-->PONE-D-25-62476-->-->Effectiveness of an immersive virtual reality-based therapeutic exercise programme with altered visual feedback in patients with fibromyalgia: A study protocol for a randomised controlled trial-->-->PLOS One

Dear Dr. Amer Cuenca,

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PLOS One

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This work was supported by grants from the University CEU Cardenal Herrera (GIR25/41).

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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

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: Overall Assessment

This Study Protocol “Effectiveness of an immersive virtual reality-based therapeutic exercise programme with altered visual feedback in patients with fibromyalgia: A study protocol for a randomised controlled trial” presents a well-designed, two-arm, parallel-group RCT evaluating the effectiveness of an immersive virtual reality (IVR) therapeutic exercise programme incorporating altered visual feedback for individuals with fibromyalgia (FM). From a statistical and methodological perspective, the planned trial is conceptually sound, adheres to SPIRIT 2025 guidance, and incorporates several strengths: prespecified outcomes, a justified sample-size calculation, a detailed randomisation and blinding strategy, and appropriate use of covariate-adjusted models.

Nevertheless, several aspects would benefit from clarification or refinement to ensure full transparency, reproducibility, and appropriateness of statistical analyses, especially considering the complexity of the intervention and the breadth of outcomes being collected.

My major and minor statistical comments follow.

________________________________________

Major Comments

1. Sample Size Justification: Effect Size Assumptions Need Clarification

The sample size uses an assumed SD = 20 and an MCID of ≈14% on the FIQR to detect between-group differences using ANCOVA. However:

• The protocol does not state the absolute expected mean FIQR score on which the 14% MCID is computed.

• It is unclear whether the authors powered the study for between-group mean difference or group × time interaction.

Recommendation:

Explicitly report the assumed baseline FIQR mean, the corresponding absolute MCID value, the expected post-intervention difference, and whether the model used in the power calculation aligns with the final analysis approach (ANCOVA vs. repeated-measures ANCOVA). Provide the full numeric parameters used in G*Power for reproducibility.

________________________________________

2. Choice of Analysis Method: Repeated-Measures ANCOVA May Not Be Appropriate

The plan states that two-way repeated-measures ANCOVA will be used, adjusting for covariates (sex, FIQR cluster, baseline scores).

Two key concerns:

• Repeated-measures ANCOVA is not a standard or well-defined model.

• Adjusting for baseline within a repeated-measures framework typically leads to statistical redundancy and may violate model assumptions.

Recommendation:

Use a linear mixed-effects model (LMM), which is the standard for RCTs with repeated measures, missing data handled under MAR, and covariate adjustment. LMMs also allow random intercepts (and slopes if appropriate), avoid sphericity assumptions, and appropriately model within-subject correlation.

________________________________________

3. Multiple Secondary Outcomes: No Adjustment Strategy Specified

The study includes an exceptionally large set of secondary outcomes (psychological scales, sensory testing, mobility tests, physiological measures, IVR tolerance, motivation, and more).

Given the number of endpoints, there is a substantial risk of false positives.

Recommendation:

Specify a plan for multiplicity control, such as:

• Designating key secondary outcomes a priori and controlling FDR across them, or

• Applying hierarchical testing, or

• Clearly stating that secondary outcomes are exploratory without inferential claim.

PLOS ONE’s policies permit exploratory outcomes, but this must be stated unambiguously.

________________________________________

4. Handling of Missing Data: Multiple Imputation Needs Additional Specification

The protocol states that multiple imputations will be used assuming data missing at random (MAR).

Issues requiring clarification:

• The number of imputations is not specified.

• The imputation model variables are not described.

• MAR assumption justification is absent.

• For longitudinal outcomes, multilevel imputation or model-based approaches are usually preferred.

Recommendation:

Specify:

1. Number of imputations (≥20 recommended).

2. Variables included in the imputation model (all predictors, outcomes, and auxiliary variables).

3. Whether imputation will be performed separately by randomized group.

4. Whether imputation will incorporate repeated-measures structure (e.g., MICE with time indicators).

________________________________________

5. Randomisation: Stratification and Block Sizes Are Appropriate but Require Clarification

Randomisation uses stratified block permutation across eight strata (sex × FIQR severity clusters) with block sizes 2–4.

Concerns:

• FIQR cluster derives from Pérez-Aranda et al., but the method for real-time assignment of clusters in the trial is not fully described.

• The number of strata (8) for a target N=80 may result in unstable allocation within small strata.

Recommendation:

Report:

• The decision process and data required to assign FIQR cluster at baseline.

• Expected sample per stratum and any minimum-size rule.

• Whether randomisation performance (e.g., imbalance assessment) will be monitored.

________________________________________

6. Quantitative Sensory Testing (QST): Statistical Plan Requires Additional Detail

The QST section is detailed in measurement procedures, but statistical treatment lacks specification (PPT, TS, CPM outcomes).

Required clarifications:

• Will PPT, TS, and CPM be analysed as continuous outcomes in ANCOVA/LMM?

• Will outliers (common in QST data) be handled through transformation or robust methods?

• How will bilateral PPT sites be modelled (averaged, modelled separately, or nested within subject)?

________________________________________

7. Per-Protocol vs. Intention-to-Treat

While ITT analysis is planned, the protocol does not describe conditions for per-protocol analysis or adherence thresholds.

