Dose Ranging Study of Carbidopa-levodopa
Condition: Age-related Macular Degeneration
MeSH terms: Macular Degeneration
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      Age-related macular degeneration (AMD) is the most common cause of blindness, in individuals
      over the age of 50, in the developed world. AMD becomes more common as people age, and is
      more common in lightly pigmented individuals. AMD appears more common in patients with
      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.
    

Intervention name(s): Carbidopa-Levodopa, 25 Mg-100 Mg Oral Tablet
Intervention type(s): Drug
Intervention description(s): See Arm description
Other intervention name(s): Sinemet
Intervention MeSH terms: Levodopa; Carbidopa; Carbidopa, levodopa drug combination
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: L-DOPA; GPR143; PEDF; VEGF