Reviewer’s report
Title: 
Tolvaptan therapy of Chinese cirrhotic patients with ascites after
insufficient diuretic routine medication responses: A Phase III clinical trial
Version: 
2 
Date: 
18 Mar 2020
Reviewer's report:
PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses a
testable research question(s) (brief or other article types: is there a clear
objective)?
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with technical rigor
to allow confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work
technically sound? If not, can revisions be made to make the work technically
sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: 
The subject is interesting but the design of the study is not appropriate to draw
ferm conclusions. 
The strength of the study lies in the great number of patients included. But,
because of the significant heterogeneity in the included population, the high
number may be the only explanation for the positive results (mainly because
different proportion in studied groups (1:2:4 in placebo:7.5 mg: 15mg,
respectively). Moreover, from the beginning there is significant difference
between groups in the study's end-points (higher body weight and abdominal
circumference in the placebo group).
REQUESTED REVISIONS: 
Issues:
1. the included population seems to be very heterogenous (different doses of
diuretics, different stages of decompensation). This heterogeneity is also
demonstrated by 15 deaths in only 8 days of follow up (probably very seak
patients). We suggest to perform subgroups analysis: patients with high dose of
diuretics and uncontroled ascites; patients with hiponatremia). According to the
sample size calculations this subgoup analysis will maintain the needed
population. 
In the discussion the authors stated that the treatment proved to be efficient in the
subgroup of patients with Na<135, but this is not covered by results. 
2. abdominal circumference is not sufficiently objective as end-point for
treatment efficiency assessment in patients with ascites. How the investigator
standardised the measurement? 
3. A more efficient way to evaluate the diuresis is to measure 24h Natriuresis,
because the urinary output depend also on the liquid intake in patients without
renal failure. 
4. what were the diet recommendations during the study period (low salt diet
recommendation) and how the compliance was assessed?). 
5. improvement of ascites, as end-point, cannot be based only in chages in
abdominal circumference. It would be better by analysing the changes in body
weight. 
6. The authors concluded that treatment decrease the incidence of bleeding but
this is not covered by results. What was the source of bleeding? what kind of
patients (previous bleeding, +/- prophylaxis ). More details are needed.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the
authors.
No
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Acceptable
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
I agree to the open peer review policy of the journal. I understand that my name
will be included on my report to the authors and, if the manuscript is accepted
for publication, my named report including any attachments I upload will be
posted on the website along with the authors' responses. 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/
). I understand that any comments
which I do not wish to be included in my named report can be included as
confidential comments to the editors, which will not be published.
I agree to the open peer review policy of the journal
Reviewer’s report
Title: 
Tolvaptan therapy of Chinese cirrhotic patients with ascites after
insufficient diuretic routine medication responses: A Phase III clinical trial
Version: 
2 
Date: 
18 Mar 2020
Reviewer's report:
PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses a
testable research question(s) (brief or other article types: is there a clear
objective)?
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with technical rigor
to allow confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work
technically sound? If not, can revisions be made to make the work technically
sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: 
The subject is interesting but the design of the study is not appropriate to draw
ferm conclusions. 
The strength of the study lies in the great number of patients included. But,
because of the significant heterogeneity in the included population, the high
number may be the only explanation for the positive results (mainly because
different proportion in studied groups (1:2:4 in placebo:7.5 mg: 15mg,
respectively). Moreover, from the beginning there is significant difference
between groups in the study's end-points (higher body weight and abdominal
circumference in the placebo group).
REQUESTED REVISIONS: 
Issues:
1. the included population seems to be very heterogenous (different doses of
diuretics, different stages of decompensation). This heterogeneity is also
demonstrated by 15 deaths in only 8 days of follow up (probably very seak
patients). We suggest to perform subgroups analysis: patients with high dose of
diuretics and uncontroled ascites; patients with hiponatremia). According to the
sample size calculations this subgoup analysis will maintain the needed
population. 
In the discussion the authors stated that the treatment proved to be efficient in the
subgroup of patients with Na<135, but this is not covered by results. 
