<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03022318</url>
  </required_header>
  <id_info>
    <org_study_id>0001</org_study_id>
    <nct_id>NCT03022318</nct_id>
  </id_info>
  <brief_title>Carbidopa-levodopa in Neovascular AMD</brief_title>
  <official_title>Short Term Effects of Carbidopa-levodopa in Neovascular AMD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Snyder, Robert W., M.D., Ph.D., P.C.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Snyder, Robert W., M.D., Ph.D., P.C.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      From 3 large patient databases, patients diagnosed with AMD who have never taken&#xD;
      levodopa(L-DOPA) containing medications have a mean age of diagnosis at 71 years. Patients&#xD;
      who have been treated with L-DOPA containing medications have a mean age of diagnosis of AMD&#xD;
      at 79 years.&#xD;
&#xD;
      L-DOPA binds to GPR143 in the retinal pigment epithelium, and releases PEDF, which protects&#xD;
      the retina and downregulates VEGF, which is the cause of neovascularization.&#xD;
&#xD;
      The Investigators will evaluate the safety and tolerability of carbidopa-levodopa in patients&#xD;
      with Neovascular AMD, and measure the effects on visual acuity and retinal abnormalities due&#xD;
      to &quot;wet&quot; (neovascular) AMD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Age-related macular degeneration (AMD) is the most common cause of blindness, in individuals&#xD;
      over the age of 50, in the developed world. AMD becomes more common as people age, and is&#xD;
      more common in lightly pigmented individuals. AMD appears more common in patients with&#xD;
      Parkinson's Disease, than in those without. The AREDS nutritional supplements are effective&#xD;
      in slowing the progress of intermediate AMD(5). Most AMD is &quot;dry AMD&quot;, which progresses&#xD;
      relatively slowly and may impair vision, but usually does not lead to legal blindness. There&#xD;
      are two forms of AMD, &quot;wet AMD&quot; and geographic atrophy (GA), that can cause more profound&#xD;
      vision loss. In aggregate they occur in about 25% patients with AMD. Wet AMD is due to new&#xD;
      growth of abnormal blood vessels under the retina. The new blood vessels are believed to be&#xD;
      due to an excessive release of vascular endothelial growth factor (VEGF) by the retinal&#xD;
      pigment epithelium(RPE) cells. Wet AMD is now effectively treated with intraocular injections&#xD;
      of VEGF inhibitors. Geographic Atrophy, the other form of advanced AMD, represents focal&#xD;
      death of the RPE cells and overlying neurosensory retina. There is no current treatment for&#xD;
      GA. It is suspected that GA is due in part to a localized inflammatory response, damage to&#xD;
      RPE cells and loss of RPE cell function. It may also be speculated that stimulation of RPE&#xD;
      cells to release a potent neurotrophic factor, pigment epithelium derived factor (PEDF) may&#xD;
      slow progression of GA.&#xD;
&#xD;
      In 2008, Dr. Brian McKay identified a receptor, G protein coupled receptor #143(GPR143), on&#xD;
      the surface of RPE cells and discovered that L-DOPA was the natural ligand or stimulator of&#xD;
      GPR143. Dr McKay showed that treatment of RPE cells with exogenous L-DOPA resulted in the&#xD;
      release of additional PEDF. In subsequent work Dr McKay's group also showed that L-DOPA&#xD;
      stimulation of PEDF in RPE cells was also associated with a decrease in VEGF. Thus, Dr McKay&#xD;
      hypothesized that exogenous L-DOPA may prevent the onset of AMD or progression to wet AMD.&#xD;
&#xD;
      In 2015, Dr McKay and his associates published a paper that showed that patients, who had&#xD;
      been treated with L-DOPA, had a delay in the onset of AMD by 8 years, compared to patients&#xD;
      who had not been treated with L-DOPA. In addition, those who had AMD and went on to develop&#xD;
