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Eradication of Helicobacter pylori in functional dyspepsia: randomised double blind placebo controlled trial with 12 months follow up

Nicholas J Talley, Jef Janssens, Karsten Lauritsen, István Rácz, Elisabeth Bolling-Sternevald on behalf of the Optimal Regimen Cures HelicobacterInduced Dyspepsia (ORCHID) Study Group

Department of Medicine, University of Sydney, Nepean Hospital, Penrith, New South Wales 2751, Australia

Nicholas J Talley, professor

KUL Gasthuisberg, Dienst Maag-en Darmziekten, Leuven, Belgium 3000

Jef Janssens, professor

Department of Medical Gastroenterology, Odense University, Denmark 5000

Karsten Lauritsen, specialist

Petz Aladar Teaching and County Hospital, Gyôr, Hungary 9002

István Rácz, specialist

Department of Biomedicine and Surgery, University of Linköping, Molndal, Sweden 581 85

Elisabeth Bolling-Sternevald, scientist

Correspondence to: Professor Talley talley{at}


Objectives To determine whether eradication of Helicobacter pylori relieves the symptoms of functional dyspepsia.

Design Multicentre randomised double blind placebo controlled trial.

Subjects 278 patients infected with H pylori who had functional dyspepsia.

Setting Predominantly secondary care centres in Australia, New Zealand, and Europe.

Intervention Patients randomised to receive omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily or placebo for 7 days. Patients were followed up for 12 months.

Main outcome measures Symptom status (assessed by diary cards) and presence of H pylori (assessed by gastric biopsies and 13C-urea breath testing using urea labelled with carbon-13).

Results H pylori was eradicated in 113 patients (85%) in the treatment group and 6 patients (4%) in the placebo group. At 12 months follow up there was no significant difference between the proportion of patients treated successfully by intention to treat in the eradication arm (24%, 95% confidence interval 17% to 32%) and the proportion of patients treated successfully by intention to treat in the placebo group (22%, 15% to 30%). Changes in symptom scores and quality of life did not significantly differ between the treatment and placebo groups. When the groups were combined, there was a significant association between treatment success and chronic gastritis score at 12 months; 41/127 (32%) patients with no or mild gastritis were successfully treated compared with 21/123 (17%) patients with persistent gastritis (P=0.008).

Conclusion No convincing evidence was found that eradication of H pylori relieves the symptoms of functional dyspepsia 12 months after treatment.


Most patients with dyspepsia—defined as persistent or recurrent pain or discomfort centred in the upper abdomen—have no evidence of chronic peptic ulceration, reflux oesophagitis, malignancy, or other identifiabledisease(1.1)(2.1)(3.1)(4.1); these patients are classed as having functional (or non-ulcer) dyspepsia. An estimated 30% to 70% of patients with functional dyspepsia have co-existent Helicobacter pylori gastritis,(3.1) (5.1)(6.1)(7.1) but it is unclear whether H pylori infection causes symptoms in the absence of peptic ulceration.(8.1)(9.1)(10.1)

Carefully conducted randomised controlled trials should be able to determine whether or not H pylori is a cause of functional dyspepsia. If H pylori was a major cause of dyspepsia then the symptoms would be expected to abate when H pylori was eradicated.(11.1) Although several comparatively small trials have been published the results have been conflicting and the methods have been generally suboptimal.(8.1) (9.1) Moreover, only a minority of these studies have tested whether eradication of H pylori improves the symptoms of functional dyspepsia long term. As it may take at least 12 months for gastritis, as confirmed by histology, to return to normal, it may be that long term follow up is required to observe a clinically significant resolution of symptoms in functional dyspepsia.(12.1) (13.1)

We postulated that H pylori is a direct cause of around 20% of cases of functional dyspepsia. To test this hypothesis, we conducted a multicentre randomised double blind placebo controlled trial with 12 months follow up to determine the long term benefit of eradicating H pylori. The study protocol was approved by the appropriate ethics committees, and written informed consent was obtained from the participants.

