Dear Dr. Mac Grory,

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Academic Editor

PLOS One

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“BMG is supported by the National Institutes of Health (K23HL161426, R03HL178686, and UG3NS138219), the American Heart Association (23MRFSCD1077188 & 25GLP1450119), Duke Bass Connections, the Duke Office of Physician-Scientist Development, and the Duke University Office of the Provost.

CP has nothing to disclose.

PL received speakers’ honoraria/consulting fees from Santhera, Novartis, Lissac-Optic2000, Alexion, and Amgen.

SJR has nothing to disclose.

ØKJ: Allergan (speaker, consultant), Bayer (speaker, consultant), Chiesi Farmaceutici (speaker), Roche (consultant), and SJJ Solutions (speaker, consultant, and royalties).

MCM Allergan (consultant), Bayer (speaker, consultant), Roche (speaker, consultant), Apellis (consultant), Novartis (consultant) and SJJ Solutions (consultant, and royalties).

JT has nothing to disclose.

MSS received research support from Bayer, Fielmann, Topcon, the German Federal Ministry of Education and Research, the Else Kröner Fresenius Foundation, the Danger Foundation, the Christiansen Foundation and the Claire-Jung Foundation as well as speakers’ honoraria/consulting fees from Abbvie, Alcon, Apellis, Astellas, Atheneum, Bayer, Heexal, Nordic Pharma, Novartis, Roche, SHS, Stada, and TelemedC.

CG has nothing to disclose.

OMD is supported by the Arizona Department of Health Services (ADHS14-052688).

VB is a consultant for GenSight Biologics and Topcon Medical and is supported in part by the National Institutes of Health’s National Eye Institute core grant P30-EY06360 (Department of Ophthalmology, Emory University School of Medicine) and by a departmental grant from Research to Prevent Blindness (New York, NY).

BG has nothing to disclose.

AHA has received honoraria for advice or lecturing from BMS/Pfizer, Abbvie, Teva, Novartis, Lilly, Lundbeck and Teva and research grants from the Norwegian Program for Clinical Therapy Research in the specialist health service (Klinbeforsk), the South-Eastern Norway Regional Health Authority, EU, The Norwegian Health Association, Odd Fellow, BMS, Pfizer, and Boehringer-Ingelheim.

SP received research support from BMS/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories and Werfen as well as speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen.

MS is supported by the National Institutes of Health (R56AG074279, K76AG060001, R01AG078803 and R21AG070859).”

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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?

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??>

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?-->?>

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

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

Reviewer #1: Yes

Reviewer #2: Yes

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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.

Reviewer #1: Authors present the protocol for a systematic review and individual patient data meta-analysis of trials which randomized patients with CRAO to intravenous thrombolysis. There is currently no approved acute revascularization treatment for CRAO and off-label treatments in everyday clinical practice are widely used with great uncertainty. Although there is a need for robust high-quality evidence for supporting such treatment decisions, patient recruitment in trials of acute treatments in CRAO is significantly limited because its occurrence is not as frequent as acute ischemic stroke and because of hospital admission delays. It is unlikely that any single RCT will be powered to demonstrate statistically significant but relevant visual functional improvement. Here lies the importance of this IPDMA, which will probably influence treatment guidelines worldwide. I congratulate the authors for this cooperation effort.

I have only minor comments:

1. Studies performing MRI in patients with CRAO show a relatively high proportion of patients with silent acute ischemic lesions, but concurrent ischemic stroke (i.e. clinical neurological symptoms associated with acute ischemic lesions) is rare. This should be corrected in the introduction.

2. After the recent publication of THEIA, the phrase “with no published cases when treatment was given within 4.5 hours of time last known well” is no longer true. Please correct.

3. Under the paragraph “Rational for individual participant data meta-analysis” please update the part referring to THEIA, which is now published.

4. Please use another term (or sentence) for describing “grey literature”, for readability.

5. Please specific in which time window will sICH be defined (also according to SITS-MOST?).

6. The different trials which will be included in the IPMA appear to have defined the primary endpoint differently. I think it would be useful for the readers that the authors explain why they chose logMAR 0.50 as the primary endpoint, and what it means in terms of visual function (it it described under the section “Secondary Endpoints” but it should be presented under the section “Primary Endpoint”).

