Combination of Topical Heparin and Levomenol in the Treatment of Atopic Dermatitis: A SCORing Atopic Dermatitis (SCORAD) Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a very interesting manuscript regarding the efficacy of a topical combination agent with heparin & levomenol for the treatment of atopic dermatitis. Here are some recommendations that can improve the manuscript:

1. The addition of pictures of patients pre- and post - treatment with the combination agent would be valuable.

2. How often was the therapy applied in all groups?

3. Some patients with severe or moderate baseline SCORAD parameters demonstrated significant improvement after the 8-week treatment regimen. Were these results achieved solely with monotherapy using topical treatment or combination with systemic therapy?

4. You mentioned that the control group received a topical treatment without any active substance, but still achieved improvement in skin dryness. Was this an emollient? If so, consider comparing the 2 options.

5. Consider pointing out the safety profile of the treatment.

Author Response

Thanks for the useful comments, please find the answers to the questions below. If you would prefer that these details to the manuscript, this would be no problem. We just wanted to avoid the duplication of information were already gave in the original publication.

1. The addition of pictures of patients pre- and post – treatment with the combination agent would be valuable.

Unfortunately, there are no pictures of patients available. When the study was performed in 2005, this was not part of the investigation.

2. How often was the therapy applied in all groups?

The application was twice daily, in the morning and the evening after washing or showering.

3. Some patients with severe or moderate baseline SCORAD parameters demonstrated significant improvement after the 8-week treatment regimen. Were these results achieved solely with monotherapy using topical treatment or combination with systemic therapy?

Systemic therapy was an exclusion parameter. Only patients could be included who did not require therapy with corticosteroids. Even other topical treatments were excluded.

4. You mentioned that the control group received a topical treatment without any active substance, but still achieved improvement in skin dryness. Was this an emollient? If so, consider comparing the 2 options.

The control treatment was the cream base of the study medication. The study medication for all four study arms was provided by the manufacturer Gehrlicher in Germany. The created the cream base first and then incorporated either heparin or levomenol or both, whereas no active was added to the control group.

The active groups therefore received exactly the same cream composition as the control group, with the exception of the added active constituents (no emollient).

The cream base is based on almond oil, middle chain triglyerides, tetradecane-1-ol, cetylalcohol , stearylalcohol, citric acid, collagen peptides, vitamin E, dexpanthenol, polyethylenglycol myristyl and stearyl ethers and water, preserved by sorbic acid and salicylic acid. As this composition might be expected to have a certain effect on flares of atopic dermatitis, the comparison was made with the cream base as a placebo. Any effect of heparin and/or levomenol would thus come on top.

The excipients were not mentioned in the original paper or this secondary analysis. We added them to the current text.

5. Consider pointing out the safety profile of the treatment.

It was mentioned in the original study that no adverse effects were detected and that the overall rating of tolerability was excellent.

Reviewer 2 Report

Comments and Suggestions for Authors

I recommend publishing the article as it provides valuable information on a pathology (AD) with a major impact on patients' quality of life and significant management challenges, due to the adverse effects of current therapies and the polymorphism in treatment response.

We know that the impact on quality of life is severe, not only due to the appearance of visible lesions but especially because of the symptoms (itching), which hinder daily activities and disrupt sleep.

I believe that research results providing information on symptom relief are extremely important, especially when these solutions can be applied in daily practice and are easily accessible. Implementing new and effective methods in routine practice can significantly contribute to improving patients' quality of life, particularly in cases of conditions that affect both physical health and mental well-being.

Could the authors specify if there were any limitations to the study?

Comments on the Quality of English Language

English language is ok

Author Response

Thanks for this excellent suggestion, we overlooked this detail.

Could the authors specify whether there are any limitations to the study?

Limitations were added to the conclusions. They refer to the small number of patients with symptoms of progressed stages of episodes of atopic dermatitis, especially lichenification. The small number relates to the authorized use of the combination product in early stages of episodes, it does therefore not give any information on useability or non-useability in later stages.

Reviewer 3 Report

Comments and Suggestions for Authors

I read with great interest the manuscript, however I have concerns regarding the ethics as it is based only on the results of another study without the original author's consent - it should be better placed as commentary to this specific study.