Subjects and methods

Overall, 278 consecutive patients were recruited from 40 centres in Australia, New Zealand, and nine European countries; 244 patients (89%) were from secondary care. The remaining 31 patients (11%) were from primary care and were recruited only from the United Kingdom. Twenty centres recruited six or more patients.


Study population—Dyspepsia was defined as pain or discomfort centred in the upper abdomen.(1.1) Adult patients were asked to participate in the trial if they had had dyspepsia as their main symptom for at least 3 months, if they had normal endoscopic findings in the oesophagus, stomach, and duodenum, and if they gave a positive result for H pylori on a screening test (Helisal, Cortecs Diagnostics, UK). Patients who were excluded on the basis of the results of endoscopy had reflux oesophagitis (any oesophageal mucosal break), Barrett’s oesophagus, chronic gastric or duodenal ulceration, duodenal erosions, malignancy, or more than five gastric erosions. Patients were also excluded if they had unexplained weight loss, vomiting, dysphagia, or other evidence of significant disease. Patients were not permitted to continue their treatment with H2 receptor antagonists, prostaglandins, or prokinetics during the 7 days before enrolment or to use a proton-pump inhibitor, antibiotics, or bismuth during the 30 days before enrolment. Patients with a documented history of peptic ulcer disease or gastro-oesophageal reflux disease were excluded.

Run-in period—After endoscopy, patients were required to fill out a diary card with scores for their dyspepsia symptoms during a 7 day run-in period. Only patients who had at least 3 days of at least moderate dyspepsia symptoms were randomised. No study drug was dispensed during the run-in week.

Treatment period—If patients had sufficient symptoms during the run-in week they underwent a 13C-urea breath test using urea labelled with carbon-13 at the randomisation visit. Patients were randomised to receive either omeprazole 20 mg twice daily, amoxicillin 1000 mg twice daily, and clarithromycin 500 mg twice daily or placebo for 1 week. If patients had taken at least 12 out of 14 doses of drug or placebo they were considered to be compliant; no patients were withdrawn from the study because of poor compliance.

Follow up period—The patients were followed up 1, 3, 6, 9, and 12 months after cessation of study treatment. Diary cards (filled out the week before each visit) were collected at each visit, quality of life forms were filled out by the patients at the 6 and 12 month visit, and a urea breath test and upper endoscopy were performed at the 3 and 12 month visits. A weak antacid (with a neutralising capacity of around 13 mmol of hydrochloric acid per tablet) was dispensed at each visit during follow up and its consumption was recorded at each visit. During follow up, patients could receive treatment for dyspeptic symptoms from their doctor but all drugs used were recorded. Treatment for eradicating H pylori was not allowed.

Primary outcome measures

Patients recorded the severity of their dyspepsia symptoms on diary cards using a validated Likert scale comprising 7 grades: none, minimal, mild, moderate, moderately severe, severe, very severe.(14.1)

At each endoscopic evaluation, two antral and two corpus biopsy specimens were taken for histological assessment. The corpus biopsies were taken 6 cm and 7 cm from the cardia along the greater curvature. The antral biopsies were taken from the anterior and posterior wall, 2 cm proximal to the pylorus. Specimens were processed using the paraffin embedding technique, sectioned at 4 ìm perpendicularly to the mucosal surface, and stained with haematoxylin and eosin and with the Steiner silver method.

The biopsies were histologically graded according to the Houston modification of the Sydney system for chronic gastritis.(15.1) H pylori status was graded from none (0) to severe (3). All specimens were reviewed by an experienced gastrointestinal pathologist blinded to the treatment group. Urea breath testing was performed using a standard well validated European protocol.(16.1)

At pre-entry, before patients could enter the study two test results for H pylori had to be positive; by screening test (Helisal rapid blood test or a rapid urease test) and by either urea breath testing or histological assessment.

