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Levodopa Treatment Not Associated with Accelerated Progression in Parkinson's Disease: Presented at AAN

By Paula Moyer

HONOLULU, HI -- April 3, 2003 -- Treatment with levodopa does not hasten the rate of progression of Parkinson's disease (PD) and it may have a slowing effect, according to a multicenter study.

"We found no evidence that levodopa is harmful, but we also could not conclude that it was protective against progression [of the disease]," said Stanley Fahn, MD, H. Houston Merritt Professor of Neurology, and Director, Center for Parkinson's Disease and other Movement Disorders, Columbia University, New York.

Dr. Fahn presented the results of the Earlier vs. Later Levodopa in Parkinson's Disease (ELLDOPA) here April 1^st at the 55^th Annual Meeting of the American Academy of Neurology.

Earlier research showed conflicting results regarding whether levodopa was neurotoxic or neuroprotective. To determine the drug effect on PD progression, Dr. Fahn and co-investigators enrolled 361 patients to participate in a parallel group, double-blind, randomized study, with three dosage treatment arms with one placebo arm.

The 92 patients in the low carbidopa/levodopa dose arm received 12.5/50 mg three times daily; 88 patients in the medium dose arm received 25/100 mg three times daily; 91 patients in the high dose arm received 50/200 mg three times daily. The placebo arm consisted of 90 patients.

All patients had early PD of less than 2 years duration and none required symptomatic therapy. The drug dosage was escalated over 9 weeks and was then maintained until the 40^th week, when active treatment was withdrawn over a 3-day period.

After 2 weeks without active treatment, the investigators conducted a final assessment of each patient's PD severity using the Unified Parkinson Disease Rating Scale (UPDRS). They also used single photon emission computed tomography (SPECT) to assess the change in beta-CIT uptake, quantifying the percent change in the striatal dopamine transporter between baseline and Week 40. Among the 361 subjects, 142 were included in the neuroimaging sub-study.

When they compared the change between baseline and the 42^nd week in total UPDRS among the four arms the investigators found that patients benefited from all levodopa dosages compared to placebo throughout the study, and that this benefit persisted in the two weeks after they stopped treatment.

Changes in total UPDRS scores from baseline to the 42^nd week averaged -1.4 for the group receiving a total levodopa dose of 600 mg daily. For the group receiving a total of 300 mg daily, the change averaged +1.9. The group receiving a total of 150 mg daily had an average change of +1.9. The placebo group had an average change of +7.8 (P< 0.0001).

Similar benefits were noted in other measurements of PD severity, Dr. Fahn reported, including the quality of life scores (P< 0.0001) and the Schwab-England Activities of Daily Living scores (P=0.0039).

Rates of nausea and dyskinesias were significantly higher in the levodopa groups (P=0.001 and P=0.0001, respectively) with more of these effects seen at higher dosages. Therefore, he said, the 150 mg daily and 300 mg daily doses may be better tolerated than the 600 mg daily dose.

The percent decline of beta-CIT uptake in the striatum was significantly more pronounced in the levodopa groups than the placebo group, Dr. Fahn reported. Those rates per group were -7.2% for the 600 mg group, -4% for the 300 mg group, -6% for the 150 mg group, and -1.4% for placebo (P=0.035).

These findings show that levodopa alleviates the signs and symptoms of early PD in a dose-dependent manner, Dr. Fahn said. Although the study's washout design would not have detected a more sustained symptomatic benefit, the findings suggest that levodopa may slow the rate of disease progression, he added.

Although the clinical findings did not demonstrate any evidence of levodopa toxicity in early PD, results of the beta-CIT SPECT sub-study suggest that levodopa caused a more rapid decline in the integrity of the dopamine transporter located in the nigrostriatal nerve terminals. Because these findings are conflicting, investigators should continue to study the effect of levodopa on PD, he said.

The study was funded by a grant from the National Institutes of Health. The carbidopa/levodopa and matching placebo tablets were donated by Teva Pharmaceuticals Industries of Netanya, Israel.


[Study title: Does Levodopa Slow or Hasten the Rate of Progression of Parkinson Disease? The Results of the Elldopa Trial. S09.003]

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