LEAP
(2019)Objective
Levodopa – To determine whether delayed initiation of levodopa has a disease-modifying effect in patients with early Parkinson's disease.
Study Summary
• Motor complications and adverse events were similar between groups.
Intervention
Randomized, double-blind, placebo-controlled, delayed-start trial. Patients were assigned to receive either levodopa 100 mg + carbidopa 25 mg TID for 80 weeks (early-start), or placebo for 40 weeks followed by the same levodopa regimen for 40 weeks (delayed-start). Primary outcome: change in total UPDRS score from baseline to week 80. Secondary outcomes included rate of progression, quality of life, cognition, and depression scores.
Inclusion Criteria
Patients ≥30 years old with clinical diagnosis of Parkinson's disease within past 2 years, insufficient disability to require antiparkinson therapy, and life expectancy >2 years. Excluded if prior antiparkinson drug use, dementia, or atypical parkinsonism.
Study Design
Arms: Early Levodopa vs. Delayed Levodopa
Patients per Arm: Early: 222; Delayed: 223
Outcome
• Rate of symptom progression (weeks 4–40): 0.04 vs. 0.06 UPDRS points/week (difference –0.02)
• No significant difference in quality of life (PDQ-39), cognition (MMSE), depression (BDI-II), or disability (ALDS) at week 80
• Adverse events: nausea more common in early-start (23% vs. 14% during first 40 weeks); motor complications not significantly different
Bottom Line
Levodopa does not have a disease-modifying effect in early PD: after 80-week delayed-start design, no significant difference between early and delayed levodopa groups in UPDRS total score (-1.0; 95% CI -2.6 to 0.5; P=0.44). Levodopa 100mg TID. 445 patients. Published NEJM 2019.
Major Points
- No disease-modifying effect: UPDRS total at 80 weeks -1.0 difference (early vs delayed); P=0.44.
- Delayed-start design: 40 weeks levodopa vs placebo, then 40 weeks all on levodopa.
- 445 early PD patients not requiring dopaminergic therapy. 1:1 randomization.
- Levodopa 100mg/carbidopa 25mg TID (300mg/day levodopa).
- Symptomatic benefit confirmed: early group better at 40 weeks (-3.2; P<0.001). Gap closed by 80 weeks.
- Disproves 'levodopa toxicity' hypothesis — no evidence levodopa accelerates disease.
- UPDRS-III: -1.5 at 80 weeks (P=0.15). UPDRS-II: -0.2 (P=0.70).
- AEs: dyskinesia 3.5% early vs 2.2% delayed at 80 weeks. Nausea similar.
- Published NEJM 2019 (Verschuur et al., PD-LEAP investigators). Dutch multicenter.
- Landmark trial settling longstanding debate about levodopa timing in PD.
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled, delayed-start trial
- Randomization
- Yes
- Blinding
- Patients and investigators were blinded to treatment allocation
- Sample Size
- 445
- Follow-up
- 80 weeks
- Centers
- 50
- Countries
- Netherlands
Primary Outcome
Definition: Change in total UPDRS score from baseline to week 80
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| −2.0 ± 8.2 | −1.0 ± 7.6 | - (−3.0 to 1.1) | 0.44 |
Limitations & Criticisms
- Study duration (80 weeks) may be insufficient to detect long-term disease-modifying effects
- Dose and duration of levodopa may not reflect broader clinical practice
- Exclusion of patients needing immediate treatment may reduce generalizability
Citation
N Engl J Med 2019;380:315–324. doi:10.1056/NEJMoa1809983