A randomized trial comparing seven-day ranitidine bismuth citrate and clarithromycin dual therapy to seven-day omeprazole , clarithromycin and amoxicillin triple therapy for the eradication of Helicobacter pylori

1Dalhousie University, Department of Medicine, Division of Gastroenterology, Halifax, Nova Scotia; 2McMaster University, Hamilton, Ontario; 3McGill University Health Centre, Montreal, Quebec; 4Centre de Gastro-enterologie de Montreal, Montreal, Quebec; 5Saint John Regional Hospital, Saint John, New Brunswick; 6Hopital Saint Francois dAssise, Quebec City, Quebec; 7GlaxoSmithKline Beecham (Canada) Inc, Mississauga, Ontario Correspondence: Dr Sander Veldhuyzen van Zanten, Dalhousie University, Department of Medicine, Division of Gastroenterology, 1278 Tower Road, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia B3H 2Y9. Telephone 902-473-1499, fax 902-473-4406, e-mail Zanten@dal.ca Received for publication May 8, 2003. Accepted May 14, 2003 S Veldhuyzen van Zanten, N Chiba, A Barkun, et al. A randomized trial comparing seven-day ranitidine bismuth citrate and clarithromycin dual therapy to seven-day omeprazole, clarithromycin and amoxicillin triple therapy for the eradication of Helicobacter pylori. Can J Gastroenterol 2003;17(9):533-538.

T here is increasing consensus that all patients known to be infected with Helicobacter pylori should be offered treatment (1,2).The target success rate for acceptable therapies to cure Helicobacter infection has been set at 80% or higher, based on intention-to-treat analysis of randomized controlled trials.Apart from high efficacy, treatments should be simple, well tolerated and safe.Ranitidine bismuth citrate ([RBC], Pylorid, Glaxo Wellcome Inc, Canada) is the first approved drug specifically developed for the treatment of H pylori infection (3).Over the last five years the most successful treatments have been either triple therapy consisting of a proton pump inhibitor (PPI) and clarithromycin with either amoxicillin or metronidazole (PPI-CA or PPI-CM) or quadruple therapy consisting of a PPI with a bismuth compound, metronidazole and tetracycline (1,2).Dual therapy with RBC and clarithromycin (RBC-C) can achieve cure rates of H pylori infection in the range of 70% to 96% (4,5).However, this success is achieved with 14-day therapy while triple therapies are successful in seven days.The longer duration of RBC-C therapy makes it more expensive and less convenient.However, because the RBC-C regimen uses only two drugs, it is simpler and potentially better tolerated than triple therapies.One study showed that the duration of RBC-C therapy could be decreased to seven days without loss of efficacy (6).
The objective of the current study was to compare the efficacy and safety of seven-day dual therapy of RBC-C to sevenday triple therapy with omeprazole, clarithromycin and amoxicillin (OCA).Patient satisfaction with treatment was also assessed.

METHODS
This was a computer randomized open-label study carried out in 18 gastroenterology centres and one general practitioner/family practitioner centre across Canada.Patients suffering from chronic dyspepsia with or without proven previous peptic ulcer disease who underwent upper gastrointestinal endoscopy were eligible for the study if they were H pylori positive.Presence of H pylori was determined by a rapid urease test.Patients needed to have confirmation of infection with H pylori by a 13 C-urea breath test ( 13 C-UBT) to be enrolled in the study.
The following were the exclusion criteria: presence of an active duodenal or gastric ulcer observed on endoscopy, history of gastroesophageal reflux disease or endoscopic esophagitis that required ongoing treatment with acid suppressive therapy, renal insufficiency, serious comorbidity precluding participation in the study, or known allergy to any of the drugs used in the study.The use of antibiotics or bismuth-containing medications were not allowed in the four weeks before enrollment.The use of nonsteroidal antiinflammatory drugs was not allowed in the study, but acetylsalicylic acid up to 325 mg a day could be taken.Patients who were taking acid suppressive therapy had to be off H 2 -blockers or PPIs for at least four weeks before entry into the study.Patients were allowed to have up to one previous attempt at curing H pylori infection.The protocol was approved by the research ethics board of each participating centre.Informed written consent was obtained from each patient.

Treatments
Patients were randomized to receive either dual therapy with RBC-C (RBC 400 mg twice a day and clarithromycin 500 mg twice a day) or OCA triple therapy consisting of omeprazole 20 mg, clarithromycin 500 mg and amoxicillin 1000 mg, given twice daily for seven days.Assignment of treatments was randomized using tables of random numbers.Investigators and research personnel were blinded until treatment allocation was assigned.Once patients were assigned their treatment, the medications were provided in an unblinded fashion.Treatment started within 10 days of the endoscopy and 13 C-UBT.Compliance was assessed by history and pill count of returned medication.A patient was considered compliant if the patient took 80% of all prescribed medications.

