Ignite Creation Date:
2024-05-06 @ 8:59 AM
Last Modification Date:
2024-10-26 @ 12:08 PM
Study NCT ID:
NCT02873351
Status:
WITHDRAWN
Last Update Posted:
2019-04-05
First Post:
2016-07-26
Brief Title:
A Safety and Efficacy Study of Carbidopa-levodopa in Patients With Macular Degeneration
Sponsor:
Snyder Robert W MD PhD PC
Organization:
Snyder Robert W MD PhD PC
Study Overview
Official Title:
Pilot Study of L-DOPA Safety and Tolerability in Patients With AMD and Proof of Concept That L-DOPA Improves Surrogate Biomarkers in Patients With Moderate to Advanced AMD
Status:
WITHDRAWN
Status Verified Date:
2017-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Decided to do studies in patients with AMD
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 AMD and measure the effects on surrogate functional biomarkers of 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 AMD and measure the effects on surrogate functional biomarkers of 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 world12 AMD becomes more common as people age and is more common in lightly pigmented individuals3 AMD appears more common in patients with Parkinsons Disease than in those without4 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 AMD5 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 cells6 Wet AMD is now effectively treated with intraocular injections of VEGF inhibitors2 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 function7 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 GPR1438 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 VEGF9 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-DOPA10 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 treatment10 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 disease11 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 safety study to examine whether L-DOPA has a positive effect on surrogate biomarkers of AMD The surrogate markers to be evaluated are dark adaptation1213 best corrected visual acuity BCVA low luminance visual acuityLLVA14 and the size and numbers of drusen15 and reticular pseudodrusen16 A previous trial with retinol in 104 patients significantly improved dark adaptation in 30 days17 Therefore the Investigators expect to see improvement with L-DOPA in a relatively short time This study will also help the Investigators prepare for a Phase 3 study of L-DOPA in AMD
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 nausea18 by 90 However some patients require additional supplemental carbidopa Carbidopa has very limited side effects when given alone18 Therefore the Investigators plan to use 35 mg of carbidopa with each 100 mg of levodopa in order to control adverse events in almost all participants
L-DOPA is the natural ligand for GPR143 in the RPE cells8 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 effect19
Treatments
1 Carbidopa-levodopa 35-100 mg dosed hs for 45 days followed by carbidopa-levodopa 35-100 mg dosed in the morning with supper and hs for 45 days The second dosing period is the equivalent of a moderate dose of carbidopa-levodopa in patients with Parkinsons disease maximum daily dose 200-800 mg
2 Placebo dosed hs for 45 days followed by placebo dosed in the morning with supper and hs for 45 days
Placebo and active medication will be dosed as capsules identical in appearance
Number of participants Not yet recruiting stratified by non-study eye being normal dry AMD or wet AMD and randomized using a table of random numbers Estimated screen failure rate is 50 The sample size is based on a successful study treating patients with impaired dark adaptation with retinol which showed significant improvement in 30 days with 52 patients per study arm
Duration 87-114 days 80-100 days of treatment Visits 1 screening and 2randomization can be scheduled within 1 week The first visit after Randomization Visit 3 will occur 40-50 days after Visit 2 Visit 4 end of study will occur 40-50 days after Visit 3 This schedule allows a 10 day window for study visits for logistic reasons and patient convenience
Overall trial duration for enrollment and treatment screening 5 patients per week will be approximately 10 months
Primary Endpoint A statistically significant improvement by carbidopa-levodopa treatment in any of dark adaptation BCVA LLVA drusen or reticular pseudodrusen measured by spectral domainSD optical coherence tomographyOCT
Measurements
1 Demographics at Visit 1
2 Medical History and Physical Examination at Visit 1
3 ElectrocardiogramECG complete blood countCBC Chem 20 and HbA1C at Visit 1
4 Vital signs at Visits 1345 and 6
5 Non-directed assessment of adverse events at Visits 12 3 and 4
6 Ophthalmic history and comprehensive eye examination including dark adaptation and SD OCT at Visit 2 Baseline
7 Low luminance questionnaire at visits 2 3 and 4
8 Pill count at Visits 3 and 4
9 Re-measurement of dark adaptation visual acuity under normal and low light conditions and SD OCT at Visits 3 and 4 End of Study
Statistics Analysis of Variance with Independent Variables
1 Active Drug vs Placebo
2 Logarithm of daily dose of active drug
3 Duration of treatment measurements at Visits 3 4 5 and 6
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 GPR1438 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 VEGF9 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-DOPA10 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 treatment10 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 disease11 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 safety study to examine whether L-DOPA has a positive effect on surrogate biomarkers of AMD The surrogate markers to be evaluated are dark adaptation1213 best corrected visual acuity BCVA low luminance visual acuityLLVA14 and the size and numbers of drusen15 and reticular pseudodrusen16 A previous trial with retinol in 104 patients significantly improved dark adaptation in 30 days17 Therefore the Investigators expect to see improvement with L-DOPA in a relatively short time This study will also help the Investigators prepare for a Phase 3 study of L-DOPA in AMD
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 nausea18 by 90 However some patients require additional supplemental carbidopa Carbidopa has very limited side effects when given alone18 Therefore the Investigators plan to use 35 mg of carbidopa with each 100 mg of levodopa in order to control adverse events in almost all participants
L-DOPA is the natural ligand for GPR143 in the RPE cells8 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 effect19
Treatments
1 Carbidopa-levodopa 35-100 mg dosed hs for 45 days followed by carbidopa-levodopa 35-100 mg dosed in the morning with supper and hs for 45 days The second dosing period is the equivalent of a moderate dose of carbidopa-levodopa in patients with Parkinsons disease maximum daily dose 200-800 mg
2 Placebo dosed hs for 45 days followed by placebo dosed in the morning with supper and hs for 45 days
Placebo and active medication will be dosed as capsules identical in appearance
Number of participants Not yet recruiting stratified by non-study eye being normal dry AMD or wet AMD and randomized using a table of random numbers Estimated screen failure rate is 50 The sample size is based on a successful study treating patients with impaired dark adaptation with retinol which showed significant improvement in 30 days with 52 patients per study arm
Duration 87-114 days 80-100 days of treatment Visits 1 screening and 2randomization can be scheduled within 1 week The first visit after Randomization Visit 3 will occur 40-50 days after Visit 2 Visit 4 end of study will occur 40-50 days after Visit 3 This schedule allows a 10 day window for study visits for logistic reasons and patient convenience
Overall trial duration for enrollment and treatment screening 5 patients per week will be approximately 10 months
Primary Endpoint A statistically significant improvement by carbidopa-levodopa treatment in any of dark adaptation BCVA LLVA drusen or reticular pseudodrusen measured by spectral domainSD optical coherence tomographyOCT
Measurements
1 Demographics at Visit 1
2 Medical History and Physical Examination at Visit 1
3 ElectrocardiogramECG complete blood countCBC Chem 20 and HbA1C at Visit 1
4 Vital signs at Visits 1345 and 6
5 Non-directed assessment of adverse events at Visits 12 3 and 4
6 Ophthalmic history and comprehensive eye examination including dark adaptation and SD OCT at Visit 2 Baseline
7 Low luminance questionnaire at visits 2 3 and 4
8 Pill count at Visits 3 and 4
9 Re-measurement of dark adaptation visual acuity under normal and low light conditions and SD OCT at Visits 3 and 4 End of Study
Statistics Analysis of Variance with Independent Variables
1 Active Drug vs Placebo
2 Logarithm of daily dose of active drug
3 Duration of treatment measurements at Visits 3 4 5 and 6
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