PONE-D-24-00185Effects of Cinnamomum zeylanicum (Ceylon cinnamon) extract on lipid profile, glucose levels and its safety in adults: A randomized, double-blind, controlled trialPLOS ONE

Dear Dr. Ajanthan,

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PLOS ONE

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Financial support for this research was provided by SDS Spices Pvt Ltd. This funding covered the costs associated with staff at research sites, including the reimbursement of authors Dimuthu Muthukuda and Arunasalam Pathmeswaran for the time devoted to this study. The authors declare that this funding did not influence the study design, data collection, analysis, interpretation, or the decision to publish these findings."

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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: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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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

Reviewer #2: Yes

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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

Reviewer #2: Yes

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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: Comments

For the sample size calculation, whether a formula or sample size calculator/software was used to derive the sample size is to be stated.

The information on the effect size, how the correlation coefficient of 0.9 between baseline and six-month measurements was incorporated into the sample size calculation, and the sample size before the attrition rate 15% is to be stated.

Line 173-174, although complete case analysis is easy to implement, it can contribute to biased results if the missing data are not missing completely at random (MCAR). Perhaps a statement on handling missing data could be added by exploring the pattern of missing data and the possible imputation method, model-based approaches etc if required.

Line 172-174, the ANCOVA analysis is unclear. More details are to be provided. The dependent variable, independent variable(s), and covariate variable are to be stated. Whether the dependent variable refers to LDL-C at 3 months or changes from baseline to 3 months is to be clearly stated. From Table 2 presentation, it indicates the dependent variable LDL-C is at 3 months.

A statement on the fulfillment of ANCOVA assumptions is to be provided.

Line 176-177, the treatment and potential subgroups are to be mentioned and the name of statistical test that will be employed is to be mentioned.

Line 178, the actual citation for the statistical software R is to be provided.

Table 1 Female, typo 6.07%.

Table 1, for the glycemic status variable, the subcategories are not to be directly below the same alignment with the glycemic status available. Since symbol % has been indicated in the first column of those variables, all individual symbol % could be omitted.

Table 2, the table requires cosmetic changes and to follow the journal requirement. Mean, SD, 95% CI, statistical test is to be denoted in the table footnote. For Hb available, AST, eGFR, ACR, BMI for p >0.9, the actual p-value is to be provided. The decimal point for the p-value is to be standardized in the table and text. One decimal point is to be avoided. This applies to others where applicable. The word mean fall is to be avoided and replaced with another word.

Line 212, P=0.036 to be replaced as p=0.036

Line 215-220, the adjusted findings are to be “discussed” as well apart from the unadjusted findings.

Effect size indices could be presented.

Table 3, how the independent variable was coded for the multivariate linear regression is to be stated. For the adjusted analysis, model fit is to stated.

Table 3, Beta is to be labeled as standardized coefficients and denoted in the table footnote.

Table 3 anthropometrics and vitals (for p >0.9), the actual p-value is to be presented. Similarly, the decimal point for the p-value, beta coefficient and 95%CI is to be standardized. One decimal point for the p-value is to be avoided. This applies to others where applicable.

Line 221, multivariate linear regression is to be stated in the statistical analyses section. The use of multivariate linear regression is to be clearly stated, e.g. whether the focus is on estimating treatment effects at follow-up etc and whether adjusting for baseline values is required.

Line 221-222, the word ‘at 3 months’ is to be stated.

Line 239, (-63), (95% CI to be presented as (-63, 95%C….)

Line 246, the timepoint baseline -3 months is to be stated.

Line 254, the timepoint or changes are to be stated.

Table 5 is to be cited in the text.

Table 6, the decimal point for the p-value is to be standardized. One decimal point is to be avoided.

References did not adhere to the format specified by the journal.

Reviewer #2: Dear Authors

I read your manuscript carefully; your work is acceptable with minor revise. Please apply the following comments.

Article entitled “Effects of Cinnamomum zeylanicum (Ceylon cinnamon) extract on lipid profile, glucose levels and its safety in adults: A randomized, double-blind, controlled trial” has been written in a good way; It is an interesting topic. Authors only address following minor revisions:

Abstract:

-Your Keywords should written based on MeSH term.

Introduction:

In the introduction, you should first discuss the role of complementary therapies (natural compounds) products in human health and chronic diseases prevention and treatment, also its role in improving glycemic indices and lipid profile levels in adults, then discuss the probable role of cinnamon in glycemic and lipid profile indices. You can also use the following references in your article for strengthen the introduction and discussion sections. These references are helpful.

1) Ranasinghe, P., Galappaththy, P., Constantine, G. R., et al. (2017). Cinnamomum zeylanicum (Ceylon cinnamon) as a potential pharmaceutical agent for type-2 diabetes mellitus: study protocol for a randomized controlled trial. Trials, 18, 1-8.

2) Gheflati et al. The effects of cinnamon supplementation on adipokines and appetite-regulating hormones: A systematic review of randomized clinical trials.

3) The effect of conjugated linoleic acids on inflammation, oxidative stress, body composition and physical performance: a comprehensive review of putative molecular mechanisms (Nutrition & Metabolism).

4) Does propolis have any effect on rheumatoid arthritis? A review study (Food Science & Nutrition).

5) Nattagh‐Eshtivani et al. The role of Pycnogenol in the control of inflammation and oxidative stress in chronic diseases: Molecular aspects.

6) Effects of Momordica charantia L on blood pressure: a systematic review and meta-analysis of randomized clinical trials (International Journal of Food Properties).

7) Bahari et al. The effect of Royal jelly on liver enzymes and glycemic indices: A systematic review and meta-analysis of randomized clinical trials.

