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5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis
GASTROENTEROLOGY 1987;92:1894-8
5-Aminosalicylic Acid Enema in the Treatment of Distal Ulcerative Colitis, Proctosigmoiditis, and Proctitis LLOYD R. SUTHERLAND, FRANCOIS MARTIN, SCOTT GREER, MALCOLM ROBINSON, NORTON GREENBERGER, FRED SAIBIL, and THOMAS MARTIN, JOSEPH SPARR, ED PROKIPCHUK, LOWELL BORGEN Departments of Gastroenterology at the University of Calgary, Calgary, Canada; University of Montreal, Montreal, Canada; Scripps Medical Clinic, La Jolla, California; Oklahoma City Clinic, Oklahoma City, Oklahoma; Kansas University, Lawrence, Kansas; University of Toronto, Toronto, Canada; St. Paul Gastroenterology, St. Paul, Minnesota; Atlantic Gastroenterology, New Jersey; and Clinical Research Department, Reid-Rowell, Inc., Baudette, Minnesota
The eficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon. Seventy-six patients received active medication and 77 received a placebo. There were 20 dropouts (6 in the active group and 14 in the placebo group) during the study because of insuficient ejjïcacy. After 6 wk of therapy, 48 of the 76 patients (63%) receiving 5-aminosalicylic acid were considered to be “much improved” by the study physician compared to 22 of the 77 patients (29%) on placebo (p=O.O01). A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess effcacy. Mean disease activity index declined 55% for patients on 5-aminosalicylic acid and 24% for patients on placebo [p=O.OOOl). Analysis of subgroups indicated that patients most likely to respond were those with disease conjïned to the 20-40 cm from the anus. Response was not affected by concurrent sulfasalazine, but patients requiring concurrent oral steroids had a diminished response. Rapid onset of eficacy was shown by a significant reduction in recta1 bleeding within 3 days of treatment initiation. 5-Aminosalicylic acid enemas are wel1 tolerated and are of benefit in the treatment of ulcerative colitis conjïned to the distal colon.
Received March 27, 1986. Accepted December 1, 1986. Address requests for reprints to: Dr. L. R. Sutherland, 3330 Hospita1 Drive NW, Room 1414, Calgary, Alberta, Canada T2N
For the past 40 yr sulfasalazine has played an important role in the treatment of inflammatory bowel disease. Studies done 25 yr ago confirmed its effectiveness in treating mild ulcerative colitis (1) and in prolonging the interval between episodes of acute colitis (2). The drug was synthesized by chemically linking sulfapyridine, a nonabsorbable sulfa moiety, to Ei-aminosalicylic acid (5-ASA) (3). The use of sulfasalazine has been limited by side effects that are thought to be related to the sulfa portion of the molecule. These adverse effects include those that are dose-related (nausea, vomiting, headache, malaise, and hemolysis) and those that are not (fever, rash, lymphadenopathy, agranulocytosis, pneumonitis). Recent studies have suggested that 5-ASA is the active ingredient in sulfasalazine (4-6). Attention has thus focused on the preparation of pure 5-ASA either as a retention enema, suppository, or slowrelease tablet (7-10). Other investigators have studied the use of 4-aminosalicylate enemas (11). We report on the results of a study of a 5-ASA enema preparation in patients with active distal ulcerative colitis. Although both 2- and 4-g enema have been tested, we elected to assess the efficacy of the 4-g enema. The purpose of the study was to evaluate the efficacy and safety of a 5-ASA enema (ROWASA, Reid-Rowell Inc., Baudette, Minn.) preparation in the treatment of active ulcerative colitis confined to the distal large intestine. It was also our intent to
4Nl.
This work was sponsored by Reid-Rowell Inc., Baudette, Minnesota, and Interfalk Canada, Beloil, PQ, Canada. 0 1987 by the American Gastroenterological Association 0016-5085/87/$3.50
Abbreviations used in this paper: 5-ASA, 5-aminosalicylic DAI, disease activity index.
acid;
5-ASA ENEMAS IN ULCERATIVE
June 1987
examine the benefits, if any, of using the preparation in patients already on but not responsive to conventional treatment. Finally, through a maintenance program (to be reported separately) we proposed to evaluate the safety and efficacy of two doses of 5-ASA enemas in maintaining remission of disease.
