Early Levodopa Neither Protective Nor Harmful in Parkinson’s

Early levodopa treatment in Parkinson’s disease appeared to be neither neuroprotective nor harmful, the LEAP randomized clinical trial found.

Levodopa, which has been used to control Parkinson’s symptoms for nearly half a century, showed no between-group difference in motor scores at 80 weeks regardless of whether it was started early or late, reported Rob de Bie, MD, PhD, of the University of Amsterdam, the Netherlands, and co-authors in the New England Journal of Medicine.

“There has been a longstanding concern that starting levodopa early could accelerate the disease or have other long-term adverse consequences,” de Bie said in a statement. “Physicians have often withheld the drug early in the disease and delayed starting it until the patients experienced more overt disability.”

The practice of restricting levodopa by treating Parkinson’s with other medications evolved in the 1980s and 1990s, noted Susan Bressman, MD, and Rachel Saunders-Pullman, MD, MPH, both of the Icahn School of Medicine at Mount Sinai in New York City, in an accompanying editorial.

“This approach was derived from concerns about the common complications associated with levodopa — involuntary movements (dyskinesia) and fluctuations of motor control, including a wearing-­off of the medication effect and a delayed onset of the medication effect — that are observed in up to one half of patients after 2 years of treatment,” they wrote.

“There was also concern that levodopa was neurotoxic and that it enhanced neurodegeneration through reactive oxygen species and oxidative stress,” Bressman and Saunders-Pullman continued. “In contrast, some investigators suggested that levodopa could induce beneficial trophic effects.”

LEAP (Levodopa in Early PD), a multicenter trial in the Netherlands, aimed to clarify ambiguous findings from the 2004 ELLDOPA study, which suggested that, clinically, levodopa may slow the progression of Parkinson’s disease or exert a prolonged effect on the symptoms of the disease. In contrast, ELLDOPA neuroimaging data suggested that levodopa either accelerated the loss of dopamine nerve terminals or modified the striatal dopamine transporter.

In LEAP, researchers randomized 445 patients with early Parkinson’s disease to receive levodopa 100 mg in combination with carbidopa 25 mg, both three times per day, for 80 weeks (early-start group, n=222) or 40 weeks (delayed-start group, n=223) from 2011 to 2016. The premise was that the early-start group would have longer exposure to potential disease-­modifying effects and — if levodopa slowed disease progression — better clinical outcomes at 80 weeks. In the first 40 weeks, patients received levodopa or placebo; in the second 40 weeks, participants in both groups received the drug.

The trial was designed so that if a disability involving activities of daily living developed in the first 40 weeks, a patient could switch to open-label levodopa. Because of this, 87 patients in the delayed-start group received levodopa before week 40, and 24 patients in the early-start group proceeded to open-label treatment with the same dose of levodopa.

The study’s primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS). Scores on UPDRS range from 0 to 176, with higher scores signifying more severe disease. At baseline, the mean UPDRS was 28.1 points in the early-start group and 29.3 points in the delayed-start group; other baseline clinical characteristics and demographics were similar between the two groups.

At week 80, the change in UPDRS score from baseline to week 80 was −1.0 points in the early-start group and −2.0 points in the late-start group (difference 1.0 point, 95% CI −1.5 to 3.5, P=0.44), implying that levodopa had no disease-modifying effect.

Rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups, suggesting patients in the early-start group were not negatively affected by their longer exposure to the drug.

This trial supports current practice, Bressman and Saunders-Pullman observed; its results, 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 wrote.

LEAP looked at only one dose of levodopa — a compromise between higher doses, which are associated with a greater risk of side effects, and lower, less effective doses, de Bie’s group noted. Whether higher doses, longer periods of administration, or later initiation might alter the course of Parkinson’s disease should be studied, they suggested.

And despite a number of patients proceeding to open-label levodopa treatment in the first 40 weeks, the per-protocol analyses, which took the switch into account, showed similar results to those found in the intention-to-treat analysis, the authors added.