One-week low-dose triple therapy for Helicobacter pylori is sufficient for relief from symptoms and healing of duodenal ulcers

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1 Aliment Pharmacol Ther 1997; 11: One-week low-dose triple therapy for Helicobacter pylori is sufficient for relief from symptoms and healing of duodenal ulcers J. LABENZ*, J.-P. IDSTRO M, B. TILLENBURG*, U. PEITZ*, R. J. ADAMEK &G.BO RSCH* *Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany; Astra Ha ssle AB, Mo lndal, Sweden; and Department of Medicine, St Josef Hospital, Ruhr University of Bochum, Bochum, Germany Accepted for publication 9 July 1996 SUMMARY Aim: To test the hypothesis that 1-week low-dose triple therapy for H. pylori is sufficient for relief from dyspeptic symptoms and healing of duodenal ulcers. Methods: Fifty-nine out-patients with duodenal ulcers and positive rapid urease test participated in this randomized, double-blind, two-centre study. All patients were treated for 1 week with omeprazole 20 mg b.d., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. In a double-blind fashion, patients were then randomly treated for another 3 weeks with either omeprazole 20 mg once daily or an identical-looking placebo. Patients were investigated endoscopically before treatment for H. pylori, after 2 weeks and after 4 weeks. H. pylori infection was assessed by a C-urea breath test at the time of enrolment and 4 weeks after cessation of any study medication. Results: Fifty-two patients were included in the all patients treated analysis of efficacy. The overall H. pylori cure rate was 96% (95% CI %), with no difference between the treatment groups. After 2 weeks duodenal ulcer healing was confirmed in 91% (95% CI %) of patients treated with omeprazole and in 76% (95% CI 60 91%) in the placebo group (P 0.14). After 4 weeks all ulcers had healed. Relief from dyspeptic symptoms and adverse events (13.8 and 16.7%) did not differ between the treatment groups. Conclusions: One-week low-dose triple therapy consisting of omeprazole, clarithromycin and metronidazole is a highly effective and well-tolerated approach to the cure of H. pylori infection in patients with a duodenal ulcer. Our data suggest that continuation of antisecretory drug therapy beyond anti-h. pylori therapy is actually excessive regarding relief from dyspeptic symptoms and healing of duodenal ulcers. INTRODUCTION Almost all duodenal ulcer patients are infected with Helicobacter pylori which is probably the most important factor in the pathogenesis of this chronic relapsing disease. This statement is supported by the overwhelming evidence derived from intervention trials. It has been shown that successful treatment of the bacteria acceler- Correspondence to: Dr J. Labenz, Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Moltkestraβe 61, D Essen, Germany. ates duodenal ulcer healing, heals duodenal ulcers refractory to antisecretory drugs, prevents ulcer recurrences and, most probably, ulcer complications as well, and leads to a significant improvement of the quality of life of duodenal ulcer patients. Moreover, H. pylori treatment is probably the most economic approach to the long-term management of duodenal ulcer disease. Thus, treating H. pylori infection is now strongly recommended in all duodenal ulcer patients whether on first presentation or with relapsing ulcers. The optimal treatment of H. pylori infection, however, is still a matter of debate Blackwell Science Ltd 89

