Comparison of once-a-day versus twice-a-day clarithromycin triple therapy for h

COMPARISON OF ONCE-A-DAY VERSUS TWICE-A-DAY
CLARITHROMYCIN TRIPLE THERAPY
FOR HELICOBACTER PYLORI ERADICATION
Department of Medicine, Section of Gastroenterology, Cardinal Santos Medical Center, San Juan, Metro Manila ABSTRACT

Background/ Aim: Eradication therapy with Esomeprazole, Amoxicillin and
Clarithromycin is used extensively, however the efficacy of once-a-day Clarithromycin have not been determined. This study was conducted to compare the efficacy and safety profile of once-a-day Clarithromycin triple therapy with the standard triple therapy as a treatment for Helicobacter pylori (H. pylori) infected patients. Methods: This
randomized, open, parallel-controlled study was conducted at Cardinal Santos Medical Center from July 2005 to November 2005. A total of 40 consecutive patients who were H. pylori positive proven by rapid urease test were included and randomly assigned to once-a-day or twice-a-day Clarithromycin triple therapy. Eighteen patients were administered with once-a-day Clarithromycin therapy including Esomeprazole 40 mg b.i.d. and Amoxicillin 1 g b.i.d. for 7 days. Twenty two patients received a standard 7-day triple therapy consisting of Esomeprazole 40 mg b.i.d., Clarithromycin 500 mg b.i.d. and Amoxicillin 1 g b.i.d. The eradication rates were evaluated by the (13) C-Urea breath test at least 4 weeks after completion of a course of treatment. Results: Thirty six patients
completed the trial and 4 patients dropped out. The eradication rates in twice-a-day therapeutic group and once-a-day therapeutic group (intention to treat [n=22] / per protocol [n=18]) were 95% / 95% (p=0.832) and 88% / 67% (p=0.02) respectively. Short lasting and self-limiting side effects including taste disturbance and diarrhea were reported in 8 patients (36%) in the once-a-day group and 6 patients (33%) in the twice-a- day group with odds ratio of 1.75. Conclusion: Once-a-day and twice-a-day
Clarithromycin- based triple therapies were both effective and safe in eradicating H. pylori in the patient population studied. Category: Stomach and Duodenum
Article: Experimental (Randomized Controlled Trial)
Key Words: Helicobacter pylori
Once-a-day Clarithromycin-based triple therapy INTRODUCTION
Helicobacter pylori (H. pylori) infection, which is presenting 30- 60% of the population in developed countries and in more than 60% in developing countries, is established to be a major cause of gastritis, peptic ulcer disease and gastric cancer.1 It is a serious, chronic, transmissible infectious disease which is preceded by long H. pylori resides in the surface of the stomach within the mucus as well as attached mucus cells. H. pylori can also be found within epithelial cells. These various niches provide a challenge for antimicrobial therapy. In addition, the gastric lumen is a hostile environment for antimicrobial therapy because the drugs must penetrate thick mucus and may need to be active at pH levels below neutral. Despite these difficulties, relatively effective therapies have been identified, primarily through the process of trial Currently therapy with proton pump inhibitors such as Esomeprazole and two antibiotics, Amoxicillin and Clarithromycin is the most frequently prescribed medication for the eradication of H. pylori.3, 4, 5 Non-recurrence of gastric and duodenal ulcer is strictly dependent on the success of H. pylori eradication and the persistence of infection is a negative prognostic marker 6, thus the need for effective H. pylori eradication. An obstacle to effective therapy is poor compliance with the prescribed medication as with any other disease requiring multiple drugs for therapy. Simplifying an effective therapy is ideal using less medication and/ or shorted duration. Although the modified-release formulation of Clarithromycin (OD tablet) has demonstrated bioequivalence to the immediate-release formulation (500 mg tablet) 7, the effectiveness of this new formulation in H. pylori eradication has not been This therapeutic trial is designed to compare the clinical success rate (percentage of patients with successful cure of H. pylori) and safety of once-daily dosing and the standard twice-daily regimens of Clarithromycin triple therapy in documented H. pylori OBJECTIVES
To compare the efficacy and safety of once-a-day Clarithromycin and twice-a-day Clarithromycin-based triple therapy in the eradication of Helicobacter pylori 1. To determine the proportion of patients with a negative urea breath test among patients receiving twice-a-day Clarithromycin versus those receiving once-a- 2. To determine the odds ratio of adverse events in both treatment groups MATERIALS AND METHODS
Adult patients of either sex, with duodenal ulcer or erosive / superficial gastropathy, or both, who were H. pylori positive (as determined by rapid urease test- Cu test) seen at the Endoscopy Unit of Cardinal Santos Medical Center from July 2005 to Patients with more than one previous attempt to eradicate H. pylori, those with active peptic ulcer and active bleeding from gastrointestinal tract were excluded. Other exclusion criteria were regular treatment with non-steroidal anti-inflammatory drugs, concomitant antimicrobial agents and allergy to any of the study drug. This study was approved by the Ethics Committee of the Cardinal Santos Medical Center before commencement of patient enrollment. Informed consent was obtained from This study was a prospective, randomized, open-label, blinded endpoint (PROBE) trial with parallel-group design. Eligible patients were randomized to 1 of 2 treatment groups (Table 1) by a process of transparent envelopes. Equivalent number of pieces of paper, determined based on the calculated sample size, were placed on sealed transparent envelopes. Each paper will indicate the group allocation of patients who will be included in the study. Patients were allocated the next transparent envelope once they have NOTE: Esomeprazole and Amoxicillin were administered twice a day daily for 7 days. The twice-a-day therapeutic group received 500mg of Clarithromycin, twice a day while patients allocated in the once-a-day therapeutic group received once-a-day At the first visit (VISIT 1), patient underwent endoscopy with biopsy specimen taken from the antrum and body, where rapid urease test (Cu test) was performed to confirm infection. Patients returned for clinic visit (VISIT 2) after the 7-day treatment period for symptom, adverse event and compliance assessment. (13) C-Urea breath test (UBT) was performed 4 weeks after the end of treatment (VISIT 3). Eradication was defined as a negative UBT test 4 weeks after cessation of therapy. Those patients included in once-a-day therapeutic group with a positive UBT after 4 weeks of therapy (treatment failure) were given the standard treatment for H. pylori for The primary measure of efficacy was the eradication of H. pylori as determined by the results of UBT at Visit 3. The two-sample binomial test was used to evaluate the results. Success rate for once-a-day therapeutic group was set at 94% based on MACH 2 Study. 