Half-Dose Photodynamic Therapy Versus Eplerenone in Chronic Central Serous Chorioretinopathy (SPECTRA): A Randomized Controlled Trial


To compare the efficacy and safety between half-dose photodynamic therapy (PDT) and eplerenone therapy for treating chronic central serous chorioretinopathy (cCSC).


This was a multicenter, open-label, randomized controlled trial.


This investigator-initiated trial was conducted in 3 academic medical centers in the Netherlands. Eligible patients were randomized at a 1:1 ratio to receive either indocyanine green angiography-guided half-dose PDT or oral eplerenone for 12 weeks. Both anatomical and functional outcomes were evaluated at 3 months after the start of treatment.


A total of 107 patients were randomly assigned to receive either half-dose PDT (n = 53) or eplerenone treatment (n = 54). Thirteen patients (3 in the PDT group and 10 in the eplerenone group) did not adhere to the study protocol. At the 3-month evaluation visit, 78% of patients in the PDT group had complete resolution of subretinal fluid accumulation compared to only 17% of patients in the eplerenone group ( P < .001). Mean best-corrected visual acuity in Early Treatment of Diabetic Retinopathy Study letters at the 3-month evaluation visit was 83.7 ± 10.8 and 82.8 ± 9.0 in the PDT and eplerenone groups, respectively ( P = .555). In addition, mean retinal sensitivity on microperimetry was 25.4 ± 3.4 dB and 23.9 ± 4.0 dB in the PDT and eplerenone groups, respectively ( P = .041). Finally, mean vision-related quality of life scores were 87.2 ± 8.5 and 83.8 ± 12.1 in the PDT and eplerenone groups, respectively ( P = .094). Three patients (6%) in the PDT group experienced adverse events during the study compared to 18 patients (33%) in the eplerenone group.


Half-dose PDT is superior to oral eplerenone for cCSC with respect to both short-term safety and efficacy outcomes.

C entral serous chorioretinopathy (CSC) is a relatively common eye disease characterized by the accumulation of subretinal fluid (SRF) in the macula, resulting in central vision loss and reduced vision-related quality of life. , CSC is up to 8 times more prevalent in men than in women and is often associated with the use of corticosteroids. Although the underlying pathogenesis in CSC is poorly understood, impaired choroidal function is thought to play a primary role, with choroidal congestion, stasis, and hyperpermeability resulting in reduced function of the retinal pigment epithelium (RPE). Breakdown of the outer blood–retina barrier in the RPE causes SRF to accumulate under the retina, resulting in serous retinal detachment and separation of the photoreceptors from the RPE. CSC is categorized as either acute CSC or chronic CSC (cCSC) based on the duration of symptoms and findings on multimodal imaging. In acute CSC, the SRF typically resolves spontaneously within 4 months, with complete or near-complete restoration of vision. In cCSC, the SRF generally persists for 4 to 6 months or longer, leading to irreversible changes in the RPE, photoreceptor damage, and persistent vision loss.

With cCSC, early diagnosis and treatment are essential for limiting the loss of visual function. A wide range of potential treatments have been described for cCSC with mixed results. Due to the relatively low number of prospective randomized trials performed to date, the optimal treatment in cCSC remains controversial, although a number of retrospective studies and one large prospective randomized controlled trial (the Half-Dose Photodynamic Therapy versus High-Density Subthreshold Micropulse Laser Treatment in Patients with Chronic Central Serous Chorioretinopathy (PLACE) trial) have reported that photodynamic therapy (PDT) using the photosensitizer verteporfin can lead to the complete resolution of SRF in 67% to 100% of cCSC cases. , PDT primarily targets the choroidal vasculature, and its beneficial effects have been hypothesized to stem from vascular remodeling due to the release of free oxygen radicals. Remodeling of the choroid may therefore lead to reduced choroidal hyperpermeability, which can stop SRF leakage. By targeting choroidal abnormalities with the PDT laser spot using indocyanine green angiography (ICGA) guidance, it may be possible to treat the underlying abnormal tissue with the highest efficacy. , Several PDT algorithms have been described using reduced treatment intensity compared to the original settings, thereby minimizing potential side effects without compromising treatment efficacy. Currently, many clinicians use half-dose verteporfin (i.e., 3 mg/m 2 rather than 6 mg/m 2 ), as this so-called “half-dose PDT” approach minimizes the already low risk of systemic side effects associated with verteporfin infusion.

