| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Helicobacter pylori infection |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10019375 |
| E.1.2 | Term | Helicobacter infections |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to compare the rate of Helicobacter pylori eradication following quadruple therapy by a single triple capsule of bismuth subcitrate potassium, metronidazole, and tetracycline, given with omeprazole (OBMT) vs omeprazole, amoxicillin and clarithromycin (OAC) in Helicobacter pylori positive patients. |
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| E.2.2 | Secondary objectives of the trial |
1. To compare eradication outcomes in patients with presence/past history of peptic ulcers at baseline vs those without.
2. To evaluate the effect of resistance of Helicobacter pylori to metronidazole and clarithromycin on the efficacy of these treatments.
3. To evaluate the rate of secondary resistance induced by these treatments.
4. To assess the safety and tolerability of these therapeutic regimens with respect to patient-reported and investigator-observed adverse events, clinical laboratory abnormalities and plasma Bi concentrations.
5. To evaluate compliance to treatment.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Male or non-pregnant, non-nursing female, 18 years of age and older
• Women of childbearing potential must use a medically acceptable birth control method for the duration of the study and for 30 days thereafter. Women who are not of childbearing potential will be defined as post-menopausal (no presence of menses for at least 12 months if > 50 years of age, or no presence of menses for 24 months if ≤ 50 years of age) or surgically sterilized (tubal ligation for at least 6 months, ovariectomy or hysterectomy)
• Positive for Helicobacter pylori by both C-13 UBT and at least one of two positive results among histologic examination and culture, including PCR (Polymerase Chain Reaction).
• Presence of upper gastrointestinal symptoms
• Mental and legal ability to give written informed consent
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| E.4 | Principal exclusion criteria |
• Previous surgery of the upper gastrointestinal tract (except appendectomy, polypectomy, or cholecystectomy)
• Presence or history of clinically significant impairment of renal function, hepatic function, or liver disease
• Presence or history of severe or unstable cardiovascular, pulmonary or endocrine disease
• Presence or history of Zollinger Ellison Syndrome
• Any current or recent (within 1 month of screening) hematemesis, melena, or documented gastrointestinal bleeding or iron-deficiency anaemia of clinical significance
• Malignant disease of any kind except for successfully treated skin cancer (basal or squamous cell) during the previous 5 years
• Barrett’s esophagus or high-grade dysplasia
• Dysphagia or vomiting as major symptoms
• Drug, alcohol or medication abuse within the past year
• Continuous use of anti-ulcer drugs, including H2 receptor antagonists, sucralfate and prostaglandins during the 2 weeks preceding the C 13 UBT at screening
• Continuous use of proton pump inhibitor in the 2 weeks preceding the C 13 UBT at screening
• Chronic use of NSAIDs, except for acetyl-salicylic acid 100 mg or less daily
• Requirement for anticoagulants/platelet aggregation inhibitors except for cardiovascular disease prevention (for example acetyl-salicylic at a dose not exceeding 100 mg daily) and systemic glucocorticoids (because of association with ulcer disease)
• Use of systemic antibiotics in the month before screening
• Regular use (> 3 times per week) of bismuth compounds in the month before randomization.
• Presence of a contraindication to the use of metronidazole: active neurological disorder, history of blood dyscrasia, uncorrected hypothyroidism, uncorrected hypoadrenalism, alcoholism, concomitant use of disulfiram or use of disulfiram within the previous two weeks (can cause psychotic reactions), known hypersensitivity to metronidazole or any of its excipients; tetracycline: known hypersensitivity to tetracyclines or any of its excipients; clarithromycin: known hypersensitivity to macrolides or any of its excipients, use of cisapride, pimozide, terfenadine, astemizole, ergotamine/dihydroergotamine, use of colchicine (SmPC Section 4.4; colchicine toxicity reported, deaths in some such patients), use of HMG-CoA Reductase Inhibitors (SmPC Section 4.5; Rhabdomyolysis has been reported), use of quinidine or disopyramide (SmPC Section 4.5; post marketing reports of Torsade de Pointes); amoxicillin: hypersensitivity to penicillin or B lactam antibiotics (e.g. Cephalosporins) or any of its excipients, Glandular Fever (cause exanthema); omeprazole: known hypersensitivity to omeprazole or any of its excipients, patients with rare hereditary problems of galactose intolerance, Lapp Lactase deficiency, Glucose-Galactose malabsoption; bismuth: hypersensitivity to bismuth or any of its excipients; Maalox Plus®: hypersensitivity to Maalox or any of its excipients, patients with rare hereditary problems of fructose intolerance.
• Use of any experimental drug within the 30 days prior to randomization and throughout the entire study.
• Previous attempt by a recognized antibiotic treatment to eradicate an adequately documented infection by Helicobacter pylori.
• Known hypersensitivity to or previous adverse experience(s) with citric acid or any of the study drugs.
• Patient known to be positive for HIV, hepatitis, or other diseases transmissible by blood or biopsy samples.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
A one-sided 97.5% confidence interval on the difference of proportions (OBMT eradication rate – OAC eradication rate) will be derived using asymptotic normal approximation procedure and we will conclude to non-inferiority of OBMT if the lower bound of the confidence interval is greater than or equal to -10%.
If, and only if, we conclude to non-inferiority of OBMT over OAC using the Per Protocol population, the same confidence interval will be derived using the ITT population. If the lower bound of this confidence interval is greater than 0, we will conclude to superiority of OBMT over OAC.
The type I error rate is controlled by first testing non-inferiority using the Per Protocol population and, only if non inferiority is demonstrated, then testing for superiority using the ITT population.
This stepwise procedure does not require any type I error rate adjustment28,29.
Non-inferiority will be evaluated using both the Per Protocol population (primary) and the ITT population (supportive).
Superiority will be evaluated using both ITT population (primary) and the Per Protocol population (Supportive)
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| evaluator-blinded, non-inferiority |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 16 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 16 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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