GASTROENTEROLOGY 1982;82:41-5 ALIMENT ARY TRACT Comparison of the Healing Capacities of and Cimetidine in the Short Term Treatment of Duodenal Ulcer: A Double-Blind Randomized Trial FRANCOIS MARTIN, ALAIN FARLEY, MICHEL GAGNON, and DAVID BENSEMANA Service de Gastroenterologie, H6pital St-Luc, Universite de Montreal, Canada Fifty-nine outpatients with endoscopically proven duodenal ulcer were evaluated for 4-8 wk in a randomized, double-blind trial comparing sucralfate, a sulfated disaccharide, (1 g,.5 h before each meal and at bedtime) with cimetidine (3 mg,.5 h before each meal and at bedtime). Ulcer symptoms and their relief were recorded by patients in a diary, along with data on cigarette, alcohol, coffee, and drug intake. Duodenoscopy was performed after 4 wk to assess healing, and was repeated after 8 wk if healing had not occurred by the 4-wk evaluation. Twenty-four of 3 patients taking sucralfate (8.%) and 22 of 29 patients taking cimetidine (75.9%) had their ulcer completely healed after 4 wk. The overall healing rates after 8 wk for the sucralfate and cimetidine groups were 9.% (27 of 3 patients) and 86.2% (25 of 29 patients), respectively. There were no significant differences between the two treatment groups in ulcer healing, symptom relief, and side effects. Symptoms were relieved equally with respect to time and efficacy. Minor adverse experiences were reported in each treatment group. None of these experiences were serious enough to warrant discontinuation of treatment. These results suggest that sucralfate is as effective as cimetidine in the short-term treatment of duodenal ulcer. It has been hypothesized (1) that the integrity of the gastroduodenal mucosa directly influences the development of peptic ulcer; that the intact mucosa Received June 26, 1981. Accepted October 8, 1981. Address requests for reprints to: Francois Martin, M.D., Service de Gastroenterologie, H6pital St-Luc, Universite de Montreal, 158 Rue St-Denis, Montreal H2X 3J4, Canada. This study was sponsored by Nordic Laboratories Inc., 2775 Rue Bovet St., Chomedey, Laval, P.Q. H7S 2A4 Canada. The authors thank Mrs. Helen St-Onge and Mrs. P. Lemaire for their nursing assistance, and David Katterhenrich for his editorial assistance. 1982 by the American Gastroenterological Association 16-585/82/341-5$2.5 resists insult while the damaged mucosa is subject to degradation by acid, pep~in, and bile, factors thought to be etiologic in the disease., an aluminum salt of a sulfated disaccharide, is virtually unabsorbed and is thought to act locally at the site of an ulcer as a barrier to each of these three erosive factors (2-9). The efficacy and safety of sucralfate in duodenal ulcer therapy have been assessed in three short-term, randomized, double-blind, placebo-controlled trials in which endoscopy was used (1-12). A total of 328 patients were evaluated for efficacy in these trials. The healing rates for sucralfate ranged from 75% to 92%, vs. from 44% to 64% for placebo. In each of the above studies sucralfate was shown to be statistically superior to placebo. Few adverse experiences were reported. The most frequent complaint was constipation. Recent discussion has centered on the ethical questions surrounding placebo-controlled duodenal ulcer studies (13) in light of the accepted benefits and wide use of antacid and cimetidine therapy. It appears ethical and useful, therefore, to compare sucralfate with an active control agent. The cimetidine-controlled sucralfate trial which foilows was designed to compare the two agents in terms of healing capacity, symptom relief, and side effects. A strict double-blind, double-placebo scheme was used. Patients and Methods Symptomatic adult outpatients with endoscopically confirmed duodenal ulcers were candidates for this 4-8-wk study. Sixty-two patients met the selection criteria and entered the study after providing written informed consent. The protocol, which was approved by the Research and Ethical Committee of St-Luc Hospital, required that patients be excluded for the following reasons: age
