Randomized Delayed-Start Trial of Levodopa in Parkinson’s Disease

Abstract

BACKGROUNDLevodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated. METHODSIn a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The 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 range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week. RESULTS

Three-Year Gait and Axial Outcomes of Bilateral STN and GPi Parkinson’s Disease Deep Brain Stimulation

“…A chi-square test was used to compare gender between groups. The Mann-Whitney U-test was used to compare the differences between groups in the mean change of gait score, axial score, UPDRS-II total score, and UPDRS-III total score from baseline to 36 months (Verschuur et al, 2019). The one-way repeated measures ANOVA was applied to test for an effect of DBS target and follow-up time for each score.…”

The “Long and Winding Road” of the Disease‐Modifying Effects of Levodopa Has Not Ended Yet

“…It is used to minimize the power of expectations, which is especially important in PD . In the LEAP trial, Verschuur and colleagues reported interesting patients’ assumptions about treatment allocation (Table S6 in ref. ): nearly 75% of the delayed‐start group participants correctly guessed their allocation (vs. 38.4% of the early‐start group).…”

“…In the LEAP trial, Verschuur and colleagues reported interesting patients’ assumptions about treatment allocation (Table S6 in ref. ): nearly 75% of the delayed‐start group participants correctly guessed their allocation (vs. 38.4% of the early‐start group). This represents a nonnegligible relative risk of correct versus not knowing or wrong assumption of 1.94 (95% confidence interval, 1.60–2.35).…”

“…In this context, the publication of the results of the recent Levodopa in Early Parkinson Disease (LEAP) trial have raised a lot of interest, as the primary objective of this large study aimed specifically at studying the effect of levodopa on disease progression using a sophisticated methodological approach with a "delayed-start" design in placebo-controlled, randomized, double-blind conditions. 19 In this trial that included a total of 445 PD patients, the participants were randomized to receive levodopa in combination with carbidopa for 80 weeks or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks, incorporating either the early or the delayed-start group, respectively. In the end, there was no significant difference between the total score on the Unified Parkinson's Disease Rating Scale, suggesting therefore that levodopa has no other effect than a short-term symptomatic effect, without evidence of any impact on PD progression.…”

Does levodopa have a disease‐modifying effect in Parkinson's disease? Evidence from a delayed‐start trial

“…Considering the ELLDOPA trial as a point of reference in an attempt to resolve the uncertainty regarding the levodopa disease‐modifying effect, Verschuur and colleagues conducted the Levodopa in Early Parkinson's Disease (LEAP) trial with a delayed‐start design. A total of 445 early‐stage PD patients were randomly assigned: 222 to the early‐start group (100/25 mg of levodopa/carbidopa 3 times per day for 80 weeks) and 223 to the delayed‐start group (placebo for 40 weeks followed by levodopa/carbidopa for the subsequent 40 weeks).…”