A Steroid Enema, Budesonide, Lacking Systemic Effects for the Treatment of Distal Ulcerative Colitis or Proctitis A.
A '
DANIELSSON, R. LOFBERG, T. PERSSON, L. SALDE, R. SCHIOLER, 0 . SUHR & R. WILLEN
- - *
Umei; Dept. of Medicine, Huddinge University Hospital, Huddinge; Astra Draco, Lund; Dept. of Surgery, Jonkoping Hospital, Jonkoping; and Dept. of Pathology, University Hospital, Lurid;Danielsson A, Lofberg R, Persson T, Salde L, Schioler R, Suhr 0, WillCn R. A steroid enema, budesonide, lacking systemic effects for the treatment of distal ulcerative colitis or proctitis. Scand J Gastroenterol 1992, 27, 9-12
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 11/19/14 For personal use only.
r The aim of this study was to evaluate whether budesonide enema (2 mg/100 ml) had a significantly better
effect than placebo in the treatment of distal ulcerative colitis or proctitis. The trial was of controlled, randomized, double-blind design and included 41 treated patients. The treatment time was 4 weeks, with revisits after 2 and 4 weeks. If no improvement was seen, the patient could be switched over to open-label therapy with budesonide enema. Sigmoidoscopy, histology, blood chemistry, and diary cards were used for estimating the effect of treatment. The results showed that budesonide was superior to placebo. Sigmoidoscopy and biopsy scores improved significantly ( p < 0.01) in budesonide-treated patients compared with placebo. Significantly more patients switched over to open budesonide treatment in the placebo group owing to lack of efficacy compared with budesonide ( p < 0,001). No drug-related adverse experiences occurred, and there was no decrease in endogenous morning plasma cortisol levels. It is concluded that budesonide enema appears to be an effective and safe treatment for distal ulcerative colitis and proctitiy
Key words: Budesonide; cortisol; enema; proctitis; ulcerative colitis Ake Danielsson, M . D., Dept. of Medicine, Section for Gastroenterology, University Hospital, S-901 87 Umed, Sweden
Corticosteroids are, together with sulphasalazine and 5acetylsalicylic acid (5-ASA), the most important drugs for treatment of active ulcerative colitis (UC) or proctitis. Existing steroid enemas frequently used for treatment of active distal UC have a relatively moderate therapeutic effect but sometimes have a marked effect on the hypothalamic-pituitary-adrenal (HPA) axis (1-3). Patients with inflammatory bowel disease have decreased mineral content of the bone, and osteoporosis may develop also in young patients. The pathogenesis of this bone loss seems to be multifactorial, but a systemic corticosteroid effect is likely to be one important contributory factor (4). Budesonide is a potent corticosteroid with a high topical activity but very little or no systemic effect in therapeutic doses. Budesonide has in dermatologic, nasal, and pulmonary formulations shown a better distinction between beneficial and adverse effects than most other steroids. Budesonide is rapidly inactivated in the liver, and because of its extensive first-pass metabolism, orally or rectally given budesonide has a low bioavailability; that is, despite 100% absorption only about 15% of the active compound reaches the systemic circulation after rectal administration ( 5 , 6 ) . Budesonide has an affinity for the glucocorticoid receptor which is about 15 times that of prednisolone (6). Only a few controlled clinical trials with steroid enemas
have been published, and the net effect of these drugs is therefore largely unknown. However, it has been demonstrated that budesonide enema, containing 2 mg/100 ml, is significantly better than prednisolone enema (25 mg/100 ml) for treatment of distal UC or proctitis. Budesonide in this dose did not significantly depress plasma cortisol levels, whereas prednisolone did. However, the vehicle used in that trial was a preliminary formulation (7). The aims of the present investigation were to compare the efficacy of an enema formulation of budesonide with placebo in patients with distal UC or proctitis, record possible adverse reactions, and study the effect on plasma cortisol levels. The primary study variables were endoscopic and histologic rating scores and laboratory variables. Secondary variables were bowel symptoms and general well-being, obtained from diary cards. MATERIALS AND METHODS
Study design The study was a double-blind, parallel-group, placebocontrolled multicentre trial of 4 weeks' duration. The doubleblind trial could be followed by 4 weeks of open-label budesonide enema if treatment results were deemed unsatisfactory after 2 or 4 weeks. Four centres participated in
10
A. Danielsson
et al.
