ORIGINAL ARTICLE
Clarithromycin Versus Metronidazole as First-line Helicobacter pylori Eradication A Multicenter, Prospective, Randomized Controlled Study in Japan Toshihiro Nishizawa, MD, PhD,*w Takama Maekawa, MD, PhD,z Noriko Watanabe, MD, PhD,y Naohiko Harada, MD, PhD,8 Yasuo Hosoda, MD, PhD,z Masahiro Yoshinaga, MD, PhD,# Toshiyuki Yoshio, MD, PhD,** Hajime Ohta, MD,ww Syuuji Inoue, MD, PhD,zz Tatsuya Toyokawa, MD, PhD,yy Haruhiro Yamashita, MD,88 Hiroki Saito, MD,zz Toshio Kuwai, MD, PhD,## Shunsuke Katayama, MD, PhD,*** Eiji Masuda, MD, PhD,www Hideharu Miyabayashi, MD,zzz Toshio Kimura, MD, PhD,yyy Yuko Nishizawa, MPharm,888 Masahiko Takahashi, MD, PhD,* and Hidekazu Suzuki, MD, PhDw
Background: Helicobacter pylori eradication rates achieved with a first-line regimen of clarithromycin (CLR) combined with amoxicillin (AMX) and a proton pump inhibitor have recently fallen to r80% because of the increasing incidence of CLR resistance in Japan. This randomized multicenter trial aimed to compare the eradication success of 2 first-line triple therapy regimens: rabeprazole, amoxicillin, and clarithromycin (RAC) versus rabeprazole, amoxicillin, and metronidazole (RAM).
Received for publication January 28, 2014; accepted May 8, 2014. From the *Division of Gastroenterology, National Hospital Organization, Tokyo Medical Center; wDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine; 888Department of Pharmacy, National Center for Global Health and Medicine, Tokyo; zDivision of Gastroenterology, National Hospital Organization, Kyoto Medical Center, Kyoto; yDivision of Gastroenterology, National Hospital Organization, Mie Central Medical Center, Mie; 8Division of Gastroenterology, National Kyushu Medical Center, Fukuoka; zDivision of Gastroenterology, National Hospital Organization, Saitama National Hospital, Wako; #Division of Gastroenterology, National Hospital Organization, Beppu Medical Center, Beppu; **Division of Gastroenterology, National Hospital Organization, Osaka Medical Center; wwwDivision of Gastroenterology, National Hospital Organization, Osaka Minami Medical Center, Kawachinagano, Osaka; wwDivision of Gastroenterology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Ishikawa; yyDivision of Gastroenterology, National Hospital Organization, Fukuyama Medical Center; ##Division of Gastroenterology, National Hospital Organization, Kure Medical Center, Hiroshima; 88Division of Gastroenterology, National Hospital Organization, Okayama Medical Center, Okayama; zzDivision of Gastroenterology, National Hospital Organization, Asahikawa Medical Center, Asahikawa; yyyDivision of Gastroenterology, National Hospital Organization, Hokkaido Medical Center, Sapporo, Hokkaido; ***Division of Gastroenterology, National Hospital Organization, Yonago Medical Center, Yonago, Tottori, Japan; zzDivision of Gastroenterology, Kochi National Hospital, Kochi; and zzzDivision of Gastroenterology, National Hospital Organization, Matsumoto Medical Center, Mesa, Matsumoto, Nagano. Supported by a Grant from the National Hospital Organization [No. H24-NHO (gastroenterology)-01 to T.N.]. The authors declare that they have nothing to disclose. Reprints: Hidekazu Suzuki, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 1608582, Japan (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
468 | www.jcge.com
Methods: A total of 124 consecutive patients infected with H. pylori were randomized into one of two 7-day therapeutic regimens: RAC (n = 60) or RAM (n = 64). Eradication was confirmed by the 13 C-urea breath test. Adverse effects were also assessed. Results: Intention-to-treat and per protocol H. pylori eradication rates were 73.3%/77.2% in the RAC group and 90.6%/93.5% in the RAM group. The eradication rate of RAM therapy was significantly higher than that of RAC therapy. CLR, metronidazole, and AMX resistance was found in 36.2%, 2.1%, and 0% of patients, respectively. In addition, no relevant differences in adverse effects were observed. Conclusions: Metronidazole-based therapy (RAM) was superior to standard CLR-based therapy (RAC) for first-line H. pylori eradication. This reflects the progressive increase in CLR resistance observed in Japan. Key Words: metronidazole, clarithromycin, eradication, Helicobacter pylori