Several studies have suggested a link between CSC and both corticosteroid use and impaired mineralocorticoid receptor (MR) function. , , MR overactivation in cCSC may upregulate the endothelial vasodilatory potassium channel KCa2.3 (also known as SK3), causing hyperpolarization of endothelial cells and underlying smooth muscle cells, resulting in the choroidal vasodilatation often present in patients with cCSC. , In addition, several studies suggest that MR antagonists may be useful in treating cCSC, reporting a decrease in SRF, a reduction in choroidal thickness, and an improvement in best-corrected visual acuity (BCVA). , In these studies, oral eplerenone was generally favored over other oral MR antagonists such as spironolactone due to its relatively low affinity for steroid receptors, thus providing a more favorable safety profile. Finally, a systemic treatment approach may be desired in cCSC, as up to 40% of patients can present with bilateral disease activity. , Despite these studies, however, a recent randomized, double-blind, placebo-controlled trial (Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI trial)) found no significant differences between eplerenone and placebo; specifically, in the placebo group, 11% and 30% of cases had complete resolution of SRF at 3 months and 1 year, respectively, compared to 10% and 16%, respectively, in the eplerenone treatment group.

To date, efficacy and safety have not been compared between half-dose PDT and eplerenone treatment for cCSC in a randomized controlled setting. We therefore performed an investigator-initiated, multicenter, open-label, randomized controlled trial in order to compare short-term treatment outcome and safety between half-dose PDT and oral eplerenone treatment in cCSC.



In this multicenter, open-label, randomized controlled trial, patients with cCSC were randomized to receive either half-dose PDT or oral eplerenone treatment. Eligible patients were enrolled at Amsterdam University Medical Center (Amsterdam, the Netherlands), Leiden University Medical Center (Leiden, the Netherlands), or Radboud University Medical Center (Nijmegen, the Netherlands). The study conformed to the tenets of the Declaration of Helsinki, and all participating centers received approval from their respective institutional review boards. Ethics approval was obtained from the medical ethics committee of Leiden University Medical Center (NL59158.058.16), and written informed consent was obtained from all participants. This trial was overseen by a data-monitoring committee consisting of 3 independent committee members with no competing interests; this committee provided advice regarding the quality of the data, evidence with respect to treatment harm, and advice regarding changes to the protocol—or termination of the trial—if deemed necessary. The SPECTRA trial (Half-Dose Photodynamic Therapy Versus Eplerenone: Treatment Trial for Chronic Central Serous Chorioretinopathy) is registered at ClinicalTrials.gov. The study protocol is available as supplemental material at AJO.com ).


Men and women aged 18 years or older at the time of enrollment with a confirmed diagnosis of cCSC in at least 1 eye were eligible for inclusion. Additional inclusion criteria included the presence of foveal SRF on optical coherence tomography (OCT) scanning and the presence of subjective disease-related loss of vision for at least 6 weeks but not longer than 18 months. In addition, at least one area of fluorescein leakage had to be visible on fluorescein angiography (FA), along with RPE window defects compatible with cCSC, with areas of corresponding hyperfluorescence visible on ICGA.

Patients who received previous treatment for CSC (including cCSC), previous treatment with an MR antagonist for another indication, or were treated with corticosteroids within the past 3 months were excluded. We also excluded patients who presented with evidence of another diagnosis that could explain either their vision loss or the accumulation of SRF. Other exclusion criteria included the presence of chorioretinal atrophy on OCT, myopia >6 diopters, intraretinal fluid on OCT, the presence of drusen in the affected or unaffected eye, signs of neovascularization on multimodal imaging, and a serum potassium level >5.5 mEq/L and/or a creatinine clearance rate of ≤30 mL/min. Finally, patients with a contraindication to receiving FA, ICGA, PDT, and/or eplerenone were excluded. The complete list of inclusion and exclusion criteria is provided in Table 1 .


Inclusion and Exclusion Criteria of the SPECTRA Trial.