Table I. Endoscopic and histologic scores Endoscopic grading Grade 0 Normal mucosa Granularity, oedema, lack of normal vascular pattern Grade 1 Grade 2 Hyperaemia, friability, petechiae (and all of grade 1) Grade 3 Ulcerations (and all of grades 1 and 2)
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 11/19/14 For personal use only.
Histologic grading Essentially normal mucosa Class 1 Isolated inflammatory cells or cell aggregates of either lymphoplasmacytic cells or eosinophilic Class 2 granulocytes Marked increase of inflammatory cells, some with changes in secretory cells. Slight atrophy Class 3 Definite, markcd atrophy, crypt abscesses, follicle formation in deeper cell layers, massive Class 4 increase of acute inflammatory cells, and pus Ulcerations with pus, atrophy, crypt abscesses, and deep follicles Class S
the trial. The trial was carried out in accordance with the Declaration of Helsinki and was approved by the ethics committees of participating hospitals.
Patients Patients with active distal UC or proctitis, confirmed by endoscopy, who had passed blood with the stools during the last week before randomization were included in the trial. Patients of both sexes, between 16 and 65 years old, nonpregnant, and who were candidates for steroid enema treatment were included. Oral or rectal steroid treatment during the month preceding the study was an exclusion criterion. Patients receiving sulphasalazine continued medication at a constant dose. Study drug and design The investigational drug was budesonide, 2 mg/100 ml. given as an enema or placebo. The enema bottle with a rectal cannula contained 1IS ml of an isotonic aqueous solution. A tablet containing 2.3mg budesonide in a lactose base or placebo was added to the enema solution just before use. The tablets were designed to disintegrate within 30 sec, and riboflavine in the tablet gave the solution a yellow colour, indicating complete disintegration. The bottle was to be shaken before administration and given at bedtime with the patient lying on the left side, in accordance with an enclosed instruction leaflet. Because 1&15% of the content remained in the bottle, each dose contained at an average 2.0mg budesonide. The drugs were randomized in balanced blocks, using a computer program. The patients were to meet the investigators on the 1st day (before treatment) and after 14 t 3 and 28 t 5 days of treatment. If a patient failed t o improve after 2 or 4 weeks of treatment, an open-label treatment with budesonide could start.
more or less signs of inflammation within each grade. For inclusion into the trial, an initial score of at least 2 was stipulated. The definition of the scoring system was presented to all investigators on a video tape, which was available during the trial. Biopsy specimens were taken from the rectal mucosa at all visits, stained, and mounted in accordance with the routines of the respective hospital but were evaluated blindly by a single pathologist (R. Willen). The histologic grading of the specimens was performed by the method of Floren et al. (8) (Table I). Diary cards were filled in daily by the patient, each card covering 1 week of treatment. The cards recorded information about bowel functions-that is, frequency and consistency of stools and presence of blood and mucus. Visual analogue scales were used to assess ‘general wellbeing’.
