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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

Aim

: To investigate the efficacy of two omeprazole triple therapies for the eradication of Helicobacter pylori, ulcer healing and ulcer relapse during a 6-month treatment-free period in patients with active duodenal ulcer.

Methods

: This was a double-blind, randomized study in 15 centres across Canada. Patients (n = 149) were randomized to omeprazole 20 mg once daily (O) or one of two 1-week b.d. eradication regimens: omeprazole 20 mg, metronidazole 400 mg and clarithromycin 250 mg (OMC) or omeprazole 20 mg, amoxycillin 1000 mg and clarithromycin 500 mg (OAC). All patients were treated for three additional weeks with omeprazole 20 mg once daily. Ulcer healing was assessed by endoscopy after 4 weeks of study therapy. H. pylori eradication was determined by a 13C-urea breath test and histology, performed at pre-entry, at 4 weeks after the end of all therapy and at 6 months.

Results

: The intention-to-treat (intention-to-treat) analysis contained 146 patients and the per protocol (per protocol) analysis, 114 patients. The eradication rates were (intention-to-treat/per protocol): OMC—85% and 92%, OAC—78% and 87% and O—0% (O). Ulcer healing (intention-to-treat) was greater than 90% in all groups. The differences in the eradication and relapse rates between O vs. OMC and O vs. OAC were statistically significant (all, < 0.001). Treatment was well tolerated and compliance was high.

Conclusion

: The OMC and OAC 1-week treatment regimens are safe and effective for eradication, healing and the prevention of relapse in duodenal ulcer patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

There is unequivocal evidence that Helicobacter pylori infection is the most important cause of chronic active (type B) gastritis and peptic ulcer disease and that eradication of this organism reduces the relapse rate of peptic ulceration.1[2][3][4][5][6]–7 There is consensus that H. pylori infection should be treated in all patients with acute duodenal or gastric ulcers and in patients with a history of peptic ulcer disease who are on maintenance therapy for control of their disease.3, 8[9]–10

In a previous study (MACH1) the triple therapies with the highest eradication rates were: omeprazole (20 mg), clarithromycin (500 mg or 250 mg) combined with either amoxycillin (1000 mg)—OAC or metronidazole (400 mg)—OMC.11 As the MACH1 study was done in patients with duodenal ulcer disease, active or in remission, the DU-MACH was performed to investigate the efficacy of these treatment regimens in patients with active duodenal ulcer. The aims of the study were to compare OAC and OMC to omeprazole alone, with regard to the eradication of H. pylori, ulcer healing, ulcer relapse, gastritis patterns and symptom relief and to document the frequency of adverse events.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

The study was a double-blind randomized multicentre study with three parallel groups, performed in 15 centres across Canada. The study was approved by the research ethics committee of each participating centre and informed written consent was obtained from each patient. Patients older than 18 years with an endoscopically proven duodenal ulcer (≥ 5 mm in diameter) testing positive for H. pylori were eligible.

The following exclusion criteria were used: patients with bleeding ulcers or ulcers other than in the duodenum, gastro-oesophageal reflux disease requiring antisecretory treatment, women lactating, pregnant or of childbearing potential without adequate contraception, contraindication to study drugs, the use of amoxycillin, metronidazole or clarithromycin during one month before the study, regular use of NSAIDs, including ASAs, severe concurrent disease, malignant disease and substance abuse. Patients were allowed to have had one previous attempt to eradicate H. pylori.

Patients were randomized to one of the following 1-week therapies: OMC (omeprazole 20 mg, metronidazole 400 mg and clarithromycin 250 mg, all b.d.), OAC (omeprazole 20 mg, amoxycillin 1000 mg and clarithromycin 500 mg all b.d.) or O (omeprazole 20 mg once daily). All patients received omeprazole 20 mg once daily for an additional 3 weeks. Patient compliance was checked by counting the returned study medication.

Endoscopy with biopsy was performed at entry and 4 weeks and 6 months post-therapy. Healing was assessed by endoscopy after 4 weeks of treatment. Patients with an unhealed ulcer at that time were allowed to continue in the study without treatment, but they were withdrawn from the study if they still had an ulcer at the follow-up endoscopy 4 weeks post-therapy.

To be eligible for the study, the patient had to have a positive screening test (the standard test employed was the HUT; Astra Chemicals GmbH, Germany). To be included in the intention-to-treat analysis (intention-to-treat) the infection had to be confirmed by either or both of 13C-urea breath test11 or the histology. In the case of protocol violations which were likely to influence the response variable, or its assessment, patients were excluded from the per protocol (per protocol) analysis. The eradication and relapse rates were estimated with 95% confidence intervals. Treatment groups were compared with Fisher's exact test.