Materials and Methods Om trial utilized a 6-wk, randomized, doubleblind, placebo-controlled design. Eight centers (five in the United States and three in Canada) participated in the trial. The protocol was reviewed by the individual Ethics Committees or Internal Review Boards of the participating institutions. Written informed consent was obtained from each before entrance into the study. The study population 318 yr old, who had ulcerwas composed of outpatients, ative colitis involving a minimum of 5 cm to a maximum of 50 cm of colon as measured continuously from the anus and confirmed by sigmoidoscopy (with biopsy specimens taken from an area of active disease and above the disease boundary). Patients also had to have a minimum score of 3 on a 12-point disease activity index (see Table 5). Pregnant women were excluded. History of salicylate allergy, disease involving more than 50 cm of colon, previous bowel resection, or clinically significant hepatic or renal disease were also grounds for exclusion. NO rectally administered steroid medications were allowed. Random assignment to either placebo or 4-g 5-ASA enemas (60-ml suspension per disposable unit of use retention enema, ROWASA prepared by Reid-Rowell, Inc., Baudette, Minn.) was accomplished by the assignment of patient study numbers using a table of random numbers. Double-blind medication was prepackaged to insure that an equal and random assignment within each center did occur. The medication and placebo were identical in color, consistency, and packaging. Patients were not asked at the end of the study to guess whether or not they had received active medication. Patients were not stratified as to duration of disease or extent of disease. Patients who had to discontinue the study because of treatment-related reasons (i.e., lack of efficacy or adverse effects) were not replaced. Patients terminated for non-treatment-related reasons (i.e., lost to follow-up or lack of compliance) were replaced. Statistical analysis of data was carried out on al1 patients who were entered into the study (“intent to treat”). Nonparametric data (“physician’s global assessment”) were analyzed by 2; changes in disease activity index (DAI) (an ordinal scale) were analyzed by analysis of variante. Concurrent
Medications
Pátients were allowed to use oral steroids or sulfasalazine under certain conditions. Oral steroids could be continued if the patient had taken them for more than 4 wk and if the dose was <30 mg of prednisone or equivalent. Oral sulfasalazine was allowed if the medication had been used regularly for more than 4 wk before entrance. In
Table
COLITIS
1. Disease Activity Index (Qualitative Scale With Four Subscales)
1895
Rating
1. Stool frequency 0 = Normal 1 = 1-2 Stools/day >normal 2 = 3-4 Stoolslday >normal 3 = >4 Stools/day >normal 2. Recta1 bleeding 0 = None 1 = Streaks of blood 2 = Obvious blood 3 = Mostly blood 3. Mucosal appearance 0 = Normal 1 = Mild friability 2 = Moderate friability 3 = Exudation, spontaneous bleeding 4. Physician’s rating of disease activity 0 = Normal 1 = Mild 2 = Moderate 3 = Severe Maximum
score = 12
either case, the dose of steroid or sulfasalazine constant during the 6 wk of the study. Disease
Activity
remained
Index
The DA1 (Table 1) represents an attempt to provide objective criteria for assessment of drug efficacy. It assesses four variables: (a) stool frequency, (b) recta1 bleeding, (c) sigmoidoscopic appearance of mucosa, and (d) physician’s assessment of disease severity. Each variable has a range of values for severity, with 0 representing no abnormality and 3 representing the most severe. As the variables have equal weighting, the overall DA1 can range from 0 to 12. The DA1 values calculated at day 22 and day 43 of the study represent an integration of data collected by the patient on his or her diary card for the preceding 3 wk. Procedures On entry into the study a complete history, physical examination, and flexible sigmoidoscopy was done. Biopsy specimens were obtained from the area of most extensive bowel involvement and of normal-appearing mucosa above the disease boundary. Patients were classified by the extent of disease involvement. Hemátologic (complete blood count and sedimentation rate) and biochemical parameters (SMA-12 or equivalent), including urinalysis (with microscopic examination), were assessed along with stool culture to exclude infectieus colitis. The DA1 was calculated. Patients were given a 3-wk supply of 60-ml enemas that contained either placebo or 4 g of 5-ASA in a 60-ml suspension. They were instructed to use one enema daily at bedtime. Diary cards were given to record their symptoms (stool frequency, bleeding, cramping) on a daily basis. They were also asked to record any other medications taken, other symptoms or possible side effects, and
1896
SUTHERLAND
ET AL.
GASTROENTEROLOGY
the number of hours that the enema was retained. Weekly telephone contact was made with the patients to assess patcent symptoms and to encotirage coipliance. At 3 wk repeat sigmoidoscopy was done. In addition, urine (24-h collection) and venous blood samples were obtained and analyzed for 5-ASA and its metabolite, N-açetyl&ASA. The DA1 was calculated. If there was deterioration, the patient was withdrawn from the acute study and enrolled in the maintenance study involving two doses of 5-ASA enemas. If the patient had either stabilized or improved, an addiiional 3-wk supply of medication was dispensed. At the conclusion of the study (6 wk), flexible sigmoidoscopy with biopsies of active disease and normalappearing mucosa were again done. A repeat physical examination with hematologie and biochemical assessment including urinalysis was carried out. The DA1 was again calculated. Patients who completed the trial were also allowed the option of participating in the maintenance trial.
Patients One hundred and fifty-three patients entered the trial. Ofie patient diopped out because he could not retain the enemas and was replaced. Subject characteristics are noted in Tables 2 and 3. Both groups are similar in composition as to sex, age, extent of disease, and concurrent medication. One hundred and nineteen (78%) patients had taken sulfasalazine previously. Forty-six patients stated that the therapy had been effective, 40 stated that it had been ineffective, and 33 were unsure of its effectiveness. Only z patients gave a history of sulfasalazine allergy. Ninety-eight patients (64%) had taken recta1 corticosteroids in the past, with 47 reporting a positive response, 43 reporting ineffective relief of symptoms, and 8 unsure. Twenty patients (6 on active medication and 14 on placebo) dropped out because of deterioration or unsatisfactory response before the conclusion of the study.