      wet AMD, did so 5 years later than those with no history of L-DOPA treatment. L-DOPA is an&#xD;
      intermediate in the pigmentation pathway. Dr McKay and his associates suggested that the&#xD;
      reason darkly pigmented races do not get AMD nearly as frequently as lighter pigmented races,&#xD;
      is that they produce more pigment, and thus more L-DOPA to stimulate GPR143 on RPE cells.&#xD;
      According to this hypothesis, the stimulated RPE cells release PEDF and decrease VEGF, which&#xD;
      together are responsible for the protective effect.&#xD;
&#xD;
      Since there are no established animal models for AMD, and L-DOPA has a good safety profile in&#xD;
      healthy volunteers and patients with Parkinson's disease, the Investigators propose a&#xD;
      prospective experiment to determine the safety and tolerability of L-DOPA, in a population of&#xD;
      patients with AMD. The participants will be made aware of potential side effects of L-DOPA,&#xD;
      which are listed in the Informed Consent, during the consent process. Adverse events will be&#xD;
      elicited by questioning the participants at each visit. The participants will also be advised&#xD;
      to call the site, if they have any medical problem between visits.&#xD;
&#xD;
      The Investigators will also use this study to examine whether L-DOPA has a positive effect on&#xD;
      visual acuity and pathologic retinal changes of &quot;wet&quot; AMD. The parameters to be evaluated are&#xD;
      best corrected ETDRS visual acuity, macular thickness by spectral domain optical coherence&#xD;
      tomography (SD OCT), new blood (hemorrhage) by direct retinal examination, or subjective&#xD;
      decrease in vision.&#xD;
&#xD;
      Pharmacology of L-DOPA and carbidopa:&#xD;
&#xD;
      L-DOPA is formed by 3-hydroxylation of tyrosine by tyrosine-3-monooxygenase (tyrosinase).(18)&#xD;
      The primary metabolic pathway of L-DOPA is decarboxylation by amino acid decarboxylase to&#xD;
      dopamine, which is responsible for most, but not all, of its pharmacologic effects and&#xD;
      toxicity. When carbidopa is administered with L-DOPA, systemic levels of L-DOPA double and&#xD;
      central nervous system (CNS) L-DOPA increases from about 1% of the administered dose to about&#xD;
      4%. Levodopa freely passes from the systemic circulation into the retina and brain, but&#xD;
      dopamine and carbidopa do not. Adverse events are markedly decreased when carbidopa is&#xD;
      administered with L-DOPA, because systemic levels of the toxic metabolite of L-DOPA,&#xD;
      dopamine, are markedly reduced. In most patients, 25 mg of carbidopa is sufficient to control&#xD;
      side effects of 100 mg of L-DOPA, primarily nausea, by 90%.&#xD;
&#xD;
      L-DOPA is the natural ligand for GPR143 in the RPE cells. The Investigators' intent is to&#xD;
      increase the L-DOPA available to RPE surface receptors (GPR 143) while minimizing peripheral&#xD;
      toxicity. This concept is unique, because all other uses of L-DOPA rely on CNS conversion of&#xD;
      L-DOPA to dopamine, in order to produce the desired effect.&#xD;
&#xD;
      Excess VEGF is the mediator of the retinal neovascularization and other retinal pathological&#xD;
      changes in &quot;wet&quot; AMD. Intraocular injections of anti-VEGF antibodies is the standard of care&#xD;
      in &quot;Wet&quot; AMD. Several publications, including Lim et al, show that with careful monitoring of&#xD;
      the visual acuity and retinas of patients with wet AMD, if there is no progression, there are&#xD;
      no long-term adverse consequences of delaying initiation of anti-VEGF therapy for up to 4&#xD;
      weeks. The patients will be monitored at weekly intervals, for up to 4 weeks, for indications&#xD;
      for initiation of anti-VEGF injections.&#xD;
&#xD;
      Criteria for anti-VEGF injections&#xD;
&#xD;
      This will be based on: weekly evaluation of ETDRS visual acuity (decrease of 5 letters from&#xD;
