeks; 4 trials at 4 weeks, two different budesonide doses in active Crohn's disease pediatric 8 trials at 8 weeks, and 3 trials at 12 weeks.
patients". Current status was reported as "recruitment completed At 8 weeks, there were a total of 750 patients in the 8 trials. Budes- and statistical analysis is ongoing". No publication of preliminary onide was demonstrated to be inferior to conventional steroids for data are available.
the induction of remission in active Crohn's disease, with a relativerisk of 0.85 (95% CI 0.75 to 0.97). The studies were shown tobe statistically homogenous (P = 0.83). A controlled ileal release Risk of bias in included studies
preparation was used in 5 studies ( An assessment of the methodological quality of each study was ; with the remaining made independently by two authors (CHS, EIB) using the 3 studies using the pH dependent formulation scale. There was 100% agreement on the Jadad scores.
The studies which were considered of high methodological qual- Subgroup analyses (Budesonide versus Conventional Corticos- ity were: 5/5; 5/5; Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
i. Budesonide formulation (CIR versus pH dependent) for the combined budesonide group compared to placebo. The Budesonide CIR was inferior to conventional steroids with a rela- median time to remission was shorter for budesonide than placebo tive risk of 0.84 (95% CI, 0.71 to 0.98) in a total of 449 patients (27 days versus 66 days; P < 0.05).
(; ; A sensitivity analysis restricted to good quality stud- BUDESONIDE VERSUS CONVENTIONAL CORTICOS- ies (Jadad > 3/5; ; ; ) showed similar results with a relative risk of 0.83 (95% CI, 0.69 and reported the time to remission. reported that the mean time (± SD) to achieving a CDAI < There was no statistically significant difference between budes- 150, or attainment of a minimum CDAI decrease by 60 points in onide pH dependent formulation compared to conventional patients with an entrance CDAI of < 210 points was 22.3 ± 12.1 steroids (; ) with a relative days in the budesonide group (n = 19), and 20.0 ± 17.7 days in risk of 0.87 (95% CI, 0.71 to 1.07) in 301 patients. A sensitivity the methylprednisolone group (n = 24); P = 0.51. con- analysis restricted to good quality studies (; cluded that budesonide worked faster than conventional steroids ) showed similar results (RR 0.87; 95% CI, 0.70 to 1.07).
in achieving symptomatic remission. The mean time to remission ii. Disease location (Ileum and/or the right colon) was 27 days (range 23 to 31 days) in the budesonide group com- A pooled analysis of six studies of patients with terminal ileal, or pared to 41 days (range 36 to 46 days) in the beclomethasone ileo-colonic disease, not extending past the hepatic flexure, dipropionate group (P < 0.05; Personal communication, A. Tursi).
; ; BUDESONIDE VERSUS MESALAMINE ; showed a non significant trend in favour demonstrated that there was no statistically signif- of conventional steroids with a relative risk for remission of 0.86 icant difference in the median time to remission in the budesonide (95% CI, 0.75 to 1.00; P = 0.05).
group compared to mesalamine (28 versus 58 days, P = 0.12). This iii. Disease severity (CDAI > 300) information was available as an erratum to the paper (N. Engl J There were two studies (which exam- Med 2001;345:1652-a), as the original paper incorrectly demon- ined the proportion of patients with severe disease (CDAI > 300) strated a statistically significant result.
who achieved remission. The pooled relative risk of remission was c. MEAN CHANGE IN CDAI
0.52 (95% CI, 0.28 to 0.95), in favour of conventional steroids.
BUDESONIDE VERSUS PLACEBO These results suggest that budesonide is inferior to conventional It was not possible to metanalyse the change in CDAI for budes- steroids for the treatment of severe Crohn's disease.
onide versus placebo. Both and BUDESONIDE VERSUS MESALAMINE provided figures showing the change in CDAI. Requests for addi-tional data were not answered by the sponsoring company, Astra A single trial of 182 patients compared budesonide with Zeneca, Lund, Sweden. It appeared that there was a greater change mesalamine (). There appeared to be a more in CDAI in the budesonide group compared with placebo at 8 favourable response with a longer duration of treatment with weeks (, 121 points versus 21 points respectively; budesonide. The relative risk at 2 weeks was 1.23 (95% CI, 0.85 , 118 points versus 72 points).
to 1.78), however this was not statistically significant. At 4 weeks,the relative risk was 1.26 (95% CI, 0.88 to 1.79). At 8 weeks, BUDESONIDE VERSUS CONVENTIONAL CORTICOS- the relative risk was 1.63 (95% CI, 1.23 to 2.16; P = 0.0007); at 12 weeks, the relative risk was 1.59 (95% CI, 1.17 to 2.15; P =0.003), and finally at 16 weeks, the relative risk was 1.79 (95% There was limited information available on the change in CDAI.
CI, 1.28 to 2.50; P = 0.0007).
Published and non-published information on CDAI were analysedfor six studies with a total of 539 patients. ; b. TIME TO REMISSION
and provided the change in The time to remission was not reported in most of the trials, and CDAI at 8 weeks in text and figure format, while despite correspondence with the authors, additional information and made the outcome assessment at 10 weeks.
on standard deviations or standard errors of the mean were un- Where relevant, SEMs were converted to SDs using the formula SD=SEM. n, and the change in CDAI and SD was imputed BUDESONIDE VERSUS PLACEBO using Follmann's method (). Where only a figure documented that the time to remission did not was provided, and the raw data were not available, two authors differ between the 9 mg and 15 mg budesonide groups (P = (CHS, EIB) independently interpreted the values from the graphs 0.70). However, data on the time to remission in the budesonide and subsequently reached a consensus. When the two time points groups compared to placebo were not provided. were combined, there was a statistically larger change in CDAI performed a post hoc analysis comparing the time to remission in the conventional corticosteroid group, with the weighted mean Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
difference in CDAI of 42.27 points (95% CI, 14.86 to 69.67).
Three trials, with a total of 201 patients reported the proportion provided PCDAI data. There was a larger decrease of participants with plasma cortisol below the normal range (150 in PCDAI ± SD in the prednisone group (13.4 ± 10.6) compared nmol per liter) (; to budesonide (9.3 ± 14.8).
The relative risk was 0.53 (95% CI 0.43 to 0.65), such that signif-icantly more budesonide participants had plasma cortisol levels in BUDESONIDE VERSUS MESALAMINE the normal range at eight weeks compared with those treated withconventional corticosteroids. Adrenal stimulation tests were con- reported a statistically significant decrease in ducted in three trials ; CDAI scores in favour of budesonide at all time points (weeks 2, which demonstrated that patients treated with budesonide were 4, 8, 12 and 16). At the primary outcome interval of 8 weeks, the significantly less likely than patients who received conventional change in CDAI (mean ± SD) in the budesonide group was 131 corticosteroids to have an abnormal response to ACTH stimula- ± 78 compared to 89 ± 123 in the mesalazine group (P = 0.007).
tion (RR 0.65, 95% CI 0.55 to 0.78).
d. CLINICAL, HISTOLOGIC, ENDOSCOPIC IMPROVE-
BUDESONIDE VERSUS MESALAMINE reported that adverse events were more com- The included studies did not provide adequate histologic or en- mon in patients treated with mesalamine (71.9%) compared to doscopic outcomes for metanalysis.
budesonide (63.4%). The number of patients with serious adverse events (hospitalisation) (19.1% versus 11.8%, P = 0.16) and se- BUDESONIDE VERSUS PLACEBO vere adverse events (inability to work or take part in normal activ- The two trials comparing budesonide to placebo (; ities) (24.7% versus 12.9%, P = 0.04) were more frequent in the ) showed no difference in the proportion of re- mesalamine group. Only one serious adverse event in each group ported corticosteroid-related adverse events with a relative risk of was considered to be possibly related to treatment: fever and ag- 0.99 (95%CI, 0.78 to 1.25; P = 0.92). There was a significantly gressive behaviour in the mesalamine and budesonide groups re- smaller proportion of withdrawals due to disease worsening in the budesonide group (RR 0.39, 95% CI 0.17 to 0.89), but no dif- Adrenal function was better preserved in patients treated with ference in withdrawals due to adverse effects (RR 1.16, 95% CI mesalamine than with budesonide. Sixty-seven per cent of budes- 0.45 to 2.99). Neither study specified the percentage of patients onide patients and 83% of mesalamine patients had normal plasma undergoing surgery or provided mortality statistics.
cortisol values before cosyntropin challenge (P = 0.06). Ninety With respect to adrenal suppression, an impaired response to per cent of budesonide patients and 100% of mesalamine patients ACTH stimulation was significantly more common in patients re- had a normal increase in cortisol in response to cosyntropin (P = ceiving budesonide compared to placebo (RR 2.60, 95% CI 1.69 QUALITY OF LIFE
BUDESONIDE VERSUS CONVENTIONAL CORTICOS-TEROIDS Only five trials measured quality of life as an outcome measure (; Six trials with a total of 703 patients reported the frequency of corticosteroid-related adverse events ; BUDESONIDE VERSUS PLACEBO and reported change in quality of life Patients treated with budesonide had significantly fewer corticos- as an outcome. There was no statistically significant difference teroid-related adverse events than those treated with conventional in the improvement in IBDQ scores between 9 mg budesonide corticosteroids (RR 0.64, 95% CI 0.54 to 0.76). While compared to placebo (P = 0.15). The weighted mean difference reported adverse events, it was not clear if these were treatment in score was 16.79 (-6.34 to 39.91).
related. There was no statistically significant difference in the pro- BUDESONIDE VERSUS CONVENTIONAL CORTICOS- portion of patients who withdrew due to an adverse event (RR 0.57, 95% CI 0.18 to 1.84; ; reported the change in quality of life as an outcome.
