Reviewer ’s report  
 
Title: Hypophosphataemia after ferric carboxymaltose is un related to symptoms, intestinal 
inflammation or vitamin D status  
 
Version: 0 Date: 11 Feb 2020  
 
Reviewer: Trond Espen Detlie  
 
Reviewer's report:  
 
Overall a nice paper with important insi ght in a current and little described problem.  
 
I have some minor remarks to the manuscript:  
 
In general I think the authors should consider to use less abbreviations so the text would be a 
little easier to read.  
 
Also the use of the term "trough level" in  regard of serum phosphate level seems wrong (line 
199) and should be avoided. The term "nadir" to describe the lowest level of phosphate etc also 
seems wrong since most people use this term in other medical circumstances.  
 
1. In the abstract from line 95 starting with: "Intact fibroblast growth factor levels increased.... " I 
would leave this out from the abstract since it is well addressed in the paper as well as not 
directly addressed in the background in the abstract.  
 
2. In the section Materials and Me thods:  
 
- Line 143 in Subjects: I think the authors should include the definition they used to define iron 
deficiency and iron deficiency anaemia. What criteria they used to identify patients who where in 
need of high dose IV iron. Also, describe in more de tails how they selected the patients for this 
study, did all patients consent? Any loss to follow -up? 
 
3. Protocol and analysis:  
 
- Line 153: questioning of gastrointestinal symptoms: I know it is described later in the 
manuscript, but I think also the auth ors should in this section name what scoring system or index 
they used in this study. Same goes for adverse events; what criteria did they use to identify AE 
and SAE?  
 
4. Results:  
 
- I think the authors should consider to address the same order of the resul ts as mentioned in 
Endpoints ( or the other way around). This is of course of minor importance but makes the paper 
easier to read I think.  
 
- In the section "Change in serum phosphate" I would encourage the authors to also include the 
number of patients who  developed hypophosphatemia at any time during the observation period. 
this would also do well in a table; the number of patients with hypophosphatemia could be 
displayed from each study visit?  
 
-In the section "Predictors of hypophosphatemia" line 235 DBP results are conveyed, but I can 
not see or find any information or table in regard to the results?  
 
- Line 239 to 247: This section should be removed from the manuscript. It has no relevance to 
what has been identified as endpoints. Also the timeframe since  last infusion with FCM is far too 
long. The longest duration of observed hypophosphatemia after a single infusion with FCM is 6 
months I believe. Therefore it would be very unsatisfactory to compare effect in patients who 
have received an infusion 2 years  ago and call it recurrent infusion. Also 5 patients is a very 
small number to give any statistical information. Hence, this section is somewhat misleading.  
 
5. Discussion:  
 
- Line 272 to 275: I think the authors should (if possible) comment on who developed late AEs 
and how we know it is not correlated to hypophosphatemia. The figure 1c illustrates this nicely 
and should perhaps be referred to?  
Line 283: The observation perio d in this study is 28 days/4 weeks. Why does it say 4 -6 weeks in 
this sentence? If referring to other studies a reference should be used here. Also, if referring to 
other studies it should be mentioned that a minority of patients actually have persistent 
hypophosphatemia up to 6 months after a single infusion of FCM.  
 
-Line 289: I think it should be pointed out that this study also showed that 50 % of the patients 
who developed hypophosphatemia and still had hypophosphatemia at 6 weeks also had 
hypophosphate mia up to 6 months.  
 
-Line 309 to 317 that mention the correlation with DBP is hard to understand. Also, DBP is not 
commonly used in most medical centers and should be better explained. I would suggest to 
rewrite this section.  
 
-Line 340 to 343: This is corr ect. However, the reader is left with the impression that the risk of 
developing hypophosphatemia is high in all iv iron products which is not the case. I would say 
that the risk of developing hypophosphatemia is generally low, but significantly increased and 
high in the case of FCM...  
 
To conclude: A well written manuscript with an interesting topic and findings. I recommend 
publication after some minor editing.  
 
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.  
 
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 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 financial ly from the publication of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financi ally 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 organiz ation 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 th e 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 interest. However, I have received funding, reimbursement s 
and fees from Pharmacosmos as well as reimbursements and fees from  Vifor Pharma within the 
last 5  years. Both suppliers of high dose IV iron products.  
 