      previous visit); increased macular thickness (compared to normal and previous visit as&#xD;
      measured by OCT; new blood (hemorrhage) on direct retinal examination; or subjective decrease&#xD;
      in vision. If any of these criteria are met, or if, in the opinion of the Ophthalmologist,&#xD;
      the patient requires anti-VEGF therapy, the patient will have an anti-VEGF intraocular&#xD;
      injection. If none of these criteria are met at visits 2, 3 or 4, with patient agreement,&#xD;
      anti-VEGF injection will not be done, and the patient will be reevaluated in 1 week. The&#xD;
      patients will receive an anti-VEGF injection at the end of the 4th week, if they have not&#xD;
      received one earlier. Whenever a patient receives the first anti-VEGF injection,&#xD;
      participation in this protocol will end. At that point, the patient will be able to enroll in&#xD;
      Study 0002, Proof of Concept and Dose Ranging Study of carbidopa-levodopa in Neovascular AMD.&#xD;
&#xD;
      Treatments:&#xD;
&#xD;
      Randomized assignment to carbidopa-levodopa 25-100 mg tablets dosed hs or carbidopa-levodopa&#xD;
      25-100 mg tablets dosed 3 times daily, in the morning, with supper and hs. The second dosing&#xD;
      regimen is the equivalent of a moderate dose of carbidopa-levodopa in patients with&#xD;
      Parkinson's disease (maximum daily dose of levodopa 200-800 mg).&#xD;
&#xD;
      Number of participants: Up to 52 completed, randomized using a table of random numbers.&#xD;
&#xD;
      Informed Consent will be completed at the first visit. Duration: up to 32 days of treatment.&#xD;
      Visits will occur at 5-8 day intervals. Overall trial duration for enrollment and treatment,&#xD;
      screening 5 patients per week, will be approximately 10 months.&#xD;
&#xD;
      Primary Endpoint: A statistically significant improvement (5 letters) by carbidopa-levodopa&#xD;
      treatment in ETDRS visual acuity.&#xD;
&#xD;
      Measurements:&#xD;
&#xD;
      Demographics at Visit 1; Medical History and Physical Examination at Visit 1;&#xD;
      Electrocardiogram(ECG), complete blood count(CBC), Chem 20 and HbA1C at Visit 1; Vital signs&#xD;
      at Visits 1,2,3,4 and 5; Non-directed assessment of adverse events at Visits 1,2,3,4 and 5.&#xD;
      SD OCT at Visits 1,2,3,4,5; Pill count at Visits 2,3,4 and 5;&#xD;
&#xD;
      Statistics: Analysis of Variance with Independent Variables for each arm and comparing arms:&#xD;
&#xD;
      ETDRS visual acuity, central retinal (macular) thickness, presence of hemorrage and duration&#xD;
      of treatment prior to initiation of anti VEGF intraocular injections.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2, 2017</start_date>
  <completion_date type="Actual">May 4, 2020</completion_date>
  <primary_completion_date type="Actual">December 26, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in ETDRS visual acuity</measure>
    <time_frame>From start of study to first anti-VEGF injection (8-32 days)</time_frame>
    <description>The study will be terminated after the first anti-VEGF injection, which can occur 1,2,3 or 4 weeks after the start of the wtudy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in central retinal (macular) thickness</measure>
    <time_frame>From start of study to first anti-VEGF injection (8-32 days)</time_frame>
    <description>Central retinal thickness measured by SD OCT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New retinal blood (hemorrhage)</measure>
    <time_frame>From start of study to first anti-VEGF injection (8-32 days)</time_frame>
    <description>Visible blood on direct retinal examination</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment Emergent Adverse Events</measure>
    <time_frame>From start of study to first anti-VEGF injection (8-32 days)</time_frame>
    <description>Vital signs, eye examinations and nondirected subjective adverse events</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Age-related Macular Degeneration</condition>