Table
2. Patient
Characteristics 5-ASA
Number of patients Sex ratio (M:F) Age (mean] Diagnosis Proctitis Proctosigmoiditis Distal ulcerative colitis Duration cif disease (yr) Number of prior episodes Percent first episode Prior (and concurrent) oral steroids Prior (and concurrent] recta1 steroids Prior (and concurrent] sulfasalazine Dropouts 5-ASA, 5-aminosalicylic
acid.
76 39:37 40
Placebo 77 40:37 38
28 29 19 6.7 5.7 20 42 (15)
24 41 12 7.4 5.1 16 43 (17)
49 (0) 62 (21) 6
49 (01 57 (13) 14
TobJe 3. Potient Disease Characteristics Study)
Vol. 92, No. 6
[on Entrance 5-ASA
Average disease boundary (cm) Extent of disease 5-20 cm 21-40 cm 41-50 cm
Average duration of present episode (days) 5-ASA, 5-aminosalicylic
to
Placebo
26
27
21 29 25 198
28 28 22 la9
acid.
Results Response
to Therapy
Response to therapy was assessed in three ways. The physician’s global assessment of the patient at the end of the study period was the first way of the 76 patients (63%) on (Table 4). Forty-eight 5-ASA and 22 of the 77 patients (29%) on placebo were rated as “much improved.” The differente between the two groups was statistically significant (p
Table
4. Response
to Therapy
Physician’s overall assessment “Much Improved” Percent decrease in DA1 After 22 days After 43 days At end point 5-ASA, 5-aminosalicylic by xZ analysis.
5-ASA
Placebo
P”
48/76 (63%)
22/77 (29%)
48% 60% 55%
20% 32% 22%
<0.0001 <0.0001 <0.0001
acid; DAI, disease activity.
’ Determined
5-ASA ENEMAS IN ULCERATIVE COLITIS
June 1987
Tabje
5.
Summary
ofEffcacy
Results Treatment group
Efficacy parameter Overall DA1 Stool frequency
index
Recta1 bleeding
index
Mucosal appearance Physician’s
index
assessment
1897
of disease severity
-Baseline 7.42 7.70 1.58 1.92 1.82 1.73 2.17 2.18 1.86 1.87
5-ASA Placebo 5-ASA Placebo 5-ASA Placebo 5-ASA Placebo 5-ASA Placebo
Observation” Day 22 4.05b 6.03 1.11e 1.47 0.59' 1.21 1.22b 1.74 1.13" 1.62
Day 43 2.67" 5.07 0.84" 1.31 0.34" 0.87 0.79" 1.44 0.70" 1.39
End point 3.37" 5.83 l.Olb 1.50 0.51‘ 1.11 0.96" 1.61 0.88C 1.55
Change from baseline to end point -55.07yocsd -22.58% -0.57 -0.41 -1.30c -0.61 -1.21c -0.56 -o.97c -0.30
ANOVA, analysis of variante; 5-ASA, 5-aminosalicylic acid; DAI, disease activity. ’ Mean value. b Significant 5-ASAlplacebo differente; p < 0.01, analysis of variante. ’ Significant E_AS.+/placebo differente; p < 0.001, analysis of variante. d Percent change for overall DA1 only. e Significant 5-ASA/placebo differente; p < 0.05, analysis of variante.
In addition to the clinical data, analysis of the patient diary data confirmed the significant 5-ASArelated improvement in recta1 bleeding. Moreover, the diary data indicated that a statistically significant (p-CO.0001) reduction in bleeding occurred within 3 days after the start of 5-ASA enema treatment. When response to therapy was determined by physician rating, there was a reasonable correlation between extent of disease and response, with the exception of disease confined to
Table
6. Response Disease
to Therapy
in Relation
to Extent
of
Extent of disease at entry (cm)
Percent of patients rated “Much Improved”
Percent decrease in DA1
5-ASA
p”
5-ASA
5-20 2140 41-50
71 59 62
NS 0.001 0.001
66 58 59
Placebo 43 25 14
Placebo 38 -9 30
pb 0.03 0.0001 0.06
5-ASA, S-aminosalicylic acid; DAI, disease activity. ’ Determined by x2 analysis. b Determined by analysis of variance.
analysis as wel1 as the posttreatment biopsy assessment wil1 be the subject of a separate manuscript. Side Effects Patients were asked to record on their diary cards any unusual occurrences during the study period. Side effects were few and insignificant. Of the patients receiving 5-ASA, several patients (7) complained of headache, 1 patient reported mild hair loss, and 1 patient had mild swelling of the ankles and feet related to a previously recognized cardiac condition. Patients on placebo reported nausea and vomiting (2), headache (4), rashes (2), arthralgia (l), periorbital edema (l), and diarrhea (1). NO clinically significant changes were observed in hematology, blood chemistry, or urinalysis.
