Carbidopa-levodopa in Neovascular AMD
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.
    

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.

      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.
    

Intervention name(s): carbidopa-levodopa 25-100 mg tablets
Intervention type(s): Drug
Intervention description(s): See arm/group descriptions
Intervention MeSH terms: Levodopa; Carbidopa; Carbidopa, levodopa drug combination
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: GPR143; PEDF; VEGF; LDOPA