; There were insufficient data The changes in IBDQ scores were similar in both groups: budes- to metanalyse withdrawals due to disease worsening. onide (135.9 ± 28.2 to 162.0 ± 34.0) and prednisone (130.1 ± reported withdrawal from the study as a result of requiring surgery.
31.8 to 164.4 ± 36.0). reported that there was a sig- There was one patient in both the budesonide and 6-methylpred- nificantly larger improvement in IBDQ in patients treated with nisolone groups (6.7% and 11.1% respectively) who withdrew budesonide 9 mg (64 to 198) compared to those treated with be- early from the study for this reason. None of the studies reported clomethasone dipropionate (68 to 176) at the end of an 8 week mortality outcomes.
treatment period (P < 0.05).
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
BUDESONIDE VERSUS MESALAMINE suggesting that these patients may have had less severe Crohn's (secondary analysis of measured disease and perhaps been more responsive to budesonide. This ob- the change in quality of life using the Psychological General Well- servation is important, as a subsequent subgroup analysis focusing Being Score (PGWB) and concluded that patients treated with on patients with severe Crohn's disease clearly demonstrated that budesonide experienced significantly greater improvement in qual- budesonide was less effective than conventional corticosteroids for ity of life than the group treated with mesalazine after 2, 8, 12, induction of remission. Given the potential confounders of dis- and 16 weeks.
ease location and severity, it is difficult to directly compare theefficacy of the two formulations of budesonide in the absence ofa head-to-head trial. Therefore, it is concluded that budesonide issuperior to placebo or mesalamine, but inferior to conventional D I S C U S S I O N
corticosteroids, particularly when a patient has severe disease ordisease with extensive colonic involvement.
Conventional corticosteroids, including prednisone and 6- There were insufficient data to determine if budesonide improved methylprednisolone have been a mainstay of therapy for the in- the time to remission compared to placebo, conventional corti- duction of remission in patients with Crohn's disease. However, costeroids or mesalamine. With respect to the change in disease use of this class of drugs is tempered by potentially significant ad- activity, there was a significantly larger reduction in CDAI when verse events. Given the chronic nature of this inflammatory disor- budesonide was compared to conventional corticosteroids. It ap- der, and the potential need for multiple courses of steroids to treat peared that there was a greater mean change in CDAI in patients recurrent flares, there was a need to develop a new corticosteroid treated with budesonide compared with placebo or mesalamine.
formulation that would have the therapeutic effect of corticos- However there were insufficient data to provide a formal pooled teroids, but without its inherent side effects. It was expected that budesonide, with its delayed release formulation, location specificdelivery, (terminal ileum and ascending colon), and its 85% firstpass metabolism in the liver, may achieve this.
Adverse events are of major concern to clinicians treating patients This systematic review has demonstrated that budesonide is clearly with Crohn's disease. Patients treated with budesonide had sig- superior to placebo or mesalamine (5-aminosalicylic acid) for in- nificantly fewer corticosteroid-related adverse events compared to duction of remission in Crohn's disease. Budesonide exhibited those treated with conventional corticosteroids. There was no dif- inferior efficacy when compared to conventional corticosteroids.
ference in the proportion of patients reporting corticosteroid-re- These results are similar to those found in previous meta-analy- lated side effects when budesonide was compared to placebo. There ses (; ; found that were a smaller number of withdrawals due to disease worsening budesonide is approximately 13% less effective than conventional in patients treated with budesonide compared to placebo. There corticosteroids for induction of remission in Crohn's disease which were no differences in quality of life between the groups. However, is similar to an estimate of 15% in this review. However, the study it may be possible that these acute therapy trials were of insuffi- design of the 8 conventional corticosteroid comparison trials dif- cient duration for more manifest adverse effects or complications fered from usual clinical practice and may have overestimated the of corticosteroid therapy to influence health-related quality of life efficacy of budesonide. Budesonide was given at 'full' dose (9 mg) in the long term. The effect of corticosteroids on adrenal function for the first eight weeks of the study (the primary outcome eval- was tested by comparing baseline cortisol levels and the response to uation time point of most of the trials), and then decreased, but ACTH stimulation. An impaired response to ACTH stimulation not discontinued at the final study evaluation, whilst the conven- was significantly more common in patients receiving budesonide tional corticosteroids were given at full dose for two weeks, and compared to placebo or mesalamine. However, adrenal function then tapered, such that at the conclusion of most studies, patients was better preserved in patients receiving budesonide compared had been weaned off steroids. Budesonide CIR was inferior to conventional corticosteroids. Unfortunately, growth suppression, conventional corticosteroids in a subgroup analysis of budesonide a significant long term adverse effect of corticosteroid use in chil- formulation. These patients had Crohn's disease limited to the ter- dren was not assessed. The trials had insufficient follow up dura- minal ileum and right colon. Further analysis was performed by tion to assess this outcome.
disease location, which suggested that budesonide may be infe-rior to conventional corticosteroids for induction of remission inpatients with terminal ileal or ileo-colonic disease, not extending beyond the hepatic flexure. While the budesonide pH dependentformulation appeared to be of equal efficacy to conventional corti- Implications for practice
costeroids, these studies included patients with a lower CDAI (150versus > 200 for the CIR studies; ; ), Budesonide is more effective than placebo or mesalamine for in- Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
duction of remission in active ileo-caecal Crohn's disease. Although to consider in pediatric patients in whom there is the potential for short-term efficacy with budesonide is less than with conventional corticosteroid-related growth suppression. In adults, further study steroids, particularly in patients with severe disease or more ex- may be warranted to evaluate the impact of budesonide on bone tensive colonic involvement, the likelihood of adverse events and mineral density.
adrenal suppression is lower.
Implications for research
While it is clear that budesonide is less efficacious than conven-tional corticosteroids, one must remain cognizant that the study We thank Ms. Elizabeth Uleryk (Director, Hospital Library, The design of the conventional corticosteroid comparison trials may Hospital for Sick Children) for aiding in the search strategy used have overestimated the effect size of budesonide due to full dose in this review.
budesonide being compared to a tapering dose of conventional Funding for the IBD/FBD Review Group (October 1, 2005 - corticosteroids. There is currently only a single controlled trial September 30, 2010) has been provided by the Canadian Insti- comparing budesonide with a 5-aminosalicylic acid compound.
tutes of Health Research (CIHR) Knowledge Translation Branch; Further analysis should be performed when the identified on- the Canadian Agency for Drugs and Technologies in Health going study by Falk Pharm GmbH (ClinicalTrials.gov identifier (CADTH); and the CIHR Institutes of Health Services and Pol- NCT00300118) comparing 4.5 g mesalazine with 9 mg budes- icy Research; Musculoskeletal Health and Arthritis; Gender and onide is completed. Further research is required to evaluate the Health; Human Development, Child and Youth Health; Nutri- long-term adverse event profile of budesonide. While budesonide tion, Metabolism and Diabetes; and Infection and Immunity.
appears to be less toxic than conventional corticosteroids in short-term trials, it does suppress adrenal function. The long-term ef- Miss Ila Stewart has provided support for the IBD/FBD Review fects of budesonide on bone metabolism are especially important Group through the Olive Stewart Fund.
R E F E R E N C E S
References to studies included in this review
Gross 1996 {published and unpublished data}
Gross V, Andus T, Caesar I, Bischoff SC, Lochs H, Tromm A, et Bar-Meir 1998 {published and unpublished data}
al.Oral pH-modified release budesonide versus 6- Bar-Meir S, Chowers Y, Lavy A, Abramovitch D, Sternberg A, methylprednisolone in active Crohn's disease. German/Austrian Leichtmann G, et al.Budesonide versus prednisone in the treatment Budesonide Study Group. Eur J Gastroenterol Hepatol 1996;8(9):
of active Crohn's disease. Gastroenterology 1998;115(4):835–40.
Campieri 1997 {published data only}
Irvine 2000 {published data only}
Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG. Oral Irvine EJ, Greenberg GR, Feagan BG, Martin F, Sutherland LR, budesonide is as effective as oral prednisolone in active Crohn's Thomson AB, et al.Quality of life rapidly improves with budesonide disease. The Global Budesonide Study Group. Gut 1997;41(2):
therapy for active Crohn's disease. Canadian Inflammatory Bowel Disease Study Group. Inflamm Bowel Dis 2000;6(3):181–7.
