Ignite Creation Date:
2024-05-06 @ 9:36 AM
Last Modification Date:
2024-10-26 @ 12:16 PM
Study NCT ID:
NCT03022318
Status:
COMPLETED
Last Update Posted:
2020-12-11
First Post:
2017-01-12
Brief Title:
Carbidopa-levodopa in Neovascular AMD
Sponsor:
Snyder Robert W MD PhD PC
Organization:
Snyder Robert W MD PhD PC
Study Overview
Official Title:
Short Term Effects of Carbidopa-levodopa in Neovascular AMD
Status:
COMPLETED
Status Verified Date:
2020-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
From 3 large patient databases patients diagnosed with AMD who have never taken levodopaL-DOPA containing medications have a mean age of diagnosis at 71 years Patients who have been treated with L-DOPA containing medications have a mean age of diagnosis of AMD at 79 years
L-DOPA binds to GPR143 in the retinal pigment epithelium and releases PEDF which protects the retina and downregulates VEGF which is the cause of neovascularization
The Investigators will evaluate the safety and tolerability of carbidopa-levodopa in patients with Neovascular AMD and measure the effects on visual acuity and retinal abnormalities due to wet neovascular AMD
L-DOPA binds to GPR143 in the retinal pigment epithelium and releases PEDF which protects the retina and downregulates VEGF which is the cause of neovascularization
The Investigators will evaluate the safety and tolerability of carbidopa-levodopa in patients with Neovascular AMD and measure the effects on visual acuity and retinal abnormalities due to wet neovascular AMD
Detailed Description:
Age-related macular degeneration AMD is the most common cause of blindness in individuals over the age of 50 in the developed world AMD becomes more common as people age and is more common in lightly pigmented individuals AMD appears more common in patients with Parkinsons Disease than in those without The AREDS nutritional supplements are effective in slowing the progress of intermediate AMD5 Most AMD is dry AMD which progresses relatively slowly and may impair vision but usually does not lead to legal blindness There are two forms of AMD wet AMD and geographic atrophy GA that can cause more profound vision loss In aggregate they occur in about 25 patients with AMD Wet AMD is due to new growth of abnormal blood vessels under the retina The new blood vessels are believed to be due to an excessive release of vascular endothelial growth factor VEGF by the retinal pigment epitheliumRPE cells Wet AMD is now effectively treated with intraocular injections of VEGF inhibitors Geographic Atrophy the other form of advanced AMD represents focal death of the RPE cells and overlying neurosensory retina There is no current treatment for GA It is suspected that GA is due in part to a localized inflammatory response damage to RPE cells and loss of RPE cell function It may also be speculated that stimulation of RPE cells to release a potent neurotrophic factor pigment epithelium derived factor PEDF may slow progression of GA
In 2008 Dr Brian McKay identified a receptor G protein coupled receptor 143GPR143 on the surface of RPE cells and discovered that L-DOPA was the natural ligand or stimulator of GPR143 Dr McKay showed that treatment of RPE cells with exogenous L-DOPA resulted in the release of additional PEDF In subsequent work Dr McKays group also showed that L-DOPA stimulation of PEDF in RPE cells was also associated with a decrease in VEGF Thus Dr McKay hypothesized that exogenous L-DOPA may prevent the onset of AMD or progression to wet AMD
In 2015 Dr McKay and his associates published a paper that showed that patients who had been treated with L-DOPA had a delay in the onset of AMD by 8 years compared to patients who had not been treated with L-DOPA In addition those who had AMD and went on to develop wet AMD did so 5 years later than those with no history of L-DOPA treatment L-DOPA is an intermediate in the pigmentation pathway Dr McKay and his associates suggested that the reason darkly pigmented races do not get AMD nearly as frequently as lighter pigmented races is that they produce more pigment and thus more L-DOPA to stimulate GPR143 on RPE cells According to this hypothesis the stimulated RPE cells release PEDF and decrease VEGF which together are responsible for the protective effect
Since there are no established animal models for AMD and L-DOPA has a good safety profile in healthy volunteers and patients with Parkinsons disease the Investigators propose a prospective experiment to determine the safety and tolerability of L-DOPA in a population of patients with AMD The participants will be made aware of potential side effects of L-DOPA which are listed in the Informed Consent during the consent process Adverse events will be elicited by questioning the participants at each visit The participants will also be advised to call the site if they have any medical problem between visits
The Investigators will also use this study to examine whether L-DOPA has a positive effect on visual acuity and pathologic retinal changes of wet AMD The parameters to be evaluated are best corrected ETDRS visual acuity macular thickness by spectral domain optical coherence tomography SD OCT new blood hemorrhage by direct retinal examination or subjective decrease in vision
Pharmacology of L-DOPA and carbidopa
