Levodopa Shows No Disease-modifying Effects in Parkinson’s, Study Finds

Levodopa/carbidopa treatment is effective in managing Parkinson’s motor symptoms, but does not protect against disease progression among patients with early disease, a study shows.

The research, “Randomized Delayed-Start Trial of Levodopa in Parkinson’s Disease” was published in The New England Journal of Medicine.

Levodopa is the main treatment for Parkinson’s disease. However, neurologists might delay prescribing levodopa for different reasons, including concern about the development of levodopa-induced dyskinesias (abnormal, uncontrolled, involuntary movements), which is one of the most common dose-limiting side effects of this treatment approach.

In an earlier clinical trial, called ELLDOPA , 361 patients with early Parkinson’s disease received levodopa or placebo for 40 weeks. Two weeks after that, clinical examination showed that the participants who had received levodopa had a slower disease progression than those on placebo. However, brain imaging studies revealed that levodopa had either accelerated the death of dopaminergic neurons, or it had modified the protein responsible for the transport of dopamine in brain nerve cells.

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“Therefore, whether levodopa has an effect on the progression of Parkinson’s disease beyond its immediate benefit with respect to symptoms remains unknown,” scientists wrote.

Now, researchers from the University of Amsterdam designed a multicenter, randomized, placebo-controlled, delayed-start trial to assess levodopa’s effect on patients with early Parkinson’s disease who had insufficient disability to receive anti-Parkinson medication: the Levodopa in Early Parkinson’s Disease (LEAP) study (ISRCTN30518857).

Patients who had received their diagnosis within the previous two years were randomly assigned to an early-start group (207 subjects): levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks; or to a delayed-start group (210 participants): placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks.

The study’s primary endpoint (goal) was the difference in the mean change, from trial initiation to week 80, in the total score on the Unified Parkinson’s Disease Rating Scale (UPDRS). That tool assesses both motor and non-motor symptoms associated with Parkinson’s disease (higher scores indicate more severe disease).

Secondary outcomes included the progression of symptoms between weeks 4 and 40 and between weeks 44 and 80, as measured by the category scores on the UPDRS; disability; cognitive impairment; depression; and disease-related quality of life.

At week 80, there was no significant difference between the early-start and delayed-start group regarding motor and non-motor symptoms, as measured by the UPDRS, indicating that levodopa had no disease-modifying effect.

To test if early treatment initiation was prognostically better than a delayed one or vice-versa, scientists compared symptoms’ progression rate in week 4-40 and week 44-80. Once again, no significant changes were observed between groups in either study period.

No significant changes in therapy-related motor fluctuations, including dyskinesias, were found between groups. During the first 40 weeks, patients on the early-start group complained more of nausea (23%), compared to the participants on the delayed-start group (14.3%).

Also, no significant differences were observed regarding disability, cognitive impairment, depression and disease-related quality of life between the groups.

“We conclude that treatment with levodopa at a dose of 100 mg three times per day in combination with carbidopa at a dose of 25 mg three times per day had no disease-modifying effect, either beneficial or detrimental, on early Parkinson’s disease among patients who were evaluated over the course of 80 weeks. 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,” researchers concluded.