Photodynamic laser therapy with verteporfin versus placebo for chronic central serous chorioretinopathy: the Paint RCT

Background: Central serous chorio-retinopathy (CSCR) is a common retinal disease where sub-retinal fluid spontaneously occurs. This results in reduced visual function in circa 30%. There are no proven treatments.

Research questions: 1) Is ½ dose PDT laser with verteporfin better than placebo at improving visual function? 2) Can mechanistic studies identify biomarkers that predict response to therapy? Aims: 1) Perform a placebo-controlled RCT to test efficacy & safety of ½ dose PDT laser with verteporfin in CSCR

2) Conduct mechanistic studies to: a. test whether genotypes predict response to PDT. b. evaluate if structural biomarkers predict response to treatment.

Methods: A multicentre, double-masked, placebo-controlled clinical efficacy & safety RCT including mechanistic evaluation to compare ½ dose PDT laser with placebo in patients with CSCR.

Population: Patients with CSCR > 4 months duration. Intervention: ½ dose PDT laser Comparator: Sham laser. Rescue therapy: If any participant experiences of drop in BCVA of 10 letters or more (compared to baseline) during the trial they will be offered the local standard of care (likely to be PDT).

Outcomes: Primary: Difference between groups in mean best corrected visual acuity (BCVA) at 12 months. Secondary: Difference in a) LLVA and b) amount of retinal leakage, calculated using optical coherence tomography (OCT) mean central retinal sub-field thickness (CRST) measurements at 12 months. The safety profile of ½ dose PDT laser will also be compared to the control arm.

Assessments:

1. BCVA, LLVA and macular morphology assessed by optical coherence tomography (OCT) and OCT angiography (OCT-A) at baseline, 4, 8, and 12 months.

2. Fundus fluorescein angiography and fundus autofluorescence (FAF) at baseline and 12 months to assess retinal leakage and RPE function. 3. Quality of life assessments at baseline and 12 months. 4. Blood sample for DNA at baseline.

Sample size: A sample size of 45 patients in each of the 2 groups would be sufficient to detect a difference of 5 letters in BCVA between the PDT & placebo arms with 90% power and 5% significance (2 tailed). In our previous CSCR trial 12% of participants had a reduction by 10 or more letters from baseline at any visit and 7 % of patients withdrew from treatment.

Therefore the total sample size has been increased to 140 to allow for up to 10% dropout over the 12 month period and to account for 15 % of patients needing rescue treatment.

Statistical analyses: A linear mixed model analysis will be performed for the primary outcome BCVA to estimate the main effect of treatment at 12-months using data over all available follow up visits (i.e. time in study) and eyes-within-patients. Analyses will be on an intention to treat basis. Analyses of secondary outcomes measured at baseline & during follow up will use similar modelling strategies, as appropriate.

Safety outcomes will be reported as proportion of patients with the event & 95% confidence intervals for each arm.

Timelines: We propose a 50 month study: 8 month start-up; 24 months recruitment with 10-12 patients per site as each site sees a minimum of 20 eligible patients annually (with an 8 month internal pilot); 12 months follow-up; 6 months for analysis & publication.

Impact: This study should change management of CSCR worldwide as it will be the first definitive placebo controlled RCT evaluating PDT laser in the treatment of CSCR.