L-DOPA is formed by 3-hydroxylation of tyrosine by tyrosine-3-monooxygenase tyrosinase18 The primary metabolic pathway of L-DOPA is decarboxylation by amino acid decarboxylase to dopamine which is responsible for most but not all of its pharmacologic effects and toxicity When carbidopa is administered with L-DOPA systemic levels of L-DOPA double and central nervous system CNS L-DOPA increases from about 1 of the administered dose to about 4 Levodopa freely passes from the systemic circulation into the retina and brain but dopamine and carbidopa do not Adverse events are markedly decreased when carbidopa is administered with L-DOPA because systemic levels of the toxic metabolite of L-DOPA dopamine are markedly reduced In most patients 25 mg of carbidopa is sufficient to control side effects of 100 mg of L-DOPA primarily nausea by 90
L-DOPA is the natural ligand for GPR143 in the RPE cells The Investigators intent is to increase the L-DOPA available to RPE surface receptors GPR 143 while minimizing peripheral toxicity This concept is unique because all other uses of L-DOPA rely on CNS conversion of L-DOPA to dopamine in order to produce the desired effect
Excess VEGF is the mediator of the retinal neovascularization and other retinal pathological changes in wet AMD Intraocular injections of anti-VEGF antibodies is the standard of care in Wet AMD Several publications including Lim et al show that with careful monitoring of the visual acuity and retinas of patients with wet AMD if there is no progression there are no long-term adverse consequences of delaying initiation of anti-VEGF therapy for up to 4 weeks The patients will be monitored at weekly intervals for up to 4 weeks for indications for initiation of anti-VEGF injections
Criteria for anti-VEGF injections
This will be based on weekly evaluation of ETDRS visual acuity decrease of 5 letters from previous visit increased macular thickness compared to normal and previous visit as measured by OCT new blood hemorrhage on direct retinal examination or subjective decrease in vision If any of these criteria are met or if in the opinion of the Ophthalmologist the patient requires anti-VEGF therapy the patient will have an anti-VEGF intraocular injection If none of these criteria are met at visits 2 3 or 4 with patient agreement anti-VEGF injection will not be done and the patient will be reevaluated in 1 week The patients will receive an anti-VEGF injection at the end of the 4th week if they have not received one earlier Whenever a patient receives the first anti-VEGF injection participation in this protocol will end At that point the patient will be able to enroll in Study 0002 Proof of Concept and Dose Ranging Study of carbidopa-levodopa in Neovascular AMD
Treatments
Randomized assignment to carbidopa-levodopa 25-100 mg tablets dosed hs or carbidopa-levodopa 25-100 mg tablets dosed 3 times daily in the morning with supper and hs The second dosing regimen is the equivalent of a moderate dose of carbidopa-levodopa in patients with Parkinsons disease maximum daily dose of levodopa 200-800 mg
Number of participants Up to 52 completed randomized using a table of random numbers
Informed Consent will be completed at the first visit Duration up to 32 days of treatment Visits will occur at 5-8 day intervals Overall trial duration for enrollment and treatment screening 5 patients per week will be approximately 10 months
Primary Endpoint A statistically significant improvement 5 letters by carbidopa-levodopa treatment in ETDRS visual acuity
Measurements
Demographics at Visit 1 Medical History and Physical Examination at Visit 1 ElectrocardiogramECG complete blood countCBC Chem 20 and HbA1C at Visit 1 Vital signs at Visits 1234 and 5 Non-directed assessment of adverse events at Visits 1234 and 5 SD OCT at Visits 12345 Pill count at Visits 234 and 5
Statistics Analysis of Variance with Independent Variables for each arm and comparing arms
ETDRS visual acuity central retinal macular thickness presence of hemorrage and duration of treatment prior to initiation of anti VEGF intraocular injections
In 2008 Dr Brian McKay identified a receptor G protein coupled receptor 143GPR143 on the surface of RPE cells and discovered that L-DOPA was the natural ligand or stimulator of GPR143 Dr McKay showed that treatment of RPE cells with exogenous L-DOPA resulted in the release of additional PEDF In subsequent work Dr McKays group also showed that L-DOPA stimulation of PEDF in RPE cells was also associated with a decrease in VEGF Thus Dr McKay hypothesized that exogenous L-DOPA may prevent the onset of AMD or progression to wet AMD
In 2015 Dr McKay and his associates published a paper that showed that patients who had been treated with L-DOPA had a delay in the onset of AMD by 8 years compared to patients who had not been treated with L-DOPA In addition those who had AMD and went on to develop wet AMD did so 5 years later than those with no history of L-DOPA treatment L-DOPA is an intermediate in the pigmentation pathway Dr McKay and his associates suggested that the reason darkly pigmented races do not get AMD nearly as frequently as lighter pigmented races is that they produce more pigment and thus more L-DOPA to stimulate GPR143 on RPE cells According to this hypothesis the stimulated RPE cells release PEDF and decrease VEGF which together are responsible for the protective effect
