Reviewer ’s report  
 
Title: BAT117213: ILEAL BILE ACID TRANSPORTER (IBAT) I NHIBITION AS A  
TREATMENT FOR PRURITUS IN PRIMARY BILIARY CIRRHOSIS: STUDY PROTOCOL  
FOR A RANDOMISED CONTROLLED TRIAL  
 
Version: 0 Date: 30 May 2016  
 
Reviewer: Paul Dawson  
 
Reviewer's report:  
 
Pruritus is a debilitating symptom of cholestatic liver disease and is commonly reported by 
patients with primary biliary cholangitis. Despite the magnitude of this clinical problem, progress 
towards understanding the pathogenesis of cholestatic pruritus has been slow and the 
effectiveness of current interventions is still rather limited. it is believed that cholestasis results 
in hepatic release of unnamed pruritogens that act to stimulate specific neural itch fibers in the 
skin. A list of candidate pruri togens has been assembled over the years and includes bile acids, 
endogenous opiates, and lysophosphatic acid. With regard to bile acids, the evidence remains 
contradictory and the evidence in support of the use of bile acids sequestrants as first -line 
therapy for cholestatic pruritus is weak.  
The strengths of the current trial include the novel agent (IBAT inhibitor), randomized cross -
over design, and improved methods for tracking pruritus. The exploratory and mechanistic 
studies are predicted to provide important new information regarding how interruption of the 
enterohepatic circulation affects metabonomic endpoints and the gut microbiota.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately suppo rted by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
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 
manu script?  
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 -finan cial 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 . 
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 websit e along with the authors' 
responses. I agree for my report to be made available under an Open Acce ss 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: BAT117213: ILEAL BILE ACID TRANSPORTER (IBAT) I NHIBITION AS A  
TREATMENT FOR PRURITUS IN PRIMARY BILIARY CIRRHOSIS: STUDY PROTOCOL  
FOR A RANDOMISED CONTROLLED TRIAL  
 
Version: 0 Date: 30 May 2016  
 
Reviewer: Paul Dawson  
 
Reviewer's report:  
 
Pruritus is a debilitating symptom of cholestatic liver disease and is commonly reported by 
patients with primary biliary cholangitis. Despite the magnitude of this clinical problem, progress 
towards understanding the pathogenesis of cholestatic pruritus has been slow and the 
effectiveness of current interventions is still rather limited. it is believed that cholestasis results 
in hepatic release of unnamed pruritogens that act to stimulate specific neural itch fibers in the 
skin. A list of candidate pruri togens has been assembled over the years and includes bile acids, 
endogenous opiates, and lysophosphatic acid. With regard to bile acids, the evidence remains 
contradictory and the evidence in support of the use of bile acids sequestrants as first -line 
therapy for cholestatic pruritus is weak.  
The strengths of the current trial include the novel agent (IBAT inhibitor), randomized cross -
over design, and improved methods for tracking pruritus. The exploratory and mechanistic 
studies are predicted to provide important new information regarding how interruption of the 
enterohepatic circulation affects metabonomic endpoints and the gut microbiota.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately suppo rted by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
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 
manu script?  
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 -finan cial 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 . 
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 websit e along with the authors' 
responses. I agree for my report to be made available under an Open Acce ss 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: BAT117213: ILEAL BILE ACID TRANSPORTER (IBAT) I NHIBITION AS A  
TREATMENT FOR PRURITUS IN PRIMARY BILIARY CIRRHOSIS: STUDY PROTOCOL  
FOR A RANDOMISED CONTROLLED TRIAL  
 
Version: 0 Date: 30 May 2016  
 
Reviewer: Paul Dawson  
 
Reviewer's report:  
 
Pruritus is a debilitating symptom of cholestatic liver disease and is commonly reported by 
patients with primary biliary cholangitis. Despite the magnitude of this clinical problem, progress 
towards understanding the pathogenesis of cholestatic pruritus has been slow and the 
effectiveness of current interventions is still rather limited. it is believed that cholestasis results 
in hepatic release of unnamed pruritogens that act to stimulate specific neural itch fibers in the 
skin. A list of candidate pruri togens has been assembled over the years and includes bile acids, 
endogenous opiates, and lysophosphatic acid. With regard to bile acids, the evidence remains 
contradictory and the evidence in support of the use of bile acids sequestrants as first -line 
therapy for cholestatic pruritus is weak.  
The strengths of the current trial include the novel agent (IBAT inhibitor), randomized cross -
over design, and improved methods for tracking pruritus. The exploratory and mechanistic 
studies are predicted to provide important new information regarding how interruption of the 
enterohepatic circulation affects metabonomic endpoints and the gut microbiota.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately suppo rted by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
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 
manu script?  
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 -finan cial 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 . 
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 websit e along with the authors' 
responses. I agree for my report to be made available under an Open Acce ss 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