Table 11. Demographic and clinical data of patients included in the trial Budesonidc enema (n = 20) ~~
~~~~
~~~
Sex ratio (M/F) Age (years) Years since diagnosis Exacerbation (months) On SASP* maintenance treatment ( n )
11:Y 3x2 I1
5.1 t 7.5 5.7 t 7.7 7
12:Y 3 Y k 13 6.4 2 7.6 5.1 2 14.7
3
Mean values 2 SD. * SASP = sulphasalazine
Table 111. Treatment failures. Number of patients who switchcd over from blind therapy to open-label budesonide in the respective groups Switch to open therapy
Clinical assessments The macroscopic appearance of the rectal mucosa was classified in a four-grade scale (0-3) (Table 1). A subdivision into ‘moderate’ and ‘intense’ could also be made, indicating
~
Placebo enema ( n = 21)
Placebo Budesonide
16 4
Remaining on therapy
Total
I1
Rudesonide in Ulcerative Colitis and Proctitis 3.c
Clinical effects The protocol permitted switch to open-label therapy with budesonide if no improvement was achieved. In the placebo group 16 of 21 patiqnts switched to open budesonide treatment, compared with only 4 of 20 in the budesonide group ( p < 0.001) (Table 111). There was asignificant improvement with regard to general well-being in favour of budesonide after 2 weeks of treatment (32%; p < 0.05). There was also improvement in bowel functions, which, however, did not reach statistical significance. No adverse events attributed to the study drug were recorded in either of the groups during the blind or open parts of the study. No significant changes were noted in blood chemistry.
T 2.5
2.0 W
a
0 V v)
>
1.5
V
xz v)
Sigmoidoscopy Patients treated with budesonide improved significantly better than the placebo group in endoscopy scores. The difference was statistically significant after 4 weeks of treatment ( p < 0.01) but not after 2 weeks ( p = 0.07). The statistical evaluation was carried out as ‘intention to treat’-that is, including 16 patients in the placebo group who had
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 11/19/14 For personal use only.
W
1.o
0.5
4.5
0
I
WEEK 0
I
WEEK 2
WEEK 4
T
Fig. 1. Effects of budesonide (W) (n = 20) and placebo (0-4) (n = 21) enema treatment on endoscopic grading (0-3) after 2 and 4 weeks of treatment, presented as initially randomized. Open-label treatment with budesonide after treatment failure with placebo (A-A) (n = 16). The values are expressed as mean 2 SEM.
Laboratory assessments Routine blood chemistry was carried out biweekly. Plasma cortisol samples were drawn in the morning and always at the same time for each patient, frozen, stored, and delivered to Astra Draco AB, Lund, for analysis using a high-performance liquid chromatography method (9).
4.0
3.5
a
0
0 ul
>
ul
n
0 3.0
Statistical evaluations The two groups were compared with regard to changes in the assessed variables at the different visits. The main efficacy variables were changes in sigmoidoscopy and biopsy scores. Student’s t test, chi-square and Wilcoxon’s rank sum tests were used.
2.5
RESULTS
2.0
A total of 43 patients entered the study, but 2 were excluded because of erroneous inclusion. One had total colitis, and the other had suspected Crohn’s disease. The remaining 41 patients, of whom 23 were men, were randomized to budesonide ( n = 20) or to placebo ( n = 21) treatment. The two groups were well matched (Table 11).
I
WEEK 0
1
WEEK 2
~~
~
WEEK 4
Fig. 2. Effects of budesonide (W-W) (n = 20) and placebo (H) ( n = 21) enema treatment on histology grading (1-5) after 2 and 4 weeks of treatment, presented as initially randomized. Open-label treatment with budesonide after treatment failure with placebo (A-A) ( n = 16). The values are expressed as mean SEM.
*
12
A.
Danielsson eK al.
Table IV. Plasma cortisol during treatment with placebo or budesonide (nmol/l; mean 2 SD)
Placebo (n = 21) Budesonide ( n = 20)
0 weeks
2 weeks
4 weeks
411 t 149 464 2 146
389 2 149 440 t 120
447 t 89 466 2 91
switched over from placebo to open-label therapy with budesonide after 2 weeks of treatment (Fig. 1). Patients receiving budesonide enema after treatment failure with placebo also demonstrated a marked improvement in endoscopy score (Fig. 1).
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 11/19/14 For personal use only.
