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6th International Congress of Parkinson's Disease and Movement Disorders June 13, 2000 Clinical trials in Parkinson's disease: new releases The earlier vs. later Levodopa (ELLDOPA) study: a clinical trial to evaluate levodopa's effect on the natural history of Parkinson's disease S. Fahn (New York, USA) With the awareness that levodopa could increase oxidant stress in dopaminergic neurons, concern has arisen whether such stress can lead to more rapid progression of the disease itself, i.e. enhance further neurodegeneration of dopaminergic neurons. However, administering levodopa to healthy animals and to non-parkinsonian humans have failed to find any loss of dopaminergic neurons in the substantia nigra. But results of dopa studies in non-parkinsonian humans is insufficient evidence to claim that levodopa is not toxic to people who have PD. In such individuals, it is possible that supplying exogenous levodopa would augment any oxidative stress their dopamine neurons may be undergoing. Studies in rodent models of PD have provided mixed results. Thus, there is genuine uncertainty what effect on dopaminergic neurons levodopa therapy in patients with PD will actually have. The question as to whether levodopa hastens or slows the progression of PD can be answered only in patients with the disease. The ELLDOPA study, a placebo-controlled, randomized, double-blind clinical trial currently being conducted by the Parkinson Study Group, seeks to determine levodopa's effect on the natural history of PD. A total of 360 subjects with early, mild PD, not yet requiring symptomatic treatment are to be enrolled in a total of 35 clinical sites in North America. Subjects will be randomly assigned to one of four treatment groups, with 90 subjects in each treatment arm: (1) placebo; (2) carbidopa/levodopa 12.5/50 mg t.i.d.; (3) carbidopa/levodopa 25/100 mg t.i.d.; and (4) carbidopa/levodopa 50/200 mg t.i.d. The plateau dose of levodopa is to be reached after a gradual increase in dosage to avoid induction of adverse effects. Teva Pharmaceuticals (Netanya, Israel) has generously provided the carbidopa/levodopa and matching placebo tablets for this study. After 40 weeks of treatment, a step-down 3-day washout of investigation medications occurs. The subjects return 14 days after all medications have been eliminated to assess changes in UPDRS at this time points to obtain a dose-response curve, which is the primary objective. The secondary objectives of ELLDOPA are to determine 1) the change in the dopamine transporter in the striatum, based on ß-CIT SPECT scans at base line and just prior to the Week-40 visit, 2) when the long-duration response to levodopa is lost; 3) if the dosage of levodopa is a factor in the loss of the long-duration response; 4) the presence of fatigue is in patients with early disease and how severe it is; and 5) how early initiation or the dosage of levodopa affects signs and symptoms of PD, the quality of life, and fatigue. Although a longer duration of exposure to levodopa or placebo would be desirable to increase the power of the study, we have limited the trial to 40 weeks (9 months) to keep all subjects in the study and minimize premature terminations from the trial, which could occur if parkinsonian symptoms worsen to the point where symptomatic treatment is necessary. No other anti-PD medication will be allowed in the trial to avoid the possible confounding influence of other drugs on the natural history of PD.