D'Haens 1998 {published data only}
D'Haens G, Verstraete A, Cheyns K, Aerden I, Bouillon R, Levine 2003 {published data only}
Rutgeerts P. Bone turnover during short-term therapy with Levine A, Weizman Z, Broide E, Shamir R, Shaoul R, Pacht A, et methylprednisolone or budesonide in Crohn's disease. Aliment al.A comparison of budesonide and prednisone for the treatment of active pediatric Crohn disease. J Pediatr Gastroenterol Nutr 2003;36
Escher 2004 {published data only}
Escher JC, European Collaborative Research Group on Budesonide Rutgeerts 1994 {published data only}
in Paediatric IBD. Budesonide versus prednisolone for the Rutgeerts P, Lofberg R, Malchow H, Lamers C, Olaison G, Jewell treatment of active Crohn's disease in children: a randomized, D, et al.A comparison of budesonide with prednisolone for active double-blind, controlled, multicentre trial. Eur J Gastroenterol Crohn's disease. N Engl J Med 1994;331(13):842–5.
Greenberg 1994 {published data only}
Thomsen 1998 {published data only}
Greenberg GR, Feagan BG, Martin F, Sutherland LR, Thomson Thomsen OO, Cortot A, Jewell D, Wright JP, Winter T, Veloso FT, AB, Williams CN, et al.Oral budesonide for active Crohn's disease.
et al.A comparison of budesonide and mesalamine for active Canadian Inflammatory Bowel Disease Study Group. N Engl J Med Crohn's disease. International Budesonide-Mesalamine Study Group. N Engl J Med 1998;339(6):670–4.
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Thomsen 2002 {published data only}
Gelbmann 2001 {published data only}
Thomsen OO, Cortot A, Jewell D, Wright JP, Winter T, Veloso FT, Gelbmann CM, Rogler G, Gierend M, Gross V, Scholmerich J, et al.Budesonide and mesalazine in active Crohn's disease: a Andus T. Association of HLA-DR genotypes and IL-1ra gene comparison of the effects on quality of life. Am J Gastroenterol polymorphism with treatment failure of budesonide and disease patterns in Crohn's disease. Eur J Gastroenterol Hepatol 2001;13
Tremaine 2002 {published and unpublished data}
Tremaine WJ, Hanauer SB, Katz S, Winston BD, Levine JG, Green 2001 {published data only}
Persson T, et al.Budesonide CIR capsules one or twice daily in Green JR, Lobo AJ, Giaffer M, Travis S, Watkins HC. Maintenance active Crohn's disease. A randomized placebo controlled study in of Crohn's disease over 12 months: fixed versus flexible dosing the USA. Am J Gastroenterol 2002;97(7):1748–54.
regimen using budesonide controlled ileal release capsules. Aliment Tursi 2006 {published and unpublished data}
Tursi A, Giorgetti GM, Brandimarte G, Elisei W, Aiello F.
Greenberg 1996 {published data only}
Beclomethasone dipropionate for the treatment of mild-to- Greenberg GR, Feagan BG, Martin F, Sutherland LR, Thomson moderate Crohn's disease: an open-label, budesonide-controlled, AB, Williams CN, et al.Oral budesonide as maintenance treatment randomized study. Med Sci Monit 2006;12(6):PI29–32.
for Crohn's disease: a placebo-controlled, dose-ranging study.
Van Ierssel 1995 {published data only}
Canadian Inflammatory Bowel Disease Study Group.
Van Ierssel AJ, Van der Sluys Veer A, Verspaget HW, Griffioen G, Van Hogezand RA, Lamers CB. Budesonide and prednisolonesuppress peripheral blood natural killer cells in Crohn's disease.
Gross 1997a {published data only}
Aliment Pharmacol Ther 1995;9(2):173–8.
Gross V, Caesar I, Andus T, Vogelsang H, Adler G, Malchow H, etal.Replacement of systemic steroids by oral budesonide in patients References to studies excluded from this review
with post-active or chronic Crohn's ileocolitis - a dose-findingstudy. Gastroenterology 1997; Vol. 112, issue 4:A987.
Anonymous 1999 {published data only}
Anonymous. Comparison of budesonide with mesalazine in Gross 1997b {published data only}
Crohn's disease. [Dutch]. Geneesmiddelenbulletin 1999;33(2):21–2.
Gross V, Caesar I, Andus T, Vogelsang H, Adler G, Malchow H, et Caesar 1997 {published data only}
al.Dose-finding study with oral budesonide in patients with active Caesar I, Gross V, Roth M, Andus T, Schmidt C, Raedsch R, et Crohn's ileocolitis. Gastroenterology 1997; Vol. 112, issue 4:A986.
al.Treatment of active and postactive ileal and colonic Crohn's Gross 1998 {published data only}
disease with oral pH-modified-release budesonide. German Gross V, Andus T, Ecker KW, Raedler A, Loeschke K, Plauth M, et Budesonide Study Group. Hepatogastroenterology 1997;44(14):
al.Low dose oral pH modified release budesonide for maintenance of steroid induced remission in Crohn's disease. The Budesonide Cortot 2001 {published data only}
Study Group. Gut 1998;42(4):493–6.
Cortot A, Colombel JF, Rutgeerts P, Lauritsen K, Malchow H,Hamling J, et al.Switch from systemic steroids to budesonide in Hanauer 2005 {published data only}
steroid dependent patients with inactive Crohn's disease. Gut 2001; Hanauer S, Sandborn WJ, Persson A, Persson T. Budesonide as maintenance treatment in Crohn's disease: a placebo-controlled Ecker 2003 {published data only}
trial. Aliment Pharmacol Ther 2005;21(4):363–71.
Ecker KW, Stallmach A, Seitz G, Gierend M, Greinwald R, Hellers 1999 {published data only}
Achenbach U. Oral budesonide significantly improves water Hellers G, Cortot A, Jewell D, Leijonmarck CE, Lofberg R, absorption in patients with ileostomy for Crohn disease. Scand J Malchow H, et al.Oral budesonide for prevention of postsurgical recurrence in Crohn's disease. The IOIBD Budesonide Study Ewe 1999 {published data only}
Ewe K, Bottger T, Buhr HJ, Ecker KW, Otto HF. Low-dose Herfarth 2004 {published data only}
budesonide treatment for prevention of postoperative recurrence of Herfarth H, Gross V, Andus T, Caesar I, Vogelsang H, Adler G, et Crohn's disease: a multicentre randomized placebo-controlled trial.
al.Analysis of the therapeutic efficacy of different doses of German Budesonide Study Group. Eur J Gastroenterol Hepatol budesonide in patients with active Crohn's ileocolitis depending on disease activity and localization. Int J Colorectal Dis 2004;19(2):
Ferguson 1998 {published data only}
Ferguson A, Campieri M, Doe W, Persson T, Nygard G. Oralbudesonide as maintenance therapy in Crohn's disease--results of a Irvine 1996 {published data only}
12-month study. Global Budesonide Study Group. Aliment Irvine EJ. Effects of budesonide therapy on quality of life in active Crohn's disease. Research & Clinical Forums 1996;18(1):81–9.
Florin 2000 {published data only}
Kundhal 2001 {published data only}
Florin TH, Graffner H, Nilsson LG, Persson T. Treatment of joint Kundhal P, Zachos M, Holmes JL, Griffiths AM. Controlled ileal pain in Crohn's patients with budesonide controlled ileal release.
release budesonide in pediatric Crohn disease: efficacy and effect on Clin Exp Pharmacol Physiol 2000;27(4):295–8.
growth. J Pediatr Gastroenterol Nutr 2001;33(1):75–80.
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Levine 2002 {published data only}
steroids on circulating leukocytes in Crohn's disease. Am J Levine A. Evaluation of oral budesonide for treatment of mild and moderate exacerbations of Crohn's disease in children. J Pediatr
2002;140(1):75–80.
References to ongoing studies
Lofberg 1993 {published data only}
Astra Zeneca {published data only}
Lofberg R, Danielsson A, Salde L. Oral budesonide in active Efficacy and safety study of D9421-C 9 mg and 15 mg versus Crohn's disease. Aliment Pharmacol Ther 1993;7(6):611–6.
placebo in Japanese patients with active Crohn's disease. Ongoing Lofberg 1996 {published data only}
study October 2007.
Lofberg R, Rutgeerts P, Malchow H, Lamers C, Danielsson A, Belgian IBD Research {unpublished data only}
Olaison G, et al.Budesonide prolongs time to relapse in ileal and The ideal management of Crohn's disease: Top down versus step up ileocaecal Crohn's disease. A placebo controlled one year study. Gut strategies. A prospective controlled trial in the Benelux. Ongoing study Recruitment Status: Completed Lowry 1999 {published data only}
Lowry PW, Sandborn WJ. A comparison of budesonide and mesalamine for active Crohn's disease. Gastroenterology 1999;116
Start Date: May 2001 Completion Date: January 2004.
