Esomeprazole is the first proton pump inhibitor to be developed as an optical isomer for the treatment of acid-related diseases.
Esomeprazole is the first proton pump inhibitor to be developed as an optical isomer for the treatment of acid-related diseases.
Four hundred and forty eight duodenal ulcer patients with Helicobacter pylori infection, confirmed by 13C-urea breath test (UBT), and no current ulcer, were randomised to double-blind treatment with esomeprazole 20 mg twice daily (b.d.) (n=224) or omeprazole 20 mg b.d. (n=224), in combination with amoxicillin 1 g b.d. and clarithromycin 500 mg b.d. for 1 week (EAC and OAC, respectively). A negative UBT at both 4 and 8 weeks after completing therapy indicated successful H. pylori eradication.
Intention-to-treat (ITT) analysis comprised 400 patients (EAC, n=204; OAC, n=196) and per protocol (PP) analysis 377 patients (EAC, n=192; OAC, n=185). Eradication rates (95% confidence intervals) for ITT and PP populations were: EAC, 90% (85–94%) and 91% (86–94%); OAC, 88% (82–92%) and 91% (86–95%). Between-group differences in eradication rates were not statistically significant. Both regimens were well tolerated, with an adverse event profile and frequency typical of proton pump inhibitor plus antibiotic combination therapy.
Esomeprazole-based triple therapy for 1 week is highly effective in eradicating H. pylori infection in duodenal ulcer disease, offers comparable efficacy to omeprazole-based therapy, and is well tolerated.
Unequivocal evidence supports the causal role of Helicobacter pylori in the pathogenesis of peptic ulcer disease.1 It is generally accepted that eradication of this organism not only cures the infection and causes a regression of the associated gastritis but also results in cure of the disease, as advocated by numerous management guidelines.2–6 World-wide, the recommended eradication approach is triple therapy, comprising an antisecretory agent plus two antibiotics given for 1 week. Triple therapy regimens including omeprazole, amoxicillin or metronidazole plus clarithromycin are widely accepted and used. When omeprazole is combined with amoxicillin and clarithromycin (at dosages of 1 g b.d. and 500 mg b.d., respectively), eradication rates in excess of 80% can be achieved in patients with both active and inactive pathology.7–10
Omeprazole, as with other available proton pump inhibitors, is a substituted benzimidazole which exists as a racemic mixture of the R- and S-isomers. Esomeprazole (Nexium) is the first proton pump inhibitor to be developed as an optical isomer. Early clinical studies have shown that both esomeprazole 40 mg and 20 mg achieve greater and more sustained acid control than omeprazole 20 mg, with a similar tolerability and safety profile.11 Moreover, esomeprazole shows a more rapid onset of acid-suppressant effect than omeprazole and less interindividual variation in acid control,11, 12 thereby providing greater predictability of response. To date, however, no study has evaluated the efficacy of esomeprazole, as part of a triple therapy regimen, for the eradication of H. pylori.
The aim of the present study was to compare the efficacy of both esomeprazole and omeprazole, in combination with amoxicillin and clarithromycin, for the eradication of H. pylori in patients with duodenal ulcer (duodenal ulcer) disease. A secondary objective was to evaluate the tolerability of esomeprazole as part of a triple therapy eradication regimen.
The study was a double-blind, randomised, parallel-group study conducted at 56 centres in Europe and Canada, performed according to both internationally accepted guidelines for clinical trials in Helicobacter pylori infection13 and the principles of the Declaration of Helsinki. The study protocol was approved by a local independent Ethics Committee for each centre prior to study commencement. Informed written consent was obtained from all patients.
Patients who were 18 years of age or older, with a history of at least one episode of endoscopically or radiologically documented duodenal ulcer disease and testing positive for H. pylori with a rapid Helicobacter urease test (HUT) were eligible for inclusion. Exclusion criteria included current duodenal, gastric, prepyloric or pyloric ulcer, complications of duodenal ulcer disease (e.g. pyloric stenosis), treatment with medication for all acid related symptoms and/or peptic ulcer disease, e.g. antacids/antisecretory drugs (any such treatment must be stopped at least 3 days before the UBT test at visit 1), history of oesophageal, gastric or duodenal surgery, pregnancy or lactation, inadequate contraception (applicable for women of childbearing potential), contraindications to study drugs, treatment with amoxicillin, clarithromycin or bismuth-containing drugs during the month preceding the study, severe concurrent disease, malignancy and substance abuse.
