Clinical trial NCT04356716
Conditions: Choroidal Ischemia Vitelliform Macular Dystrophy Age-related Macular Degeneration Central Serous Retinopathy Retinitis Pigmentosa
Keywords: Sildenafil Viagra Revatio
Sponsor: Columbia University
Start date: 2014-11-11; Completion date: 2020-02-18
Enrollment: 22 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The hypothesis of this study is to determine if there is a benefit afforded by the use of systemic Sildenafil to patients with choroidal and retinal degenerations and dystrophies, such as vitelliform degeneration, dry and reticular age-related macular degeneration (AMD) as well as patients with hereditary and acquired retinal dystrophies such as retinitis pigmentosa and central serous retinopathy.

Detailed description:
Age-Related Macular Degeneration (AMD) is a sight-threatening visual disturbance that affects the macula in older ages. It is irreversible if the pigment epithelium is lost (dry AMD), but wet AMD can be arrested or delayed with the use of intraocular injections of one of 3 different compounds. All three drugs are injected into the eye in minute doses of usually 0.1 ml. These are usually injected at 4 to 6 week intervals and treatment may be extended for several years. Different patterns of injection times are followed but usually are monthly for 12 or more months, or monthly for 3 months and then extended observation at one to two month intervals unless vision (visual acuity) declines or Optical Coherence Tomography-angiography (OCT-A) shows recurrence of fluid or increase in size or amount of drusen (deposits of lipofuscin) in the retina. Vitelliform macular degeneration is a disorder that causes visual loss due to drusen in the macula, which have been shown to be identical to the deposits seen in macular degeneration. The goal of therapy in this proposal is to use sildenafil to increase choroidal blood flow to treat dry AMD and slow the progression of visual loss in vitelliform and age-related dry AMD as well as other macular, retinal and choroidal degenerations and dystrophies, as well as reduce or eliminate the number of injections required by slowing down transformation of dry AMD to wet AMD in treated patients.

Arms: arm 1: Medical record review for participants that are prescribed Sildenafil off-label as part of standard of care treatment for disease. arm 2: Participants are prescribed sildenafil 40-80 mg daily.
Interventions: intervention 1: Sildenafil intervention 2: Standard of Care Sildenafil intervention 3: Ocular Coherence Tomography-Angiography (OCT-A) intervention 4: Visual Acuity (VA)
Intervention descriptions: intervention 1: Initial Sildenafil dosage will be weight dependent. Participants will start at 40 mg daily (20mg in the morning, 20 mg in the evening) or 60 mg daily (40mg in the morning and 20 mg in the evening). Sildenafil dosage may be increased to up to 80mg daily (20-40mg in the morning and 20-40mg in the evening) based on the response to lower doses. If the participant has not had improvement after initial treatment, the dose may be increased, at the discretion of the study physician. intervention 2: Medical record review of participants that receive Sildenafil as part of standard of care. intervention 3: Retinal photographs will be taken at each study visit. intervention 4: Visual acuity will be measured with Snellen Eye Chart at each study visit.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
Sildenafil for Treatment of Choroidal Ischemia 
 
 
 
NCT04356716 
April 8, 2020 
 
 


BACKGROUND 
 
Research Aims & Abstracts 
The hypothesis of our study is to determine if there is a benefit afforded by the use of 
systemic Sildenafil to patients with choroidal and retinal degenerations and dystrophies, such as 
vitelliform degeneration, dry and reticular AMD as well as patients with hereditary and acquired 
retinal dystrophies such as retinitis pigmentosa and central serous retinopathy. We theorize that 
Sildenafil will enhance choroidal perfusion and slow the progression of dry and reticular AMD, as 
well as vitelliform degneration, and the associated decrease in vision, as well as reduce the 
frequency of intraocular injections of anti-VEGF medications. In addition, in patients with 
acquired retinal conditions such as central serous retinopathy we theorize that sildenafil will 
enhance resorption of sub-retinal fluid. 
We have shown that choroidal insufficiency is one of the causes of macular degeneration. 
Vitelliform degeneration has been shown to have deposits in the macula that are the same as those 
in AMD. We have, in a small, off-label series of patients, found that Sildenafil, the generic form 
of Viagra, can increase choroidal perfusion, and possibly delay or ameliorate AMD, and it should 
have a similar effect in retinal degenerations and dystropies or other choroidal degenerative 
conditions. The drug being offered is Sildenafil similar to the dosage used to treat other diseases 
such as pulmonary hypertension. The only contraindication that we are aware of is that it cannot 
be used on patients taking nitrates for heart disease. 
 
Study Purpose and Rationale 
Age-Related Macular Degeneration (AMD) is a sight-threatening visual disturbance that 
affects the macula in older ages. It is irreversible if the pigment epithelium is lost, but wet AMD 
can be arrested or delayed with the use of intraocular injections of 3 compounds at this time: 
1. Avastin: an anti-VEGF (Vascular Endothelial Growth Factor) drug used in ophthalmic 
off-label use for AM, manufactured by Genentech 
2. Lucentis: an Anti-VEGF drug with FDA approval also by Genentech. 
3. Eyela: a VEGF trap drug developed by Regeneron. 
All three drugs are injected into the eye in minute doses of usually 0.1 mL. These are 
usually injected at 4 to 6 week intervals and treatment may be extended for several years. Different 