Biopsies
In the budesonide group a marked decrease in histologic grading score was noted (Fig. 2). The difference between the two groups was statistically significant after 2 weeks ( p < 0.05) and 4 weeks ( p < 0.01), although 16 patients changed the treatment from placebo to open-label budesonide after 2 weeks. Patients receiving budesonide after failure to improve with placebo also showed a marked improvement (Fig. 2).
Plasma cortisol Neither budesonide nor placebo treatment depressed endogenous plasma cortisol levels (Table IV). DISCUSSION Treatment of active distal UC and proctitis with budesonide enema (2 mg/l00 ml) was superior to placebo treatment as assessed by both endoscopy and histology. These variables showed significant improvements in the budesonide-treated group compared with placebo. A significantly greater proportion of the placebo-treated patients switched over to open-label budesonide therapy owing to lack of effect. The present results confirm previous findings that budesonide enema is an efficient treatment for distal UC or proctitis (7). A new system for administration of the drug has been developed, in which the vehicle and budesonide are stored apart until immediately before use. This new 'binary' system was used in the present trial and had a clinical effect similar to that of the previous formulation. Intrarectal steroids are frequently used in the treatment of distal UC and proctitis. The results of investigations concerning adrenal suppression after rectal administration of prednisolone have been discordant (3, lo), and the effect on the HPA axis may depend on the kind of prednisolone salt used (11). Whether the steroid effect is purely topical the or at least partly systemic has also been discussed. to have a Same plasma concentration Prednisolone better therapeutic effect when administered as an enema Received 11 June 1991 Accepted 25 July 1991
than orally (12). Newer glucocorticosteroid preparations have been developed with higher topical effect and reduced systemic effects (6). Kumana et al. (13) have shown that beclomethasone dipropionate (1 mg) given as retention enema had no effect on the HPA axis but was still as effective as betamethasone (5 mg). From the present and a previous study (7) it can be concluded that rectal administration of budesonide is significantly more effective than both placebo and prednisolone enemas and that the effect is local, since plasma cortisol levels remained unchanged during budesonide treatment. This is the first controlled trial in which budesonide enema is compared with placebo. The administered dose corresponds to that given in a previous study comparing the effect with prednisolone enema (7). Budesonide is effective in the treatment of active distal UC and proctitis and seems to be superior to both placebo and prednisolone enemas, without altering the levels of endogenous plasma cortisol. REFERENCES 1 . Truelove SC, Witts W. Cortisone in ulcerative colitis. Final report on a therapeutical trial. Br Med J 1955,2, 1041-1048 2. Flavell Matts SGF. Intrarectal treatment of 100 cases of ulcerative colitis with prcdnisolone-21-phosphate enemata. Br Med J 1961, 1, 165-168 3.Flavell Matts SGF, Wharton BA, Kelleher J , Walters G. Adrenal cortical and pituitary function after intrarectal steroid therapy. Br Med J 1963,2,2426 4.Compston JE, Judd D, Crawley E O et al. Osteoporosis in patients with inflammatory bowel disease. Gut 1987,28, 410-
415 5. Clissold SP, Heel RC. Budesonide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis. Drugs 1984, 28, 485-518 6.Brattsand R . Overview of newer glucocorticosteroid preparations for inflammatory bowel disease. Can J Gastroenterol
1990,4, 241-252 7. Danielsson A, Hellers G , Lyrenas E, et al. A controlled randomized trial of budesonide versus prednisolone retention enemas in active distal ulcerative colitis. Scand J Gastroenterol
1987,22, 987-992 8.FlorCn C-H, Benoni C, WillCn R. Histological and colonoscopic assessment of disease extension in ulcerative colitis. Scand J Gastroenterol 1987,22,459-462 9.van den Berg JMH, Mol CHR, Deelder RS, Thijssen JHH. A quantitative assay of cortisol in human plasma by high performance liquid chromatography using a selective chemically bonded stationary phase. Clin Chim Acta 1977,78, 165-172 10. Halvorsen S,Myren J, Aakvaag A. On the absorption of prednisone and prednisolone disodium phosphate after rectal administration. Scand J Gastroenterol 1969,4,581-584 11. Lee DAH, Taylor M, James VTH, Walker G. Rectally administrated prednisolone-evidence for a predominantly local action. Gut 1980. 21. 215-218 12.Hamilton I, Pinder IF, Dickinson RJ, Ruddell WSJ, Dixon MF, Axon ATR. A Of prednisolone with lowdose oral prednisolone in the treatment of acute distal ulcerative colitis, ~i~ colon Rectum 1984,27,701-702 13.Kumana CR, Seaton T, Meghji M, Castelli M, Benson R, Sivakumaran T. Beclomethasone dipropionate enemas for treating inflammatory bowel disease without producing Cushing's syndrome or hypothalamic pituitary adrenal suppression. Lancet 1982, 1, 57S583
