PONE-D-24-20969Optimization of individualized faricimab dosing for patients with diabetic macular edema: protocol for the SWAN open-label, single-arm clinical trialPLOS ONE

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Toshinori Murata: Speaker Fees: Bayer, Novartis, Santen, Zeiss Meditec: Consultant: Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd., Hoya, Kowa, Wakamoto

Shintaro Nakao: Consultant: Alcon, Boehringer Ingelheim, Novartis, Riverfield; Speaker Fees: Bayer, Boehringer Ingelheim, Chugai Pharmaceutical Co., Ltd., Hoya, Kowa, Machida, Mitsubishi Tanabe, Novartis, Novo Nordisk, Otsuka, Santen, Senju, Wakamoto

Masahiko Shimura: Consultant: Bayer, Boehringer Ingelheim, Chugai, HOYA, Nikki HD, Roche, Wakamoto; Lecture Fees: Bayer, Chugai, Kowa, Novartis, Otsuka, Senju

Miho Nozaki: Speaker Fees: Bayer, Canon, Chugai Pharmaceutical Co., Ltd., Kowa, Nikon, Novartis Pharma KK, Santen, Senju, Sumitomo Pharma Co., Ltd., Topcon Medical, Wakamoto

Kiyoshi Suzuma: Speaker Fees: AMO, Alcon, Bayer, Chugai Pharmaceutical Co., Ltd., HOYA, Kowa, Novartis, Senju

Consultant: Senju, Chugai Pharmaceutical Co., Ltd., Boehringer Ingelheim

Taiji Nagaoka: Consultant: Boehringer Ingelheim, Novartis, TES Holdings; Speaker Fees: Bayer, Chugai Pharmaceutical Co., Ltd., Hoya, Kowa, Mitsubishi Tanabe, Novartis, Santen, Senju, Wakamoto; Research Fees: Daicel, Kowa, LTT, Santen

Masahiko Sugimoto: Research Fees: Alcon Japan, Bayer, Chugai Pharmaceutical Co., Ltd., Novartis; Speaker Fees: Alcon Japan, Bayer, Kowa, Novartis, Senju, Wakamoto

Yoshihiro Takamura: Lecture Fees: Chugai Pharmaceutical Co., Ltd. 

Tomoaki Murakami: Speaker Fees: Bayer, Canon, Chugai Pharmaceutical Co., Ltd., Johnson & Johnson, Kowa, Novartis Pharma KK, Santen; Consultant: Boehringer Ingelheim

Keisuke Iwasaki: Employee: Chugai Pharmaceutical Co., Ltd. 

Jun Tsujimura: Employee: Chugai Pharmaceutical Co., Ltd.

Shigeo Yoshida: Consultant: Chugai Pharmaceutical Co., Ltd., Novartis; Speaker Fees: Bayer, Chugai Pharmaceutical Co., Ltd., Novartis, Senju; Research Fees: Kowa, Otsuka, Senju 

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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: 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: 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?

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Reviewer #1: Yes

Reviewer #2: No

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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 manuscript is a introduction of SWAN trial, a 2-year, open-label, single-arm, interventional, multicenter trial enrolling adults with center-involving DME treated with faricimab 0.6mg.

Improvement of vision outcomes and reduction of treatment burden are warranted for anti-VEGF therapy and faricimab is expected to resolve such unmet needs.

The SWAN trial is excellently organized prospective study. I am looking forward to the authors’ continue success.

I think that the manuscript is suitable for the publication in the PLOS ONE.