Concurrent treatment with drugs that might affect the efficacy and safety of study medication were also reasons for exclusion, as was regular use of nonsteroidal anti-inflammatory drugs (including aspirin at doses > 165 mg/day). Patients were permitted to have had one previous attempt at H. pylori eradication, provided this had occurred > 1 month prior to study inclusion.
Those patients meeting the inclusion criteria were randomised to either: EAC (esomeprazole 20 mg, amoxicillin 1 g and clarithromycin 500 mg, all twice daily [b.d.]) or OAC (omeprazole 20 mg, amoxicillin 1 g and clarithromycin 500 mg, all b.d.). Patients were instructed to take the three study medications together, once in the morning before breakfast and again in the evening 12 h later, for 7 days. Compliance was checked by counting unused returned study medication at the completion of treatment.
To be eligible for inclusion in the study, patients were required to demonstrate positive H. pylori infection as shown by a positive rapid urease test (HUT) of endoscopy biopsy samples from either the antrum or the corpus (two biopsy samples from each site was recommended but one sample was considered as sufficient). Endoscopy was performed within 7 days of the start of therapy. Infection was further confirmed by a 13C-urea breath test (UBT)7 before the start of therapy. The UBT was repeated at 4 and 8 weeks post-therapy for determination of H. pylori eradication. Only patients with a negative UBT result at both follow-up visits were considered to be H. pylori-negative.
The intensity of epigastric pain and heartburn was assessed at baseline, after completion of the study therapy and at 4 and 8 weeks post-therapy. Symptoms were graded on a 4-point scale: none; mild (aware of symptoms, but easily tolerated); moderate (discomfort sufficient to cause interference with normal activities); and severe (incapacitating, with inability to perform normal activities).
All spontaneously reported adverse events, as well as those elicited by open questioning or observed by the investigator, were recorded. Routine laboratory safety variables, including blood and urine parameters, were assessed before, during and at the end of the study.
The primary efficacy variable was H. pylori eradication. From previous studies it was assumed that eradication rates for both therapies would be at least 85%. With 170 patients in each treatment group the true eradication rate could be estimated as the observed rate ± 6%, using a two-sided 95% confidence interval (95% CI). Allowing for 15% nonevaluable patients, the planned sample size for the study was 400 patients (i.e. 200 patients/group).
Statistical analyses were performed according to the intention-to-treat (ITT) and per protocol (PP) principles. All randomised patients who had taken at least one dose of study medication were included in the ITT analysis, except those in whom HUT-positive H. pylori infection status was not verified by a positive UBT at the baseline visit. Patients in whom infection status was unknown after treatment were considered as treatment failures for the purposes of the ITT analysis. All patients excluded from the ITT analysis were also excluded from the PP analysis; the latter analysis also excluded patients with unknown H. pylori status post-therapy and those with major protocol violations that could have influenced the outcomes of the study (e.g. insufficient compliance, i.e. less than 75% of any study drug taken, use of disallowed medication). For both the ITT and PP analyses, the proportions of patients in whom H. pylori eradication was successful were used to estimate the true eradication rates. A two-sided 95% CI (exact) was calculated for each treatment group, while the between-group difference in eradication rate was expressed as a two-sided 95% CI (based on a normal approximation). Multiple logistic regression analysis was also performed to determine whether eradication rates were influenced by gender, age, country, duration of duodenal ulcer disease or previous attempt at eradication therapy.
A total of 448 patients were randomised to receive study medication at 56 centres (1–32 patients/centre) in six countries, of whom 432 completed the study (EAC, n=220; OAC, n=212). The main reasons for premature study discontinuation (n=16) were adverse events, unwillingness to continue and loss to follow-up. In total, 48 of the 448 patients randomised to the study were excluded from the ITT analysis: 46 were excluded because their H. pylori-positive status was not verified by the UBT at the baseline visit, and 2 were excluded for failure to take any study medication. Additionally, 23 patients were excluded from the PP analysis, mainly because of insufficient intake of study drug (n=10) or use of disallowed concomitant medication (n=9) (see Figure 1).
