Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT03451500 |
| Other study ID # |
0004 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2018 |
| Est. completion date |
October 31, 2019 |
Study information
| Verified date |
April 2024 |
| Source |
Snyder, Robert W., M.D., Ph.D., P.C. |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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 Dry AMD and Geographic Atrophy, and measure the effects
on visual acuity, area of geographic atrophy and other retinal abnormalities due to "dry"
AMD.
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 LDOPA 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 LDOPA, 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.
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 "dry" AMD with geographic atrophy.
The parameters to be evaluated are best corrected ETDRS visual acuity, area of geographic
atrophy by Fundus AutoFluorescence (FAF), macular thickness by spectral domain optical
coherence tomography (SD OCT), new blood (hemorrhage) by direct retinal examination, and
subjective decrease in vision.
Treatments:
Study participants will receive randomly assigned, single blind, commercially available
carbidopa-levodopa 25-100 mg, two tablets once daily hs, or two tablets dosed TID (three
times daily), in the morning, with supper and hs for one month, or placebo two tablets dosed
three times daily, in the morning, with supper and hs (200-600 mg of levodopa daily). This is
the equivalent of low to moderate doses of carbidopa-levodopa in patients with Parkinson's
disease (daily dose of levodopa 200-800 mg). If a study participant experiences non-serious,
but bothersome adverse effects while taking the study medication, the dose may be reduced to
1 tablet hs, or 1 tablet TID.
Number of subjects: 154 randomized.
Duration: 12 months of treatment, with visits at Baseline, 1 week, 1 month, 3 months, 6
months, 9 months and 12 months.
Primary Endpoint: A statistically significant difference in progression of area of geographic
atrophy with carbidopa-levodopa treatment compared to treatment with placebo.
Measurements and Activities:
1. Informed Consent at Baseline;
2. Ophthalmic history and comprehensive eye examination; including visual acuity, with best
optical correction, using an EDTRS chart, in both eyes prior to randomization,
ophthalmoscopic examination, a subjective vision questionnaire and SD OCT with FAF;
3. Repeat assessment of visual acuity using an EDTRS chart, subjective vision
questionnaire, ophthalmoscopic examination, and SD OCT at 1, 3, 6 9, and 12 month
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, 4, 5, 6 and 7;
8. Pill count at visits 3, 4, 5, 6 and 7;
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.
Statistics: Statistics will be generated for, at a minimum, , area of geographic atrophty,
ETDRS visual acuity, central retinal thickness and presence of hemorrhage. Within patient
trajectories for these outcomes will be plotted, incorporating information on dose and
duration. Analysis of Variance may be conducted to relate logarithm of dose and duration of
treatment to the outcomes listed above.
