Title: Vonoprazan-based triple and dual therapy versus bismuth-based quadruple therapy for
Helicobacter pylori infection in China: A three-arm, randomised clinical trial protocol
Version: 1 Date: 31 May 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?
No – there are minor issues
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 is certainly not the first vonoprazon based H Pylori eradication
clinical trial as many trials preceded this one. Specifically the recent published clinical trail
in Front Pharmacol. 2023 May 5;14:1143969. doi: 10.3389/fphar.2023.1143969. eCollection
2023. contradict the statement “However, no randomised controlled trials have compared VPZ-
based therapy and BI-based quadruple therapy. “ While the authors may state that this trial was
published only recently, clinical trials.gov  NCT05097846. mentions start day of June 17, 2021
for the trial published in Front Pharmacol. Suggestion is to remove claims as “first”.
This trial explored VPZ + doxycycline + furazolidone, VPZ + doxycycline + amoxicillin, against
bismuth based regimens (esomeprazole (EPZ) + bismuth + doxycycline + furazolidone, and
EPZ + colloidal bismuth + doxycycline + amoxicillin for 14 days). The outcome was that in the
Chinese population, 14-day VPZ-containing triple therapy was safe and more effective and can
be used clinically as first-line H. pylori treatment. https://pubmed.ncbi.nlm.nih.gov/37214450/
So what is the rationale to start this trial?
REQUESTED REVISIONS:
There are already 8 systemic reviews / meta-analysis out on this topic (vonoprazon based H
Pylori eradication) , so this is a crowed space. (PMID 28497487 28884937 31211144 31914442
33839101 35247003 35716370 36527456 37015201) So on the upside it is a popular theme, on
the flipside many trials have been done and data from trials have been aggregated already.
All in all, I think that the authors should make the clear why another clinical trial is needed and
what information it will yield that may change practice. The risk is that the authors take on an
enormous effort at the expense of patients and that regardless of the results nothing will change.
The flowchart (figure 1) starts with “Screening of patients diagnosed with H. pylori” .  I think
that the authors need to make clear which patients will be screened. Are all comers screened
regardless of presentation, do the authors offer symptom based testing or do they have another
protocol in place? Table 1 with in / exclusion criteria do not help much here. This is very relevant
to translate the data to other populations.
I was unable to land on Chinese Clinical Trial Registry (No. ChiCTR2200056375) website.
Registered on February 4, 2022,https://www.chictr.org.cn/showproj.aspx?proj=141314
(Google gave me Your search - ChiCTR2200056375 - did not match any documents.) This does
not give this reviewer much comfort, in particular since the trial is already recruiting
ADDITIONAL REQUESTS/SUGGESTIONS:
This is a single center study. While the institute may be as sizable as it is, it comes with
specific referral streams coming from specific populations. A multicentric approach has many
advantages and I urge the applicants to go down this route.
The manuscript comes with a completed Standard Protocol Items: Recommendations for
Interventional Trials form (SPIRIT) This enhances the understanding of the trial.
Apparently there is no single test that selects patients (eligible patients that agreed to an initial H.
pylori culture will undergo either an upper endoscopy with biopsy or collect a stool specimen).
Can the authors explain whether the sensitivity / specificity of both tests are comparable in their
institute? Why 2 tests? In particular does the likelihood of false positive results differ between
tests?
The outcome is assessed with a different test than the initial test that is used to screen patients.
Why is that? Why not use the C13 breath test to select / recruit and assess outcome?
Title: Vonoprazan-based triple and dual therapy versus bismuth-based quadruple therapy for
Helicobacter pylori infection in China: A three-arm, randomised clinical trial protocol
Version: 1 Date: 31 May 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?
No – there are minor issues
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 is certainly not the first vonoprazon based H Pylori eradication
clinical trial as many trials preceded this one. Specifically the recent published clinical trail
in Front Pharmacol. 2023 May 5;14:1143969. doi: 10.3389/fphar.2023.1143969. eCollection
2023. contradict the statement “However, no randomised controlled trials have compared VPZ-
based therapy and BI-based quadruple therapy. “ While the authors may state that this trial was
published only recently, clinical trials.gov  NCT05097846. mentions start day of June 17, 2021
for the trial published in Front Pharmacol. Suggestion is to remove claims as “first”.
This trial explored VPZ + doxycycline + furazolidone, VPZ + doxycycline + amoxicillin, against
bismuth based regimens (esomeprazole (EPZ) + bismuth + doxycycline + furazolidone, and
EPZ + colloidal bismuth + doxycycline + amoxicillin for 14 days). The outcome was that in the
Chinese population, 14-day VPZ-containing triple therapy was safe and more effective and can
be used clinically as first-line H. pylori treatment. https://pubmed.ncbi.nlm.nih.gov/37214450/
So what is the rationale to start this trial?
REQUESTED REVISIONS:
There are already 8 systemic reviews / meta-analysis out on this topic (vonoprazon based H
Pylori eradication) , so this is a crowed space. (PMID 28497487 28884937 31211144 31914442
33839101 35247003 35716370 36527456 37015201) So on the upside it is a popular theme, on
the flipside many trials have been done and data from trials have been aggregated already.
