<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/NCT03023059</url>
  </required_header>
  <id_info>
    <org_study_id>0002</org_study_id>
    <nct_id>NCT03023059</nct_id>
  </id_info>
  <brief_title>Dose Ranging Study of Carbidopa-levodopa</brief_title>
  <official_title>Proof of Concept and Dose Ranging Study 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;
&#xD;
      The Investigators will evaluate the safety and tolerability of carbidopa-levodopa in patients&#xD;
      with Neovascular AMD who are already on treatment with anti-VEGF intraocular injections, and&#xD;
      measure the effects on visual acuity, retinal abnormalities due to &quot;wet&quot; AMD, and document&#xD;
      the number of anti-VEGF injections required during the study.&#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;
      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;
      Pathogenesis of Neovascular AMD.&#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 all have had anti-VEGF therapy initiated. The patients will be&#xD;
      monitored at monthly intervals, for up to 3 months, for indications for administration of&#xD;
      anti-VEGF injections.&#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;
      Treatments:&#xD;
&#xD;
      Patients will receive open label, commercially available carbidopa-levodopa 25-100 mg, one&#xD;
      tablet once daily hs for one month, followed by one tablet dosed TID (three times daily), in&#xD;
      the morning, with supper and hs for one month, followed by two tablets dosed three times&#xD;
      daily, in the morning, with supper and hs for one month (100-600 mg of levodopa daily). This&#xD;
      is the equivalent of very low to moderate doses of carbidopa-levodopa in patients with&#xD;
      Parkinson's disease (daily dose of levodopa 200-800 mg). Patients entering this study after&#xD;
      completing Study 001 will receive one month of the dose that he or she received in Study 001,&#xD;
      and one month each of any doses higher than the dose that he or she received in Study 001.&#xD;
&#xD;
      Examples:&#xD;
&#xD;
        1. If the patient received carbidopa-levodopa 25-100 mg once daily in Study 001, he or she&#xD;
           will receive one month of treatment with each of the 3 daily doses of&#xD;
           carbidopa-levodopa.&#xD;
&#xD;
        2. If the patient received carbidopa-levodopa 25-100 mg TID in Study 001, he or she will&#xD;
           receive one month of carbidopa-levodopa 25-100 mg TID, followed by one month of&#xD;
           carbidopa-levodopa 25-100 mg, 2 tablets TID.&#xD;
&#xD;
      Each patient will receive an injection of anti-VEGF medication on the day carbidopa-levodopa&#xD;
      dosing begins in this study. Each patient will be evaluated at monthly (25-35 day) intervals&#xD;
      and injected or not, based upon the criteria listed below, which are based on clinical&#xD;
      practice standard of care.&#xD;
&#xD;
      Criteria for anti-VEGF injections&#xD;
&#xD;
      All patients will have had at least one anti-VEGF intraocular injection prior to entering the&#xD;
      study. Additional injections will be based on: monthly evaluation of ETDRS visual acuity&#xD;
      (decrease of 5 letters from previous visit); increased macular thickness (compared to normal&#xD;
      and previous visit as measured by SD OCT; new blood (hemorrhage) on direct retinal&#xD;
      examination; or subjective decrease in vision. If any of these criteria are met, or if, in&#xD;
      the opinion of the Ophthalmologist, the patient requires anti-VEGF therapy, the patient will&#xD;
      have an anti-VEGF intraocular injection. If none of these criteria are met at visits 2, 3 or&#xD;
      4, with patient agreement, anti-VEGF injection will not be done, and the patient will be&#xD;
      reevaluated in 1 month. The study will end at Visit 5, and patients will begin standard of&#xD;
      care treatment with anti-VEGF injections. Patients who have completed Study 0001, Short term&#xD;
      effects of carbidopa-levodopa in Neovascular AMD, will be eligible to enroll in the current&#xD;
      study, Study 0002, Proof of Concept and Dose Ranging Study of carbidopa-levodopa in&#xD;
      Neovascular AMD.&#xD;
&#xD;
      Number of subjects: 52 completed Duration: up to 112 days of treatment. Primary Endpoint: A&#xD;
      statistically significant improvement (5 letters) by carbidopa-levodopa treatment in ETDRS&#xD;
      visual acuity.&#xD;
&#xD;
      Measurements and Activities:&#xD;
&#xD;
        1. Informed Consent at Baseline;&#xD;
&#xD;
        2. Ophthalmic history and comprehensive eye examination; including visual acuity, wearing&#xD;
           any prescription lenses, using an EDTRS chart, in both eyes prior to randomization, and&#xD;
           ophthalmoscopic examination, and SD OCT;&#xD;
&#xD;
        3. Repeat assessment of visual acuity using an EDTRS chart, ophthalmoscopic examination,&#xD;
           and SD OCT at monthly visits;&#xD;
&#xD;
        4. Demographics at Baseline;&#xD;
&#xD;
        5. Medical History, Vital Signs and Physical Examination at Baseline;&#xD;
&#xD;
        6. ECG, CBC, Chem 20 and HbA1C at Baseline;&#xD;
&#xD;
        7. Dispense study medication at visits 2, 3 and 4;&#xD;
&#xD;
        8. Pill count at visits 3, 4 and 5;&#xD;
&#xD;
        9. Non-directed assessment of adverse events at each visit, including classification as to&#xD;
           severity, seriousness and body system.&#xD;
&#xD;
       10. Concomitant medications at each visit.&#xD;
