The effectiveness of apomorphine hydrocloride in the acute symptomatic treatment of the recurring episodes of hypomobility, "off" episodes ("end-of-dose wearing off" and unpredictable "on/off" episodes), in patients with advanced Parkinson's disease was established in three randomized, controlled trials of apomorphine hydrocloride given subcutaneously (Studies 1, 2, and 3). At baseline in these trials, the mean duration of Parkinson's disease was approximately 11 years. Whereas all patients were using concomitant L-dopa at baseline, 86% of patients were using a concomitant oral dopaminergic agonist, 31% were using a concomitant catechol-ortho-methyl transferase (COMT) inhibitor, and 10% were using a concomitant monoamine B oxidase inhibitor. Study 1 was conducted in patients who did not have prior exposure to apomorphine hydrocloride (i.e., apomorphine hydrocloride naïve) and Studies 2 and 3 were conducted in patients with at least 3 months of apomorphine hydrocloride use immediately prior to study enrollment. Almost all patients without prior exposure to apomorphine hydrocloride began taking an antiemetic (trimethobenzamide) three days prior to starting apomorphine hydrocloride and 50% of patients were able to discontinue the concomitant antiemetic, on average 2 months after initiating apomorphine hydrocloride.

The change from baseline in Part III (Motor Examination) of the Unified Parkinson's Disease Rating Scale (UPDRS) served as the primary outcome assessment measure in each study. Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings (e.g., tremor, rigidity, bradykinesia, postural instability, etc.) in patients with Parkinson's disease.

Study 1

Study 1 was a randomized, double-blind, placebo-controlled, parallel-group trial in 29 patients with advanced Parkinson's disease who had at least 2 hours of "off" time per day despite an optimized oral regimen for Parkinson's disease including levodopa and an oral dopaminergic agonist. Patients with atypical Parkinson's disease, psychosis, dementia, hypotension, or those taking dopamine antagonists were excluded from participation. In an office setting, hypomobility was allowed to occur by withholding the patients' Parkinson's disease medications overnight. The following morning, patients (in a hypomobile state) were started on study treatment in a 2:1 ratio (2 mg of apomorphine hydrocloride or placebo given subcutaneously). At least 2 hours after the first dose, patients were given additional doses of study medication until they achieved a "therapeutic response" (defined as a response similar to the patient's response to their usual dose of levodopa) or until 10 mg of apomorphine hydrocloride or placebo equivalent was given. At each injection re-dosing, the study drug dose was increased in 2 mg increments up to 4 mg, 6 mg, 8 mg, 10 mg of apomorphine hydrocloride) or placebo equivalent.

Of the 20 patients randomized to apomorphine hydrocloride, 18 achieved a "therapeutic response" at about 20 minutes. The mean apomorphine hydrocloride dose was 5.4 mg (3 patients on 2 mg, 7 patients on 4 mg, 5 patients on 6 mg, 3 patients on 8 mg, and 2 patients on 10 mg). In contrast, of the 9 placebo-treated patients, none reached a "therapeutic response." The mean change from baseline for UPDRS Part III score for apomorphine hydrocloride group (highest dose) was statistically significant compared to that for the placebo group (Table 2).

Study 2

Study 2 used a randomized, placebo-controlled crossover design of 17 patients with Parkinson's disease who had been using apomorphine hydrocloride for at least 3 months. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received either a single dose of subcutaneous apomorphine hydrocloride (at their usual dose) and placebo on different days in random order. UPDRS Part III scores were evaluated over time. The mean dose of apomorphine hydrocloride was 4 mg (2 patients on 2 mg, 9 patients on 3 mg, 2 patients on 4 mg, and 1 patient each on 4.5 mg, 5 mg, 8 mg, and 10 mg). The mean change from baseline UPDRS Part III score for the apomorphine hydrocloride group was statistically significant compared to that for the placebo group (Table 3).

Study 3

Study 3 used a randomized withdrawal design in 4 parallel groups from 62 patients (apomorphine hydrocloride-35; Placebo-27) with Parkinson's disease who had been using apomorphine hydrocloride for at least 3 months. Patients were randomized to one of the following 4 treatments dosed once by subcutaneous administration: apomorphine hydrocloride at the usual dose (mean dose 4.6 mg), placebo at a volume matching the usual apomorphine hydrocloride dose, apomorphine hydrocloride at the usual dose + 2 mg (0.2 mL) (mean dose 5.8 mg), or placebo at a volume matching the usual apomorphine hydrocloride dose + 0.2 mL. Patients received their usual morning doses of Parkinson's disease medications and were followed until hypomobility occurred, at which time they received the randomized treatment. apomorphine hydrocloride doses ranged between 2 mg – 10 mg. The mean change from baseline for the apomorphine hydrocloride group for UPDRS Part III scores at 20 minutes post dosing was statistically significant compared to that for the placebo group (Table 4). Figure 2 describes the mean change from baseline in UPDRS Motor Scores over time for pooled apomorphine hydrocloride and placebo administration.

In Study 3, the mean changes from baseline for UPDRS Part III scores at 20 minutes post dosing for the apomorphine hydrocloride and higher dose apomorphine hydrocloride groups were 24 and 25, respectively. This result suggests that patients chronically treated at a dose of 4 mg might derive little additional benefit from a dose increment of 2 mg. There was also an increased incidence of adverse reactions in patients randomized to higher apomorphine hydrocloride dose.