Ignite Creation Date:
2024-05-06 @ 9:37 AM
Last Modification Date:
2024-10-26 @ 12:16 PM
Study NCT ID:
NCT03023059
Status:
COMPLETED
Last Update Posted:
2020-12-11
First Post:
2017-01-13
Brief Title:
Dose Ranging Study of Carbidopa-levodopa
Sponsor:
Snyder Robert W MD PhD PC
Organization:
Snyder Robert W MD PhD PC
Study Overview
Official Title:
Proof of Concept and Dose Ranging Study 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
The Investigators will evaluate the safety and tolerability of carbidopa-levodopa in patients with Neovascular AMD who are already on treatment with anti-VEGF intraocular injections and measure the effects on visual acuity retinal abnormalities due to wet AMD and document the number of anti-VEGF injections required during the study
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
The Investigators will evaluate the safety and tolerability of carbidopa-levodopa in patients with Neovascular AMD who are already on treatment with anti-VEGF intraocular injections and measure the effects on visual acuity retinal abnormalities due to wet AMD and document the number of anti-VEGF injections required during the study
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
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
Pathogenesis of Neovascular AMD
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 all have had anti-VEGF therapy initiated The patients will be monitored at monthly intervals for up to 3 months for indications for administration of anti-VEGF injections
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
Treatments
Patients will receive open label commercially available carbidopa-levodopa 25-100 mg one tablet once daily hs for one month followed by one tablet dosed TID three times daily in the morning with supper and hs for one month followed by two tablets dosed three times daily in the morning with supper and hs for one month 100-600 mg of levodopa daily This is the equivalent of very low to moderate doses of carbidopa-levodopa in patients with Parkinsons disease daily dose of levodopa 200-800 mg Patients entering this study after completing Study 001 will receive one month of the dose that he or she received in Study 001 and one month each of any doses higher than the dose that he or she received in Study 001
Examples
1 If the patient received carbidopa-levodopa 25-100 mg once daily in Study 001 he or she will receive one month of treatment with each of the 3 daily doses of carbidopa-levodopa
2 If the patient received carbidopa-levodopa 25-100 mg TID in Study 001 he or she will receive one month of carbidopa-levodopa 25-100 mg TID followed by one month of carbidopa-levodopa 25-100 mg 2 tablets TID
Each patient will receive an injection of anti-VEGF medication on the day carbidopa-levodopa dosing begins in this study Each patient will be evaluated at monthly 25-35 day intervals and injected or not based upon the criteria listed below which are based on clinical practice standard of care
Criteria for anti-VEGF injections
All patients will have had at least one anti-VEGF intraocular injection prior to entering the study Additional injections will be based on monthly evaluation of ETDRS visual acuity decrease of 5 letters from previous visit increased macular thickness compared to normal and previous visit as measured by SD 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 month The study will end at Visit 5 and patients will begin standard of care treatment with anti-VEGF injections Patients who have completed Study 0001 Short term effects of carbidopa-levodopa in Neovascular AMD will be eligible to enroll in the current study Study 0002 Proof of Concept and Dose Ranging Study of carbidopa-levodopa in Neovascular AMD
Number of subjects 52 completed Duration up to 112 days of treatment Primary Endpoint A statistically significant improvement 5 letters by carbidopa-levodopa treatment in ETDRS visual acuity
Measurements and Activities
1 Informed Consent at Baseline
2 Ophthalmic history and comprehensive eye examination including visual acuity wearing any prescription lenses using an EDTRS chart in both eyes prior to randomization and ophthalmoscopic examination and SD OCT
3 Repeat assessment of visual acuity using an EDTRS chart ophthalmoscopic examination and SD OCT at monthly visits
4 Demographics at Baseline
5 Medical History Vital Signs and Physical Examination at Baseline
6 ECG CBC Chem 20 and HbA1C at Baseline
7 Dispense study medication at visits 2 3 and 4
8 Pill count at visits 3 4 and 5
9 Non-directed assessment of adverse events at each visit including classification as to severity seriousness and body system
10 Concomitant medications at each visit
11 If a patient had the baseline evaluation in Study 001 that will be used as the baseline evaluation for this study
