CME Author: Vicki Brower
Study Authors: C.V.M. Verschuur, S.R. Suwijn, et al.
Target Audience and Goals:
Neurologists, internists, and family medicine specialists
The goal was to determine whether levodopa, given early in Parkinson’s disease with carbidopa, is disease-modifying and safe.
- Does giving levodopa to early-stage Parkinson’s disease patients slow the progression of the disease, and if so, is it also safe, or does it accelerate disease progression?
- Do trial results suggest a change in prescribing practices for Parkinson’s patients?
Study Synopsis and Perspective:
Early levodopa treatment in Parkinson’s disease (PD) appeared to be neither neuroprotective nor harmful, the LEAP randomized clinical trial found.
Levodopa, which has been used to control PD symptoms for nearly half a century, showed no between-group difference in motor scores at 80 weeks, regardless of whether treatment was initiated early or late, reported Rob de Bie, MD, PhD, of the University of Amsterdam, 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 PD 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, enhancing neurodegeneration through reactive oxygen species and oxidative stress. “In contrast, some investigators suggested that levodopa could induce beneficial trophic effects.”
LEAP (Levodopa in Early PD), a multicenter trial conducted in the Netherlands, aimed to clarify ambiguous findings from the 2004 ELLDOPA study, which suggested that, clinically, levodopa may slow the progression of PD 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 the LEAP study, researchers randomized 445 patients with early PD 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 idea behind this trial design 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.
Researchers also designed the trial 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 scores from baseline to week 80 was −1.0 point 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.
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.
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.
Notably, the LEAP study looked at only one dose of levodopa — a compromise dose 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 recommended.
Source References: New England Journal of Medicine, Jan. 24, 2019; DOI:10.1056/NEJMoa1809983
Editorial: New England Journal of Medicine, Jan. 24, 2019; DOI:10.1056/NEJMe1814611
Study Highlights: Explanation of Findings
This study showed an effect of levodopa on symptoms of Parkinson’s disease in the first 40 weeks of the trial (the placebo-controlled phase of the trial) but no significant difference in UPDRS scores at week 80 (with all patients receiving active treatment from week 40 on). The findings indicated that the severity of parkinsonian symptoms at the end of the trial did not differ significantly between patients who received early initiation of the drug and those who received delayed initiation, and implied that levodopa had no disease-modifying effect on Parkinson’s disease over the period of the trial, the researchers observed.
They designed the randomized, double-blind, placebo-controlled trial to determine whether the drug had any disease-modifying effect on symptoms, by employing a delayed start, two-phase design. In the first phase, because half of the patients received a placebo, it would be clear whether the disease had, by week 40, disease-modifying effects. In the second phase, all patients received the drug, with half the group receiving it in later-stage disease for 40 weeks, the other half completing 80 weeks by trial’s end. Any difference at week 80, then, would be due to disease-modifying effects.
During the first 40 weeks of the study, the incidence of nausea was higher in the early-start treated group than in the delayed-start group (23% vs 14.3%, P=0.02). At 80 weeks, the percentage of patients with motor complications, including dyskinesias and fluctuation in motor response, did not differ significantly between the two groups.
The editorialists noted the “how and when” to prescribe levodopa have been controversial issues. Concern with complications of the drug, such as dyskinesia, and a wearing-off of therapeutic effects, combined with the worry that the drug itself had neurotoxic effects of enhancing neurodegeneration through reactive oxygen species and oxidative stress, was weighed against other evidence that levodopa could induce beneficial trophic effects.
Designed to clarify the ambiguous results in the previous ELLDOPA trial, the LEAP study supported maintaining current prescribing practices, as the drug was not harmful when given longer, and also was not disease-modifying. There is no reason to delay therapy when clinically needed, and there is also no indication that early initiation of levodopa slows symptom progression, the authors and editorialists stated.
There were a number of limitations to the study. Because 39% of patients in the delayed-start group needed symptomatic relief during the first phase of the trial, and took levodopa early, “this finding limits the power of comparison between the groups in assessing the effect of disease modification,” the editorialists wrote. “A per-protocol analysis that included only patients who completed their originally assigned treatment also did not show evidence of slowing of progression of symptoms with early initiation of levodopa, but the trial was probably insufficiently powered to allow firm conclusions.”
They noted that newer studies are addressing the disease’s heterogeneity, including those that are based on genotype, and testing targeted treatments that may be found to be disease-modifying.