8) Barghchi et al. The effects of Chlorella vulgaris on cardiovascular risk factors: A comprehensive review on putative molecular mechanisms.

Methods:

-Please more explain about randomization and blinding.

-Please mention your sample size calculation formula and related study.

- Have you considered medication intake for this study? And did you adjust their effects?

Results:

- Dietary intake (carbohydrates, protein, fat) as well as some micronutrients such as omega-3 fatty acids can affect blood sugar and lipid profile. Why did you not report food intake? (Please report it in table).

Discussion:

-The Discussion section is poor. Please complete your discussion using the references mentioned and related article and discuss about probably mechanism effects of this compound and also improve its grammatical errors.

Conclusion:

- Good presented.

Overall:

- I found some grammatical errors in your work. Please revise in again by a native person.

Best Regard

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Reviewer #1: No

Reviewer #2: No

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PONE-D-24-00185R1Effects of Cinnamomum zeylanicum (Ceylon cinnamon) extract on lipid profile, glucose levels and its safety in adults: A randomized, double-blind, controlled trialPLOS ONE

Dear Dr. Ajanthan,

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.

Please submit your revised manuscript by Feb 01 2025 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. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Nishant Kumar, Ph.D

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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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

Reviewer #3: (No Response)

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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: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #3: I Don't Know

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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

Reviewer #3: Yes

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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

Reviewer #3: No

**********

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: The authors have put in great effort to address the comments.

Minor comment:

For Table 2, the 95% confidence interval for Cohen D is to be denoted in the table footnote.

Reviewer #3: I have carefully read through your work, and I appreciate the efforts you have put into conducting this relevant clinical trial. I have the following feedback to help strengthen your manuscript:

1. English Language and formatting consistency:

The English language used throughout the manuscript is generally clear and appropriate for a scientific publication. However, there are a few instances where the phrasing could be improved for clarity, such as the sentences in lines 378-384. Please revise carefully the whole manuscript.

- The manuscript would benefit from a thorough review of grammar, punctuation, and capitalization to ensure consistency throughout the document. For example, the term "Cinnamomum zeylanicum" should be capitalized consistently, but cinnamon shouldn’t (see, for example, line 46).

2. Abstract:

- In the objective section, you mention evaluating LDL-c levels, but you also measured other parameters, such as fasting blood sugar (FBS), that you mention on the results. It would be helpful to clarify the outcome of interest in the objective.

- Could you please provide the justification for choosing the 1000 mg/day dose of Cinnamomum zeylanicum extract? This information should also be included in the methods section (lines 149-150).

- The statement about a "significant interaction effect" (lines 22-23) could use some additional clarification.

- The two concluding sentences in the abstract should not be separated by a period.

3. Introduction:

- The reference for the sentence in line 42 is missing. Could you please provide the appropriate citation?

- It would be interesting to know the potential advantages of using Cinnamomum zeylanicum, which has a lower coumarin content, and the rationale for conducting this study.

4. Materials and methods:

- Please double-check the amount of PAC A per 100g of the cinnamon extract reported in line 142 (15298 mg of PAC A per 100g) and revise if necessary.

- For clarity, it would be helpful to define the abbreviations used in the manuscript, such as IMP (line 158), HbA1c (line 186), SBP and DBP (line 188), AST, ALT, and eGFR (line 190). Please revise all the abbreviations throughout the text.

5. Results:

- Lines 238-239: It is unclear what the "normal levels at baseline" were for the outcomes presented. Please specify the actual baseline values and what is considered the normal/healthy range for these measures.

- The presentation of Tables 2 and 3 should be improved. The number of participants per group should be clearly stated in the tables rather than using a footnote. Additionally, the formatting of the data (e.g. "Mean (SD); n (%)") should be consistent across all parameters.

- Lines 267-269: please provide the actual numerical values that support the conclusions drawn from the results, rather than just stating the observations qualitatively.

- The quality of both figures should be improved to ensure the data is clearly visible and interpretable.

6. Discussion:

- Consistency of period: Throughout the manuscript, you refer to the trial duration as both 3 months and 12 weeks. While these are equivalent, it would be best to use a single, consistent period to avoid any potential confusion.

- Strengths and limitations: I would recommend mentioning the key strengths and limitations of your study together at the end of the discussion section. This will help provide the reader with a clear overview of the merits and potential shortcomings of your work.

- Rationale for dose selection: In the discussion, you compare your results to studies using different dosages of cinnamon extract. It would be helpful to explicitly explain in the introduction or methods why you selected the 1000 mg/day dose for your trial.

- Mechanism of action: Your discussion of the putative mechanism of action for the cinnamon extract effects is interesting. If possible, can you provide any information on the specific molecules present in the extract that may be responsible for these effects?

- Liver and kidney profile details: When mentioning the liver and kidney profile findings, it would be useful to specify which parameters from Table 2 are related to these organ functions, as some readers may not be familiar with interpreting these results.

- Missing data: Please clarify what you mean by "missing data" when discussing the study limitations.

Overall, this appears to be a well-designed and conducted study that could make a relevant contribution to the literature on the metabolic effects of cinnamon supplementation. With the revisions suggested above, I believe your manuscript will be suitable for publication.

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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

Reviewer #3: No

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[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.

Effects of Cinnamomum zeylanicum (Ceylon cinnamon) extract on lipid profile, glucose levels and its safety in adults: A randomized, double-blind, controlled trial

PONE-D-24-00185R2

Dear Dr. Ajanthan

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,

Nishant Kumar, 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: Partly

**********

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: Open and close bracket missing for

Table 3 HDL-C: -1.48, 2.24

Table 4 Serum creatinine: -0.07, 0.04

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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

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