Phase III success with extended-release carbidopa–levodopa formulation

By Eleanor McDermid, Senior medwireNews Reporter

An extended-release formulation of carbidopa-levodopa reduces the amount of off-time in patients with Parkinson's disease, show results from a phase III randomized trial.

This results in apparent "clinically meaningful" improvements in motor function, report lead researcher Robert Hauser (University of South Florida, Tampa, USA) and co-workers. Furthermore, patients do not need to take their medication as often if given an extended-release formulation.

"These findings are exciting and reignite the long hope for improved levodopa delivery, despite previous disappointing experiences with other controlled-release formulations," says Olivier Rascol (University UPS of Toulouse III, France) in a commentary accompanying the paper in The Lancet Neurology.

The 471 patients recruited to the trial first underwent a 3-week period during which the investigators ascertained the optimal dose of immediate-release carbidopa-levodopa for each patient. This was followed by a 6-week dose-conversion phase during which the optimal dose of the immediate-release drug was used as a basis to determine the ideal dose of the extended-release formulation.

The 393 patients who completed these phases were randomly assigned to receive 13 weeks' treatment with either the immediate- or extended-release formulation. At study entry, these patients had an average daily off-time of 5.97 hours.

By the end of the randomized treatment period, this fell to 3.87 hours in the extended-release group compared with 4.88 hours in the immediate-release group, a significant difference. Off-time as a percentage of waking hours fell by 13.1% in the extended-release group versus 6.2% in the immediate-release group.

The average on-time without troublesome dyskinesia was significantly greater in patients taking the extended- versus immediate-release formulation by the end of the study, while on-time with troublesome dyskinesia did not differ between groups. The latter finding "suggests that levodopa peaks were not substantially increased and extended-release carbidopa-levodopa dosing was clinically appropriate," says the team.

Patients taking the extended-release formulation had significantly greater improvements on the Patient and the Clinical Global Impression of Change scales than those taking immediate-release carbidopa-levodopa. They also improved more on the Unified PD Rating Scale in both the on- and off-medication states.

The most common adverse events in the extended-release group were insomnia, nausea, and falls, while depression was most common in the immediate-release group.

In his commentary, Rascol notes that although extended-release carbidopa-levodopa may be a step forward, no matter how well patients respond to the drug, they will still experience levodopa-resistant symptoms and deteriorating function over time. "Improving the mode of delivery of carbidopa-levodopa will not change this fact."

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