42 MARTIN ET AL. GASTROENTEROLOGY Vol. 82, No. 3 a Date!- I Nul [ Severe 1 # OunCes Antacid #Aspirins -#Ounces Alcohol #Cigarettes #Cups Coffee Side Effects [ [ [[ [[ [ Figure 1. Patient diary. under 18 yr, pregnancy or absence of reliable birth control, alcoholism, drug-induced duodenal ulcer, complicated duodenal ulcer like stenosis, postbulbar ulcers, prepyloric ulcers, channel ulcers, giant antral ulcers, simultaneous gastric and duodenal ulcers, and hemorrhage or perforation. Patients with chronic conditions that required drugs known to have ulcerogenic properties were excluded. However, patients were not excluded if they took less than 12 mg acetylsalicylic acid per wk. All patients underwent a prestudy fiberoptic duodenoscopy that provided objective evidence on the presence of the crater, an estimation of its,size using an open biopsy forceps, and its anatomic site within the duodenum. other prestudy information was obtained: a complete medical and social history, ail ulcer disease history, routine laboratory study results (urine, serum chemistry, hematology), gastric acid study results, and serum gastrin measurements (fasting and 2 h postprandial). The prestudy information was gathered for estabiishing baselines to determine if the groups were comparable, and in the case of the gastric acid and serum gastrin tests, to reasonably exclude patients with gastiinoma. Following the initial evaluations patients were randomly assigned to treatment with either sucralfate or cimetidine according to a table of random numbers. All patients were to bike two white tablets [active 5 mg sucralfate tabiets (Nordic Laboratories Inc., Canada, lot no. 5885L7) or identical white placebo tablets] and one green tablet [an active 3-mg cimetidine tablet (lots no. 1558 and 1559) or an identical green placebo j; the three tablets were to be taken.5 h before each of three meals and before retiring (4 mg of sucralfate or 12 mg of cimetidine daily). patients received the cimetidine placebo While cimetidine patients received the sucralfate placebo. A special coating process was used to obtain visually identical tablets of cimetidine and its corresponding placebo. The process was studied and found not to affect the dissolution rate of the tablet. Every 2 wk each patient was given 14 envelopes, each containing a 1-day supply of the drug. The envelopes were code-labeled to insure blinding. Unused medication was to be returned to the investigator at every 2-wk interval. The returned tablets were counted to estimate compliance. Antacid was not supplied or recommended by the invl;lstigator. However, any amount of antacid taken was to be recorded in a patient diary. All patients were medically evaluated every 2 wk at which time compliance was checked and any side effects were. recorded. All were endoscoped after 4 wk to assess whether complete ulcer healing had occurred. The presence or absence of duodenitis played no role in the evaluation of ulcer healing. Partially healed ulcers Were considered unhealed. Patients with unhealed ulcers after 4 wk were continued on the same treatment for an additional 4 wk and then underwent ariother endoscopy. In order to assess symptomatic relief, patients were asked to record daily in their diary their level of discomfort from ulcer symptoms on a -1 continuum ( = nb discomfort, 1 = severe discomfort) (see Figure 1). The diary also permitted the recording of coffee, alcohol, and concomitant drug intilke, including antacid. In addition, patients listed in their diaries all adverse experiences. The endoscopists were unaware of the patient's symptom responses. The routine laboratory tests conducted prestudy were repeated after 4 and 8 wk to provide further safety data. Each patient's final medical examination and laboratory evaluation were mandatory for inclusion in the analyses of efficacy. Results Treatment Groups Of the 62 patients who entered the study, 3 were excluded from the final efficacy analyses. Two were in the sucralfate group (1 patient refused endoscopy and another was lost to follow-up). One patient in the cimetidine group with a prepyloric ulcer was excluded. The resulting population cif59 patients consisted of 3 in the sucralfate group and 29 in the cimetidine group. None of the demographic distributions were statistieally different as tested by Fisher's exact test (Table 1). The population was predominantly male with a median age close to 4 yr in each group (age range 19-63 yr). All patients were white. Table 2 identifies the intrabulbar ulcer locations for patients in each treatment group, and provides the mean estimated pretreatment ulcer sizes. Table 1 also presents the results of the prestudy gastric acid tests and the serum gastrin measurements. Statistical comparisons between treatment groups showed no statistical differences (Student's t test). No individual values were outside the normal limits associated with duodenal ulcer disease. Gastrinoma therefore appeared to have been absent within the population. Healing Capacities Healing rates for the two treatment groups after 4 and 8 wk of treatment are shown in Tabie 3. Of the patients who received sucralfate, 24 of 3 (8.%) were healed after 4 wk, compared with 22 of 29 (75.9%) of the patients who received cimetidine. Patients in whom healing was observed at 4 wk did not continue receiving treatment.
