Gut 1997; 41: 209–214 209 Oral budesonide is as eVective as oral prednisolone in active Crohn’s disease Gut: first published as 10.1136/gut.41.2.209 on 1 August 1997. Downloaded from M Campieri, A Ferguson, W Doe, T Persson, L-G Nilsson, and the Global Budesonide Study Group Abstract unfortunately their therapeutic eYcacy is Background—The use of corticosteroids counterbalanced by unwanted side eVects in active Crohn’s disease often becomes attributable to their absorption and pharmaco- limited by side eVects. Budesonide is a logical (systemic) action or to their suppression potent corticosteroid with low systemic of endogenous adrenal function.3 Moreover, in bioavailability due to an extensive first clinical practice it has often been diYcult to pass liver metabolism. wean patients oV systemically active GCS Aims—To compare the eYcacy and safety without triggering a relapse of the disease. New of two dosage regimens of budesonide and GCS have been developed which possess prednisolone in patients with active potent topical anti-inflammatory activity and Crohn’s disease aVecting the ileum and/or with a systemic activity less than conventional the ascending colon. GCS.4 The unique therapeutic ratio of the new Patients and methods—One hundred and analogues is due to a high potency combined seventy eight patients were randomised to with their extensive and rapid first pass liver receive budesonide controlled ileal release metabolism, where the metabolites have mini- (CIR) capsules 9 mg once daily or 4.5 mg mal or no GCS activity. twice daily, or prednisolone tablets 40 mg Budesonide is the most extensively studied once daily. The treatment period was 12 compound of this new group of GCS. When weeks. The primary eYcacy variable was administered by inhalation, budesonide has clinical remission, defined as a Crohn’s been found to be eVective and safe in the treat- Disease Activity Index (CDAI) of 150 or ment of both asthma and rhinitis.5 Given as an less. enema, it has also been found to be as eVective Results—After eight weeks of treatment, as conventional GCS enemas in the treatment remission occurred in 60% of patients of distal ulcerative colitis but has the clear http://gut.bmj.com/ receiving budesonide once daily or pred- advantage of producing significantly less adre- nisolone and in 42% of those receiving nal suppression than conventional GCS.6–9 budesonide twice daily (p=0.062). The Budesonide has also been developed in a presence of glucocorticoid associated side gastric resistant formulation (Entocort® cap- eVects was similar in all groups; however, sules, Astra Draco, Lund, Sweden) containing Medical and moon face was more common in the pred- pellets with slow release properties; this prepa- Gastroenterological nisolone group (p=0.0005). The highest ration allows the drug to be delivered mainly to Clinic, University of on September 28, 2021 by guest. Protected copyright. frequency of impaired adrenal function, as 10 Bologna, Italy the ileum and ascending colon. The proper- M Campieri measured by a short ACTH test, was found ties of this formulation, together with the high in the prednisolone group (p=0.0023). GCS potency and extensive first pass liver Department of Conclusions—Budesonide CIR, adminis- metabolism of budesonide, oVer improved Medicine, University tered at 9 mg once daily or 4.5 mg twice therapy for Crohn’s disease by reducing the of Edinburgh, daily, is comparable to prednisolone in Edinburgh risk of steroid associated side eVects. In previ- inducing remission in active Crohn’s 11–13 A Ferguson ous studies, budesonide controlled intesti- disease. The single dose administration is nal release (CIR) capsules 9 mg daily were Division of Molecular as promptly eVective as prednisolone and eVective in inducing remission in patients with Medicine, John Curtin represents a simpler and safer therapeutic active Crohn’s disease aVecting the ileum and School of Medical approach, with a considerable reduction the ascending colon. In a placebo controlled Research, Canberra, in side eVects. dose finding study,12 budesonide CIR 4.5 mg Australia (Gut 1997; 41: 209–214) W Doe twice daily was found to be the lowest eVective Keywords: adrenal function; CDAI; glucocorticoid; dose, while in a study designed to compare Astra Draco AB, Lund, glucocorticoid associated side eVects budesonide 9 mg once daily and prednisolone Sweden 40 mg,13 both agents were equally eVective in T Persson L-G Nilsson inducing remission. Crohn’s disease is a chronic inflammatory dis- However, prednisolone reduced the mean Correspondence to: order of unknown aetiology. Although any por- Crohn’s Disease Activity Index (CDAI) scores Professor M Campieri, tion of the digestive tract from mouth to anus significantly more, whereas budesonide 9 mg Medical and Gastroenterological Clinic, may be involved, the most commonly aVected once daily gave rise to significantly fewer University of Bologna, parts are the distal ileum and the ascending glucocorticoid associated