Conditions: Central Serous Chorioretinopathy
Keywords: Central Serous Chorioretinopathy Eplerenone Optical Coherence Tomography Enhanced Depth Imaging Subretinal Fluid
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
* The goal of the study is to examine the short-term effects and safety of a systemic anti-aldosterone medication, eplerenone, in a small group of patients with central serous chorioretinopathy (CSCR).
* There is currently no standard treatment or therapy for either acute or chronic CSCR, a potentially debilitating eye disease.
* There is evidence in both animals and humans that high blood serum corticosteroid levels can cause or worsen CSCR or findings similar to CSCR in the choroid and retina
* Eplerenone, a mineralocorticoid receptor antagonist, has been shown to be of visual and anatomic benefit in a small series of 4 patients with chronic CSCR, suggesting that decreasing mineralocorticoid action in the eye may improve signs and symptoms of CSCR
* The investigators' aim is to evaluate a standardized dose of eplerenone in a controlled prospective fashion for both acute and chronic CSCR.
* The study consists of taking a standard dose of eplerenone, 50mg once daily, for 1 month
* Over the course of the month, patients will be monitored for side effects, as well as visual and anatomical response to the medication

Detailed description:
* The investigators hypothesize that aldosterone inhibition with eplerenone will decrease choroidal vessel vasodilation, focal leakage, and choroidal thickness in patients with both acute and chronic CSCR, leading to resolution of subretinal fluid and ultimately an improvement in symptoms.
* Resolution of sub-retinal fluid will be the primary outcome, which can be precisely measured using optical coherence tomography (OCT)
* Secondary outcomes will include: Change in macular thickness measured with OCT, in central macular circle thickness on OCT, change in visual acuity, change in dye leakage characteristics on fluorescein angiography, change in OCT characteristics of the fellow eye, and safety and tolerability characteristics
* In acute CSCR, subretinal fluid often resolves on its own, but it often takes several months (the literature shows that \~20% of patients have complete resolution of sub-retinal fluid on OCT 1 month after presentation)
* Chronic CSCR is defined as persistent fluid on OCT after 3 months of symptom onset, or recurrence of signs and symptoms within 1 year after the prior episode
* In this study, the investigators will not make a distinction between acute and chronic CSCR
* Eplerenone, a generic medication, is a potassium sparing diuretic, which is FDA approved to treat heart failure as well as high blood pressure, but is not FDA approved for treatment of central serous chorioretinopathy.
* The most important side effect of eplerenone is elevation of serum potassium and decrease of blood pressure
* Patients will therefore be screened with routine blood tests as suggested by the package insert of the medication, and serum potassium and blood pressure will be monitored routinely as directed by the medication package insert
* Study visits will be performed at therapy initiation, 1 week, 2 weeks, and 4 weeks

Arms:
arm 1: All patients in this study will receive Eplerenone 50mg once daily for 4 weeks.

Interventions: intervention 1: Eplerenone 50mg
Intervention descriptions: intervention 1: All patients will receive the same dose of eplerenone.

Protocol document:
Prot_SAP_000.pdf: 
Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 1 of 23 
Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
 
 
Protocol  
 
IRB#: 10722 
Principal Investigator: Andre J. Witkin, MD 
Co-investigators: Jordana Fein, MD, Jay Duker, MD, Elias Reichel, MD, Adam Rogers, 
MD, Caroline Baumal, MD, Nadia Waheed, MD, Roger Goldberg, MD, Marissa Weber, 
MD 
Coordinators: Julie Burt, Melody Velasquez, Olivia Sahnas 
 
Part I 
Aim and Hypotheses: 
We would like to examine the short-term effects and safety of a systemic anti-
aldosterone medication, eplerenone, in a small group of patients with central serous 
chorioretinopathy (CSCR), an idiopathic eye disease which affects the central vision 
and is known to be worsened or potentiated by elevated systemic corticosteroid levels.   
In rat eyes, mineralocorticoid challenges have been shown to cause similar 
changes in the retina and choroid (choroidal vessel vasodilation, focal leakage, and 
increased choroidal thickness) as found in human patients with CSCR, suggesting that 
mineralocorticoids may play a role in potentiating CSCR.[1]  Eplerenone, a 
mineralocorticoid receptor antagonist, has been shown to be of visual and anatomic 
benefit in a small retrospective series of 4 patients with chronic CSCR, suggesting that 
decreasing mineralocorticoid action in the eye may improve signs and symptoms of 
CSCR.[1]  This data is enticing, and is the only current published evidence that 
eplerenone may be used to treat CSCR.  However, in their study, the investigators only 
evaluated patients with chronic CSCR, and did so in a retrospective and uncontrolled 
fashion in only 4 patients.[1] 
Our aim is to evaluate a standardized dose of eplerenone in a controlled 
prospective fashion for both acute and chronic CSCR.  We hypothesize that aldosterone 
inhibition with eplerenone will decrease choroidal vessel vasodilation, focal leakage, 
and choroidal thickness in patients with both acute and chronic CSCR, leading to 
resolution of subretinal fluid and ultimately an improvement in symptoms. Sub-retinal 
fluid can be precisely measured using optical coherence tomography (OCT), an imaging 
technique discussed below. 
 
