The Lancet · Saturday 25 October 1975
TREATMENT OF DUODENAL ULCER BY METIAMIDE A Multicentre Trial"
Summary
In a multicentre double-blind trial 68 patients with endoscopically confirmed duodenal ulceration received metiamide (36 patients) or placebo (32 patients) for four weeks. Healing of doudenal ulcers was significantly increased in patients receiving metiamide (67%) compared with those on placebo (25%). There was also an associated significant decrease in daytime pain and antacid consumption in those on metiamide. Introduction
BURIMAMIDE was the first Hj-receptor antagonist to be evaluated in man and shown to inhibit gastric-acid secretion. I 2 Metiamide succeeded burimamide and was the first histamine H 2-receptor antagonist to be evaluated clinically. It inhibits resting and stimulated gastric-acid and pepsin secretion.v !" Treatment with metiamide is reported to be associated with relief. from the pain of duodenal ulceration and a reduction in antacid consumption.!' and an open study suggested that its administration was followed by a high rate of healing in endoscopically confirmed duodenal ulcers.P To substantiate these initial findings, a multicentre endoscopically monitored double-blind trial was undertaken to assess whether its administration would increase the rate of healing when compared with that of placebo.
Patients and Methods The trial was conducted simultaneously in the hospital centres listed and coordinated by the clinical research group of Smith Kline and French Laboratories. Patients entering the trial were aged sixteen and over, with symptoms of proven duodenal ulceration, who had not responded to conventional medi'Participants: L. R. CELESTIN (FrenchayHospital,Bristol); V.HARVEY (Gloucester Royal Infirmary); J. H. B. SAUNDERS, K. G. WORMSLEY (Ninewells Hospital, Dundee); J. A. H. FORREST, R. F. A. LOGAN, D. 1. C. SHEARMAN (Royal Infirmary, Edinburgh); D. FERMONT, S. J. HAGGlE, J. H. WYLLIE (University College Hospital, London); M. ALBINus, M. H. THOMPSON, C. W. VENABLES (RoyalVictoria Infirmary, Newcastle); W. L. BURLAND, W. A. M. DUNCAN, B. W. HAWKINS, P. C. SHARPE (Smith Kline and French Laboratories, Welwyn Garden City, Hertfordshire). 7939
cal treatment, and in whom surgery was regarded as the only alternative treatment. Patients in whom evidence of renal, hepatic, allergic, cardiac, or respiratory diseases was strong and those receiving chronic medication for these or other conditions were excluded from the study. So also were pregnant or lactating patients, patients in whom surgery for peptic ulceration had been previously performed, other than the simple repair of a perforation, and patients who had significant and unexplained biochemical abnormalities on routine laboratory testing of blood and urine before entry. These included hsemoglobin concentration, red and white blood-cell indices, platelet and reticulocyte counts, plasma-electrolytes, serum-transarninases, serum-alkaline-phosphatase, plasma-ereatinine, tests of thyroid function, microscopy of urine, and tests for proteinuria and glycosuria. Those patients meeting the criteria and consenting to enter the study underwent endoscopy to confirm the presence of a duodenal ulcer within 4 days of being randomly allocated to treatment with metiamide or placebo. AU treatments other than antacid were withdrawn during the trial. Treatment in the first phase of the trial consisted of rnetiamide 200 mg (1 tablet) taken immediately after the three main meals and 400 mg (2 tablets) at bedtime, or placebo, identical in taste and appearance, containing lactose. Treatment lasted 4 weeks. In the second phase of the study the dose of rnetiamide was increased to 300 mg (2 tablets) three times a day immediately after meals and 400 mg (2 tablets) at bedtime, and the placebo therapy was increased proponionately. Random allocation of patients to metiamide or placebo treatment was continued. Each patient was given a supply of unmarked 'Rennie' antacid tablets (specially prepared by Nicholas Research Laboratories) with instructions to take these as often as necessary to relieve pain/indigestion. Each patient was asked to complete a diary card twice daily, recording his daytime and nocturnal pain and antacid consumption. Dietary advice was limited to a suggestion that foods causing discomfort should be avoided. Diary cards were returned each week and reviewed. Patients were seen, interviewed, and examined at weekly intervals. Unused test medicines and antacids were counted and the laboratory tests repeated. Endoscopy was repeated within 48 hours of completion of treatment in each case by the same operator using the same instruments and technique as used for the pre-treatment examination. The presence of ulceration and the severity and extent of duodenitis (a visual assessment of presumed inflammation of the duodenum) were recorded by a scored system. Laboratory tests were repeated a week after the completion of treatment. Results were analysed using the test to assess healing and effect on duodenitis and for pre-trial comparison of severity of pain in the treatment groups. AU other results were
"1:
780
T HE LANCET, OCTOBE R
compared using the anal ysis of vari ance with comparison of means or individual observations using the t test.