side eVects and less Policlinico S Orsola, Via 1 Massarenti, 9, I-40138 colon. To date, glucocorticoids (GCS)— suppression of endogenous cortisol produc- Bologna, Italy. prednisone or prednisolone—have been the tion. It was felt important to study further the Accepted for publication most eVective drugs in inducing clinical remis- clinical eYcacy of budesonide and the impact 23 January 1997 sion in these patients with Crohn’s disease2; on the adrenal glands in comparison with 210 Campieri, Ferguson, Doe, Persson, Nilsson prednisolone, and whether there were any drugs during their actual treatment period or if diVerences if budesonide was given once or they interrupted the study drugs for more than twice daily. five consecutive days. Gut: first published as 10.1136/gut.41.2.209 on 1 August 1997. Downloaded from CLINICAL ASSESSMENT Methods At entry, patients’ demographic characteristics, SELECTION OF PATIENTS relevant current and past diagnoses, current Twenty six investigational centres in the United medication, and history of previous bowel sur- Kingdom, Ireland, Italy, Australia, New Zea- gery were recorded. The distal part of the colon land, Germany, Sweden, Belgium, and The was assessed by sigmoidoscopy to exclude Netherlands participated in the study. inflammation in the rectum. Disease extent was Eligible patients were older than 18 years of confirmed by endoscopy or radiology assess- age, with a confirmed diagnosis of active ment if not done within the 24 months prior to Crohn’s disease, as defined by a score of 200 or 14 the first visit. higher on the CDAI. The extent of disease CDAI was the main clinical assessment for had to be defined within 24 months before determination of drug eYcacy and it was randomisation; entry was restricted to patients calculated at the randomisation visit and at all with disease involving the ileum and/or the subsequent visits. Remission was defined as a ascending colon but not extending beyond the CDAI of 150 or less. The patients were hepatic flexure. Patients who had undergone provided with diary cards for all weeks of the ileostomy or more extensive resection of the study. On these, they recorded (each evening) ileum (>100 cm), and those with severe disease the number of stools, general well being, requiring imminent surgery, were not enrolled abdominal pain, and intake of study in the study. They were not eligible if they had medication. Adverse events were also recorded complications including abscesses, perfora- at each visit, as responses to a standard tions, or active fistulas. Patients with concomi- question (“Have you had any health problems tant active peptic ulcer or clinically important or symptoms not usually associated with your hepatic, renal, cardiovascular, or psychiatric bowel disorder since the last visit?”). Scores conditions were also excluded. Immunosup- from the seven days preceding the clinic visit pressive drugs were allowed until three months were used for the CDAI calculation. before the study, 5-aminosalicylates and met- The following analyses were done at each ronidazole until the day before the study, and visit and used as measures of inflammation: corticosteroids allowed until one week before erythrocyte sedimentation rate (ESR), platelet the study. The trial was performed in accord- particle concentration, serum C-reactive pro- ance with the Declaration of Helsinki and was tein (CRP) (before treatment and after four approved by the Ethics Committees at all cen- and 12 weeks), and serum orosomucoid. tres; all patients gave written or oral informed Safety assessments consisted of the record- http://gut.bmj.com/ consent. ing of any symptoms, clinical and haematologi- cal measurements, and an examination by the STUDY DESIGN investigator for corticosteroid associated side The trial was a randomised double blind, dou- eVects. Blood samples for plasma cortisol ble dummy study. A baseline CDAI was analysis were drawn between 7.30 and obtained during a run-in period of three to 9.30 am, always at the same time on each seven days. The patients were subsequently occasion. on September 28, 2021 by guest. Protected copyright. randomised to treatment with either budeso- nide CIR capsules 9 mg once daily or 4.5 mg SHORT ACTH TEST twice daily or prednisolone 40 mg once daily. The responses to the short ACTH test Budesonide CIR was tapered to 6 mg after (Synacthen®, Ciba-Geigy), at randomisation eight weeks and to 3 mg after a further two and after eight weeks of treatment, were weeks. Prednisolone was tapered to 30 mg after analysed with regard to plasma cortisol con- two weeks and then continuously throughout centrations before and 30 minutes after the the study, reaching 5 mg after nine weeks. The ACTH injection; the magnitude of the increase 5 mg dose was then continued for three weeks was determined. Plasma cortisol concentration so that the total treatment period was 12 weeks. was analysed both at the centre and at Astra Follow up visits were carried out after two, Draco AB.