Post-therapy, a patient was considered H. pylori positive if the histology or the UBT or both were positive. For histology, biopsies were taken: three from the antrum, ≈ 1–2 cm proximal to the pylorus and two from the body, ≈ 10 cm from cardia along the large curvature. Biopsies were fixed in 10% formalin and stained with Haematoxylin–eosin and by the Giemsa method. They were assessed blindly by a central pathologist. Evaluation was also done for gastritis parameters according to the Sydney system.12

At inclusion and at each visit, the severity of epigastric pain, heartburn and overall dyspeptic symptoms during the 2 days prior to the visit were recorded. The symptoms were graded on a four-point scale as: `none', `mild' (awareness of sign or symptom, but easily tolerated), `moderate' (discomfort sufficient to cause interference with normal activities) or `severe' (incapacitating, with inability to perform normal activities). If symptoms suggestive of an ulcer relapse occurred, an endoscopy was performed. If a duodenal ulcer or duodenal erosions were detected, the patient was classified as having had a relapse and was withdrawn from the study, otherwise the patient was allowed to continue in the study. Standard laboratory screening was performed at entry and at 1 and 4 weeks after randomization.

The sample size calculation was based on an eradication rate in the omeprazole/antibiotic groups of 90%, and 5% in the omeprazole monotherapy arm. In order to have a 95% confidence interval of the true difference in eradication rates estimated as ±13% there was a need for 41 evaluable patients on each arm of the study. Allowing for a 15% drop-out rate, the required sample size was 145 patients.

The possible influence of prognostic factors (therapy, previous eradication attempt, age, sex and smoking) on eradication and on relapse was tested using logistic regression analysis.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

One-hundred and forty-nine patients were randomised to this study. Fifteen centres recruited 10 patients each on average (range 2–26). One-hundred and forty-six patients were included in the intention-to-treat analysis. Figure 1 presents the disposition of all patients. The number of excluded patients was similar for all treatment groups. Baseline characteristics are as listed in Table 1.

image

Figure 1. . Disposition of all patients. *Eleven patients were excluded from the per protocol eradication analysis because their H. pylori status was assessed before 28 days after the end of all study therapy. Six of these cases were in the active groups in the range of day 23–27.

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Table 1.  . Baseline characteristics (intention-to-treat) Thumbnail image of

During the first week of therapy, 98% of the patients took 75% or more of each study drug. No patient reported compliance below 75% but three patients (OMC, n = 2; OAC, n = 1) had unknown compliance. During weeks 2–4, 95% of the patients took 75% or more of the open omeprazole treatment. Seven patients took <75% of the study drug or had unknown compliance (OAC, n = 3; OMC, n = 2; O, n = 2).

In comparing the results of the 13C-UBT and histology at entry, at 4 weeks and 6 months after therapy, assuming that all histology results are correct, the sensitivity of the UBT was estimated to be 99%, 96% and 97%. Conversely, taking the 13C-UBT results as true, the sensitivity of histology was 99%, 96% and 97%, respectively. No patient changed H. pylori status (from negative to positive) during the 6 month follow-up period. The urea breath test and histological assessments did not agree for two patients at entry, for three patients at the 4-week assessment, and for two patients at 6 months.

For both the intention-to-treat and per protocol analysis the difference in eradication rates between OMC vs. O and between OAC vs. O was statistically significant (< 0.001) (Table 2). The difference between OMC and OAC was not statistically significant. Three of the six confirmed H. pylori positive failures on OAC therapy occurred at one centre (nine randomised patients in total).

Table 2.  . Helicobacter pylori eradication rates: intention-to-treat and per protocol estimates and 95% confidence intervals Thumbnail image of

Logistic regression analysis showed an association (< 0.02) between a previous eradication attempt and failure to eradicate. Compliance was not included in the analysis since all patients took >75% of the 1-week medications and only those patients receiving active eradication treatment were included, as no patient receiving omeprazole alone had a cure of their infection. For the ulcer healing logistic regression analysis, statistical significance was reached for eradication outcome (< 0.001), indicating that those patients who had a successful eradication had a lower probability of relapse.

Ulcer healing rate, as assessed at the end of all study treatments on an intention-to-treat basis, was 94% for the OMC group, 92% for the OAC group and 90% for the omeprazole group. Only three patients, all in the omeprazole arm, had unhealed ulcers at 8 weeks.

