| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Central serous chorio-retinopathy |
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| E.1.1.1 | Medical condition in easily understood language |
| fluid build up under the tissue at the back of the eye (the retina) causing vision distortion. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007974 |
| E.1.2 | Term | Central serous retinopathy |
| E.1.2 | System Organ Class | 100000004853 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate whether vision following eplerenone therapy alongside usual care is superior to placebo with usual care in eyes with chronic Central serous chorio-retinopathy. |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study are:
a) To evaluate whether eplerenone treatment is better than placebo for resolution of fluid build up under the retina
b) To describe the safety profile of eplerenone treatment (compared to placebo)
c) To evaluate whether participant-reported visual function improves with eplerenone treatment compared to placebo
d) to describe how the other parts of the eye (choroid and retinal pigment epithelium) responds to treatment in Central serous chorio-retinopathy.
e) To evaluate how vision in low lighting changes with eplerenone treatment.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sub-study on mechanistic evaluation:
Objectives
1. To generate a biobank of DNA, serum and plasma for future mechanistic studies.
2. To explore treatment response by conducting imaging studies of retina and choroid.
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| E.3 | Principal inclusion criteria |
Participant may enter study if ALL of the following apply
1. Participants will be aged ≥18 years and ≤ 60 years
2. Visual impairment due to CSCR of ≥ 4 months duration defined as:
a. subfoveal presence of SRF on OCT
AND
b. characteristic appearance of CSCR on FFA and Indocyanine-green angiography (ICGA).
AND
c. investigator believes that there is sufficient evidence from either patient history, case note documentation or appearance of the macula that CSCR has been present for at least 4 months.
3. Women must have a negative pregnancy test and be willing to use effective contraception* for the duration of the participation in the trial and for 3 months after, be surgically sterile or post-menopausal for >12 months.
4. Able to provide written informed consent.
The following apply to the study eye:
5. A study eye should have an Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA score greater than 53 letters and less than 86 letters.
6. A study eye should have clear ocular media and adequate pupillary dilatation to permit photography.
* this includes: progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of action, male or female condom with or without spermicide cap, diaphragm or sponge with spermicide, combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal),
progestogen-only hormonal contraception associated with inhibition of ovulation: (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, sexual abstinence.
NB pregnancy test only need to be repeated if there is reason to suspect the participant has become pregnant.
There are no special precautions/contraceptive requirements for male participants with female partners of child bearing potential.
It is rare but not impossible for patients to present with CSCR in both eyes or CSCR may develop in the fellow eye during the trial. We propose to measure eye-specific outcomes such as BCVA in both eyes throughout the trial, designating eyes as study eyes or not. Statistical analyses will take into account the availability of data for two eligible eyes in one patient.
If both eyes present with CSCR at baseline, the clinical trial site will decide which is the primary eye and this eye will have retinal imaging performed first. The primary eye would usually be the one with most active disease/most sub-retinal fluid. It will be identified by OCT imaging and subsequent investigations such as fluorescein and indocyanine green angiography will then be performed initially on this eye. If a patient presents with one affected eye and the fellow eye subsequently develops CSCR the eye first affected will always be the primary study eye.
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| E.4 | Principal exclusion criteria |
Participant may not enter study if ANY of the following apply
1. Hyperkalaemia (serum potassium level > 5.0 mmol/L).
2. Hepatic or renal impairment (Patients with severe renal insufficiency (Estimated glomerular filtration rate, eGFR < 30 mL per minute per 1.73 m2) or Patients with severe hepatic insufficiency (Child-Pugh Class C).
3. Pregnancy or breast feeding.
4. Known allergy to fluorescein or indocyanine green.
5. Patients receiving potassium-sparing diuretics, potassium-supplements, or inhibitors of CYP 3A4 (e.g.amiodarone, diltiazem, fluconazole, itraconazole, ketoconazole, ritonavir, nelfinavir, saquinavir clarithromycin, telithromycin, erythromycin, verapamil, spironolactone and nefazodone)).Patients taking furosemide are eligible.
6. Patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g. ibuprofen, naproxen).
7. Patients receiving the combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin receptor blocker (ARB) with eplerenone.
8. Patients receiving lithium, cyclosporine or tacrolimus.
9. Hypersensitivity or known allergy to eplerenone or to any of the excipients.
10. Known hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
11. Patients receiving high doses of Aspirin (>75mg).
The following additional exclusions apply to a study eye only (i.e. they may be present for a non-study eye):
12. Evidence of choroidal neovascularization.
13. Previous or current treatment with eplerenone for any reason or previous or current treatment with photodynamic laser therapy / any anti-VEGF therapy in the study eye / any intra-ocular steroid use / thermal laser therapy for CSCR
14. Presence of any other disease which could cause retinal or SRF to accumulate e.g. diabetic retinopathy, polypoidal choroidal vasculopathy, domed shaped maculopathy or choroidal hemangioma or affect visual acuity.
15. Myopia > -6 dioptres
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary outcome is the BCVA at the 12 month visit, adjusted for baseline BCVA, measured using validated ETDRS vision charts with measurements made in accordance with a standardised protocol for trials in medical retina. Refracted visual acuity will be done at baseline, 4 weeks, 3, 6, 9 and 12 months. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Refracted visual acuity will be done at baseline, 4 weeks, 3, 6 9 and 12 months. |
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| E.5.2 | Secondary end point(s) |
1. Low luminance visual acuity. This is measured immediately after measuring BCVA by adding a 2 log neutral density filter and recording the number of letters read.
2. CSRT as measured by OCT estimated at 12 months, including CSRT measured at interim visits and adjusted for baseline CSRT.
3. Change in sub-retinal fluid thickness as measured by OCT
4. Systemic and ocular adverse events at any time during the 12 month follow-up period
5. Proportion of patients with macular atrophy of the RPE defined as hypoautofluorescence at 12 months
6. Area change in macular RPE hypoautofluorescence at 12 months.
7. Choroidal thickness as measured by enhanced depth imaging OCT at 12 months, adjusted for baseline choroidal thickness. Measurements to be made sub-foveally.
8. Proportion of patients with reduced choroidal permeability on ICG at 12 months
9. Time to resolution of SRF.
10. Classification of all study eyes as complete, partial or no resolution of SRF at each time point of the study. Partial resolution of SRF is defined as a decrease of >25 % of CMT from baseline due to resolution of SRF. A non-responder is defined as having an increase in SRF or decrease in SRF ≤25% from baseline. Recurrence will be defined as the appearance of new SRF in a study eye after complete resolution of SRF at any point.
11. Patient-reported visual function using Visual Function Questionnaire VFQ 25 will be assessed at baseline and 12 months.
12. Classification of all study eyes by each FFA phenotype, such as smoke stack, ink-blot and chronic epitheliopathy
13. Classification of all study eyes as early, late, or non responder. An early responder is defined as complete or partial resolution of sub-foveal SRF by 3 months. A late responder is defined as complete or partial resolution of sub-foveal SRF after 6 months.
14. Incidence of CSCR in the fellow eye as measured by OCT, FFA, ICGA or AF.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Low luminance visual acuity and OCT are done at baseline, 4 weeks and months 3, 6, 9 and 12. Other imaging tests forming part of the secondary outcomes will be assessed at baseline and 12 months. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial as a whole is when all follow-up is completed, data collected and cleaned and the database is locked. This is to allow all data to be collected and validated prior to the end of the study. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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