Background: 
Epidemiology of CSCR 
Central Serous Chorioretinopathy (CSCR) is a disease of the choroid and retina 
that causes subretinal fluid to accumulate in the macula, the central and most important 
part of the retina.[2]  CSCR is the fourth most commonly observed disease in a typical 
clinical practice of retinal disorders, after macular degeneration, diabetic retinopathy, 
and retinal vein occlusion, and affects 1 in 10,000 individuals over their lifetime.[3]  
Because of the involvement of the macula, CSCR causes distortion and blurring of 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 2 of 23 
central vision.[2]  It is most commonly idiopathic in nature, although CSCR has been 
associated with both exogenous (e.g., anabolic or prescribed corticosteroids, intra-
articular corticosteroid injections, inhaled corticosteroids) and endogenous (e.g., 
Cushing’s disease, etc.) increases in serum corticosteroid levels.[4]  Systemic 
hypertension has also been associated with CSCR.[5]  CSCR has been associated with 
high stress, and is more common in men.[2,6]  CSCR typically affects people of middle-
age, although it can occur in patients younger than 20 and older than 60 as well.[7]  In 
the U.S., the disease is more common in Asian and Caucasian populations than in other 
racial groups.[8]   
 
Prognosis of CSCR 
There are two forms of the disease, acute CSCR and chronic CSCR.[8]  In the 
acute phase, there is rapid accumulation of subretinal fluid in the macula.  The fluid is 
then resorbed spontaneously, typically over 6-12 weeks.[8-11]  Importantly for our 
study, only about 20% of patients with acute CSCR have complete resolution of fluid on 
OCT by 1 month.  This was shown in randomized studies by Chan et al (4 of 19 
patients) and Ratanasukon et al (6 of 29 patients).[12,13]  Another study of 20 patients 
with acute CSCR showed the mean time to complete resolution of subretinal fluid on 
OCT was 65 days (range, 28–155).[14]  In our clinical experience at Tufts, 10% or less 
of patients have complete resolution of subretinal fluid on OCT by 1 month after 
presentation. 
Of note, even after fluid resorption, visual changes may still be reported by 
patients for several months after the initial episode.[15]  The definition of chronic CSCR 
has not been agreed upon, but most of the literature defines it as sub-retinal fluid lasting 
more than 3 months, or recurrence of the disease within 1 year.[8-12]  Chronic CSCR is 
also more likely to be bilateral, while acute CSCR more typically affects one eye at a 
time.  Approximately 30-50% of all CSCR patients have recurrences of the disease, 
either in the same eye, opposite eye, or both eyes.[8,12]  Patients with chronic CSCR 
can also develop intra-retinal fluid in addition to sub-retinal fluid. 
 
Pathophysiology of CSCR 
The pathophysiology of CSCR remains unclear, but recent studies using 
specialized imaging techniques have been helpful.  CSCR is thought to be caused by 
an underlying abnormality in vascular permeability in the choroidal vessels, leading to 
elevation of the retinal pigment epithelium (RPE) from Bruch’s membrane.  The 
separated RPE may then undergo tiny rips, leading to direct connection between the 
choroid and the subretinal space.  The RPE pump, which usually prevents accumulation 
of fluid under the retina, then dysfunctions or is overwhelmed, leading to build-up of 
serous fluid under the retina, the typical and characteristic feature of CSCR.[8,12]  The 
abnormality in choroidal circulation is often bilateral. A familial predisposition is 
occasionally observed, although no clearly-defined pattern of inheritance has been 
elucidated. 
 
Imaging in CSCR 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 3 of 23 
Specialized imaging techniques are typically used to diagnose and follow 
patients with CSCR.  Fluorescein angiography (FA) is the gold standard to diagnose the 
disease.  The most characteristic finding is an expanding point of fluorescein leakage 
under the neurosensory detachment of the macula, seen in approximately 90% of 
patients.[8]  Multiple points of leakage can be seen in some patients, particularly in 
chronic CSCR.[16]  FA can be used to direct focal laser photocoagulation treatment or 
photodynamic therapy (both discussed below).   
Optical coherence tomography (OCT) is also useful in diagnosing CSCR, and 
can be very helpful in monitoring disease activity over time.  OCT takes images of the 
macula in cross-section with very high resolution (~5 um), allowing precise visualization 
and quantification of retinal thickness and amount of subretinal fluid over time.  OCT 
can also demonstrate focal RPE detachments in patients with CSCR, in both affected 
and unaffected eyes.[17,18]  Special OCT imaging protocols, called Enhanced Depth 
Imaging (EDI), allow improved visualization of choroidal thickness, which has been 
shown to be significantly thicker in patients with CSCR than in age-matched 
controls.[19]  In patients with chronic CSCR, OCT can sometimes demonstrate 
intraretinal fluid in addition to subretinal fluid. 
Other specialized imaging modalities, such as indocyanine green angiography 
(ICGA) and fundus autofluorescence, can also be used to help with the diagnosis.[8]  
Fundus autofluorescence detects subtle changes in the RPE, which can be affected in 
characteristic patterns in CSCR.  ICGA highlights choroidal circulation, and can be 
particularly helpful for directing focal laser treatment or photodynamic therapy (both 
discussed below). 
 
Treatment of CSCR 
There have been few randomized trials looking at treatment of CSCR, and there 
is no gold standard for therapy.  Without treatment, many patients have spontaneous 
resolution of fluid within three months of diagnosis.  Focal laser photocoagulation has 
been used for treatment of some patients with acute CSCR.  Studies suggest that this 
can hasten fluid resorption and decrease the rate of recurrence, but does not alter long-
term visual prognosis.[20,21]  Laser can only be used if there’s a localized area of 
leakage on fluorescein angiography away from the center of the macula.  Laser burns 
almost always leave a retinal scar and can result in a permanent scotoma.  The scar 
can also lead to secondary formation of choroidal neovascularization.   Therefore, focal 
laser is only advisable in select patients.[8] 
Photodynamic therapy (PDT) is another type of laser treatment that was 
originally developed (and is FDA-approved) for neovascular age-related macular 
degeneration.  PDT involves injecting a light-activated dye, verteporfin, intravenously, 
and then directing a “cold” laser to the region of interest in the retina.  PDT offers a 
more directed treatment to the abnormal choroidal vessels, and can be targeted to the 
central macula as well as to multiple areas of leakage on fluorescein angiography.  PDT 
has been used successfully in treating both acute and chronic CSCR.[12,22,23]  In a 
randomized trial by Chan et al examining PDT for acute CSCR, 80% of patients (31 of 
39) had complete resolution of fluid in the PDT arm one month after treatment, versus 
20% of patients (4 of 19) in the control arm.[12]  A number of trials have used PDT in 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 4 of 23 
chronic CSCR, and the treatment seems to resolve fluid on OCT by one month in 50-
100% of patients.[8,22-26] 
However, PDT has a number of side effects, and it is not FDA-approved for the 
treatment of CSCR.  Side effects include RPE changes, choriocapillary hypoperfusion, 
and choroidal neovascular membrane development, as well as severe skin 
reactions.[23]  To decrease some of the ocular side effects, researchers have attempted 
to decrease the power of laser used; this is called “low-fluence” PDT.  Small 
comparative studies suggest that low-fluence PDT is as effective as standard-fluence 
PDT, with fewer ocular side effects.[25,26]  Most retina specialists now consider using 
low-fluence PDT for treatment of chronic CSCR. 
A number of other small studies have shown possible benefits from a variety of 
systemic medications for acute and/or chronic CSCR, including steroid hormone 
antagonists (ketoconazole, mifeprestone, eplerenone, finasteride),[1,27-29] adrenergic 
receptor antagonists (metoprolol, propranolol),[30,31] and carbonic anhydrase inhibitors 
(acetazolamide).[32]  The most promising results seem to be with steroid hormone 
antagonists: finasteride, mifeprestone, and eplerenone.  Eplenerone is of particular 
interest, as this medication does not have as many anti-testosterone side effects as the 
other two agents. 
 
