The oral intake of specific Bioactive Collagen Peptides (BCP) improves gait and quality of life in canine osteoarthritis patients—A translational large animal model for a nutritional therapy option

Britta Dobenecker; Linda Franziska Böswald; Sven Reese; Stephanie Steigmeier-Raith; Lukas Trillig; Steffen Oesser; Michael Schunck; Andrea Meyer-Lindenberg; Jutta Hugenberg

doi:10.1371/journal.pone.0308378

Peer Review History

Original SubmissionMarch 13, 2024
23 Apr 2024 Decision Letter - Ewa Tomaszewska, Editor PONE-D-24-10151The oral intake of specific Bioactive Collagen Peptides (BCP) improves gait and quality of life in canine osteoarthritis patients - a translational large animal model for a nutritional therapy optionPLOS ONE Dear Dr. Dobenecker, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. ============================== Dear Authors,please provide all additional information.with best regardsEwa Tomaszewska ============================== Please submit your revised manuscript by Jun 07 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf 2. Please note that funding information should not appear in any section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript. 3. Thank you for stating the following financial disclosure: "CRI, Collagen Research Institute GmbH, Kiel, Germany. Supplements/placebo in this study were funded by GELITA AG, Germany." Please state what role the funders took in the study. If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript." If this statement is not correct you must amend it as needed. Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf. 4. Thank you for stating the following in the Competing Interests section: "Steffen Oesser is co-inventor of patents concerning the use of collagen peptides. Michael Schunck is employed by CRI, Kiel, Germany. Julia Hugenberg is employed by GELITA AG, Eberbach, Germany. At the time of investigation, Britta Dobenecker, Linda Böswald, Sven Reese, Stephanie Steigmeier-Raith, Lukas Trillig, and Andrea Meyer-Lindenberg were employed by LMU Munich, Germany, which received financial compensation for the study. Britta Dobenecker and Linda Böswald received compensation from CRI for medical writing, and Sven Reese for statistical analyses." We note that one or more of the authors are employed by a commercial company: GELITA AG, Eberbach, Germany a. 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Please note that supplementary tables (should remain/ be uploaded) as separate "supporting information" files Additional Editor Comments: Dear Authors, some issues should be clarify: 1. L170- the dog's regular meal. This should be presented in table with basal ingreadients. 2. L 175- Further information are needed about the dogs, such as their breed, sex, and age distribution, to understand the population's diversity. 3. Details about the severity of osteoarthritis among the patients, possibly categorized into mild, moderate, and severe. 4. Information on any past treatments or therapies for osteoarthritis and their outcomes. 5. Details about the specific diagnostic methods used to confirm OA and how severity was assessed. 6. Further clarification on the specific inclusion and exclusion criteria, including any health checks or requirements for participation. 7. More information on the study's design, including duration, controls, randomization methods, and blinding, to understand the study's structure. 8. Indications that the study complied with ethical guidelines and that appropriate consent was obtained from the dogs' owners. 9. Information about the follow-up process and how the researchers monitored the dogs' health and progress during and after the study. 10. the dosages, and frequency of administration of all suplemments should be included. It cannot be described as "with a minimum of...". who decided about the final dose? The treatment should be described precisely. 11. was the normal distribution of the data checked? 12. it should be described in detail how the dogs were assigned to these three groups, and what the dogs in the groups looked like - exactly age, weight, sex, degree of OA. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript describes the primary results on oral supplementation of BCP in the treatment of OA in dogs. It is very usefull for veterinary clinicians. I have only a few questions before publication. line 173: Have the authors excluded all locomotry disese, that may be misdiagnosed with OA ? line 243-245: What did author mean: "unknown" - please explain. ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0308378.r001
Revision 1
