Reduced-fluence photodynamic therapy versus placebo for central serous chorioretinopathy (REPLAY trial): rationale and study protocol of a pivotal double-blind randomised controlled trial

Abstract

Introduction

Chronic central serous chorioretinopathy (CSC) can cause progressive and permanent vision loss. Although photodynamic therapy (PDT) is a primary treatment option globally, it is not approved for CSC worldwide, limiting therapeutic access. The REPLAY trial is a phase III, investigator-initiated trial to evaluate the efficacy and safety of reduced-fluence PDT (rf-PDT) for chronic CSC to seek the first regulatory approval globally.

Methods and analysis

This study comprises two cohorts. The ‘untreated cohort’ is a multicentre, randomised, placebo-controlled, double-masked trial involving 60 patients with untreated, fovea-involving chronic CSC, randomised 2:1 to receive a single rf-PDT or placebo treatment. The ‘previously treated cohort’ is a single-arm, open-label trial for up to 10 patients with recurrent CSC after PDT. The primary endpoint for both cohorts is the proportion of eyes with a complete resolution of subfoveal fluid at 12 weeks post-treatment, assessed by optical coherence tomography. Secondary endpoints include changes in best-corrected visual acuity, central choroidal thickness, recurrence rates and incidence of adverse events over a 48 week follow-up.

Ethics and dissemination

The study protocol was approved by the Kyoto University Hospital Institutional Review Board, IRB of Chiba University Hospital, Tokyo Women’s Medical University Institutional Review Board and Institutional Review Board of Kansai Medical University Hospital. Written informed consent is obtained from all participants. The results will be disseminated through publication in a peer-reviewed journal and presentations at scientific conferences.

Trial registration number

jRCT2051230156 (URL: https://jrct.mhlw.go.jp/latest-detail/jRCT2051230156).

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This pivotal randomised trial uses a double-masked, placebo-controlled design to minimise bias in efficacy and safety evaluation.

• Stratification into untreated and previously treated cohorts enables assessment across two predefined CSC populations under a standardised protocol.

• The primary endpoint is an objective anatomical measure assessed with optical coherence tomography, ensuring reproducible outcome evaluation.

• Masked outcome assessment and procedure standardisation across centres support the internal validity of the trial.

• A limitation is that only a single PDT session is administered; therefore, efficacy of retreatment cannot be evaluated within this protocol.

Introduction

Central serous chorioretinopathy (CSC) is a macular disease characterised by serous detachment of the neurosensory retina, which causes visual disturbances such as central scotoma, metamorphopsia and micropsia.¹ It predominantly affects middle-aged men in high-stress occupations.²,⁴ While many cases are acute and resolve spontaneously, chronic CSC can lead to irreversible damage to the retinal pigment epithelium (RPE), resulting in permanent vision loss. A recent hypothesis suggests that choroidal venous overload associated with scleral thickening may be involved in the pathophysiology of the disease.^{5 6} A recent long-term observational study reported that 12.8% of patients with chronic CSC became legally blind over a mean follow-up of 11.3 years, highlighting the unfavourable visual prognosis of the condition.⁷ Furthermore, CSC can cause macular neovascularisation called pachychoroid neovascularisation, which shares its pathology with age-related macular degeneration (AMD).⁸,¹¹

Current therapeutic options for chronic CSC are limited. Focal laser photocoagulation is applicable only for extrafoveal leakage points and can cause scotomas.¹² Although other treatments such as micropulse laser¹³ and mineralocorticoid receptor antagonists¹⁴ have been investigated, their efficacy remains unestablished. Globally, photodynamic therapy (PDT) is widely recognised as the first-line treatment for chronic CSC.¹²