patterns of injection times are followed but usually are monthly for 12 or more months, or monthly 
for 3 months and then extended observation at monthly intervals unless vision declines or OCT 
shows recurrence of fluid in the retina. Vitelliform macular degeneration is a disorder that causes 
visual loss due to deposits of liopfuscin in the macula, which have been shown to be identical to 
the deposits seen in macular degeneration. The goal of therapy in our proposal is to reduce or 
eliminate the number of injections by slowing down transformation of dry to wet AMD in treated 
patients, or to slow progression of visual loss in vitelliform and age-related dry AMD as well as 
other macular, retinal and choroidal degenerations and dystrophies. Sight preservation is the 
ultimate goal, using a systemic drug that reduces the need for injections where indicated. 
We wish to continue a study of the effects of PDE-5 and PDE-6 inhibitor drugs such as 
Sildenafil (Viagra) on the choroid, which we have shown to be ischemic in most dry age-related 
macular degeneration (AMD) (BJO 2013). We have also shown that Sildenafil (Viagra) can 
increase both choroidal thickness and perfusion in normal subjects. Sildenafil is used in medicine 
to increase blood flow in such diseases as pulmonary hypertension and Reynaud's disease. The 
only contraindication of these anti-VEGF drugs is the concomitant use of nitrates, as it could lower 
blood pressure. 
A small off-label clinical series of patients with AMD (four patients) has indicated a 
beneficial result in two areas: a longer time between injections of Lucentis for AMD and increased 
contrast sensitivity. In addition, one patient had rapid resolution of subretinal drusen material. 
Thus, a reduced requirement for injections for wet AMD and heightened or brighter environmental 
viewing are possible. In dry AMD we are hoping for delay of conversion to the wet form and 
possibly reduction of drusen in dry AMD. 
We plan to study the results for Sildenafil 20 - 40 mg orally two times a day (a dosage used 
in treating pulmonary hypertension) in treating vitelliform degeneration or dry AMD, including 
patients who have had wet AMD in the fellow eye. A small cohort of patients who have a form of 
dry AMD termed Reticular AMD will also be studied. This form of AMD has small drusen that 
present as "pox-like" finely scattered drusen that can progress to AMD. Patients with Reticular 
AMD offer the advantage of small lipid volume and thus are a potentially easier group to quantify 
resolution using a PDE-5 and PDE-6 inhibitor such as Sildenafil. In addition, we will include other 
degenerative diseases of the choroid and retina as well as hereditary and acquired retinal 


dystrophies, such as central serous retinopathy and retinitis pigmentosa, that may benefit from 
increased choroidal blood flow. 
 
Study Design 
Patients will be enrolled to receive Sildenafil as part of the study. We will also review 
records of patients who are receiving Sildenafil as part of their standard of care. The study will 
enroll up to 25 patients with dry AMD, reticular AMD or a combination of wet and dry AMD as 
well as other macular, retinal and choroidal degenerations and dystrophies. The visual acuity and 
ocular coherent tomography (OCT) evaluation will be performed as noted under study procedures. 
We plan to continue the study until up to 25 patients have completed five years of follow-up. This 
will include patients who are receiving Sildenafil as part of the study and patients who receive 
Sildenafil for standard care whose charts will be reviewed. 
Criteria of visual acuity and number of Lucentis (or other anti-VEGF drugs) injections will 
be monitored and compared with well documented studies using Lucentis or Avastin or Eylea. 
OCT and ultrasound measurement of drusen change will be performed and quantified by size and 
number of drusen. 
Patients referred for diagnosis and treatment of AMD as well as other macular, retinal and 
choroidal degenerations and dystrophies in the practices of Columbia Ophthalmology doctors will 
be offered inclusion in the study if they have drusen and normal vision in at least one eye. In the 
course of the study, measurements of vision and Optical Coherence Tomography (OCT). Fundus 
photography will also be performed at initial exam and if changes are noted on OCT or clinical 
exam. Visual acuity will be measured. 
Systemic Sildenafil will be prescribed for twice a day use. Initial Sildenafil dosage will be 
weight dependent. Patients will start at 40 mg daily (20 mg in the morning, 20 mg in the evening) 
or 60 mg daily (40 mg in the morning and 20 mg in the evening). The patient will be followed 
monthly or bi-monthly as is usual. Sildenafil dosage may be increased to up to 80mg daily (20-
40mg in the morning and 20-40mg in the evening) based on the response to lower doses. If the 
subject has not had improvement after initial treatment, their dose may be increased, at the 
discretion of the study physician. 
Visual acuity along with OCT will be performed at each visit. If available, ultrasound 
perfusion measurements will be performed within approximately 6 months of starting medication 


and approximately 12 months after starting medication. Patients will be treated with Sildenafil 
only if they choose to enroll in the study. 
Patients with AMD will continue to take sildenafil until otherwise directed. Patients with 
retinal dystrophies and degenerations will take sildenafil until otherwise directed. Patients with 
central serous retinopathy and other dystrophies with fluid-filled structures will stop one month 
after OCT testing shows a resorption of fluid from ocular structures. If the fluid-filled structures 
return, we may restart sildenafil treatment after observing these structures on OCT. 
 
STATISTICAL PROCEDURES 
 
Statistical evaluation will be provided for data using a standard T-test. Patients will be 
asked to participate for a period of up to 5 years. Results are deterministic, either drusen will 
improve or they will not. Secondly, the period between injections for wet AMD will be extended 
or not, compared to the standard treatment protocol. Improvement or maintenance from baseline 
of visual acuity, contrast sensitivity and OCT and fundus appearance are the end points.