7. Please correct “European Stroke Organization annual conference” to European Stroke Organisation Conference”.

Reviewer #2: This registered report protocol is well written, timely, and methodologically robust. The clinical question is highly relevant, the rationale for an IPD meta-analysis is clearly articulated, and the planned analyses are detailed, appropriate, and transparent. I support publication after addressing the following minor points for clarification and completeness:

1. Justification of the 0–4.5 hour time window

You have chosen a ≤4.5 h time frame from last known well (LKW) to IV thrombolysis (IVT), aligned with cerebral ischemic stroke practice and with much of the CRAO thrombolysis literature. However, in CRAO there is an ongoing debate about the role of collateral flow and retinal “penumbra” and whether some patients may retain salvageable tissue beyond 4.5 hours.

• Please expand the rationale for choosing 4.5 hours rather than including trials with treatment up to 24 hours (or other extended windows).

• It would be helpful to explicitly relate this to:

o The non-human primate data suggesting variable retinal tolerance (e.g., the 105 vs 240 minute survival times and how these were interpreted).

o The hypothesis that collateral choroidal flow and individual vascular risk profiles might modulate the true therapeutic window.

o The practical/clinical trade-off between maximizing internal validity (homogeneous early time window) vs external validity (relevance to real-world late presenters).

Even if you ultimately keep the 0–4.5 h window as an inclusion criterion, a more explicit discussion in the Methods and/or Discussion of why late-presenting patients (e.g., up to 24 h) and extended windows are not incorporated would strengthen the protocol and preempt future interpretative debates.

2. More granular onset-to-treatment time subgroup analyses

You already plan to model time-to-treatment and its association with visual outcomes. Given the central importance of timing in CRAO, I would encourage you to pre-specify more granular time windows as part of your subgroup or sensitivity analyses.

For example, you could consider:

• 0–1.5 hours

• 1.5–3 hours

• 3–4.5 hours

• (If data permit, an exploratory >4.5 h subgroup where such patients exist in any contributing trial.)

This does not have to change your primary analysis, which can remain continuous (or modeled with splines), but explicitly listing these time strata as planned exploratory subgroups would:

• Enhance interpretability for clinicians (who often think in discrete time windows).

• Potentially identify clinically meaningful thresholds within the 0–4.5 h window.

• Make it easier to align your findings with how stroke systems of care are organized in practice.

3. Safety endpoints – explicit inclusion of angioedema

In the Methods you already plan to collect several safety endpoints, including symptomatic ICH and systemic hemorrhage. You also mention angioedema later in the text, but it would be helpful to:

• Explicitly list “orolingual angioedema” among the predefined safety endpoints in the main safety endpoint section, alongside sICH and systemic hemorrhage.

• Clarify whether angioedema will be:

o Analysed descriptively only (expected low incidence), or

o Included in any pooled or exploratory safety models, if numbers permit.

Given the known association of IVT with orolingual angioedema, this explicit inclusion will be reassuring both for readers and guideline developers focusing on safety.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: Yes: Klearchos Psychogios

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Intravenous Thrombolysis for Acute Central Retinal Artery Occlusion: Protocol For a Systematic Review and Individual Participant Data Meta-Analysis of Randomized Controlled Trials

PONE-D-25-53172R1

Dear Dr. Mac Grory,

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,

Ogugua Ndubuisi Okonkwo, M.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?

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??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

PLOS ONE

Reviewer #1: Yes

Reviewer #2: Yes

**********

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.

Reviewer #1: I have no further comments. All questions were addressed by the authors and the manuscript was changed accordingly.

Reviewer #2: The authors have adequately addressed all previous comments, and the revised manuscript is substantially improved. Congratulations on this important effort. I eagerly anticipate the final results of the IPD analysis, which will be of great importance to the field.

**********

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: Klearchos Psychogios

**********