Reviewer’s report
Title: 
Strategies for discontinuation of proton pump inhibitors (PPIs) in patients
with long-term PPI administration: a randomized controlled trial
Version: 
0 
Date: 
28 Jun 2021
Reviewer: 
Holmfridur Helgadottir
Reviewer's report:
This study protocol is for a randomized controlled trial designed to examine
strategies for discontinuation of PPIs in Japan. This is a very important topic and
we are in need for good evidence based methods on how best to advise patients
to deprescribe PPIs: is it more successful to taper the dose down before
discontinuation or to abruptly discontinue?
There are some concerns to be raised about this protocol:
The authors are including both PPIs and PCABs in the same study. Although
PCABs have been shown to be non-inferior to PPIs in the treatment of acid-
related disorders they lead to a significantly greater gastrin elevation compared
with PPIs. This is a major concern, and should be taken into consideration when
analyzing the data. Gastrin has been found to be an independent predictor of PPI
requirement in the Swedish study published in 2006 on the discontinuation of
PPIs after long-term treatment. I would have recommended to stratify the
randomization according to different acid suppressive agents included in the
study (PPIs vs. PCABs) to ensure equal ratio of different agents in group A and
group B. 
I agree with the authors that many patients/people on PPIs lack both explanation
that discontinuation is recommended in many cases and need for follow up. So
there is need to take into consideration, who are these patients included in the
study: reflux patients with symptom based diagnose or did they all have an
endoscopy verified diagnose of reflux oesophagitis, because there is difference in
comparison of GERD vs.NERD and one would believe that discontinuation
would be more successful in the NERD group. How will this be addressed and
accounted for. 
Do the participants get any information on lifestyle changes, that is self-
treatment of reflux disease (weight loss, stop smoking, no late night meals,
elevate the head of the bed…)
Gastrin levels, will there be taken blood test during the study process? Is this a
factor considered contributing to failure in additional analysis - what background
factors are there to be analyzed: BMI, hiatus hernia, diet habits, gender,
gastrin,dosage, 
agent ...
Why is the step down process only 2 weeks. The other group can take 7 tablets
of their previous medication as rescue medicine in the first two weeks (every
other day for the first two weeks) without that being an issue at follow up visit at
week 4. Then the to groups are not much different - PPIs tend to have effect up
to 48 hours because of their irreversible binding to the H,K-ATPase. 
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registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
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Yes
Declaration of competing interests
Please complete a declaration of competing
interests, considering the following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please publish my name with my
report.
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
Strategies for discontinuation of proton pump inhibitors (PPIs) in patients
with long-term PPI administration: a randomized controlled trial
Version: 
0 
Date: 
28 Jun 2021
Reviewer: 
Holmfridur Helgadottir
Reviewer's report:
This study protocol is for a randomized controlled trial designed to examine
strategies for discontinuation of PPIs in Japan. This is a very important topic and
we are in need for good evidence based methods on how best to advise patients
to deprescribe PPIs: is it more successful to taper the dose down before
discontinuation or to abruptly discontinue?
There are some concerns to be raised about this protocol:
The authors are including both PPIs and PCABs in the same study. Although
PCABs have been shown to be non-inferior to PPIs in the treatment of acid-
related disorders they lead to a significantly greater gastrin elevation compared
with PPIs. This is a major concern, and should be taken into consideration when
analyzing the data. Gastrin has been found to be an independent predictor of PPI
requirement in the Swedish study published in 2006 on the discontinuation of
PPIs after long-term treatment. I would have recommended to stratify the
randomization according to different acid suppressive agents included in the
study (PPIs vs. PCABs) to ensure equal ratio of different agents in group A and
group B. 
I agree with the authors that many patients/people on PPIs lack both explanation
that discontinuation is recommended in many cases and need for follow up. So
there is need to take into consideration, who are these patients included in the
study: reflux patients with symptom based diagnose or did they all have an
endoscopy verified diagnose of reflux oesophagitis, because there is difference in
comparison of GERD vs.NERD and one would believe that discontinuation
would be more successful in the NERD group. How will this be addressed and
accounted for. 
