PONE-D-24-53860Pilot Feasibility Trial of Improving Neurodevelopmental ouTcomes After prenatal Cannabinoid in uTero exposure (INTACT) Study Protocol for a Multi-Center TrialPLOS ONE

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Academic Editor

PLOS ONE

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 [The Environmental influences on Child Health Outcomes (ECHO) Program, Office of the Director, National Institutes of Health, supported this research under the award numbers U24OD024957, UG1OD024947, UG1OD024955, and UG1OD030019.]. 

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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

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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

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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: No

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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: No

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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

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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: This is a protocol to conduct a feasibility pilot study of a novel program (not clinical intervention) to improve neurodevelopmental outcomes in infants prenatally exposed to cannabinoids as the basis for a future randomized controlled trial. The investigators will conduct the feasibility trial in three ISPCTN sites to assess the following variables: participant recruitment, participant completion when the infant is 12 months of age, and completion of overall total number of INTACT intervention coaching sessions. This information will inform a future randomized controlled trial. Thus, no clinical outcome assessment will be completed in this feasibility pilot study.

Two states (Vermont, New Mexico) having legal use and one state (South Dakota) having legal medical use will participate. It appears that this research group gave much thought and consideration for understanding and negotiating the challenges of the cannabis environment and subject protection.

The recruitment and retention strategies are well outlined. (outpatient, inpatient, community, virtual). The 20 dyads is the basic sample size which is small as expected in this pilot setting. The interventions (INTACT coaching and PALS training) are all well planned .

The statistics for analysis are exact methods due to the small sample size. So the exact approach such as the Clopper Pearson method is reasonable for the hypothesis for testing the adequacy of the samples in the three objectives. The Clopper Pearson approach, which is exact and routine, for this aspect will suffice. The statistical analysis section is brief and descriptive as expected for this feasibility effort. Presumably for the success of the INTACT methodology and other endpoints in a future comparative trial the investigators are considering a more involved inferential approach to the analysis. Section 8.1 in the included protocol draft includes mainly comparison of proportions. Hopefully , given a larger study, some more sophisticated multivariate models or general linear models approaches will be entertained.

The data management section of this pilot is rather brief. It needs an expansion of quality control methodology for data collection in the field as well as for central data processing in the main database.

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Reviewer #1: No

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The Protocol for a Pilot Feasibility Trial of Improving Neurodevelopmental ouTcomes After prenatal Cannabinoid in uTero exposure (INTACT) Study for a Multi-Center Trial

PONE-D-24-53860R1

Dear Dr. Maxwell,

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,

Andrea Mastinu

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

**********

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

**********

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

**********

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

**********

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 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: No Comment.

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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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