Mantzaris 2003 {published data only}
Mantzaris GJ, Petraki K, Sfakianakis M, Archavlis E, Christidou A, Falk Pharma GmbH {unpublished data only}
Chadio-Iordanides H, et al.Budesonide versus mesalamine for Oral budesonide vs. oral mesalazine in active CD. Ongoing study maintaining remission in patients refusing other September 2004.
immunomodulators for steroid-dependent Crohn's disease. Clin Novacek 1995 {published data only}
Barnes 2005
Novacek G, Kleinberger M, Vogelsang H, Moser G, Lochs H.
Barnes PJ. Molecular mechanisms and cellular effects of Budesonide in glucocorticoid dependent chronic active Crohn's glucocorticosteroids. Immunol Allergy Clin North Am 2005;25(3):
disease; a pilot study. Z Gastroenterol 1995;33(5):251–4.
Roth 1993 {published data only}
Roth M, Gross V, Scholmerich J, Ueberschaer B, Ewe K. Treatment Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical of active Crohn's disease with an oral slow-release budesonide aspects and established and evolving therapies. Lancet 2007;369
formulation. Am J Gastroenterol 1993;88(6):968–9.
Sandborn 2005 {published data only}
Best 1976
Sandborn WJ, Lofberg R, Feagan BG, Hanauer SB, Campieri M, Best WR, Becktel JM, Singleton JW, Kern F, Jr. Development of a Greenberg GR. Budesonide for maintenance of remission in Crohn's disease activity index. National Cooperative Crohn's patients with Crohn's disease in medically induced remission: a Disease Study. Gastroenterology 1976;70(3):439–44.
predetermined pooled analysis of four randomized, double-blind, Clark 1999
placebo-controlled trials. Am J Gastroenterol 2005;100(8):1780–7.
Clark HD, Wells GA, Huet C, McAlister FA, Salmi LR, Fergusson Schoon 2005 {published data only}
D, et al.Assessing the quality of randomized trials: reliability of the Schoon EJ, Bollani S, Mills PR, Israeli E, Felsenberg D, Ljunghall Jadad scale. Control Clin Trials 1999;20(5):448–52.
S, et al.Bone mineral density in relation to efficacy and side effects Fedorak 2005
of budesonide and prednisolone in Crohn's disease. Clin Fedorak RN, Bistritz L. Targeted delivery, safety, and efficacy of oral enteric-coated formulations of budesonide. Adv Drug Deliv Rev Simms 2001 {published data only}
Simms L, Steinhart AH. Budesonide for maintenance of remission in Crohn's disease. Cochrane Database of Systematic Reviews 2001, Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for Issue 1.[Art. No.: CD002913. DOI: 10.1002/ overviews of clinical trials with continuous response. J Clin Steinhart 2002 {published data only}
Hanauer 2006
Steinhart AH, Feagan BG, Wong CJ, Vandervoort M, Mikolainis S, Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, Croitoru K, et al.Combined budesonide and antibiotic therapy for MacIntosh D, et al.Human anti-tumor necrosis factor monoclonal active Crohn's disease: a randomized controlled trial.
antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.
Gastroenterology 2006;130(2):323-33; quiz 591.
Tillinger 1998 {published data only}
Harvey 1980
Tillinger W, Gasche C, Reinisch W, Lichtenberger C, Bakos S, Harvey RF, Bradshaw JM. A simple index of Crohn's-disease Dejaco C, et al.Influence of topically and systemically active Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Higgins 2003
Issue 4.[Art. No.: CD000296. DOI: 10.1002/ Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557–60.
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Papi C, LUchetti R, Montanti S, Koch M, Capurso L. Budesonide Higgins JPT, Green S, editors. Assessment of study quality.
in the treatment of Crohn's disease: a meta-analysis. Aliment Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006]; Section 6. The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, 2006.
Sandborn WJ, Feagan BG, Stoinov S, Honiball PJ, Rutgeerts P, Hyams 1991
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Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of included studies [ordered by study ID]
Randomized, double-blind, double-dummy multi-centre trial comparing budesonide with prednisone.
14 Israeli sites with 7-31 patients per centre. Randomised within centres according to a computer basedrandomization schedule (ratio 1:1, block size 4; information supplied by Dr. R. Greinwald of Dr. FalkPharma). Jadad score 5/5.
Male and female patients, 18-70 years old, with active Crohn's disease. Patients with CDAI score between150 and 350 were included. Patients with disease in terminal ileum and/or colon (including distal colonand rectum) were included. A similar number of patients were excluded from the budesonide (n=16) andprednisone (n=14) groups due to major violations.
Budesonide (Budenofalk)3 mg three times a day for 8 weeks or prednisone 40 mg once daily for the first2 weeks followed by 30 mg daily in the third week; thereafter, the dose was decreased by 5 mg per weekuntil end of study (8 weeks total). Compliance was checked by pill count.
Primary outcome variable was response without steroid related adverse events. Secondary outcomes wereresponse with adverse events, and overall response (with and without adverse events). Response was definedas reduction of the CDAI below 150 or a reduction by 60 points or more for patients in whom CDAI atthe time of inclusion was below 210 points.
1) Used pH-dependent formulation of budesonide (Budenofalk, Dr Falk Pharma, Freiburg, Germany).
2) Included patients with disease in the distal colon and rectum (27 patients had colonic involvementonly)3) Additional information (i.e. on method of randomisation)supplied by Dr. R. Greinwald of Dr. FalkPharma4) The definition of 'response' was identical to the other studies definition of 'remission' Risk of bias
Allocation concealment? Randomized, double blind, double dummy multi-centre trial comparing budesonide and prednisolone.
Conducted at 26 centres in 9 countries. Randomisation was performed centrally by a computer (infor-mation obtained from authors). Jadad score 5/5.
Male and female patients, older than 18 years of age, with active Crohn's disease, defined by a CDAI of>= 200. Entry was restricted to patients with disease involving the ileum and/or the ascending colon, butnot extending beyond the hepatic flexure.
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Budesonide 9 mg once daily, budesonide 4.5 mg twice daily or prednisolone 40 mg once daily. Budesonidewas tapered to 6 mg after eight weeks and to 3 mg after a further two weeks. Prednisolone was tapered to30 mg after two weeks and further tapered throughout the study, reaching 5 mg after nine weeks. The 5mg dose was then continued for three weeks so that the total treatment period was 12 weeks. Medicationswere provided in identical blister packages. Compliance was assessed by pill counts.
Primary outcome variable was remission, defined as a CDAI of <=150. Adverse events were also assessed.
1) Used controlled ileal release formulation (Entocort, Astra Draco, Lund, Sweden).
2) Additional information concering realy withdrawal was provided by the Publication did not specifyfrom which group withdrawals occurred in publication - this information was obtained from sponsor3) Additional information was obtained from sponsor Risk of bias
Allocation concealment? D'Haens 1998
Randomized, single-centre trial comparing budesonide with methylprednisolone. Jadad score 2/5.
Male and female patients, with active Crohn's disease of the ileum or right colon, CDAI >200 wereincluded.
Budesonide CIR 9 mg once a day or methylprednisolone at a tapering regime for 10 weeks. Methylpred-nisolone was provided at 32 mg for 3 weeks, tapered by 4 mg per week.
Primary outcome variables were parameters of osteoblast and osteoclast function. There were no remissiondata, however, CDAI was a secondary outcome.
1) Used controlled ileal release formulation (Entocort, Astra Zeneca, Lund Sweden).
2) Methylprednisolone 32 mg is equivalent to 40 mg prednisone.
3) Response and remission were not formally defined.
Risk of bias
Allocation concealment? Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Escher 2004
Randomized, double-blind, double dummy multi-center trial comparing budesonide with prednisolonein pediatric patients. 36 European sites in 8 European countries. Randomization was performed usingcomputer generated sequences in blocks by country and stratum (stratification was performed accordingto pubertal stage so that 50% of the patients in each treatment group were prepubertal, as defined byTanner stage <=II). Jadad score = 5/5.
Male and female patients, 6-16 years of age, with active Crohn's disease as defined by a CDAI of >=200.
(A modified PCDAI was also used to assess disease activity). Patients were included if disease was confinedto the ileum and/or ascending colon.
Budesonide 9 mg daily for 8 weeks, followed by 6 mg for 4 weeks, irrespective of age or weight of thepatient; or prednisolone in a dose determined by body weight: 1 mg/kg daily for 4 weeks, followed by 8weeks of tapering to a dose of 2.5 mg/day. Total treatment duration was 12 weeks.
Primary outcome measure was clinical remission at 8 weeks, defined as a CDAI of <=150. Secondaryoutcomes included the frequency of adverse events and adrenal function, measured as morning plasmacortisol levels and ACTH stimulation tests.
1) Used a controlled ileal release formulation (Entocort, Astra Zeneca, Lund Sweden).
Risk of bias
Allocation concealment? Randomized, double-blind, placebo controlled, multi centre trial. 27 Canadian sites (total of 258 patients)stratified according to treatment centre and use of corticosteroid treatment for longer than two weeks inthe preceding year. Total number of patients was 258. Information was obtained from the study sponsorregarding the method of randomisation. The study utilised a centrally generated computer randomisationsequence. Jadad score 5/5.
