Review for 10.1186/s12876-023-03100-y (2023)

Title: Efficacy comparison of 7- and 14-day P-CAB based bismuth-containing quadruple
regimen with PPI based bismuth-containing quadruple regimen for Helicobacter pylori
infection: rationale and design of an open-label, multicenter, randomized controlled trial
Version: 0 Date: 11 Oct 2023
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Is there a clear objective that addresses a testable research question(s)?
Yes - there is a clear objective
STUDY DESIGN - Is the chosen study design appropriate for the research question and does
the methodology align well with the established recommendations for the chosen study design?
No - there are minor issues
METHODOLOGY - Does the document provide sufficient explanation of the methods such that
the planned analyses would appear to have the technical rigor needed to allow confidence in the
results being obtained?
No - there are minor issues
STATISTICS - (For protocols with a statistical analysis plan) Are the statistical methods
appropriate?
No - there are issues with the statistical approach described in the protocol
SUPPORTING RESULTS - (For reports that present preliminary results) Do the presented
results clearly relate to the study objective and support the need for the study?
N/A - no results are presented
ETHICAL STATEMENTS AND APPROVALS - For protocols involving humans, animals or
both, has adherence to all relevant ethical guidelines and ethical treatment of subjects been
addressed in the description of the study design?
Yes - these items are addressed appropriately
OVERALL MANUSCRIPT POTENTIAL - Are the study design and methodological approach
sound? If not, can revisions be made to make the work technically sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: This clinical trial proposal from Korea aims to compare the
effectiveness and side effects of two potassium-competitive acid blocker (P-CAB) based
regimens—7-day and 14-day P-CAB-based bismuth-containing quadruple regimen (PC-BMT)
—with a 14-day proton pump inhibitor (PPI)-based bismuth-containing quadruple regimen
(P-BMT) for eradicating Helicobacter pylori (H. pylori) in patients with high clarithromycin
resistance. The study will involve 366 treatment-naive patients across five teaching hospitals.
Tegoprazan, bismuth subcitrate, metronidazole, and tetracycline are components of the
regimens. Eradication rates, adverse events, and drug compliance will be assessed and compared.
Antibiotic resistance testing will be conducted, and results will be analyzed using intention-to-
treat and per-protocol analyses. The study hypothesizes that both 7-day and 14-day PC-BMT
will be well-tolerated, achieve similar eradication rates as 14-day P-BMT, and exhibit fewer
adverse effects and higher drug compliance due to the shorter treatment duration.
REQUESTED REVISIONS:
The trial has been registered with the Korean Clinical Research Information Service registry,
KCT0007444.
The lead issue here revolves around clarithromycin resistance of H. pylori and the search for
modalities to overcome that.. In addition the authors were interested in the efficacy of H. pylori
eradication regimen consisting of Potassium-competitive acid blockers rather than proton pump
inhibitors on the premise that the increase pH more effectively. So the proposed trial investigates
shorter (7 day) and longer (14 day) potassium-competitive acid blockers based regimen with the
conventional 14 day proton pump inhibitor based regimen. The outcome centers on eradication
rates  .
The introduction mentions that clarithromycin resistance of H. pylori is an issue and that
bismuth-containing quadruple regimen may help here. They also note that bismuth based
regimens come with (high) adverse events (and is difficult to obtain in some parts in the World).
So why not to design a study that omits bismuth?
What will be the strategy of the authors with missing data for the antibiotic resistance tests that
they do? The highlight this as an asset “availability of antibiotic susceptibility data is another
major strength” but I have no doubt that there will be missing data.
I would like to see a number of limitations in the discussion, apart from the strengths that the
authors highlight.
In addition, the discussion mentions that the  higher incidence of adverse events could be the
main reason for poor compliance, leading to treatment failure and subsequent development of
resistant bacterial strains. So how do the authors cope with this challenge?
The use of “self-report questionnaires” is questionable. Are these questionnaires validated?
The focus of the questions is on adverse events and I am not sure whether a categorization of
adverse events in 3 levels will be the most optimal choice. I urge the authors to use a validated
questionnaire on adverse events such as the NCI PRO-CTCAE (Patient-Reported Outcomes
version of the Common Terminology Criteria for Adverse Events): This is a patient-reported
version of the CTCAE, designed to capture adverse events directly from patients.
there are several validated questionnaires designed to assess adherence in drug trials and here
follows a list of 4 common questionnaires.
Morisky Medication Adherence Scale (MMAS): The MMAS is a widely used questionnaire that
assesses medication adherence. It includes a series of simple questions to evaluate adherence
behavior.
Medication Adherence Report Scale (MARS): The MARS is a self-report questionnaire that
assesses adherence to medication. It includes items related to medication-taking behavior, beliefs
about medications, and the impact of medications on daily life.
Adherence to Refills and Medications Scale (ARMS): The ARMS is a self-report scale that
assesses medication adherence by examining medication refill behavior.
Brief Medication Questionnaire (BMQ): The BMQ is a self-report questionnaire that assesses
medication adherence and identifies factors that may affect adherence.
I would use the CONSORT (Consolidated Standards of Reporting Trials) statement which  is
a set of guidelines developed to improve the quality and transparency of reporting randomized
controlled trials. The guidelines provide a structured framework for reporting various aspects
of clinical trials.
ADDITIONAL REQUESTS/SUGGESTIONS:
I would advertise this more clearly as a non-inferiority trial. I have 2 major issues.
Choice of Margin: Determining the non-inferiority margin is crucial. It represents the maximum
clinically acceptable difference between the new treatment and the active control. Selecting
an appropriate margin requires a careful balance between clinical relevance and statistical
feasibility. The protocol fails to mention which margin is acceptable to the authors
Sample Size Calculation: Non-inferiority trials often require larger sample sizes compared to
superiority trials. This is because a smaller treatment effect must be detected with sufficient
precision. Inadequate sample sizes can lead to a failure to establish non-inferiority even when
it exists. So without a clear predefined margin it is impossible to assess the group size. The
number of 97 people for each arm seems small to me , as in a non-inferiority model with a non-
inferiority margin of 7%, one-sided alpha of 0.025, power of 90%, and 5% drop-out, a total of
574 patients are required to establish non-inferiority.
Many non-inferiority trials include a test of superiority as a secondary analysis. If the trial fails to
show non-inferiority, demonstrating superiority can add context to the results. I urge the authors
to include such an analysis.