Assessment of H pylori status
At endoscopy, biopsies were taken from the antrum and the corpus, and tested by a rapid urease test for H pylori (CLOtest, Tri-Med Specialties Inc, USA).Positive results were confirmed by a positive 13 C-UBT (PYLORITEST, Isodiagnostika Inc, Canada) before enrollment in the study.This test has previously been validated (7).The test was considered positive for H pylori if excess 13 CO 2 per mil was 3.5 or higher. 13C-UBTs were performed at least four to six weeks and 12 to 14 weeks after the completion of the seven-day treatment.
Patients were considered negative for H pylori infection only if both follow-up 13 C-UBTs were negative and evaluable.

Other assessments
Specific patient symptoms were assessed using a checklist.Patients were seen at the end of the treatment phase to document side effects.A patient satisfaction questionnaire measuring five treatment attributes was developed for this study by GlaxoSmithKline.The instrument has not been previously validated.It was completed by the patient before and after the one-week treatment period.

Study populations
The safety population was defined as any patient who was randomized and had received at least one dose of study medication.The intent-to-treat (ITT) population was defined as any randomized subject with confirmed H pylori infection (results of both UBT and CLOtest positive).Patients with discordant UBT results at the week 4 and week 12 follow-up were considered treatment failures in the ITT analysis.The per-protocol (PP) population was defined as subsets of the ITT population.Subjects in the PP population were required to be compliant with study medication, return for follow-up evaluations within the allotted timeframe and not receive concurrent medication known to interfere with the assessment of H pylori status, such as antibiotics.
For the PP analysis, patients were excluded if the week 4 or week 12 evaluation was missing or unavailable, occurred less than 26 days (week 4) or less than 77 days (Week 12) after the end of treatment, or was discordant with either the four-or 12-week evaluation.

Statistical methods
The primary outcome measure was the H pylori infection eradication rate in the ITT population.The proportion of patients with H pylori eradication in each treatment group was estimated along with the 95% CI for each proportion.The difference in the proportion of eradication success between treatment groups was reported, including the exact 95% CI for the difference in proportions (8).Treatment groups were also compared using a Fisher's Exact Test, appropriate for a two-by-two contingency table.An identical analysis strategy was adopted for the analysis of the eradication rates in the PP population, considered a secondary outcome measure in this study.
Another secondary outcome, patient satisfaction, was assessed by the patient before and after the one-week treatment period.The pretreatment questionnaire measured how important the attributes were in general on a five-point scale from "not at all important" to "extremely important".The post-treatment questionnaire measured how important the attributes were in relation to the randomized treatment regimen that they had just completed on a five-point scale from "very dissatisfied" to "very satisfied".Post-treatment responses were analyzed by collapsing the five-point scale into a binary outcome consisting of either "satisfied" (very satisfied or somewhat satisfied) or "not satisfied" (neutral or somewhat dissatisfied or very dissatisfied) and then compared using a χ 2 test for binary outcomes (9,10).The analysis was done initially based on all patients and then repeated based on the subset of patients who attached some importance (pretreatment) to the given attribute.

Sample size
Based on the assumption that the ITT eradication rates would be at least 85% (1,11,12), a sample size of 150 patients per treatment group was required to ensure that the width of the 95% CI for the difference in eradication rates would not exceed 16 percentage points.

