PONE-D-23-30057A Single-Blind, Randomized, Controlled Trial Evaluating the Effectiveness of a Structured, Multi-Component Training Module for Family Caregivers of Persons with Parkinson’s diseasePLOS ONE

Dear Dr. Mohd Amin,

Thank you for submitting your manuscript to PLOS ONE. As you will see below, whilst recognising the considerable  value of a study on this topic, the reviewers had considerable concerns about the protocol - as do I. Therefore, after careful consideration, whilst we feel that the protocol has merit, it does not fully meet PLOS ONE’s publication criteria as it currently stands. Unfortunately, I realise it may now be too late to make all the changes that would adequately address these concerns, as you have already started the trial. However, should you believe that you are able to fully address all the points made during the review process, then you are welcome to submit a revised version of the manuscript for further consideration.

Please submit any revised manuscript by Mar 15 2024 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.

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We look forward to receiving your revised manuscript if you feel this is appropriate.

Kind regards,

Antony Bayer

Academic Editor

PLOS ONE

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4. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical.

5. Please amend the manuscript submission data (via Edit Submission) to include author Dr. Hanif Farhan Mohd Rasdi.

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Additional Editor Comments:

In general the protocol needs to be much more precise and detailed. Using the protocol, it should be possible for a reader to be able to conduct the trial identically at another site. Terms such as "such as" (16 times) are not appropriate.

More information is needed to explain and justify the sample size. It seems rather optimistic by comparison with other similar trials. Was the patient population in ref 15 (Bueno) the same as proposed in this trial? Ref 16 included patients with HY stage 1-3.  How was the "effect size of 0.41" derived? If a significant clinical benefit can be shown with 36 dyads, is it appropriate to recruit another 24 merely to have 60 dyads to enable economic benefits to be assessed (or is a 40% drop out expected?) No detail is given about the cost analysis or how the relevant data for this will be collected.

There should be only one primary outcome. If TUG is chosen, then why would any difference not be due to general fitness secondary to the regular caregiver training rather than something specific to PD?  If UPDRS is the primary outcome, how does this impact on sample size? Why was an outcome such as PDQ-39 or NMSQ not considered? 

Why only HY stage 1-2? Such patients are only minimally impaired & unlikely to show large deterioration within 6 months, meaning it is likely to be very challenging to show benefit of intervention over control. Is follow up long enough?

Other considerations include: Is the intervention instead of, or in addition to usual care? How will blinding of the outcome assessments be assured? Will patients' medication be optimised before randomisation? Why is there an upper age of 75? Is this clinically (and ethically) justified?

The numbering of the references seems to have gone wrong and the reference citation is not consistent. The names of authors also need to be checked (e.g. Zarit not Zarith)

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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: Partly

Reviewer #2: Partly

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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: Partly

Reviewer #2: Partly

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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

Reviewer #2: 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

Reviewer #2: 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

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: This is a very important and significant study.

Some suggestions for the authors;

1. Under Introduction section, have an "Objectives section" to make the primary and secondary objective distinct.

2. More details re randomisation method, i.e. who generated the randomisation schedule? Allocation ratio, ?variable block randomisation etc...

3. In the Data analysis, this is an RCT mention that results will be reported in accordance with the CONSORT 2010 guidelines

4. Define intention to treat population.

5.Finalisation of analysis plan prior to unblinding of the data.

6. Briefly Mention handling of missing data?

7. What about non-compliance or adherence, consideration of how this will be handled

8. Any consideration of sensitivity analysis, i.e to be detailed in analysis plan, but perhaps to consider impact of non-adherence on treatment effect.

9. Mentioning drop-outs due to intention to treat may not be appropriate. Intention to treat relates to including all in the analysis regardless of the randomised group and regardless of non-compliance. Consideration of drop-outs (line 226) in studies is to make sure that the study is powered enough to ensure that you can still answer the research question, please consider revising this statement,

Reviewer #2: This study aimed to design a structured, multi-component training program for caregivers to implement at home for patients with PD. While the aim of the study may have its merit, there are multiple study design details need to be clarified in order to determine the novelty as well as importance of the study.

Introduction

1. In the introduction, it is not clear why the authors want to focus the structured training programs for caregivers. Some discussion should be added regarding the potential advantages and disadvantages of having the caregivers to train people with PD.

Methods

1. Page 6, line 157-170: the study hypothesis should be moved to the Introduction section, following research aim.

i. If the primary goal is to reduce cost, then cost-effectiveness analysis should be placed as the primary outcome.

2. Page 8-9:

i. Why focus on patients with PD at Hoehn and Yahr stage I & II? The early stages of patients are still active and can engage in various outdoor activities. Additionally, patients with PD at this stage do not need full-time caregivers to take care of them. Thus, the exclusion criteria of the caregiver in Table 1 seems to be awkward. Why not include patients with PD at Stage III? Patients at later stages would suffer a lot of motor and non-motor symptoms, and would thus significantly impact their ADLs and quality of life. They might also rely more on their caregivers as well as having longer time to stay at home.

ii. Since caregivers will be the primary person providing the intervention for this study, the relationship of the patients with their caregivers should be considered. Additionally, the compliance and education level of the caregivers should also be considered.

3. Page 9-10: The calculation of sample size needs to be revised. Based on my understanding of the study goal and study design, each patient with PD should be matched with 1 caregiver, so the sample size should consider as pairs instead of calculating patients and caregivers as each individual leading to a double size sample. Hence, according to the sample size calculation, 30 pairs of patient-caregiver should be recruited for each group leading to 60 pairs (60 patients and 60 caregivers) in total.

4. Page 12: Explain more detail about the caregiver training sessions, including the number of sessions, the duration of each session, and the way to make sure the caregivers can implement the techniques properly.

5. Page 13: What will be the treatment dosage of the control group? Will it be the same as the Experimental group? In Table 2, there seemed to be not equivalent in the treatment dosage. This will be a huge confounding factor.

6. Table 2: the content that the family members going to apply is too vague. How to make sure whether the family members know what to provide to the patient at what timing?

7. Page 14 outcome measures:

i. Why choose TUG as the primary outcome? The hypothesis put cost-effectiveness as the primary benefit of the experimental group.

ii. The authors talked a lot about non-motor symptoms in the Introduction. However, there are very limited outcomes evaluating non-motor symptoms, except for some parts of UPDRS. I would suggest the authors add more outcomes testing non-motor symptoms for this study.

Discussion

1. Why establishing a protocol in Malaysia is important? Why cannot the authors use the same protocol established in other countries? Are there any specific culture-specific health care issues in Malaysia that require the conduction of this trial?

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Reviewer #1: No

Reviewer #2: No

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A Single-Blind, Randomised Control Trial on the Effectiveness of a Structured Multi Component Training Module for Family Caregiver of Persons with Parkinson’s Disease: A Study Protocol

PONE-D-23-30057R1

Dear Dr. Mohd Amin,

Thank you for your revised manuscript that now addresses previous concerns (and that will require your trial registration with ANZCTR to be updated). 

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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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,

Antony Bayer

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: No further comments - all have been addressed.

Reviewer #2: The revised manuscript is much improved from the previous version, and the authors have addressed my previous concerns.

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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: No

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