Reviewer #2: From the statistical viewpoint, it is a curiosity that the authors did not consider possibility of using an adaptive design for a single arm trial. It is helpful such a discussion be included in the paper. The adaptive design has the potential of requiring fewer patients to be enrolled and less time to conclude whether the proposed treatment is effective or not. For example, a most common trial of this kind is the celebrated Simon Two-Stage design for a Phase 2 trials discussed and implemented in clinical trials with many variations thereof. It has two stages and assumes the primary endpoint is binary (responders or not) and depending on the observed proportion of responders in stage 1, the trial may or may not move to the second stage to continue to assess the efficacy of the treatment. Here a null hypothesized success rate is postulated along with an alternative hypothesis that postulates a higher rate of success. The strategy is that if the null hypothesis is not met, the treatment is not effective and the trial terminates. If it is not rejected the trial proceeds to the second stage. In each stage, the number of patients and number of responders have to be determined after the user-selected type 1 and 2 errors for testing the hypotheses are specified. The design problem is then to determine the number of patients and the number of responders required in Stage 1, and if the trial proceeds to Stage 2, the additional number of patients needed and the additional number of responders needed to conclude efficacy of the treatment.

Clarifications:

It was stated in the abstract and elsewhere that “The primary endpoint is change in best-corrected visual acuity (BCVA) from baseline at 1 year (averaged over weeks 52, 56, and 60)” This seems unclear to me what is meant by the averaging referred to in the parentheses. Please clarify.

In the abstract, not clear secondary/exploratory endpoints mean. Are you treating secondary and exploratory endpoints equivalent? If not, make clear what are secondary endpoints and what are exploratory endpoints. The result sections can use a rewrite to make clearer each of the variables involved and the threshold for success – the sentence right now is hard to understand because it is long and somewhat convoluted.

The description of the proposed trial and the two previous trials (YOSEMITE (NCT03622580) and RHINE (NCT03622593)) should be contrasted in a diagram or schematic form to facilitate understanding of the treatment regimen involved. Right now, they are wordy going from lines 69 to 90, which can cloud comprehension.

Statistical analyses:

In the sample size calculation, the study is powered for detecting a postulated difference. Can the author discussed whether the postulated difference of interest is a meaningful outcome from the clinical perspective since a significant difference may not correspond to a clinically meaningful difference.

A 35% dropout rate is anticipated in the first year. Please justify where this number is coming from and whether the proposed analyses account for possible values other than a 35% dropout rate.

There are several secondary variables to be evaluated, such as determining the proportions of patients who meet predefined thresholds for BCVA (i.e., decimal visual acuity ≥0.5, ≥0.7, ≥1.0, or ≤0.1) over time, in addition to many others. Is there going to be a single composite measure that describes whether the patients did well or not, based on the secondary variables?

Remaining comments pertain to the last paragraph prior to “Trial status” on page 25, where the authors stated that “BCVA analyses will follow the mixed effect model for repeated measures, which will include visit (categorical variable) and baseline BCVA (continuous variable) as fixed effects and will assume an unstructured covariance structure for modeling intrasubject error. For missing data, missing-at-random will be assumed.”

a. Why is the variable 'visit' is treated as a categorical variable and not as a continuous variable in real time? In the trial, patients are supposed to visit at designated time points, and they rarely do so in practice. What happens if patients show up at different time points? What is the threshold before the reading is considered invalid because the timing is unacceptably different from that specified in the protocol? For example, patients are required to visit a clinic for testing at least every 2 months – what happens if patient show up ½ month late? Is this a valid data point? Further, treating the variable visit as a categorical variable has implicit constraints imposed on the interpretation of the results.

b. Please make clearer what are the random components in the mixed effects model alluded to?

c. Are the authors going to fit other covariance structures and select the best fitting model for prediction purposes?

d. To ensure reproducibility, please mention what statistical package or software is going to be used to analyze the data.

e. Missing data are assumed to be missing-at-random. It is helpful to elaborate how the authors are going to check whether such an assumption is valid – in particular, are statistical diagnostic tools going to be employed to ascertain whether such an assumption seems valid, and if so how?

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Reviewer #1: Yes: Taiichi Hikichi

Reviewer #2: No

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Optimization of individualized faricimab dosing for patients with diabetic macular edema: protocol for the SWAN open-label, single-arm clinical trial

PONE-D-24-20969R1

Dear Dr. Hirano

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Jiro Kogo

Academic Editor

PLOS ONE