HONOLULU—Concerns that levodopa may accelerate Parkinson’s disease progression were partially allayed by the results of the Early versus Late Levodopa (ELLDOPA) in Parkinson’s Disease study—but contradictory results from the neuroimaging branch of the same trial left the question ultimately unresolved. According to Stanley Fahn, MD, “The clinical outcomes did not show that levodopa hastened worsening of the disease but rather that levodopa may have slowed the rate of progression,” while “in contrast to the clinical results, the imaging substudy suggests that levodopa caused a more rapid decline in the nigrostriatal nerve terminals,” he added.

THE ELLDOPA TRIAL

The purpose of the study was to determine if levodopa alters the natural course of Parkinson’s disease, remarked Dr. Fahn at the 55th Annual Meeting of the American Academy of Neurology. “Does it hasten it, slow it, or have no effect?”

The ELLDOPA study, conducted by the Parkinson’s Study Group, was a randomized, double-blind, placebo-controlled, parallel-group, multisite clinical trial. Participants were patients with early Parkinson’s disease (diagnosed no more than three years) who were not otherwise receiving antiparkinsonian medications and were not in symptomatic therapy.

The investigators enrolled 360 participants, dividing them randomly into four numerically equal arms: low-, middle-, and high-dose carbidopa/levodopa, and placebo. The active treatment groups were titrated during a course of nine weeks to their respective doses (150, 300, and 600 mg/day). “Then they went for 40 weeks, began a three-day washout, and were followed for two more weeks without any medication,” Dr. Fahn said. He is the H. Houston Merritt Professor of Neurology and Director of the Center for Parkinson’s Disease and Other Movement Disorders at Columbia University College of Physicians and Surgeons in New York City.

The primary outcome variables of the trial were the change in severity as measured by the total Unified Parkinson’s Disease Rating Scale (UPDRS) scores from baseline to week 42. The primary rater saw the participants only twice, at baseline and at week 42, in an effort to maintain blindness, Dr. Fahn noted. The treating investigators were also blinded, but they followed the patients throughout their course. A subset of 135 patients underwent before-and-after neuroimaging studies, for which the percentage change in the striatal dopamine transporter between baseline and week 40 assessed by ß-CIT uptake measured by spectroscopy was the primary imaging outcome, he added.

There was no statistical difference in any baseline characteristics, including race, age, sex, and onset and duration of disease, Dr. Fahn said. UPDRS scores ranged from 27.3 to 29.4. Of the 361 patients randomized, 311 completed the study.

PROOF POSITIVE—THE CLINICAL TRIAL RESULTS

The ELLDOPA trial returned the most significant results in the 600-mg/day group, according to the primary raters. The placebo group had deterioration during the 40-week course and saw little change after the washout, Dr. Fahn reported. The 150-mg/day group had improvement that started to lose its effect by 40 weeks. Greater improvement was seen in the 300- and 600-mg/day groups, and the 600-mg/ day dosage maintained its effects a little longer than the 300-mg/day dosage. “After two weeks of washout, patients in the 600-mg/day group were still improved over baseline by 1.4 points, whereas the placebo group worsened by 7.8 points,” he added. These improvements were also true of the motor and activities of daily living components of the UPDRS.

“The treating investigators also saw these highly significant differences between the treatment group and the placebo group,” Dr. Fahn continued. “Their scores are a little bit different; they had about a 2-point greater score on the UPDRS from the treating investigator than the primary rater, but they’re more or less parallel to each other. And the same is true for the motor and activities of daily living component.”

Once the washout was completed, all active treatment groups had returned to baseline, “but most of the worsening occurred after one week,” said Dr. Fahn. None of the three treatment groups ever recorded UPDRS scores worse than those of the placebo group, “so there was no evidence of any hastening of the disease, at least after a two-week washout of the drug,” he added. “If it was worsened, it should have been greater than placebo; if it was neuroprotective, it should have been better than placebo—and it was.”

FACING SOME ADVERSITY

As far as adverse events, “there was a little more headache in the 600-mg/day group, and a little more increased muscle tone and dystonia,” Dr. Fahn said. Infection and nausea were reported in the upward groups, and more somnolence, though that didn’t quite reach statistical significance. There was more leg pain in the untreated and low-dose groups, he added.

Dopaminergic adverse events included dyskinesias and a trend for wearing off in the 600-mg/day group as compared with the lower-dose groups. However, freezing was more prevalent in the lower- than the higher-dose groups.

PROOF NEGATIVE—THE NEUROIMAGING RESULTS

Dr. Fahn reported that there were no differences at baseline on any of the striatal ß-CIT spectroscopy scores. At nine months, “the percent decline of ß-CIT uptake was significantly more pronounced in the levodopa groups than the placebo group” (–7.2%, –4%, –6%, and –1.4% for the 600-, 300-, 150-mg/day and placebo groups, respectively). “So we’re getting contradictory results from what we’re seeing on ß-CIT spectroscopy and what we’re seeing clinically.”

What does this mean? Dr. Fahn wondered. “The clinical component failed to find any evidence that levodopa treatment is harmful or hastens the progression of Parkinson’s disease, but because of uncertainty that levodopa’s long sustained benefit may derive from a more prolonged pharmacologic or plasticity effect, we cannot conclude that levodopa has been proven to be protective,” he said.

“Maybe there’s a new concept. Maybe there’s a third type of benefit. We know that there’s a short-duration benefit, we know that there’s a long-duration benefit—but maybe there’s even a more extended benefit,” he proposed. “If there is, the duration of any such benefit is unknown, and a much longer washout period than was attempted in ELLDOPA would have to be used to detect such an enduring change before we can actually say there is neuroprotection.”

As far as the imaging study, “we can’t make any claims about that, either,” Dr. Fahn admitted. “The interpretation is uncertain because it’s a small group and a short duration and we cannot exclude the possibility that levodopa does not have an effect on dopamine binding that could explain the decreased ß-CIT uptake. Even though pilot studies failed to show this, a bigger study and longer duration might show an effect, and therefore there’s still uncertainty about all of this.”

FINAL DOSAGE

In conclusion, Dr. Fahn addressed the issue of what is the best dosage of levodopa to treat patients with Parkinson’s disease. “Low doses—150 or 300 mg/day—are clearly effective, but less so than the 600-mg/day dosage, both in degree and duration of benefit. Although clinical benefit with 600 mg is superior and lasts longer, it is associated with dyskinesias and a tendency for more wearing off. So the current method of customizing the dose to fit the individual patient is very reasonable,” he said.

Commenting on the ELLDOPA trial results, Dr. Fahn emphasized that “These contradictory findings warrant further investigation into the effect of levodopa on Parkinson’s disease, and a pharmacologic effect by levodopa on this type of imaging study needs to be investigated.”

NR

—C. Justin Romano

Suggested Reading
Fahn S. Parkinson disease, the effect of levodopa, and the ELLDOPA trial. Earlier versus Later L-DOPA. Arch Neurol. 1999;56:529-535.

Return to table of contents