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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

Background : The high prevalence of Helicobacter pylori resistance to metronidazole demands treatments more effective than standard bismuth-based triple therapy against these strains.

Aim : To evaluate the H. pylori eradication rate in both metronidazole-sensitive and -resistant strains following quadruple therapy using single-triple capsules of bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole.

Methods : One hundred and seventy valid patients with duodenal ulcer, gastric ulcer or non-ulcer dyspepsia were treated in eight centres located in five countries. H. pylori was confirmed at baseline using 13C-urea breath test, histology and/or culture. Patients received three single-triple capsules q.i.d. and omeprazole, 20 mg b.d., for 10 days. Each capsule contained bismuth biskalcitrate, 140 mg (as 40 mg Bi2O3 equivalent), metronidazole, 125 mg, and tetracycline, 125 mg. 13C-Urea breath test was repeated at least 4 and 8 weeks post-treatment.

Results : Overall eradication rates were 93% (158/170) by modified intention-to-treat analysis and 97% (142/146) by per protocol analysis. Eradication rates were 93% (40/43) and 95% (38/40) for strains resistant to metronidazole and 95% (82/86) and 99% (75/76) for strains sensitive to metronidazole by modified intention-to-treat and per protocol analysis, respectively.

Conclusion : This omeprazole–bismuth biskalcitrate–metronidazole–tetracycline 10-day regimen is a very effective and well-tolerated treatment, which overcomes metronidazole resistance.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

It has been almost two decades since the micro-organism Helicobacter pylori was identified in association with gastritis and peptic ulcer1 and successfully cultured.2 The link between H. pylori eradication and the cure of duodenal and gastric ulcer disease is now widely accepted. A strong association has also been demonstrated between various disorders of the upper gastrointestinal tract (including gastric carcinoma) and infection of the gastric mucosa by H. pylori.3–5 Evidence also exists that the eradication of H. pylori induces the regression of mucosa-associated lymphoid tissue lymphoma.6–10

The Maastricht Consensus Report from the European H. pylori Study Group advocates the testing for and eradication of H. pylori in a large variety of patients presenting with gastrointestinal symptoms.11 Many treatments have been tested for the eradication of H. pylori,12 including a successful approach using bismuth-based triple therapy with a bismuth salt, metronidazole and tetracycline. However, the high resistance of H. pylori to metronidazole has required the development of a new mode of treatment. Results from trials have confirmed that the addition of a proton pump inhibitor to bismuth-based triple therapy increases the eradication rate, even in metronidazole-resistant H. pylori strains.13–15 However, in order to comply with this quadruple therapy, patients must take tablets and capsules from four different bottles, some four times a day and some twice or once a day.

A new single-triple capsule containing bismuth biskalcitrate, metronidazole and tetracycline, administered with a proton pump inhibitor, was investigated in this study. This regimen was selected for development based on effectiveness, treatment duration, patient convenience, safety and cost.16–20 The ‘three-in-one’ feature of this capsule was designed to increase acceptability and compliance, as the patient would need to take three of the four medications from the same bottle at the same times. This study was designed to assess the efficacy and safety of this regimen for the eradication of H. pylori. In addition, the investigation of the effect of metronidazole resistance and disease type (peptic ulcer vs. non-ulcer dyspepsia) on the eradication rate was also planned a priori and evaluated.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

This was an open-label, multicentre study of the efficacy and safety of quadruple therapy using a single-triple capsule containing bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole, in the eradication of H. pylori. Ethics approval was granted at all participating centres.

Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

Patients were male or female, aged 18–75 years, suffering from dyspepsia with or without ulcer disease, and testing positive for H. pylori by 13C-urea breath test. This positive result had to be confirmed by histology and/or culture of pre-treatment biopsies of the gastric mucosa. Sensitivity to metronidazole was also assessed from these biopsies. Eligible patients then received quadruple therapy with single-triple capsules (Helizide, Axcan Pharma Inc., Mont-Saint-Hilaire, Montréal, Québec, Canada), each containing bismuth biskalcitrate, 140 mg (equivalent to 40 mg Bi2O3), metronidazole, 125 mg, and tetracycline, 125 mg, given as three capsules q.i.d., after meals and at bedtime, with omeprazole (Prilosec, AstraZeneca LP, Wilmington, DE, USA), 20 mg b.d., after morning and evening meals. This regimen provides daily doses of: Bi2O3, 480 mg; metronidazole, 1500 mg; tetracycline, 1500 mg; and omeprazole, 40 mg.

At the screening visit, patients underwent a medical history, physical examination, blood testing, pregnancy test if applicable, 13C-urea breath test and endoscopy with biopsies (three from the antrum and two from the corpus). One biopsy from the antrum was used for on-site rapid urease test, one from the antrum and one from the corpus were processed to histology, and one from the antrum and one from the corpus were used for culture and to assess metronidazole resistance.

Medication was dispensed at the screening visit if the patient had a positive rapid urease test. This result had to be confirmed by 13C-urea breath test and histology or culture (results obtained later). Within 4 days after the end of treatment, the patient again had a physical examination, pregnancy test if applicable and laboratory tests. 13C-Urea breath test was performed between 29 and 35 days after the end of treatment and, if the result was negative, was repeated between 57 and 64 days after the end of treatment. Eradication was defined as two negative 13C-urea breath tests performed at least 4 and 8 weeks after the end of treatment. Patients who remained symptomatic, H. pylori-positive or both at the end of the study received treatment as judged appropriate by the investigator, and were followed outside the scope of this study. Adverse events were assessed at each visit throughout the study by open general questioning.

Evaluations

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

All histology slides were read at local laboratories, with H. pylori identified by morphology. 13C-Urea breath tests were analysed at a central facility (INFAI, Bochum, Germany). Clinical laboratory assessments were carried out at local laboratories and consisted of standard haematology, serum chemistry, urinalysis and serum pregnancy tests. Cultures and metronidazole sensitivity were also performed at a central facility (F. Megraud, Bordeaux, France) by agar dilution, with results classified as positive, negative or inconclusive. Strains were classified as metronidazole resistant if their minimum inhibitory concentration was > 8 mg/L or metronidazole sensitive if their minimum inhibitory concentration was ≤ 8 mg/L. Investigators classified adverse events by severity and assessed whether there was a relationship between the event and the study medication. Assignment to disease type (peptic ulcer or non-ulcer dyspepsia) was based on disease history and/or baseline endoscopy results.

Analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

A sample size of 138 eligible patients was required based on a 90% projected eradication rate with a 0.95 confidence interval of 10%. Modified intention-to-treat (MITT) and per protocol analyses were used to assess the eradication rates overall and by subgroup. Comparisons between subgroups were planned a priori and performed by Fisher's exact test, with the level of significance set at 0.05.

Patient disposition

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

Investigators screened 187 patients. Ten failed to meet the required inclusion and exclusion criteria and did not receive any study medication, leaving 177 patients who received at least one dose of study medication and were included in the safety group. There were 170 patients in the modified intention-to-treat group, as seven patients were further excluded because they did not meet the inclusion criteria of being positive for H. pylori by 13C-urea breath test plus history and/or culture. Twenty-four patients had major protocol violations or failed to complete the study, leaving 146 patients in the per protocol group. Of these 24 exclusions, 10 took forbidden drugs during the trial (mostly proton pump inhibitors or antibiotics), seven had their 13C-urea breath test performed outside the allowed time windows, six had adverse events and stopped participation and one withdrew voluntarily. There were no significant differences between the MITT and per protocol groups in terms of age, gender, race and clinical factors at baseline (Table 1). Compliance was defined as taking at least 75% of the study drug and was evaluated by capsule count. The compliance level was 95% in the MITT group and 97% in the per protocol group.

