Budesonide for Maintenance of Remission in Patients With Crohn's Disease in Medically Induced Remission: A Predetermined Pooled Analysis of Four Randomized, Double-Blind, Placebo-Controlled Trials

William J. Sandborn, M.D.; Robert Lüofberg, M.D.; Brian G. Feagan, M.D.; Stephen B. Hanauer, M.D.; Massimo Campieri, M.D.; Gordon R. Greenberg, M.D.

Disclosures

Am J Gastroenterol. 2005;100(8):1780-1787. 

In This Article

Materials and Methods

The four studies were performed between April 1991 and August 1998. Eligible patients were men and women at least 18 yr of age with a confirmed diagnosis of CD involving the ileum and/or ascending colon and a previous relapse with mildly to moderately active disease (defined as a CD activity index [CDAI] score between 200 and 450 inclusive) successfully treated (in clinical remission with CDAI score 150) within 10-12 wk with either oral budesonide 3, 9g, or 15 mg daily, a tapering course of prednisolone or placebo. For those patients treated with a tapering course of prednisolone, the following tapering schedule was used: 40 mg (weeks 1–2); 30 mg (weeks 3–4); 25 mg (week 5); 20 mg (week 6); 15 mg (week 7); 10 mg (week 8); 5 mg (weeks 9–10); and 2 mg (weeks 11–12); further dose titration was allowed to the level of no glucocorticosteroid intake, as judged by the investigator.

The following patients were not eligible: pregnant or lactating women; those who were allergic to budesonide or other corticosteroids; those with septic complication, abscess, local complication, active fistula (with the exception of chronic nondraining asymptomatic anorectal fistula), obstruction, stricture with proximal dilation confirmed by colonoscopy or small bowel x-ray within 180 days of entry into preceding induction of remission study; those with a known history of left-sided or rectal CD (except for scattered aphthous ulcers) confirmed by colonoscopy within 180 days of entry into the preceding induction of remission study; those with local or systemic infection (including septic lesions in the perianal region); those with active peptic ulcer disease; those with diabetes; those with clinically significant hepatic, renal, respiratory, musculoskeletal, cardiovascular, endocrine, neurologic, psychiatric, or other significant diseases; those who were alcohol or drug abusers; those receiving H2-blockers or proton pump inhibitors; those receiving parenteral, enteral, or polymeric nutrition; those with another disease that contraindicated corticosteroids; those that were taking any corticosteroids during the course of the study; those with a planned in-patient hospitalization during the study; those with a history of carcinoma (excluding basal and squamous cell carcinoma) within 5 yr of entry into the preceding induction of remission study; those with enteric pathogens, Clostridium difficile toxin, ova, or parasites during screening for the preceding induction of remission study; those with ileostomy or colostomy; those with previous gastric surgery except for closure of perforation or selective vagotomy; those with resection of the ileum totaling more than 100 cm or any resection distal to the midtransverse colon; those with histologically documented gastrointestinal (GI) carcinoma or dysplasia within 5 yr of entry into the preceding induction of remission study; and those with recent (within 3 months) exposure to live viruses (including immunizations) such as chickenpox, measles, or polio, or to tuberculosis.

Patients receiving loperamide and other opiates were eligible. Patients treated with other drugs for CD including metronidazole, tinidazole, sulfasalazine, mesalamine formulations, and 4-aminosalicylate were not eligible. Similarly, patients treated with any immunosuppressive agent including azathioprine, 6-mercaptopurine, methotrexate, cyclosporine A, and tacrolimus within 90 days were not eligible. Patients who had received glucocorticosteroids (oral, parenteral, inhaled, rectal, nasal, and topical) within 14 days were not eligible. Patients treated with cholestyramine were not eligible. Patients who had received another investigational drug within 30 days were not eligible.

Patients received 3 or 6 mg budesonide capsules or placebo capsules once daily before breakfast. The capsules were administered before breakfast. A double-dummy technique was utilized to conceal the treatment assignment. Two capsules were administered in 1 of 3 combinations: 2 placebo capsules; 1 placebo capsule and 1 budesonide 3 mg capsule; or 2 budesonide 3 mg capsules. The placebo capsules were identical in appearance (size, color, and shape) to the budesonide capsules.

All 4 of the 52-wk studies were randomized, double-blind, placebo-controlled maintenance of remission trials, with similar study designs performed at a total of 95 centers in Australia, Belgium, Canada, Denmark, Germany, Ireland, Italy, the Netherlands, Sweden, the United Kingdom, and the United States ( Table 1 ).[12–15] Patients entering the maintenance studies were in remission, defined as a CDAI ≤150, and had previously been treated with budesonide, prednisolone, or placebo during the active phase of CD (CDAI ≥ 200) during a preceding induction of remission study. The first visit of the maintenance studies coincided with the final visit of the induction studies. Eligible patients were randomized to budesonide 6 mg, budesonide 3 mg, or placebo in a l:1:1 ratio (3 studies), or they were randomized to budesonide 6 mg or placebo in a 1:1 ratio (1 study). The randomization schedules for each of the 4 studies were generated with a computer by an unblinded statistician at AstraZeneca (Lund, Sweden).