In the intention-to-treat analysis, ulcer relapse was significantly less frequent (< 0.001) in patients treated with OMC (4 of 48, 8%) and OAC (6 of 50, 12%) compared to O (25 of 48, 52%). No patient had a symptomatic ulcer relapse without also having an active ulcer.

A life table analysis of the intention-to-treat remission rates is plotted in Figure 2. The per protocol relapse data gave similar results. Following healing, relapse rates were much higher (= 0.001) in the omeprazole group with 21 patients (44%) relapsing over the 6-month follow-up period compared to only two patients (4%) in the OMC group and four patients (8%) in the OAC group during the same period. The final H. pylori status was available for every patient who had an ulcer relapse, but not available for all patients classified as failures (including those not healed or discontinued). The follow-up status in these patients was: OMC (n = 4)—one negative, one positive and two unknown, OAC (n = 6) one negative, three positive and two unknown, O (n = 25)—23 positive (two not healed) and two unknown. When the OAC and OMC groups are combined regarding data for ulcer relapse vs. H. pylori status, the incidence of an ulcer relapse for those with a negative H. pylori status was 2.5% (2/80) and 36% (4/11) for those with a positive status.

image

Figure 2. . Proportion of patients in remission (intention-to-treat analysis).

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Histology

High levels of H. pylori colonization, inflammation and activity were seen at entry predominantly in antrum and less in corpus. Low grade antral atrophy and intestinal metaplasia were infrequent in the antrum and rare in the corpus. After therapy with OMC and OAC, the antral scores of activity, inflammation and epithelial degeneration rapidly improved in those patients in whom treatment was successful. Although 6-month data was not available for approximately one-third of the patients in the omeprazole treatment group (due to relapse and discontinuation), the scores of all the histological variables were largely unchanged. In the corpus H. pylori colonization, activity and inflammation decreased with successful eradication. For atrophy, lymphoid follicles in the lamina propria and intestinal metaplasia, there were no changes in any of the treatment groups (data not shown).

Symptoms

The number of patients with symptoms decreased in all treatment groups during therapy and improved up to 4 weeks with no differences between the treatment groups. After the treatment phase there was a clear trend for a higher severity of overall symptoms.

( Figure 3), epigastric pain and heartburn in patients in whom H. pylori was not successfully eradicated. As can seen in Figure 2, the proportion of patients who were withdrawn because of an ulcer relapse increased over time, especially at 3 to 6 months.

image

Figure 3. . Overall symptoms by eradication outcome at randomization and during 6 months follow-up.

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Safety

In general, all therapies were well tolerated. Three patients stopped the medication because of adverse events: OAC—one patient (anxiety, tremors, blood in urine), O—two patients (abdominal pain, hives). The overall reported frequency of adverse events was evenly distributed among the treatment groups. The five most common adverse events are listed in Table 3. Diarrhoea, including loose stools, and taste disturbance were most common in the OAC group.

Table 3.  .  Percentage of patients listed according to the five most commonly reported adverse events Thumbnail image of

A statistically significant (< 0.001) increase in ALAT and ASAT was seen at the end of the first week of treatment in the OMC group when compared to O alone. These increases were, in most cases, within the normal range and return to normal over the following 3 weeks.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

The results of this study confirm the high eradication rates of H. pylori, excellent tolerability and high patient compliance for both the OMC and the OAC treatment regimens.

The eradication rates for patients receiving the OMC regimen in this study (85% (intention-to-treat) and 92% (per protocol)) were slightly lower compared to those in the MACH 1 study (correspondingly, 90% and 94%), but similar to the MACH 2 (correspondingly, 87% and 91%) and GU-MACH studies (correspondingly, 86% and 93%).11, 13, 14 The resistance of H. pylori to antibiotics was not assessed in this study. However, the success rate of OMC was high, despite a known prevalence of metronidazole resistance in Canada which varies from 18 to 48%.15, 16 The results of the MACH 2 study support the efficacy of OMC, as it was shown that metronidazole resistance can be partially overcome by adding omeprazole to metronidazole and clarithromycin.13 In this study, the eradication rate for the OAC regimen was slightly lower at 78% (intention-to-treat) and 87% (per protocol) than was previously found in the MACH 1 (91% and 98%, respectively) and MACH 2 study (94% and 95%, respectively), but similar to those reported in the GU-MACH study (79% and 83%, respectively) and to those reported from a meta-analysis by Unge.11, 13, 14, 17 He found 84–96% eradication for omeprazole in combination with clarithromycin and either a nitroimidazole or amoxycillin. Clarithromycin resistance may influence the efficacy of the OAC regimen, with reported decreases in efficacy from 92% in susceptible strains to 50% in resistance strains.18 However, the reported prevalence of clarithromycin resistance in Canada is low (< 3%), and is therefore unlikely to contribute significantly to any decrease in the eradication rate.15, 19 In this study, 50% of the OAC treatment failures arose from one centre and the eradication rate was slightly higher (OAC = 83%, intention-to-treat) when the data was analysed excluding this centre. In contrast to the MACH 2 study, in this study a previous eradication attempt significantly decreased the chance of a successful cure. These patients accounted for only 10% of this study population, resulting in small numbers in the logistic regression analysis (eradication failure/total with a previous attempt: OAC = 3/5, OMC = 1/2, O = 5/5).