(J Clin Gastroenterol 2015;49:468–471)
E
radication of Helicobacter pylori infection has been reported as an effective strategy in the treatment of peptic ulcers and gastric mucosa-associated lymphoid tissue lymphoma, in addition to the prevention of gastric cancer.1–4 A first-line eradication regimen of clarithromycin (CLR) combined with amoxicillin (AMX), and a proton pump inhibitor (PPI) is covered under national health insurance in Japan.5 Although the mean nationwide CLR resistance rate determined by the Japanese Society of Chemotherapy was 7.0% in 2000, it has increased to 27.2% in 2006.6 The success rate of first-line treatment using CLR combined with AMX and a PPI has recently fallen to r80% because of an increasing incidence of CLR resistance. A second-line regimen using metronidazole (MNZ) combined with AMX and a PPI is also covered under national health insurance in Japan. The prevalence of H. pylori resistant to MNZ in Japan is reportedly 5% to 12%, and the success rate of the second-line regimen that uses MNZ combined with AMX and a PPI has been maintained at approximately 90%.7,8 Given the recent surge in CLR J Clin Gastroenterol
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Volume 49, Number 6, July 2015
J Clin Gastroenterol
Volume 49, Number 6, July 2015
resistance compared with MNZ resistance, a first-line regimen of MNZ combined with AMX and a PPI may be best suited for use in Japan. Although we have previously shown that MNZ-based therapy was superior to standard CLRbased therapy for the first-line eradication of H. pylori,9 the prior study had a single-center, nonrandomized, retrospective design. CLR-based therapy is still used as first-line eradication regimen in Japan. This study aimed to compare the efficacy and tolerability of a first-line CLR-based H. pylori eradication regimen with an MNZ-based regimen in a multicenter randomized controlled study.
METHODS Patients The present study was a randomized, prospective, multicenter trial with 16 participating Japanese hospitals affiliated with the National Hospital Organization. A total of 124 patients (51 men, 73 women; age: 60.8 ± 13.5 y, mean ± SD) referred to us between November 2012 and January 2014 were enrolled. The patients recruited in every center were consecutive. Patients diagnosed with atrophic gastritis by endoscopic examinations were included in the present study. Exclusion criteria were as follows: (1) age less than 18 years; (2) presence of clinically significant underlying disease (hepatic or renal disease); (3) history of gastric surgery; (4) allergy to any of the drugs used in the study; (5) pregnant or nursing women; (6) serious coexisting illness that could interfere with the study; (7) peptic ulcer; and (8) previous H. pylori eradication therapy. The study was conducted with the approval of the Ethics Committee of the National Hospital Organization Tokyo Medical Center, and informed consent was obtained from all patients. The clinical trial registration number of the University Hospital Medical Information Network was R000009454. The presence of H. pylori before first-line eradication therapy was confirmed with the 13C-urea breath test (UBT) or the microaerobic bacterial culture method. The culture method was used so that antibiotic sensitivity testing could be performed simultaneously. Patients were randomized to receive one of the following treatments: (i) rabeprazole, amoxicillin, and clarithromycin (RAC): triple therapy consisting of rabeprazole 10 mg, AMX 750 mg, and CLR 400 mg, twice daily for 7 days; or (ii) rabeprazole, amoxicillin, and metronidazole (RAM): triple therapy consisting of rabeprazole10 mg, AMX 750 mg, and MNZ 250 mg, twice daily for 7 days. Compliance with medication was checked immediately after stopping treatment by counting the number of returned pills. Successful H. pylori eradication was defined as a negative result of the UBT at the end of 12 weeks after treatment completion. The cut-off value used was 2.5%.10 All patients had to have been off PPI for a minimum of 2 weeks at the time of UBT test. If the UBT result was inconclusive (2.5% to 5.0%), the test was rescheduled for a later date.