Eplerenone for CSCR 
Eplerenone is a selective aldosterone-receptor antagonist that was originally 
approved by the FDA in 2002 for the treatment of hypertension, and was subsequently 
approved in 2003 for patients with congestive heart failure (CHF) after myocardial 
infarction.  Eplerenone is a derivative of spironolactone, a non-selective aldosterone-
receptor antagonist, and has 1 to 2 times the potency of spironolactone.  The most 
striking difference between the 2 drugs is in their affinity for androgen and progesterone 
receptors. Eplerenone has up to a 500-fold lower affinity for these receptors compared 
with spironolactone, which translates into a 3- to 10-fold decrease in progestogenic and 
antiandrogenic adverse effects.[33,34]   
 
In the vasculature, increased aldosterone (mineralocorticoid) levels can lead to 
increased inflammation, increased vascular reactive oxygen species, and decreased 
nitric oxide production.  These effects alter endothelial and smooth muscle in blood 
vessels, affecting the contractility properties of arteries, arterial tone, and blood 
pressure.[35]  In the retina, mineralocorticoid levels may affect both the choroidal and 
retinal circulations.  Zhao and colleagues recently demonstrated in rats that intravenous 
mineralocorticoid injection induced choroidal vessel dilation and leakage and increased 
choroidal thickness, findings that are similar to those found in patients with CSCR.[1]  
They postulated a potential benefit of mineralocorticoid inhibition in patients with CSCR.   
Zhao and colleagues then described encouraging results of eplerenone 
treatment in four patients with chronic CSCR.[1]  They gave two patients 25 mg of 
eplerenone daily for one week, followed by a higher dose of 50 mg daily for four weeks.  
The other two patients received 50 mg eplerenone for three months.  All four patients 
demonstrated complete resolution of subretinal fluid on OCT.  In addition, after five 
months of follow-up, none of the patients had a recurrence of fluid on OCT.  Similar 
results in about twenty patients have been reported to us by Peter Kaiser of the Cole 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 5 of 23 
Eye Institute at the Cleveland Clinic.[36]  He has used 25 mg daily eplerenone in 
patients with chronic CSCR, and noted that most patients demonstrated a positive 
response by four weeks. 
Eplerenone is a relatively safe medication, but it can lead to raised serum 
potassium levels (i.e., hyperkalemia), which can be potentially life-threatening.  In a 
large clinical trial of patients with CHF, the incidence of serious hyperkalemia, defined 
as a serum potassium concentration ≥6 mEq/L, was 5.5% in the eplerenone group and 
3.9% in the placebo group.  Patients with a lower creatinine clearance at baseline had a 
higher incidence of serious hyperkalemia.[37]   
Eplerenone comes in two doses, 25 mg and 50 mg.  The standard dose for 
treatment of hypertension is 50 mg daily.  For patients with an inadequate blood 
pressure response to 50 mg, the dosage is increased to 50 mg twice daily. For 
treatment of CHF, patients are started on 25 mg, and escalated to 50 mg within four 
weeks.  Dose adjustment in CHF patients takes place based on serum potassium levels 
as follows: <5.0 mEq/L – Increase to 50 mg once daily; 5.0–5.4 mEq/L – Maintain dose; 
5.5–5.9 mEq/L – Decrease to 25 mg every other day; ≥ 6.0 mEq/L – Withhold and 
restart at 25 mg every other day when potassium levels fall to <5.5 mEq/L.[38] 
The other notable side effects with aldosterone-receptor antagonist medications 
are related to cross-reactivity with sex hormone receptors.  Eplerenone has a much 
lower incidence of anti-sex hormone effects than spironolactone.  With eplerenone, sex 
hormone-related events, such as breast enlargement in men, breast pain, or menstrual 
abnormalities, have been reported in up to 2.5% of patients, although some studies 
reported no such events.[39-41]   
Because of the elevations in serum potassium concentrations and consequent 
increased risk for hyperkalemia with eplerenone, use of this drug is contraindicated in 
patients at increased risk for hyperkalemia, including those with a serum potassium 
concentration >5.5 mEq/L, type 2 diabetes and microalbuminuria, a serum creatinine 
concentration >2 mg/dL in men and >1.8 mg/dL in women, or a creatinine clearance 
<50 mL/min, and during concomitant administration of potassium supplements, 
potassium-sparing diuretics, and/or potent CYP3A4 inhibitors.[38]  It is recommended to 
check serum potassium and creatinine before initiating eplerenone therapy, followed by 
serum potassium within the first week and at one month after the start of treatment.[38]   
 
