Reviewer ’s report  
 
Title: Efficacy and safety of eflornithine (CPP -1X)/sulindac combination therapy versus each as 
monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a 
randomized, double -blind, Phase III tri al 
 
 
Version: 0 Date: 09 Apr 2016 
 
 
Reviewer: Jatin  Roper  
 
 
Reviewer's report:  
 
This study conducts a randomized, double -blinded, phase III clinical trial, studying the use of 
eflornithine and sulindac combination therapy in the chemoprevention of FAP progression. 
Eflornithine and sulindac work synergistically to decrease the levels of polyamines (PA) in the 
intestinal mucosa by inhibiting ornithine decarboxylase (ODC), which decreases the synthesis of 
PA, and upregulating the PA transport genes, which increases the elimination of PA, 
respectively. The reduced levels of PA is hypothesized to have an impact on the natural history 
and progression of FAP.  
 
As of 1st of February 2016 ,138 patients have been enrolled in the study and have been 
randomized to three groups of (1) eflornithine/sulindac, (2) eflornithine/placebo and ( 3) 
placebo/sulindac therapies for 24 months with regular follow -ups thereafter.  
 
This study is noteworthy for enrolling a greater number of patient than prior chemoprevention 
studies for FAP, and for selecting clinically meaningful endpoints. The authors a re to be 
commended for reaching 95% of the enrollment goal on schedule. Also of note are the built in 
controls and checks to ensure complete and unbiased polyp counts on colonoscopy videos and 
still images. An additional strength of the study is the relati vely long follow up of 24 months.  
 
  
Specific comments:  
 
1. The authors do not include a placebo / placebo group. This decision should be explained.  
2.  In figure 1 legend, ODC1 is misspelled as OCD1  
3.The Lynch study is described in great detail in the Disc ussion, which studied celecoxib with 
DFMO. The authors should explain why they chose to study sulindac instead of celecoxib as a 
combination agent with ODC (or not both agents), since celecoxib has also been shown to inhibit 
polyamine synthesis.  
4. It woul d be useful to measure intestinal PA levels in study patients from biopsies. The authors 
seem to hint at this by stating that biopsies will be taken for research purposes.  
 
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 supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in t he 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 futu re? 
 
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 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 website along with the authors'  
responses. I agree for my report to be made available under an Open Access C reative 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: Efficacy and safety of eflornithine (CPP -1X)/sulindac combination therapy versus each as 
monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a 
randomized, double -blind, Phase III tri al 
 
 
Version: 0 Date: 09 Apr 2016 
 
 
Reviewer: Jatin  Roper  
 
 
Reviewer's report:  
 
This study conducts a randomized, double -blinded, phase III clinical trial, studying the use of 
eflornithine and sulindac combination therapy in the chemoprevention of FAP progression. 
Eflornithine and sulindac work synergistically to decrease the levels of polyamines (PA) in the 
intestinal mucosa by inhibiting ornithine decarboxylase (ODC), which decreases the synthesis of 
PA, and upregulating the PA transport genes, which increases the elimination of PA, 
respectively. The reduced levels of PA is hypothesized to have an impact on the natural history 
and progression of FAP.  
 
As of 1st of February 2016 ,138 patients have been enrolled in the study and have been 
randomized to three groups of (1) eflornithine/sulindac, (2) eflornithine/placebo and ( 3) 
placebo/sulindac therapies for 24 months with regular follow -ups thereafter.  
 
This study is noteworthy for enrolling a greater number of patient than prior chemoprevention 
studies for FAP, and for selecting clinically meaningful endpoints. The authors a re to be 
commended for reaching 95% of the enrollment goal on schedule. Also of note are the built in 
controls and checks to ensure complete and unbiased polyp counts on colonoscopy videos and 
still images. An additional strength of the study is the relati vely long follow up of 24 months.  
 
  
Specific comments:  
 
1. The authors do not include a placebo / placebo group. This decision should be explained.  
2.  In figure 1 legend, ODC1 is misspelled as OCD1  
3.The Lynch study is described in great detail in the Disc ussion, which studied celecoxib with 
DFMO. The authors should explain why they chose to study sulindac instead of celecoxib as a 
combination agent with ODC (or not both agents), since celecoxib has also been shown to inhibit 
polyamine synthesis.  
4. It woul d be useful to measure intestinal PA levels in study patients from biopsies. The authors 
seem to hint at this by stating that biopsies will be taken for research purposes.  
 
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 supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in t he 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 futu re? 
 
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 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 website along with the authors'  
responses. I agree for my report to be made available under an Open Access C reative 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: Efficacy and safety of eflornithine (CPP -1X)/sulindac combination therapy versus each as 
monotherapy in patients with familial adenomatous polyposis (FAP): design and rationale of a 
randomized, double -blind, Phase III tri al 
 
 
Version: 0 Date: 09 Apr 2016 
 
 
Reviewer: Jatin  Roper  
 
 
Reviewer's report:  
 
This study conducts a randomized, double -blinded, phase III clinical trial, studying the use of 
eflornithine and sulindac combination therapy in the chemoprevention of FAP progression. 
Eflornithine and sulindac work synergistically to decrease the levels of polyamines (PA) in the 
intestinal mucosa by inhibiting ornithine decarboxylase (ODC), which decreases the synthesis of 
PA, and upregulating the PA transport genes, which increases the elimination of PA, 
respectively. The reduced levels of PA is hypothesized to have an impact on the natural history 
and progression of FAP.  
 
As of 1st of February 2016 ,138 patients have been enrolled in the study and have been 
randomized to three groups of (1) eflornithine/sulindac, (2) eflornithine/placebo and ( 3) 
placebo/sulindac therapies for 24 months with regular follow -ups thereafter.  
 
This study is noteworthy for enrolling a greater number of patient than prior chemoprevention 
studies for FAP, and for selecting clinically meaningful endpoints. The authors a re to be 
commended for reaching 95% of the enrollment goal on schedule. Also of note are the built in 
controls and checks to ensure complete and unbiased polyp counts on colonoscopy videos and 
still images. An additional strength of the study is the relati vely long follow up of 24 months.  
 
  
Specific comments:  
 
1. The authors do not include a placebo / placebo group. This decision should be explained.  
2.  In figure 1 legend, ODC1 is misspelled as OCD1  
3.The Lynch study is described in great detail in the Disc ussion, which studied celecoxib with 
DFMO. The authors should explain why they chose to study sulindac instead of celecoxib as a 
combination agent with ODC (or not both agents), since celecoxib has also been shown to inhibit 
polyamine synthesis.  
4. It woul d be useful to measure intestinal PA levels in study patients from biopsies. The authors 
seem to hint at this by stating that biopsies will be taken for research purposes.  
 
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 supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Yes 
 
Are you able to assess any statistics in t he 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 futu re? 
 
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 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 website along with the authors'  
responses. I agree for my report to be made available under an Open Access C reative 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