Antibiotic Sensitivity Testing The sensitivity of H. pylori to each antibiotic was tested using the agar dilution method.11 It was performed in random at Tokyo Medical Center and Kyoto Medical Center. The breakpoint was set at 1 mg/mL for CLR, 8 mg/ mL for MNZ, and 0.5 mg/mL for AMX, and a strain was r
deemed resistant when its minimum inhibitory concentration was equal to or exceeded the breakpoint value.12–15
Endpoints and Subgroup Analyses The primary endpoint was the eradication rate in the intention-to-treat (ITT) and per protocol (PP) populations. The secondary endpoints were antibiotic resistance rates in each group. Subgroup analyses were conducted based on antibiotic resistance status. Eradication rates were compared between the CLR-resistant and CLR-sensitive groups.
Adverse Events Adverse events were defined as undesirable medical symptoms or conditions that emerge in patients treated with the study drug (including changes in laboratory values) regardless of causal relationship during drug administration. Adverse events were documented at the conclusion of treatment using a direct questioning approach by each investigator. Investigators were blinded to patients’ assigned treatments. The degree of symptoms was scored as 0 (absent), 1 (mild), 2 (moderate), or 3 (severe). The frequency of adverse events was compared between the RAC and RAM groups.
Calculation of Sample Size According to a previous trial,7,9 eradication rates in the first-line eradication population were 75% in the RAC group and 92% in the RAM group. Assuming an eradication rate of 75% for RAC and 92% for RAM, an a-error of 0.05, a b-error of 0.20, and power of 0.80, 120 participants, including 60 in the RAC group and 60 in the RAM group, would be required. Taking into consideration the censored cases, 124 participants (62 in the RAC group and 62 in the RAM group) had to be recruited for the study.
Randomization
Study Protocol
Copyright
CLR Versus MNZ in First-line H. pylori Eradication
Eligible participants were sequentially randomized in a 1:1 ratio according to a computer-generated randomization list. The randomization list was managed at the Tokyo Medical Centre, Clinical Research Centre. Physicians determined patients’ eligibility for this study and allocated the next available number on entry into the trial. Study drugs and dosing instructions were packed into a sealed envelope with an assigned treatment number.
Statistical Analysis Statistical analysis of intergroup differences in eradication rates was performed using the w2 test. Betweengroup comparisons of patient characteristics (sex, age, resistance rates) were conducted using the w2 test, Fisher exact test, and Student t test, as appropriate. P-values of
Clarithromycin Versus Metronidazole as First-line Helicobacter pylori Eradication A Multicenter, Prospective, Randomized Controlled Study in Japan Toshihiro Nishizawa, MD, PhD,*w Takama Maekawa, MD, PhD,z Noriko Watanabe, MD, PhD,y Naohiko Harada, MD, PhD,8 Yasuo Hosoda, MD, PhD,z Masahiro Yoshinaga, MD, PhD,# Toshiyuki Yoshio, MD, PhD,** Hajime Ohta, MD,ww Syuuji Inoue, MD, PhD,zz Tatsuya Toyokawa, MD, PhD,yy Haruhiro Yamashita, MD,88 Hiroki Saito, MD,zz Toshio Kuwai, MD, PhD,## Shunsuke Katayama, MD, PhD,*** Eiji Masuda, MD, PhD,www Hideharu Miyabayashi, MD,zzz Toshio Kimura, MD, PhD,yyy Yuko Nishizawa, MPharm,888 Masahiko Takahashi, MD, PhD,* and Hidekazu Suzuki, MD, PhDw
Background: Helicobacter pylori eradication rates achieved with a first-line regimen of clarithromycin (CLR) combined with amoxicillin (AMX) and a proton pump inhibitor have recently fallen to r80% because of the increasing incidence of CLR resistance in Japan. This randomized multicenter trial aimed to compare the eradication success of 2 first-line triple therapy regimens: rabeprazole, amoxicillin, and clarithromycin (RAC) versus rabeprazole, amoxicillin, and metronidazole (RAM).
