Nabilone treatment for severe behavioral problems in adults with intellectual and developmental disabilities: Protocol for a phase I open-label clinical trial

Hsiang-Yuan Lin; Elia Abi-Jaoude; Pushpal Desarkar; Wei Wang; Stephanie H. Ameis; Meng-Chuan Lai; Yona Lunsky; Tarek K. Rajji

doi:10.1371/journal.pone.0282114

Peer Review History

Original SubmissionNovember 9, 2022
27 Dec 2022 Decision Letter - Robert Didden, Editor PONE-D-22-30722Nabilone treatment for severe behavioral problems in adults with intellectual and developmental disabilities: protocol for a phase I open-label clinical trialPLOS ONE Dear Dr. Lin, 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 comments from the 2 reviewers are straightforward, and you should have no problems in addressing them. The revised paper may make a nice contribution to the literature, especially in the field of IDD. Please submit your revised manuscript by Feb 10 2023 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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If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. 5. 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 If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references.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 If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [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 ******** 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: No 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: Generally, the protocol appears fairly thorough and should yield useful data. Since the safety assessments are an important part of this protocol, albeit the adverse event profile is expected to be good, please provide an additional paragraph or two under the assessments which is more in keeping with industry standards describing these assessments. Please cover the coding to be used and how the various types of adverse events will be defined. Is there any requirement for reporting adverse events to a regulatory or oversight body in this trial? If so, please detail these requirements and their implementation. For analysis of the adverse event data, please plan to produce industry standard adverse event tables, typically consisting of overall adverse events, serious adverse events, attribution to study drug, and tabulation by system and organ class. If other types of adverse events are planned to be defined, such as serious adverse events or unexpected adverse events, please describe these. Tolerability will be declared if 80% of the participants complete the study protocol. Does completion include the tapering phase? This phase is not necessarily related to ongoing treatment with nabilone, but it is also reasonable to include this phase as representing all phases of treatment. What will be the definition of completing the study protocol? The statistical analysis appears to be based on paired t-tests. This is not unreasonable, though the hypothesized power will depend somewhat on the actual distributions under consideration. Will any adjustments for multiple testing be made? If not, please explain briefly, and if so, please describe the planned adjustments. Since this study will not be placebo-controlled, it should be noted that if resulting effects are chosen on the basis of their size, that they will almost certainly be overinflated and one could expect a regression to the mean effect in a future study. Also, the results from this study will be conflated with any effects that would manifest over time in this population after selection. It would be best if the authors can show that any such effects are either non-existent or expected to be minimal. If the data management software and statistical analysis software to be used are known, please describe them in the statistical methods section. Reviewer #2: This is a very good quality study protocol. I have only 2 minor remarks that should be addressed. 1. In line 150, the authors claim that current evidence suggests that nabilone could be promising - however, from the manuscript this is not really clear. Pleas explain this more in detail. 2. In the manuscript it is mentioned that one of the goals is to assess adherence, however this is not mentioned in the abstract and not pointed out in the manuscript. ****** 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? 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Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0282114.r001
Revision 1
28 Jan 2023 Author Response Reviewer #1: General comment. Generally, the protocol appears fairly thorough and should yield useful data. Re: Thanks for your positive appraisal and constructive suggestions. We have addressed each of your comments as follows. R1.1. Since the safety assessments are an important part of this protocol, albeit the adverse event profile is expected to be good, please provide an additional paragraph or two under the assessments which is more in keeping with industry standards describing these assessments. R1.2. Please cover the coding to be used and how the various types of adverse events will be defined. Is there any requirement for reporting adverse events to a regulatory or oversight body in this trial? If so, please detail these requirements and their implementation. R1.3. For analysis of the adverse event data, please plan to produce industry standard