Part II 
 
Experimental Protocol: 
Study Design 
- 
Prospective, consecutive, non-randomized, non-blinded, non-comparative 
interventional pilot study 
- 
Eligible patients will be those who present with CSCR, both acute and chronic 
types 
- 
20 patients will be enrolled; participation is voluntary and all interested patients 
must provide written informed consent to take part in the study 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
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- 
Chronic CSCR will be defined as persistent subretinal fluid on OCT 3 months 
after initial presentation to the eye clinic, and <50% reduction in fluid thickness on 
OCT after 3 months.  
- 
Only one eye of a participant will be included in the study, although both eyes will 
be evaluated.  In patients with bilateral CSCR, the worse eye will be the study 
eye.   
- 
Patients will be evaluated and treated at the New England Eye Center (NEEC) 
- 
All participants will receive a standard ophthalmic examination as well as color 
fundus photographs, fluorescein angiography, and macular OCT (see below for 
specific imaging protocol).  
- 
Treatment will be the standard dose of eplerenone, 50 mg pills taken one pill 
dailyover four weeks  
- 
Subjects participation will include 4 visits to the NEEC:  
o Treatment initiation  
o 1 week after initiation 
o 2 weeks after initiation 
o 4 weeks after initiation   
- 
Prior to initiating treatment, all subjects will have laboratory testing to confirm 
healthy ranges of the following lab tests will include: serum potassium, creatinine, 
electrolytes, liver function tests, uric acid, and fasting cholesterol. 
- 
Serum potassium and creatinine levels will be re-tested at the 1 week visit. 
- 
All lab tests will be repeated at the 4 week visit  
- 
Blood pressure will be measured at each visit 
- 
A database of enrolled participants will be maintained on a password protected 
desktop computer at the New England Eye Center.   
- 
When the study is complete, all data will be de-identified and coded. 
 
Study Assessments/Schematic 
 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 7 of 23 
 
 
Initial Diagnosis and Enrollment 
1. In order to diagnose CSCR, patients typically undergo a routine ophthalmic 
examination, fundus photographs, fluorescein angiography, and OCT images. 
Patients may undergo fundus autofluorescence testing or indocyanine green 
angiography at the discretion of the physician to confirm the diagnosis of CSCR.  
These tests are done routinely in the eye clinic and are not included as part of 
the study protocol. 
 
2. Once a potential participant with CSCR is identified, he or she will be invited to 
participate in this study. Participation is voluntary; potential participants may 
refuse to participate in this study and their medical care will not be affected in any 
way.  Written informed consent will be obtained by one of the investigators, at the 
initial diagnosis visit.  If the patients wish, they can consider whether or not to 
enroll in the study, and enroll at a later date if they so choose.  If any non-English 
subjects are eligible for enrollment in the study, they will be enrolled using 
interpreters and IRB approved short forms as per the Tufts MC / TUHS IRB Short 
Form Policy.  The investigator will discuss and explain the study to the potential 
participant. Special care will be taken to avoid the possibility of coercion in 
soliciting volunteers. Informed consent documents will be kept on file at the New 
England Eye Center. Strict confidentiality will be observed for participant record 
information required for documenting study results. The participants will be 
informed that the study adheres to the Health Insurance Portability and 
Accountability Act (HIPAA) and participants will have the opportunity to ask 
questions about the study.  Understanding of the study will be assessed by the 
investigator or sub-investigator; the patient will be required to demonstrate a 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 8 of 23 
clear appreciation and understanding of the facts, implications, and future 
consequences of being enrolled in the study. 
 
3. Before enrollment, patients will be offered focal laser therapy and/or 
photodynamic therapy (PDT) if the physician feels this treatment may be 
warranted. Notably, there is no standard of care for either acute or chronic 
CSCR. It is unknown whether PDT may be more effective in treating CSCR if 
given sooner. In addition, prior authorization from medical insurance is needed 
for photodynamic therapy, and patients often have to wait a few weeks before 
PDT can be administered, therefore the process of prior authorization may be 
initiated concurrently to enrollment in this study if the physician feels PDT may be 
warranted after completion of the study. 
 
4. Screening Period: Prior to starting eplerenone therapy, there will be a screening 
period (1 week) when serum potassium and creatinine will be evaluated.  
Patients will be excluded if they have a serum potassium concentration ≥5.0 
mEq/L, a serum creatinine concentration >2 mg/dL in men and >1.8 mg/dL in 
women, or a creatinine clearance <50 mL/min, or during concomitant 
administration of potassium supplements, potassium-sparing diuretics, and/or 
potent CYP3A4 inhibitors (see below under Exclusion Criteria). Additional serum 
tests of electrolytes, liver function tests, uric acid, and a fasting cholesterol panel 
will be obtained before initiating therapy.  Although there are no exclusion criteria 
based on these additional laboratory tests, values will be compared to those after 
1 month of therapy and abnormalities will be included in safety outcome 
evaluation at the end of the study.  7.5 to 10 ml of blood will be collected at this 
visit, as well as a urine sample. 
 
5. Eplerenone is contraindicated in patients who have both type 2 diabetes and 
microalbuminuria. If a patient has type 2 diabetes, a urinalysis will be performed 
prior to starting treatment.  Patients with type 2 diabetes and microalbuminuria 
will be excluded from the study.  
 
Eplerenone is considered a pregnancy class B medication, which means that animal 
reproduction studies have failed to demonstrate a risk to the fetus and there are no 
adequate and well-controlled studies in pregnant women, or that animal studies have 
shown an adverse effect, but that adequate and well-controlled studies in pregnant 
women have failed to demonstrate a risk to the fetus in any trimester.  Women of 
child-bearing potential will be tested for pregnancy at during the initial screening 
testing, with a urine pregnancy test. 
Study Visits 
1. After the screening period, patients will come to the NEEC for the first official 
study visit, the “Treatment Initiation Visit”, which includes specific vision 
screening, blood pressure measurement, and OCT imaging as per study protocol. 
Patients will be given a bottle containing 28 tablets of eplerenone 50mg, and will 
start eplenerone the same day. Medication will be provided by the Tufts Research 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 9 of 23 
Pharmacy.  Patients will then return to the clinic at 1 week, 2 weeks, and 4 weeks 
after baseline. 
 