Received for publication January 28, 2014; accepted May 8, 2014. From the *Division of Gastroenterology, National Hospital Organization, Tokyo Medical Center; wDivision of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine; 888Department of Pharmacy, National Center for Global Health and Medicine, Tokyo; zDivision of Gastroenterology, National Hospital Organization, Kyoto Medical Center, Kyoto; yDivision of Gastroenterology, National Hospital Organization, Mie Central Medical Center, Mie; 8Division of Gastroenterology, National Kyushu Medical Center, Fukuoka; zDivision of Gastroenterology, National Hospital Organization, Saitama National Hospital, Wako; #Division of Gastroenterology, National Hospital Organization, Beppu Medical Center, Beppu; **Division of Gastroenterology, National Hospital Organization, Osaka Medical Center; wwwDivision of Gastroenterology, National Hospital Organization, Osaka Minami Medical Center, Kawachinagano, Osaka; wwDivision of Gastroenterology, National Hospital Organization, Kanazawa Medical Center, Kanazawa, Ishikawa; yyDivision of Gastroenterology, National Hospital Organization, Fukuyama Medical Center; ##Division of Gastroenterology, National Hospital Organization, Kure Medical Center, Hiroshima; 88Division of Gastroenterology, National Hospital Organization, Okayama Medical Center, Okayama; zzDivision of Gastroenterology, National Hospital Organization, Asahikawa Medical Center, Asahikawa; yyyDivision of Gastroenterology, National Hospital Organization, Hokkaido Medical Center, Sapporo, Hokkaido; ***Division of Gastroenterology, National Hospital Organization, Yonago Medical Center, Yonago, Tottori, Japan; zzDivision of Gastroenterology, Kochi National Hospital, Kochi; and zzzDivision of Gastroenterology, National Hospital Organization, Matsumoto Medical Center, Mesa, Matsumoto, Nagano. Supported by a Grant from the National Hospital Organization [No. H24-NHO (gastroenterology)-01 to T.N.]. The authors declare that they have nothing to disclose. Reprints: Hidekazu Suzuki, MD, PhD, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 1608582, Japan (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
468 | www.jcge.com
Methods: A total of 124 consecutive patients infected with H. pylori were randomized into one of two 7-day therapeutic regimens: RAC (n = 60) or RAM (n = 64). Eradication was confirmed by the 13 C-urea breath test. Adverse effects were also assessed. Results: Intention-to-treat and per protocol H. pylori eradication rates were 73.3%/77.2% in the RAC group and 90.6%/93.5% in the RAM group. The eradication rate of RAM therapy was significantly higher than that of RAC therapy. CLR, metronidazole, and AMX resistance was found in 36.2%, 2.1%, and 0% of patients, respectively. In addition, no relevant differences in adverse effects were observed. Conclusions: Metronidazole-based therapy (RAM) was superior to standard CLR-based therapy (RAC) for first-line H. pylori eradication. This reflects the progressive increase in CLR resistance observed in Japan. Key Words: metronidazole, clarithromycin, eradication, Helicobacter pylori
(J Clin Gastroenterol 2015;49:468–471)
E
radication of Helicobacter pylori infection has been reported as an effective strategy in the treatment of peptic ulcers and gastric mucosa-associated lymphoid tissue lymphoma, in addition to the prevention of gastric cancer.1–4 A first-line eradication regimen of clarithromycin (CLR) combined with amoxicillin (AMX), and a proton pump inhibitor (PPI) is covered under national health insurance in Japan.5 Although the mean nationwide CLR resistance rate determined by the Japanese Society of Chemotherapy was 7.0% in 2000, it has increased to 27.2% in 2006.6 The success rate of first-line treatment using CLR combined with AMX and a PPI has recently fallen to r80% because of an increasing incidence of CLR resistance. A second-line regimen using metronidazole (MNZ) combined with AMX and a PPI is also covered under national health insurance in Japan. The prevalence of H. pylori resistant to MNZ in Japan is reportedly 5% to 12%, and the success rate of the second-line regimen that uses MNZ combined with AMX and a PPI has been maintained at approximately 90%.7,8 Given the recent surge in CLR J Clin Gastroenterol
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Volume 49, Number 6, July 2015
J Clin Gastroenterol
Volume 49, Number 6, July 2015
resistance compared with MNZ resistance, a first-line regimen of MNZ combined with AMX and a PPI may be best suited for use in Japan. Although we have previously shown that MNZ-based therapy was superior to standard CLRbased therapy for the first-line eradication of H. pylori,9 the prior study had a single-center, nonrandomized, retrospective design. CLR-based therapy is still used as first-line eradication regimen in Japan. This study aimed to compare the efficacy and tolerability of a first-line CLR-based H. pylori eradication regimen with an MNZ-based regimen in a multicenter randomized controlled study.