 
 
 
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 f or 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 in cluded as confidential comments 
to the editors, which will not be pu blished.  
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title: Hypophosphataemia after ferric carboxymaltose is un related to symptoms, intestinal 
inflammation or vitamin D status  
 
Version: 0 Date: 11 Feb 2020  
 
Reviewer: Trond Espen Detlie  
 
Reviewer's report:  
 
Overall a nice paper with important insi ght in a current and little described problem.  
 
I have some minor remarks to the manuscript:  
 
In general I think the authors should consider to use less abbreviations so the text would be a 
little easier to read.  
 
Also the use of the term "trough level" in  regard of serum phosphate level seems wrong (line 
199) and should be avoided. The term "nadir" to describe the lowest level of phosphate etc also 
seems wrong since most people use this term in other medical circumstances.  
 
1. In the abstract from line 95 starting with: "Intact fibroblast growth factor levels increased.... " I 
would leave this out from the abstract since it is well addressed in the paper as well as not 
directly addressed in the background in the abstract.  
 
2. In the section Materials and Me thods:  
 
- Line 143 in Subjects: I think the authors should include the definition they used to define iron 
deficiency and iron deficiency anaemia. What criteria they used to identify patients who where in 
need of high dose IV iron. Also, describe in more de tails how they selected the patients for this 
study, did all patients consent? Any loss to follow -up? 
 
3. Protocol and analysis:  
 
- Line 153: questioning of gastrointestinal symptoms: I know it is described later in the 
manuscript, but I think also the auth ors should in this section name what scoring system or index 
they used in this study. Same goes for adverse events; what criteria did they use to identify AE 
and SAE?  
 
4. Results:  
 
- I think the authors should consider to address the same order of the resul ts as mentioned in 
Endpoints ( or the other way around). This is of course of minor importance but makes the paper 
easier to read I think.  
 
- In the section "Change in serum phosphate" I would encourage the authors to also include the 
number of patients who  developed hypophosphatemia at any time during the observation period. 
this would also do well in a table; the number of patients with hypophosphatemia could be 
displayed from each study visit?  
 
-In the section "Predictors of hypophosphatemia" line 235 DBP results are conveyed, but I can 
not see or find any information or table in regard to the results?  
 
- Line 239 to 247: This section should be removed from the manuscript. It has no relevance to 
what has been identified as endpoints. Also the timeframe since  last infusion with FCM is far too 
long. The longest duration of observed hypophosphatemia after a single infusion with FCM is 6 
months I believe. Therefore it would be very unsatisfactory to compare effect in patients who 
have received an infusion 2 years  ago and call it recurrent infusion. Also 5 patients is a very 
small number to give any statistical information. Hence, this section is somewhat misleading.  
 
5. Discussion:  
 
- Line 272 to 275: I think the authors should (if possible) comment on who developed late AEs 
and how we know it is not correlated to hypophosphatemia. The figure 1c illustrates this nicely 
and should perhaps be referred to?  
Line 283: The observation perio d in this study is 28 days/4 weeks. Why does it say 4 -6 weeks in 
this sentence? If referring to other studies a reference should be used here. Also, if referring to 
other studies it should be mentioned that a minority of patients actually have persistent 
hypophosphatemia up to 6 months after a single infusion of FCM.  
 
-Line 289: I think it should be pointed out that this study also showed that 50 % of the patients 
who developed hypophosphatemia and still had hypophosphatemia at 6 weeks also had 
hypophosphate mia up to 6 months.  
 
-Line 309 to 317 that mention the correlation with DBP is hard to understand. Also, DBP is not 
commonly used in most medical centers and should be better explained. I would suggest to 
rewrite this section.  
 
-Line 340 to 343: This is corr ect. However, the reader is left with the impression that the risk of 
developing hypophosphatemia is high in all iv iron products which is not the case. I would say 
that the risk of developing hypophosphatemia is generally low, but significantly increased and 
high in the case of FCM...  
 
To conclude: A well written manuscript with an interesting topic and findings. I recommend 
publication after some minor editing.  
 
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.  
 
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 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 financial ly from the publication of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financi ally 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 organiz ation 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 th e 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 interest. However, I have received funding, reimbursement s 
and fees from Pharmacosmos as well as reimbursements and fees from  Vifor Pharma within the 
last 5  years. Both suppliers of high dose IV iron products.  
 