  <arm_group>
    <arm_group_label>once daily</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>carbidopa-levodopa 25-100 mg tablets once daily hs for up to 32 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3 times daily</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>carbidopa-levodopa 25-100 mg tablets 3 times daily,in the morning, with supper and hs for up to 32 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>carbidopa-levodopa 25-100 mg tablets</intervention_name>
    <description>See arm/group descriptions</description>
    <arm_group_label>3 times daily</arm_group_label>
    <arm_group_label>once daily</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. A diagnosis of AMD with choroidal neovascularization (CNV) in one eye;&#xD;
&#xD;
          2. Not previously treated with anti-VEGF injections;&#xD;
&#xD;
          3. Normal or dry AMD of any grade in the second eye;&#xD;
&#xD;
          4. Age 50-85 years;&#xD;
&#xD;
          5. Willingness to maintain AREDS vitamin supplements throughout the study, or remain off&#xD;
             these supplements for the duration of the study, if not taking them prior to the&#xD;
             study;&#xD;
&#xD;
          6. Signed Informed Consent.&#xD;
&#xD;
             -&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any current use of L-DOPA containing medication or dopamine agonist medication, or any&#xD;
             planned use of any of these agents, except for study medication, during the study;&#xD;
&#xD;
          2. Concurrent use of monoamine oxidase (MAO) inhibitors;&#xD;
&#xD;
          3. Any eye condition, disease, or history of trauma in either eye, which can impair&#xD;
             vision, except cataract or cataract surgery;&#xD;
&#xD;
          4. BCVA worse than 20/160 in the better eye;&#xD;
&#xD;
          5. Wet AMD in the second eye;&#xD;
&#xD;
          6. Neurologic conditions which can impair vision;&#xD;
&#xD;
          7. Parkinson's Disease;&#xD;
&#xD;
          8. Significant orthostatic hypotension, defined as a drop in systolic blood pressure,&#xD;
             immediately upon changing from the supine to standing position, of &gt;19 mmHg, or a&#xD;
             symptomatic drop in systolic blood pressure, immediately upon changing from the supine&#xD;
             to standing position;&#xD;
&#xD;
          9. Significant ECG abnormalities, as judged by the Investigator;&#xD;
&#xD;
         10. Estimated glomerular filtration rate (eGFR) &lt;20 ml/min;&#xD;
&#xD;
         11. Liver enzymes &gt;3 X the upper limit of normal;&#xD;
&#xD;
         12. HbA1C &gt;9.0;&#xD;
&#xD;
         13. Any other significant lab abnormalities, as judged by the Investigator;&#xD;
&#xD;
         14. Women of childbearing potential;&#xD;
&#xD;
         15. Known retinal hemorrhage;&#xD;
&#xD;
         16. Subjects who are not fluent in English.&#xD;
&#xD;
             -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Robert W Snyder, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Robert W Snyder, MD, PhD, PC</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Timothy C Fagan, MD</last_name>
    <role>Study Director</role>
    <affiliation>Robert W Snyder, MD, PhD, PC</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Robert W Snyder, MD, PhD, PC</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85712</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004 Nov;82(11):844-51. Epub 2004 Dec 14.</citation>
    <PMID>15640920</PMID>
  </reference>
  <reference>
    <citation>Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008 Jun 12;358(24):2606-17. doi: 10.1056/NEJMra0801537. No abstract available. Erratum In: N Engl J Med. 2008 Oct 16;359(16): 1736.</citation>
    <PMID>18550876</PMID>
  </reference>
  <reference>
    <citation>Bressler SB, Munoz B, Solomon SD, West SK; Salisbury Eye Evaluation (SEE) Study Team. Racial differences in the prevalence of age-related macular degeneration: the Salisbury Eye Evaluation (SEE) Project. Arch Ophthalmol. 2008 Feb;126(2):241-5. doi: 10.1001/archophthalmol.2007.53.</citation>