The efficacy of PDT for CSC was first reported by Yannuzzi et al. in 2003.¹⁵ Initially, full-fluence PDT, the standard PDT approved for AMD, was performed. Subsequently, it was reported that reduced-intensity PDT could achieve effects comparable to the full-dose treatment while reducing the risk of complications, and it is now commonly used for CSC.¹² Due to its high efficacy, few studies have appropriately compared it with a control group. However, in 2008, Chan et al conducted a double-masked, placebo-controlled randomised trial of half-dose PDT for acute CSC and demonstrated its high efficacy.¹⁶ Furthermore, in 2022, our group demonstrated the effect of half-fluence PDT for chronic CSC against an untreated control group by adjusting for baseline characteristics using propensity scores.¹⁷ Nevertheless, no large, prospective, placebo-controlled randomised trial has been conducted to evaluate rf-PDT specifically for chronic CSC.

PDT is thought to work by reducing the choroidal hyperpermeability that underlies the pathophysiology of CSC, thereby promoting the resolution of subretinal fluid. However, PDT is not approved for CSC in any country and is used off-label.¹² In Japan, treatments without regulatory approval are not covered by national health insurance, forcing patients to bear the full cost of treatment.

Therefore, we designed the Reduced-fluence Photodynamic Therapy vs Placebo for Central Serous Chorioretinopathy (REPLAY) trial, a multicentre, investigator-initiated, phase III pivotal trial to evaluate the efficacy and safety of rf-PDT for chronic CSC, with the ultimate goal of obtaining regulatory approval and insurance reimbursement in Japan. This paper describes the study design and protocol.

Methods and analysis

Study setting

This multicentre, randomised, double-masked, placebo-controlled trial will be conducted at four tertiary ophthalmology centres in Japan: Kyoto University Hospital (Kyoto), Chiba University Hospital (Chiba), Kansai Medical University Hospital (Hirakata), and Tokyo Women’s Medical University Hospital (Tokyo). Additional sites may be added subject to IRB approval and registry update.

Trial status

Protocol V 1.6, dated 1 August 2025. Recruitment began in January 2024 and is ongoing. As of 1 September 2025, 51 of the 60 planned patients in the untreated cohort and 3 of the 10 planned patients in the previously treated cohort have been enrolled. The estimated study completion date is December 2026.

Study design

Study design is illustrated in figure 1. This study consists of two cohorts:

Figure 1. Study design of the REPLAY trial. This figure illustrates the overall design of the REPLAY trial, consisting of two cohorts. (A) Untreated cohort: Patients with chronic central serous chorioretinopathy (CSC) without prior photodynamic therapy (PDT) undergo screening based on predefined eligibility criteria and are randomised in a double-masked, placebo-controlled manner (2:1 allocation) to receive either reduced-fluence photodynamic therapy (rf-PDT) or placebo treatment. The primary endpoint is the proportion of eyes achieving complete resolution of subfoveal fluid at week 12, assessed by optical coherence tomography (OCT). Secondary endpoints include anatomical and functional outcomes evaluated up to week 48, as well as safety outcomes. (B) Previously treated cohort: Patients with chronic CSC who have previously undergone PDT are enrolled in an exploratory, single-arm cohort and receive rf-PDT. Anatomical and functional outcomes, as well as safety, are assessed longitudinally up to week 48. FAF, fundus autofluorescence; FA/ICGA, fluorescein angiography/indocyanine green angiography.

1. Untreated cohort: A multicentre, randomised, placebo-controlled, double-masked, parallel-group trial for patients with untreated chronic CSC.

2. Previously treated cohort: A multicentre, single-arm, open-label trial for patients with recurrent chronic CSC who have previously undergone PDT.

Eligibility criteria

• Patients diagnosed with chronic CSC via one or more of the following: OCT, fluorescein angiography/indocyanine green angiography (FA/ICGA), or fundus autofluorescence (FAF). Chronic CSC was diagnosed when retinal pigment epithelium damage was evident and CSC findings had persisted for ≥3 months.

• Based on the patient interview, symptom duration of at least 3 months and no more than 12 months from the estimated onset date (or recurrence date for the previously treated cohort) at the time of enrolment.

• Fovea-involving serous retinal detachment in one eye only.

