Randomized Delayed-Start Trial of Levodopa in Parkinson Disease

Arnold is a 62-year-old man who received a diagnosis of Parkinson disease 3 months ago. His symptoms commenced with a unilateral tremor and now includes troublesome rigidity and bradykinesia. Sooner or later, Arnold will need to start levodopa treatment.

However, an area of uncertainty is whether levodopa should be started early or later in the course of the disease, and whether starting levodopa early modifies disease progress. This uncertainly stems from varying study results that have shown both slowing of clinical symptom progression and accelerated rates of decline in the levodopa transporters assessed via single-photon-emission computed tomography when levodopa was commenced early.

A recently published trial in NEJM by Verschuur et al. addressed this uncertainty in patients with recently diagnosed Parkinson disease. Patients were randomized to receive early- or delayed-start oral levodopa and carbidopa. The results showed that time of levodopa initiation had no effect on clinical outcomes, suggesting that levodopa does not modify the natural course of Parkinson disease.

The following NEJM Journal Watch summary explains the findings.

Levodopa remains the single best treatment for Parkinson disease (PD). Whether levodopa has a disease-modifying effect remains unknown. A multicenter, double-blind, placebo-controlled, delayed start trial compared the effects of “early-start” levodopa (100 mg 3 times daily) plus carbidopa (25 mg 3times daily) for 80 weeks versus “delayed-start” levodopa for 40 weeks after receiving placebo for 40 weeks. Mean change from baseline to week 80 in the total Unified Parkinson's Disease Rating Scale (UPDRS) score was the primary outcome. 

There were 445 patients randomly assigned. The change in UPDRS score from baseline to week 80 was not significantly different between early and delayed start (early start, −1.0±13.1 points; delayed start, −2.0±13.0 points; difference, 1.0 point. Rates of PD progression, dyskinesia, and motor fluctuations were no different between groups. Although 39% of the delayed-start group received levodopa in the first 40 weeks, a per-protocol analysis also showed no difference in the primary outcome between the groups.

Comment: Levodopa remains the most important and effective treatment for Parkinson disease, and its introduction to the PD armamentarium has undoubtedly improved quality of life and reduced morbidity and mortality. The current well-designed, well-executed study addresses the question raised in previous studies of whether levodopa might be neuroprotective. It is not. The current study also bolsters our confidence that levodopa is safe even in early PD and that patients and doctors should not fear prescribing it.

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Angela is a 2018-2019 NEJM editorial fellow. She is an endocrine fellow who trained at Flinders Medical Centre and the Royal Adelaide Hospital. Angela recieved her medical degree from the University of Adelaide, and masters of public health from the University of Sydney. Her clinical and research interests are in the areas of glucocorticoid and cardiovascular endocrinology and diabetes medicine.