Comments on the Quality of English Language

Overall good use of English language.

Author Response

Thank you for point pointing out this issue. We clearly do not want to create the impression of plagiarsm.

I read with great interest the manuscript, however I have concerns regarding the ethics as it is based only on the results of another study without the original author's consent - it should be better placed as commentary to this specific study.

We agree that this impression can be created by the fact that we did not include the original principal investigator, Dr. Arenberger, his wife as well as the investigators Dr. Drozenová and Dr. Holcová on the list of authors. The reason for this is not negligence, it is the passing of time.

The study protocol for the clinical trial was submitted to the authorities in 2005. The first patient was enrolled on 31. August 2005, the last examination of the last patient took place on 24. October 2007. The Integrated Clinical Trial Report was finalized in 2008 and the original publication was submitted in October 2010. Although the name of the first author of this secondary analysis did not appear on the publication of 2010, it was the identical person who wrote the article. Back in 2010 it was not yet standard to also put the medical writer on the authors list or at least mention this person as a contributor. Now, 16 years after the finalization of the study report and 19 years after “first patient in” the original authors could no longer be contacted, although we tried.

The only co-author still available was Mrs. Hladiková, who at the time of the original study was responsible for the biometric analysis. Without her this new analysis would not have been possible.

Might a dedication to the original authors, especially to Prof. Arenberger, solve the problem?

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is suitable for publication! Congratulations!

Author Response

Thank you for reviewing and the conclusion. Due to the comments of another reviewer we added a few more details to inclusion and exclusion criteria, dosing scheme and duration of treatment, and differences in outcome in various age groups. We hope the additions are acceptable.

Reviewer 3 Report

Comments and Suggestions for Authors

I read with great interest the manuscript.

As I have not yet received any feedback from the editorial office regarding the concerns I previously raised, it is possible that there may be no issue.

There have been some improvements since the previous review. However, I have some comments:

Abstract:

-line 4: “indidual SCORAD...” should be corrected for spelling

Main Text:

-in the study design it would be helpful to mention the frequency and location of the application of the corresponding medication (e.g., "The corresponding medication was applied to the affected eczematous skin areas twice daily over a period of 8 weeks" [reference 5]). Additionally, the inclusion and exclusion criteria should be clearly stated.

- It is worth noticing that children and young people up to the age of 18 represent a substantial proportion of the study population. I believe it would be valuable to valuable to include a comment on whether there were any differences in effectiveness across the various age groups.

 

Overall, this article needs work, but I believe it can be improved with some amendments.

Comments on the Quality of English Language

Overall, good use of English language.

Author Response

As I have not yet received any feedback from the editorial office regarding the concerns I previously raised, it is possible that there may be no issue.

We also hope that our explanation about the issue with the authorship was sufficiently clear.

There have been some improvements since the previous review. However, I have some comments:

Abstract:

-line 4: “indidual SCORAD...” should be corrected for spelling

Thanks for point this out – the typo has been corrected.

Main Text:

-in the study design it would be helpful to mention the frequency and location of the application of the corresponding medication (e.g., "The corresponding medication was applied to the affected eczematous skin areas twice daily over a period of 8 weeks" [reference 5]).

We had omitted this information because we did not want to duplicate information from the original study. However, we agree that it is better to include these details because we cannot assume that the reader will consult the original paper. We followed the suggestion and added this phrase.

Additionally, the inclusion and exclusion criteria should be clearly stated.

As above, we agree that it makes sense to repeat this information from the original study. Some details on the inclusion and exclusion criteria were added.

- It is worth noticing that children and young people up to the age of 18 represent a substantial proportion of the study population. I believe it would be valuable to valuable to include a comment on whether there were any differences in effectiveness across the various age groups.

The original study reported a subgroup analysis for children of 0-6 and 7-12 years of age, which at the time was made because regulators had called for such data in the process of the authorization of the use in children. No statistically significant difference was found between these two age groups. No further analysis had been made for children versus adults or adolescents versus children/adolescent versus adults. Even though no corresponding statistical analysis was made, the individual data listings do not indicate specific differences when sorted by age. We would not expect any significant difference. An additional paragraph was added to the results section.