Statistics Descriptive statistics will be generated for at a minimum ETDRS visual acuity central retinal thickness amount of intraretinal and subretinal fluid and presence of hemorrhage Within patient trajectories for these outcomes will be plotted incorporating information on dose and duration Due to the small sample size model-based analyses will be considered only to be exploratory Analysis of Variance may be conducted to relate logarithm of dose and duration of treatment to the outcomes listed above
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
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
Pathogenesis of Neovascular AMD
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 all have had anti-VEGF therapy initiated The patients will be monitored at monthly intervals for up to 3 months for indications for administration of anti-VEGF injections
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
Treatments
Patients will receive open label commercially available carbidopa-levodopa 25-100 mg one tablet once daily hs for one month followed by one tablet dosed TID three times daily in the morning with supper and hs for one month followed by two tablets dosed three times daily in the morning with supper and hs for one month 100-600 mg of levodopa daily This is the equivalent of very low to moderate doses of carbidopa-levodopa in patients with Parkinsons disease daily dose of levodopa 200-800 mg Patients entering this study after completing Study 001 will receive one month of the dose that he or she received in Study 001 and one month each of any doses higher than the dose that he or she received in Study 001
Examples
1 If the patient received carbidopa-levodopa 25-100 mg once daily in Study 001 he or she will receive one month of treatment with each of the 3 daily doses of carbidopa-levodopa
2 If the patient received carbidopa-levodopa 25-100 mg TID in Study 001 he or she will receive one month of carbidopa-levodopa 25-100 mg TID followed by one month of carbidopa-levodopa 25-100 mg 2 tablets TID
Each patient will receive an injection of anti-VEGF medication on the day carbidopa-levodopa dosing begins in this study Each patient will be evaluated at monthly 25-35 day intervals and injected or not based upon the criteria listed below which are based on clinical practice standard of care
Criteria for anti-VEGF injections
All patients will have had at least one anti-VEGF intraocular injection prior to entering the study Additional injections will be based on monthly evaluation of ETDRS visual acuity decrease of 5 letters from previous visit increased macular thickness compared to normal and previous visit as measured by SD 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 month The study will end at Visit 5 and patients will begin standard of care treatment with anti-VEGF injections Patients who have completed Study 0001 Short term effects of carbidopa-levodopa in Neovascular AMD will be eligible to enroll in the current study Study 0002 Proof of Concept and Dose Ranging Study of carbidopa-levodopa in Neovascular AMD
Number of subjects 52 completed Duration up to 112 days of treatment Primary Endpoint A statistically significant improvement 5 letters by carbidopa-levodopa treatment in ETDRS visual acuity
Measurements and Activities
1 Informed Consent at Baseline
2 Ophthalmic history and comprehensive eye examination including visual acuity wearing any prescription lenses using an EDTRS chart in both eyes prior to randomization and ophthalmoscopic examination and SD OCT
3 Repeat assessment of visual acuity using an EDTRS chart ophthalmoscopic examination and SD OCT at monthly visits
4 Demographics at Baseline
5 Medical History Vital Signs and Physical Examination at Baseline
6 ECG CBC Chem 20 and HbA1C at Baseline
7 Dispense study medication at visits 2 3 and 4
8 Pill count at visits 3 4 and 5
9 Non-directed assessment of adverse events at each visit including classification as to severity seriousness and body system
10 Concomitant medications at each visit
11 If a patient had the baseline evaluation in Study 001 that will be used as the baseline evaluation for this study
Statistics Descriptive statistics will be generated for at a minimum ETDRS visual acuity central retinal thickness amount of intraretinal and subretinal fluid and presence of hemorrhage Within patient trajectories for these outcomes will be plotted incorporating information on dose and duration Due to the small sample size model-based analyses will be considered only to be exploratory Analysis of Variance may be conducted to relate logarithm of dose and duration of treatment to the outcomes listed above
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