Short Term Effects of Carbidopa-levodopa in Neovascular AMD
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Change in Best Corrected Visual Acuity
研究概览
简要总结
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.
详细描述
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% of 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 the 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 problems 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 50 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A diagnosis of AMD with choroidal neovascularization (CNV) in one eye;
- •Not previously treated with anti-VEGF injections;
- •Normal or dry AMD of any grade in the second eye;
- •Age 50-85 years;
- •Willingness to maintain AREDS vitamin supplements throughout the study, or remain off these supplements for the duration of the study, if not taking them prior to the study;
- •Signed Informed Consent.
排除标准
- •Any current use of L-DOPA containing medication or dopamine agonist medication, or any planned use of any of these agents, except for study medication, during the study;
- •Concurrent use of monoamine oxidase (MAO) inhibitors;
- •Any eye condition, disease, or history of trauma in either eye, which can impair vision, except cataract or cataract surgery;
- •Best Corrected Visual Acuity (BCVA )worse than 20/160 in the better eye;
- •Wet AMD in the second eye;
- •Neurologic conditions which can impair vision;
- •Parkinson's Disease;
- •Significant orthostatic hypotension, defined as a drop in systolic blood pressure, immediately upon changing from the supine to standing position, of >19 mmHg, or a symptomatic drop in systolic blood pressure, immediately upon changing from the supine to standing position;
- •Significant ECG abnormalities, as judged by the Investigator;
- •Estimated glomerular filtration rate (eGFR) <20 ml/min;
- •Liver enzymes >3 X the upper limit of normal;
- •HbA1C >9.0;
- •Any other significant lab abnormalities, as judged by the Investigator;
- •Women of childbearing potential;
- •Known retinal hemorrhage;
- •Subjects who are not fluent in English.
研究组 & 干预措施
once daily
carbidopa-levodopa 25-100 mg tablets once daily hs for up to 32 days
干预措施: carbidopa-levodopa 25-100 mg tablets (Drug)
3 times daily
carbidopa-levodopa 25-100 mg tablets 3 times daily,in the morning, with supper and hs for up to 32 days
干预措施: carbidopa-levodopa 25-100 mg tablets (Drug)
结局指标
主要结局
Change in Best Corrected Visual Acuity
时间窗: From start of study to first anti-vascular endothelial growth factor (VEGF) injection (8-32 days)
This outcome is a measure of letters correctly identified using an Early Treatment Diabetic Retinopathy Study chart. The higher the number of letters identified, the better the participant's visual acuity.
次要结局
- Change in Central Retinal (Macular) Thickness(From start of study to first anti-VEGF injection (8-32 days).)
- Percent Change in Retinal Fluid From Baseline(From start of study to first anti-VEGF injection (8-32 days))
- Treatment Emergent Adverse Events(From start of study to first anti-VEGF injection (8-32 days))