Male and female patients, > 18 years of age, with active Crohn's disease as defined by a CDAI of >= 200.
Eligible patients had disease involving the ileum or the ileum and colon, disease did not extend beyondthe hepatic flexure.
Budesonide 3, 9, 15 mg or placebo for 8 weeks. Compliance was assessed by pill counts.
Primary outcome measure was remission, defined as a CDAI score of <=150. Secondary outcomes includeddisease specific quality of life, adverse events and adrenal function (plasma cortisol and ACTH tests).
1) Used a controlled ileal release formulation (Entocort CIR, Astra Draco, Lund, Sweden).
2) Additional information provided by study sponsor, Astra Zeneca.
Risk of bias
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Allocation concealment? Gross 1996
Randomized, double-blind, double dummy multi centre trial comparing budesonide to 6-methylpred-nisolone. 16 German and Austrian sites. Computer based randomization schedule (ratio 1:1, block size4). Jadad score 4/5.
Male and female patients with active Crohn's disease between the ages of 18 and 70. CDAI >150 < or =to 350 included. There were no restrictions on the extent of colonic involvement.
Budesonide 3 mg three times daily or tapering doses of methylprednisolone for 8 weeks. Methylpred-nisolone patients received 48 mg daily during week 1, 32 mg during week 2, 24 mg during week 3, 20mg during week 4, 16 mg during week 5, 12 mg during week 6, and 8 mg in week 7 and 8. Compliancewas assessed but the method was not described.
Disease remission defined by a CDAI < 150 points after eight weeks or a CDAI decrease > 60 points inpatients with an entry CDAI <210. Secondary outcomes were mean CDAI, AUC (area under the curve)of the CDAI, time to response, time to failure, influence of the localization of Crohn's disease and adverseevents.
1) Used pH-dependent formulation of budesonide (Budenofalk, Dr Falk Pharma, Freiburg, Germany)2) Further information received from Dr. R. Greinwald, Dr. Falk Pharma Risk of bias
Allocation concealment? Irvine 2000
Secondary analysis of Greenberg 1994 study, with additional information on quality of life.
As per Greenberg 1994 study As per Greenberg 1994 study The primary outcome was the change in health related quality of life scores and subscores as measured bythe Inflammatory Bowel Disease Questionnaire (IBDQ).
Risk of bias
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Irvine 2000
Allocation concealment? Levine 2003
Randomized, open trial comparing budesonide to prednisone in 13 paediatric gastroenterology clinics inIsrael. Jadad score 2/5.
Male and female patients, aged 8-18 years of age, with active Crohn's disease as defined by a PCDAIbetween 12.5 and 40 points were included. Disease location was defined as right-sided (ileum to hepaticflexure) or left-sided (distal to the hepatic flexure).
Budesonide 3 mg three times daily or tapering doses of prednisone for 10 weeks. Prednisone patientsreceived 40 mg/d for 2 weeks, 30 mg/d during week 3, 25 mg/d during week 4, 20 mg/d during week 5,15 mg/d during week 5, 10 mg/d during weeks 7 and 8, and 10 mg on alternate days for weeks 9 and 10.
Disease remission defined by a PCDAI <= 10 points after twelve weeks. The secondary outcome was theadverse event profile.
1) pH modified release budesonide formulation (Budeson, Falk Pharma, Germany).
2) per-protocol results were reported.
Risk of bias
Allocation concealment? Randomized double-blind,double dummy, multi centre trial comparing budesonide to prednisolone. 11European sites with separate randomization blocks of four at each centre. Jadad score 5/5.
Male and female patients, 18 years and older, with active Crohn's disease as defined by CDAI > 200 andwith disease confined to the ileal or ileocecal region (with or without involvement of the ascending colon).
Budesonide 9 mg daily for eight weeks and then 6 mg daily for the last two weeks or prednisolone 40 mgdaily for two weeks, 30 mg for two weeks, 25 mg for two weeks, then a wean by 5 mg each week for thelast four weeks. Compliance was verified by pill counts.
Primary outcome variable was disease remission at 10 weeks. Remission defined as a CDAI < 150 or adecrease of at least 100 points in the score at each visit. Adverse events, including corticosteroid effectsand adrenal function (cortisol levels) were assessed.
1) Used controlled ileal release formulation of budesonide (Entocort CIR, Astra Draco, Lund, Sweden).
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Risk of bias
Allocation concealment? Thomsen 1998
Randomized, double-blind, double-dummy, multi centre trial comparing budesonide to mesalamine.
Conducted in 25 centres. Patients were randomised separately at each centre using permuted blocks offour using sealed, opaque treatment-code envelopes. Jadad score 5/5.
Male and female patients, 18 years of age and older, with active Crohn's disease as defined by CDAI scorebetween 200 to 400. Eligible patients had disease confined to the distal ileum, the ileocecal region, andthe ascending colon.
Budesonide 9 mg once daily or 2 g of mesalamine twice daily for 16 weeks. Compliance was assessed bypill counts Primary outcome was remission rate, defined by a CDAI <= 150. Secondary endpoints were changes inCDAI, time to remission, changes in the Psychological General Well-Being index, changes in adrenalfunction (plasma cortisol and ACTH tests), and adverse events.
1) Used controlled ileal release formulation of budesonide (Entocort, Astra Draco, Lund, Sweden).
Risk of bias
Allocation concealment? Thomsen 2002
Secondary analysis of Thomsen 1998 study, with additional information on quality of life.
As per Thomsen 1998 study.
As per Thomsen 1998 study.
The primary outcome was change in health related quality of life scores as measured by the PsychologicalGeneral Well-Being index (PGWB) at baseline and after 2, 4, 8, 12 and 16 weeks of treatment.
Risk of bias
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Thomsen 2002
Allocation concealment? Randomized, double-blind, placebo-controlled multi centre trial. 24 US centres. Computer generatedrandomized schedule, with randomization to treatment groups in balanced blocks of 5 patients. 2:2:1randomization (budesonide: budesonide: placebo). Jadad score 5/5.
Male and female patients 18 years of age and older with active Crohn's disease as defined by CDAI between200 and 450. Only patients with Crohn's disease limited to the ileum and/or the ascending colon wereeligible.
Budesonide 9 mg od, 4.5 mg bid or placebo for 10 weeks. Compliance was assessed by pill counts at eachvisit.
Primary outcome measure was remission rate, defined by a CDAI < 150 at 8 weeks. Secondary outcomemeasures were: treatment benefit (defined as remission or a decrease in the CDAI score of at least 100points from baseline), CDAI, changes in the quality of life as assessed by the IBDQ and the SF-36, andeffects of treatment on adrenal cortisol production.
1) Used controlled ileal release formulation of budesonide (Astra Zeneca, Lund, Sweden).
Risk of bias
Allocation concealment? Tursi 2006
Randomized, non-blinded multi centre trial conducted in Italy comparing budesonide to beclomethasonedipropionate. Method of randomisation was not reported. Jadad score 2/5.
30 adult patients (16-71 years) with newly diagnosed mild-to-moderately active, non-fistulizing, non-obstructive Crohn's disease defined by a CDAI score between 150 and 250 were included. Patients withdisease in the terminal ileum and/or the caecum, ascending or transverse colon were included.
Budesonide (pH dependent)9 mg a day for 8 weeks or beclomethasone dipropionate 10 mg a day for 8weeks. Compliance was monitored by pill counts.
The primary outcome was symptomatic remission based on clinical evaluation and a reduction in CDAI<=150 after 8 weeks of treatment. Secondary endpoints included clinical response (defined as an im-provement in symptoms and disease activity by at least 50 points); time to symptomatic remission; andimprovement in health-related quality of life (IBDQL). Adverse events were also recorded and graded byintensity.
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Tursi 2006
1) Used controlled ileal release formulation of budesonide (Entocir, Sofar S.p.A, Trezzano Rosa [MI],Italy).
Risk of bias
Allocation concealment? Van Ierssel 1995
Randomized, double-blind, double-dummy, single centre trial (Netherlands)comparing budesonide to atapering course of prednisolone. Jadad score 2/5. The method used to generate the sequence of randomi-sation, the method of double blinding and a description of withdrawals and dropouts was not provided.
Male and female patients ranging from 20-60 years with active Crohn's disease as defined by CDAI >=200. Only patients with Crohn's disease affecting the ileocaecal region were eligible.
Budesonide (controlled ileal release formulation)9 mg once a day for the first 8 weeks, then 6 mg a dayfor the subsequent 2 weeks. The dose of prednisolone was 40 mg/day in the first 2 weeks, 30 mg/day inweeks 3 and 4, 25 mg/day in weeks 5 and 6, 20 mg/day in week 7, 15 mg/day in week 8, 10 mg/dayin week 9 and 5 mg/day in the last week (week 10) of the study. No concurrent therapy was permittedduring the 2 weeks prior to, or during the study.