Since there are no established animal models for AMD and L-DOPA has a good safety profile in healthy volunteers and patients with Parkinsons disease the Investigators propose a prospective experiment to determine the safety and tolerability of L-DOPA in a population of patients with AMD The participants will be made aware of potential side effects of L-DOPA which are listed in the Informed Consent during the consent process Adverse events will be elicited by questioning the participants at each visit The participants will also be advised to call the site if they have any medical problem between visits
The Investigators will also use this study to examine whether L-DOPA has a positive effect on visual acuity and pathologic retinal changes of wet AMD The parameters to be evaluated are best corrected ETDRS visual acuity macular thickness by spectral domain optical coherence tomography SD OCT new blood hemorrhage by direct retinal examination or subjective decrease in vision
Pharmacology of L-DOPA and carbidopa
L-DOPA is formed by 3-hydroxylation of tyrosine by tyrosine-3-monooxygenase tyrosinase18 The primary metabolic pathway of L-DOPA is decarboxylation by amino acid decarboxylase to dopamine which is responsible for most but not all of its pharmacologic effects and toxicity When carbidopa is administered with L-DOPA systemic levels of L-DOPA double and central nervous system CNS L-DOPA increases from about 1 of the administered dose to about 4 Levodopa freely passes from the systemic circulation into the retina and brain but dopamine and carbidopa do not Adverse events are markedly decreased when carbidopa is administered with L-DOPA because systemic levels of the toxic metabolite of L-DOPA dopamine are markedly reduced In most patients 25 mg of carbidopa is sufficient to control side effects of 100 mg of L-DOPA primarily nausea by 90
L-DOPA is the natural ligand for GPR143 in the RPE cells The Investigators intent is to increase the L-DOPA available to RPE surface receptors GPR 143 while minimizing peripheral toxicity This concept is unique because all other uses of L-DOPA rely on CNS conversion of L-DOPA to dopamine in order to produce the desired effect
Excess VEGF is the mediator of the retinal neovascularization and other retinal pathological changes in wet AMD Intraocular injections of anti-VEGF antibodies is the standard of care in Wet AMD Several publications including Lim et al show that with careful monitoring of the visual acuity and retinas of patients with wet AMD if there is no progression there are no long-term adverse consequences of delaying initiation of anti-VEGF therapy for up to 4 weeks The patients will be monitored at weekly intervals for up to 4 weeks for indications for initiation of anti-VEGF injections
Criteria for anti-VEGF injections
This will be based on weekly evaluation of ETDRS visual acuity decrease of 5 letters from previous visit increased macular thickness compared to normal and previous visit as measured by OCT new blood hemorrhage on direct retinal examination or subjective decrease in vision If any of these criteria are met or if in the opinion of the Ophthalmologist the patient requires anti-VEGF therapy the patient will have an anti-VEGF intraocular injection If none of these criteria are met at visits 2 3 or 4 with patient agreement anti-VEGF injection will not be done and the patient will be reevaluated in 1 week The patients will receive an anti-VEGF injection at the end of the 4th week if they have not received one earlier Whenever a patient receives the first anti-VEGF injection participation in this protocol will end At that point the patient will be able to enroll in Study 0002 Proof of Concept and Dose Ranging Study of carbidopa-levodopa in Neovascular AMD
Treatments
Randomized assignment to carbidopa-levodopa 25-100 mg tablets dosed hs or carbidopa-levodopa 25-100 mg tablets dosed 3 times daily in the morning with supper and hs The second dosing regimen is the equivalent of a moderate dose of carbidopa-levodopa in patients with Parkinsons disease maximum daily dose of levodopa 200-800 mg
Number of participants Up to 52 completed randomized using a table of random numbers
Informed Consent will be completed at the first visit Duration up to 32 days of treatment Visits will occur at 5-8 day intervals Overall trial duration for enrollment and treatment screening 5 patients per week will be approximately 10 months
Primary Endpoint A statistically significant improvement 5 letters by carbidopa-levodopa treatment in ETDRS visual acuity
Measurements
Demographics at Visit 1 Medical History and Physical Examination at Visit 1 ElectrocardiogramECG complete blood countCBC Chem 20 and HbA1C at Visit 1 Vital signs at Visits 1234 and 5 Non-directed assessment of adverse events at Visits 1234 and 5 SD OCT at Visits 12345 Pill count at Visits 234 and 5
Statistics Analysis of Variance with Independent Variables for each arm and comparing arms
ETDRS visual acuity central retinal macular thickness presence of hemorrage and duration of treatment prior to initiation of anti VEGF intraocular injections
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None