All in all, I think that the authors should make the clear why another clinical trial is needed and
what information it will yield that may change practice. The risk is that the authors take on an
enormous effort at the expense of patients and that regardless of the results nothing will change.
The flowchart (figure 1) starts with “Screening of patients diagnosed with H. pylori” .  I think
that the authors need to make clear which patients will be screened. Are all comers screened
regardless of presentation, do the authors offer symptom based testing or do they have another
protocol in place? Table 1 with in / exclusion criteria do not help much here. This is very relevant
to translate the data to other populations.
I was unable to land on Chinese Clinical Trial Registry (No. ChiCTR2200056375) website.
Registered on February 4, 2022,https://www.chictr.org.cn/showproj.aspx?proj=141314
(Google gave me Your search - ChiCTR2200056375 - did not match any documents.) This does
not give this reviewer much comfort, in particular since the trial is already recruiting
ADDITIONAL REQUESTS/SUGGESTIONS:
This is a single center study. While the institute may be as sizable as it is, it comes with
specific referral streams coming from specific populations. A multicentric approach has many
advantages and I urge the applicants to go down this route.
The manuscript comes with a completed Standard Protocol Items: Recommendations for
Interventional Trials form (SPIRIT) This enhances the understanding of the trial.
Apparently there is no single test that selects patients (eligible patients that agreed to an initial H.
pylori culture will undergo either an upper endoscopy with biopsy or collect a stool specimen).
Can the authors explain whether the sensitivity / specificity of both tests are comparable in their
institute? Why 2 tests? In particular does the likelihood of false positive results differ between
tests?
The outcome is assessed with a different test than the initial test that is used to screen patients.
Why is that? Why not use the C13 breath test to select / recruit and assess outcome?
Please review this paper.
user
Title: Vonoprazan-based triple and dual therapy versus bismuth-based quadruple therapy for
Helicobacter pylori infection in China: A three-arm, randomised clinical trial protocol
Version: 1 Date: 31 May 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?
No – there are minor issues
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 is certainly not the first vonoprazon based H Pylori eradication
clinical trial as many trials preceded this one. Specifically the recent published clinical trail
in Front Pharmacol. 2023 May 5;14:1143969. doi: 10.3389/fphar.2023.1143969. eCollection
2023. contradict the statement “However, no randomised controlled trials have compared VPZ-
based therapy and BI-based quadruple therapy. “ While the authors may state that this trial was
published only recently, clinical trials.gov  NCT05097846. mentions start day of June 17, 2021
for the trial published in Front Pharmacol. Suggestion is to remove claims as “first”.
This trial explored VPZ + doxycycline + furazolidone, VPZ + doxycycline + amoxicillin, against
bismuth based regimens (esomeprazole (EPZ) + bismuth + doxycycline + furazolidone, and
EPZ + colloidal bismuth + doxycycline + amoxicillin for 14 days). The outcome was that in the
Chinese population, 14-day VPZ-containing triple therapy was safe and more effective and can
be used clinically as first-line H. pylori treatment. https://pubmed.ncbi.nlm.nih.gov/37214450/
So what is the rationale to start this trial?
REQUESTED REVISIONS:
There are already 8 systemic reviews / meta-analysis out on this topic (vonoprazon based H
Pylori eradication) , so this is a crowed space. (PMID 28497487 28884937 31211144 31914442
33839101 35247003 35716370 36527456 37015201) So on the upside it is a popular theme, on
the flipside many trials have been done and data from trials have been aggregated already.
All in all, I think that the authors should make the clear why another clinical trial is needed and
what information it will yield that may change practice. The risk is that the authors take on an
enormous effort at the expense of patients and that regardless of the results nothing will change.
The flowchart (figure 1) starts with “Screening of patients diagnosed with H. pylori” .  I think
that the authors need to make clear which patients will be screened. Are all comers screened
regardless of presentation, do the authors offer symptom based testing or do they have another
protocol in place? Table 1 with in / exclusion criteria do not help much here. This is very relevant
to translate the data to other populations.
I was unable to land on Chinese Clinical Trial Registry (No. ChiCTR2200056375) website.
Registered on February 4, 2022,https://www.chictr.org.cn/showproj.aspx?proj=141314
(Google gave me Your search - ChiCTR2200056375 - did not match any documents.) This does
not give this reviewer much comfort, in particular since the trial is already recruiting
ADDITIONAL REQUESTS/SUGGESTIONS:
This is a single center study. While the institute may be as sizable as it is, it comes with
specific referral streams coming from specific populations. A multicentric approach has many
advantages and I urge the applicants to go down this route.
The manuscript comes with a completed Standard Protocol Items: Recommendations for
Interventional Trials form (SPIRIT) This enhances the understanding of the trial.
Apparently there is no single test that selects patients (eligible patients that agreed to an initial H.
pylori culture will undergo either an upper endoscopy with biopsy or collect a stool specimen).
Can the authors explain whether the sensitivity / specificity of both tests are comparable in their
institute? Why 2 tests? In particular does the likelihood of false positive results differ between
tests?
The outcome is assessed with a different test than the initial test that is used to screen patients.
Why is that? Why not use the C13 breath test to select / recruit and assess outcome?
assistant