The primary outcome was the effect of oral budesonide and prednisolone on peripheral blood naturalkiller (NK) cell activity in patients with active ileocaecal Crohn's disease. Secondary outcomes included:remission (CDAI < = 150), and change in CDAI.
1) Used controlled ileal release formulation of budesonide (Astra Draco, Lund, Sweden).
Risk of bias
Allocation concealment? Characteristics of excluded studies [ordered by study ID]
Commentary, not a randomised controlled trial.
Open label, no comparison group.
Existing corticosteroid use prior to randomising to budesonide or placebo.
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cohort comprised surgical patients (ileostomy)without detectable inflammatory activity.
Maintenance study.
Maintenance study.
Secondary analysis of included randomised controlled trials.
Maintenance study.
Maintenance study.
Maintenance study.
Randomized, double-blind dose-finding study.
All participants received budesonide, no other comparison groups used.
Randomized, double-blind dose-finding study to assess success of switching from conventional systemic steroidsto budesonide. All participants were pre-treated with corticosteroids.
Maintenance study.
Maintenance study.
Maintenance study.
Comparison of the therapeutic efficacy of different doses of budesonide. All participants received budesonide.
More complete data are presented in the Irvine 2000 paper (see included studies).
Case series.
Case-control study of pediatric patients Open, uncontrolled study in 21 patients, all patients received budesonide.
Maintenance study.
Commentary on existing randomized controlled trials.
Maintenance study.
All patients received budesonide.
Pooled analysis of four randomized, double-blind, placebo-controlled trials of maintenance therapy.
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Budesonide doses were not fixed. p 114, "after [this] initial period, treatment doses could then be adjusted bythe managing clinicians according to disease activity until the study termination at 2 years" Cochrane systematic review of budesonide for the maintenance of remission in Crohn's disease.
Budesonide used in both treatment groups.
Did not define remission.
Only looked at decrease in CDAIThe first 12 patients participating in this study also took part in a prospective multicentre, double-blind , double-dummy trial by Gross et al. These patients had already been accounted for in the Gross paper.
Characteristics of ongoing studies [ordered by study ID]
Astra Zeneca
Trial name or title Efficacy and safety study of D9421-C 9 mg and 15 mg versus placebo in Japanese patients with active Crohn'sdisease.
Male and female patients, 18 - 65 years of age, with active Crohn's disease (CDAI limits not provided).
Drug: D9421-C (Budesonide)9 mg or 15 mg or placebo.
Primary outcome measure is remission after 8-weeks of treatment defined by a CDAI score of <= 150.
Secondary outcomes include: remission after 2-weeks and 4-weeks of treatment, time to first remission, changein CDAI score, and safety.
Contact information Study Director: Masataka Date, MD, PhD AstraZeneca ClinicalTrials.gov Identifier: NCT00573469; Recruiting.
Study ID Numbers: D9421C00002Health Authority: Japan: Pharmaceuticals and Medical Devices Agency Belgian IBD Research
Trial name or title The ideal management of Crohn's disease: Top down versus step up strategies. A prospective controlled trialin the Benelux Male and female patients, 16 - 75 years of age, with active Crohn's disease, CDAI>200.
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Belgian IBD Research
Drug: Infliximab+azathioprine, ormethylprednisolone or budesonide Primary outcome measure is remission without corticosteroids and without surgical resection [6 and 12months after inclusion ]Secondary outcomes include time to relapse after successful induction therapy [within 24 months]; theproportion of patients receiving infliximab, methylprednisolone and antimetabolites [within 24 months];the median serum C-reactive protein concentration [24 months]; the proportion of patients experiencingadverse events [24 months ]; the mean endoscopic severity scores and the proportion of patients withoutulcers [after 24 months].
Recruitment Status: CompletedEnrolment: 129Start Date: May 2001Completion Date: January 2004 Contact information Study Director: Geert R D'Haens, MD, PhD Belgian IBD Research GroupImelda GI Clinical Research Center Bonheiden, Belgium, 2820 ClinicalTrials.gov Identifier: NCT00554710; Completed recruitment.
Falk Pharma GmbH
Trial name or title Oral budesonide vs. oral mesalazine in active CD Male and female patients, 18 - 70 years of age, with active Crohn's disease (CDAI between 200 and 400) .
Eligible patients have disease involving the terminal ileum, ascending colon or ileocolitis.
Drug: Budesonide 9 mg a day, orDrug: Mesalazine 4.5g a day.
Primary outcome measure is rate of remission.
Secondary outcomes include: response to treatment, time to response, time to remission, physician globalassessment and quality of life.
Contact information Ralf Mohrbacher 49 761 1514-0 Ext.156 [email protected] Ev. Krankenhaus Hattingen GmbH, Hattingen, 45525, Germany ClinicalTrials.gov identifier NCT00300118; Recruiting.
Study ID Numbers: BUC-52/CDA, 2004-001213-34First Received: March 7, 2006Last Updated: September 10, 2007Health Authority: Germany: Federal Institute for Drugs and Medical Devices Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparison 1. Budesonide 9 mg vs. placebo
Outcome or subgroup title
Effect size
Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) 2.97 [1.67, 5.29] Risk Ratio (M-H, Random, 95% CI) 1.67 [1.12, 2.47] Risk Ratio (M-H, Random, 95% CI) 1.96 [1.19, 3.23] Risk Ratio (M-H, Random, 95% CI) 0.98 [0.77, 1.24] Risk Ratio (M-H, Random, 95% CI) 1.16 [0.45, 2.99] Risk Ratio (M-H, Random, 95% CI) 0.39 [0.17, 0.89] Risk Ratio (M-H, Random, 95% CI) 2.60 [1.69, 4.00] Mean Difference (IV, Random, 95% CI) 16.79 [-6.34, 39.91] Comparison 2. Budesonide 9 mg vs. conventional steroids
Outcome or subgroup title
Effect size
Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) 0.91 [0.72, 1.13] Risk Ratio (M-H, Random, 95% CI) 0.71 [0.59, 0.85] Risk Ratio (M-H, Random, 95% CI) 0.85 [0.75, 0.97] Risk Ratio (M-H, Random, 95% CI) 1.02 [0.81, 1.30] Risk Ratio (M-H, Random, 95% CI) 0.52 [0.28, 0.95] Risk Ratio (M-H, Random, 95% CI) 0.86 [0.75, 1.00] Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) 0.84 [0.71, 0.98] Risk Ratio (M-H, Random, 95% CI) 0.83 [0.69, 0.98] Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) 0.87 [0.71, 1.07] Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Risk Ratio (M-H, Random, 95% CI) 0.87 [0.70, 1.07] Mean Difference (IV, Random, 95% CI) -42.27 [-69.67, -14.86] Risk Ratio (M-H, Random, 95% CI) 0.64 [0.54, 0.76] Risk Ratio (M-H, Random, 95% CI) 0.57 [0.18, 1.84] Risk Ratio (M-H, Random, 95% CI) 1.0 [0.07, 14.55] Risk Ratio (M-H, Random, 95% CI) 0.65 [0.55, 0.78] Risk Ratio (M-H, Random, 95% CI) 0.53 [0.43, 0.65] Mean Difference (IV, Random, 95% CI) -2.49 [-10.52, 5.54] Comparison 3. Budesonide 9 mg vs. mesalamine
Outcome or subgroup title
Effect size
Risk Ratio (M-H, Random, 95% CI) Risk Ratio (M-H, Random, 95% CI) 1.23 [0.85, 1.78] Risk Ratio (M-H, Random, 95% CI) 1.26 [0.88, 1.79] Risk Ratio (M-H, Random, 95% CI) 1.63 [1.23, 2.16] Risk Ratio (M-H, Random, 95% CI) 1.59 [1.17, 2.15] Risk Ratio (M-H, Random, 95% CI) 1.79 [1.28, 2.50] Risk Ratio (M-H, Random, 95% CI) 3.80 [1.19, 12.15] Risk Ratio (M-H, Random, 95% CI) 0.36 [0.10, 1.31] Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.1. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 1 Induction of clinical remission (CDAI
< = 150).
Budesonide for induction of remission in Crohn's disease 1 Budesonide 9 mg vs. placebo 1 Induction of clinical remission (CDAI < = 150) Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 3.09 [ 1.41, 6.79 ] 2.84 [ 1.21, 6.63 ] Subtotal (95% CI)
2.97 [ 1.67, 5.29 ]
Total events: 75 (Budesonide), 12 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.02, df = 1 (P = 0.88); I2 =0.0% Test for overall effect: Z = 3.70 (P = 0.00022) 2.16 [ 1.15, 4.08 ] 1.43 [ 0.88, 2.31 ] Subtotal (95% CI)
1.67 [ 1.12, 2.47 ]
Total events: 94 (Budesonide), 24 (Placebo) Heterogeneity: Tau2 = 0.00; Chi2 = 1.05, df = 1 (P = 0.31); I2 =5% Test for overall effect: Z = 2.54 (P = 0.011) 2.58 [ 1.49, 4.45 ] 1.55 [ 0.96, 2.49 ] Subtotal (95% CI)
1.96 [ 1.19, 3.23 ]
Total events: 109 (Budesonide), 26 (Placebo) Heterogeneity: Tau2 = 0.06; Chi2 = 1.91, df = 1 (P = 0.17); I2 =48% Test for overall effect: Z = 2.64 (P = 0.0082) Favours budesonide Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.2. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 2 Corticosteroid related adverse events.