After treatment, H pylori status was assessed at 3 and 12 months. If any of the gold standard assessments (urea breath test or histology) were positive, patients were considered to be positive for H pylori. If only one test result was available, the outcome of that test determined the H pylori status. If both test results were missing at a visit, H pylori status was recorded as unknown.

Secondary outcome measures

The gastrointestinal symptom rating scale was used to score dyspepsia symptoms. This scale is a well validated self administered instrument comprising 15 items, which measure abdominal pain, reflux, indigestion (wind, bloating), diarrhoea, and constipation.(17.1) (18.1) The psychological general well being index was used to score the patients’ quality of life. This index is a well validated self administered generic instrument comprising 22 items, which measure subjective well being.(18.1)(19.1)(20.1)

Patients were subdivided into symptom subgroups (ulcer-like and dysmotility-like dyspepsia) on the basis of their responses to the gastrointestinal symptom rating scale. The subgroups were defined by a cut-off score so as to be reasonably consistent with the Rome classification.(1.1) Ulcer-like dyspepsia was defined as at least moderate stomach pain and hunger pain in the week before follow up. Dysmotility-like dyspepsia was defined by two or more of at least moderate bloating, nausea, stomach rumblings, or belching in the week before follow up. None of the subgroups was mutually exclusive.

Statistical analyses

Patients were excluded from the intention to treat analysis who were negative for H pylori at pre-entry or who were without any assessment of treatment efficacy after randomisation (fig 1(F1)). The treatment groups were compared for symptom relief with a Mantel Haenszel test stratified by country and for healing of gastritis with a Mantel Haenszel test stratified by baseline gastritis.

Fig 1 Flow of participants through trial

Patients who reported on the diary card no more than minimal dyspepsia symptoms during any of the 7 days before the 12 month visit were considered a priori to be a treatment success. If patients took drugs for dyspepsia (other than antacids) within 2 weeks before the 12 month visit they were considered treatment failures. If patients had no symptom assessment at 12 months but a valid assessment at or after the 6 month visit then the last value was extended in the intention to treat analysis.

Active and chronic gastritis were considered healed when both antrum and corpus specimens had an inflammation score of zero.(15.1) The presence of no or mild chronic gastritis (score of 0 or 1) was also analysed. When no endoscopy data existed at the 12 month visit, data from the 3 month endoscopic evaluation were used for the analysis, and if no endoscopy had been performed after the pre-entry visit, the patient was considered not healed in the analysis.

The treatment groups were compared for change in the total score of the gastrointestinal symptom rating scale and psychological general well being index from the first visit to the last visit in the study, using the baseline value as a covariate in an analysis of covariance model. When an item score was missing, the mean of the questions completed by the patient within the dimension was imputed provided that at least 60% of the questions within the dimension had been answered by the patient.

With a sample size of 275 patients, the power of the study was 94% provided the true proportions of responders was 20% and 40% in the two groups (assuming an á level of 0.05 based on a two sided ÷2 test). The proportion of responders expected in the placebo group was based on data for symptom turnover in the population.(21.1)

Randomisation was in blocks of four in proportions of 1:1 according to a computer generated list. Randomisation numbers were distributed to the study centres; these were assigned in consecutive order by responsible investigators.

Identical placebos were used. Investigators and patients were blinded to all data, including H pylori assessments after randomisation, until the study was fully completed. Individually numbered opaque envelopes containing the treatment code for treatment allocation were kept at each study site. These envelopes were sealed and none were opened during the study.


One hundred and thirty five patients (52 men) were randomised to treatment and 143 patients (48 men) were randomised to placebo (fig 1(F1)). Three patients (two in the treatment group and one in the placebo group) were withdrawn from the analysis because of unavailability of data after randomisation.

The two groups were well balanced for demographic and clinical features (table 1).


Eradication of H pylori and healing of gastritis

Both urea breath testing and histology results were available for 237 patients (86%) enabling infection status to be recorded at follow up. At 12 months, 113 patients (85%) in the treatment arm had been successfully treated for H pylori infection compared with 6 patients (4%) in the placebo group. However, 108 patients (81%) in the treatment group had no or mild chronicgastritis at 12 months compared with 18 patients (13%) in the placebo group (table 2).