Recommendation:

Specify whether:

• A per-protocol set will also be reported.

• Exercise dose or session attendance will be incorporated into sensitivity analyses.

________________________________________

Minor Comments

1. Effect Size Reporting

Partial eta-squared is appropriate, but confidence intervals for effect sizes should also be reported when possible.

2. Covariate Inclusion

Adjusting only for sex, baseline FIQR, and baseline outcome may be insufficient if strong prognostic variables exist (e.g., medication use, FM symptom severity, kinesiophobia). Consider prespecifying additional adjustment factors or providing a rationale for the limited covariate set.

3. Rescue Medication

The plan instructs participants to avoid analgesics 24 hours before assessments. Clarify whether medication use will be recorded and included as a covariate or descriptive variable.

4. Intervention Fidelity Metrics

Session-level variables (e.g., RPE, repetitions, pain pre/post) are being collected but are not included in the analysis plan. Clarify whether these will inform adherence, dose-response exploration, or moderation analysis.

5. Adverse Event Statistical Reporting

Although AEs will be reported descriptively, specify whether incidence rates between groups will be compared statistically (risk ratios or risk differences).

Reviewer #2: Summary

The work is a study protocol of a randomized controlled clinical trial research project. The clinical trial is targeted at potentially improving the nonpharmacologic treatment given to fibromyalgia, a very common disease with a substantial impact on global health care and population. In this study, the IVR is designed to manipulate the vision, making the patient feel as though they are experiencing reduced body movement compared to the actual motion.

Comments

1. According to your 5th reference (Cabo-Meseguer A, Cerdá-Olmedo G, Trillo-Mata JL. Fibromialgia: prevalencia, perfiles epidemiológicos y costes económicos. Med Clin (Barc). 2017;149:441–448. doi:10.1016/j.medcli.2017.06.008), the annual expenditure of fibromyalgia treatment in Spain is more than 12,993 million euros, but on line 55, you stated 4.2 billion; you need to clarify the discrepancy. Furthermore, your 5th reference is focused on Spain, so if you want to mention figures related to the USA, I recommend you use studies done in the USA.

2. The abbreviations EG and CG are used in lines 122 and 125, but the extended versions are mentioned in176 and 177; correct that.

3. In the “Ethical approval and registration” section, I recommend you include a statement that shows that participants can drop out of the study at any time without any fear of being denied any health service at your hospital or other health care facilities.

4. The authors need to mention the reason for stratifying the patients by strata, considering sex and FM severity in the manuscript.

5. TENS, AE, and RPE are included only as abbreviations; include the extended versions as well.

6. Your study is going to use fully immersive VR technology, but you described it as immersive VR. According to the classification, immersive can be fully or semi-immersive. Therefore, for better clarity, you should consistently use the term fully immersive VR.

Questions

1.Wouldn't using different diagnostic criteria for the diagnosis of fibromyalgia affect your statistical findings?

2.What language are you going to use to assess the FIQR; Central Sensitisation Inventory (CSI); Multidimensional Fatigue Inventory (MFI-20); Pittsburgh Sleep Quality Index (PSQI); EQ-5D-5L? and the other scores?

3. Is the presence of comorbidities like hormonal abnormalities, respiratory illnesses profile of the samples going to be assessed?

4.Did you consider concurrent rheumatological disease, such as rheumatoidarthritis or osteoarthritis, as exclusion criteria?

5. What are the parts of the device to be used in the VR treatment?

6. What types of videos or games are going to be used for VR treatment?

7. What are the operational definitions of the “physiological, psychological, and physical outcomes” of fibromyalgia?

8. Why do you want to include only those patients with a pain intensity score of ≥3?

9. What are the comorbidities and/or symptoms that you will consider as  contraindications for IVR and exercise-based interventions?

10. Why did you select 6 weeks for the duration of therapy? And how did you determine the 2 times per week frequency of sessions? And why did you select 60 minutes for the duration of a session?

11. Why did you choose HTC Vive Pro?

12. Why did you choose 20% arm underestimation during flexion and 10% underestimation during extension specifically?

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Reviewer #1: Yes: Dr Shah-Jalal Sarker

Reviewer #2: No

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Attachments

Attachment

Submitted filename: Comments.docx

Effectiveness of a fully immersive virtual reality-based therapeutic exercise programme with altered visual feedback in patients with fibromyalgia: A study protocol for a randomised controlled trial

PONE-D-25-62476R1

Dear Dr. Cuenca,

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.

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Kind regards,

Hui-Juan Cao, 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

**********

-->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: The authors have made substantial improvements to the manuscript. The protocol is now technically sound and suitable for publication. However, the following minor points should be considered to improve clarity and interpretability:

Clarity of Statistical Framework

The description of the LMM and cLDA approach is technically correct but may be difficult for non-statistical readers. A brief plain-language explanation of the primary treatment effect would improve accessibility.

Missing Data Assumption (MAR)

While the analytical approach is appropriate, the manuscript would benefit from a short statement discussing the plausibility and limitations of the missing-at-random assumption in this clinical context.

Secondary Outcomes

Although appropriately designated as exploratory, the large number of secondary outcomes remains extensive. Highlighting a small subset of key secondary outcomes may aid interpretability.

Readability

Some sections—particularly the statistical methods—could be streamlined to improve readability without reducing methodological rigor.

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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: Yes: Dr Shah-Jalal Sarker

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