Budesonide for induction of remission in Crohn's disease 1 Budesonide 9 mg vs. placebo 2 Corticosteroid related adverse events Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 0.94 [ 0.52, 1.70 ] 0.98 [ 0.76, 1.28 ] Total (95% CI)
0.98 [ 0.77, 1.24 ]
Total events: 115 (Budesonide), 43 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.02, df = 1 (P = 0.89); I2 =0.0% Test for overall effect: Z = 0.21 (P = 0.84) Favours budesonide Analysis 1.3. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 3 Withdrawal due to adverse events.
Budesonide for induction of remission in Crohn's disease 1 Budesonide 9 mg vs. placebo 3 Withdrawal due to adverse events Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 1.08 [ 0.23, 5.16 ] 1.20 [ 0.36, 3.99 ] Total (95% CI)
1.16 [ 0.45, 2.99 ]
Total events: 17 (Budesonide), 6 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.01, df = 1 (P = 0.92); I2 =0.0% Test for overall effect: Z = 0.30 (P = 0.76) Favours budesonide Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.4. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 4 Withdrawal due to disease worsening.
Budesonide for induction of remission in Crohn's disease 1 Budesonide 9 mg vs. placebo 4 Withdrawal due to disease worsening Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 0.54 [ 0.33, 0.88 ] 0.23 [ 0.09, 0.59 ] Total (95% CI)
0.39 [ 0.17, 0.89 ]
Total events: 23 (Budesonide), 40 (Placebo) Heterogeneity: Tau2 = 0.23; Chi2 = 2.55, df = 1 (P = 0.11); I2 =61% Test for overall effect: Z = 2.24 (P = 0.025) Favours budesonide Analysis 1.5. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 5 Abnormal ACTH test.
Budesonide for induction of remission in Crohn's disease 1 Budesonide 9 mg vs. placebo 5 Abnormal ACTH test Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 2.50 [ 1.44, 4.33 ] 2.76 [ 1.38, 5.53 ] Total (95% CI)
2.60 [ 1.69, 4.00 ]
Total events: 105 (Budesonide), 20 (Placebo) Heterogeneity: Tau2 = 0.0; Chi2 = 0.05, df = 1 (P = 0.82); I2 =0.0% Test for overall effect: Z = 4.34 (P = 0.000014) Favours budesonide Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 1.6. Comparison 1 Budesonide 9 mg vs. placebo, Outcome 6 Change in IBDQ score.
Budesonide for induction of remission in Crohn's disease 1 Budesonide 9 mg vs. placebo 6 Change in IBDQ score Study or subgroup 28.40 [ 16.34, 40.46 ] 4.80 [ -8.60, 18.20 ] Total (95% CI)
16.79 [ -6.34, 39.91 ]
Heterogeneity: Tau2 = 236.17; Chi2 = 6.58, df = 1 (P = 0.01); I2 =85% Test for overall effect: Z = 1.42 (P = 0.15) Favours budesonide Analysis 2.1. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 1 Induction of clinical
remission (CDAI < = 150).
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 1 Induction of clinical remission (CDAI < = 150) Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 1.02 [ 0.67, 1.55 ] 1.08 [ 0.60, 1.95 ] 0.81 [ 0.60, 1.10 ] Subtotal (95% CI)
0.91 [ 0.72, 1.13 ]
Total events: 94 (Budesonide), 81 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 1.19, df = 2 (P = 0.55); I2 =0.0% Test for overall effect: Z = 0.87 (P = 0.39) 0.79 [ 0.60, 1.03 ] 0.76 [ 0.46, 1.26 ] Favours conv steroid Favours budesonide (Continued . . ) Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . Continued) Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 0.83 [ 0.43, 1.60 ] 0.59 [ 0.43, 0.79 ] Subtotal (95% CI)
0.71 [ 0.59, 0.85 ]
Total events: 112 (Budesonide), 119 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 2.41, df = 3 (P = 0.49); I2 =0.0% Test for overall effect: Z = 3.77 (P = 0.00016) 0.92 [ 0.71, 1.19 ] 0.85 [ 0.65, 1.12 ] 0.83 [ 0.52, 1.34 ] 0.77 [ 0.53, 1.11 ] 0.98 [ 0.44, 2.19 ] 0.80 [ 0.62, 1.04 ] 1.25 [ 0.69, 2.26 ] 0.63 [ 0.33, 1.17 ] Subtotal (95% CI)
0.85 [ 0.75, 0.97 ]
Total events: 211 (Budesonide), 210 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 3.52, df = 7 (P = 0.83); I2 =0.0% Test for overall effect: Z = 2.51 (P = 0.012) 1.04 [ 0.78, 1.39 ] 1.01 [ 0.60, 1.71 ] 0.95 [ 0.47, 1.92 ] Subtotal (95% CI)
1.02 [ 0.81, 1.30 ]
Total events: 87 (Budesonide), 52 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 0.06, df = 2 (P = 0.97); I2 =0.0% Test for overall effect: Z = 0.18 (P = 0.86) Favours conv steroid Favours budesonide Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.2. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 2 Induction of clinical
remission at 8 weeks (severe disease, CDAI > = 300).
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 2 Induction of clinical remission at 8 weeks (severe disease, CDAI > = 300) Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 0.42 [ 0.18, 0.96 ] 0.67 [ 0.27, 1.66 ] Total (95% CI)
0.52 [ 0.28, 0.95 ]
Total events: 11 (Budesonide), 13 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 0.55, df = 1 (P = 0.46); I2 =0.0% Test for overall effect: Z = 2.12 (P = 0.034) Favours conv steroid Favours budesonide Analysis 2.3. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 3 Induction of clinical
remission at 8 weeks (Ileal or right sided ileocolonic disease).
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 3 Induction of clinical remission at 8 weeks (Ileal or right sided ileocolonic disease) Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 1.11 [ 0.80, 1.56 ] 0.85 [ 0.65, 1.12 ] 0.83 [ 0.52, 1.34 ] 0.87 [ 0.46, 1.64 ] 0.80 [ 0.62, 1.04 ] 0.63 [ 0.33, 1.17 ] Total (95% CI)
0.86 [ 0.75, 1.00 ]
Total events: 161 (Budesonide), 157 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 3.60, df = 5 (P = 0.61); I2 =0.0% Test for overall effect: Z = 1.96 (P = 0.050) Favours conv steroid Favours budesonide Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.4. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 4 Induction of clinical
remission at 8 weeks (CIR formulation).
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 4 Induction of clinical remission at 8 weeks (CIR formulation) Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 0.85 [ 0.65, 1.12 ] 0.83 [ 0.52, 1.34 ] 0.80 [ 0.62, 1.04 ] 1.25 [ 0.69, 2.26 ] 0.63 [ 0.33, 1.17 ] Subtotal (95% CI)
0.84 [ 0.71, 0.98 ]
Total events: 133 (Budesonide), 124 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 2.69, df = 4 (P = 0.61); I2 =0.0% Test for overall effect: Z = 2.17 (P = 0.030) 2 Sensitivity analysis: Jadad score > = 3 0.85 [ 0.65, 1.12 ] 0.83 [ 0.52, 1.34 ] 0.80 [ 0.62, 1.04 ] Subtotal (95% CI)
0.83 [ 0.69, 0.98 ]
Total events: 118 (Budesonide), 108 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 0.09, df = 2 (P = 0.96); I2 =0.0% Test for overall effect: Z = 2.15 (P = 0.032) Favours conv steroid Favours budesonide Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.5. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 5 Induction of clinical
remission at 8 weeks (pH dependent formulation).
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 5 Induction of clinical remission at 8 weeks (pH dependent formulation) Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 0.92 [ 0.71, 1.19 ] 0.77 [ 0.53, 1.11 ] 0.98 [ 0.44, 2.19 ] Subtotal (95% CI)
0.87 [ 0.71, 1.07 ]
Total events: 78 (Budesonide), 86 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 0.72, df = 2 (P = 0.70); I2 =0.0% Test for overall effect: Z = 1.30 (P = 0.19) 2 Sensitivity analysis: Jadad score > = 3 0.92 [ 0.71, 1.19 ] 0.77 [ 0.53, 1.11 ] Subtotal (95% CI)
0.87 [ 0.70, 1.07 ]
Total events: 70 (Budesonide), 80 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 0.63, df = 1 (P = 0.43); I2 =0.0% Test for overall effect: Z = 1.34 (P = 0.18) Favours conv steroid Favours budesonide Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.6. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 6 Change in CDAI.