RESULTS
Patients were enrolled from October 1998 until November 1999.Three hundred thirteen patients were enrolled.A summary of the disposition of patients in this study is provided in Table 1.Patient numbers in both groups were very similar.Treatment groups were similar with respect to demographics and baseline characteristics (Table 2).
The ITT population consisted of 305 patients and the PP population, 222 patients.The largest group of patients (N=56, 18% of randomized patients) excluded from the PP analysis were those with missing or discordant UBT results at week 4 and week 12 or those who had follow-up evaluations outside the target time windows (less than 26 days at week 4 or less than 77 days at week 12).Of these 56 patients, at least one follow-up 13 C-UBT result was missing in 28 patients (8.9%).Both 13 C-UBT results were missing in 10 patients and only one UBT was available in 18 patients.There were 15 patients (5% of randomized patients) who had discordant UBT results between their week 4 and week 12 follow-up evaluations.Following repeat tests for those patients with unevaluable UBT results, the number of patients with discordant results was reduced to eight.Patients with discordant results were considered to be treatment failures in the ITT analysis.
The H pylori eradication proportions according to the ITT and PP populations show that the OCA triple regimen was significantly better than RBC-C dual therapy in the ITT and PP groups' analysis (Table 3).The ITT difference between OCA and RBC-C was 12% (95% CI 2% to 22%, P=0.030).For the PP analysis, the difference was 12% (95% CI 4% to 19%, P=0.007).Twenty patients (6%) had received a prior attempt at eradication.The ITT eradication rates for these patients were 63% (five of eight) for OCA compared with 25% (three of 12) for RBC-C.
There was no significant difference in eradication rates between the two treatment groups in patients with a prior ulcer history (OCA 80% or 47 of 59, RBC-C 65% or 34 of 52), based on the ITT population (95% CI 2% to 31%, P=0.133, Fisher's Exact Test).Similar results were noted in the comple-ment of ITT patients without prior ulcer history.The eradication rate in all patients with a prior ulcer history was 73% (81 of 111) versus 71% (138 of 194 patients) without a prior ulcer history, irrespective of treatment group.Other variables such as age and sex were not predictors of treatment success.
As shown in Table 4, patients in the RBC-C treatment group were significantly more satisfied than patients in the OCA treatment group, with respect to the number of drugs that were prescribed (82% versus 69%, P=0.008) and the number of pills that they took each day (81% versus 62%, P=0.001).Conversely, patients in the OCA treatment group were more satisfied with the relief that they received from their study medication than patients in the RBC-C treatment group (71% versus 62%, P=0.039).There were no statistically significant treatment differences with the number of side effects experienced while on treatment (P>0.35).
Overall, compliance with study medication was high.Approximately 89% of patients took 14 doses of all study

Side effects
Both treatments were generally well tolerated.The incidence of adverse events occurring in at least 5% of patients overall is summarized in Table 5.Most of these side effects were minor and did not lead to discontinuation in the study.Patients randomized to OCA reported a higher frequency of diarrhea (41%), compared with 29% for RBC-C.Patients randomized to RBC-C reported a high frequency of abnormal stool color (38%) versus 4% for OCA.Taste disturbance was present in 8% of RBC-C and 12% of OCA-treated patients.Four serious side effects occurred during the study.One patient treated with OCA had an acetaminophen overdose in the follow-up phase.Three RBC-C treated patients respectively had angina pectoris, pulmonary edema and pseudomembranous colitis.The report of pseudomembranous colitis was classified by the investigator as having a reasonable possibility that it was caused by the study medication.This patient recovered without serious consequences, as did the other patients.In total, only four patients withdrew from the study because of adverse effects -one randomized to OCA (allergic reaction) and three to RBC-C (angina pectoris, headache, dizzy spells).