Baseline demographics and clinical characteristics of the 400 patients included in the ITT analysis are shown in Table 1. Overall, the ITT population was predominantly male (64%), and most patients were less than 65 years of age (75%). Approximately one-third of patients were smokers, and most had a history of duodenal ulcer disease for > 5 years (62%). Patient disposition is summarized in Figure 1.
Overall, compliance with study medication was high, with more than 90% of patients in each treatment group taking > 75% of the study therapy.
Eradication rates for the EAC and OAC regimens are shown in Table 2. Both regimens achieved eradication rates of around 90%. There were no statistically significant differences in eradication rates between patients treated with EAC and those who received OAC.
Multiple logistic regression analysis showed no significant effect of age, gender, country or duration of duodenal ulcer disease on the rate of eradication (data not shown). However, previous attempts at eradication therapy reduced the likelihood of a successful outcome. Thus, for the ITT population, cure was achieved in 13/18 (72%; 95% CI: 47–90%) and 18/25 (72%; 95% CI: 51–88%) of EAC-and OAC-treated patients, respectively, who had previously undergone attempted eradication.
Excellent correlation was apparent between the UBT results at 4 and 8 weeks post-therapy. Only 1 patient (of 380 patients with UBT findings at both timepoints) was H. pylori-positive at 8 weeks, after testing negative for the infection at 4 weeks post-therapy.
Assessment of gastrointestinal symptoms showed an improvement in the frequency and severity of epigastric pain that continued during the remainder of the study period (Figure 2). This improvement was more pronounced among those who achieved cure of H. pylori infection (Figure 3). For heartburn, a decrease in symptom frequency and severity was also apparent on completion of eradication therapy (Figure 4). Some patients in both groups, however, experienced a recurrence of heartburn during follow-up, although the frequency of this symptom was still lower than at baseline.
A total of 446 patients received at least one dose of study medication and were therefore included in the safety analysis. Triple therapy with esomeprazole was well tolerated, with an adverse event profile and frequency comparable to that of the omeprazole-based regimen (Table 3). In total, 58.5% of EAC recipients and 54.5% of those treated with OAC reported at least one adverse event during eradication therapy. The most common adverse events were diarrhoea/loose stools and taste perversion, which are typical of those observed when proton pump inhibitors are used in combination with antibiotics for H. pylori eradication. Eight patients in total discontinued therapy as a result of adverse events (EAC: diarrhoea [two patients], diarrhoea/dizziness [one patient], rash [one patient]; OAC: diarrhoea/taste perversion [one patient], anxiety/palpitations/tinnitus [one patient], rash [one patient], headache [one patient]). One serious adverse event occurred during eradication therapy (stroke in one patient receiving OAC), although this was considered unrelated to the study medication. There were no clinically relevant changes in laboratory safety variables during eradication therapy with either esomeprazole- or omeprazole-based regimens.
This is the first double-blind, randomised clinical study to report on the efficacy of esomeprazole as part of a 1-week triple therapy regimen with amoxicillin and clarithromycin, for eradication of H. pylori in patients with duodenal ulcer disease. The results for the esomeprazole-based combination demonstrate high cure rates, coupled with good tolerability and high patient compliance, which are well above the eradication rate of 80% as proposed by the Maastricht and other international guidelines.2, 4 Both regimens achieved eradication rates of around 90%, and in each case the lower limit of the 95% CI was greater than 80%. Moreover, the excellent correlation between the UBT results at 4 and 8 weeks post-therapy lends support to previous findings indicating that the use of a single UBT at 4 weeks after the completion of triple therapy is sufficient for documenting H. pylori eradication.7–10
In the present study, 11% of patients had previously received a course of therapy aimed at eradication of H. pylori. Although there was a tendency for lower rates of eradication in these patients, the overall eradication rates are maintained well above current standards. There are a number of possible explanations for this finding, including antibacterial resistance among H. pylori strains. Clarithromycin resistance is reported to affect the outcome of H. pylori eradication therapy,8, 14–16 and this study included centres from several countries (e.g. France, Spain) where clarithromycin resistance is of increasing concern. Although resistance to antibiotics was not assessed in the present study, this represents the most likely explanation.