Table 1.  Demographic data of modified intention-to-treat and per protocol groups at baseline
FactorModified intention- to-treat group (n = 170)Per protocol group (n = 146)
Mean age ± s.d. (years)51.7 ± 12.651.2 ± 12.6
Gender (female/male)69 (41%)/101 (59%)57 (39%)/89 (61%)
Race
 Caucasian151 (89%)129 (88%)
 Black6 (3.5%)5 (3.4%)
 Asian10 (6%)9 (6%)
 Other3 (1.8%)3 (2.1%)

Efficacy

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

The primary focus of the study was to determine the confidence intervals of the eradication rate of H. pylori for both MITT and per protocol groups (Table 2). Eradication was achieved in 158/170 (93%) of MITT and 142/146 (97%) of per protocol groups. Sensitivity to metronidazole has been successfully assessed in strains obtained at baseline from 129 patients: 86 patients had strains sensitive to metronidazole, while 43 had strains resistant to metronidazole. Sensitivity could not be evaluated in the strains obtained at baseline from the 29 patients screened and included. There was no significant difference (P = 0.69) in the eradication rate between those with and without metronidazole resistance in the MITT group, with rates of 40/43 (93%) and 82/86 (95%), respectively. The same observation was made in the per protocol group, with eradication rates of 38/40 (95%) and 75/76 (99%) (P = 0.27) for the metronidazole-sensitive and -resistant strains, respectively. Eradication rates by country were similar (Table 3).

Table 2.  Eradication numbers and rates (overall and by metronidazole resistance) of Helicobacter pylori (with 95% confidence intervals) for modified intention-to-treat and per protocol analyses
 Modified intention-to-treat (n = 170)Per protocol (n = 146)
Overall158 (93%)142 (97%)
(89.1–96.8%)(94.6–99.9%)
Metronidazole resistance
 Resistant40/43 (93%)38/40 (95%)
(85.4–100.6%)(88.2–101.8%)
 Sensitive82/86 (95%)75/76 (99%)
(90.9–99.8%)(96.1–101.2%)
P value (resistant vs. sensitive) 0.690.27
Table 3.  Eradication numbers and rates of Helicobacter pylori by country for modified intention-to-treat and per protocol analyses
 Modified intention-to-treatPer protocol
Australia48/51 (94.1%)43/45 (95.6%)
Canada46/49 (93.9%)42/42 (100%)
Ireland24/27 (88.9%)23/23 (100%)
The Netherlands34/37 (91.9%)28/30 (93.3%)
USA6/6 (100%)6/6 (100%)

The eradication rates of H. pylori by disease type are presented in Table 4. There was no significant difference in the eradication rates between duodenal ulcer (90% and 94%), gastric ulcer (100% and 100%) and non-ulcer dyspepsia (94% and 98%) patients for the MITT and per protocol groups, respectively.

Table 4.  Eradication numbers and rates of Helicobacter pylori (with 95% confidence intervals) by disease type
Disease typeModified intention-to-treat (n = 170)Per protocol (n = 146)
Duodenal ulcer39/43 (90%)34/36 (94%)
(82.0–99.4%)(87.0–101.9%)
Gastric ulcer14/14 (100%)12/12 (100%)
(100–100%)(100–100%)
Non-ulcer dyspepsia46/49 (94%)40/41 (98%)
(87.2–100.6%)(92.8–102.3%)
P value across disease types 0.990.99

Safety

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

The numbers of adverse events and patients affected are presented in Table 5. Of the 401 non-serious events in 118 patients that were related to treatment, only 16 were classified as severe and these occurred in 12 patients. These severe events were diarrhoea (three patients), abdominal pain (two patients), vomiting (two patients), nausea, somnolence, rash, increase in serum glutamic pyruvic transaminase, eructations, palpitations, pyrosis, furunculosis and hypertonia (one patient each).

