ELLDOPA
(2004)Objective
The ELLDOPA trial (Earlier versus Later Levodopa Therapy in Parkinson Disease) investigated whether initiating levodopa earlier in Parkinson's disease alters disease progression or simply improves symptoms.
Study Summary
• Patients on 600 mg/day showed net improvement even after withdrawal
• Imaging suggested more dopamine transporter loss with levodopa
Intervention
Randomized, double-blind, placebo-controlled trial of carbidopa–levodopa at 3 doses (150, 300, 600 mg/day) vs. placebo in early PD. Duration: 40 weeks of treatment followed by 2-week washout. A SPECT substudy assessed dopamine transporter density using [123I]β-CIT.
Inclusion Criteria
• Age ≥30 years
• Diagnosis of Parkinson's disease within 2 years
• Modified Hoehn–Yahr stage <3
• Not expected to require symptomatic therapy within 9 months
Study Design
Arms: Placebo, Levodopa 150 mg/day, Levodopa 300 mg/day, Levodopa 600 mg/day
Patients per Arm: Placebo: 90, 150 mg: 92, 300 mg: 88, 600 mg: 91
Outcome
• [123I]β-CIT uptake declined more in levodopa group: –7.2% vs. –1.4% in placebo (P=0.036)
• Dyskinesias occurred in 16.5% of 600 mg group vs. 3.3% of placebo
Bottom Line
Levodopa treatment in early PD improves clinical outcomes in a dose-dependent fashion, but imaging showed increased dopamine transporter loss, suggesting no disease-modifying benefit and potential neurotoxicity.
Major Points
- 361 patients with early PD randomized to placebo or carbidopa–levodopa at 150, 300, or 600 mg/day for 40 weeks
- After 40 weeks, treatment was stopped and patients were evaluated 2 weeks later to assess for potential disease-modifying effects independent of symptomatic benefit
- UPDRS scores showed less worsening (or net improvement) in levodopa groups, particularly at 600 mg/day
- SPECT imaging using [123I]β-CIT revealed greater dopamine transporter loss in the levodopa-treated groups, with a dose-response relationship
- Dyskinesias were more frequent with higher doses of levodopa (16.5% at 600 mg/day)
- Trial raised questions about potential neurotoxicity of levodopa despite clear symptomatic benefit
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, dose-ranging trial with imaging substudy
- Randomization
- Yes
- Blinding
- Participants and investigators were blinded to treatment allocation
- Sample Size
- 361
- Follow-up
- 42 weeks (40 weeks treatment + 2-week washout)
- Centers
- 36
- Countries
- USA
Primary Outcome
Definition: Change in UPDRS total score from baseline to week 42 (2 weeks after stopping treatment)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| +7.8 points | 150 mg: +1.9; 300 mg: +0.4; 600 mg: –1.4 | - | <0.001 (600 mg vs placebo) |
Limitations & Criticisms
- Two-week washout may not have fully eliminated symptomatic effects of levodopa
- SPECT imaging changes may reflect pharmacologic downregulation rather than true neurotoxicity
- No long-term follow-up beyond 42 weeks to assess durability
- Imaging results apply only to substudy cohort (n=119)
Citation
N Engl J Med 2004;351:2498–2508. doi:10.1056/NEJMoa033447