A '
DANIELSSON, R. LOFBERG, T. PERSSON, L. SALDE, R. SCHIOLER, 0 . SUHR & R. WILLEN
- - *
Umei; Dept. of Medicine, Huddinge University Hospital, Huddinge; Astra Draco, Lund; Dept. of Surgery, Jonkoping Hospital, Jonkoping; and Dept. of Pathology, University Hospital, Lurid;Danielsson A, Lofberg R, Persson T, Salde L, Schioler R, Suhr 0, WillCn R. A steroid enema, budesonide, lacking systemic effects for the treatment of distal ulcerative colitis or proctitis. Scand J Gastroenterol 1992, 27, 9-12
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 11/19/14 For personal use only.
r The aim of this study was to evaluate whether budesonide enema (2 mg/100 ml) had a significantly better
effect than placebo in the treatment of distal ulcerative colitis or proctitis. The trial was of controlled, randomized, double-blind design and included 41 treated patients. The treatment time was 4 weeks, with revisits after 2 and 4 weeks. If no improvement was seen, the patient could be switched over to open-label therapy with budesonide enema. Sigmoidoscopy, histology, blood chemistry, and diary cards were used for estimating the effect of treatment. The results showed that budesonide was superior to placebo. Sigmoidoscopy and biopsy scores improved significantly ( p < 0.01) in budesonide-treated patients compared with placebo. Significantly more patients switched over to open budesonide treatment in the placebo group owing to lack of efficacy compared with budesonide ( p < 0,001). No drug-related adverse experiences occurred, and there was no decrease in endogenous morning plasma cortisol levels. It is concluded that budesonide enema appears to be an effective and safe treatment for distal ulcerative colitis and proctitiy
Key words: Budesonide; cortisol; enema; proctitis; ulcerative colitis Ake Danielsson, M . D., Dept. of Medicine, Section for Gastroenterology, University Hospital, S-901 87 Umed, Sweden
Corticosteroids are, together with sulphasalazine and 5acetylsalicylic acid (5-ASA), the most important drugs for treatment of active ulcerative colitis (UC) or proctitis. Existing steroid enemas frequently used for treatment of active distal UC have a relatively moderate therapeutic effect but sometimes have a marked effect on the hypothalamic-pituitary-adrenal (HPA) axis (1-3). Patients with inflammatory bowel disease have decreased mineral content of the bone, and osteoporosis may develop also in young patients. The pathogenesis of this bone loss seems to be multifactorial, but a systemic corticosteroid effect is likely to be one important contributory factor (4). Budesonide is a potent corticosteroid with a high topical activity but very little or no systemic effect in therapeutic doses. Budesonide has in dermatologic, nasal, and pulmonary formulations shown a better distinction between beneficial and adverse effects than most other steroids. Budesonide is rapidly inactivated in the liver, and because of its extensive first-pass metabolism, orally or rectally given budesonide has a low bioavailability; that is, despite 100% absorption only about 15% of the active compound reaches the systemic circulation after rectal administration ( 5 , 6 ) . Budesonide has an affinity for the glucocorticoid receptor which is about 15 times that of prednisolone (6). Only a few controlled clinical trials with steroid enemas
have been published, and the net effect of these drugs is therefore largely unknown. However, it has been demonstrated that budesonide enema, containing 2 mg/100 ml, is significantly better than prednisolone enema (25 mg/100 ml) for treatment of distal UC or proctitis. Budesonide in this dose did not significantly depress plasma cortisol levels, whereas prednisolone did. However, the vehicle used in that trial was a preliminary formulation (7). The aims of the present investigation were to compare the efficacy of an enema formulation of budesonide with placebo in patients with distal UC or proctitis, record possible adverse reactions, and study the effect on plasma cortisol levels. The primary study variables were endoscopic and histologic rating scores and laboratory variables. Secondary variables were bowel symptoms and general well-being, obtained from diary cards. MATERIALS AND METHODS
Study design The study was a double-blind, parallel-group, placebocontrolled multicentre trial of 4 weeks' duration. The doubleblind trial could be followed by 4 weeks of open-label budesonide enema if treatment results were deemed unsatisfactory after 2 or 4 weeks. Four centres participated in
10
A. Danielsson
et al.