Results Seventy -six pat ients met the criteria for entry into the trial. T went y-one received metiamide 1 g daily, seventeen received 1· 3 g daily, and th irt y-eight received placebo. Seven pat ients were withdrawn from the trial before completing 4 weeks' treatment, five had rece ived placebo, and two metiamide. Of the five pat ients receiving placebo who were withdrawn, four had worsening symptoms warranting a chan ge in treatment and one had influenza. One pat ient receiving metiamide spontaneously stopped treatment because of headaches, and one was withdrawn because of influenzal illness associated with abnormal liver-funct ion tests, subsequently attributed to biliary disease. One more patient receiving placebo completed 4 weeks' treatment but did not have a second endoscopy and was not included in the anal ysis TABL E I-
Trea tme nt
PAT IENTS COM PL ET ING THE STUDY
M
F
Metiamidel gdaily 14 Metia midel -3 g d aily 14 Placebo 25
7 I 7
Mean d uration Mean durat ion Mean age of ulcer disease of current relapse (mon ths) (yr ) (yr) 8 ·8 10·3 9·0
40·3 42·7 47-7
4·3 4·0 3·2
TABLE II- RE SUL T S Of ENDOS COP IC EXAMINATION IN ALL PATIE NTS AT 4 WEEKS
Duodenal ulcera tion T reatment Metiamide I g daily Metiamide 1·3 gdai ly Placebo
Duodenitis
Healed
Not healed
Improved
13 (62%) 11 ( 73%) 8 (2 5%)
8
10
10
I
4
8
6
1
24
7
23
2
Not improved Never pre sent
of results. The results in the sixty-eight patients satisfac torily completing the tr ial were analysed; twenty-one received metiamide 1 g daily, fifteen received metiamide 1·3 g daily; and thirty-two received placebo (table I). There were no significant differences among the three group s for age, sex, duration of peptic-ulcer disease, or the duration of the current relapse. Nor were there significant differences in the frequency and severity of daytime pa in in the week before trea tment. However, fewer patients in the placebo-treated group reported nocturnal pain during the week before tr eatm ent (1'< 0·01).
Ulcer H ealing and Duodenit is Th ere was complete healing of ulcer s in 62% of metiarnide-treated patients at the 1 g dose and in 73% at the 1·3 g dose, whilst only 25% of those on placebo therapy healed (table II ). These differences were significant (p
TREATMENT OF DUODENAL ULCER BY METIAMIDE A Multicentre Trial"
Summary
In a multicentre double-blind trial 68 patients with endoscopically confirmed duodenal ulceration received metiamide (36 patients) or placebo (32 patients) for four weeks. Healing of doudenal ulcers was significantly increased in patients receiving metiamide (67%) compared with those on placebo (25%). There was also an associated significant decrease in daytime pain and antacid consumption in those on metiamide. Introduction
BURIMAMIDE was the first Hj-receptor antagonist to be evaluated in man and shown to inhibit gastric-acid secretion. I 2 Metiamide succeeded burimamide and was the first histamine H 2-receptor antagonist to be evaluated clinically. It inhibits resting and stimulated gastric-acid and pepsin secretion.v !" Treatment with metiamide is reported to be associated with relief. from the pain of duodenal ulceration and a reduction in antacid consumption.!' and an open study suggested that its administration was followed by a high rate of healing in endoscopically confirmed duodenal ulcers.P To substantiate these initial findings, a multicentre endoscopically monitored double-blind trial was undertaken to assess whether its administration would increase the rate of healing when compared with that of placebo.
