The LEAP trial: levodopa not associated with a disease-modifying effect in Parkinson’s disease

1. During an 80-week trial period of patient’s with early Parkinson’s disease (PD), there was no difference in the severity of symptoms between patients treated with levodopa-carbidopa for all 80 weeks (early-start group) versus those treated with levodopa-carbidopa for the second 40 weeks (delayed-start group).

2. There was no significant difference between the rates of dyskinesia and levodopa-related motor fluctuations at 80 weeks between the early-start and delayed-start groups.

Evidence Rating Level: 1 (Excellent)   

Study Rundown: Though the ELLDOPA trial demonstrated that patients with early PD received clinical benefit from levodopa two weeks after the medication was stopped, it is unclear whether this due to disease-modifying activity or prolonged symptomatic relief. To differentiate between disease-modifying and symptomatic effects, the Levodopa in Early Parkinson’s Disease (LEAP) trial randomized patients to levodopa-carbidopa for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa-carbidopa for 40 weeks (delayed-start group). The authors found no significant difference in the primary outcome – change from baseline to week 80 in the Unified Parkinson’s Disease Rating Scale (UPDRS) – at the end of the trial period. The primary outcome was further supported by a noninferiority analysis of disease progression between the groups in the second phase of the trial. Among secondary outcomes, there was no significant difference in disability, cognitive impairment, depression, or quality of life. The results of this trial suggest that levodopa does not have a disease-modifying effect on the progression of PD.

This trial was designed in two phases to differentiate between a prolonged effect on PD symptoms and a disease-modifying effect, and additionally included a prespecified progression analysis to further support the findings. Limitations include the absence confirmatory neuroimaging, given the high rate of clinical misdiagnosis in PD. Furthermore, the author’s used an intermediate dose of levodopa-carbidopa, and thus the results may differ with a higher or lower dose.

Click to read the study in NEJM

Click to read an accompanying editorial in NEJM

Relevant Reading: Levodopa and the progression of Parkinson’s Disease

In-Depth [randomized controlled trial]: Patients diagnosed with PD (n=445) were randomized to treatment with levodopa (100mg three times daily) and carbidopa (25mg three times daily) for 80 weeks (early-start group; n=222) or with placebo for 40 weeks followed by levodopa-carbidopa for 40 weeks (delayed-start group; n=223). The primary outcome was the difference between the early- and delayed-start groups in mean change from baseline to week 80 in the total score on the UPDRS. Secondary outcomes at 80 weeks included disability assessed by the Academic Medical Center Linear Disability Score (ALDS), cognitive impairment assessed by the Mini-Mental State Examination (MMSE), depression assessed by the Beck Depression Inventory II (BDI-II), and quality of life assessed by the Parkinson’s Disease Questionnaire-39 (PDQ-39).

Among the 445 patients randomized, 207 patients in the early-start group and 210 patients in the delayed-start group completed the 80-week trial. The mean change in UPDRS in the early-start group was -1.0±13.1 points vs. -2.0±13.0 points in the delayed-start group (between-group difference 1.0; 95% confidence interval [CI], -1.5 to 3.5; P=0.44). The change in UPDRS from baseline to week 40 was -3.1±10.2 in the early-start group vs. 2.0±12.3 in the delayed-start group (difference, -5.1 points; 95% CI, -7.2 to -2.9). Between weeks 4 and 40, the change in UPDRS points per week (measure of progression) was 0.04±0.23 in the early-start group vs. 0.06±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The rate of change between weeks 44 and 80 were 0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10), which did not meet non-inferiority of early to delayed receipt of levodopa. There was no significant difference between the two groups in ALDS, MMSE, BDI-II, and PDQ-39 scores. The early-start group had a higher incidence of nausea in the first 40 weeks of the trial (23.0% vs 14.3%; P=0.02). At 80 weeks, there was no significant difference in motor complications between the groups.

Image: PD

©2019 2 Minute Medicine, Inc. All rights reserved. No works may be reproduced without expressed written consent from 2 Minute Medicine, Inc. Inquire about licensing here. No article should be construed as medical advice and is not intended as such by the authors or by 2 Minute Medicine, Inc