Table I. Endoscopic and histologic scores Endoscopic grading Grade 0 Normal mucosa Granularity, oedema, lack of normal vascular pattern Grade 1 Grade 2 Hyperaemia, friability, petechiae (and all of grade 1) Grade 3 Ulcerations (and all of grades 1 and 2)
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 11/19/14 For personal use only.
Histologic grading Essentially normal mucosa Class 1 Isolated inflammatory cells or cell aggregates of either lymphoplasmacytic cells or eosinophilic Class 2 granulocytes Marked increase of inflammatory cells, some with changes in secretory cells. Slight atrophy Class 3 Definite, markcd atrophy, crypt abscesses, follicle formation in deeper cell layers, massive Class 4 increase of acute inflammatory cells, and pus Ulcerations with pus, atrophy, crypt abscesses, and deep follicles Class S
the trial. The trial was carried out in accordance with the Declaration of Helsinki and was approved by the ethics committees of participating hospitals.
Patients Patients with active distal UC or proctitis, confirmed by endoscopy, who had passed blood with the stools during the last week before randomization were included in the trial. Patients of both sexes, between 16 and 65 years old, nonpregnant, and who were candidates for steroid enema treatment were included. Oral or rectal steroid treatment during the month preceding the study was an exclusion criterion. Patients receiving sulphasalazine continued medication at a constant dose. Study drug and design The investigational drug was budesonide, 2 mg/100 ml. given as an enema or placebo. The enema bottle with a rectal cannula contained 1IS ml of an isotonic aqueous solution. A tablet containing 2.3mg budesonide in a lactose base or placebo was added to the enema solution just before use. The tablets were designed to disintegrate within 30 sec, and riboflavine in the tablet gave the solution a yellow colour, indicating complete disintegration. The bottle was to be shaken before administration and given at bedtime with the patient lying on the left side, in accordance with an enclosed instruction leaflet. Because 1&15% of the content remained in the bottle, each dose contained at an average 2.0mg budesonide. The drugs were randomized in balanced blocks, using a computer program. The patients were to meet the investigators on the 1st day (before treatment) and after 14 t 3 and 28 t 5 days of treatment. If a patient failed t o improve after 2 or 4 weeks of treatment, an open-label treatment with budesonide could start.
more or less signs of inflammation within each grade. For inclusion into the trial, an initial score of at least 2 was stipulated. The definition of the scoring system was presented to all investigators on a video tape, which was available during the trial. Biopsy specimens were taken from the rectal mucosa at all visits, stained, and mounted in accordance with the routines of the respective hospital but were evaluated blindly by a single pathologist (R. Willen). The histologic grading of the specimens was performed by the method of Floren et al. (8) (Table I). Diary cards were filled in daily by the patient, each card covering 1 week of treatment. The cards recorded information about bowel functions-that is, frequency and consistency of stools and presence of blood and mucus. Visual analogue scales were used to assess ‘general wellbeing’.