2. At baseline and all subsequent study visits, participants will be examined by an 
ophthalmologist at the NEEC using conventional techniques. The eye 
examination will include visual acuity testing using the ETDRS chart, extra-ocular 
motility, intraocular pressure measurement, and a routine slit lamp and dilated 
fundus examination. Manifest refraction will be performed at the baseline visit and 
at week 4. Pupils will be dilated with standard dilating drops given via one drop to 
both eyes one-half hour prior to eye examination). 
 
3. Visual Acuity: Best-corrected visual acuity is a secondary endpoint in this study.  
Refraction and testing of visual acuity will be standardized using the ETDRS 
protocol. Certified refractionists and visual acuity examiners will be used. 
Examination lanes will utilize a starting distance of 4 meters according to the 
ETDRS protocol. Refraction will be performed at the baseline visit and at 4 weeks. 
 
4. Optical Coherence Tomography (OCT): OCT images will be acquired at each 
visit. The ophthalmic photographers will be responsible for explaining how the 
non-invasive OCT images are obtained, as occurs with all of our patients 
routinely.  OCT will be obtained using a commercially available, FDA-approved 
system, the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). Both eyes will be 
scanned using an internal fixation point. The length of the test using Cirrus HD-
OCT is approximately 5 minutes per eye. Scan protocols capturing 1 to 5 images 
with high image definition from a focal location can be used for qualitative 
assessment of the retinal structure. A denser scan pattern, the macular cube 
scan, captures 128 512-line images within a 6 mm x 6 mm area centered on the 
macula, allowing calculation of retinal thicknesses and volumes with high 
precision. Scan protocols include: 
a. Cirrus HD-OCT 5 line raster scan 
b. Cirrus HD-OCT single line scan 
c. Cirrus HD-OCT 512x128 macular cube scan 
d. Cirrus HD-OCT Enhanced Depth Imaging (EDI) scan 
 
5. Fluorescein Angiography: Fluorescein angiography will be acquired at diagnosis 
and at 4 weeks after treatment initiation. Angiography will be explained to patients 
by either the physician or the ophthalmic nurse administering the intravenous dye. 
Patients routinely give verbal consent stating they understand the procedure and 
potential risks of fluorescein angiography. The procedure involved a special 
water-soluble dye (fluorescein) that is injected intravenously.  As the dye passes 
through the blood vessels of the choroid and retina, the photographer takes a 
series of photographs in rapid succession, over a period of 5-10 minutes. The 
possible side effects of fluorescein angiography are discussed below. 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
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Laboratory Testing: After initial screening, serum potassium and creatinine will be 
evaluated at 1 and 4 weeks after baseline. See below for dosing adjustment 
instructions based on potassium levels. Additional serum tests of electrolytes, 
liver function tests, uric acid, and a fasting cholesterol panel will be obtained 
before treatment and 4 weeks after baseline   
Baseline and 4-week visits: Serum potassium, sodium, BUN, creatinine, glucose, 
chloride, total CO2, calcium, AST, ALT, GGT, alkaline phosphatase, total and 
direct bilirubin, uric acid, albumin, total protein, fasting total cholesterol, fasting 
LDL, fasting LDL, fasting triglycerides.  The initial and final blood draws will  be 
roughly 7.5 to 10 ml of blood, or 2 teaspoons.   
 
6. 1-week visit: Serum potassium and serum creatinine.  The 1-week blood draws 
will be roughly 4 ml of blood, or 1 teaspoon.   
 
 
7. Blood pressure: Systolic and diastolic blood pressure will be recorded at all visits.  
Blood pressure will be measured in the seated position. When blood pressure is 
scheduled at the same time point as a blood sample draw, the blood pressure will 
be measured first. 
 
8. The subject’s participation in the research may be terminated by the principal 
investigator or co-investigator if there is any type of medical emergency or 
urgency that needs to be attended to first. If a subject decides to withdraw from 
the research, the patient will be offered routine ophthalmologic care at NEEC. If 
the patient prefers, he or she can be referred to an outside ophthalmologist for 
continued eye care.  The subject’s data and collected blood and urine samples 
will be discarded, although the reason for screen failure will be noted after the 
patient demographic data is de-identified. 
 
Eligibility  
 
Both male and female participants of any race will be enrolled.  
 
Inclusion Criteria: 
1. Age 18 or over 
2. Ability to give written informed consent 
3. Presence of sub-retinal fluid under the fovea as seen on OCT 
4. Diagnosis of Acute or Chronic CSCR: 
a. Acute CSCR: First presentation to eye clinic with visual symptoms, 
including decreased vision or visual distortion, and the characteristic 
appearance of CSCR on examination, fluorescein angiography, and 
OCT. 
b. Chronic CSCR: Previous diagnosis of CSCR, persistent subretinal fluid 
on OCT 3 months after initial presentation to the eye clinic, and <50% 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
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reduction in fluid thickness on OCT after 3 months.  Patients who have 
had previous treatment for CSCR may be included.   
 
Exclusion Criteria: 
1. Age less than 18 
2. Persons with impaired decision-making ability. 
3. Women who are known to be pregnant or are actively trying to conceive. 
4. Additional eye disease affecting the macula or posterior retina. 
5. At screening, serum potassium concentration ≥5.0 mEq/L, a serum creatinine 
concentration >2 mg/dL in men and >1.8 mg/dL in women, or a creatinine 
clearance <50 mL/min, and during concomitant administration of potassium 
supplements, potassium-sparing diuretics, and/or potent CYP3A4 inhibitors 
(amifostine, cyclosporine, fluconazole, itraconazole, ketoconazole, 
mifeprestone, posaconazole, potassium salts, Rituximab, 
tacrolimus,voriconazole, nefazodone, troleandomycin, clarithomycin, ritonavir, 
or nelfinavir). 
6. Patients with type 2 diabetes will be screened for microalbuminuria with a 
urinalysis. If microalbuminuria is present, these patients will be excluded. 
 
Data Elements 
The data elements to be collected from each participant include age, gender, visual 
acuity, intraocular pressure, lens status, and retinal examination findings, color fundus 
photographs, fluorescein angiography images, and OCT images. 
 