    <PMID>18268216</PMID>
  </reference>
  <reference>
    <citation>Ferrara N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat Med. 2010 Oct;16(10):1107-11. doi: 10.1038/nm1010-1107. No abstract available.</citation>
    <PMID>20930754</PMID>
  </reference>
  <reference>
    <citation>Lopez VM, Decatur CL, Stamer WD, Lynch RM, McKay BS. L-DOPA is an endogenous ligand for OA1. PLoS Biol. 2008 Sep 30;6(9):e236. doi: 10.1371/journal.pbio.0060236.</citation>
    <PMID>18828673</PMID>
  </reference>
  <reference>
    <citation>Falk T, Congrove NR, Zhang S, McCourt AD, Sherman SJ, McKay BS. PEDF and VEGF-A output from human retinal pigment epithelial cells grown on novel microcarriers. J Biomed Biotechnol. 2012;2012:278932. doi: 10.1155/2012/278932. Epub 2012 Apr 2.</citation>
    <PMID>22547925</PMID>
  </reference>
  <reference>
    <citation>Brilliant MH, Vaziri K, Connor TB Jr, Schwartz SG, Carroll JJ, McCarty CA, Schrodi SJ, Hebbring SJ, Kishor KS, Flynn HW Jr, Moshfeghi AA, Moshfeghi DM, Fini ME, McKay BS. Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration. Am J Med. 2016 Mar;129(3):292-8. doi: 10.1016/j.amjmed.2015.10.015. Epub 2015 Oct 30.</citation>
    <PMID>26524704</PMID>
  </reference>
  <reference>
    <citation>Westfall TC, Westfall DP. Neurotransmission: The Autonomic and Somatic Motor nervous Systems. Pharmacological Basis of Therapeutics, 12th Edition, 171-218, McGraw-HILL, 2011.</citation>
  </reference>
  <reference>
    <citation>Standaert DG, Roberson ED. Treatment of Central Nervous System Degenerative Disorders. Pharmacological Basis of Therapeutics, 12th Edition, 609-628, McGraw-HILL, 2011.</citation>
  </reference>
  <reference>
    <citation>Lim JH, Wickremasinghe SS, Xie J, Chauhan DS, Baird PN, Robman LD, Hageman G, Guymer RH. Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Am J Ophthalmol. 2012 Apr;153(4):678-86, 686.e1-2. doi: 10.1016/j.ajo.2011.09.013. Epub 2012 Jan 14.</citation>
    <PMID>22245460</PMID>
  </reference>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>January 12, 2017</study_first_submitted>
  <study_first_submitted_qc>January 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 16, 2017</study_first_posted>
  <last_update_submitted>December 10, 2020</last_update_submitted>
  <last_update_submitted_qc>December 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 11, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>GPR143</keyword>
  <keyword>PEDF</keyword>
  <keyword>VEGF</keyword>
  <keyword>LDOPA</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Degeneration</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Levodopa</mesh_term>
    <mesh_term>Carbidopa</mesh_term>
    <mesh_term>Carbidopa, levodopa drug combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03022318
org study id: 0001
nct id: NCT03022318
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
From 3 large patient databases, patients diagnosed with AMD who have never taken
      levodopa(L-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.
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
      Parkinson's Disease, than in those without. The AREDS nutritional supplements are effective
      in slowing the progress of intermediate AMD(5). 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 epithelium(RPE) 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 #143(GPR143), 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 McKay's 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 Parkinson's 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 (tyrosinase).(18)
      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
      Parkinson's 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;
      Electrocardiogram(ECG), complete blood count(CBC), Chem 20 and HbA1C at Visit 1; Vital signs
      at Visits 1,2,3,4 and 5; Non-directed assessment of adverse events at Visits 1,2,3,4 and 5.
