No Effect of Levodopa on Parkinson's Progression

January 25, 2019

Use of levodopa in early Parkinson's disease does not have any disease-modifying effect, either beneficial or detrimental, a new study suggests.

"There was no difference in Parkinson's symptoms or levodopa side effects at 80 weeks in those patients who started taking the drug at week 1 and those who started at week 40," senior author Rob de Bie, MD, PhD, University of Amsterdam, the Netherlands, told Medscape Medical News.

"This suggests that levodopa does not have any effect on disease progression — either positive or negative."

He explained that patients and physicians can be reluctant to start levodopa because there is a fear that prolonged use may be associated with faster disease progression, a wearing off of efficacy, or increased side effects.

"But our data give us reassurance that levodopa does not increase disease progression," he said.

"This should have a big impact on clinical practice," he added. "Patients can now start taking levodopa with confidence whenever they need to control symptoms without the worry that it may be having an adverse effect. The disease will still progress, and the levodopa may need to be used more frequently, but this does not appear to be related to past use of the drug."

The study was published online January 24 in the New England Journal of Medicine.

In an accompanying editorial, Susan Bressman, MD, and Rachel Saunders-Pullman, MD, MPH, Icahn School of Medicine at Mount Sinai, New York City, say this trial supports current practice.

"There is no evidence that early initiation of levodopa slows progression of the disease; on the other hand, there is no reason to delay therapy when it is clinically indicated. The results of the current trial, taken together with those of other trials, support treatment that is guided by clinical need and that uses the lowest dose that provides a satisfactory clinical effect," they write.

In their article, de Bie and colleagues explain that levodopa is the main treatment for Parkinson's disease but that physicians may delay initiating treatment for various reasons, including concern about the induction of dyskinesias. However, almost all patients ultimately receive levodopa to control motor symptoms.

They note that an earlier study provided mixed results on the effect of levodopa on disease progression.

The ELLDOPA study compared levodopa with placebo for 40 weeks. Patients who received the drug had fewer symptoms at 2 weeks after stopping the treatment than those who had been receiving placebo, suggesting that levodopa may slow the progression of Parkinson's disease or have a prolonged effect on symptoms.

However, neuroimaging data from that trial suggested either that levodopa had the detrimental effect of accelerating the loss of dopamine nerve terminals or that it modified the striatal dopamine transporter.

The investigators suggested that one way of distinguishing a possible disease-modifying effect of levodopa from an effect on symptoms would be to conduct a delayed-start trial. In the first phase, patients would receive either the active drug or placebo. A difference between the groups at the end of this phase may be the result of an effect on symptoms, or it may be a disease-modifying effect, or both.

During the second phase, both groups would receive the active drug, and persistent differences between the groups at the end of this phase could be presumed to be the result of a disease-modifying effect, because the effects of the drug on symptoms at that time would be the same in both groups.

The current study, known as LEAP, had such a design. In the LEAP trial, 445 patients with early Parkinson's disease were randomly assigned to receive either levodopa (100 mg) plus carbidopa (25 mg) three times per day for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa/carbidopa for 40 weeks (delayed-start group).

The mean Unified Parkinson's Disease Rating Scale (UPDRS) scores at baseline were 28.1 in the early-start group and 29.3 in the delayed-start group. The change in UPDRS score from baseline to week 80 was −1.0 points in the early-start group and −2.0 in the delayed-start group, a nonsignificant difference, which the authors say implies that levodopa had no disease-modifying effect.

Secondary outcomes supported this conclusion. Progression rates in the second phase of the trial did not show a benefit to the early-start group. In addition, no significant differences were observed between the groups with respect to the rates of dyskinesia and levodopa-related fluctuations, which suggests that the patients in the early-start group were not negatively affected by their longer exposure to levodopa, the researchers say.

The dose of levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) that was used in the trial was chosen as a compromise between higher doses, which are associated with a greater risk for side effects, and lower, less effective doses.

Whether higher doses of the drug, longer periods of administration, or initiation of the drug at later stages of the disease could alter the course of Parkinson's disease warrants evaluation in future trials, the authors state.

In their editorial, Bressman and Saunders-Pullman point out that 39% of patients initially allocated to receive placebo in the study actually started taking levodopa in the first phase because of the need for symptom relief. Although results of a per-protocol analysis that included only patients who completed their originally assigned treatment were similar to the results of the intention-to-treat analysis, the trial was probably insufficiently powered to allow firm conclusions, they say.

They add that trials of disease-modifying agents for the treatment of Parkinson's disease are underway.

"The potential for identifying effective disease-modifying agents and for advancing the field beyond the conundrum of early use as compared with later use of levodopa is promising," they conclude.

The LEAP trial was supported by grants from the Netherlands Organization for Health Research and Development, Parkinson Vereniging (a Dutch patient organization), and Stichting Parkinsonfonds and Stichting Parkinson Nederland (Dutch funding organizations for Parkinson's disease research). de Bie receives grant support from GE Health and Medtronic.

N Engl J Med. Published online January 23, 2019. Abstract, Editorial

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