Primary Outcome 
Presence or absence of subretinal fluid and/or intraretinal fluid on OCT after 4 weeks of 
treatment with 50 mg of eplerenone. 
 
Secondary (Exploratory) Outcomes 
- 
Change in central macular circle thickness on OCT, automatically calculated with 
OCT software after 1, 2, and 4 weeks of treatment 
- 
Change in thickness of subretinal fluid under the fovea on OCT, manually 
calculated after 1, 2, and 4 weeks of treatment 
- 
Change in thickness of choroid under the fovea on enhanced-depth imaging 
OCT, manually calculated, after 1, 2, and 4 weeks of treatment 
- 
Change in best-corrected visual acuity before and after 4 weeks of treatment 
- 
Change in dye leakage characteristics on fluorescein angiography before and 
after 4 weeks of treatment 
- 
Change in the same OCT characteristics listed above, in the fellow eye 
- 
Proportion of acute vs. chronic CSCR patients 
- 
Safety and tolerability characteristics in this patient population via clinical 
laboratory data, blood pressure, and adverse events  
 
Data Safety and Monitoring Plan 
 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 12 of 23 
See below for details regarding monitoring of adverse events (AEs) and serious adverse 
events (SAEs). Data will be monitored with the patients’ safety in mind. All adverse 
effects will be recorded by the Principal Investigator and Co-Investigators and will be 
reported to the IRB at the conclusion of the study. Should an SAE occur, it will be 
reported immediately to the Tufts MC / TUHS IRB by the Principal Investigator within 24 
hours. The Principal Investigator and Co-Investigators will be responsible for collecting 
the patient data information. The information will then be de-identified and coded. The 
key to the code will only be accessed by the investigators. 
 
Dose adjustment and/or stopping criteria 
 
Serum potassium criteria 
If serum potassium is 5.0 mEq/L and <5.5mEq/L at 1 week after initiation, dosing will 
be decreased to 25 mg every day and serum potassium will be rechecked at 1 week. If 
serum potassium is still 5.0 mEq/L and <5.5mEq/L after 1 additional week, dosing will 
be decreased to 25 mg every other day and serum potassium will be rechecked at 1 
week. If serum potassium is still 5.0 mEq/L and <5.5mEq/L after 1 additional week, 
dosing will be withheld. If serum potassium is ≥ 5.5 mEq/L at 1 week, eplerenone will be 
withheld. 
 
See below for definition of adverse events and serious adverse events. 
 
Statistical Analysis 
 
The primary outcome will be described by the proportion of patients without subretinal 
fluid on OCT at the end of the study period (see below for sample size and precision 
estimates). The 95% confidence interval (CI) for this proportion will also be estimated. 
Descriptive statistics are considered appropriate for this pilot study since there is 
currently no standard treatment for CSCR, and the data from this study may be used to 
design future, rigorous trials of eplenerone. 
 
Changes in continuous secondary outcome measures will be described using mean, 
median, min/max, and standard deviations, and categorical secondary outcome 
measures will be described using frequencies and proportions. 
 
Sample Size and Precision Calculations 
The natural history of acute CSCR is to improve on its own. Studies have shown, 
however, that fluid resolution typically takes at least 6 weeks, and often takes as long as 
3 months or longer. In a randomized study by Chan et al examining effects of half-dose 
photodynamic therapy in patients with acute CSCR, 20% of patients had complete 
resolution of fluid on OCT after 4 weeks, compared to 80% of patients treated with 
PDT.[12] Similar rates of complete fluid resolution have been reported after treatment 
with PDT, as well as in a small sample of patients with chronic CSCR treated with 
eplerenone.[1, 22-26] Based on these assumptions, a calculation was performed to 
determine the width of confidence intervals for the proportion of patients successfully 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 13 of 23 
treated with eplerenone. If the treatment is effective for 70% of patients, a sample size 
of 10 patients will give a 95% confidence interval width of 0.586 that includes a lower 
bound of 0.348 (see range of widths with sample sizes of 10 and 15 below). The 
Research Design Center of the Clinical and Translational Sciences Institute at Tufts 
Medical Center assisted with these calculations. 
 
Numeric Results for Two-Sided Confidence Intervals for One Proportion Confidence 
Interval Formula: Exact 
 
References 
Fleiss, J. L., Levin, B., Paik, M.C. 2003. Statistical Methods for Rates and Proportions. 
Third Edition. John Wiley & Sons. New York. 
Newcombe, R. G. 1998. 'Two-Sided Confidence Intervals for the Single Proportion: 
Comparison of Seven Methods.'  Statistics in Medicine, 17, pp. 857-872. 
 
Safety Analysis 
Safety data will be presented in tabular format and will be summarized descriptively. 
 
PART III 
 
1. 
How will participants be recruited?  
Participants will be recruited from the practices of the primary investigator and 
co-investigators.  
 
2. 
Number of participants needed?  
The maximum number of participants over the entire study is expected to 
be 20. 
 
3. 
Will participants receive any payment or other compensation for participation?   
No. There are no costs to subjects participating in this research study and 
he or she will not be billed for the visit.  Eplerenone will be provided by the 
New England Eye Center. 
 
4. 
Will participants be studied outside NEEC premises?   
No.   
 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 14 of 23 
5. 
Will the facilities of the Clinical Research Center be used?   
No. 
 
6. 
Will drugs be used?   
Yes.  Eplerenone 50mg, an oral medication FDA-approved for use in 
systemic hypertension and congestive heart failure, will be used off-label 
for treatment of all patients in this study.  Patients will be provided the 
medication by the investigational team.  Funding is being provided by the 
Research Fund of the Ophthalmology Department at Tufts Medical 
Center. 
 
7. 
Will radiation or radioactive materials be employed?   
No. 
 
8. 
Will special diets be used?   
No. 
 
9. 
Will participants experience physical pain or stress?  
While some patients experience distorted vision as a result of CSCR, no 
additional physical distress to patients is expected as a result of this study. 
 