9 Jul 2024 Author Response also added as MS Word file (see attached files) Dear reviewers Thank you for your time and efforts invested in reviewing our manuscript. We amended the manuscript based on your comments and tried to implement all your suggestions thoroughly. Please find our response to your comments below. Regarding the journal requirements: 1. The style was adapted to the requirements 2. Funding information was deleted from the text (funding statement only) 3. The funding section was reworded: Supplements/placebo in this study were funded by GELITA AG, Germany. The funder had no influence on study design, the collection, analysis and interpretation of data, the decision to publish, and the preparation of the manuscript. The funder [JH] provided support in the form of financial compensation for authors, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. 4. The conflict of interest section was reworded because the study was solely funded by GELITA AG. Conflict of interest: J Jutta Hugenberg is employed by GELITA AG, Eberbach, Germany. At the time of investigation, Britta Dobenecker, Linda Böswald, Sven Reese, Stephanie Steigmeier-Raith, Lukas Trillig, and Andrea Meyer-Lindenberg were employed by LMU Munich, Germany, which received financial compensation for the study. This does not alter our adherence to PLOS ONE policies on sharing data and materials. 5. In the methods section the following information was added: All procedures and protocols were conducted in accordance with the guidelines of the Protection of Animals Act and the study was approved in written format by the responsible committee for animal welfare of the Veterinary Faculty, Ludwig-Maximilians-University, Munich (reference number 192-11-11-2019). 6. The tables 1 to 3 were included as part of the main manuscript 1. L170- the dog's regular meal. This should be presented in table with basal ingredients. Authors’ response: There was a huge variety of diet compositions that the enrolled patients received. It was made sure that no diet components containing nutraceuticals were fed 6 weeks prior to the start of the trial (see also line 181ff: Medications such as analgesics, corticosteroids or nutraceuticals for orthopedic applications had to be discontinued at least 6 weeks prior to enrolment to allow for participation in the study). It was decided to abstain from performing a complex and time-consuming ration calculation and diet evaluation for all dogs, especially because the feeding regime remained constant throughout the trial (the owners were informed that the diet of the dog should not be changed during the study phase). To underline this, the following sentence was added to the passage ‘patients’ in chapter ‘methods’ (line 187): The owners were asked not to change the dog’s diet during the study period. 2. L 175- Further information are needed about the dogs, such as their breed, sex, and age distribution, to understand the population's diversity. Authors’ response: Table 2 gives the body weight (mean ± standard deviation), the age and lists the breeds of the canine patients in each group. We added the gender of the patients to this table. 3. Details about the severity of osteoarthritis among the patients, possibly categorized into mild, moderate, and severe. Authors’ response: One important inclusion criterion was that the consequences of the OA, which had to be diagnosed by a vet, was measurable in the treadmill examination at T0 (see also the following sentence in the materials & methods section: Only dogs with abnormal gait parameters of at least one limb at T0 in combination with the veterinary diagnosis of OA were eligible for the study). Therefore, only dogs with clinical signs that showed during the treadmill measurements were eligible; this equates to the lower threshold for severity. On the other hand, participation was not possible in cases where the medication could not be discontinued for at least 4.5 months due to the severity of the condition. Only dogs which did not depend on medication or nutraceuticals were eligible for the study. This automatically excludes cases of more pronounced severity. The severity of AO in the study population can be overall categorized as mild to moderate). This information was added to the discussion. Apart from this, a main problem here is that clinical signs and the degree of OA do not correlate well enough to rank the OA of canine patients. The same applies more or less to the treadmill /force plate measurements. The SI (symmetry index) probably gives the best estimate but this often does not suffice to rank correctly. Even evaluation of radiological methods can deviate depending on the applied scoring systems that often cannot be converted from the specific joint they are validated for. 4. Information on any past treatments or therapies for osteoarthritis and their outcomes. Authors’ response: This information was not specifically collected. It was made sure that any medication including the use of nutraceuticals was discontinued at least 6 weeks 5. Details about the specific diagnostic methods used to confirm OA and how severity was assessed. Authors’ response: We accepted the veterinarian’s statement that OA was diagnosed in an individual. Regarding the severity of the OA please see the response to the comment #3. 