Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial Peter Malfertheiner, Franco Bazzoli, Jean-Charles Delchier, Krysztof Celinski, Monique Giguere, Marc Riviere, Francis Megraud, for the Pylera Study Group Lancet Vol 377 : March 12, 2011 소화기 내과 R4 강 경환 Journal Conference

Introduction Infection with H. pylori is a substantial public health problem → affects 20–50% of people in industrialised nations and up to 80% in less-developed countries Helicobacter 2004; 9 (suppl 1): 67–72 H. pylori is associated with many gastroduodenal disorders, including peptic ulcer disease, gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphoma → eradication of H pylori is advocated to prevent the development of this disease N Engl J Med 2002; 347: 1175–86 Lancet 2009; 374: 1449–61 Helicobacter 2010; 15: 1–20 J Gastroenterol Hepatol 2009; 24: 1587–1600

Introduction In all international guidelines, treatment with OAC (standard therapy) is recommended as first-line therapy if clarithromycin resistance ≤20% Gut 2007; 56: 772–81 Am J Gastroenterol 2007; 102: 1808–25 J Gastroenterol Hepatol 2009; 24: 1587–1600 Bismuth-containing therapy is proposed in regions with high in-vitro resistance to clarithromycin or metronidazole, because the addition of bismuth to other antibiotic regimens has been shown to improve H. pylori eradication Aliment Pharmacol Ther 2005; 21: 165–68 Antimicrobial resistance rates have increased and treatments for H. pylori need assessment J Antimicrob Chemother 2010; 65: 327–32 Gut 2010; 59: 1143–53

Aliment Pharmacol Ther 2003; 17: 415–20

Am J Gastroenterol 2003; 98: 562–67

Introduction Aim - To assess efficacy and safety of quadruple therapy for 10 days VS standard therapy given for 7 days for the eradication of H. pylori - Special attention has been directed to pretherapeutic H. pylori resistance to clarithromycin and metronidazole and the effect of resistance on the efficacy of treatment

Methods - A randomised, open-label, non-inferiority, phase 3 trial in 39 sites in Europe - Between June 11, 2008, and June 22, 2009 Inclusion Criteria  Age≥18 years  Confirmed H pylori and upper GI symptoms  Women were eligible if they were not pregnant or nursing (Childbearing potential →Use medically acceptable contraception for the duration of the study and 30 days thereafter) Exclusion Criteria  Previously used antibiotics to eradicate adequately recorded infection with H pylori  Contraindications to study drugs  Substantial organ impairment  Severe or unstable cardiopulmonary or endocrine disease  Surgery of the UGI tract  Evidence of bleeding or IDA  Barrett’s oesophagus  High-grade dysplasia, dysphagia, or history of malignancy  History of drug or alcohol misuse within 1yr  Continuously used antiulcer drugs (Including PPIs during the 2 weeks before the 13C UBT)  Antibiotics or bismuth compounds ( ≥3times /wk,1 month before screening)  Systemic glucocorticoids, NSAIDs, or anticoagulation (except acetylsalicylic acid ≤100 mg per day)

Methods 10-day quadruple regimen(OMBT)7-day standard regimen(OAC) Three in one capsule : Bismuth subcitrate 140mg Tetracycline 125mg Metronidazole 125mg 3 Capsules q.i.d Omeprazole 20mg b.i.d Amoxicillin 1g Clarithromycin 500mg Omeprazole 20mg b.i.d

Methods  All patient with (+) UBT →Endoscopy & Six Bx (4 from pyloric antrum, 2 from gastric body) →Rapid urease test, histology, microbiology including culture & testing for metronidazole and clarithromycin resistance  Patients had to be positive for H. pylori by both UBT & rapid urease test, and with one confirmatory test for participation (histology, culture, or PCR)  Patients were randomly assigned (1:1) quadruple or standard therapy according to a predetermined list independently generated by Quintiles Canada  Patients were asked to refrain from consuming alcohol during the entire treatment period and for 48h after the last dose, and not to take the study drugs with milk, other dairy products, or antacids  Urea breath tests at the 6 wk or 10wks  Plasma bismuth concentrations at baseline, end of treatment, and end of study  Clarithromycin Resistance: MIC ≥1·00μg/mL Intermediate resistance: 0·25μg/mL≤ MIC <1·00μg/mL Sensitivity: MIC <0·25 μg/mL  Metronidazole Resistance: MIC >8μg/mL Sensitivity: MIC ≤8μg/mL

Methods Our assessment for non-inferiority was in the per-protocol population, with subsequent assessment for superiority in the intention-to-treat population (ie, all participants randomly assigned treatment, pre-established non-inferiority margin of –10%) Post-hoc analyses : A different definition of eradication (one or more negative urea breath tests at the 6wk or 10wk)

Methods Primary efficacy outcome  H. pylori eradication ( two (-) urea breath tests at 6wk & 10wk ) Secondary objectives  Eradication as a function of antibiotic resistance  Safety through adverse events, laboratory abnormalities  Plasma bismuth concentrations (baseline, end of treatment, and end of study)  Compliance through pill count

Results

Metronidazole sensitivity 71%(103/145) Metronidazole sensitivity 69%(90/131) Clarithromycin sensitivity 77%(112/145) Clarithromycin sensitivity 81%(106/131)

Results → should be interpreted with caution in view of the small number of patients in this subgroup Detectable plasma bismuth concentrations (undetectable baseline values of <4 μg/L) → All bismuth concentrations were below the toxic threshold (50μg/L) Sem Hop 1977; 53: 1663–69 Compliance exceeded 95% in both treatment groups Baseline 3(1%) of 210 End of Tx 45(22%) of 209 (4– 20μg/L) End of study 5(3%) of 200 Quadruple therapyStandard therapyP value Patients with non-ulcer dyspepsia 93%[147 of 158]67%[95 of 141]p<0·0001 Patients with PUD95%[18 of 19]83%[15 of 18]p=0·340

Quadruple therapyStandard therapy 4 patients (7 serious adverse event) Eczema Psychotic episode UTI(E. coli or P. mirabilis) Renal artery stenosis Acute renal failure Small bowel neuroendocrine carcinoma → 2 pts withdrew 3 patients ( 9 serious adverse event) Arrhythmia Emesis Pyrexia Dehydration Undernourishment Vascular dementia Acute appendicitis Exacerbation of chronic pancreatitis Aggravation of the general condition → 3 pts withdrew

Conclusion Quadruple therapy should be considered for first-line treatment in view of the rising prevalence of clarithromycin-resistant H pylori, especially since quadruple therapy provides superior eradication with similar safety and tolerability to standard therapy