METHODS Patients The present study was a randomized, prospective, multicenter trial with 16 participating Japanese hospitals affiliated with the National Hospital Organization. A total of 124 patients (51 men, 73 women; age: 60.8 ± 13.5 y, mean ± SD) referred to us between November 2012 and January 2014 were enrolled. The patients recruited in every center were consecutive. Patients diagnosed with atrophic gastritis by endoscopic examinations were included in the present study. Exclusion criteria were as follows: (1) age less than 18 years; (2) presence of clinically significant underlying disease (hepatic or renal disease); (3) history of gastric surgery; (4) allergy to any of the drugs used in the study; (5) pregnant or nursing women; (6) serious coexisting illness that could interfere with the study; (7) peptic ulcer; and (8) previous H. pylori eradication therapy. The study was conducted with the approval of the Ethics Committee of the National Hospital Organization Tokyo Medical Center, and informed consent was obtained from all patients. The clinical trial registration number of the University Hospital Medical Information Network was R000009454. The presence of H. pylori before first-line eradication therapy was confirmed with the 13C-urea breath test (UBT) or the microaerobic bacterial culture method. The culture method was used so that antibiotic sensitivity testing could be performed simultaneously. Patients were randomized to receive one of the following treatments: (i) rabeprazole, amoxicillin, and clarithromycin (RAC): triple therapy consisting of rabeprazole 10 mg, AMX 750 mg, and CLR 400 mg, twice daily for 7 days; or (ii) rabeprazole, amoxicillin, and metronidazole (RAM): triple therapy consisting of rabeprazole10 mg, AMX 750 mg, and MNZ 250 mg, twice daily for 7 days. Compliance with medication was checked immediately after stopping treatment by counting the number of returned pills. Successful H. pylori eradication was defined as a negative result of the UBT at the end of 12 weeks after treatment completion. The cut-off value used was 2.5%.10 All patients had to have been off PPI for a minimum of 2 weeks at the time of UBT test. If the UBT result was inconclusive (2.5% to 5.0%), the test was rescheduled for a later date.
Antibiotic Sensitivity Testing The sensitivity of H. pylori to each antibiotic was tested using the agar dilution method.11 It was performed in random at Tokyo Medical Center and Kyoto Medical Center. The breakpoint was set at 1 mg/mL for CLR, 8 mg/ mL for MNZ, and 0.5 mg/mL for AMX, and a strain was r
deemed resistant when its minimum inhibitory concentration was equal to or exceeded the breakpoint value.12–15
Endpoints and Subgroup Analyses The primary endpoint was the eradication rate in the intention-to-treat (ITT) and per protocol (PP) populations. The secondary endpoints were antibiotic resistance rates in each group. Subgroup analyses were conducted based on antibiotic resistance status. Eradication rates were compared between the CLR-resistant and CLR-sensitive groups.
Adverse Events Adverse events were defined as undesirable medical symptoms or conditions that emerge in patients treated with the study drug (including changes in laboratory values) regardless of causal relationship during drug administration. Adverse events were documented at the conclusion of treatment using a direct questioning approach by each investigator. Investigators were blinded to patients’ assigned treatments. The degree of symptoms was scored as 0 (absent), 1 (mild), 2 (moderate), or 3 (severe). The frequency of adverse events was compared between the RAC and RAM groups.
Calculation of Sample Size According to a previous trial,7,9 eradication rates in the first-line eradication population were 75% in the RAC group and 92% in the RAM group. Assuming an eradication rate of 75% for RAC and 92% for RAM, an a-error of 0.05, a b-error of 0.20, and power of 0.80, 120 participants, including 60 in the RAC group and 60 in the RAM group, would be required. Taking into consideration the censored cases, 124 participants (62 in the RAC group and 62 in the RAM group) had to be recruited for the study.
Randomization
Study Protocol
Copyright
CLR Versus MNZ in First-line H. pylori Eradication
Eligible participants were sequentially randomized in a 1:1 ratio according to a computer-generated randomization list. The randomization list was managed at the Tokyo Medical Centre, Clinical Research Centre. Physicians determined patients’ eligibility for this study and allocated the next available number on entry into the trial. Study drugs and dosing instructions were packed into a sealed envelope with an assigned treatment number.
Statistical Analysis Statistical analysis of intergroup differences in eradication rates was performed using the w2 test. Betweengroup comparisons of patient characteristics (sex, age, resistance rates) were conducted using the w2 test, Fisher exact test, and Student t test, as appropriate. P-values of
