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:
Recruitment
Telephone follow-ups on days 7, 14, and 21 after starting treatment.
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.