DISCUSSION
Currently, PPI-based triple therapies with clarithromycin and either amoxicillin or metronidazole are the most commonly recommended regimens worldwide (1,2).The recommended duration is seven days in most countries and 10 days in the USA.In the meta-analyses by Unge et al (11,12) the pooled one-week eradication rate for PPI-CA is 85% and 83% for PPI-CM.The eradication rate for the dual therapy of RBC-C given for 14 days has been reported in the range of 73% to 84% (5,13,14).One study, only reported in abstract form, has shown that decreasing the duration of RBC-C treatment from 14 to seven days does not lead to a loss in efficacy (6).A shorter course of treatment is helpful in improving compliance and reducing treatment costs.Indeed, in this study, patient satisfaction was greater in the RBC-C treatment group than in the OCA treatment group with respect to the number of medications that were prescribed and the number of pills taken each   day.Both treatments were well tolerated with mostly mild side effects, that seldomly led to discontinuation of therapy.Despite these potential advantages, RBC-C dual therapy given for seven days was not as effective as OCA triple therapy in this study (ITT 66% versus 78%, PP 84% versus 95%, respectively).The difference between RBC-C and OCA was statistically significant.We consider the 12% difference to be clinically meaningful, especially since subsequent studies using RBC-based triple therapy with clarithromycin and either amoxycillin or metronidazole achieve higher cure rates that are equal to PPI-based triple therapy.
Both treatment regimens were not as effective as reported in prior studies.Although more effective than RBC-C, the 78% eradication rate with OCA was slightly below the ITT target eradication rate of 80%, recommended in several consensus guidelines (1,2).These results cannot be explained by a higher failure rate in patients with previous attempts of eradication, as only 20 patients had such prior attempts and exclusion of these patients did not alter the results.However, the PP results are well above 80% for both treatments.There was no significant difference in cure rates in patients with or without a history of ulcers in the past, suggesting that this does not influence treatment results.However, this is based on a subgroup analysis.The study was not powered to specifically answer the question of whether a prior ulcer history is a predictor of treatment results.
Triple therapy using a PPI with clarithromycin and amoxicillin has been tested in several clinical trials in Canada.In the DU-MACH Study, seven-day treatment with OCA achieved a cure of H pylori infection ITT 78%, PP 87% (15).In a separate Canadian study comparing omeprazole to esomeprazole with clarithromycin and amoxicillin, ITT results were 90% and 88%, and PP results were both 91% (16).
One possible explanation for a decrease in cure rates of H pylori infection is clarithromycin resistance.However, the little available data on resistance to clarithromycin in Canada show that the rates are low, from 2% to 4% (17)(18)(19).This is in contrast to data from the USA where higher rates of clarithromycin resistance of 6% to 15% have been reported (20)(21)(22).Clarithromycin resistance was not assessed in this study.However, it is possible that H pylori resistance to clarithromycin has increased in Canada as a result of more widespread use, and this deserves further study.
Studies have shown that triple therapy of RBC-C with either metronidazole or amoxicillin achieve similar high eradication rates ranging from 80% to 90% as the PPI triple therapies (23).Consequently, RBC-C triple therapy appears to have largely replaced the RBC-C dual therapy.Interestingly, in a recent meta-analysis by Gisbert et al (24) it was shown that, when RBC is given together with clarithromycin and metronidazole, the success rate was slightly higher when compared with PPI triple therapy with clarithromycin and metronidazole.Although most included studies did not provide data on the effect of metronidazole resistance on eradication rates, the study did suggest that in the presence of metronidazole resistance, RBC-C triple therapy is better able to overcome metronidazole resistance than a triple PPI-CM regimen (23).Another systematic review confirmed this finding (25).
In our study, two UBTs were administered four to six and 12 to 14 weeks after the seven-day treatment.UBT has the advantage that it does not require endoscopy, and if 13 C-urea is used rather than 14 C-urea, the test can be done outside hospi-tals (26).The study protocol required two UBT's done six to eight weeks apart.In this study 15 of 313 patients (4.8%) had discordant results between follow-up evaluations.This suggests that in future clinical trials, a single UBT, performed at least four weeks after treatment is completed, is sufficient to document cure of the infection.
In this study, patient satisfaction data was collected prestudy and following one week of treatment.As little work had been done in this area, an importance-performance questionnaire was designed with the intent of determining first which factors were important to patients, and second, how the treatments compared with respect to the attributes that were deemed important.The results of the analysis, however, demonstrated that despite the perceived importance of baseline attributes, such as fewer medications and lower number of pills, this did not have any impact on the patient's level of satisfaction after seven days of treatment.Thus, the design and validation of future questionnaires may only need to be performed assessing post-treatment satisfaction.Patients were more satisfied in the RBC-C group with the number of drugs and the number of pills that they were required to take each day, indicating that patients are concerned about taking large amounts of medications.Patients in the OCA group were more satisfied than RBC-C treated patients with the relief that they received from the treatment, indicating a link between symptoms and treatment success.
In conclusion, a seven-day dual therapy regimen of RBC-C was not as effective as a seven-day OCA triple therapy.This suggests that when prescribing RBC, a seven-day RBC-C triple therapy with either amoxicillin or metronidazole would be preferred over RBC-C dual therapy.Unfortunately, due to lack of physician demand, RBC is no longer available in Canada and several other countries.

RBC dual therapy compared
with omeprazole triple therapy Can J Gastroenterol Vol 17 No 9 September 2003 535

ACKNOWLEDGEMENTS:
This research was sponsored by GlaxoSmithKline (Canada) Incorporated.The authors would like to express their gratitude to the following additional investigators for their participation in the this study: Drs P Campbell, L Cohen, W Depew, D Duerksen, R Hunt, R LaHaie, B Lasko, C Massicotte, P Paré, I Prokopiw, E Shaffer and AH Steinhart.Dr Veldhuyzen van Zanten is the recipient of a Nova Scotia Clinical Research Scholar Award.RBC dual therapy compared with omeprazole triple therapy Can J Gastroenterol Vol 17 No 9 September 2003 537

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TABLE 4 Patient satisfaction questionnaire -post-treatment satisfaction with respect to prescribed treatment regimen -intent-to- treat population (n=305)
*One patient did not have any questionnaire data; † SATISFIED Patients who were either VERY or SOMEWHAT SATISFIED; ‡ NOT SATISFIED Patients who were either NEUTRAL or SOMEWHAT/VERY DISSATISFIED; § Cochran-Mantel-Haenszel Statistic (Modified Ridit Scores) -Van-Elterans Test.OCA Omeprazole, clarithromycin, amoxicillin; RBC-C Ranitidine bismuth citrate-clarithromycin