10. 
Will a questionnaire by used?   
No. 
 
11. 
Are personal interviews involved?   
No. 
 
12. 
Will participants experience psychological stress?   
No. 
 
13. 
Does this study involve planned deception of participants?   
No. 
 
14. 
Can information acquired through this investigation adversely affect a 
participant’s relationships with other individuals?   
No. 
 
15. 
Please explain how subjects’ anonymity will be protected, and/or 
confidentiality of data will be preserved.   
The data obtained from the study will be retained by Dr. Witkin and will be 
stored at NEEC for a minimum of 8 years per institutional policy.  
Members of the research study team including the principle and co-
investigators will analyze the data.  If results of this study are reported in 
medical journals or at meetings, subjects will not be identified by name, by 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 15 of 23 
recognizable photograph, or by any other means.  The subjects’ medical 
records will be maintained according to the NEEC requirements. 
 
Only the Primary investigators, Sub-investigators, and Clinical Research 
Coordinators will have access to research records.  Electronic and paper 
data may place subject confidentiality at risk.  To minimize or eliminate 
confidentiality risks, all study patients are communicated with in a private 
exam room, and all study data is coded and kept in locked file cabinets in 
the locked research room or on a password protected file on a computer 
which remains in the research room.  All study charts are de-identified and 
all data inputted is de-identified.  Research data, documents, reports, 
scans, and specimens, will only be shared amongst research team 
members.  No data will be sent out of Tufts.  Data will be recorded in study 
charts which are de-identified; no patient identifiers are listed on the chart.  
A numeric code will be assigned chronologically to each study patient.  
Research documents, files, and reports will be kept in the research office 
at the New England Eye center, on the 10th floor of the Biewend building.  
Files will be kept in the locked study file room in the eye department 
location at BD4.  Screen failure data will not be retained. 
 
PART IV 
 
A. 
Please summarize the risks to the individual subject, and the benefits, if any: 
 
Potential benefits: 
In acute CSCR, the benefit of participating in the study relates to the hypothetical 
hastened resolution of subretinal fluid and an associated improvement in visual 
symptoms and visual acuity.  In chronic CSCR, the benefit of participating in the study 
relates to the hypothetical resolution of subretinal and intraretinal fluid, and an 
associated improvement in visual symptoms and visual acuity. 
 
Potential risks and discomforts: 
Patients will be required to commit time for frequent visits to the eye clinic over the 
course of 4-5 weeks.  There will be 3 separate blood sample draws.  Ophthalmic 
imaging will be performed at each visit.  Fluorescein angiography will be performed at 
initial diagnosis and at the final visit. 
 
At each visit, patients may experience corneal irritation or drying.  This irritation may 
result from staring at the light in the OCT machines.  This side effect would be treated 
with artificial tears with essentially immediate relief.  There may be minor discomfort 
caused by the light associated with the OCT imaging procedure.  However, no pain or 
stress is expected as a result of the imaging. The light exposure for the OCT 
instruments is within documented safe limits set by the American National Standards 
Institute (ANSI).  Since these measurements are being performed optically, there is no 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
Page 16 of 23 
contact required with the eye itself.  All light exposures are kept within documented safe 
limits set by the American National Standards Institute (ANSI) for normal eyes.   
 
The risks associated with the intraocular drops for dilating the eyes are minimal.  These 
drops are used for all routine examinations by an ophthalmologist. The drops used to 
dilate the eye include tropicamide 1% and phenylephrine 2.5%.  Side effects of 
tropicamide include an increase in the pressure of the eye, stinging, dryness of the 
mouth, blurred vision, increased sensitivity to light, increased heart rate, headache, or 
allergic reaction.  Known side effects of phenylephrine include allergic reaction, irregular 
or fast heart rate, high blood pressure, burning, stinging, increased redness of the eye, 
tearing, blurred vision, headache, tremor, nausea, sweating, nervousness, dizziness, or 
drowsiness. Any of these symptoms would be managed according to standard protocol 
used in our office setting, as we use these drops on every patient undergoing a dilated 
eye examination. 
 
Phenylephrine, one of the standard eye drops used for pupil dilation, is considered a 
pregnancy class C drug, which means that animal reproduction studies have shown an 
adverse effect on the fetus but that there are no adequate and well-controlled studies in 
humans.  However, this eye drop is given routinely to patients in the office without a 
pregnancy test first, as well as to pregnant women who require a dilated eye 
examination, because the risk is felt to be minimal.   
 
Fluorescein angiography will be performed at diagnosis and 4 weeks after initiation of 
treatment.  Side effects will be discussed with each patient and verbal consent will be 
attained by treating physician and the photography department prior to performing this 
test for patients: 
- 
Typically, after the fluorescein dye has been injected the patient’s skin may 
appear yellow. This lasts for a period of several hours.  This discoloration 
disappears once the dye has been filtered out of the bloodstream by the kidneys. 
- 
Because the kidneys filter the dye from the bloodstream the patients’ urine will be 
a very bright yellow-orange color for 24-36 hours.   
- 
Approximately 20% of patients may experience nausea from the dye. This, 
however, usually passes within a minute.  
- 
If the dye happens to leak out of the blood vessel at the time of injection, the 
patient may feel a burning sensation and may also notice a yellow discoloration 
of the skin. These symptoms pass on their own.   
- 
Allergic reactions to fluorescein dye are rare. If they occur, they usually cause a 
skin rash and itching. This is usually treated with oral or injectable antihistamines, 
depending on the severity of the symptoms.   
- 
Less common severe allergic reactions are cardiorespiratory reactions such as 
low blood pressure or shortness of breath (~1 in 4000 persons).  Severe life-
threatening allergic reactions are very uncommon (~1 in 200,000 persons). 
 