6. Further clarification on the specific inclusion and exclusion criteria, including any health checks or requirements for participation. Authors’ response: All inclusion and exclusion criteria are mentioned in the materials and methods section (body weight range, no other diseases requiring pain medication, medication such as analgesics and corticosteroids or their use for more than 2 days, respectively, use of nutraceuticals 6 weeks before or during the study, acceptance to participate in the study / treadmill measurements) 7. More information on the study's design, including duration, controls, randomization methods, and blinding, to understand the study's structure. Authors’ response: We have added the following information to the manuscript: The study was conducted between 2017 and 2021. A sentence was added to materials and methods explaining the randomization process: The patients were allocated to the coded and therefore blinded supplements, i.e. study groups, according to the order in which they entered the study. Blinding: In the materials & methods section (dietary supplements) the following sentences explain the blinding during the study: All supplements consisted of a fine white powder and were packaged in ready-to-use pouches labeled only with a code and feeding instructions. The identical appearance allowed for double-blind use, i.e., neither the supervising veterinarians nor the dog owners knew which supplement each dog received at the trial. We added the following information: The study unblinding occurred after completion of the statistical evaluation of all results (to materials & methods, dietary supplements). As well as: After the formal analysis of all results, the allocation of the dogs to the three study groups was unblended (materials & methods, statistical evaluation). Further point: The patients of the placebo group acted as a control. 8. Indications that the study complied with ethical guidelines and that appropriate consent was obtained from the dogs' owners. Authors’ response: The following information was added at the beginning of the materials & methods section: All procedures and protocols were conducted in accordance with the guidelines of the Protection of Animals Act and the study was approved by the representative of the Veterinary Faculty for animal welfare. 9. Information about the follow-up process and how the researchers monitored the dogs' health and progress during and after the study. Authors’ response: A follow-up was not systematically done, just in single cases when the owners requested a supplement for further use. The dogs were not monitored during the study. The researchers were available in case of specific questions or incidents (e.g., exclusion of a dog in case of pain medication for more than 2 days etc.). 10. the dosages, and frequency of administration of all suplemments should be included. It cannot be described as "with a minimum of...". who decided about the final dose? The treatment should be described precisely. Authors’ response: The owner were supplied with enough dietary supplement prepacked in pouches for the whole study period. The packages were stored refrigerated and added directly to wet food or diluted in a small amount of water and then added to a dry food on a daily basis. We adapted the information in the materials & methods section as follows: The BCP dosage was based on studies by Oesser et al. (2007) in mice [57] and results from field studies in dogs [40,58,59] with 240 ± 95mg BCP/kg BW. In the n3FA group, the dogs received 700 ± 115mg n3FA/kg BW combined with ≥ 2mg of vitamin E/kg BW, following regulation EG 2020/354 recommendations [56]. Dogs in the PLA group received 240 ± 50mg of the cellulose mixture per kg BW. 11. was the normal distribution of the data checked? Authors’ response: Of course. A colleague specialized in statistics was involved in the statistical analysis of results. 12. it should be described in detail how the dogs were assigned to these three groups, and what the dogs in the groups looked like - exactly age, weight, sex, degree of OA. Authors’ response: Details about the dogs enrolled in the study can be found in table 2. More details, e.g., the degree of OA, were added to the text (see answer to the issue #3). Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0308378.r002
23 Jul 2024 Decision Letter - Ewa Tomaszewska, Editor The oral intake of specific Bioactive Collagen Peptides (BCP) improves gait and quality of life in canine osteoarthritis patients - a translational large animal model for a nutritional therapy option PONE-D-24-10151R1 Dear Dr. Britta Dobenecker, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Ewa Tomaszewska, DVM Ph.D Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Tha authors made all indicated corrections. I accept the manuscript in present form and reccommend it for publications ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ******** https://doi.org/10.1371/journal.pone.0308378.r003
Formally Accepted
10 Sep 2024 Acceptance Letter - Ewa Tomaszewska, Editor PONE-D-24-10151R1 PLOS ONE Dear Dr. Dobenecker, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Professor Ewa Tomaszewska Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0308378.r004

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