Discussion Traditional treatment of ulcerative colitis has rested on the use of sulfasalazine and either topical or systemic corticosteroids. The use of either of these therapeutic modalities unfortunately can be associated with significant side effects. 5-Aminosalicylic acid appears to be a useful addition to the medical therapy of ulcerative colitis. Azad Khan (4) conducted a set of elegant experiments using retention enemas of the parent drug and its two initial metabolites, sulfapyridine and 5-ASA. They demonstrated that histologie improvement occurred with the 5-ASA and parent compound enemas but not with the sulfapyridine. Since that time there has been great interest in the preparation of 5-ASA. In Great Britain the drug has been prepared with an acrylic-based resin that dissolves at pH 7. Studies have shown that the drug is
1898 SUTHERLAND ET AL.
released ih the colon (5) and that it is effective in maintaining remission in patients with ulcerative colitis (6). In Italy 5-Á SA enemas were shown to be superior to 100-mg hydrocortisone enemas (12). The majority of patients who were unable to take sulfasalazine have been able to tolerate 5-ASA (~$14). In this study patients were able to tolerate a once-a-day 4-g enema and most achieved a significant improvement or remission. .Our dropout rate might have been lower if there had not been the option of exiting from the double-blind aspect of the acute study to enter the maintenance arm which guaranteed active medication. Few patients in the study reported side effects and, in fact, more patients on placebo (11) reported adverse reactions than those on active medication (6). The DA1 was designed to be a simple index to assess treatment response. Although it has not been previously validated, it incorporates many of the subscales used by other investigators. It demonstrated efficacy both as an overall index and individually with each component subscale. Mucosal appearance has been suggested to correlate best with other measures of disease activity (15). In our study patients receiving active medication had a significant improvement in mucosal àppearance as compared to those receiving the placebo (Table 5). The overall assessment of the patient by the study physician upon completion of the study did correlate wel1 with the DAI score (p=O.OOOl). The only exception was discordance between the physician’s overall global assessment and the DA1 in patients with disease confined to
GASTROENTEROLOGY Vol. 92. No. 6
References 1. Baron JH, Connell AM, Lennard-Jones JE, Jones FA. Sulphasalazine and salicylazosulphadimidine in ulcerative colitis. Lancet 1962;i:1094-6. 2. Dissanayake AS, Truelove SC. A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulphasalazine. Gut 1973;14:923-6. 3. Svartz N. Salazyopyrin, a new sulfanilamide preparation. Acts Med Stand 1942;110(Fasc. 6):577-98. 4. Azad Khan KA, Piris j, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 1977;0ct:892-5. 5. Dew MJ, Ryder RKJ, Evans BK, Rhodes J. Colonic release of 5-aminosalicylic acid from an oral preparation in active ulcerative colitis. Br J Clin Pharmacol 1983;16:i85-7. 6. Dew MJ, Hughes P, Harries AD, Williams G, Evans BK, Rhodes J. Maintenance or remission in ulcerative colitis with oral preparation of 5 amino salicylic acid. Br Med J 1982; 285:105. 7. Janssens J, Geboes K, Delanote C, et al. 5-aminosahcylic acid (5-ASA) enemas are effective in patients with iesistant ulcerative rectosigmoiditis (abstr). Gastroenterology 1983;84:1198. 8. Hanauer SB, Schultz PA, Kirsner JB. Treatment of refractory proctitis with 5-ASA enemas (abstr]. Gastroenterology 1985; 88:1412. 9. Barber GB, Lee DE, Antonioli DA, et al. Refractory distal ulcerative colitis responsive to 5-aminosalicylate enemas. Am J Gastroenterol 1985;80:612-4. 10. Hetze1 DJ, Bocher F, Imhoff DM, et al. Azodisalicylate (ADS) in ihe treatment of ulcerative colitis (UC). A controlled trial and assessment of drug disposition (abstr). Gastroenterology 1985;88:1418. 11. Ginsberg AL, Steinberg WM, Nochomovitz LE. Evaluation of 4-aminosalicylate enemas in patients with left sided ulcerative colitis (abstr]. Gastroenterology 1984:86:1089. 12. Campieri N, Lanfranchi GA, Bazzochi G, et al. Treatment of ulcerative colitis with high-dose 5-aminosalicylic acid enemas. Lancet 1981;ii:270-1. 13. Dew MJ, Harries AD, Evans BK, Rhodes J. Treatment of ulcerative colitis with oral 5 amino salicylic acid in patients unable to take sulphasalazine. Lancet 1983;ii:aOl. 14. Campieri N, Lanfranchi G, Brignola C, Bazzocchi G, Minguzzi M,, Calari M. 5-Aminosalicylic acid as recta1 enema in ulcerative colitis patients unable to take sulphasalazine. Lancet 1984;i:403. 15. Powell-Tuck J, Day DW, Buckell NA, et al. Correlations between sigmoidoscopic appearances and other measures of disease activitv in ulcerative colitis. Die. Dis Sci 1982; 27:533-7. -