2. abdominal circumference is not sufficiently objective as end-point for
treatment efficiency assessment in patients with ascites. How the investigator
standardised the measurement? 
3. A more efficient way to evaluate the diuresis is to measure 24h Natriuresis,
because the urinary output depend also on the liquid intake in patients without
renal failure. 
4. what were the diet recommendations during the study period (low salt diet
recommendation) and how the compliance was assessed?). 
5. improvement of ascites, as end-point, cannot be based only in chages in
abdominal circumference. It would be better by analysing the changes in body
weight. 
6. The authors concluded that treatment decrease the incidence of bleeding but
this is not covered by results. What was the source of bleeding? what kind of
patients (previous bleeding, +/- prophylaxis ). More details are needed.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the
authors.
No
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Acceptable
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
I agree to the open peer review policy of the journal. I understand that my name
will be included on my report to the authors and, if the manuscript is accepted
for publication, my named report including any attachments I upload will be
posted on the website along with the authors' responses. 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/
). I understand that any comments
which I do not wish to be included in my named report can be included as
confidential comments to the editors, which will not be published.
I agree to the open peer review policy of the journal
Please review this paper.
user
Reviewer’s report
Title: 
Tolvaptan therapy of Chinese cirrhotic patients with ascites after
insufficient diuretic routine medication responses: A Phase III clinical trial
Version: 
2 
Date: 
18 Mar 2020
Reviewer's report:
PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses a
testable research question(s) (brief or other article types: is there a clear
objective)?
No - there are minor issues
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with technical rigor
to allow confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work
technically sound? If not, can revisions be made to make the work technically
sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: 
The subject is interesting but the design of the study is not appropriate to draw
ferm conclusions. 
The strength of the study lies in the great number of patients included. But,
because of the significant heterogeneity in the included population, the high
number may be the only explanation for the positive results (mainly because
different proportion in studied groups (1:2:4 in placebo:7.5 mg: 15mg,
respectively). Moreover, from the beginning there is significant difference
between groups in the study's end-points (higher body weight and abdominal
circumference in the placebo group).
REQUESTED REVISIONS: 
Issues:
1. the included population seems to be very heterogenous (different doses of
diuretics, different stages of decompensation). This heterogeneity is also
demonstrated by 15 deaths in only 8 days of follow up (probably very seak
patients). We suggest to perform subgroups analysis: patients with high dose of
diuretics and uncontroled ascites; patients with hiponatremia). According to the
sample size calculations this subgoup analysis will maintain the needed
population. 
In the discussion the authors stated that the treatment proved to be efficient in the
subgroup of patients with Na<135, but this is not covered by results. 
2. abdominal circumference is not sufficiently objective as end-point for
treatment efficiency assessment in patients with ascites. How the investigator
standardised the measurement? 
3. A more efficient way to evaluate the diuresis is to measure 24h Natriuresis,
because the urinary output depend also on the liquid intake in patients without
renal failure. 
4. what were the diet recommendations during the study period (low salt diet
recommendation) and how the compliance was assessed?). 
5. improvement of ascites, as end-point, cannot be based only in chages in
abdominal circumference. It would be better by analysing the changes in body
weight. 
6. The authors concluded that treatment decrease the incidence of bleeding but
this is not covered by results. What was the source of bleeding? what kind of
patients (previous bleeding, +/- prophylaxis ). More details are needed.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
No
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the
authors.
No
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
No
Are you able to assess any statistics in the manuscript or would you
recommend an additional statistical review?
If an additional statistical review is recommended, please specify what aspects
require further assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Acceptable
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
I agree to the open peer review policy of the journal. I understand that my name
will be included on my report to the authors and, if the manuscript is accepted
for publication, my named report including any attachments I upload will be
posted on the website along with the authors' responses. 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/
). I understand that any comments
which I do not wish to be included in my named report can be included as
confidential comments to the editors, which will not be published.
I agree to the open peer review policy of the journal
assistant