At baseline, about one-third of patients were experiencing gastrointestinal symptoms of epigastric pain and/or heartburn. As the study enrolled only patients with a history of duodenal ulcer disease, such symptoms can probably be explained by H. pylori-related gastritis and/or concomitant gastro-oesophageal reflux disease (GERD). Such symptoms showed a decrease in frequency and severity following 1 week of eradication therapy, and the two treatment groups showed comparable efficacy in this regard. For epigastric pain, this improvement was maintained throughout follow-up and was more pronounced among those who achieved cure of the infection,10 which supports a role for H. pylori-related gastritis as a cause of such symptoms. In the case of heartburn, however, there was a tendency for symptoms to recur during follow-up, albeit with reduced frequency, suggesting the presence of underlying GERD. In this regard, it is noteworthy that up to 30% of patients with duodenal ulcer disease or ulcer-like dyspepsia have underlying GERD.17
A safety assessment showed that esomeprazole-based triple therapy was well tolerated, with a similar profile and frequency of adverse events to that reported for the OAC comparator group. The most commonly reported adverse events were diarrhoea and taste perversion, which were most likely attributable to amoxicillin and clarithromycin, respectively. Such adverse events, which seldom led to a discontinuation of treatment in the present study, are typical of those observed when a proton pump inhibitor is used in combination with antibiotics for the eradication of H. pylori.7–10
In conclusion, a 1-week esomeprazole-based triple therapy regimen is highly effective in eradicating H. pylori infection in patients with duodenal ulcer disease, and offers comparable efficacy to omeprazole-based triple therapy. The 90% eradication rate exceeds that recommended in the Maastricht and other international guidelines. EAC therapy was well tolerated in this patient group.
This study was sponsored AstraZeneca R&D, Mölndal, Sweden.
We thank the following investigators for their collaboration in this study: Canada: Dr P. Paré, Québec PQ, Dr A. Barkun, Montréal PQ, Dr C. Fallone, Montréal PQ, Dr M. Gaetano, Westmount PQ, Dr N. Chiba, Guelph ON, Dr G. Chan, Winnipeg MB, Dr A. B. R. Thomson, Edmonton AB; Denmark: Dr L. Hendel, Birkerød, Dr S. Kiilerich, Hillerød, Dr J. Præst, Herning, Dr H. Jakobsen, Vig St, Dr C. Thordal, Holstebro; France: Dr Dupas, Amiens Cedex, Dr Chaussade Paris Cedex 14, Dr Roche, Paris Cedex 14, Dr Mion, Lyon Cedex 3, Dr Goldfain, Dreux, Dr Nalet, Montelimar Cedex, Dr Bigard, Vandoeuvre Les Nancy; Germany: Dr K.-H. Bolle, Kronach, Dr U. Diete, Magdeburg, Dr A. Kocjan, Lüdenscheid, Dr H.-J. Schulz, Berlin, Dr M. Schumacher, Wolmirstedt; Spain: Dr M. Papo, Tarragona, Dr M. Figa, Girona, Dr X. Ribot, Olot (Girona), Dr M. R. Moreno, Granada, Dr A. López Morante, Burgos, Dr L. Martin, Cadiz, Dr P. Gonzalez, Alcazar de San Juan-Cuidad Real, Dr J. M. Herrerias, Sevilla, Dr L. Vidal, Palamós (Gerona); Sweden: Dr P. Ekström, Sandviken, Dr L. Carling, Bollnäs, Dr B. Hallerbäck, Trollhättan, Dr H. Tanghöj, Eskilstuna, Dr S. Back, Gävle, Dr B. Ohlin, Karlskrona, Dr G. Edlund, Östersund, Dr R. Befrits, Stockholm, Dr E. Thorhallsson, Växjö, Dr G. Lundegårdh, Luleå, Dr A. Sylwan, Umeå, Dr S. Sjöstedt, Nyköping, Dr E. Tveit, Kungälv, Dr R. Edin, Varberg.
Dr Veldhuyzen van Zanten is a recipient of a Nova Scotia Clinical Research Award.