3 The success rate for twice-a-day therapeutic group was projected at 80% on an intention to treat basis upon the recommendation of the Maastricht Consensus Report. 8 We calculated that 90 patients would be required to show equivalence between the two study groups, with a power of 80% with an = 0.05 (two-tailed). Analysis was performed on an intention to treat (ITT) and per protocol basis. ITT patients included all those enrolled and randomized to treatment groups. This included those who took no or incomplete medication or those with delayed exclusions due to lost to follow-up evaluation (not returning for visit 2 or 3), or had deviated significantly from the study protocol (e.g. intake of interval antibiotics). For the per protocol analysis, these It was assumed that H. pylori had not been eradicated if the patient did not return for UBT at Visit 3, that is, a worst case analysis. Forty patients were initially recruited for the ITT analysis. Table 2 shows the baseline characteristics of the 40 eligible patients. Demographic characteristics were similar in the two groups, as were symptoms at initial assessment. Of these 40 patients, 36 patients were eligible for inclusion in the per protocol analysis. Two patients who were excluded had not attended visit 3, the other two patients did not complete the TABLE 2. Pretreatment Clinical and Demographic Characteristics The proportion of patients in whom H. pylori was successfully eradicated for the per protocol and the intention to treat patient populations are shown in Table 3. In the ITT population, both groups are found to have equal performance using binomial test for proportion with p-value of 0.832. Evaluating the results using the per protocol analysis TABLE 3. Proportion of patients with negative Urea Breath Test 7 days after treatment The safety analysis was done on all 38 patients who had taken at least one dose of the medications. The most frequently reported adverse events were diarrhea and taste Eight patients experienced diarrhea while 6 patients reported taste disturbance. Both groups were equal in terms of the occurrence of adverse effects, using the binomial Odds ratio was used to determine occurrence of adverse effects on both groups which revealed a value of 1.75. However, no patients withdrew from the study as a result TABLE 4. Patients Experiencing Adverse Events in Each Treatment Group DISCUSSION
This study has shown that once-a-day Clarithromycin and twice-a-day Clarithromycin triple therapy, given for 7 days effectively eradicates H. pylori. The proportion of patients in once-a-day therapeutic group in whom H. pylori was successfully eradicated was comparable with twice-a-day therapeutic group in the ITT population, having a success rate of 88%. This eradication rate is consistent with other studies using Clarithromycin and proton-pump inhibitor triple therapies. 4, 5, 9, 10 However, unlike many studies reported in Europe 3, per protocol eradication rates above 90% were not achieved for the once-a-day therapeutic group which was only 67%. The higher number of patients excluded in the once-a-day therapeutic group might have influenced The results suggests that giving once-a-day or twice-a-day Clarithromycin triple therapy results in significantly equivalent eradication efficacies, although there was a trend for lesser eradication rate for once-a-day therapeutic group in the per protocol population. The use, however, of fewer tablets has perceived increased compliance value. It has been suggested that eradication rates vary between patients subgroups. In particular, patients with non-ulcer dyspepsia have been reported to have lower eradication rates than patients with ulcer disease.11, 12 In this study, a majority of the patients in once- a-day and twice-a-day therapeutic group ( 78% and 73% respectively) showed high eradication rates in both intention to treat and per protocol populations despite being The use of Urea Breath Test (UBT) as assessment for the primary outcome of this study has been proven to have a very high sensitivity as reported by previous trials 3, 9 reporting a 95% agreement between UBT and histological assessments. This test is a highly sensitive method for assessing H. pylori status both before and after therapy and that the reliability of the method is such that a single post-therapy UBT is sufficient in The number of patients reporting adverse effects was relatively similar in both groups, with calculated Odds ratio of 1.75 which was relatively small since statistically both groups have the same performance. No patients withdrew from the study because of these side effects, thus the treatments were generally well tolerated. The high incidence of taste related adverse events is a frequently reported occurrence with Clarithromycin and was thought to be dose-dependent.3 That however was not observed in our study. Diarrhea and GIT disturbances is also a well documented side effect of Amoxicillin, a broad-spectrum penicillin antibiotic.14 Reports of this adverse event among our study patients were consistent with current knowledge of treatment with these drugs. CONCLUSION
Once-a-day and twice-a-day Clarithromycin- based triple therapies were both effective and safe in eradicating H. pylori in the patient population studied. RECOMMENDATIONS
Calculated sample size must be achieved to determine absolute comparability Data concerning the pretreatment antimicrobial sensitivities, which were not included in this study, may also proved useful in providing conclusive results. REFERENCES
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