March 1982 SUCRALF A TE AND CIMETIDINE IN DUODENAL ULCER 43 Table 1. Demographic Data Cimetidine No. patients 3 29 Age (yr, mean) 42.6 38.7 (range, 19-59) (range, 21-63) Sex:M 19 24 F 11 5 No. smokers 22 22 First episode 7 6 Relapse (No. patients) 23 23 (No. of relapses/yr, mean ± SE) 1.6 ±.17 1.95 ±.22 Duration of disease 7.7 9.16 (yr, mean) (range, 2-2) (range, 1-3) Basal acid output (BAD) (meq/h ± SE) 4.54 ±.81 3.77 ±.57 Maximum acid output (MAO) 32.39 ± 2.89 29.9 ± 1.98 Peak acid output (PAD) 42.2 ± 3.8 4.1 ± 2.66 Fasting serum gastrin levels (pg/ml ± SE) 8.33 ± 4.94 76.88 ± 4.43 Postprandial serum gastrin levels 131.84 ± 11.49 123.77 ± 1.78 None of the differences were significant: Fisher's exact test, Student's t-test. After 8 wk the overall healing rate in the sucralfate group was 9.% (27 of 3 patients) vs. 86.2% (25 of 29 patients) in the cimetidine group. The similar results of sucralfate and cimetidine treatment were not significantly different at either evaluation as tested by Fisher's exact test. Symptomatic Improvement Symptomatic improvement was assessed using scores recorded by the patients on the 1-point symptom severity scale that was included in the Table 2. Intrabulbar Ulcer Locations Treatment group Anterior Superior Inferior Posterior Pretreatment 11 4 7 ulcer sizea 9.9 mm (mean) Standard error 1 case: 1.6 mm 1 case: 3 cases: 2 ulcers (1 posterior, 1 anterior) pyloric side of the bulb not recorded Cimetidine Pretreatment ulcer sizea 1.5 mm (mean) 9 7 3 Standard error 1 case: mediobulbar.72 mm 1 case: pyloric side of the bulb 3 cases: not recorded a No statistically significant difference in pretreatment ulcer size was found between groups: Wilcoxon ranked sum test. 3 5 Table 3. Healing Capacities Complete healing Four weeks b Eight weeks (overall) (n = 3) 24 (8.%) 27 (9.%) Cimetidine Statistical (n = 29) significancea 22 (75.9%) 25 (86.2%) NS NS a NS-No statistically significant difference between groups: Fisher's exact test. b Patients with healed ulcers after 4 wk did not continue to receive treatment. patient diaries. Figure 2 is included to illustrate the symptomatic relief profiles of both drugs during the first 4 wk, when data from all patients were collected. Safety No reports of side effects were serious enough to warrant discontinuation of treatment. The highest incidence of any specific side effect was mild constipation, with 7 sucralfate reports and 2 cimetidine reports (not significantly different, Fisher's exact test). patients also had a higher incidence of headache (six reports vs. three for cimetidine patients), but the frequencies were not different enough to attach any statistical significance. The routine laboratory tests conducted after 4 and 8 wk of treatment revealed no unusual trends and no statistically significant differences between groups. The investigators felt that constipation was the only side effect possibly drug related. Compliance, Antacid Consumption, Patient Habits Compliance with the dosage regimens was excellent in both treatment groups. pa- -.,, 1 5. I- o Cimetidine a: Moderate 4.5 II.. ::E 4. (,,) en u. -'... > w -' z <C... ::E Nul 3.5 3. DAYS Figure 2. Severity of symptoms (weeks 1-4).