Do the participants get any information on lifestyle changes, that is self-
treatment of reflux disease (weight loss, stop smoking, no late night meals,
elevate the head of the bed…)
Gastrin levels, will there be taken blood test during the study process? Is this a
factor considered contributing to failure in additional analysis - what background
factors are there to be analyzed: BMI, hiatus hernia, diet habits, gender,
gastrin,dosage, 
agent ...
Why is the step down process only 2 weeks. The other group can take 7 tablets
of their previous medication as rescue medicine in the first two weeks (every
other day for the first two weeks) without that being an issue at follow up visit at
week 4. Then the to groups are not much different - PPIs tend to have effect up
to 48 hours because of their irreversible binding to the H,K-ATPase. 
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
Declaration of competing interests
Please complete a declaration of competing
interests, considering the following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please publish my name with my
report.
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
Strategies for discontinuation of proton pump inhibitors (PPIs) in patients
with long-term PPI administration: a randomized controlled trial
Version: 
0 
Date: 
28 Jun 2021
Reviewer: 
Holmfridur Helgadottir
Reviewer's report:
This study protocol is for a randomized controlled trial designed to examine
strategies for discontinuation of PPIs in Japan. This is a very important topic and
we are in need for good evidence based methods on how best to advise patients
to deprescribe PPIs: is it more successful to taper the dose down before
discontinuation or to abruptly discontinue?
There are some concerns to be raised about this protocol:
The authors are including both PPIs and PCABs in the same study. Although
PCABs have been shown to be non-inferior to PPIs in the treatment of acid-
related disorders they lead to a significantly greater gastrin elevation compared
with PPIs. This is a major concern, and should be taken into consideration when
analyzing the data. Gastrin has been found to be an independent predictor of PPI
requirement in the Swedish study published in 2006 on the discontinuation of
PPIs after long-term treatment. I would have recommended to stratify the
randomization according to different acid suppressive agents included in the
study (PPIs vs. PCABs) to ensure equal ratio of different agents in group A and
group B. 
I agree with the authors that many patients/people on PPIs lack both explanation
that discontinuation is recommended in many cases and need for follow up. So
there is need to take into consideration, who are these patients included in the
study: reflux patients with symptom based diagnose or did they all have an
endoscopy verified diagnose of reflux oesophagitis, because there is difference in
comparison of GERD vs.NERD and one would believe that discontinuation
would be more successful in the NERD group. How will this be addressed and
accounted for. 
Do the participants get any information on lifestyle changes, that is self-
treatment of reflux disease (weight loss, stop smoking, no late night meals,
elevate the head of the bed…)
Gastrin levels, will there be taken blood test during the study process? Is this a
factor considered contributing to failure in additional analysis - what background
factors are there to be analyzed: BMI, hiatus hernia, diet habits, gender,
gastrin,dosage, 
agent ...
Why is the step down process only 2 weeks. The other group can take 7 tablets
of their previous medication as rescue medicine in the first two weeks (every
other day for the first two weeks) without that being an issue at follow up visit at
week 4. Then the to groups are not much different - PPIs tend to have effect up
to 48 hours because of their irreversible binding to the H,K-ATPase. 
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
Yes
Declaration of competing interests
Please complete a declaration of competing
interests, considering the following questions:
1
. 
Have you in the past five years received reimbursements, fees, funding, or
salary from an organisation that may in any way gain or lose financially
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
5
. 
Do you have any other financial competing interests?
6
. 
Do you have any non-financial competing interests in relation to this
paper?
If you can answer no to all of the above, write 'I declare that I have no competing
interests' below. If your reply is yes to any, please give details below.
I declare that I have no competing interests
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please publish my name with my
report.
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
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