Clinical trial NCT05664685: Optimized Bismuth Quadruple Therapy vs Triple Standard Therapy for Helicobacter Pylori Eradication
Official title: Optimized Bismuth Quadruple Therapy vs Triple Standard Therapy for Helicobacter Pylori Eradication: Clinical Efficacy Randomized Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Helicobacter Pylori Infection
Lead sponsor: Pontificia Universidad Catolica de Chile
Sponsor class: OTHER
First posted: 2022-12-27
Enrollment: 127
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, multicenter, controlled, double-blind clinical trial with two parallel arms. The control group will receive the current Standard Triple Therapy for the eradication of H. pylori. It consists in omeprazole + amoxicillin + clarithromycin for 14 days. The intervention group will be administered Quadruple Therapy with Bismuth, that consists in esomeprazole + amoxicillin + metronidazole + bismuth subsalicylate for 14 days
Primary purpose: TREATMENT

Brief summary: This study have as primary aim "To compare the H. pylori eradication rate between the quadruple bismuth therapy versus the standard triple therapy recommended by the AUGE Clinical Guidelines for Helicobacter pylori eradication treatment in peptic ulcer patients."

Briefly, this is a randomized, multicenter, controlled, double-blind clinical trial with two parallel arms. The control group will receive the current Standard Triple Therapy for the eradication of H. pylori. It consists of omeprazole + amoxicillin + clarithromycin for 14 days. The intervention group will be administered Quadruple Therapy with Bismuth, which consists in esomeprazole + amoxicillin + metronidazole + bismuth subsalicylate for 14 days

Detailed description: Participants, all with helicobacter pylory test positive, will be recruited into the UC-CHRISTUS Health Network located in the City of Santiago de Chile for this randomized controlled clinical trial.

The intervention group will be treated with Esomeprazole 40 mg every 8 hours, Amoxicillin 1 gr every 8 hours, Metronidazole 500 mg every 8 hours, Bismuth subsalicylate 369 mg every 8 hours. The control group will be treated with Omeprazole 20mg every 12 hours, Amoxicillin 1 gr every 12 hours, Clarithromycin 500 mg every 12 hours, Placebo identical to Bismuth Subsalicylate, 3 times daily.

The primary outcome is H. pylori Eradication. To determine eradication, participants of these study will be invited 8 to 12 weeks after the end of the administered therapy.

As secondary outcomes, will be recorded the Incidence of Adverse Drug Reactions (ADRs) through a questionnaire that will be performed to determine the occurrence of any adverse effect attributable to the therapy. The incidence of bloating, abdominal pain, bitter taste, constipation, diarrhea, dizziness, dyspepsia, epigastric pain, halitosis, headache, loss of appetite, nausea, vomiting, oral ulcers, skin rashes, and drowsiness will be directly recorded. Symptoms reported by participants spontaneously in follow-up phone calls will also be recorded. The time of commencement and duration of the therapy will be recorded. Also will be measured the H. pylori Antibiotic Resistance and Host CYP2C19 polymorphisms determination.

Covariates will be recorded at recruitment. For ADRs and therapeutic adherence telephone follow-up will be performed on days 7 and 14 and 21 after initiation of the therapy. The last follow-up will be performed in person at the time of the UBT.

Sample size calculation

For sample size calculations the following are considered: the expected Eradication rate with the control therapy scheme 82%, the expected eradication rate with the intervention therapy scheme: 97%, the expected absolute difference between therapies 15%, Power 80%, and confidence 95%

This calculation results that 65 participants per branch are needed. Calculations were performed with the statistical program Stata 15. Considering a loss of 10.0%, 72 patients per branch are considered. In addition, the investigators considered 30 additional patients in case the groups resulting from randomization are not balanced, and it is necessary to adjust the effectiveness of the treatments, by 3 variables to be able to make a regression analysis. With this, a total of 102 patients per branch will be included in this study.

Methods used to generate the sequence for patient random assignment to branches For the assignment of participants in the intervention or control branches, a list of random numbers will be used to sequence containers containing the control or intervention treatments. The containers will be delivered to the study participants according to the order in which participants are recruited.

The mechanism used to implement branch random assignment

For the anonymization of the sequence, the research team will delegate the generation of the random sequence and the numbering of the containers to a team that has no participation or knowledge of the design of the study, the collection, or the analysis of data.

Generation of the assignment sequence, recruitment of participants, and assignment of participants to the intervention's responsibilities.