 
 
 
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 f or 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 in cluded as confidential comments 
to the editors, which will not be pu blished.  
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title: Hypophosphataemia after ferric carboxymaltose is un related to symptoms, intestinal 
inflammation or vitamin D status  
 
Version: 0 Date: 11 Feb 2020  
 
Reviewer: Trond Espen Detlie  
 
Reviewer's report:  
 
Overall a nice paper with important insi ght in a current and little described problem.  
 
I have some minor remarks to the manuscript:  
 
In general I think the authors should consider to use less abbreviations so the text would be a 
little easier to read.  
 
Also the use of the term "trough level" in  regard of serum phosphate level seems wrong (line 
199) and should be avoided. The term "nadir" to describe the lowest level of phosphate etc also 
seems wrong since most people use this term in other medical circumstances.  
 
1. In the abstract from line 95 starting with: "Intact fibroblast growth factor levels increased.... " I 
would leave this out from the abstract since it is well addressed in the paper as well as not 
directly addressed in the background in the abstract.  
 
2. In the section Materials and Me thods:  
 
- Line 143 in Subjects: I think the authors should include the definition they used to define iron 
deficiency and iron deficiency anaemia. What criteria they used to identify patients who where in 
need of high dose IV iron. Also, describe in more de tails how they selected the patients for this 
study, did all patients consent? Any loss to follow -up? 
 
3. Protocol and analysis:  
 
- Line 153: questioning of gastrointestinal symptoms: I know it is described later in the 
manuscript, but I think also the auth ors should in this section name what scoring system or index 
they used in this study. Same goes for adverse events; what criteria did they use to identify AE 
and SAE?  
 
4. Results:  
 
- I think the authors should consider to address the same order of the resul ts as mentioned in 
Endpoints ( or the other way around). This is of course of minor importance but makes the paper 
easier to read I think.  
 
- In the section "Change in serum phosphate" I would encourage the authors to also include the 
number of patients who  developed hypophosphatemia at any time during the observation period. 
this would also do well in a table; the number of patients with hypophosphatemia could be 
displayed from each study visit?  
 
-In the section "Predictors of hypophosphatemia" line 235 DBP results are conveyed, but I can 
not see or find any information or table in regard to the results?  
 
- Line 239 to 247: This section should be removed from the manuscript. It has no relevance to 
what has been identified as endpoints. Also the timeframe since  last infusion with FCM is far too 
long. The longest duration of observed hypophosphatemia after a single infusion with FCM is 6 
months I believe. Therefore it would be very unsatisfactory to compare effect in patients who 
have received an infusion 2 years  ago and call it recurrent infusion. Also 5 patients is a very 
small number to give any statistical information. Hence, this section is somewhat misleading.  
 
5. Discussion:  
 
- Line 272 to 275: I think the authors should (if possible) comment on who developed late AEs 
and how we know it is not correlated to hypophosphatemia. The figure 1c illustrates this nicely 
and should perhaps be referred to?  
Line 283: The observation perio d in this study is 28 days/4 weeks. Why does it say 4 -6 weeks in 
this sentence? If referring to other studies a reference should be used here. Also, if referring to 
other studies it should be mentioned that a minority of patients actually have persistent 
hypophosphatemia up to 6 months after a single infusion of FCM.  
 
-Line 289: I think it should be pointed out that this study also showed that 50 % of the patients 
who developed hypophosphatemia and still had hypophosphatemia at 6 weeks also had 
hypophosphate mia up to 6 months.  
 
-Line 309 to 317 that mention the correlation with DBP is hard to understand. Also, DBP is not 
commonly used in most medical centers and should be better explained. I would suggest to 
rewrite this section.  
 
-Line 340 to 343: This is corr ect. However, the reader is left with the impression that the risk of 
developing hypophosphatemia is high in all iv iron products which is not the case. I would say 
that the risk of developing hypophosphatemia is generally low, but significantly increased and 
high in the case of FCM...  
 
To conclude: A well written manuscript with an interesting topic and findings. I recommend 
publication after some minor editing.  
 
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.  
 
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 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 financial ly from the publication of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation t hat may in any way gain or lose 
financi ally 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 organiz ation 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 th e 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 interest. However, I have received funding, reimbursement s 
and fees from Pharmacosmos as well as reimbursements and fees from  Vifor Pharma within the 
last 5  years. Both suppliers of high dose IV iron products.  
 
 
 
 
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 f or 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 in cluded as confidential comments 
to the editors, which will not be pu blished.  
 
I agree to the open peer review policy of the journal  
assistant