• For the untreated cohort: no prior history of PDT. For the previously treated cohort: a history of PDT for chronic CSC with subsequent recurrence.

• Age 18 years or older and younger than 70 years at the time of consent.

• Written informed consent was provided by the patient.

Exclusion criteria

1. Regarding the study eye:

   • Best-corrected visual acuity worse than 20/200.

   • For the untreated cohort: any prior treatment with macular laser photocoagulation, PDT or anti-VEGF agents.

   • For the previously treated cohort: any prior treatment with macular laser photocoagulation or anti-VEGF agents.

   • Presence of cystoid macular oedema or advanced chorioretinal atrophy in the macula.

   • Concomitant ocular conditions likely to affect vision, such as age-related macular degeneration, myopic choroidal neovascularisation, angioid streaks, posterior inferior staphyloma or severe glaucoma.

   • High myopia, defined as a spherical equivalent of less than −6.0 dioptres or an axial length of 26.5 mm or greater.

   • History of any intraocular surgery other than cataract surgery.

   • Poor fundus view that precludes observation.

2. Regarding the fellow eye:

   • Best-corrected visual acuity worse than 20/200

3. Systemic and other criteria:

   • Continuous systemic steroid therapy.

   • Presence of severe infections or other severe comorbidities (eg, systemic debilitation, severe diabetes, severe heart disease, severe cerebrovascular disease, liver cirrhosis, pheochromocytoma, porphyria, active malignancy).

   • History of severe allergy to fluorescein, indocyanine green, verteporfin, mydriatics (eg, tropicamide), or iodine.

   • Women who are pregnant, possibly pregnant or breastfeeding, or women of childbearing potential not willing to use adequate contraception during the study period.

   • Participation in another interventional clinical trial within 6 months prior to enrolment.

   • Any other condition that the investigator judges as inappropriate for study participation.

Participant withdrawal

Participants can withdraw from the study at any time for any reason. The investigator may also withdraw a participant from the study if it is considered that continuing would be detrimental to the participant’s well-being, such as in the case of an adverse event or disease progression.

Interventions

Eligible patients will be enrolled through a central web-based registration system (Electronic Data Capture system).

(1) Untreated Cohort

Participants are randomly assigned in a 2:1 ratio to either the rf-PDT group or the placebo group using a stratified block randomisation method with the duration of symptoms (3 to <6 months / 6 to 12 months) as the stratification factor.

• rf-PDT Group: Participants will receive a 10-min intravenous infusion of verteporfin (CV-001) at a dose of 6 mg/m² of body surface area, diluted to a total volume of 30 mL with 5% dextrose solution. 15 minutes after the start of the infusion, a 689±3 nm laser will be delivered to the lesion using an ophthalmic PDT laser system (VitraPDT) at an energy of 25 J/cm² (300 mW/cm² for 83 s).

The detailed procedures for laser application are standardised across all participating institutions according to the study's Standard Operating Procedure (SOP). Key aspects of this standardised procedure include:

• Spot size determination: The irradiation spot is determined based on baseline FA/ICGA. The spot must cover all fluorescein leakage points from FA and, as much as possible, the area of choroidal vascular hyperpermeability (CVH) identified on ICGA. A safety margin of at least 1,000 µm is added to the diameter of this target area to determine the final irradiation spot size. The spot diameter is set to a minimum of 4,000 µm and a maximum of 7,200 µm. The nasal edge of the treatment spot must be at least 200 µm away from the temporal margin of the optic disc. Split-spot irradiation is not permitted in this study.

• Equipment and calibration: The VitraPDT laser system (Quantel Medical, France) is used at all sites. All devices undergo standardised calibration according to the manufacturer's instructions prior to the trial and annually thereafter, as well as prior to each treatment procedure.

• Operator training: All treating physicians are required to be board-certified ophthalmologists with specific training and certification in PDT.