Inclusion Criteria
≥18 years of age and able to give written informed consent
Active cCSC
Subjective visual loss for >6 weeks, interpreted as onset of active disease
Foveal SRF on OCT at the baseline examination
≥1 area of ill-defined hyperfluorescent leakage on FA with RPE window defect(s) compatible with cCSC
Hyperfluorescent areas on ICGA
Exclusion C riteria
Any previous treatment(s) for active CSC a
Previous prescription for MR antagonists for cCSC or any other disease
Current treatment with corticosteroids (topical or systemic), corticosteroid use within three months before the expected start of the trial treatment, or anticipated start of corticosteroid treatment within 2 years after the start of the trial period
Evidence of another diagnosis that could explain serous SRF and/or vision loss
BCVA <20/200 (Snellen equivalent)
Profound chorioretinal atrophy in the central macular area on ophthalmoscopy and/or OCT
Myopia >6 diopters
Vision loss and/or serous detachment on OCT lasting less than 6 weeks
Continuous and/or progressive vision loss lasting >18 months or serous detachment on OCT lasting >18 months
No hyperfluorescence on ICGA
Intraretinal fluid on OCT
Contraindications for FA or ICGA
Contraindications for receiving PDT treatment such as pregnancy, porphyria, or severely impaired liver function.
Known contraindications for starting eplerenone treatment such as hyperkalemia, abnormal renal clearance, severe hepatic insufficiency (Child-Pugh score of C), type 2 diabetes mellitus with microalbuminuria, use of potassium supplements, potassium-sparing diuretics, potent CYP3A4 inhibitors, or the combined use of an ACE inhibitor and an angiotensin receptor‒blocking agent
Soft drusen in the affected eye or unaffected eye, or signs of choroidal neovascularization in the affected eye on ophthalmoscopy and/or FA/ICGA

ACE = angiotensin-converting enzyme; BCVA = best-corrected visual acuity; cCSC = chronic central serous chorioretinopathy; CSC = central serous chorioretinopathy; CYP3A4 = cytochrome P450 3A4; FA = fluorescein angiography; ICGA = indocyanine green angiography; OCT = optical coherence tomography; PDT = photodynamic therapy; RPE = retinal pigment epithelium; SPECTRA = Half-Dose Photodynamic Therapy Versus Eplerenone in Chronic Central Serous Chorioretinopathy; SRF = subretinal fluid.

a A previous prescription for an oral medication (e.g., acetazolamide) for cCSC, with the exception of a prescription for an MR antagonist, was not an exclusion criterion for this study.


Eligible patients were randomly assigned to their respective treatment groups (at a ratio of 1:1) using a web-based random numbers generator with block randomization. Block size also varied randomly between 2, 4, and 6 cases. The random number generator was designed at the Department of Medical Statistics at Leiden University Medical Center. The randomization schedule was designed by an independent statistician, and the randomization codes were stored in both the case report form and the digital database. Randomization was stratified per study center. The type of treatment administered to each patient could be concealed from neither the patients nor the researchers due to the nature of the interventions and because serum potassium levels were measured regularly in the eplerenone group.


All clinicians and researchers involved in collecting the data were trained and certified, and all data were obtained using standard operating procedures. The demographics, medical history, and lifestyle of each patient were recorded at their baseline visit. In addition, the following measurements were obtained at baseline and at the 3-month follow-up visit: BCVA in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters; retinal sensitivity on microperimetry using a Macular Integrity Assessment Microperimeter (CenterVue); the National Eye Institute Visual Functioning Questionnaire 25-item version (NEI VFQ-25) composite score; fundus photography; fundus autofluorescence imaging; OCT scanning; and FA, ICGA, and OCT angiography. Fundus photography was performed using a TRC-50 series fundus camera (Topcon). Fundus autofluorescence, OCT, FA, and ICGA were obtained using the Spectralis HRA+OCT machine (Heidelberg Engineering). OCT angiography was obtained using the RS 3000 (Nidek), the Heidelberg (Heidelberg Engineering), and the Optovue devices.


The pupil of the eye to be treated was dilated using topical tropicamide 1.0% and phenylephrine 2.5%. All patients received an intravenous drip through which 3 mg/m 2 verteporfin was administered over a period of 10 minutes. Fifteen minutes after starting the infusion of verteporfin, (Novartis) an anesthetic eye drop (oxybuprocaine 0.4% or equivalent) was administered, a PDT contact lens (1.5 × magnification) (Volk Optical), was positioned on the eye, and laser treatment was applied to the treatment area. The area to be treated was determined based on hyperfluorescent area(s) on mid-phase (approximately 10 minutes) ICGA, which corresponds to macular SRF on OCT and hyperfluorescent leakage points on the mid-phase (approximately 3 minutes) FA. The size of the laser spot was based on the diameter of the hyperfluorescent area(s) on ICGA, plus an additional 1 mm. The optic disc and an area within 200 μm of the optic disc were excluded from laser treatment. PDT was applied at 50 J/cm 2 (i.e., standard) fluency with a laser wavelength of 689 nm and a duration of 83 seconds.