      SD OCT at Visits 1,2,3,4,5; Pill count at Visits 2,3,4 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.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in ETDRS visual acuity
time frame: From start of study to first anti-VEGF injection (8-32 days)
description: The study will be terminated after the first anti-VEGF injection, which can occur 1,2,3 or 4 weeks after the start of the wtudy
measure: Change in central retinal (macular) thickness
time frame: From start of study to first anti-VEGF injection (8-32 days)
description: Central retinal thickness measured by SD OCT
measure: New retinal blood (hemorrhage)
time frame: From start of study to first anti-VEGF injection (8-32 days)
description: Visible blood on direct retinal examination
measure: Treatment Emergent Adverse Events
time frame: From start of study to first anti-VEGF injection (8-32 days)
description: Vital signs, eye examinations and nondirected subjective adverse events
arm group label: once daily
arm group type: Experimental
description: carbidopa-levodopa 25-100 mg tablets once daily hs for up to 32 days
arm group label: 3 times daily
arm group type: Experimental
description: carbidopa-levodopa 25-100 mg tablets 3 times daily,in the morning, with supper and hs for up to 32 days
intervention type: Drug
intervention name: carbidopa-levodopa 25-100 mg tablets
description: See arm/group descriptions
arm group label: 3 times daily
arm group label: once daily
criteria: 
gender: All
minimum age: 50 Years
maximum age: 85 Years
healthy volunteers: No
last name: Robert W Snyder, MD, PhD
role: Principal Investigator
affiliation: Robert W Snyder, MD, PhD, PC
last name: Timothy C Fagan, MD
role: Study Director
affiliation: Robert W Snyder, MD, PhD, PC
facility: 
country: United States
citation: Resnikoff S, Pascolini D, Etya'ale D, Kocur I, Pararajasegaram R, Pokharel GP, Mariotti SP. Global data on visual impairment in the year 2002. Bull World Health Organ. 2004 Nov;82(11):844-51. Epub 2004 Dec 14.
PMID: 15640920
citation: Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008 Jun 12;358(24):2606-17. doi: 10.1056/NEJMra0801537. No abstract available. Erratum In: N Engl J Med. 2008 Oct 16;359(16): 1736.
PMID: 18550876
citation: Bressler SB, Munoz B, Solomon SD, West SK; Salisbury Eye Evaluation (SEE) Study Team. Racial differences in the prevalence of age-related macular degeneration: the Salisbury Eye Evaluation (SEE) Project. Arch Ophthalmol. 2008 Feb;126(2):241-5. doi: 10.1001/archophthalmol.2007.53.
PMID: 18268216
citation: Ferrara N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat Med. 2010 Oct;16(10):1107-11. doi: 10.1038/nm1010-1107. No abstract available.
PMID: 20930754
citation: Lopez VM, Decatur CL, Stamer WD, Lynch RM, McKay BS. L-DOPA is an endogenous ligand for OA1. PLoS Biol. 2008 Sep 30;6(9):e236. doi: 10.1371/journal.pbio.0060236.
PMID: 18828673
citation: Falk T, Congrove NR, Zhang S, McCourt AD, Sherman SJ, McKay BS. PEDF and VEGF-A output from human retinal pigment epithelial cells grown on novel microcarriers. J Biomed Biotechnol. 2012;2012:278932. doi: 10.1155/2012/278932. Epub 2012 Apr 2.
PMID: 22547925
citation: Brilliant MH, Vaziri K, Connor TB Jr, Schwartz SG, Carroll JJ, McCarty CA, Schrodi SJ, Hebbring SJ, Kishor KS, Flynn HW Jr, Moshfeghi AA, Moshfeghi DM, Fini ME, McKay BS. Mining Retrospective Data for Virtual Prospective Drug Repurposing: L-DOPA and Age-related Macular Degeneration. Am J Med. 2016 Mar;129(3):292-8. doi: 10.1016/j.amjmed.2015.10.015. Epub 2015 Oct 30.
PMID: 26524704
citation: Westfall TC, Westfall DP. Neurotransmission: The Autonomic and Somatic Motor nervous Systems. Pharmacological Basis of Therapeutics, 12th Edition, 171-218, McGraw-HILL, 2011.
citation: Standaert DG, Roberson ED. Treatment of Central Nervous System Degenerative Disorders. Pharmacological Basis of Therapeutics, 12th Edition, 609-628, McGraw-HILL, 2011.
citation: Lim JH, Wickremasinghe SS, Xie J, Chauhan DS, Baird PN, Robman LD, Hageman G, Guymer RH. Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Am J Ophthalmol. 2012 Apr;153(4):678-86, 686.e1-2. doi: 10.1016/j.ajo.2011.09.013. Epub 2012 Jan 14.
PMID: 22245460
responsible party type: Sponsor
mesh term: Macular Degeneration
mesh term: Levodopa
mesh term: Carbidopa
mesh term: Carbidopa, levodopa drug combination
sharing ipd: No