PONE-D-24-19436Psilocybin-Assisted Massed Cognitive Processing Therapy for Chronic Posttraumatic Stress Disorder: Protocol for an Open-Label TrialPLOS ONE

Dear Dr. Bhat,

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"I have read the journal's policy and the authors of this manuscript have the following competing interests: VB is supported by an Academic Scholar Award from the University of Toronto Department of Psychiatry and has received research support from the Canadian Institutes of Health Research, Brain & Behavior Foundation, Ontario Ministry of Health Innovation Funds, Royal College of Physicians and Surgeons of Canada, Department of National Defense (Government of Canada), New Frontiers in Research Fund, Associated Medical Services Inc. Healthcare, American Foundation for Suicide Prevention, Roche Canada, Novartis, and Eisai. RJ is the CMO of Mydecine Innovation Group."

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Additional Editor Comments:

I agree on the pivotal importance of your work and I fully endorse your manuscript. Please, as per the reviewer #1 request, provide in your test a more specific details on the nature of your analysis vs review. This very simple comment that I am asking you to add, it will make your manuscript perfect.

I am also very sorry for the long time taken in this peer-review process.

Feel free to contact me anytime.

A+

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

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3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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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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 #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently. Further please note that any ‘statistical review’ is generally done under the assumption that study specific methodological [as well as execution] issues are perfectly taken care of by the investigator(s). This review is not an exception to that and so does not cover clinical aspects {however, seldom comments are made only if those issues are intimately / scientifically related & intermingle with ‘statistical aspects’ of the study}. Agreed that ‘statistical methods’ are used as just tools here, however, they are vital part of methodology [and so should be given due importance]. I look at the manuscript in/with statistical view point, other reviewer(s) look(s) at it with different angle so that in totality the review is very comprehensive. However, there should be efforts from authors side to improve (may be by taking clues from reviewer’s comments). Therefore, please do not limit the revision only (with respect) to comments made here.

COMMENTS: Although there is no major flaw [study/manuscript is already of acceptable level], I have different opinion / observations/concerns regarding (very) few issues which are given below, if agreed, try to incorporate them (as this study is at planning/protocol stage only)]:

In ‘Abstract-Background’ section it is stated that “This open-label pilot study will examine the feasibility, tolerability, and preliminary efficacy of a single dose 25 mg psilocybin, combined with 1 week of massed CPT in chronic PTSD”. However, in the title “pilot / feasibility study” is not mentioned. Why? You may know that many things are often ignored (loosely looked at / evaluated) in case of ‘pilot studies’ [typically involving a small number of subjects], and that more latitude [i.e., leeway, freedom, liberty] in statistical requirements is observed/given. Nevertheless, pilot nature of the study is expected to be mentioned in the title itself.

For a pilot study it is alright to have ‘single-arm design’, [or it is alright when that is the only possibility’], however, it is very essential to keep the limitations in mind while interpreting results. This study being ‘pilot’ (feasibility study) in nature, sample size is not a big issue. However, few important methodological issues need to be very rigorous (to the maximum possible extent) followed. Very good that in section ‘5. Reporting’ you stated “Outcomes will be reported according to CONSORT reporting guidelines” and quoted reference 39 [Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med 2010; 8: 18], however, please note that this being a ‘single-arm design’ pilot study many items are not applicable {and so keep the limitations in mind}. You may be aware of one important reference, namely: “Introducing the CONSORT extension to pilot trials: enhancing the design, conduct and reporting of pilot or feasibility trials” by Luciana P. F. Abbade, Joelcio F. Abbade and Lehana Thabane.

As said in section ‘7. Discussion’ [This open label trial is primarily interested in precise estimates of feasibility, tolerability, efficacy and safety outcome variability, in patients with chronic PTSD that will aid in the planning of a larger, sufficiently powered RCT. PTSD is a disabling and severe psychiatric disorder, and it is imperative to develop rapid-acting interventions and increase the efficacy of current front-line treatments. This open-label trial is a first step towards what may be a promising intervention for chronic PTSD. Findings from this study may help to develop psilocybin-assisted iCPT as a novel and rapid acting intervention for individuals suffering with chronic PTSD] and because you intend to use many scales [Assessments will consist of several clinical scales (CAPS-5, PCL-5, PHQ-9, GAD-7, DES-II, PSQI, QRI, WHO-5, IPF, PMBS, BEAQ, MPFI-24, WAI-SF, DERS-SF, SCF-SF, PIQ, CTQ-SF, EBI, ASC, APEQ) to measure symptoms severity and efficacy], by rightly guessing that you all (team) are likely be involved in the planning of a larger, sufficiently powered RCT subsequently and in this context, I request all authors to read the following note pasted from one standard textbook on ‘Medical Research Methodology’ [though I am sure that the authors already know these things]:

Though the measures/tools used are appropriate often times, most of them are likely to yield data that are in [at the most] ‘ordinal’ level of measurement [and not in ratio level of measurement for sure {as the score two times higher does not indicate presence of that parameter/phenomenon as double (for example, a Visual Analogue Scales VAS score or say ‘depression’ score)}]. Then application of suitable non-parametric (or distribution free) test(s) is/are indicated/advisable [even if distribution may be ‘Gaussian’ (also called ‘normal’)]. Agreed that there is/are no non-parametric test(s)/technique(s) available to be used as alternative in all situation(s), but should be used whenever/wherever they are available. Therefore, in short use suitable non-parametric test(s)/technique(s) while dealing with data that are in ‘ordinal’ level of measurement even if [despite that] the distribution may be ‘Gaussian’. Testing ‘normality’ in sample [by using any normality test(s)} is not required/desired while dealing with data that are in ‘ordinal’ level of measurement [as most of the normality tests are not valid for ‘ordinal’ data].

In section ‘4. Statistical analysis’ you have mentioned ‘non-parametric’ test [Wilcoxon signed rank test comparing CAPS-5 scores from the baseline to the primary endpoint will be the main analysis] which shows that right things are known to the team and so this a sort of reminder to keep mind.

As pointed out in ‘important note’ above “This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ should be assessed separately/independently. In my opinion, to make this article finally acceptable (which is quite possible and easy), a small amount of re-vision (re-drafting) may be needed. ‘Minor revision’ is recommended.

Reviewer #2: The abstract and introduction both outlines clearly the question of using Cognitive Processing Therapy (CPT), with psychedelic substances as an adjunct, in the treatment of chronic PTSD. The point is emphasized upon with a solid foundational background, offering context and supporting the question in focus. The points of analysis—feasibility, tolerability, and preliminary efficacy of the treatment—are clearly stated. As PTSD and psychedelics is an ongoing area of research, this specific question has the potential for valuable insights. Using specific modes of therapy may offer new avenues for PTSD/psychedelics research, as well.

The methodology and design of the trial is well-planned, with its primary, secondary, and tertiary objectives clearly stated. Safety objectives are also touched upon. The use of strict inclusion/exclusion criteria, as well as a pre-screening session for potential subjects ensures that eligibility criteria are met and that subjects are truly suitable. This gives the results true relevance and statistical power, with the outcomes measures used. Those using psychotropic medications will be required to taper, removing confounding factors from the analysis. I suggest the authors use a greater sample size than n=15, to give greater statistical power for gathered data.

The treatment section describes in sufficient detail the use of psilocybin in combination with psychotherapy sessions given at regular intervals, plus the use of a wearable device to passively gather physiological data through the duration. Mentioning specifically the treatment regimen for psilocybin administration, the schedule for psychotherapy sessions, and the timeframe for use of the wearable device allows this experimental procedure to be reliably replicated. The use of their Digital Phenotype Profile Definition (DPP) also serves as another means of replicability, relying on mathematical models based on continuously incoming subject data. The schema and calendars offered also adequately illustrates the study design and schedule.

In the abstract, the authors clearly state that the data analyzed at the conclusion of this trial will be used in the design and execution of a “multi-site, large-scale randomized control trial to assess the efficacy of psilocybin-assisted CPT for PTSD”; I believe this implies the data gathered will be preliminary and used to guide subsequent trials exploring this question. Beyond this, exactly where/how data will be made publicly available is not mentioned. The authors may consider referencing this preliminary research in the prospective manuscript detailing the larger-scale trial, come that time.

This manuscript is well-written, with grammatically correct English and proper diction and syntax. Their ideas, methods, and rationale are elaborated upon with adequate depth, and each aspect of the trial is clearly expressed. I believe the extensive background the authors give on both psychological and physiological aspects, and how these will be accounted for throughout the trial will help readers fully grasp the questions this research is trying to answer, and how the researchers will go about answering them. I believe this trial has the potential to offer insight into important questions, offering a more nuanced analysis of psychedelics as an adjunct in the treatment of PTSD. I would suggest this trial be executed and the data analyzed, published, and used as a framework for the larger scale work the authors are planning.

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Reviewer #1: No

Reviewer #2: Yes: Christopher Matthew Teske

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Attachments

Attachment

Submitted filename: renamed_4f500.docx

Psilocybin-Assisted Massed Cognitive Processing Therapy for Chronic Posttraumatic Stress Disorder: Protocol for an Open-Label Pilot Feasibility Trial

PONE-D-24-19436R1

Dear Dr. Bhat,

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.

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Kind regards,

Jan Christopher Cwik, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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

**********

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 #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: COMMENTS: I am very happy to note that all of the comments made on earlier draft are/were considered positively & are attended satisfactorily, I recommend the acceptance without any hesitation [rather happily now].

Reviewer #2: The authors have adequately addressed the initial concerns of the reviewers. After careful review of the revised version, I beleive this manuscript is now 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 #2: Yes: Christopher Matthew Teske

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