5-Aminosalicylic Acid Enema in the Treatment of Distal Ulcerative Colitis, Proctosigmoiditis, and Proctitis LLOYD R. SUTHERLAND, FRANCOIS MARTIN, SCOTT GREER, MALCOLM ROBINSON, NORTON GREENBERGER, FRED SAIBIL, and THOMAS MARTIN, JOSEPH SPARR, ED PROKIPCHUK, LOWELL BORGEN Departments of Gastroenterology at the University of Calgary, Calgary, Canada; University of Montreal, Montreal, Canada; Scripps Medical Clinic, La Jolla, California; Oklahoma City Clinic, Oklahoma City, Oklahoma; Kansas University, Lawrence, Kansas; University of Toronto, Toronto, Canada; St. Paul Gastroenterology, St. Paul, Minnesota; Atlantic Gastroenterology, New Jersey; and Clinical Research Department, Reid-Rowell, Inc., Baudette, Minnesota
The eficacy and safety of 4-g 5-aminosalicylic acid enemas were assessed in 153 patients with ulcerative colitis involving up to 50 cm of distal colon. Seventy-six patients received active medication and 77 received a placebo. There were 20 dropouts (6 in the active group and 14 in the placebo group) during the study because of insuficient ejjïcacy. After 6 wk of therapy, 48 of the 76 patients (63%) receiving 5-aminosalicylic acid were considered to be “much improved” by the study physician compared to 22 of the 77 patients (29%) on placebo (p=O.O01). A disease activity index based on patient symptoms and sigmoidoscopic appearance was used to assess effcacy. Mean disease activity index declined 55% for patients on 5-aminosalicylic acid and 24% for patients on placebo [p=O.OOOl). Analysis of subgroups indicated that patients most likely to respond were those with disease conjïned to the 20-40 cm from the anus. Response was not affected by concurrent sulfasalazine, but patients requiring concurrent oral steroids had a diminished response. Rapid onset of eficacy was shown by a significant reduction in recta1 bleeding within 3 days of treatment initiation. 5-Aminosalicylic acid enemas are wel1 tolerated and are of benefit in the treatment of ulcerative colitis conjïned to the distal colon.
Received March 27, 1986. Accepted December 1, 1986. Address requests for reprints to: Dr. L. R. Sutherland, 3330 Hospita1 Drive NW, Room 1414, Calgary, Alberta, Canada T2N
For the past 40 yr sulfasalazine has played an important role in the treatment of inflammatory bowel disease. Studies done 25 yr ago confirmed its effectiveness in treating mild ulcerative colitis (1) and in prolonging the interval between episodes of acute colitis (2). The drug was synthesized by chemically linking sulfapyridine, a nonabsorbable sulfa moiety, to Ei-aminosalicylic acid (5-ASA) (3). The use of sulfasalazine has been limited by side effects that are thought to be related to the sulfa portion of the molecule. These adverse effects include those that are dose-related (nausea, vomiting, headache, malaise, and hemolysis) and those that are not (fever, rash, lymphadenopathy, agranulocytosis, pneumonitis). Recent studies have suggested that 5-ASA is the active ingredient in sulfasalazine (4-6). Attention has thus focused on the preparation of pure 5-ASA either as a retention enema, suppository, or slowrelease tablet (7-10). Other investigators have studied the use of 4-aminosalicylate enemas (11). We report on the results of a study of a 5-ASA enema preparation in patients with active distal ulcerative colitis. Although both 2- and 4-g enema have been tested, we elected to assess the efficacy of the 4-g enema. The purpose of the study was to evaluate the efficacy and safety of a 5-ASA enema (ROWASA, Reid-Rowell Inc., Baudette, Minn.) preparation in the treatment of active ulcerative colitis confined to the distal large intestine. It was also our intent to
4Nl.
This work was sponsored by Reid-Rowell Inc., Baudette, Minnesota, and Interfalk Canada, Beloil, PQ, Canada. 0 1987 by the American Gastroenterological Association 0016-5085/87/$3.50
Abbreviations used in this paper: 5-ASA, 5-aminosalicylic DAI, disease activity index.
acid;
5-ASA ENEMAS IN ULCERATIVE
June 1987
examine the benefits, if any, of using the preparation in patients already on but not responsive to conventional treatment. Finally, through a maintenance program (to be reported separately) we proposed to evaluate the safety and efficacy of two doses of 5-ASA enemas in maintaining remission of disease.