• Placebo group: Participants will receive a 10-min intravenous infusion of 30 mL of 5% dextrose solution, followed by a laser application identical to that of the rf-PDT group. To maintain masking, the study drug will be prepared and administered by an unmasked staff. The syringe and infusion line will be covered with aluminium foil with reference to previous phase III trial for AMD.¹⁸ Patients, investigators and outcome assessors will remain masked to the treatment allocation throughout the study.

(2) Previously Treated Cohort

All participants in this cohort will receive open-label rf-PDT, following the same procedure as the rf-PDT group in the untreated cohort.

Patient management

As verteporfin is a photosensitising agent, all participants (including the placebo group) will be instructed to avoid exposing their skin and eyes to direct sunlight or bright indoor light for 48 hours after the infusion. To maintain blinding for all participants and investigators, these instructions on photosensitivity precautions are provided to both the rf-PDT and placebo groups.

Concomitant therapy and prohibitions

During the study period, any other treatments for CSC in the study eye, including conventional laser photocoagulation, additional PDT or anti-VEGF therapy, are prohibited. No rescue therapy is specified within this protocol for non-responders or for cases of disease progression. Continuous systemic steroid therapy is prohibited. However, the use of local steroids (eg, topical, inhaled or nasal steroids) for non-ocular conditions is permitted if the treatment is considered essential. Any other oral medications, eye drops or online supplemental materials 1 intended to treat CSC are also prohibited as they may interfere with the efficacy assessment.

Study procedures and follow-up

After the baseline assessment and treatment on Day 1, participants will attend follow-up visits at weeks 4, 12, 24, 36 and 48. The schedule of major assessments is as follows:

• Visual acuity: Decimal visual acuity will be measured at every visit. Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity will be measured at baseline, week 12 and week 48.

• OCT: OCT will be performed at every visit to assess the status of the serous retinal detachment and to measure the subfoveal choroidal thickness.

• Fundus photography: Performed at baseline and at weeks 4, 12, 24, 36 and 48.

• FA/ICGA: Performed at baseline and week 48.

• Safety assessments: Monitoring for adverse events will occur at all visits. Blood and urine tests will be conducted at baseline and week 48.

Outcomes

The follow-up period is 48 weeks post-treatment.

1. Primary Endpoint

   • The primary endpoint is the proportion of eyes with complete resolution of subfoveal fluid at week 12. Resolution is defined as the complete absence of subretinal fluid at the fovea on OCT images.

2. Secondary Endpoints

Secondary endpoints include:

• The percentage of patients in whom central macular detachment has disappeared at 24, 36 and 48 weeks after treatment.

• The percentage of patients at 12, 24, 36 and 48 weeks after treatment whose vision has either remained stable or improved.

• The number of readable characters on the ETDRS visual acuity test at 48 weeks after treatment.

• LogMAR (logarithm of the minimum angle of resolution) based on decimal visual acuity testing at 12, 24, 36 and 48 weeks after treatment.

• Duration until the disappearance of central macular detachment.

• Height and extent of central macular detachment.

• Subfoveal choroidal thickness.

• Incidence rate of macular neovascularisation.

• Rate of recurrence after the disappearance of central macular detachment.

• Frequency of adverse events and side effects.

Outcome adjudication

The primary endpoint, the complete resolution of subfoveal fluid, will be determined by the site investigator at each institution using OCT. A central reading centre will not be used for this trial. The primary endpoint is an objective anatomical outcome based on OCT imaging, which provides high-resolution cross-sectional images of the retina. The determination of the presence or absence of subfoveal fluid is a standard and highly reproducible assessment for board-certified ophthalmologists, minimising the potential for significant inter-rater variability. To ensure consistency, all investigators will adhere to a common definition of resolution as the complete absence of subretinal fluid at the fovea.

Patient and public involvement

No patients or members of the public were involved in the design, conduct, reporting or dissemination plans of this research.

