Dr Rob de BieRob de Bie, MD, PhD
Levodopa, the gold-standard treatment for Parkinson disease for the last 5 decades, has been shown to lack a disease-modifying effect in combination with carbidopa, according to new results from the ELLDOPA trial.1

The multicenter, double-blind, placebo-controlled, delayed-start trial ultimately showed that there was no significant difference between the group of patients who were treated early with levodopa (n = 222) or in a delayed fashion (n = 223) in Unified Parkinson’s Disease Rating Scale (UPDRS) score (P = .44). Those in the early-start group showed a change in score from baseline of -1.0 ±13.1 points while the delayed-start group showed a change of -2.0 ±13.0 points at 80 weeks (difference, 1.0 point; 95% CI, -1.5 to 3.5).

Additionally, an analysis adjusted for baseline scores on the UPDRS also showed no significant difference between the groups at 80 weeks (difference, 0.6 points; 95% CI, −1.8 to 3.0; P=0.60)

The investigators, led by Rob de Bie, MD, PhD, a professor of movement disorders at the University of Amsterdam, noted that the findings imply that there was no disease-modifying effect, “either beneficial or detrimental,” on Parkinson disease over the period of the trial with 100-mg levodopa thrice daily in combination with 25-mg carbidopa thrice daily.

“Whether higher doses of the drug, longer periods of administration, or initiation of the drug at later stages of the disease could alter the course of Parkinson’s disease warrants evaluation in future trials,” they wrote.

Ultimately, the patients in the ELLDOPA trial were randomized 1:1 to received either oral levodopa in combination with oral carbidopa for 80 weeks, or placebo for 40 weeks followed by oral levodopa in combination with oral carbidopa for 40 weeks.  

The change in the UPDRS score from baseline to week 40 was -3.1 ±10.2 in the early-start group and 2.0±12.3 in the delayed start group (difference, -5.1 points; 95% CI, -7.2 to -2.9), which favored the early-start group and was reflective of the effect of levodopa on symptoms of the disease.

Between weeks 4 and 40, phase 1 of the trial, the rate of symptom progression, as measured by UPDRS points per week, was 0.04 ±0.23 in the early start group compared to 0.06 ±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). Between weeks 44 and 80, phase 2 of the trial, those corresponding rates were 0.10 ±0.25 and 0.03 ±0.28, respectively, representing a difference of 0.07 points (two-sided 90% CI, 0.03 to 0.10). This difference in the rate of progression between weeks 44 and 80 was not enough to justify noninferiority of the early receipt of levodopa compared to delayed receipt.

As such, Susan Bressman, MD, and Rachel Saunders-Pullman, MD, MPH, wrote in an accompanying editorial that “this trial, therefore, supports current practice.” They added that there is no existing evidence supporting that early levodopa initiation slows disease progression.2

“On the other hand, there is no reason to delay therapy when it is clinically indicated,” Bressman and Saunders-Pullman noted. “The results of the current trial, taken together with those of other trials, support treatment that is guided by clinical need and that uses the lowest dose that provides a satisfactory clinical effect.”

During the first 40 weeks of the trial, the incidence of nausea was higher in the early-start group (23.0%) than in the delayed start-group (14.3%; P = .02). At the 80-week mark, the percentage of patients with motor complications, including dyskinesias and fluctuations in motor response, did not differ significantly between the two groups.
REFERENCES
1. Verschuur CVM, Suwijn SR, Boel JA, et al. Randomized delayed-start trial of levodopa in Parkinson’s disease. N Engl J Med. 2019;380: 315-324. doi: 10.1056/NEJMoa1809983.
2. Bressman S, Saunders-Pullman R. When to start levodopa therapy for Parkinson’s disease. N Engl J Med. 2019;380: 389-390. doi: 10.1056/NEJMe1814611.