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ELLDOPA

Levodopa and the Progression of Parkinson's Disease

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Year of Publication: 2004

Authors: Parkinson Study Group (writing committee: Stanley Fahn, David Oakes, Ira Shoulson, ..., Kenneth Marek)

Journal: New England Journal of Medicine

Citation: N Engl J Med 2004;351:2498–2508. doi:10.1056/NEJMoa033447

Link: https://doi.org/10.1056/NEJMoa033447

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true

Clinical Question

Does initiating levodopa earlier in the course of Parkinson's disease modify disease progression or primarily offer symptomatic benefit?

Study Overview

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

Levodopa reduced UPDRS worsening in a dose-dependent manner
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 a 3-day step-down withdrawal and a 2-week off-drug washout (final assessment at week 42). A SPECT substudy assessed dopamine transporter density using [123I]β-CIT.

Patients per Arm

Placebo: 90, 150 mg: 92, 300 mg: 88, 600 mg: 91

Bottom Line

Levodopa treatment in early PD improves clinical outcomes in a dose-dependent fashion, but imaging showed greater dopamine transporter loss, leaving uncertainty about whether the drug offers disease modification or a prolonged symptomatic effect (or possible dopaminergic toxicity).

        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, subjects underwent a 3-day step-down withdrawal from the study drug and were then evaluated at week 42, after two weeks without the study drug, to assess for potential disease-modifying effects independent of symptomatic benefit
UPDRS total scores showed less worsening (or net improvement) in levodopa groups in a dose-dependent manner (placebo +7.8; 150 mg +1.9; 300 mg +1.9; 600 mg –1.4; P<0.001 for trend)
SPECT imaging with [123I]β-CIT revealed greater dopamine transporter loss in levodopa-treated groups (dose-response P=0.036 after excluding 19 subjects without baseline dopaminergic deficit)
Dyskinesias were more frequent with the highest levodopa dose (16.5% at 600 mg/day vs 3.3% placebo; P<0.001 for trend)
Trial raised questions about potential neurotoxicity of levodopa despite clear symptomatic benefit

      

Design

Study Type: Randomized, double-blind, placebo-controlled, dose-ranging trial with imaging substudy

Randomization: 1

Blinding: Participants, treating investigators, primary rater, and study coordinators were blinded to treatment allocation

Enrollment Period: September 1998 – August 2001

Follow-up Duration: 42 weeks (40 weeks treatment + 3-day step-down withdrawal + 2-week off-drug washout)

Centers: 38

Countries: USA, Canada

Sample Size: 361

Analysis: ANCOVA adjusted for investigator and baseline UPDRS for primary outcome; intention-to-treat (only subjects completing the 2-week washout included in the primary analysis)

Inclusion Criteria

Age ≥30 years
Diagnosis of idiopathic Parkinson's disease within the past 2 years
Modified Hoehn–Yahr stage <3
Not expected to require symptomatic therapy within 9 months
No prior treatment with dopaminergic therapy (or ≤14 days of levodopa/dopamine agonist)

Exclusion Criteria

Currently receiving antiparkinson medication
Prior exposure to levodopa or a dopamine agonist for more than 14 days
Identifiable cause of parkinsonism (atypical or secondary parkinsonism)
Tremor in any limb with UPDRS score ≥3, freezing of gait, or loss of postural reflexes
Major depression or dementia

Baseline Characteristics

Characteristic	Control	Active
Age	64.9 ± 10.3	~64.4 (weighted across 150/300/600 mg arms; 64.3±10.6, 63.8±12.1, 65.2±10.7)
Sex - Male	72%	~66% (63/67/68% across arms)
UPDRS (baseline)	27.7 ± 12.0	~28.0 (27.2±12.6, 27.5±11.6, 29.4±13.9)

Arms

Field	Control	Levodopa 150 mg/day	Levodopa 300 mg/day	Levodopa 600 mg/day
Intervention	Placebo tablets three times daily for 40 weeks	Carbidopa–levodopa 12.5/50 mg three times daily (150 mg/day total)	Carbidopa–levodopa 25/100 mg three times daily (300 mg/day total)	Carbidopa–levodopa 50/200 mg three times daily (600 mg/day total)
Duration	40 weeks treatment + 3-day step-down + 2-week off-drug washout	40 weeks treatment + 3-day step-down + 2-week off-drug washout	40 weeks treatment + 3-day step-down + 2-week off-drug washout	40 weeks treatment + 3-day step-down + 2-week off-drug washout

Outcomes

Outcome	Type	Control	Intervention	P-value
Change in UPDRS total score from baseline to week 42 (2 weeks after stopping treatment)	Primary	+7.8 ± 9.0 points	150 mg: +1.9 ± 6.0; 300 mg: +1.9 ± 6.9; 600 mg: –1.4 ± 7.7	<0.001 for trend
Percent change in striatal [123I]β-CIT SPECT uptake between baseline and week 40, after excluding 19 subjects without baseline dopaminergic deficit (n=116)	Secondary	−1.4 ± 10.0%	150 mg: −6.0 ± 10.3%; 300 mg: −4.0 ± 9.4%; 600 mg: −7.2 ± 7.6%	0.036 for dose-response
Proportion with dyskinesia	Secondary	3.3% (3/90)	150 mg: 3.3% (3/92); 300 mg: 2.3% (2/88); 600 mg: 16.5% (15/91)	<0.001 for trend
Dyskinesia	Adverse	3/90 (3.3%)	150 mg: 3/92 (3.3%); 300 mg: 2/88 (2.3%); 600 mg: 15/91 (16.5%)	<0.001 for trend
Nausea	Adverse	12/90 (13.3%)	150 mg: 15/92 (16.3%); 300 mg: 23/88 (26.1%); 600 mg: 29/91 (31.9%)	0.001 for trend
Headache	Adverse	3/90 (3.3%)	150 mg: 7/92 (7.6%); 300 mg: 5/88 (5.7%); 600 mg: 12/91 (13.2%)	0.03 for trend
Hypertonia	Adverse	1/90 (1.1%)	150 mg: 0/92 (0%); 300 mg: 1/88 (1.1%); 600 mg: 5/91 (5.5%)	0.03 for trend
Infection	Adverse	1/90 (1.1%)	150 mg: 0/92 (0%); 300 mg: 0/88 (0%); 600 mg: 6/91 (6.6%)	0.01 for trend

Subgroup Analysis

Greater symptomatic benefit at higher doses; SPECT dose-response for greater β-CIT decline with levodopa was significant only after excluding subjects without baseline dopaminergic deficit (n=116; P=0.036); in the full substudy cohort (n=135) the dose-response was not significant (P=0.15)

Criticisms

Two-week washout may not have fully eliminated symptomatic effects of levodopa (long-duration response can outlast 14 days)
SPECT β-CIT changes may reflect pharmacologic down-regulation of the dopamine transporter rather than true neurotoxicity
No long-term follow-up beyond 42 weeks to assess durability of clinical or imaging findings
Imaging results apply only to the substudy cohort (n=116 in the primary analysis after excluding 19 subjects without baseline dopaminergic deficit)

Funding

National Institute of Neurological Disorders and Stroke (NINDS grant NS34796); Department of Defense (SPECT substudy, DAMD 17-99-1-9472); General Clinical Research Center of the National Center for Research Resources, NIH (MO1-RR-00044 and MO1-RR-02066); carbidopa–levodopa and matching placebo tablets provided by Teva Pharmaceuticals (Israel)

Based on: ELLDOPA (New England Journal of Medicine, 2004)