Patients in the eplerenone group started at eplerenone 25 mg/day for 1 week, during which their serum potassium level was assessed. After 1 week, the eplerenone dose was adjusted as follows: if the patient’s serum potassium level was <5.0 mEq/L, the dose was increased to 50 mg/day; if the serum potassium level was 5.0 to 5.4 mEq/L, the dose remained at 25 mg/day; if the serum potassium level was 5.5 to 5.9 mEq/L, the dose was decreased to 25 mg every 2 days; or if the serum potassium level was ≥6.0 mEq/L, the eplerenone treatment was terminated. At 1 month after the start of eplerenone treatment, the patient’s serum potassium was measured again, and this measurement was repeated both 2 and 3 months after the start of treatment, during which the dose of eplerenone was adjusted based on the serum potassium level as described in Table 2 . The patients were instructed to return any remaining eplerenone tablets at the 3-month evaluation visit.


Treatment regimen for the patients in the eplerenone group a .

Serum Potassium (mEq/L) Action Dose Adjustment/Notes
<5.0 (in patients currently receiving 25 mg/d or 25 mg every 2 d) Increase dose From 25 mg/d to 50 mg/d; or from 25 mg every 2 d to 25 mg/d
<5.0 (in patients currently receiving 50 mg/d) No change No change
5.0–5.4 No change No change
5.5–5.9 Decrease dose From 50-25 mg/d; from 25 mg/d to 25 mg every 2 d; or from 25 mg every 2 d to withholding treatment
≥6.0 Withhold treatment Restart at 25 mg every 2 d when the potassium level is <5.5 mEq/L

a Patients enrolled in the eplerenone arm started at 25 mg eplerenone/d. Serum potassium was checked at 1 week, 1 month, 2 months, and 3 months after the start of treatment, and the eplerenone dose was adjusted accordingly.


The primary outcome was complete resolution of SRF on OCT at the 3-month evaluation visit. Secondary outcomes included the change in BCVA in ETDRS letters, the change in retinal sensitivity on microperimetry, and the change in the NEI VFQ-25 composite score. In addition, the central retinal thickness was measured according to a previously published protocol (measured as the distance between the internal limiting membrane and the ellipsoid zone on OCT), and the height of the subretinal fluid on OCT was obtained. Moreover, any adverse events were noted, and information regarding the setting for half-dose PDT, and the eplerenone doses were obtained.


A target sample size of 107 patients was calculated based on a test for the difference of proportions using 80% power, a significance (α) level of .05, and allowing for a 25% dropout rate. All patients were analyzed in the subgroup to which they were originally randomized (i.e., in accordance with the intention-to-treat principle). Summary data are reported as the mean ± SD or the number (%). Mixed effects logistic regression using the “mixed_model” function in the GLMMadaptive feature in R version 3.5.3 software (R Foundation for Statistical Computing) was performed in order to model the change in the percentage of patients with complete SRF resolution between the baseline evaluation and the 3-month evaluation. For continuous outcomes, a marginal multivariate regression model was used to analyze the changes in these outcomes over time. Where appropriate, the Wald test and F test were used for hypothesis testing. Differences between the half-dose PDT group and the eplerenone group were not examined at baseline, as any significant differences could have arisen by chance due to the randomization procedure.


From February 22, 2017, through August 28, 2019, a total of 107 patients (100 men and 7 women) were enrolled in the trial and randomly assigned to either the half-dose PDT arm (53 patients) or the eplerenone treatment arm (54 patients) ( Figure 1 ). Multimodal imaging of a cCSC patient in the half-dose PDT group is depicted in Figure 2 .

Jan 3, 2022 | Posted by in OPHTHALMOLOGY | Comments Off on Half-Dose Photodynamic Therapy Versus Eplerenone in Chronic Central Serous Chorioretinopathy (SPECTRA): A Randomized Controlled Trial

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