Levodopa is the most effective and widely used drug in ameliorating the signs and symptoms of Parkinson's disease (PD). In recent years, an increasing number of scientific reports find both levodopa and dopamine to be toxic to catecholaminergic neurons both in vitro and in vivo animal models of PD. This has led to a growing concern among neurologists and neuroscientists that levodopa treatment may be hastening the growing concern among neurologists and neuroscientists that levodopa treatment may be hastening the underlying progressive degeneration of nigral dopaminergic neurons, the pathological hallmark of PD. Since levodopa is the major drug used to treat PD, it is important to determine whether levodopa does or does not aggravate PD. The investigators in this study have a great deal of uncertainty (clinical equipoise) about the possible toxicity of levodopa. On one hand, early introduction of levodopa could lead to immediate symptomatic benefit and a higher quality of life. Alternatively, if levodopa hastens progression of dopaminergic cell loss, it will more rapidly lead to advanced disease, which ultimately fails to respond to levodopa or other anti-PD drugs. The main goal of this controlled clinical trial is to answer the question: does the early introduction of levodopa provide improved quality of life to PD patients or does it enhance the underlying progression of PD? We will enroll 360 patients with early, untreated PD into this randomized, placebo-controlled, double blinded, multi-center clinical trial. Subjects will be randomized into one of four equally sized treatment arms: carbidopa/levodopa (12.5/50, 25/100, 50/200 mg tid) and matching placebo. They will be treated for 9 months, a duration which is clinically meaningful and feasible in minimizing premature withdrawal from the trial. The primary outcome variable is the rate of PD clinical progression based on a dose-response curve, comparing baseline to post- treatment measures. PD progression will be measured by the change in total Unified Parkinson's Disease Rating Scale (UPDRS) between untreated baseline and final visit. The final visit will take place 14 days after withdrawal from experimental treatments subsequent to 9 months of follow-up on treatment. The blinded institutional primary rater, who will otherwise not be involved in clinical evaluations or medication adjustments during the trial, will perform these baseline and final UPDRS evaluations. The blinded institutional treating investigator will evaluate subjects at 3-month intervals and may adjust the frequency of dosings or add specified antidote drugs to overcome complications from study drug when judged to be clinically required. No symptomatic anti- PD drug will be openly added during the trial. Knowledge gained from this study will address the most common concern of patients, families and clinicians, namely should levodopa be delayed as long as clinically feasible or be used as early as possible.
|Fahn, Stanley; Oakes, David; Shoulson, Ira et al. (2004) Levodopa and the progression of Parkinson's disease. N Engl J Med 351:2498-508|
|Tagliati, M; Perl, D P; Drayer, B et al. (2000) Progressive dementia and gait disorder in a 78 year old woman. J Neurol Neurosurg Psychiatry 68:526-31|