adverse event tables, typically consisting of overall adverse events, serious adverse events, attribution to study drug, and tabulation by system and organ class. If other types of adverse events are planned to be defined, such as serious adverse events or unexpected adverse events, please describe these. Re: We appreciate your comments regarding the adverse events (Comments 1-3). As these 3 comments are highly relevant, we decided to respond to them together here. We have added two paragraphs in the subsection of Outcome Measures (Page 15 Line 323 to Page 17 Line 353): “ An adverse event will be defined as any untoward medical occurrence in a participant, temporally associated with his/her/their involvement in this study (from the time that the informed consent document is signed to the S-F), without regard to the possibility of a causal relationship. Adverse events will be coded using the concise but valid UKU side effect rating scale (68). We will further classify adverse events as to their severity, expectedness, and potential relatedness to the study intervention based on NIA Adverse Event and Serious Adverse Event Guidelines (September 2018). Namely, the severity of adverse events will be classified as “Mild” (being transient and requiring no therapy or evaluation), “Moderate” (of a low level of inconvenience or concern to the participant and/or the family and possibly interfering with daily activities and functioning), “Severe” (being incapacitating and requiring systemic treatment), or “Serious” (as defined in the next paragraph). Expectedness will be determined by whether the nature or severity of a given adverse event is expected to occur or not, owing to the inconsistent known information about nabilone (e.g., product monograph, case reports, or published studies). We will determine the relatedness of an event to nabilone as “Definitely Related”, “Possibly Related”, or “Not Related”, based on a temporal relationship to the use of nabilone, as well as whether the event is unexpected or unexplained given the participant’s clinical course, previous medical conditions, and concomitant medications. If nabilone is discontinued as a result of an adverse event, study personnel will document the circumstances and data leading to the discontinuation of treatment. A serious adverse event for this study is defined as any untoward medical occurrence that is believed by the investigators to be causally related to nabilone and results in any of the following: life-threatening condition (i.e., with immediate risk of death), severe or permanent disability, or inpatient hospitalization. Serious adverse events occurring after a participant is discontinued from the study will not be reported unless the investigators consider that the event may have been caused by nabilone. An adverse event that meets the criteria for a serious adverse event between study enrollment and S-F will be reported to the CAMH Research Ethics Board (REB). Given the favorable safety and tolerability profiles of nabilone, the current principle for reporting serious adverse events to the REB conforms to the requirements for reporting Unanticipated Problems (which are unexpected, are related, or possibly related to the study intervention, and involve greater risk of harm) defined by the Canadian Association of Research Ethics Boards (CAREB) guidance document on Guidance on Reporting of Unanticipated Problems Including Adverse Events to Research Ethics Boards in Canada (July 2010).” Following your suggestion, in these two paragraphs, we also highlighted the coding and classification of adverse events. Further, in the subsection of Statistical Analysis, we added a tabular presentation of the adverse events as per your suggestion. Please see Page 23 Lines 479-481: “Safety profiles will be described by the number and percentage of each adverse event in a tabular way with organ systems as the rows, and Relatedness, Expectedness, and Severity as the columns. ” R1.4. Tolerability will be declared if 80% of the participants complete the study protocol. Does completion include the tapering phase? This phase is not necessarily related to ongoing treatment with nabilone, but it is also reasonable to include this phase as representing all phases of treatment. What will be the definition of completing the study protocol? Re: Thank you for giving us this opportunity to clarify this point. We defined tolerability by the completion of the open-label treatment stage because tolerability focuses on whether the participants can tolerate the study drug and the related adverse events. This definition has been added to the study objectives on Page 7 Line 154. “ To evaluate tolerability, we hypothesize that 80% of participants will complete the open-label treatment stage.” R1. 5. The statistical analysis appears to be based on paired t-tests. This is not unreasonable, though the hypothesized power will depend somewhat on the actual distributions under consideration. Will any adjustments for multiple testing be made? If not, please explain briefly, and if so, please describe the planned adjustments. Re: As this phase 1 study aims to provide preliminary signals to inform a subsequent randomized controlled trial, we will not adjust for multiple comparisons. Please see Page 23 Line 484 to Page 24 Line 486 : “As this phase 1 study aims to provide preliminary signals to inform a subsequent randomized controlled trial (RCT), we will not adjust for multiple comparisons.” R1. 