Materials and Methods Om trial utilized a 6-wk, randomized, doubleblind, placebo-controlled design. Eight centers (five in the United States and three in Canada) participated in the trial. The protocol was reviewed by the individual Ethics Committees or Internal Review Boards of the participating institutions. Written informed consent was obtained from each before entrance into the study. The study population 318 yr old, who had ulcerwas composed of outpatients, ative colitis involving a minimum of 5 cm to a maximum of 50 cm of colon as measured continuously from the anus and confirmed by sigmoidoscopy (with biopsy specimens taken from an area of active disease and above the disease boundary). Patients also had to have a minimum score of 3 on a 12-point disease activity index (see Table 5). Pregnant women were excluded. History of salicylate allergy, disease involving more than 50 cm of colon, previous bowel resection, or clinically significant hepatic or renal disease were also grounds for exclusion. NO rectally administered steroid medications were allowed. Random assignment to either placebo or 4-g 5-ASA enemas (60-ml suspension per disposable unit of use retention enema, ROWASA prepared by Reid-Rowell, Inc., Baudette, Minn.) was accomplished by the assignment of patient study numbers using a table of random numbers. Double-blind medication was prepackaged to insure that an equal and random assignment within each center did occur. The medication and placebo were identical in color, consistency, and packaging. Patients were not asked at the end of the study to guess whether or not they had received active medication. Patients were not stratified as to duration of disease or extent of disease. Patients who had to discontinue the study because of treatment-related reasons (i.e., lack of efficacy or adverse effects) were not replaced. Patients terminated for non-treatment-related reasons (i.e., lost to follow-up or lack of compliance) were replaced. Statistical analysis of data was carried out on al1 patients who were entered into the study (“intent to treat”). Nonparametric data (“physician’s global assessment”) were analyzed by 2; changes in disease activity index (DAI) (an ordinal scale) were analyzed by analysis of variante. Concurrent
Medications
Pátients were allowed to use oral steroids or sulfasalazine under certain conditions. Oral steroids could be continued if the patient had taken them for more than 4 wk and if the dose was <30 mg of prednisone or equivalent. Oral sulfasalazine was allowed if the medication had been used regularly for more than 4 wk before entrance. In
Table
COLITIS
1. Disease Activity Index (Qualitative Scale With Four Subscales)
1895
Rating
1. Stool frequency 0 = Normal 1 = 1-2 Stools/day >normal 2 = 3-4 Stoolslday >normal 3 = >4 Stools/day >normal 2. Recta1 bleeding 0 = None 1 = Streaks of blood 2 = Obvious blood 3 = Mostly blood 3. Mucosal appearance 0 = Normal 1 = Mild friability 2 = Moderate friability 3 = Exudation, spontaneous bleeding 4. Physician’s rating of disease activity 0 = Normal 1 = Mild 2 = Moderate 3 = Severe Maximum
score = 12
either case, the dose of steroid or sulfasalazine constant during the 6 wk of the study. Disease
Activity
remained
Index
The DA1 (Table 1) represents an attempt to provide objective criteria for assessment of drug efficacy. It assesses four variables: (a) stool frequency, (b) recta1 bleeding, (c) sigmoidoscopic appearance of mucosa, and (d) physician’s assessment of disease severity. Each variable has a range of values for severity, with 0 representing no abnormality and 3 representing the most severe. As the variables have equal weighting, the overall DA1 can range from 0 to 12. The DA1 values calculated at day 22 and day 43 of the study represent an integration of data collected by the patient on his or her diary card for the preceding 3 wk. Procedures On entry into the study a complete history, physical examination, and flexible sigmoidoscopy was done. Biopsy specimens were obtained from the area of most extensive bowel involvement and of normal-appearing mucosa above the disease boundary. Patients were classified by the extent of disease involvement. Hemátologic (complete blood count and sedimentation rate) and biochemical parameters (SMA-12 or equivalent), including urinalysis (with microscopic examination), were assessed along with stool culture to exclude infectieus colitis. The DA1 was calculated. Patients were given a 3-wk supply of 60-ml enemas that contained either placebo or 4 g of 5-ASA in a 60-ml suspension. They were instructed to use one enema daily at bedtime. Diary cards were given to record their symptoms (stool frequency, bleeding, cramping) on a daily basis. They were also asked to record any other medications taken, other symptoms or possible side effects, and
1896
SUTHERLAND
ET AL.
GASTROENTEROLOGY
the number of hours that the enema was retained. Weekly telephone contact was made with the patients to assess patcent symptoms and to encotirage coipliance. At 3 wk repeat sigmoidoscopy was done. In addition, urine (24-h collection) and venous blood samples were obtained and analyzed for 5-ASA and its metabolite, N-açetyl&ASA. The DA1 was calculated. If there was deterioration, the patient was withdrawn from the acute study and enrolled in the maintenance study involving two doses of 5-ASA enemas. If the patient had either stabilized or improved, an addiiional 3-wk supply of medication was dispensed. At the conclusion of the study (6 wk), flexible sigmoidoscopy with biopsies of active disease and normalappearing mucosa were again done. A repeat physical examination with hematologie and biochemical assessment including urinalysis was carried out. The DA1 was again calculated. Patients who completed the trial were also allowed the option of participating in the maintenance trial.
Patients One hundred and fifty-three patients entered the trial. Ofie patient diopped out because he could not retain the enemas and was replaced. Subject characteristics are noted in Tables 2 and 3. Both groups are similar in composition as to sex, age, extent of disease, and concurrent medication. One hundred and nineteen (78%) patients had taken sulfasalazine previously. Forty-six patients stated that the therapy had been effective, 40 stated that it had been ineffective, and 33 were unsure of its effectiveness. Only z patients gave a history of sulfasalazine allergy. Ninety-eight patients (64%) had taken recta1 corticosteroids in the past, with 47 reporting a positive response, 43 reporting ineffective relief of symptoms, and 8 unsure. Twenty patients (6 on active medication and 14 on placebo) dropped out because of deterioration or unsatisfactory response before the conclusion of the study.