Overall, 98% of patients consumed at least 12 of 14 doses in both groups.

Symptom relief

By an intention to treat analysis, 32 patients (24%) in the treatment group and 31 patients (22%) in the placebo group were successfully treated (minimal or no dyspepsia) at 12 months (table 2(T2)). The per protocol analysis yielded similar results (table 2(T2)). There was no significant difference in treatment success among those who were negative for H pylori (35, 29%) and those who remained positive for H pylori (28, 21%). At the 12 month follow up, no dyspepsia symptoms were reported by 20 patients (15%) in the treatment group and 16 patients (11%) in the placebo group. A similar proportion of patients in each treatment arm had no or minimal dyspepsia symptoms at each follow up (fig 2(F2)). Similarly, the mean symptom score was not significantly different at each time point (fig 3(F3)). There was no inhomogeneity among countries (Breslow-Day test, P>0.20) and no difference between primary and secondary care centres.

Fig 2 Proportion of patients with no more than minimal dyspepsia symptoms on basis of diary card data (per protocol analysis)

Fig 3 Mean symptom score and SEM on diary cards at follow up visits

Mean antacid consumption over 12 months did not differ significantly between the treatment group (0.53 tablets per day) and the placebo group (0.65). Five patients (one in the treatment group and four in the placebo group) had treatment success according to the diary cards but were considered treatment failures in the analysis because they took a gastrointestinal drug other than antacid within 2 weeks of the 12 month visit.

In the ulcer-like dyspepsia group, treatment success was reported by 17/68 patients (25%) in the treatment group and 12/58 patients (21%) in the placebo group. The corresponding results for dysmotility-like dyspepsia were 14/78 patients (18%) in the treatment group and 13/73 patients (18%) in the placebo group.

The mean total score for the psychological general well being index improved from 91.0 (baseline) to 99.6 (last visit) in the treatment group and from 92.2 to 98.0 in the placebo group (fig 4(F4)). The mean total score for the gastrointestinal symptom rating scale improved from 2.91 (baseline) to 2.26 (last visit) in the treatment group and from 2.63 (baseline) to 2.33 (last visit) in the placebo group (fig 4(F4)). The change from baseline to last visit between the treatment groups was not significant for either the psychological general well being index or the gastrointestinal symptom rating scale.

Fig 4 Intention to treat analysis showing mean (SEM) scores for quality of life and severity of symptoms in patients with functional dyspepsia. Possible psychological well being index scores (top) ranged from 132 (best) to 22 (worst); possible gastrointestinal symptom rating scale (bottom) mean scores ranged from 1 (no symptoms) to 7 (worst symptoms)

Gastritis scores and symptom relief—There was no association between the severity of symptoms at baseline and the severity of gastritis in the corpus or antrum on initial biopsies. The presence or absence of atrophy was not a predictor of treatment outcome. Patients at follow up were subdivided regardless of treatment into those with a chronicgastritis score of 0 or 1 (none or mild gastritis) and those with a score of 2 or 3 (moderate or severe gastritis) in a secondary analysis. At the 12 month follow up, 41/127 patients (32%) with no or mild gastritis were treatment successes (no or minimal dyspepsia) compared with 21/123 patients (17%) with moderate or severe gastritis (P=0.008). This association was not explained by age.Of the 41 patients with none or mild gastritis at follow up, only nine had received placebo (of whom only one had complete resolution of gastritis and eight had mild gastritis).


Few large multicentre trials have rigorously evaluated the role of H pylori eradication in functional dyspepsia, and the results are conflicting.(22.1) (23.1) We elected to conduct the trial in different countries and at multiple centres in order to provide reasonably generalisable results. We found no convincing evidence that successful eradication of H pylori infection relieves or reduces symptoms in patients with functional dyspepsia over 12 months.