&#xD;
       11. If a patient had the baseline evaluation in Study 001, that will be used as the baseline&#xD;
           evaluation for this study.&#xD;
&#xD;
      Statistics: Descriptive statistics will be generated for, at a minimum, ETDRS visual acuity,&#xD;
      central retinal thickness, amount of intraretinal and subretinal fluid and presence of&#xD;
      hemorrhage. Within patient trajectories for these outcomes will be plotted, incorporating&#xD;
      information on dose and duration. Due to the small sample size, model-based analyses will be&#xD;
      considered only to be exploratory. Analysis of Variance may be conducted to relate logarithm&#xD;
      of dose and duration of treatment to the outcomes listed above.&#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">March 18, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group 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 end (78-112 days)</time_frame>
    <description>Visual acuity measured with optimum optical correction, using a standard ETDRS chart</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in central retinal (macular) thickness</measure>
    <time_frame>From start of study to end (78-112 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 end (78-112 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 end (78-112 days)</time_frame>
    <description>Vital signs, eye examinations and nondirected subjective adverse events</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">35</enrollment>
  <condition>Age-related Macular Degeneration</condition>
  <arm_group>
    <arm_group_label>Escalating dose of carbidopa-levodopa</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The intervention is that patients will receive open label, commercially available Carbidopa-Levodopa 25 Mg-100 Mg oral tablet, once daily hs for one month, followed by one tablet dosed 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 Parkinson's disease (daily dose of levodopa 200-800 mg).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carbidopa-Levodopa, 25 Mg-100 Mg Oral Tablet</intervention_name>
    <description>See Arm description</description>
    <arm_group_label>Escalating dose of carbidopa-levodopa</arm_group_label>
    <other_name>Sinemet</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. A diagnosis of AMD with choroidal neovascularization (CNV) in one eye;&#xD;
&#xD;
          2. a. Not previously treated with anti-VEGF injections; or&#xD;
&#xD;
             b. On anti-VEGF injections for at least 3 months, and meets criteria for a repeat&#xD;
             injection; or&#xD;
&#xD;
             c. Patients, who have completed Study 001, may enter this trial at the point of&#xD;
             initiation of the month of treatment with the dose of carbidopa-levodopa, that they&#xD;
             received in Study 001;&#xD;
&#xD;
          3. Normal or dry AMD of any grade in the second eye;&#xD;
&#xD;
          4. 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;
          5. Informed Consent at Baseline.&#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 20/60 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;
      </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 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 13, 2017</study_first_submitted>
  <study_first_submitted_qc>January 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 18, 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>L-DOPA</keyword>
  <keyword>GPR143</keyword>
  <keyword>PEDF</keyword>
  <keyword>VEGF</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/NCT03023059
org study id: 0002
nct id: NCT03023059
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.

      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.
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.

      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.

      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 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.

      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
      Parkinson's 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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in ETDRS visual acuity
time frame: From start of study to end (78-112 days)
description: Visual acuity measured with optimum optical correction, using a standard ETDRS chart
measure: Change in central retinal (macular) thickness
time frame: From start of study to end (78-112 days)
description: Central retinal thickness measured by SD OCT
measure: New retinal blood (hemorrhage)
time frame: From start of study to end (78-112 days)
description: Visible blood on direct retinal examination
measure: Treatment Emergent Adverse Events
time frame: From start of study to end (78-112 days)
description: Vital signs, eye examinations and nondirected subjective adverse events
arm group label: Escalating dose of carbidopa-levodopa
arm group type: Experimental
description: The intervention is that patients will receive open label, commercially available Carbidopa-Levodopa 25 Mg-100 Mg oral tablet, once daily hs for one month, followed by one tablet dosed 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 Parkinson's disease (daily dose of levodopa 200-800 mg).
intervention type: Drug
intervention name: Carbidopa-Levodopa, 25 Mg-100 Mg Oral Tablet
description: See Arm description
arm group label: Escalating dose of carbidopa-levodopa
other name: Sinemet
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 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