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LEAP

Levodopa in Early Parkinson's Disease

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Year of Publication: 2019

Authors: C.V.M. Verschuur, S.R. Suwijn, J.A. Boel, ..., R.M.A. de Bie

Journal: New England Journal of Medicine

Citation: N Engl J Med 2019;380:315–324. doi:10.1056/NEJMoa1809983

Link: https://doi.org/10.1056/NEJMoa1809983

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

Clinical Question

Does early initiation of levodopa have disease-modifying effects in Parkinson's disease compared to delayed initiation?

Bottom Line

Levodopa does not have a disease-modifying effect in early PD: after 80-week delayed-start design, no significant between-group difference in change in UPDRS total score (difference 1.0 point; 95% CI -1.5 to 3.5; P=0.44); early-start -1.0±13.1 vs delayed-start -2.0±13.0. Levodopa 100mg TID with carbidopa 25mg TID. 445 patients. Published NEJM 2019.

        Major Points
        No disease-modifying effect: UPDRS total change at 80 weeks difference 1.0 point (95% CI -1.5 to 3.5); P=0.44 (early -1.0 vs delayed -2.0).
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 (change -3.1 vs +2.0; difference -5.1; 95% CI -7.2 to -2.9). Gap closed by 80 weeks.
Disproves 'levodopa toxicity' hypothesis — no evidence levodopa accelerates disease.
AEs at 80 weeks: dyskinesia and motor fluctuations did not differ significantly between groups (exact rates in Supplementary Table S5). Nausea significantly higher with early-start in phase 1 (23.0% vs 14.3%, P=0.02).
Published NEJM 2019 (Verschuur et al., LEAP Study Group). Dutch multicenter.
Landmark trial settling longstanding debate about levodopa timing in PD.

      

Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled, delayed-start trial

Randomization: 1

Blinding: Patients and investigators were blinded to treatment allocation

Enrollment Period: 2011–2016

Follow-up Duration: 80 weeks

Centers: 57

Countries: Netherlands

Sample Size: 445

Analysis: Intention-to-treat; Student's t-test, ANCOVA, and linear mixed-model analyses

Inclusion Criteria

Idiopathic Parkinson's disease diagnosed within 2 years
Age ≥30 years
Insufficient disability to warrant antiparkinson medication at baseline
Life expectancy >2 years

Exclusion Criteria

Prior treatment with dopaminergic medication (levodopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors, amantadine)
Atypical or secondary parkinsonism
Tremor as the most prominent symptom
Dementia
Life expectancy ≤2 years

Baseline Characteristics

Characteristic	Control	Active
Age	65.5 ± 8.8	64.8 ± 8.7
Sex - Male	69.1%	70.7%
Duration of symptoms <0.5 yr	11.7% (26/223)	9.9% (22/222)
First symptom - Tremor	58.3%	59.0%
UPDRS total	29.3 ± 12.1	28.1 ± 11.4
UPDRS Part II (ADL)	7.4 ± 3.7	7.3 ± 3.6
UPDRS Part III (motor)	19.5 ± 9.4	18.4 ± 8.7
MMSE median (IQR)	29.0 (28.0–30.0)	29.0 (28.0–30.0)

Arms

Field	Early-start levodopa	Control
Intervention	Levodopa 100 mg + carbidopa 25 mg three times daily for 80 weeks	Placebo for 40 weeks, then levodopa 100 mg + carbidopa 25 mg TID for remaining 40 weeks
Duration	80 weeks	80 weeks

Outcomes

Outcome	Type	Control	Intervention	P-value
Change in total UPDRS score from baseline to week 80	Primary	−2.0 ± 13.0	−1.0 ± 13.1	0.44
UPDRS change from baseline to week 40	Secondary	+2.0 ± 12.3	−3.1 ± 10.2
Rate of progression weeks 4–40 (UPDRS points/week)	Secondary	0.06 ± 0.34	0.04 ± 0.23
Rate of progression weeks 44–80 (UPDRS points/week)	Secondary	0.03 ± 0.28	0.10 ± 0.25
PDQ-39 median (IQR) at 80 weeks	Secondary	8.3 (3.8–14.7)	7.7 (3.2–14.7)
ALDS median (IQR) at 80 weeks	Secondary	89.5 (88.7–89.5)	89.5 (88.7–89.5)
MMSE median (IQR) at 80 weeks	Secondary	29.0 (28.0–30.0)	29.0 (28.0–30.0)
BDI-II median (IQR) at 80 weeks	Secondary	6.0 (3.0–10.0)	6.0 (3.0–10.0)
Nausea (Phase 1)	Adverse	14.3%	23.0%	0.02
Nausea (Phase 2)	Adverse	18.6%	12.3%
Hallucinations (Phase 1)	Adverse	6.3%	4.5%
Dizziness (Phase 1)	Adverse	14.3%	14.9%
Worsening of parkinsonism (Phase 1)	Adverse	18.4%	14.0%
Dyskinesia (at 80 weeks)	Adverse	Not reported in primary paper (see Supplementary Table S5)	Not reported in primary paper (see Supplementary Table S5)	NS (did not differ significantly between groups)
Motor fluctuations (at 80 weeks)	Adverse	Not reported in primary paper (see Supplementary Table S5)	Not reported in primary paper (see Supplementary Table S5)	NS (did not differ significantly between groups)

Subgroup Analysis

No significant treatment effect heterogeneity by type of hospital, age, or duration of disease

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
High crossover in delayed-start arm (39% received phase 2 medication before week 40) may attenuate group differences

Funding

Netherlands Organization for Health Research and Development (ZonMw), Parkinson Vereniging, Stichting Parkinsonfonds, Stichting Parkinson Nederland; no industry involvement

Based on: LEAP (New England Journal of Medicine, 2019)