Apomorphine Reduces Off Time in First Randomized Trial

Subcutaneous apomorphine infusion significantly reduces off time in patients with Parkinson’s disease and inadequately controlled motor fluctuations, according to data published in the September issue of Lancet Neurology. The data result from the first randomized controlled trial of apomorphine in this population.

In 1988, an open-label study indicated that apomorphine had antiparkinsonian efficacy equivalent to that of levodopa. Several uncontrolled studies have indicated that it effectively reduces off time, improves dyskinesias, and allows doses of oral levodopa to be decreased.

A Multicenter European Study

Regina Katzenschlager, MD, a neurologist at Danube Hospital in Vienna, and colleagues investigated the safety and efficacy of apomorphine infusion in a randomized, placebo-controlled, double-blind trial. They enrolled patients at 23 European hospitals who had received a diagnosis of Parkinson’s disease more than three years previously and had motor fluctuations that were inadequately controlled. Patients were randomized in equal groups to 3–8-mg/h infusions of apomorphine or saline for approximately 16 h/day. The treatment period lasted for 12 weeks. During the first four weeks, investigators adjusted the dose according to efficacy and tolerability, and the remaining eight weeks were a maintenance period.

Regina Katzenschlager, MD

Patients completed home diary assessments of motor status and visited the hospital for regular evaluations. The study’s primary end point was the absolute change in off time from baseline to 12 weeks, based on diary assessments. Secondary end points included response to therapy (ie, a reduction in off time of at least two hours from baseline), absolute change in on time without troublesome dyskinesia, Patient Global Impression of Change (PGIC) score, change in levodopa dose, change in motor score, and change in quality of life.

Results Were Consistent in Prespecified Subgroups

A total of 53 patients were randomized to apomorphine, and 54 patients were randomized to placebo. The mean final dose of study drug was 4.68 mg/h in the apomorphine group and 5.76 mg/h in the placebo group.

Mean reduction in off time was significantly greater at week 12 in the apomorphine group (−2.47 h/day) than among controls (−0.58 h/day). The results were consistent in sensitivity analyses. Approximately 62% of patients in the apomorphine group responded to therapy, compared with 29% of controls.

Mean on time without troublesome dyskinesia was significantly increased in the apomorphine group (2.77 h/day), compared with the placebo group (0.80 h/day). Apomorphine also improved PGIC scores significantly at 12 weeks, compared with placebo. Mean reduction in oral levodopa dose was greater in the apomorphine group, but the difference between groups was not statistically significant. Changes in motor score and quality of life were not significantly different between groups at 12 weeks.

The treatment was well tolerated, and the researchers found no unexpected safety signals. The rate of treatment-emergent adverse events was 93% in the apomorphine group and 57% among controls. The most common adverse events were skin reactions, nausea, and somnolence. Six patients had an adverse event that prompted study withdrawal; all were in the apomorphine group. Five patients in the apomorphine group had serious adverse events, including severe hypotension, myocardial infarction, and persistently abnormal hematology test results indicating mild leukopenia and moderate anemia.

“From a practical viewpoint, our study shows that some patients tolerate and receive benefit from doses exceeding the common range of hourly flow rates currently used in practice,” said the authors. “Many centers use higher flow rates than the mean dose in our study, and it is possible that the full potential of apomorphine has not been investigated here.”