2 90 J. LABENZ et al. Since the first preliminary report in 1993, some pilot studies have indicated that a 1-week low-dose triple therapy might be a reasonable approach to the cure of H. pylori infection. In the vast majority of Helicobacter treatment trials, ulcer patients were treated with antisecretory drugs up to the follow-up investigation 4 weeks after cessation of anti-h. pylori therapy. Short-term ulcer healing studies in ulcer patients treated for H. pylori are, unfortunately, still very rare. The present study was designed to test the hypothesis that continuation of antisecretory drugs after a 1-week treatment with omeprazole, clarithromycin and metronidazole is superfluous regarding relief from dyspeptic symptoms and healing of duodenal ulcers. MATERIALS AND METHODS The study was designed as a double-blind, randomized, two-centre study with two parallel groups. The study was conducted according to the Declaration of Helsinki. The protocol was approved by the Ethical Committee of the University of Essen. Out-patients with a duodenal ulcer diameter of 5 mm, a positive rapid urease test (HUT; Astra Chemicals, Wedel, Germany), aged 18 years, who had given written informed consent, were eligible for the study. Patients with concomitant oesophagitis, an additional gastric ulcer, an upper gastrointestinal malignancy, pre-treatment with proton pump inhibitors, antibiotics or bismuth salts during the preceding 4 weeks, in pregnancy or lactation, with concurrent severe diseases, undergoing treatment with potentially ulcerogenic drugs (aspirin or non-steroidal anti-inflammatory drugs), suspected poor compliance or known allergy to one of the study drugs were excluded. All patients were initially treated for 1 week with omeprazole 20 mg b.d., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. before meals. The anti-h. pylori therapy was followed by a 3-week course with omeprazole 20 mg once daily in the morning or an identical-looking placebo. Compliance ( 90% intake of the study drugs) was checked by counting the returned pills after 1 and 4 weeks. At entry, one antrum and one body biopsy was taken and assessed for H. pylori infection by a highly accurate biopsy urease test that was read after 1, 3, 6 and 24 h, respectively., A C-urea breath test (100 mg Curea; H. pylori-positive: excess δ 5 CO ) was performed before Helicobacter treatment and at least 4 weeks (day 35 7 days) after cessation of any medication. The C-urea breath test as used in this study has been previously validated in the context of large international multicentre trials for H. pylori (reference: histology of antrum and corpus biopsies). The test proved to be highly sensitive and specific (Astra Ha ssle, data on file). Before entering the trial, after the end of Helicobacter treatment and after 2 and 4 weeks, dyspeptic symptoms (epigastric pain or discomfort, regurgitation, heartburn, nausea, vomiting, burping or belching) were recorded and scored (none, mild, moderate, severe) by a structured interview. Ulcer healing was assessed endoscopically 2 and 4 weeks after the start of treatment. In 30 patients (centre 1), pre-treatment H. pylori isolates were cultured under standard conditions. The susceptibility of H. pylori to metronidazole and clarithromycin was assessed by the E test. Two populations were pre-defined for the analysis of the efficacy data, all patients treated and per protocol. Patients with a negative C-urea breath test at entry and patients without a post-treatment H. pylori status were excluded from the all patients treated analysis. Patients with insufficient compliance ( 90% intake of the study drugs either during anti-h. pylori therapy or the healing phase) were excluded from the per protocol analysis. Patients eligible for adverse event evaluation were those given at least one dose of the study drug and for whom subsequent study information was available. The treatment groups were compared by the χ test with respect to ulcer healing after 2 and 4 weeks and cure of the infection. Ninety-five per cent confidence intervals were calculated for each of the treatment Table 1. Demographic and clinical characteristics of the study patients included in the all patients treated analysis (OCM-P, 1 week triple therapy consisting of omeprazole, clarithromycin and metronidazole followed by 3 weeks of placebo; OCM-O, 1-week triple therapy followed by 3 weeks of omeprazole 20 mg once daily) OCM-P OCM-O (n 29) (n 23) Mean age (s.d.) (years) 50 (15) 50 (15) Male female, n Smoking Past (%) Current (%) History of duodenal ulcer, n Mean ulcer size s.d. (mm) 10.5 (3.2) 8.1 (2.0)

3 LOW-DOSE TRIPLE THERAPY FOR H. PYLORI 91 differences. The symptom scores were analysed using Wilcoxon s rank sum test. The mean ulcer size before enrolment into the study was compared using an unpaired t-test. Additionally, a logistic regression was performed with treatment group, age, smoking habits and drug compliance as explanatory variables, and with cure of H. pylori infection as the dependent variable. RESULTS Fifty-nine patients were randomized into the study. Of the patients included, four had a negative breath test at entry despite a positive reaction with the rapid urease (HUT) test. During the study three patients dropped out, one because of an adverse event and two patients were lost to follow-up (post-treatment urea breath test). Thus, 52 patients were included in the all patients treated analysis. Further, 11 patients (placebo group, n 9; omeprazole group, n 2) had insufficient compliance, one during anti-h. pylori therapy and 10 patients during the healing phase. Therefore, the per protocol analysis comprised 41 patients. Besides a significant difference of the mean ulcer size (all patients treated, P 0.002; per protocol, P 0.008), the two treatment groups had similar demographic and clinical characteristics (Table 1). Cure of H. pylori infection succeeded in 50 of 52 patients included in the all patients treated analysis, with no difference between treatment groups. After 2 weeks ulcer healing was more frequently observed in patients on omeprazole compared with the placebo group, lacking statistical significance (all patients treated, P 0.14; per protocol, P 0.07). Four weeks after start of treatment all ulcers had healed (Table 2). At entry all patients complained of epigastric pain or discomfort, respectively. The study groups did not Figure 1. Overall relief from dyspeptic symptoms over time (OCM-P, 1-week triple therapy consisting of omeprazole, clarithromycin and metronidazole followed by placebo over 3 weeks; OCM-O, 1-week triple therapy consisting of omeprazole, clarithromycin and metronidazole followed by omeprazole 20 mg once daily over 3 weeks). differ with regard to pain relief. The overall relief from dyspeptic symptoms over time is given in Figure 1. All of the 59 patients randomized into the study were eligible for adverse event evaluation. The rate of adverse events was 13.8% in the omeprazole group and 16.7% in the placebo group. Only one patient stopped the anti- H. pylori therapy due to adverse events (diarrhoea, mouth disorder and flatulence). All adverse events disappeared spontaneously. No serious adverse events were observed. Twenty-eight patients of centre 1 were included in the all patients treated analysis. In eight of these 28 patients the H. pylori strains isolated pre-therapeutically were resistant to metronidazole (minimal inhibitory concentration 32 µg ml). All strains proved to be susceptible to clarithromycin. H. pylori infection was cured in all Table 2. Cure of H. pylori infection and duodenal ulcer healing in patients treated with 1-week triple therapy consisting of omeprazole, clarithromycin and metronidazole followed by placebo (OCM-P) or omeprazole 20 mg once daily (OCM-O) for 3 weeks. The 95 % confidence intervals are given in parentheses All patients treated Pre protocol OCM-P OCM-O OCM-P OCM-O (n 29) (n 23) P (n 20) (n 21) P H. pylori eradication (%) (90 100) (87 100) (86 100) (87 100) Ulcer healing after 2 weeks (%) (69 91) (80 100) (56 94) (86 100) Ulcer healing after 4 weeks (%)