Table
2. Patient
Characteristics 5-ASA
Number of patients Sex ratio (M:F) Age (mean] Diagnosis Proctitis Proctosigmoiditis Distal ulcerative colitis Duration cif disease (yr) Number of prior episodes Percent first episode Prior (and concurrent) oral steroids Prior (and concurrent] recta1 steroids Prior (and concurrent] sulfasalazine Dropouts 5-ASA, 5-aminosalicylic
acid.
76 39:37 40
Placebo 77 40:37 38
28 29 19 6.7 5.7 20 42 (15)
24 41 12 7.4 5.1 16 43 (17)
49 (0) 62 (21) 6
49 (01 57 (13) 14
TobJe 3. Potient Disease Characteristics Study)
Vol. 92, No. 6
[on Entrance 5-ASA
Average disease boundary (cm) Extent of disease 5-20 cm 21-40 cm 41-50 cm
Average duration of present episode (days) 5-ASA, 5-aminosalicylic
to
Placebo
26
27
21 29 25 198
28 28 22 la9
acid.
Results Response
to Therapy
Response to therapy was assessed in three ways. The physician’s global assessment of the patient at the end of the study period was the first way of the 76 patients (63%) on (Table 4). Forty-eight 5-ASA and 22 of the 77 patients (29%) on placebo were rated as “much improved.” The differente between the two groups was statistically significant (p
Table
4. Response
to Therapy
Physician’s overall assessment “Much Improved” Percent decrease in DA1 After 22 days After 43 days At end point 5-ASA, 5-aminosalicylic by xZ analysis.
5-ASA
Placebo
P”
48/76 (63%)
22/77 (29%)
48% 60% 55%
20% 32% 22%
<0.0001 <0.0001 <0.0001
acid; DAI, disease activity.
’ Determined
5-ASA ENEMAS IN ULCERATIVE COLITIS
June 1987
Tabje
5.
Summary
ofEffcacy
Results Treatment group
Efficacy parameter Overall DA1 Stool frequency
index
Recta1 bleeding
index
Mucosal appearance Physician’s
index
assessment
1897
of disease severity
-Baseline 7.42 7.70 1.58 1.92 1.82 1.73 2.17 2.18 1.86 1.87
5-ASA Placebo 5-ASA Placebo 5-ASA Placebo 5-ASA Placebo 5-ASA Placebo
Observation” Day 22 4.05b 6.03 1.11e 1.47 0.59' 1.21 1.22b 1.74 1.13" 1.62
Day 43 2.67" 5.07 0.84" 1.31 0.34" 0.87 0.79" 1.44 0.70" 1.39
End point 3.37" 5.83 l.Olb 1.50 0.51‘ 1.11 0.96" 1.61 0.88C 1.55
Change from baseline to end point -55.07yocsd -22.58% -0.57 -0.41 -1.30c -0.61 -1.21c -0.56 -o.97c -0.30
ANOVA, analysis of variante; 5-ASA, 5-aminosalicylic acid; DAI, disease activity. ’ Mean value. b Significant 5-ASAlplacebo differente; p < 0.01, analysis of variante. ’ Significant E_AS.+/placebo differente; p < 0.001, analysis of variante. d Percent change for overall DA1 only. e Significant 5-ASA/placebo differente; p < 0.05, analysis of variante.
In addition to the clinical data, analysis of the patient diary data confirmed the significant 5-ASArelated improvement in recta1 bleeding. Moreover, the diary data indicated that a statistically significant (p-CO.0001) reduction in bleeding occurred within 3 days after the start of 5-ASA enema treatment. When response to therapy was determined by physician rating, there was a reasonable correlation between extent of disease and response, with the exception of disease confined to
Table
6. Response Disease
to Therapy
in Relation
to Extent
of
Extent of disease at entry (cm)
Percent of patients rated “Much Improved”
Percent decrease in DA1
5-ASA
p”
5-ASA
5-20 2140 41-50
71 59 62
NS 0.001 0.001
66 58 59
Placebo 43 25 14
Placebo 38 -9 30
pb 0.03 0.0001 0.06
5-ASA, S-aminosalicylic acid; DAI, disease activity. ’ Determined by x2 analysis. b Determined by analysis of variance.
analysis as wel1 as the posttreatment biopsy assessment wil1 be the subject of a separate manuscript. Side Effects Patients were asked to record on their diary cards any unusual occurrences during the study period. Side effects were few and insignificant. Of the patients receiving 5-ASA, several patients (7) complained of headache, 1 patient reported mild hair loss, and 1 patient had mild swelling of the ankles and feet related to a previously recognized cardiac condition. Patients on placebo reported nausea and vomiting (2), headache (4), rashes (2), arthralgia (l), periorbital edema (l), and diarrhea (1). NO clinically significant changes were observed in hematology, blood chemistry, or urinalysis.
