Self-administration of an inhalable formulation of levodopa rapidly improves motor function and significantly reduces off time in people with Parkinson’s disease, according to data published in the September issue of Movement Disorders. The drug may fill an unmet need for a well-tolerated and noninvasive intervention, according to the authors.
Over time, many patients with Parkinson’s disease lose a predictable and sustained response to levodopa. Irregular intestinal absorption of oral levodopa formulations may be one cause of this reduced response. Among currently available therapies, apomorphine acts rapidly and effectively aborts off episodes. The drug is ineffective if taken orally, however, and subcutaneous injection often requires premedication with an antiemetic.
CVT-301 is an inhalable formulation of levodopa designed for pulmonary absorption. The drug is administered using a passive, breath-actuated delivery system and it improved motor function in a phase IIa dose-finding study. Peter A. LeWitt, MD, MMSc, a neurologist at Henry Ford West Bloomfield Hospital in Michigan, and colleagues conducted a phase IIb trial to evaluate the efficacy and safety of self-administered CVT-301 among patients with Parkinson’s disease in a clinical setting and at home during off episodes.
Peter A. LeWitt, MD, MMSc
Investigators Evaluated Two Doses
Dr. LeWitt’s group conducted a randomized, double-blind, controlled trial that lasted for four weeks. Eligible participants were between ages 30 and 80, had typical clinical features of Parkinson’s disease, took oral levodopa at least four times daily, and had predictable off episodes totaling two or more hours per day. People with a history of chronic respiratory disease within the previous five years or a Mini-Mental State Examination score lower than 25 were excluded.
After learning how to use the inhaler system, patients were randomized to CVT-301 or placebo (an inhalation-grade lactose monohydrate) for four weeks to treat as many as three off episodes per day. During the first two weeks, the dose of CVT-301 was 35 mg. During the second two weeks, the dose of CVT-301 was 50 mg, and the dose of placebo was increased.
The researchers assessed participants with the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III at screening and at the end of weeks 1, 2, and 4. During the latter three visits, investigators blinded to treatment assignments obtained UPDRS Part III scores for the predose off state and at 10, 20, 30, and 60 minutes post dose. Patients were rated subjectively as achieving or not achieving an on state during the 60-minute observation period. Patients also responded to the Patient Global Impression of Change scale at the end of weeks 2 and 4.
Drug Improved Motor Scores
Dr. LeWitt and colleagues enrolled 89 patients in the study. Of these participants, 86 used at least one dose of study drug, and 75 completed the study. Average age was approximately 62, and participants had received a diagnosis of Parkinson’s disease an average of nine years before study initiation. Mean off time was approximately six hours per day.
As measured in clinic by UPDRS Part III score, motor function improved significantly during off episodes after administration of CVT-301. At the end of week 1, the least-squares mean change in UPDRS Part III score was –9.9 points for 35 mg of CVT-301, compared with –5.3 points for placebo. One week later, the mean change was –10.2 points for the first 50-mg dose of CVT-301, compared with –3.5 points for placebo. At the end of week 4, the mean change was –10.0 points for 50 mg of CVT-301 versus –3.1 points for placebo.
Post hoc analyses indicated that onset of action was evident at 10 minutes for both doses of CVT-301. The mean improvement in motor scores remained significant versus placebo through the 60-minute final assessment. At 60 minutes, the week 4 treatment effect (ie, 50 mg vs placebo) exceeded the week 1 treatment effect (ie, 35 mg vs placebo) by 4.3 points.
Approximately 47% of the active group and 33% of the placebo group reported treatment-emergent adverse events. Adverse events with an incidence of 5.0% or greater in the CVT-301 group were dizziness, cough, and nausea, each of which was reported in three patients. Dyskinesia was reported in one patient in each treatment group. Two patients, both in the placebo group, experienced severe adverse events: drop attack and dyskinesia.
Results May Reflect Treatment Duration
Inhaled CVT-301 “provided rapid amelioration of off episodes,” said Dr. LeWitt. “The average improvement in motor function was similar for both dose levels. However, the average difference from placebo was numerically greater after the 50-mg dose, at least partly because of a decrease in placebo response in weeks 2 and 4, compared with week 1.” The average improvement associated with active treatment greatly exceeded the reported minimum values for a clinically relevant change in Part III scores, he added.