4 92 J. LABENZ et al. patients harbouring metronidazole-resistant strains and in 19 of 20 patients infected with metronidazole-susceptible strains. Among the prognostic factors on the probability of having H. pylori infection cured, there was a trend toward a higher cure rate in patients with lower age, lacking statistical significance (P 0.08, for both the all patients treated and the per protocol analysis). Smoking habits were not related to the outcome. DISCUSSION This double-blind, randomized, placebo-controlled study has shown that in patients with duodenal ulcers 1-week treatment with omeprazole 20 mg, clarithromycin 250 mg and metronidazole 400 mg given twice daily is sufficient for relief from dyspeptic symptoms and for healing of ulcers within 4 weeks. Two recently published randomized studies have suggested that a 1-week treatment with bismuth, tetracycline and metronidazole will heal almost all duodenal and gastric ulcers associated with H. pylori infection within 5 8 weeks., In both studies, however, self-medication with antacids was allowed which is clearly a confounding variable. Another study concludes that antibiotics alone (amoxycillin, metronidazole and clarithromycin) heal the majority of duodenal ulcers and is superior to placebo. We have shown that the healing of ulcers depends on the efficacy of Helicobacter treatment. Non-steroidal anti-inflammatory drugs (NSAIDs) may also adversely affect the healing process. The present study is the first trial to investigate shortterm ulcer healing with and without antisecretory therapy beyond a highly effective Helicobacter treatment. Considering the per protocol analysis, it appears that omeprazole accelerates duodenal ulcer healing. It seems likely that the difference in ulcer healing rates observed (20%) would become significant with more patients in the study, although the mean ulcer size was significantly larger in the placebo group. Considering the literature, there is now strong evidence that cure of H. pylori infection is a valid surrogate and can be used as the primary efficacy end-point for reduced duodenal ulcer and gastric ulcer recurrence in patients with active ulcers. Thus, it is to be expected that the cure of infection obtained by low-dose triple therapy as used in this study will effectively prevent ulcer relapse. During the past 3 years several pilot and controlled studies suggested that 1-week triple therapy consisting of omeprazole 20 mg once daily or b.d., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. or tinidazole 500 mg b.d. may cure H. pylori infection in 90% of patients., These encouraging results have been confirmed by our controlled study. Moreover, we have shown that treatment with omeprazole after stopping Helicobacter treatment does not improve the cure rate. Although comparative trials are not yet available, these novel treatment options seem to be as effective as conventional triple-therapy regimens consisting of bismuth, metronidazole and tetracycline combined with an antisecretory drug, and superior to dual therapy with omeprazole and amoxycillin or clarithromycin.,, Resistance of H. pylori to antimicrobials, in particular nitroimidazoles, may adversely affect the outcome of Helicobacter treatment., Although we performed pretherapeutic testing of bacterial susceptibility in only 28 of 52 patients included in the all patients treated analysis, the present study gives an indication that resistance to metronidazole does not have a substantial impact upon the cure rate. However, this issue remains controversial.,, An explorative analysis of our data suggested that patient s age might be a predictor of the treatment success. Recent data also indicated that smoking and pre-treatment with H -receptor antagonists may have some negative effects on the efficacy of lowdose triple therapy. Overall, the consistently high cure rates obtained in many independent studies clearly indicate that all predictors of outcome mentioned above are probably clinically insignificant. In conclusion, 1-week triple therapy consisting of omeprazole 20 mg b.d., clarithromycin 250 mg b.d. and metronidazole 400 mg b.d. is a simple, convenient and highly effective therapy regimen for H. pylori-associated duodenal ulcers. Three tablets given twice daily for 1 week are sufficient to assure rapid symptom relief, ulcer healing and cure of the ulcer diathesis in more than 90% of afflicted patients. Since our study did not include patients with ulcer complications and concurrent treatment with aspirin or NSAIDs, we recommend prescribing antisecretory drugs after Helicobacter treatment until well-designed studies confirm our findings in these subgroups of ulcer patients. ACKNOWLEDGEMENT The work was supported by a grant from AB Astra Ha ssle, Sweden.

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