At entry, each patient's demographic characteristics, medical history, and current medications were recorded. Disease activity was assessed at the baseline (randomization) visit and after 3, 6, 9, and 12 months. Patients recorded on diary cards the frequency of loose stools, the extent of their abdominal pain, and their general well-being during the 7 days before each visit. At each visit, a physical examination, quality-of-life assessment, and laboratory tests were conducted and patients were asked whether any adverse events had occurred.Clinical disease activity was assessed with the CDAI that was the primary efficacy measurement. CDAI scores ≤150 points indicate clinical remission, scores of 151–219 indicate mildly active disease, scores of 220–450 indicate moderately active disease, and scores >450 indicate severely active disease.[16,17] Disease-specific health-related quality of life was assessed with a secondary efficacy measurement, the self-administered Inflammatory Bowel Disease Questionnaire (IBDQ). The IBDQ is a previously validated instrument with four parts (bowel function, emotional status, systemic symptoms, and social function); scores <170 points indicate clinically active disease and scores ≥170 points indicate clinically inactive disease.[18] The IBDQ was only used in studies 1 and 4.

Blood samples were taken for hematological and biochemical assessments, and for measurement of plasma cortisol and C-reactive protein (CRP; measured in 3 of the studies). ACTH stimulation tests were performed at 3 months in all 4 studies, and again at 12 months in 1 of the studies.

All adverse events were recorded and graded according to the World Health Organization Adverse Reaction Terminology criteria. At each clinic visit, patients were also specifically evaluated by the investigators for any possible glucocorticosteroid-associated adverse events using a checklist that included the following signs or symptoms: moon face, buffalo hump, acne, hirsutism, skin striae, easy bruising, swelling of ankles, mood swings, depression, insomnia, hair loss, and others. Adrenal cortisol production was assessed by evaluation of basal plasma cortisol levels and ACTH-stimulated plasma cortisol responses. ACTH tests were considered normal if basal plasma cortisol levels were in the normal range for the laboratory performing the analysis, and if the plasma cortisol 30 or 60 min after ACTH stimulation was within the expected poststimulation range for the laboratory performing the analysis and/or if the rise in plasma cortisol 30 or 60 min after ACTH stimulation was within the expected poststimulation rise range for the laboratory performing the analysis (normal rise).

The intention-to-treat population included all patients who were randomized and received at least one dose of the study medication. The primary efficacy measure was the time to relapse. A relapse was defined as an increase in CDAI by at least 60 points from baseline to a value above 150, or withdrawal from the study due to worsening disease activity in the judgment of the investigator or the patient. The major secondary efficacy outcomes were time to relapse or discontinuation and the time to withdrawal. The other secondary efficacy variables were the proportion of patients with a relapse and the CDAI and IBDQ scores and the CRP concentrations at 3, 6, 9, and 12 months. The safety endpoints were: 1) adverse events; 2) glucocorticosteroid-associated adverse events; and 3) the laboratory data.

The time to relapse, time to relapse or discontinuation, and time in study were analyzed with respect to treatment using a generalized Wilcoxon test and Kaplan-Meier estimates and with respect to treatment and various prognostic factors using Cox regression models. The following independent prognostic variables were included in the regression models: treatment (placebo, budesonide 3 mg, budesonide 6 mg); CDAI score at entry into the preceding induction of remission study; CDAI score at entry into the maintenance study; study number (study number 1, 2, 3, or 4); treatment with prednisone in the preceding induction of remission study (no or yes); treatment with budesonide in the preceding induction of remission study (0, 3, 9, and 15 mg); gender (male or female); age; disease location (only ileal, colonic involvement); previous resection (no or yes); morning plasma cortisol at entry into the maintenance study; adrenal function at 3 months (normal or abnormal); disease duration; arthralgia/arthritis at entry into the preceding induction of remission study; CRP concentration >10 mg/l at entry into the preceding induction of remission study; and CRP concentration >10 mg/l at entry into the maintenance of remission study.

The proportion of patients with a relapse, mean CDAI and IBDQ scores, and CRP concentrations at 3, 6, 9, and 12 months were analyzed using models with treatment, study, and their interaction as factors. Changes in the plasma cortisol concentration after 3 and 12 months were analyzed using two-way analysis of variance with treatment and study number as factors. The proportions of patients with normal ACTH tests at 3 and 12 months were analyzed using models with treatment, study, and their interaction as factors. Adverse events were descriptively summarized by body system, preferred term and severity; and by body system, preferred term and relationship to study drug. Adverse events with an incidence of 3% or more in either treatment group, and glucocorticosteroid-associated adverse events were analyzed with two-way analysis of variance with treatment and study number as the factors. All statistical tests were two-sided. p-values of less than 0.05 were considered to indicate statistical significance.

The sample sizes in the 4 individual maintenance studies were based on the outcome of the studies in active disease. Based on a 12-month relapse rate estimate of 50% for the placebo group, this pooled analysis had an 80% probability of detecting a significant difference if the relapse rate for the budesonide 6 mg group was 34%.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....