Eplerenone is a potassium sparing diuretic, which is FDA approved to treat heart failure 
as well as high blood pressure, but is not FDA approved for treatment of central serous 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
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Protocol Version Dated: April 10th, 2013 
 
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chorioretinopathy. Eplerenone is considered a pregnancy class B medication, which 
means that animal reproduction studies have failed to demonstrate a risk to the fetus 
and there are no adequate and well-controlled studies in pregnant women, or that 
animal studies have shown an adverse effect, but adequate and well-controlled studies 
in pregnant women have failed to demonstrate a risk to the fetus in any trimester. The 
risks associated with the oral medication eplerenone are as follows:  
 
Eplerenone 50mg 
Serious side effects include: 
• Increased serum potassium 
• Increased serum cholesterol 
• Abdominal or stomach pain 
• Breast enlargement (men) 
• Arm, back, or jaw pain 
• Chest pain or discomfort 
• Chest tightness or heaviness 
• Confusion 
• Difficulty with breathing 
• Dizziness 
• Fast or irregular heartbeat 
• Headache 
• Irregular heartbeat 
• Large, hive-like swelling on the face, eyelids, lips, tongue, throat, hands, legs, 
feet, or sex organs 
• Nausea 
• Nervousness 
• Numbness or tingling in the hands, feet, or lips 
• Pain or discomfort in the arms, jaw, back, or neck 
• Rash 
• Shortness of breath 
• Sweating 
• Vomiting 
• Weakness or heaviness of the legs 
 
Less serious effects include:  
• Abnormal vaginal bleeding 
• Breast pain 
• Chills 
• Cloudy urine 
• Cough 
• Diarrhea 
• Fever 
• General feeling of discomfort or illness 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
Principal Investigator: Andre J. Witkin, MD 
Protocol Version Dated: April 10th, 2013 
 
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• Joint pain 
• Loss of appetite 
• Muscle aches and pains 
• Swelling of the breasts or breast soreness in both females and males 
• Unusual tiredness or weakness 
 
B. 
Detection and reporting of harmful effects: 
The primary investigator and/or site staff will be responsible for detecting, documenting, 
and reporting events that meet the definition of an adverse event (AE) or serious 
adverse event (SAE). 
 
AEs and SAEs will be collected from the time of informed consent into the study and 
until the last visit is completed.  Medical occurrences that begin prior to the start of 
eplerenone but after obtaining informed consent may be recorded.  Any unanticipated 
problems and AEs/SAEs will be reported as per the Tufts IRB’s unanticipated problem 
and adverse event reporting policy.   
 
Subjects will be told, verbally and in writing, that if they experience any post-procedure 
medical problems or have any questions, Dr. Witkin can be reached at (617) 636-7950 
during the day or paged through the hospital operator after hours.  If any medical 
problems occur in connection with this study, the NEEC will provide emergency care.  
 
Definition of Adverse Events (AEs) 
An AE is any untoward medical occurrence in a subject, temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
 
Events meeting the definition of an AE include: 
- 
Any abnormal laboratory test results or vital sign measurements, including those 
that worsen from baseline, and felt to be clinically significant in the judgment of 
the investigator 
- 
Exacerbation of a chronic or intermittent pre-existing condition 
- 
New conditions detected or diagnosed after the drug initiation visit, even though it 
may have been present prior to the start of the study 
- 
Signs, symptoms, or the clinical sequelae of a suspected interaction 
Events that do not meet the definition of an AE include: 
- 
Any clinically significant abnormal laboratory or vital sign findings that are 
associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the subject’s condition 
- 
Progression of the disease being studied, unless more severe than expected for 
the subject’s condition 
- 
Anticipated day-to-day fluctuations of pre-existing diseases or conditions present 
or detected at the start of the study that do not worsen 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
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Protocol Version Dated: April 10th, 2013 
 
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Definition of Serious Adverse Events (SAEs) 
If an event is not an AE as defined above, then it cannot be an SAE even if serious 
conditions are met.  An SAE is any untoward medical occurrence that: 
- 
Results in death 
- 
Is life-threatening: An event in which the subject was at risk of death at the time 
of the event, not an event which might hypothetically have cause death if it was 
more severe 
- 
Requires hospitalization: Hospitalization signifies that the subject was detained at 
the hospital for observation and/or treatment that would not have been 
appropriate in the outpatient setting.  Hospitalization for elective treatment of a 
pre-existing condition that did not worsen from baseline is not considered an AE. 
- 
Results in disability/incapacity: Substantial disruption of a person’s ability to 
conduct normal life functions.  This is not intended to represent minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma, which may interfere with everyday life but do 
not cause a substantial disruption. 
- 
Results in a congenital anomaly/birth defect 
- 
Is associated with elevation of serum potassium defined as a serum potassium 
level 6.0 mEq/L at any time-point after initiation of eplerenone therapy 
- 
May jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the other outcomes listed above 
 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
questions are the preferred method to inquire about AE occurrence.  Appropriate 
questions include: 
- 
How are you feeling? 
- 
Have you had any (other) medical problems since your last visit? 
- 
Have you taken any new medications, other than eplerenone, since your last 
visit? 
 
Recording of AEs and SAEs 
When an AE/SAE occurs, it is the responsibility of the Primary Investigator to review all 
documentation relative to the event.  The Primary Investigator will then record all 
relevant information regarding an AE/SAE.  The investigator will attempt to establish a 
diagnosis of the event based on signs, symptoms, and/or other clinical information. The 
investigator is obligated to assess the relationship between the investigational 
medication and the occurrence of each AE/SAE.  The investigator will make an 
assessment of intensity for each AE and SAE reported during the study and will assign 
it to one of the following categories: 
- 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with daily activities 


Eplerenone for Central Serous Chorioretinopathy: A Pilot Study 
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Protocol Version Dated: April 10th, 2013 
 
Page 20 of 23 
- 
Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities 
- 
Severe: An event that prevents normal everyday activities 
An AE that is assessed as severe will not be confused with an SAE.  Severity is a 
category utilized for rating the intensity of an event, and both AEs and SAEs can be 
assessed as severe.  
 
Reporting of SAEs 
Any unanticipated problems and AEs/SAEs will be reported as per the Tufts IRB’s 
unanticipated problem and adverse event reporting policy.  If the investigator does not 
have all the information regarding the SAE, he/she will not wait to receive additional 
information before notifying the IRB of the event.


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Protocol Version Dated: April 10th, 2013 
 
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