Discussion Traditional treatment of ulcerative colitis has rested on the use of sulfasalazine and either topical or systemic corticosteroids. The use of either of these therapeutic modalities unfortunately can be associated with significant side effects. 5-Aminosalicylic acid appears to be a useful addition to the medical therapy of ulcerative colitis. Azad Khan (4) conducted a set of elegant experiments using retention enemas of the parent drug and its two initial metabolites, sulfapyridine and 5-ASA. They demonstrated that histologie improvement occurred with the 5-ASA and parent compound enemas but not with the sulfapyridine. Since that time there has been great interest in the preparation of 5-ASA. In Great Britain the drug has been prepared with an acrylic-based resin that dissolves at pH 7. Studies have shown that the drug is
1898 SUTHERLAND ET AL.
released ih the colon (5) and that it is effective in maintaining remission in patients with ulcerative colitis (6). In Italy 5-Á SA enemas were shown to be superior to 100-mg hydrocortisone enemas (12). The majority of patients who were unable to take sulfasalazine have been able to tolerate 5-ASA (~$14). In this study patients were able to tolerate a once-a-day 4-g enema and most achieved a significant improvement or remission. .Our dropout rate might have been lower if there had not been the option of exiting from the double-blind aspect of the acute study to enter the maintenance arm which guaranteed active medication. Few patients in the study reported side effects and, in fact, more patients on placebo (11) reported adverse reactions than those on active medication (6). The DA1 was designed to be a simple index to assess treatment response. Although it has not been previously validated, it incorporates many of the subscales used by other investigators. It demonstrated efficacy both as an overall index and individually with each component subscale. Mucosal appearance has been suggested to correlate best with other measures of disease activity (15). In our study patients receiving active medication had a significant improvement in mucosal àppearance as compared to those receiving the placebo (Table 5). The overall assessment of the patient by the study physician upon completion of the study did correlate wel1 with the DAI score (p=O.OOOl). The only exception was discordance between the physician’s overall global assessment and the DA1 in patients with disease confined to
GASTROENTEROLOGY Vol. 92. No. 6
References 1. Baron JH, Connell AM, Lennard-Jones JE, Jones FA. Sulphasalazine and salicylazosulphadimidine in ulcerative colitis. Lancet 1962;i:1094-6. 2. Dissanayake AS, Truelove SC. A controlled therapeutic trial of long-term maintenance treatment of ulcerative colitis with sulphasalazine. Gut 1973;14:923-6. 3. Svartz N. Salazyopyrin, a new sulfanilamide preparation. Acts Med Stand 1942;110(Fasc. 6):577-98. 4. Azad Khan KA, Piris j, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 1977;0ct:892-5. 5. Dew MJ, Ryder RKJ, Evans BK, Rhodes J. Colonic release of 5-aminosalicylic acid from an oral preparation in active ulcerative colitis. Br J Clin Pharmacol 1983;16:i85-7. 6. Dew MJ, Hughes P, Harries AD, Williams G, Evans BK, Rhodes J. Maintenance or remission in ulcerative colitis with oral preparation of 5 amino salicylic acid. Br Med J 1982; 285:105. 7. Janssens J, Geboes K, Delanote C, et al. 5-aminosahcylic acid (5-ASA) enemas are effective in patients with iesistant ulcerative rectosigmoiditis (abstr). Gastroenterology 1983;84:1198. 8. Hanauer SB, Schultz PA, Kirsner JB. Treatment of refractory proctitis with 5-ASA enemas (abstr]. Gastroenterology 1985; 88:1412. 9. Barber GB, Lee DE, Antonioli DA, et al. Refractory distal ulcerative colitis responsive to 5-aminosalicylate enemas. Am J Gastroenterol 1985;80:612-4. 10. Hetze1 DJ, Bocher F, Imhoff DM, et al. Azodisalicylate (ADS) in ihe treatment of ulcerative colitis (UC). A controlled trial and assessment of drug disposition (abstr). Gastroenterology 1985;88:1418. 11. Ginsberg AL, Steinberg WM, Nochomovitz LE. Evaluation of 4-aminosalicylate enemas in patients with left sided ulcerative colitis (abstr]. Gastroenterology 1984:86:1089. 12. Campieri N, Lanfranchi GA, Bazzochi G, et al. Treatment of ulcerative colitis with high-dose 5-aminosalicylic acid enemas. Lancet 1981;ii:270-1. 13. Dew MJ, Harries AD, Evans BK, Rhodes J. Treatment of ulcerative colitis with oral 5 amino salicylic acid in patients unable to take sulphasalazine. Lancet 1983;ii:aOl. 14. Campieri N, Lanfranchi G, Brignola C, Bazzocchi G, Minguzzi M,, Calari M. 5-Aminosalicylic acid as recta1 enema in ulcerative colitis patients unable to take sulphasalazine. Lancet 1984;i:403. 15. Powell-Tuck J, Day DW, Buckell NA, et al. Correlations between sigmoidoscopic appearances and other measures of disease activitv in ulcerative colitis. Die. Dis Sci 1982; 27:533-7. -