Patients and Methods The trial was conducted simultaneously in the hospital centres listed and coordinated by the clinical research group of Smith Kline and French Laboratories. Patients entering the trial were aged sixteen and over, with symptoms of proven duodenal ulceration, who had not responded to conventional medi'Participants: L. R. CELESTIN (FrenchayHospital,Bristol); V.HARVEY (Gloucester Royal Infirmary); J. H. B. SAUNDERS, K. G. WORMSLEY (Ninewells Hospital, Dundee); J. A. H. FORREST, R. F. A. LOGAN, D. 1. C. SHEARMAN (Royal Infirmary, Edinburgh); D. FERMONT, S. J. HAGGlE, J. H. WYLLIE (University College Hospital, London); M. ALBINus, M. H. THOMPSON, C. W. VENABLES (RoyalVictoria Infirmary, Newcastle); W. L. BURLAND, W. A. M. DUNCAN, B. W. HAWKINS, P. C. SHARPE (Smith Kline and French Laboratories, Welwyn Garden City, Hertfordshire). 7939
cal treatment, and in whom surgery was regarded as the only alternative treatment. Patients in whom evidence of renal, hepatic, allergic, cardiac, or respiratory diseases was strong and those receiving chronic medication for these or other conditions were excluded from the study. So also were pregnant or lactating patients, patients in whom surgery for peptic ulceration had been previously performed, other than the simple repair of a perforation, and patients who had significant and unexplained biochemical abnormalities on routine laboratory testing of blood and urine before entry. These included hsemoglobin concentration, red and white blood-cell indices, platelet and reticulocyte counts, plasma-electrolytes, serum-transarninases, serum-alkaline-phosphatase, plasma-ereatinine, tests of thyroid function, microscopy of urine, and tests for proteinuria and glycosuria. Those patients meeting the criteria and consenting to enter the study underwent endoscopy to confirm the presence of a duodenal ulcer within 4 days of being randomly allocated to treatment with metiamide or placebo. AU treatments other than antacid were withdrawn during the trial. Treatment in the first phase of the trial consisted of rnetiamide 200 mg (1 tablet) taken immediately after the three main meals and 400 mg (2 tablets) at bedtime, or placebo, identical in taste and appearance, containing lactose. Treatment lasted 4 weeks. In the second phase of the study the dose of rnetiamide was increased to 300 mg (2 tablets) three times a day immediately after meals and 400 mg (2 tablets) at bedtime, and the placebo therapy was increased proponionately. Random allocation of patients to metiamide or placebo treatment was continued. Each patient was given a supply of unmarked 'Rennie' antacid tablets (specially prepared by Nicholas Research Laboratories) with instructions to take these as often as necessary to relieve pain/indigestion. Each patient was asked to complete a diary card twice daily, recording his daytime and nocturnal pain and antacid consumption. Dietary advice was limited to a suggestion that foods causing discomfort should be avoided. Diary cards were returned each week and reviewed. Patients were seen, interviewed, and examined at weekly intervals. Unused test medicines and antacids were counted and the laboratory tests repeated. Endoscopy was repeated within 48 hours of completion of treatment in each case by the same operator using the same instruments and technique as used for the pre-treatment examination. The presence of ulceration and the severity and extent of duodenitis (a visual assessment of presumed inflammation of the duodenum) were recorded by a scored system. Laboratory tests were repeated a week after the completion of treatment. Results were analysed using the test to assess healing and effect on duodenitis and for pre-trial comparison of severity of pain in the treatment groups. AU other results were
"1:
780
T HE LANCET, OCTOBE R
compared using the anal ysis of vari ance with comparison of means or individual observations using the t test.
Results Seventy -six pat ients met the criteria for entry into the trial. T went y-one received metiamide 1 g daily, seventeen received 1· 3 g daily, and th irt y-eight received placebo. Seven pat ients were withdrawn from the trial before completing 4 weeks' treatment, five had rece ived placebo, and two metiamide. Of the five pat ients receiving placebo who were withdrawn, four had worsening symptoms warranting a chan ge in treatment and one had influenza. One pat ient receiving metiamide spontaneously stopped treatment because of headaches, and one was withdrawn because of influenzal illness associated with abnormal liver-funct ion tests, subsequently attributed to biliary disease. One more patient receiving placebo completed 4 weeks' treatment but did not have a second endoscopy and was not included in the anal ysis TABL E I-
Trea tme nt
PAT IENTS COM PL ET ING THE STUDY
M
F
Metiamidel gdaily 14 Metia midel -3 g d aily 14 Placebo 25
7 I 7
Mean d uration Mean durat ion Mean age of ulcer disease of current relapse (mon ths) (yr ) (yr) 8 ·8 10·3 9·0
40·3 42·7 47-7
4·3 4·0 3·2
TABLE II- RE SUL T S Of ENDOS COP IC EXAMINATION IN ALL PATIE NTS AT 4 WEEKS
Duodenal ulcera tion T reatment Metiamide I g daily Metiamide 1·3 gdai ly Placebo
Duodenitis
Healed
Not healed
Improved
13 (62%) 11 ( 73%) 8 (2 5%)
8
10
10
I
4
8
6
1
24
7
23
2
Not improved Never pre sent
of results. The results in the sixty-eight patients satisfac torily completing the tr ial were analysed; twenty-one received metiamide 1 g daily, fifteen received metiamide 1·3 g daily; and thirty-two received placebo (table I). There were no significant differences among the three group s for age, sex, duration of peptic-ulcer disease, or the duration of the current relapse. Nor were there significant differences in the frequency and severity of daytime pa in in the week before trea tment. However, fewer patients in the placebo-treated group reported nocturnal pain during the week before tr eatm ent (1'< 0·01).
Ulcer H ealing and Duodenit is Th ere was complete healing of ulcer s in 62% of metiarnide-treated patients at the 1 g dose and in 73% at the 1·3 g dose, whilst only 25% of those on placebo therapy healed (table II ). These differences were significant (p