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids Study or subgroup Conventional steroid 100 123.7 (73.31) 101 126.6 (73.09) -2.90 [ -23.14, 17.34 ] -57.00 [ -130.30, 16.30 ] -89.00 [ -130.66, -47.34 ] -22.00 [ -54.39, 10.39 ] -50.00 [ -69.30, -30.70 ] -60.00 [ -120.09, 0.09 ] Total (95% CI)
100.0 % -42.27 [ -69.67, -14.86 ]
Heterogeneity: Tau2 = 770.37; Chi2 = 20.03, df = 5 (P = 0.001); I2 =75% Test for overall effect: Z = 3.02 (P = 0.0025) Favours conv steroid Favours budesonide Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.7. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 7 Corticosteroid related
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 7 Corticosteroid related adverse events Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 0.65 [ 0.50, 0.85 ] 0.80 [ 0.60, 1.07 ] 0.65 [ 0.41, 1.04 ] 0.41 [ 0.23, 0.72 ] 0.44 [ 0.21, 0.93 ] 0.60 [ 0.42, 0.86 ] Total (95% CI)
0.64 [ 0.54, 0.76 ]
Total events: 156 (Budesonide), 203 (Conventional steroid) Heterogeneity: Tau2 = 0.01; Chi2 = 5.85, df = 5 (P = 0.32); I2 =15% Test for overall effect: Z = 5.18 (P < 0.00001) Favours budesonide Favours conv steroid Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.8. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 8 Withdrawal due to
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 8 Withdrawal due to adverse events Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 1.01 [ 0.26, 3.93 ] 0.17 [ 0.02, 1.27 ] 2.91 [ 0.12, 69.08 ] 0.20 [ 0.01, 4.11 ] Total (95% CI)
0.57 [ 0.18, 1.84 ]
Total events: 6 (Budesonide), 13 (Conventional steroid) Heterogeneity: Tau2 = 0.26; Chi2 = 3.62, df = 3 (P = 0.31); I2 =17% Test for overall effect: Z = 0.93 (P = 0.35) Favours budesonide Favours conv steroid Analysis 2.9. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 9 Withdrawal due to
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 9 Withdrawal due to disease worsening Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 1.00 [ 0.07, 14.55 ] Total (95% CI)
1.00 [ 0.07, 14.55 ]
Total events: 1 (Budesonide), 1 (Placebo) Heterogeneity: not applicable Test for overall effect: Z = 0.0 (P = 1.0) Favours budesonide Favours conv steroid Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.10. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 10 Abnormal ACTH test.
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 10 Abnormal ACTH test Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 0.65 [ 0.53, 0.79 ] 0.70 [ 0.47, 1.06 ] 0.25 [ 0.01, 5.72 ] Total (95% CI)
0.65 [ 0.55, 0.78 ]
Total events: 75 (Budesonide), 66 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 0.50, df = 2 (P = 0.78); I2 =0.0% Test for overall effect: Z = 4.67 (P < 0.00001) Favours budesonide Favours conv steroid Analysis 2.11. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 11 Plasma cortisol below
normal range (150 nmol per liter).
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 11 Plasma cortisol below normal range (150 nmol per liter) Study or subgroup Conventional steroid M-H,Random,95% CI M-H,Random,95% CI 0.51 [ 0.39, 0.67 ] 0.59 [ 0.34, 1.04 ] 0.55 [ 0.38, 0.81 ] Total (95% CI)
0.53 [ 0.43, 0.65 ]
Total events: 81 (Budesonide), 109 (Conventional steroid) Heterogeneity: Tau2 = 0.0; Chi2 = 0.28, df = 2 (P = 0.87); I2 =0.0% Test for overall effect: Z = 6.06 (P < 0.00001) Favours budesonide Favours conv steroid Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 2.12. Comparison 2 Budesonide 9 mg vs. conventional steroids, Outcome 12 Decrease in
Budesonide for induction of remission in Crohn's disease 2 Budesonide 9 mg vs. conventional steroids 12 Decrease in osteocalcin levels Study or subgroup Conventional steroid 1.00 [ -0.18, 2.18 ] -7.30 [ -13.88, -0.72 ] Total (95% CI)
100.0 % -2.49 [ -10.52, 5.54 ]
Heterogeneity: Tau2 = 28.63; Chi2 = 5.92, df = 1 (P = 0.01); I2 =83% Test for overall effect: Z = 0.61 (P = 0.54) Favours budesonide Favours conv steroid Analysis 3.1. Comparison 3 Budesonide 9 mg vs. mesalamine, Outcome 1 Induction of clinical remission
(CDAI < = 150).
Budesonide for induction of remission in Crohn's disease 3 Budesonide 9 mg vs. mesalamine 1 Induction of clinical remission (CDAI < = 150) Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 1.23 [ 0.85, 1.78 ] Subtotal (95% CI)
1.23 [ 0.85, 1.78 ]
Total events: 40 (Budesonide), 31 (Mesalamine) Heterogeneity: not applicable Test for overall effect: Z = 1.12 (P = 0.26) 1.26 [ 0.88, 1.79 ] Subtotal (95% CI)
1.26 [ 0.88, 1.79 ]
Total events: 42 (Budesonide), 32 (Mesalamine) Heterogeneity: not applicable Test for overall effect: Z = 1.25 (P = 0.21) Favours mesalamine Favours budesonide (Continued . . ) Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(. . Continued) Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 1.63 [ 1.23, 2.16 ] Subtotal (95% CI)
1.63 [ 1.23, 2.16 ]
Total events: 63 (Budesonide), 37 (Mesalamine) Heterogeneity: not applicable Test for overall effect: Z = 3.38 (P = 0.00073) 1.59 [ 1.17, 2.15 ] Subtotal (95% CI)
1.59 [ 1.17, 2.15 ]
Total events: 58 (Budesonide), 35 (Mesalamine) Heterogeneity: not applicable Test for overall effect: Z = 2.99 (P = 0.0028) 1.79 [ 1.28, 2.50 ] Subtotal (95% CI)
1.79 [ 1.28, 2.50 ]
Total events: 56 (Budesonide), 30 (Mesalamine) Heterogeneity: not applicable Test for overall effect: Z = 3.40 (P = 0.00069) Favours mesalamine Favours budesonide Analysis 3.2. Comparison 3 Budesonide 9 mg vs. mesalamine, Outcome 2 Induction of clinical remission at
8 weeks (severe disease, CDAI > = 300).
Budesonide for induction of remission in Crohn's disease 3 Budesonide 9 mg vs. mesalamine 2 Induction of clinical remission at 8 weeks (severe disease, CDAI > = 300) Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 3.80 [ 1.19, 12.15 ] Total (95% CI)
3.80 [ 1.19, 12.15 ]
Total events: 11 (Budesonide), 3 (Mesalamine) Heterogeneity: not applicable Test for overall effect: Z = 2.25 (P = 0.024) Favours mesalamine Favours budesonide Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Analysis 3.3. Comparison 3 Budesonide 9 mg vs. mesalamine, Outcome 3 Withdrawal due to adverse
Budesonide for induction of remission in Crohn's disease 3 Budesonide 9 mg vs. mesalamine 3 Withdrawal due to adverse events Study or subgroup M-H,Random,95% CI M-H,Random,95% CI 0.36 [ 0.10, 1.31 ] Total (95% CI)
0.36 [ 0.10, 1.31 ]
Total events: 3 (Budesonide), 8 (Mesalamine) Heterogeneity: not applicable Test for overall effect: Z = 1.55 (P = 0.12) Favours budesonide Favours mesalamine W H A T ' S N E W
Last assessed as up-to-date: 2 March 2008.
Contact details updated Protocol first published: Issue 3, 1996 Review first published: Issue 4, 2005 New citation required and conclusions have changed Change in authors, additional conclusions due to new out-comes Converted to new review format.
New search has been performed New search with expanded search strategy, new studies in-cluded, and new secondary outcomes have been evaluated.
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CHS was responsible for the literature search, selecting and reviewing the studies, performing the analyses and writing the manuscript.
EIB acted as co-reviewer of the studies, was involved in the analyses and reviewed the manuscript.
AHS and ARO provided methodological expertise, IBD expert opinion and reviewed the manuscript.
AMG provided IBD expert opinion and reviewed the manuscript.
• CHS, AHS: Inflammatory Bowel Disease Centre, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
• CHS, EIB, AHS: Department of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.
• EIB: Clinician-Scientist Training Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
• EIB, AMG: Division of Gastroenterology, Hepatology & Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada.
• ART: Dalhousie University, Halifax, Nova Scotia, Canada.
• Richard Walter Gibbon Medical Research Fellowship, University of Western Australia, Australia.
I N D E X T E R M S
Medical Subject Headings (MeSH)
Administration, Oral; Anti-Inflammatory Agents [∗administration & dosage; adverse effects]; Budesonide [∗administration & dosage;adverse effects]; Crohn Disease [∗drug therapy]; Randomized Controlled Trials as Topic; Remission Induction MeSH check words
Budesonide for induction of remission in Crohn's disease (Review)
Copyright 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Source: http://www.ibd.com.sg/article/Management/Induction%20of%20remission/IR_Budesonide%20in%20CD.pdf