Table 11. Demographic and clinical data of patients included in the trial Budesonidc enema (n = 20) ~~
~~~~
~~~
Sex ratio (M/F) Age (years) Years since diagnosis Exacerbation (months) On SASP* maintenance treatment ( n )
11:Y 3x2 I1
5.1 t 7.5 5.7 t 7.7 7
12:Y 3 Y k 13 6.4 2 7.6 5.1 2 14.7
3
Mean values 2 SD. * SASP = sulphasalazine
Table 111. Treatment failures. Number of patients who switchcd over from blind therapy to open-label budesonide in the respective groups Switch to open therapy
Clinical assessments The macroscopic appearance of the rectal mucosa was classified in a four-grade scale (0-3) (Table 1). A subdivision into ‘moderate’ and ‘intense’ could also be made, indicating
~
Placebo enema ( n = 21)
Placebo Budesonide
16 4
Remaining on therapy
Total
I1
Rudesonide in Ulcerative Colitis and Proctitis 3.c
Clinical effects The protocol permitted switch to open-label therapy with budesonide if no improvement was achieved. In the placebo group 16 of 21 patiqnts switched to open budesonide treatment, compared with only 4 of 20 in the budesonide group ( p < 0.001) (Table 111). There was asignificant improvement with regard to general well-being in favour of budesonide after 2 weeks of treatment (32%; p < 0.05). There was also improvement in bowel functions, which, however, did not reach statistical significance. No adverse events attributed to the study drug were recorded in either of the groups during the blind or open parts of the study. No significant changes were noted in blood chemistry.
T 2.5
2.0 W
a
0 V v)
>
1.5
V
xz v)
Sigmoidoscopy Patients treated with budesonide improved significantly better than the placebo group in endoscopy scores. The difference was statistically significant after 4 weeks of treatment ( p < 0.01) but not after 2 weeks ( p = 0.07). The statistical evaluation was carried out as ‘intention to treat’-that is, including 16 patients in the placebo group who had
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 11/19/14 For personal use only.
W
1.o
0.5
4.5
0
I
WEEK 0
I
WEEK 2
WEEK 4
T
Fig. 1. Effects of budesonide (W) (n = 20) and placebo (0-4) (n = 21) enema treatment on endoscopic grading (0-3) after 2 and 4 weeks of treatment, presented as initially randomized. Open-label treatment with budesonide after treatment failure with placebo (A-A) (n = 16). The values are expressed as mean 2 SEM.
Laboratory assessments Routine blood chemistry was carried out biweekly. Plasma cortisol samples were drawn in the morning and always at the same time for each patient, frozen, stored, and delivered to Astra Draco AB, Lund, for analysis using a high-performance liquid chromatography method (9).
4.0
3.5
a
0
0 ul
>
ul
n
0 3.0
Statistical evaluations The two groups were compared with regard to changes in the assessed variables at the different visits. The main efficacy variables were changes in sigmoidoscopy and biopsy scores. Student’s t test, chi-square and Wilcoxon’s rank sum tests were used.
2.5
RESULTS
2.0
A total of 43 patients entered the study, but 2 were excluded because of erroneous inclusion. One had total colitis, and the other had suspected Crohn’s disease. The remaining 41 patients, of whom 23 were men, were randomized to budesonide ( n = 20) or to placebo ( n = 21) treatment. The two groups were well matched (Table 11).
I
WEEK 0
1
WEEK 2
~~
~
WEEK 4
Fig. 2. Effects of budesonide (W-W) (n = 20) and placebo (H) ( n = 21) enema treatment on histology grading (1-5) after 2 and 4 weeks of treatment, presented as initially randomized. Open-label treatment with budesonide after treatment failure with placebo (A-A) ( n = 16). The values are expressed as mean SEM.
*
12
A.
Danielsson eK al.
