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Supplements Implications of Early Treatment for Parkinson’s Disease [CME/CPE]

Early Pharmacologic Treatment in Parkinson's Disease

Robert A. Hauser, MD, MBA
Cabergoline was studied in a 3- to 5-year double-blind trial in 412 patients with early PD. Cabergoline monotherapy was first compared with levodopa, and then the combination of cabergoline and levodopa (once UPDRS scores decreased 30% below baseline) was compared with higher-dose levodopa monotherapy.11 Cabergoline monotherapy was associated with less than half the rate of motor complications compared with levodopa, although the cabergoline + levodopa combination (ultimately involving 65% of the initial cabergoline monotherapy patients) was not better than levodopa alone for motor complications.11

Thus, the dopamine agonists appear to be associated with a lower incidence of dyskinesia but levodopa provides greater symptomatic benefit. In imaging studies, the dopamine agonists pramipexole and ropinirole were associated with slower decline compared with levodopa, but this may be a function of greater compensatory or pharmacologic changes with levodopa compared with dopamine agonists and not a true indicator of disease progression.

Monoamine Oxidase Type B Inhibitors

Two Cochrane review publications analyzed clinical trial data with MAO-B inhibitors-primarily selegiline (deprenyl)-in early PD. A full discussion of these results is located below, but overall, the meta-analyses found that MAO-B inhibitors were effective in reducing motor fluctuations and disability, were neutral with regard to mortality, and reduced the need for levodopa. However, MAO-B inhibitors were not clearly associated with slowing disease progression.12,13

The effects of selegiline therapy on newly diagnosed PD were assessed in a double-blind, placebo-controlled study in 157 patients.14 Patients were randomly assigned to receive either selegiline 10 mg or placebo once daily until levodopa therapy became necessary. Thereafter, selegiline (or placebo) was withdrawn for an 8-week washout period to evaluate the possible symptomatic effect of selegiline. Compared with placebo, selegiline therapy significantly delayed the need for levodopa (P = .028). However, after the washout period, no significant differences in worsening of disability were observed between the 2 groups, suggesting that besides having a slight symptomatic effect, selegiline may also have neuroprotective effects.

In the second phase of the study, 140 patients received selegiline 10 mg or placebo once daily in combination with individually tailored levodopa therapy.15 Compared with placebo, selegiline slowed the progression of disease disability as measured by UPDRS total score (P = .003), motor score (P = .002), and activities of daily living score (P = .0002). After 5 years, the mean dose of levodopa was 19% higher for those given placebo compared with those given selegiline (P = .0002). Patients given selegiline had total UPDRS scores 26% better than those given placebo, and the mean difference in UPDRS total score was approximately 10 points. Results from both phases of this study, which comprised 7 years in total, suggest that selegiline delays the clinical progression of the signs and symptoms of PD. Two 5-year studies in patients with early PD reported similar results, suggesting an increasing benefit with selegiline over time.16,17

Two double-blind, delayed-start clinical trials of the MAO-B inhibitor rasagiline suggest a possible neuroprotective or disease-modifying effect. In delayed-start studies, one group is assigned to treatment for the entire study (early-start group) and another group is assigned placebo for the first phase of the study and active medication during the second phase of the study (delayed-start group). Both groups receive the same treatment in the second phase of the study and, therefore, should both experience the same symptomatic benefit. Any difference between groups at the end of the study should be due to enduring benefits accruing in the active-treatment group during the initial phase of the study (early-start group), separate from symptomatic improvement.18

The initial trial-the TEMPO (TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients) study-included 404 patients with early PD who received rasagiline 1 or 2 mg/day for 1 year or placebo for the first 6 months followed by rasagiline 2 mg/day for the following 6 months.19 At 1 year, both early-start treatment groups demonstrated significantly better UPDRS scores than the delayed-start treatment group.19 An open-label extension of the TEMPO study showed a sustained effect of less worsening in the early-start treatment group over a period of 5.5 years to 6.0 years, even as standard PD therapy was added over time.20

A 2009 study-the ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily) trial-sought to verify the results of TEMPO in a larger patient population with more stringent end points. ADAGIO involved 1176 untreated patients with PD who were given rasagiline 1 or 2 mg/day for 72 weeks or placebo for 36 weeks followed by rasagiline 1 or 2 mg/day for the next 36 weeks.21 This allowed comparison of early versus delayed start for the 1-mg/day dose and early versus delayed start for the 2-mg/day dose. The outcome for a particular dose would be considered positive for the early-start group only if 3 outcomes were met: (1) superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36 (ie, less progression in the treated group in the first phase of the study); (2) superiority to delayed-start treatment in the rate of change in score between baseline and week 72 (a difference in change from baseline to the end of the study favoring the early-start group even as both groups were receiving active medication); and (3) noninferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72 (to demonstrate that the groups were not converging over the second phase of the study).21

The rasagiline 1-mg early-start treatment group achieved all 3 outcomes, while the 2-mg group achieved 2 of the end points (the early-start group did not demonstrate significant improvement at week 72 compared with baseline)21 (Figure 3). Thus, the results of the 1-mg/day evaluation are consistent with a disease-modifying effect of rasagiline, while the results of the 2-mg/day evaluation are not. The reason for this discrepancy is not known. It has been suggested that the 2-mg/day dose provided greater symptomatic benefit and thereby masked the ability to detect a disease-modifying effect.21 Although the ADAGIO 2-mg/day analysis was negative, the ADAGIO 1-mg/day evaluation, the TEMPO study, and the TEMPO long-term extension are all consistent with a disease-modifying effect of rasagiline. Additional results from the ADAGIO trial are located in the article by Chen22 in this supplement.

Coenzyme Q10

A small, randomized, double-blind, parallel-group study in 80 patients with early PD examined the effect of 3 doses of coenzyme Q10 (300, 600, and 1200 mg) on UPDRS scores compared with placebo over 16 months.23 Treatment with coenzyme Q10 trended toward a benefit in slowing symptoms compared with placebo, and with the 1200-mg dose, the difference was significant (P = .04).23 These data were promising, but required a larger trial for confirmation.

Storch et al subsequently conducted a somewhat larger (n = 131) 3-month, randomized, double-blind, placebo-controlled trial of coenzyme Q10 in a nanoparticle formulation (100 mg 3 times daily).24 Patients included in the trial had no motor fluctuations and were on stable antiparkinsonian treatment for at least 4 weeks leading up to the trial. Patients in both groups (coenzyme Q10 or placebo) experienced significant improvements from baseline in UPDRS scores (P <.001 for placebo, P = .007 for coenzyme Q10), but the active-treatment group fared no better than placebo.24

The use of coenzyme Q10 in early untreated PD was also assessed in a randomized, double-blind, placebo-controlled futility clinical trial.25 Coenzyme Q10 was administered as a 600-mg chewable wafer 4 times daily (2400 mg/day). The primary outcome measure was changes in total UPDRS score at 1 year. Although coenzyme Q10 could not be rejected as futile, the mean changes in total UPDRS scores were not significantly greater than the predetermined futility threshold value. Further studies are needed to determine the effect of coenzyme Q10 in early PD; a large phase 3 trial in collaboration with the National Institute of Neurological Disorders and Stroke is currently recruiting participants.26

Vitamin E (Tocopherol)

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