6. Since this study will not be placebo-controlled, it should be noted that if resulting effects are chosen on the basis of their size, that they will almost certainly be overinflated and one could expect a regression to the mean effect in a future study. R1. 7. Also, the results from this study will be conflated with any effects that would manifest over time in this population after selection. It would be best if the authors can show that any such effects are either non-existent or expected to be minimal. Re: Thank you for raising these two important points on the interpretation of results. As these two comments are highly relevant, we decided to respond to them together. We totally agree with your insight on potential regression to the mean. Also, we agree that our findings may be conflated with the time effect given the open-label nature. However, a substantial proportion of people with IDD have persistent and stable challenging behaviors over time, especially in the context of our stringent inclusion criteria to define the presence of SBP. We believe the way SBPs are defined in this study could substantially reduce this caveat. We have highlighted these important considerations surrounding data interpretation in the Discussion. Please see Page 26 Lines 541-548: “Notably, if encouraging signals are detected, we acknowledge that the effect size of the identified signals may well be inflated given the small sample size and a regression to the mean effect would be expectedly in a future study (76). Further, the current design is unable to disentangle the extent to which the time effect is conflated with the treatment effect of nabilone. Nonetheless, a substantial proportion of people with IDD have persistent and stable challenging behaviors over time (75, 77, 78), especially in the context of our stringent inclusion criteria to define the presence of SBP—we expect that this stringent definition of SBP will substantially reduce the possibility of this caveat.” References: Dimian AF, Symons FJ. A systematic review of risk for the development and persistence of self-injurious behavior in intellectual and developmental disabilities. Clin Psychol Rev. 2022;94:102158. Totsika V, Hastings RP. Persistent challenging behaviour in people with an intellectual disability. Curr Opin Psychiatry. 2009;22(5):437-41. Totsika V, Toogood S, Hastings RP, Lewis S. Persistence of challenging behaviours in adults with intellectual disability over a period of 11 years. J Intellect Disabil Res. 2008;52(Pt 5):446-57. R1. 8. If the data management software and statistical analysis software to be used are known, please describe them in the statistical methods section. Re: We have specified this detail on Page 23 Lines 483 and 484: “The behavioral and clinical data will be analyzed using IBM SPSS Statistics (Version 26). “ Reviewer #2: R2.1. In line 150, the authors claim that current evidence suggests that nabilone could be promising - however, from the manuscript this is not really clear. Please explain this more in detail. Re: Thank you for this comment. We have added the rationale to justify this statement (Page 7 Lines 147 and 148): “Based on the encouraging evidence in patients with dementia (37) and Parkinson’s disease (40) as well as anecdotal clinical observations, nabilone could be a promising and novel treatment for SBPs in adults with IDD.” R2.2. In the manuscript it is mentioned that one of the goals is to assess adherence, however this is not mentioned in the abstract and not pointed out in the manuscript. Re: We thank the reviewer for bringing this point to our attention. We have mentioned the adherence as one of the objectives in Abstract (Page 2 Line 46): “Thus, we propose this first-ever Phase I pre-pilot open-label clinical trial to obtain preliminary data on the adherence, tolerability and safety profiles of nabilone in adults with IDD” In addition, the method of assessing adherence was originally stated in the subsection of Outcome Measures (Page 15 Line 321): “The primary outcome measures are adherence (as quantified by counting pill usage)” Attachments Attachment Submitted filename: PONE-D-22-30722_Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0282114.r002
8 Feb 2023 Decision Letter - Robert Didden, Editor Nabilone treatment for severe behavioral problems in adults with intellectual and developmental disabilities: protocol for a phase I open-label clinical trial PONE-D-22-30722R1 Dear Dr. Lin, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Robert Didden 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: This is a review of a revised manuscript. All issues have been dealt with in the authors' revision. ****** 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.0282114.r003
Formally Accepted
3 Apr 2023 Acceptance Letter - Robert Didden, Editor PONE-D-22-30722R1 Nabilone treatment for severe behavioral problems in adults with intellectual and developmental disabilities: protocol for a phase I open-label clinical trial Dear Dr. Lin: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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 Robert Didden Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0282114.r004

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