We speculate that there are two possible explanations for the slightly lower eradication rates of the OMC and OAC regimens compared to the MACH 1 study. First, acid suppression redistributes H. pylori, with less bacteria seen in the antrum and more in the body. The presumption is that few bacteria which remain in the stomach after the 1-week eradication regimen would normally be killed by acid when suppression is stopped. Continuing acid suppression may interfere with such a `clean-up', allowing H. pylori to survive and re-colonize. Secondly, acid suppression may increase the number of bacteria in the antral/body transitional zone, an area in animal models where H. pylori can escape eradication.20

This is the first double-blind randomized study in which the MACH OMC and OAC regimens have been compared to omeprazole alone in patients with acute duodenal ulcer disease. Ulcer healing was high for all treatment groups, with a slightly greater rate in the antibiotic groups. This is in keeping with studies which have shown that adding antibiotics to acid-suppressive therapy increases the speed of ulcer healing.21 There could also be a beneficial effect of the first week of b.d. omeprazole in the active treatment groups vs. the omeprazole alone group (o.d.). It may not be necessary to add 3 weeks of omeprazole monotherapy following the 1-week eradication treatment. On the other hand, the continuation of acid suppression may ensure rapid ulcer healing and symptom relief. Our study confirms that cure of H. pylori infection is an adequate substitute end-point in acute duodenal ulcer studies, in that most relapses of ulcers are prevented.

The high sensitivity of the UBT, as used in this study, has also been documented in the MACH 2 study.13 Interestingly, no patient was positive at 6 months if their results were negative at the 1-month follow-up visit. The 11 patients excluded from the per protocol analysis, who were tested prior to the defined time period of 28 days, also had their status confirmed at the last visit. This supports a single test as being adequate for documenting eradication.22

A clear advantage of the omeprazole-based triple therapies is their rapid relief of symptoms in patients with acute duodenal ulcers. This will give the patient confidence in the therapy and is therefore likely to encourage compliance. In patients treated with the OMC or OAC regimens, in whom treatment was successful, no marked increase of symptoms occurred during follow-up compared to an increase (usually associated with ulcer relapse) in those patients who remained infected.

Diarrhoea, including loose stools, and taste disturbance were most frequent in patients treated with the OAC regimen, with loose stools most likely to be related to the intake of amoxycillin. One might have expected that taste disturbance would be more frequent when clarithromycin and metronidazole are used together; however, this does not appear to be the case, at least when the lower dose of clarithromycin (250 mg b.d.) is used as in the OMC regimen.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

The results from the DU-MACH study demonstrate that omeprazole triple therapies with OMC or OAC are well tolerated and highly effective for the eradication of H. pylori infection, ulcer healing and the prevention of relapse in duodenal ulcer patients. Ulcer relapse is infrequent after successful eradication of the H. pylori infection.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

This work has been previously published as an abstract in Gut 1997; 41: A103 and in Can J Gastroenterol 1998; 12(Suppl. A): 92A.

We would like to acknowledge the Canadian Study Group, listed here in alphabetical order: Marc Bradette, Quebec City; Naoki Chiba, Guelph; Alan Cockeram, Saint John; Brian Craig, Saint John; Chrystian Dallaire, Quebec City; Donald Daly, Montreal; Dan Dattani, Saskatoon; Alain Farley, Montreal; John Howard, London; Harsh Kapoor, Bridgewater; Des Leddin; Halifax; Robert Luton, London; Mario Millan; Edmonton; John Reddington, Edmonton; Franzjosef Schweiger, Moncton.

Dr van Zanten is the recipient of a clinical research scholar award form the Province on Nova Scotia, Canada. Financial support was provided by Astra Hässle, Mölndal, Sweden.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References
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