Dear Dr. Synnott,

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.

The reviewers have addressed some important aspects both methdologically as concerning the relevance of the results especially as the study has been conducted a long time ago and I would ask you to very carefully consider the reviewers' comments in your revision.

Please submit your revised manuscript by Mar 19 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.

• 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.

We look forward to receiving your revised manuscript.

Kind regards,

Sascha Köpke

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. 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.   We note that the original protocol file you uploaded contains a confidentiality notice indicating that the protocol may not be shared publicly or be published. Please note, however, that the PLOS Editorial Policy requires that the original protocol be published alongside your manuscript in the event of acceptance. Please note that should your paper be accepted, all content including the protocol will be published under the Creative Commons Attribution (CC BY) 4.0 license, which means that it will be freely available online, and any third party is permitted to access, download, copy, distribute, and use these materials in any way, even commercially, with proper attribution.

Therefore, we ask that you please seek permission from the study sponsor or body imposing the restriction on sharing this document to publish this protocol under CC BY 4.0 if your work is accepted. We kindly ask that you upload a formal statement signed by an institutional representative clarifying whether you will be able to comply with this policy. Additionally, please upload a clean copy of the protocol with the confidentiality notice (and any copyrighted institutional logos or signatures) removed.

3. Thank you for stating the following financial disclosure:

“Vanda Pharmaceuticals funded this work”

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. Please ensure that you refer to Figure 2 in your text as, if accepted, production will need this reference to link the reader to the figure.

5. Please upload a copy of Figure 3, to which you refer in your text on page 14. If the figure is no longer to be included as part of the submission please remove all reference to it within the text.

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“All authors are employees of Vanda Pharmaceuticals. MHP is the CEO of Vanda Pharmaceuticals.”

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: ""This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

7. We note that you have indicated that there are restrictions to data sharing for this study. For studies involving human research participant data or other sensitive data, we encourage authors to share de-identified or anonymized data. However, when data cannot be publicly shared for ethical reasons, we allow authors to make their data sets available upon request. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

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b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of recommended repositories, please see https://journals.plos.org/plosone/s/recommended-repositories. You also have the option of uploading the data as Supporting Information files, but we would recommend depositing data directly to a data repository if possible.

Please update your Data Availability statement in the submission form accordingly.

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9. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

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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?

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: No

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Page 2 Abstract- Method: The sentence ‘Entry criteria selected for enrollment of primary insomnia patients with difficulty falling asleep’ requires revision.

Page 5: The reference number for approval by a central Institutional Review Board is to be stated.

Page 4: Full name for abbreviation SCN is to be provided e.g.suprachiasmatic nucleus.

Page 4: Typo melatnoin. MT1 Mt2 melatonin agonist is to be written as MT1 MT2 melatonin receptors agonist.

Page 5: This sentence ‘prior to the enrollment of the first patient (first posted on October 23, 2007)’ is unclear and requires further explanation.

Page 7: The exclusion criteria is to be stated.

Page 7: The number of subjects in the blocks is to be stated. For centrally, more information is to be provided e.g. who performed it from Vanda Pharmaceuticals Inc

Page 8: The terms ‘Double-blind evaluation interval and Single-blind Placebo Wash-out Night’’ are to be standardized with Figure 1b. All the assessment tools/inventories/questionnaires are to be indicated and denoted in the Figure 1b/Figure1b footnote.

Page 10: For the phrase ‘Potential for withdrawal symptoms, residual effects, and rebound effects of these two doses were investigated using validated questionnaires.’, the name of the questionnaires are to be stated.

Page 10: For the sample size calculation, sample size calculator/software or formula was used is to be stated.

Page 11: The statistical analysis software (and its version and publisher name) and the accepted statistical significant level is to be stated.

Page 11: More description/information on the MMRM and ANCOVA in the statistical analysis section is to be provided e.g. model description, covariance structure, covariates details, effect size index, multiple testing corrections/post hoc comparisons where applicable.

Page 13: Below Table 1, there is another row of demographic. This is to be omitted. BMI min-max is to be placed below the median.

Table 2, 3 & 4: Statistical tests are to denoted in the table footnote.