Trial design issues

The study aimed to overcome previously documented limitations in methodology.(8.1) (9.1) In particular, the outcome measures were known to be valid and responsive to change.(14.1) (17.1)(18.1)(19.1)(20.1) Scrupulous attention was paid to blinding of patients and investigators to minimise bias. Prospective assessment of symptoms reduced the issue of recall bias, which may affect retrospective assessments particularly if these extend over prolonged periods.(9.1) Furthermore, the study was designed to have appropriate power to detect symptom improvement or resolution in a small but clinically relevant group of patients with functional dyspepsia.

The results of previous trials have been conflicting but this is probably largely explained by their methodological limitations.(7.1) (8.1) For example, bismuth trials only evaluated suppression of infection rather than eradication, were poorly blinded, and long term follow up was not performed.(24.1)(25.1)(26.1)(27.1)(28.1)(29.1)(30.1) A meta-analysis concluded that symptoms improved in 73% of patients with non-ulcer dyspepsia who became negative for H pylori compared with 45% of those with persistent infection.(10.1) The study was, however, potentially flawed as only 10 of 34 studies that met the inclusion criteria could be analysed.(10.1)

Predictors of symptom relief

A persistent low grade inflammatory response could alter gastroduodenal sensation and hence promote the development of dyspepsia symptoms.(11.1) We observed an association between healing of chronic gastritis and treatment success but this secondary analysis must be cautiously interpreted and requires confirmation. While a longer follow up of those successfully treated might have shown a more striking extent of symptom resolution as the gastritis slowly resolved over years, our trial was not designed to address this issue.

A few studies have observed that a treatment response was limited to those patients with ulcer-like dyspepsia, but no link between dyspepsia subgroups and H pylori eradication was evident in the present study.(13.1) (31.1) Although our results may be generalisable to secondary care, we cannot exclude the possibility that such patients have more resistant symptoms than those in primary care where trials are needed.

Management implications—A popular management strategy in otherwise healthy young patients with uninvestigated dyspepsia is to non-invasively test for H pylori and to treat all infected cases.(32.1) Although controversial, such a strategy may have a number of potential benefits.(33.1) On the basis of the present results, however, only a minority who are treated would be likely to gain long term symptomatic relief, because most infected patients with dyspepsia have functional dyspepsia rather than peptic ulcer disease.(32.1)

Key messages

• Dyspepsia (pain or discomfort centred in the upper abdomen) is frequently unexplained; such patients are classed as having functional (or non-ulcer) dyspepsia

• H pylori gastritis is common in patients with functional dyspepsia but the benefits of treatment are controversial

• No significant benefit in relief of symptoms was found between patients successfully treated for H pylori infection and those with persistent infection

• Eradication of H pylori does not relieve the symptoms of functional dyspepsia

We thank members of the Optimal Regimen Cures Helicobacter Induced Dyspepsia Study Group: S Kiilerich, L Weywadt, U Tage-Jensen (Denmark); RJLF Loffeld, JA Beker, PWE Haeck (Netherlands); B Collins, J Karrasch, M Korman, R Watts (Australia); K Vetvik, K Hveem, J Østborg, S Wetterhus (Norway); GO Barbezat (New Zealand); A Obrador, J Viver, E Quintero, M Torres, J Hinojosa (Spain); M Rasmussen, R Grönfors, PE Wingren (Finland); J Hosie, S Rowlands, M Scott, C Stoddard, G Walker (United Kingdom); MA Bigard, D Goldfain, JY Begue, D Schmitz (France); Z Döbrönte, L Juhász, L Lakatos, Z Tulassay (Hungary). We also thank Ola Junghard, Niilo Havu, and Gudrun Sjögren from Astra Hässle, Sweden.

Contributors: NJT, JJ, KL, IR, and EB-S participated in the design, execution, and analysis of the study. NJT will act as guarantor for the paper.

Funding: Astra Hässle (Molndal, Sweden).

Competing interests: NJT has been a consultant for Astra Hässle (Sweden) and Abbott Laboratories (USA). EB-S is an employee of Astra Hässle.

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