44 MARTIN ET AL. GASTROENTEROLOGY Vol. 82, No.3 tients as a group took 95% of their prescribed tablets; the corresponding percentage in the cimetidine group was 96.4%. Only 6 patients in each group recorded antacid use. In all cases this use was minimal. The small amounts of antacid taken were considered to have had an insignificant effect on healing and symptom relief. Patient habits during the study regarding aspirin, alcohol, cigarettes, and coffee were examined. No patients exceeded the aspirin limit established in the protocol of 12 mg/wk. Alcohol consumption varied similarly within each treatment group. In all but 1 case where alcohol was consumed, it was taken infrequently and in small quantities. The exception, a patient on sucralfate reported alcohol intake on all but 3 days over 8 wk oftreatment (4.7 oz alcohol/day, mean). The patient's ulcer remained unhealed. All but 4 patients drank coffee regularly. In the sucralfate group, an average of 2.1 cups/patient/day were consumed, vs. 1.8 cups/patient/day in the cimetidine group. Two patients in each group drank an average of over 5 cups/day. Only one of these patients, a patient in the cimetidine group, remained unhealed (5.5 cups/day, mean). No differences between groups were found in smoking habits. All but 9 patients were regular smokers. The mean number of cigarettes/patient/day for the sucralfate and cimetidine groups were 18.8 and 17.5, respectively. No conclusions could be drawn regarding the levels of smoking and the healing results. Discussion This study was designed to compare the new drug sucralfate with the well-accepted H2 antagonist cimetidine, in the treatment of duodenal ulcer. acts nonsystemically as a barrier to acid, pepsin, and bile at the ulcer site (2-9). In contrast, it is postulated that cimetidine, by blocking histamine H2 receptors on the parietal cell, limits the ability of histamine, gastrin, and acetylcholine to stimulate acid secretion (14). Considering the two agents' dissimilar modes of action, the value of the investigation to the clinician becomes apparent. Since the effectiveness of cimetidine is widely accepted, it was considered more ethical not to include a placebo group in this particular trial. The healing rates achieved in the sucralfate and cimetidine groups after 4 wk of treatment were 8.% and 75.9%, respectively. Overall, after 8 wk of treatment the healing rates were 9.% (sucralfate) and 86.2% (cimetidine). No statistically significant difference could be shown between the two treatments. According to Peterson and Elashoff (13) the likelihood of making a type II error-declaring as "not significantly different" two treatments that are actually different-is very high when the number of patients studied and the difference between the two treatments are small. To detect such a difference usually requires a total sample size running into the thousands (a =.5; f3 ~.1). It is obvious that such a requirement is very difficult to meet. Confidence intervals on the observed differences in healing from several small studies could be used as an alternative approach in comparing a new drug to proven therapy (15). In our study the 95% confidence interval for the difference in percent healed runs from sucralfate better by 25% to cimetidine better by 17% after 4 wk and sucralfate better by 2% to cimetidine better by 13% after 8 wk. In another sucralfate--cimetidine investigation in duodenal ulcer, Marks et al. (16) found healing rates of 83% in 29 patients treated with sucralfate and 71% in 28 patients treated with cimetidine after 6 wk of treatment. The 95% confidence interval for the difference in percent healed runs from sucralfate better by 33% to cimetidine better by 1%. The sucralfate response after 4 wk in this study (8.%) was similar to those seen in the 4-wk placebo-controlled duodenal trials of McHardy et al. and Hollander et al. (11,12). The cimetidine healing response in this study after 4 wk (75.9%) was also consistent with cimetidine responses seen in other well-controlled duodenal investigations (17-19). In this trial antacid was neither recommended nor supplied. This antacid policy, combined with the fact that both test drugs were active in relieving symptoms, may be responsible for the minimal antacid consumption in both groups. The antacid policy may prove useful in future trials of active ulcer agents by minimizing antacid consumption and thereby simplifying the interpretation of results. A final point of interest concerns the assessment of symptomatic improvement. In this trial patients first recorded their level of discomfort from ulcer symptoms after initial doses of medication had been taken. This fact may explain the relatively low symptom severity means calculated for the first days of the trial (Figure 2). Prestudy recordings of symptom severity would likely enhance the usefulness of the symptom scale for evaluating drug efficacy. In conclusion, sucralfate appears to be as safe and effective as cimetidine in the short-term treatment of duodenal ulcer considering ulcer healing, symptom relief, and the low incidence of side effects. offers a new and significant approach to treating duodenal ulcer in light of its nonsystemic mode of action and efficacy.
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