The descriptive statistics/results (tables/supplementary tables) at various nights/days are to be provided prior to further data management.

Full name for OC is to be stated e.g. observed cases (OC).

Page 15 Figure 2 title: Typo 'asterisk *p value < 0.05; * p value < 0.01 (2 tailed).' ** is missing.

Supplementary Table 2: The notation for *p-value < 0.05 and **p-value < 0.01 (2-tailed) is to be removed, as no significant differences were observed. A footnote to be added to indicate that no statistical differences were noted.

Figure chart is to be clearly labelled Figure 2.

Ensure all figures/tables are cited in the text.

Not all references conform to the journal format.

Reviewer #2: The authors, all employees of the company making the product evaluated in this study, conducted a double blind placebo controlled trial with a placebo controlled run in phase among selected individuals with sleep latency disorders to evaluate the effects of tasimeteon (Heltioz) (at two different doses) to improve Latency to Persistent Sleep (LPS) primarily through polysomnography. Results showed a statistically significant improvement of approxmately 15-20 minutes in LPS for both doses averaged at days 1 and 8 (and also noted later)l vs. placebo. Effect size is modest but was also seen in patient reported sleep latency, THere were essentially no differences in outcomes for other physiologic measures of sleep. Authors stated they assessed patent reported Sleep associated quality of life and function but these more important outcomes were not provided and calls into concerns the selective reporting of findings. In the absence of clinically meaningful outcomes the data focused solely on LPS is of little clinical importance (esp given the lack of benefit for other sleep time measures). AUthors also note safety of the medication and in the discussion highlight the safety profile though the labeling in the FDA inserts notes adverse effects including liver function abnormalities, respiratory and urinary tract infections and difficulties maintaining alertness including performing functions (hardly fully safe). The authors also used a placebo controlled run in phase which in-part reduced their initially eligible by about50% to the final number randomized and has the known effect of then only enrolling and analyzng indivduals likely to adhere, with fewer adverse effects and greater benefits. The mean age of individyuals was in the 40s thus little is known on older adults. The authors note that not all data is available because some is patent identifiable. THis can be readily corrected so that others can have full access as required by PLOS. It is particularly concerning because the data in this paper is only for sleep time frames and not patient inportant measures such as function and sleep related quality (and studies were mostly done in sleep labs...not very applicable). Additionally, the study was completed in 2008 (17 years ago!!!). It is not clear to this reviewer why the results would be published at this late date and given the sponsorship, author employment, analyses plan, limited data reporting etc calls into concern selected outcome reporting and analyses. The intro and discussion are written as basic advertisments for the drug. AUthors do not mention the current price in the US ranges from about $5000-$20,000 per month for most patients. Readers should know all of this information to help decide if the product is a good value given the benefits limited to physiologic sleep latency of about 15-20 minutes in highly selected patients, no impropvement in other sleep time measures, no data on sleep related function or quality of life and stated harms in the FDA label. For some it might be worth it. THis article does not provide full transparency.

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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 #2: 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.

Dear Dr. Synnott,

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 Sep 06 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.

• 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'.

We look forward to receiving your revised manuscript.

Kind regards,

Sascha Köpke

Academic Editor

PLOS ONE

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise. 

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.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions??>

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

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

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Reviewer #1: Reference

14: JPharmSci Full name to be given,

44: JAMA, Full name to be given,

For Pairwise Chi-square contrast etc, the word contrast is to be replaced with another word.

The sentence 'The product of the adjusted baseline score by time as a covariate' requires revision e.g. an interaction term between the adjusted baseline score and time was included as a covariate

The sentence The treatment-by-baseline interaction’ could be rephrased as ‘interaction between treatment and baseline.’ This suggestion applies throughout the manuscript

**********

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

Melatonin Agonist Tasimelteon (HETLIOZ®) Improves Sleep in Patients with Primary Insomnia: A multicenter, randomized, double-blind, placebo-controlled trial.

PONE-D-24-38898R2

Dear Dr. Synnott,

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. For questions related to billing, please contact billing support .

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,

Sascha Köpke

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: (No Response)

**********

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

Reviewer #1: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: (No Response)

**********

Reviewer #1: (No Response)

**********

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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