Table IV. Plasma cortisol during treatment with placebo or budesonide (nmol/l; mean 2 SD)
Placebo (n = 21) Budesonide ( n = 20)
0 weeks
2 weeks
4 weeks
411 t 149 464 2 146
389 2 149 440 t 120
447 t 89 466 2 91
switched over from placebo to open-label therapy with budesonide after 2 weeks of treatment (Fig. 1). Patients receiving budesonide enema after treatment failure with placebo also demonstrated a marked improvement in endoscopy score (Fig. 1).
Scand J Gastroenterol Downloaded from informahealthcare.com by Nyu Medical Center on 11/19/14 For personal use only.
Biopsies
In the budesonide group a marked decrease in histologic grading score was noted (Fig. 2). The difference between the two groups was statistically significant after 2 weeks ( p < 0.05) and 4 weeks ( p < 0.01), although 16 patients changed the treatment from placebo to open-label budesonide after 2 weeks. Patients receiving budesonide after failure to improve with placebo also showed a marked improvement (Fig. 2).
Plasma cortisol Neither budesonide nor placebo treatment depressed endogenous plasma cortisol levels (Table IV). DISCUSSION Treatment of active distal UC and proctitis with budesonide enema (2 mg/l00 ml) was superior to placebo treatment as assessed by both endoscopy and histology. These variables showed significant improvements in the budesonide-treated group compared with placebo. A significantly greater proportion of the placebo-treated patients switched over to open-label budesonide therapy owing to lack of effect. The present results confirm previous findings that budesonide enema is an efficient treatment for distal UC or proctitis (7). A new system for administration of the drug has been developed, in which the vehicle and budesonide are stored apart until immediately before use. This new 'binary' system was used in the present trial and had a clinical effect similar to that of the previous formulation. Intrarectal steroids are frequently used in the treatment of distal UC and proctitis. The results of investigations concerning adrenal suppression after rectal administration of prednisolone have been discordant (3, lo), and the effect on the HPA axis may depend on the kind of prednisolone salt used (11). Whether the steroid effect is purely topical the or at least partly systemic has also been discussed. to have a Same plasma concentration Prednisolone better therapeutic effect when administered as an enema Received 11 June 1991 Accepted 25 July 1991
than orally (12). Newer glucocorticosteroid preparations have been developed with higher topical effect and reduced systemic effects (6). Kumana et al. (13) have shown that beclomethasone dipropionate (1 mg) given as retention enema had no effect on the HPA axis but was still as effective as betamethasone (5 mg). From the present and a previous study (7) it can be concluded that rectal administration of budesonide is significantly more effective than both placebo and prednisolone enemas and that the effect is local, since plasma cortisol levels remained unchanged during budesonide treatment. This is the first controlled trial in which budesonide enema is compared with placebo. The administered dose corresponds to that given in a previous study comparing the effect with prednisolone enema (7). Budesonide is effective in the treatment of active distal UC and proctitis and seems to be superior to both placebo and prednisolone enemas, without altering the levels of endogenous plasma cortisol. REFERENCES 1 . Truelove SC, Witts W. Cortisone in ulcerative colitis. Final report on a therapeutical trial. Br Med J 1955,2, 1041-1048 2. Flavell Matts SGF. Intrarectal treatment of 100 cases of ulcerative colitis with prcdnisolone-21-phosphate enemata. Br Med J 1961, 1, 165-168 3.Flavell Matts SGF, Wharton BA, Kelleher J , Walters G. Adrenal cortical and pituitary function after intrarectal steroid therapy. Br Med J 1963,2,2426 4.Compston JE, Judd D, Crawley E O et al. Osteoporosis in patients with inflammatory bowel disease. Gut 1987,28, 410-
415 5. Clissold SP, Heel RC. Budesonide. A preliminary review of its pharmacodynamic properties and therapeutic efficacy in asthma and rhinitis. Drugs 1984, 28, 485-518 6.Brattsand R . Overview of newer glucocorticosteroid preparations for inflammatory bowel disease. Can J Gastroenterol
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