Sample size

The target sample size for the untreated cohort is 60 patients (40 in the rf-PDT group, 20 in the placebo group). This was calculated based on a previous study,¹⁶ assuming a resolution rate of 80.7% in the rf-PDT group and 37.9% in the placebo group at 12 weeks for acute CSC. While the present study targets chronic CSC, there is a lack of high-quality, placebo-controlled data for this specific population. Therefore, the data from the Chan et al study was used as the best available evidence to estimate the potential treatment effect. With a two-sided significance level of 5% and 90% power, 57 patients are required. Accounting for a 5% dropout rate, the total sample size was set to 60. The previously treated cohort is exploratory and will enrol up to 10 patients.

Statistical analysis

The primary efficacy analysis will be conducted on the full analysis set (FAS), defined as all randomised patients who receive at least a partial dose of the study drug. The proportion of patients meeting the primary endpoint will be calculated for each group with its 95% CI. The difference in proportions and its 95% CI will be calculated using the Newcombe method to compare the groups. For the secondary endpoints, the proportion of eyes with complete resolution of subfoveal fluid and the recurrence rate after initial resolution will be analysed by calculating between-group differences in proportions along with their 95% CI. For the change from baseline in best-corrected visual acuity and in subfoveal choroidal thickness, between-group differences in means and their 95% CI will be calculated, and comparisons between treatment groups will be performed using unpaired t-tests. For time to resolution of subfoveal fluid, Kaplan–Meier curves will be estimated for each treatment group, and the log-rank test will be used to compare groups. Missing data will be handled under a missing at random assumption using a mixed model, and no explicit imputation will be performed. A p value<0.05 will be considered statistically significant.

Safety analyses will be performed on the safety analysis set, which includes all participants who received at least a partial dose of the study drug, and will be summarised descriptively.

Ethics and dissemination

This study will be conducted in compliance with the ethical principles of the Declaration of Helsinki and the Japanese Clinical Trials Act (Good Clinical Practice). The study protocol (V 1.6, 1 August 2025) was approved by the Kyoto University Hospital Institutional Review Board, IRB of Chiba University Hospital, Tokyo Women’s Medical University Institutional Review Board, and Institutional Review Board of Kansai Medical University Hospital. Any modifications to the protocol will be submitted for approval. IRB approval number is K101. All participants will provide written informed consent before any study-related procedures are performed. A full English translation of the informed consent form is provided as online supplemental material file 1.

The study is an investigator-initiated trial, with Kyoto University serving as the sponsor-investigator. The coordinating investigator and the study team are responsible for the study design, protocol development, data collection and analysis. Data management and statistical analysis will be conducted by the Institute for Advancement of Clinical and Translational Science (iACT), the Academic Research Organisation of Kyoto University.

An independent Data and Safety Monitoring Board (DSMB) has been established to monitor the safety and scientific integrity of the trial. The DSMB will review serious adverse events and overall study progress. The DSMB has the authority to recommend pausing or terminating the trial if there are significant safety concerns. In the case of a medical emergency where knowledge of the treatment allocation is necessary for the participant’s care, the investigator can unblind the treatment for that specific participant through a predefined procedure.

All clinical data will be recorded in a secure, password-protected electronic data capture system that complies with Good Clinical Practice and applicable regulatory requirements. Data entry will be performed by trained study personnel at each participating site. Access to the system will be role-based, and an audit trail will automatically document all data modifications. All data will be stored in compliance with relevant data protection regulations. After trial completion, the locked database will be archived securely for at least the period required by regulatory authorities. Access to the archived dataset will be restricted to authorised personnel only. On-site monitoring visits will be conducted at each participating site prior to the initiation of subject enrolment, approximately every 6 months in accordance with the progress of recruitment, and at the end of the trial. Compensation for any health-related harm resulting from trial participation will be provided according to the terms of the clinical trial compensation insurance.

The results of this trial, regardless of the outcome, will be submitted for publication in a peer-reviewed journal and presented at scientific conferences. With separate written informed consent, blood samples will be collected from participants and stored for future ancillary studies, such as genetic analysis, to explore the pathophysiology of CSC.