The research team will deliver 204 containers with the intervention or control (102 of each) to 1 member of the UC Pharmacology and Toxicology Program. The member will generate the randomization sequence, number the containers according to their result, and keep the record of the randomization sequence until the data collection is finished, and the statistical analysis is done then the blind opens. In this way responsibilities are assigned to:

A. Generation of the branch assignment sequence: UC Pharmacology and Toxicology Program B. Participant Recruitment: Principal Investigator C. Assignment of participants to the interventions: Principal investigator delivers the containers to the participants, keeping them blind by the randomization and previous numbering of the containers.

Blind status maintenance for participants and research team

To maintain a blind status to branch assignment:

A. Part of the research team that performs patients recruitment B. Part of the research team that performs follows up on participants C. Part of the research team that performs tests for confirmation of eradication of H. pylori D. Part of the research team that performs statistical analysis

Statistical methods used for group comparison of primary and secondary outcomes

The statistical analysis will be performed without knowledge of the therapy scheme assignment, or the clinical evaluation of participants included in the study. P values \<0,05 will be considered statistically significant. The analyses will be carried out under the intention-to-treat (ITT) modality.

Registration and safeguarding of the data collected

Data logging has 3 stages:

1. Recruitment
2. Telephone follow-ups on days 7, 14, and 21 after starting treatment.
3. UBT exam between 8 and 12 weeks after treatment ends.

Each stage will have a physical record on paper, which will be transcribed into the REDCap electronic registry. The paper records will be maintained under lock and key at the Toxicological and Drug Information Center (CITUC), located at Lira 63, second floor.

Regarding the quality of the data recorded

At the time of analysis, a random sample of 10% of the participants will be selected to evaluate the consistency between the physical and electronic records. If there are doubts about the quality of the information, all records will be checked. Anomalous values will also be checked in the physical register.

Data Analysis Plan

Descriptive Statistics

Descriptive statistics will be performed to determine the characteristics of the complete cohort and stratified by experimental branch. The balance of the intervention and control groups will be evaluated. If the balance is not reached, the effect will be directly adjusted with multivariate models.

Primary analysis: Comparison of treatment efficacy

The analysis will perform a comparison of eradication percentages between groups by inferential statistical tests, to determine whether the difference between the groups reaches statistical significance, and also calculate relative risk measures. There will be analyzed variables associated with positive eradication and multivariate analysis of factors associated with eradication using binomial regression.

Secondary analysis: Adverse drug reactions

Adverse reactions

Will be performed descriptive statistics, by type, particular symptom, and temporal evolution. Comparison between control and intervention branches will be analyzed by the magnitude of ADR observed. Evaluation of the association between ADR s with treatment scheme and covariates, by regression, will be performed.

Sensitivity analysis

To evaluate the robustness of the results, the analysis will be repeated in the modality by protocol to compare them with those obtained under the intention-to-treat modality. Secondly, the effect of therapeutic adherence will be evaluated. The analysis will also be stratified by the measured covariates, to evaluate sources of uncertainty, confusion, or possible interactions.

Eligibility criteria: Inclusion Criteria:

Diagnosed with H. pylori infection by positive Urease test.

Exclusion Criteria:

* Pregnant or lactating women.
* Allergy or history of adverse reaction to the following medications:
* Penicillin
* Salicylate allergy
* Omeprazole
* Has received H. pylori eradication therapy prior to the study.
* Has used PPIs 14 day prior to diagnostic testing
* Use of antibiotics within 4 weeks beforehand.
* History of gastrointestinal bleeding for the last 12 weeks.
* History of partial gastrectomy due to Gastric Cancer
* History of incipient Gastric Cancer resolved by endoscopic resection.
* History of bariatric surgery.
* Serious or malignant diseases with less than 1 year life expectancy.
* History of Clostridium difficile infection.
* History of inflammatory bowel disease.
* Chronic kidney disease, stage 3 or higher.
* Do not sign informed consent.

Primary outcomes:
measure: Helicobacter pylori erradication
timeFrame: 8-12 weeks after treatment is ended
Secondary outcomes:
measure: Incidence of Adverse Drug Reactions
timeFrame: Day 7, 14 and 21 after treatment begins
measure: Prevalence of Helicobacter pylori antibiotic resistance to Clarithromycin
timeFrame: Samples taken at the recruitment
measure: Prevalence of Host CYP2C19 polymorphisms determination
timeFrame: Samples taken at the recruitment
Other outcomes:
Locations:
city: Santiago
country: Chile
facility: Centro Médico UC-CHRISTUS San Joaquín
state: Metropolitana
city: Santiago
country: Chile
facility: Centro de especialidades médicas Marcoleta UC CHRISTUS
state: Región Metropolitana
Study officials:
affiliation: Pontificia Universidad Catolica de Chile
name: Patricio Medel, MPH
role: PRINCIPAL_INVESTIGATOR
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