Clinical Trials Of Selegiline Datatop

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The DATATOP (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism) study (70) evaluated 800 PD subjects randomized to receive selegiline 10mg/day or placebo. The total Unified Parkinson's Disease Rating Scale (UPDRS) scores were improved in the selegiline-treated group compared with placebo at one month (2.1 vs. 0.1; P < 0.001) and at three months (1.6 vs. -1.3; P < 0.001). The motor UPDRS scores also improved significantly in the selegiline compared with the placebo group at one month (1.4 vs. 0.01, P < 0.001) and at three months (0.9 vs. -0.8; P < 0.001). In the DATATOP trial, selegiline delayed the need for levodopa by approximately nine months compared with placebo. Following selegiline withdrawal, there was no loss of benefit at one month but at two months, total UPDRS had worsened 3.2 points in selegiline-treated patients compared to 0.5 in placebo-treated patients (P < 0.001). Selegiline monotherapy slowed decline in parkinsonian disability in the DATATOP trial and other clinical trials (71,72), as measured by motor or total UPDRS scores or other standardized rating scales (73).

A DATATOP open-label extension study (74) evaluated subjects who had reached endpoint (need for levodopa) in the original DATATOP trial (70). In this study (74), 352 of 371 subjects completed the 18-month follow-up; all were treated with selegiline 10mg/day and levodopa as needed. Patients originally treated with selegiline had taken levodopa for a significantly shorter period of time (P < 0.0001) and received significantly lower total cumulative levodopa dosages (P < 0.02) over that 18-month period than those initially randomized to placebo in the DATATOP trial. However, the total daily levodopa dosage at final evaluation was similar between groups, and wearing off, dyskinesia, and freezing occurred in the same proportion of patients originally treated with selegiline compared with placebo.

Subjects who completed the original DATATOP trial but did not reach the endpoint (i.e., did not require levodopa) were initially withdrawn from selegiline or placebo for two months, and then were placed on open-label selegiline 10mg/day in another extension study (75). The original treatment blind was maintained. Whereas subjects treated with selegiline had better total UPDRS scores than placebo subjects prior to selegiline withdrawal, after the two-month selegiline withdrawal, total UPDRS scores were not different between the groups. These two open-label DATATOP extension studies (74,75) suggest a symptomatic rather than neuropro-tective benefit of selegiline.

Original DATATOP subjects (n=368)who had required levodopa therapy and were on open-label selegiline underwent an independent second randomization (76). One half were assigned to continue selegiline 10mg/day and the other half received placebo. Subjects were followed over two years. There was no significant overall difference between the two groups in the primary outcome measure of occurrence of motor fluctuations. There was a nonsignificant difference in wearing off (52% placebo vs. 41% selegiline); however, dyskinesia occurred significantly more often in subjects assigned to selegiline compared with placebo (34% vs. 19%; P = 0.006). Secondary outcome measures included time until motor fluctuations, freezing of gait, confusion, and dementia. Gait freezing was reported in 29% of the placebo group and 16% of selegiline-treated subjects (P = 0.0003). In addition, there was significantly less decline in UPDRS total (P = 0.0002), motor (P = 0.0006), and activities of daily living (ADL) (P = 0.0045) subscales in the selegiline-treated group. These results again suggest a mild symptomatic benefit of selegiline with better UPDRS scores, less likelihood of freezing, and a higher rate of dyskinesia when compared with placebo (76).

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