Table 5.  Most frequent treatment-emergent adverse events [ n (%)] related to study medication
Patients with adverse eventsMild to moderate [118 (67%)]Severe [12 (6.8%)]
Adverse events38516
Stool abnormality 63 (36) 0
Taste perversion 39 (22) 0
Diarrhoea 35 (20) 3 (1.7)
Nausea 33 (19) 0
Headache 29 (16) 1 (0.6)
Abdominal pain 23 (13) 2 (1.1)
Other16310

Six patients discontinued participation because of adverse events. Together, they experienced 30 adverse events, with six being classified as severe (three diarrhoea, two vomiting and one rash); each of these events was resolved. One patient with a history of anxiety and depression, who was under treatment for these conditions, was hospitalized (serious adverse event) after experiencing anxiety, hyperventilation, nausea and abdominal pain of moderate intensity that happened on the same day. These events were possibly related to the study medication, which was then temporarily interrupted. These four events resolved 11 days after onset and the patient completed the study.

The most common types (occurrence, > 10%) of drug-related and treatment-emergent adverse events in order of occurrence were: stool abnormality, taste perversion, diarrhoea, nausea, headache and abdominal pain. There were 32 other adverse event types occurring in more than 1% of patients.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

The primary objective of this study was to evaluate the eradication rates of H. pylori following quadruple therapy using a single-triple capsule of bismuth biskalcitrate, metronidazole and tetracycline, given in combination with omeprazole. Eradication rates by both MITT and per protocol analyses were above 90%, showing the effectiveness of quadruple therapy against H. pylori as measured by existing standards.11

An important finding of this trial was that H. pylori resistance or sensitivity to metronidazole did not have any impact on the eradication rate by either MITT or per protocol analysis, with both groups having values over 90%. These results show that metronidazole resistance can be overcome if an appropriate dosage and treatment duration are used, and confirm a previous finding obtained with the same drug treatment.21 This treatment, when given for 10 days, appears to contain the appropriate combination of ingredients to overcome metronidazole resistance, a shortcoming of other bismuth-based combinations used previously.20

It was also found that the eradication rate of H. pylori did not differ by disease type, as duodenal ulcer, gastric ulcer and non-ulcer dyspepsia all showed greater than 90% eradication rates; this supports the work of others, who also showed no discernible differences by disease type when patients were treated with omeprazole–bismuth biskalcitrate–metronidazole–tetracycline.22 The small number of patients treated in some of these categories in the current trial, however, requires caution in interpreting these results.

Safety data showed that the treatment was well tolerated, as the usual profile of adverse events for this patient population was exhibited. The few patients with severe non-serious adverse events had their situations resolved, and the only patient with serious adverse events was able to complete the study. There were no deaths in the study.

This study confirms the results obtained with this drug regimen in a randomized, partially blind trial.21 The eradication rates reported here are slightly higher than those obtained in the North American trial which involved duodenal ulcer patients only.

We conclude that this single-arm study confirms that Helizide, given as three capsules q.i.d., after meals and at bedtime, with omeprazole, 20 mg b.d., for 10 days is effective and safe in eradicating H. pylori, regardless of metronidazole resistance.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References

Axcan Pharma Inc., Mont-Saint-Hilaire, Montréal, Québec, Canada supported this study.

We are grateful to the following collaborators for their assistance: Lysander Stemmerick (Quintiles, The Netherlands); Samantha Rupesinghe (Quintiles, Australia); Yves Lalonde and Annie Dufresne (Quintiles, Canada); Daniel Plante (Montréal, Canada); Donna McGuigan (Acurian, USA); Rosa Surace, Laura Aber, Luc Regnaud and Michelle Asselin (Axcan Pharma, Australia and Canada); Dr Michael Grace (Edmonton, Canada).

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Evaluations
  7. Analysis
  8. Results
  9. Patient disposition
  10. Efficacy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
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    Laine L, Hunt R, El-Zimaity H, et al. Bismuth-based quadruple therapy using a single capsule of bismuth biskalcitrate, metronidazole and tetracycline given with omeprazole vs. omeprazole, amoxicillin, and clarithromycin for eradication of H. pylori in duodenal ulcer patients. A prospective, randomized, multicenter, North American Trial. AM J Gastroenterol 2003, (in press).
    Direct Link:
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